Input: This suggests two different mechanisms of IL-1 beta pathway attenuation.


Input: Establishment of a molecular embryonic stem cell developmental toxicity assay.


Input: The mouse embryonic stem cell test (EST) is a 10-day screen for teratogenic potential developed to reduce animal use for embryotoxicity testing of chemicals (Spielmann, 2005; Spielmann et al., 1997).


Input: In this study, we used the cytotoxicity IC (50) values and transcriptional expression changes as primary endpoints in a shorter 4-day version of the EST, the molecular embryonic stem cell assay.


Input: Mouse D3 embryonic stem cells were used for cytotoxicity assessment (monolayers) or grown as embryoid bodies in low attachment plates for transcriptional profiling.


Input: Sixty-five compounds with known in vivo teratogenicity (33 teratogens and 32 nonteratogens) were evaluated to develop a model for classifying compounds with teratogenic potential.


Input: The expression of 12 developmentally regulated gene targets (nanog, fgf5, gsc, cd34, axin2, apln, chst7, lhx1, fgf8, sox17, foxa2, and cxcr4) was measured following exposure of embryoid bodies to a single compound concentration (0. 1 x the cytotoxicity IC (20)) for 4 days.


Input: In the decision-tree model, compounds with IC (50) values < 22 micro M were categorized as teratogens, whereas compounds in the two groups with IC (50) values between 22-200 micro M and > 200 micro M were categorized as teratogens if >= 8 and 12 genes, respectively, were deregulated by at least 10%.


Input: Forty-seven of 65 compounds of the training set were correctly identified (72% total concordance).


Input: In a test set of 12 additional compounds (5 teratogens, 7 nonteratogens), 10 were correctly classified by this approach (83% concordance).


Input: The false positive rate in the training and test sets was 24 and 0%, respectively, indicating that this assay has potential to identify teratogens.


Input: Differential cell-protective function of two resveratrol (trans-3, 5, 4'-trihydroxystilbene) glucosides against oxidative stress.

resveratrol (trans-3, 5, 4'-trihydroxystilbene) glucosides


Input: Resveratrol (trans-3, 5, 4'-trihydroxystilbene; RSV), a natural polyphenol, exerts a beneficial effect on health and diseases.

Resveratrol

trans-3, 5, 4'-trihydroxystilbene

RSV

polyphenol


Input: RSV targets and activates the NAD (+)-dependent protein deacetylase SIRT1; in turn, SIRT1 induces an intracellular antioxidative mechanism by inducing mitochondrial superoxide dismutase (SOD2).

RSV

NAD (+)

superoxide


Input: Most RSV found in plants is glycosylated, and the effect of these glycosylated forms on SIRT1 has not been studied.


Input: In this study, we compared the effects of RSV and two glycosyl RSVs, resveratrol-3-O-beta-d-glucoside (3G-RSV; polydatin/piceid) and resveratrol-4'-O-beta-d-glucoside (4' G-RSV), at the cellular level.

RSV

glycosyl RSVs

polydatin

piceid

4' G-RSV


Input: In oxygen radical absorbance capacity and 2, 2-diphenyl-1-picrylhydrazyl radical scavenging assays, the antioxidant activity of 3G-RSV was comparable to that of RSV, whereas the radical-scavenging efficiency of 4' G-RSV was less than 50% of that of RSV.

2, 2-diphenyl-1-picrylhydrazyl

RSV

4' G-RSV

RSV


Input: However, 4' G-RSV, but not 3G-RSV, induced SIRT1-dependent histone H3 deacetylation and SOD2 expression in mouse C2C12 skeletal myoblasts; as with RSV, SIRT1 knockdown blunted these effects.

4' G-RSV

RSV


Input: RSV and 4' G-RSV, but not 3G-RSV, mitigated oxidative stress-induced cell death in C2C12 cells and primary neonatal rat cardiomyocytes.

RSV

4' G-RSV


Input: RSV and 4' G-RSV inhibited C2C12 cell proliferation, but 3G-RSV did not.

RSV

4' G-RSV


Input: RSV was found in both the intracellular and extracellular fractions of C2C12 cells that had been incubated with 4' G-RSV, indicating that 4' G-RSV was extracellularly deglycosylated to RSV, which was then taken up by the cells.

RSV

4' G-RSV

4' G-RSV

RSV


Input: C2C12 cells did not deglycosylate 3G-RSV.


Input: Our results point to 4' G-RSV as a useful RSV prodrug with high water solubility.

4' G-RSV

RSV


Input: These data also show that the in vitro antioxidative activity of these molecules did not correlate with their ability to protect cells from oxidative stress-induced apoptosis.


Input: Metabolism and disposition of vilanterol, a long-acting beta (2)-adrenoceptor agonist for inhalation use in humans.

vilanterol


Input: The metabolism and disposition of vilanterol, a novel long-acting beta (2)-adrenoceptor agonist (LABA) for inhalation use, was investigated after oral administration in humans.

vilanterol


Input: Single oral administrations of up to 500 mu g of vilanterol were shown to be safe and well tolerated in two clinical studies in healthy men.

vilanterol


Input: In a human radiolabel study, six healthy men received a single oral dose of 200 mu g of [(14) C] vilanterol (74 kBq).

[(14) C] vilanterol


Input: Plasma, urine, and feces were collected up to 168 hours after the dose and were analyzed for vilanterol, metabolites, and radioactivity.

vilanterol


Input: At least 50% of the radioactive dose was orally absorbed.


Input: The primary route of excretion of drug-related material was via O-dealkylation to metabolites, which were mainly excreted in urine.

O


Input: Vilanterol represented a very small percentage (< 0. 5%) of the total drug-related material in plasma, indicative of extensive first-pass metabolism.

Vilanterol


Input: Circulating metabolites resulted mainly from O-dealkylation and exhibited negligible pharmacologic activity.

O


Input: The therapeutic dose level for vilanterol is 25 mu g by the inhalation route.

vilanterol


Input: At this low-dose level, the likelihood of pharmacologically inactive metabolites causing unexpected toxicity is negligible.


Input: In addition to providing an assessment of the disposition of vilanterol in human, this work highlights a number of complexities associated with determining human absorption, distribution, metabolism, and excretion (ADME) for inhaled molecules--mainly related to the low chemical doses and complications associated with the inhalation route of administration.

vilanterol


Input: Establishment of an in vitro photoallergy test using NCTC2544 cells and IL-18 production.


Input: Differentiation between photoallergenic and phototoxic reactions induced by low molecular weight compounds represents a current problem.


Input: The use of keratinocytes as a potential tool for the detection of photoallergens as opposed to photoirritants is considered an interesting strategy for developing in vitro methods.


Input: We have previously demonstrated the possibility to use the human keratinocyte cell line NCTC2455 and the production of interleukin-18 (IL-18) to screen low molecular weight sensitizers.


Input: The purpose of this work was to explore the possibility to use the NCTC2544 assay to identify photoallergens and discriminate from phototoxic chemicals.


Input: First, we identified suitable condition of UV-irradiation (3. 5 J/cm (2)) by investigating the effect of UVA irradiation on intracellular IL-18 on untreated or chloropromazine (a representative phototoxic compound)-treated NCTC2544 cells.

chloropromazine


Input: Then, the effect of UVA-irradiation over NCTC2544 cells treated with increasing concentrations of 15 compounds including photoallergens (benzophenone, 4-ter-butyl-4-methoxy-dibenzoylmethane, 2-ethylexyl-p-methoxycinnamate, ketoprofen, 6-methylcumarin); photoirritant and photoallergen (4-aminobenzoic acid, chlorpromazine, promethazine); photoirritants (acridine, ibuprofen, 8-methoxypsoralen, retinoic acid); and negative compounds (lactic acid, SDS and p-phenilendiamine) was investigated.

benzophenone

4-ter-butyl-4-methoxy-dibenzoylmethane, 2-ethylexyl-p-methoxycinnamate

ketoprofen

4-aminobenzoic acid

chlorpromazine

promethazine

acridine

ibuprofen

retinoic acid

lactic acid

SDS

p-phenilendiamine


Input: Twenty-four hours after exposure, cytotoxicity was evaluated by the MTT assay or LDH leakage, while ELISA was used to measure the production of IL-18.

MTT


Input: At the maximal concentration assayed with non-cytotoxic effects (CV80 under irradiated condition), all tested photoallergens induced a significant and a dose-dependent increase of intracellular IL-18 following UVA irratiation, whereas photoirritants failed.


Input: We suggest that this system may be useful for the in vitro evaluation of the photoallergic potential of chemicals.


Input: Differing effects of PTH 1-34, PTH 1-84, and zoledronic acid on bone microarchitecture and estimated strength in postmenopausal women with osteoporosis: an 18-month open-labeled observational study using HR-pQCT.

zoledronic acid


Input: Whereas the beneficial effects of intermittent treatment with parathyroid hormone (PTH) (intact PTH 1-84 or fragment PTH 1-34, teriparatide) on vertebral strength is well documented, treatment may not be equally effective in the peripheral skeleton.


Input: We used high-resolution peripheral quantitative computed tomography (HR-pQCT) to detail effects on compartmental geometry, density, and microarchitecture as well as finite element (FE) estimated integral strength at the distal radius and tibia in postmenopausal osteoporotic women treated with PTH 1-34 (20 micro g sc daily, n = 18) or PTH 1-84 (100 micro g sc daily, n = 20) for 18 months in an open-label, nonrandomized study.


Input: A group of postmenopausal osteoporotic women receiving zoledronic acid (5 mg infusion once yearly, n = 33) was also included.

zoledronic acid


Input: Anabolic therapy increased cortical porosity in radius (PTH 1-34 32 +/- 37%, PTH 1-84 39 +/- 32%, both p < 0. 001) and tibia (PTH 1-34 13 +/- 27%, PTH 1-84 15 +/- 22%, both p < 0. 001) with corresponding declines in cortical density.


Input: With PTH 1-34, increases in cortical thickness in radius (2. 0 +/- 3. 8%, p < 0. 05) and tibia (3. 8 +/- 10. 4%, p < 0. 01) were found.


Input: Trabecular number increased in tibia with both PTH 1-34 (4. 2 +/- 7. 1%, p < 0. 05) and PTH 1-84 (5. 3 +/- 8. 3%, p < 0. 01).


Input: Zoledronic acid did not impact cortical porosity at either site but increased cortical thickness (3. 0 +/- 3. 5%, p < 0. 01), total (2. 7 +/- 2. 5%, p < 0. 001) and cortical density (1. 5 +/- 2. 0%, p < 0. 01) in tibia as well as trabecular volume fraction in radius (2. 5 +/- 5. 1%, p < 0. 05) and tibia (2. 2 +/- 2. 2%, p < 0. 01).

Zoledronic acid


Input: FE estimated bone strength was preserved, but not increased, with PTH 1-34 and zoledronic acid at both sites, whereas it decreased with PTH 1-84 in radius (-2. 8 +/- 5. 8%, p < 0. 05) and tibia (-3. 9 +/- 4. 8%, p < 0. 001).

zoledronic acid


Input: Conclusively, divergent treatment-specific effects in cortical and trabecular bone were observed with anabolic and zoledronic acid therapy.

zoledronic acid


Input: The finding of decreased estimated strength with PTH 1-84 treatment was surprising and warrants confirmation.


Input: Deletion of CD74, a putative MIF receptor, in mice enhances osteoclastogenesis and decreases bone mass.


Input: CD74 is a type II transmembrane protein that can act as a receptor for macrophage migration inhibitory factor (MIF) and plays a role in MIF-regulated responses.


Input: We reported that MIF inhibited osteoclast formation and MIF knockout (KO) mice had decreased bone mass.


Input: We therefore examined if CD74 was involved in the ability of MIF to alter osteoclastogenesis in cultured bone marrow (BM) from wild-type (WT) and CD74-deficient (KO) male mice.


Input: We also measured the bone phenotype of CD74 KO male mice.


Input: Bone mass in the femur of 8-week-old mice was measured by micro-computed tomography and histomorphometry.


Input: Bone marrow cells from CD74 KO mice formed 15% more osteoclast-like cells (OCLs) with macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-kappa B ligand (RANKL) (both at 30 ng/mL) compared to WT.


Input: Addition of MIF to WT cultures inhibited OCL formation by 16% but had no effect on CD74KO cultures.


Input: The number of colony forming unit granulocyte-macrophage (CFU-GM) in the bone marrow of CD74 KO mice was 26% greater than in WT controls.


Input: Trabecular bone volume (TBV) in the femurs of CD74 KO male mice was decreased by 26% compared to WT.


Input: In addition, cortical area and thickness were decreased by 14% and 11%, respectively.


Input: Histomorphometric analysis demonstrated that tartrate-resistant acid phosphatase (TRAP) (+) osteoclast number and area were significantly increased in CD74 KO by 35% and 43%, respectively compared to WT.

tartrate


Input: Finally, we examined the effect of MIF on RANKL-induced-signaling pathways in bone marrow macrophage (BMM) cultures.


Input: MIF treatment decreased RANKL-induced nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and c-Fos protein in BMM cultures by 70% and 41%, respectively.


Input: Our data demonstrate that CD74 is required for MIF to affect in vitro osteoclastogenesis.


Input: Further, the bone phenotype of CD74 KO mice is similar to that of MIF KO mice.


Input: MIF treatment of WT cultures suppressed RANKL-induced activator protein 1 (AP-1) expression, which resulted in decreased osteoclast differentiation in vitro.


Input: We propose that CD74 plays a critical role in the MIF inhibition of osteoclastogenesis.


Input: Immune-induced expression of lipocalin-2 in brain endothelial cells: relationship with interleukin-6, cyclooxygenase-2 and the febrile response.


Input: Interleukin (IL)-6 is critical for the febrile response to peripheral immune challenge.


Input: However, the mechanism by which IL-6 enables fever is still unknown.


Input: To characterise the IL-6-dependent fever generating pathway, we used microarray analysis to identify differentially expressed genes in the brain of lipopolysaccharide (LPS)-treated IL-6 wild-type and knockout mice.


Input: Mice lacking IL-6 displayed a two-fold lower expression of the lipocalin-2 gene (lcn2), and this difference was confirmed by real-time reverse transcriptase-polymerase chain reaction.


Input: Conversely, the induction of lipocalin-2 protein was observed in brain vascular cells following i. p. administration of recombinant IL-6, suggesting a direct relationship between IL-6 and lipocalin-2.


Input: Immunohistochemical analysis also revealed that LPS-induced lipocalin-2 is expressed by brain endothelial cells and is partly co-localised with cyclooxygenase-2 (Cox-2), the rate-limiting enzyme for the production of inflammatory induced prostaglandin E (2) (PGE (2)), which is the key mediator of fever.

prostaglandin E (2)

PGE (2)


Input: The direct role of lipocalin-2 in fever was examined in LPS-challenged lipocalin-2 knockout mice.


Input: In both male and female mice, normal fever responses were observed at near-thermoneutral conditions (29-30 degrees C) but when recorded at normal room temperature (19-20 degrees C), the body temperature of lipocalin-2 knockout female mice displayed an attenuated fever response compared to their wild-type littermates.


Input: This difference was reflected in significantly attenuated mRNA expression of Cox-2 in the brain of lipocalin-2 knockout female mice, but not of male mice, following challenge with peripheral LPS.


Input: Our findings suggest that IL-6 influences the expression of lipocalin-2, which in turn may be involved in the control of the formation of Cox-2, and hence central PGE (2)-production.

PGE (2)


Input: We have thus identified lipocalin-2 as a new factor in the pathway of inflammatory IL-6 signalling.


Input: However, the effect of lipocalin-2 on fever is small, being sex-dependent and ambient temperature-specific, and thus lipocalin-2 cannot be considered as a major mediator of the IL-6-dependent fever generating pathway.


Input: Interspecies variation in the metabolism of zoniporide by aldehyde oxidase.

zoniporide

aldehyde


Input: 1. Aldehyde oxidase (AO) is a cytosolic enzyme that contributes to the Phase I metabolism of xenobiotics in human and preclinical species.

Aldehyde


Input: 2. Current studies explored in vitro metabolism of zoniporide in various animal species and humans using S9 fractions.

zoniporide


Input: The animal species included commonly used pharmacology and toxicology models and domestic animals such as the cat, cow or bull, pig and horse.


Input: 3. In addition, gender and strain differences in some species were also explored.


Input: 4. All animals except the dog and cat converted zoniporide to 2-oxozoniporide (M1).

zoniporide


Input: 5. Michael-Menten kinetic studies were conducted in species that turned over zoniporide to M1.

zoniporide


Input: 6. Marked differences in KM, Vmax and Clint were observed in the oxidation of zoniporide.

zoniporide


Input: 7. Although the KM and Vmax of zoniporide oxidation in male and female human S9 was similar, some gender difference was observed in animals especially, in Vmax.

zoniporide


Input: 8. The domestic animals also showed marked species differences in the AO activity and affinity toward zoniporide.

zoniporide


Input: Adverse outcome pathways during zebrafish embryogenesis: a case study with paraoxon.

paraoxon


Input: Using paraoxon as a reference acetylcholinesterase (AChE) inhibitor, the objective of this study was to develop an adverse outcome pathway (AOP) that provided quantitative linkages across levels of biological organization during zebrafish embryogenesis.

paraoxon


Input: Within normal zebrafish embryos, we first demonstrated that ache transcripts and AChE activity increased in a stage-dependent manner following segmentation.


Input: We then showed that static exposure of embryos to paraoxon (31. 2-500 nM) from 5 to 96 hpf resulted in significant stage-and concentration-dependent AChE inhibition, albeit these effects were fully reversible within 48 h following transfer to clean water.

paraoxon


Input: However, even in the presence of significant AChE inhibition, exposure to non-teratogenic paraoxon concentrations (<= 250 nM) did not adversely impact secondary motoneuron development at 96 hpf.

paraoxon


Input: Therefore, we investigated the potential effects of paraoxon exposure on spontaneous tail contractions at 26 hpf-an early locomotor behavior that results from innervation of primary (not secondary) motoneuron axons to target axial muscles.

paraoxon


Input: Based on these studies, the frequency of spontaneous tail contractions at 26 hpf-a developmental stage with minimal AChE expression and activity-was significantly higher following exposure to paraoxon concentrations as low as 31. 2 nM.

paraoxon


Input: Overall, our data suggest that (1) normal AChE activity is not required for secondary motoneuron development and (2) spontaneous tail contractions at 26 hpf are sensitive to paraoxon exposure, an effect that may be independent of AChE inhibition.

paraoxon


Input: Using a well-studied reference chemical, this study highlights the potential challenges in developing quantitative AOPs to support chemical screening and prioritization strategies.


Input: Hierarchical rutile TiO2 flower cluster-based high efficiency dye-sensitized solar cells via direct hydrothermal growth on conducting substrates.


Input: Dye-sensitized solar cells (DSSCs) based on hierarchical rutile TiO (2) flower clusters prepared by a facile, one-pot hydrothermal process exhibit a high efficiency.

TiO (2)


Input: Complex yet appealing rutile TiO (2) flower films are, for the first time, directly hydrothermally grown on a transparent conducting fluorine-doped tin oxide (FTO) substrate.

TiO (2)

fluorine-doped tin oxide

FTO


Input: The thickness and density of as-grown flower clusters can be readily tuned by tailoring growth parameters, such as growth time, the addition of cations of different valence and size, initial concentrations of precursor and cation, growth temperature, and acidity.


Input: Notably, the small lattice mismatch between the FTO substrate and rutile TiO (2) renders the epitaxial growth of a compact rutile TiO (2) layer on the FTO glass.

FTO

TiO (2)

TiO (2)

FTO


Input: Intriguingly, these TiO (2) flower clusters can then be exploited as photoanodes to produce DSSCs, yielding a power conversion efficiency of 2. 94% despite their rutile nature, which is further increased to 4. 07% upon the TiCl (4) treatment.

TiO (2)

TiCl (4)


Input: Circulating very-low-density lipoprotein from subjects with impaired glucose tolerance accelerates adrenocortical cortisol and aldosterone synthesis.

glucose

cortisol

aldosterone


Input: Apart from their role in cardiovascular homeostasis and immunomodulation, aldosterone and cortisol are also implicated in the pathogenesis of insulin resistance and type 2 diabetes mellitus (T2DM).

aldosterone

cortisol


Input: Furthermore, glycoxidative modifications of lipoproteins are increasingly recognized as an etiological factor for increased cardiovascular morbidity and mortality in prediabetic individuals.


Input: The causative relationship between in vivo lipoprotein modifications and steroidogenesis in subjects with impaired glucose tolerance (IGT), however, is not well defined.

glucose


Input: Therefore, we aimed to investigate the impact of in vivo modified lipoproteins on aldosterone and cortisol release from human adrenocortical H295R cells.

aldosterone

cortisol


Input: Following an oral glucose tolerance test, 20 individuals with normal glucose tolerance (NGT) and 20 IGT subjects were randomly selected from the ongoing PRAEDIAS prevention study in our department.

glucose

glucose


Input: Cells were incubated for 24 h with lipoproteins isolated from NGT and IGT individuals and aldosterone and cortisol release was measured in the supernatants.

aldosterone

cortisol


Input: VLDL induced a greater stimulating effect on adrenocortical aldosterone and cortisol release compared to HDL and LDL.

aldosterone

cortisol


Input: Moreover, IGT-VLDL evoked a significantly higher effect (p < 0. 05) on hormone release than NGT-VLDL.


Input: Incubation of cells with in vitro modified lipoproteins and specific pharmacological inhibitors suggests that VLDL presumably recruits ERK1/2 as one of the downstream effectors of Jak-2.


Input: In summary, in vivo modified VLDL are able to promote prediabetic hormonal dysregulation by modulating adrenocortical steroidogenesis via Jak-2-ERK dependent pathway.


Input: Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques.


Input: The melanocortin-4 receptor (MC4R) is well recognized as an important mediator of body weight homeostasis.


Input: Activation of MC4R causes dramatic weight loss in rodent models, and mutations in human are associated with obesity.


Input: This makes MC4R a logical target for pharmacological therapy for the treatment of obesity.


Input: However, previous studies in rodents and humans have observed a broad array of side effects caused by acute treatment with MC4R agonists, including increased heart rate and blood pressure.


Input: We demonstrate that treatment with a highly-selective novel MC4R agonist (BIM-22493 or RM-493) resulted in transient decreases in food intake (35%), with persistent weight loss over 8 weeks of treatment (13. 5%) in a diet-induced obese nonhuman primate model.


Input: Consistent with weight loss, these animals significantly decreased adiposity and improved glucose tolerance.

glucose


Input: Importantly, we observed no increases in blood pressure or heart rate with BIM-22493 treatment.


Input: In contrast, treatment with LY2112688, an MC4R agonist previously shown to increase blood pressure and heart rate in humans, caused increases in blood pressure and heart rate, while modestly decreasing food intake.


Input: These studies demonstrate that distinct melanocortin peptide drugs can have widely different efficacies and side effects.


Input: Adipocyte fatty acid binding protein: a novel adipokine involved in the pathogenesis of metabolic and vascular disease?

fatty acid


Input: Adipocyte fatty acid binding protein (AFABP, also known as aP2 and FABP4) has recently been introduced as a novel fat-derived circulating protein.

fatty acid


Input: AFABP serum concentrations are positively correlated with markers of the metabolic syndrome and vascular disease in various cross-sectional and interventional studies.


Input: Furthermore, a small set of prospective studies indicates that high AFABP serum levels at baseline predict the risk for metabolic and vascular morbidity and mortality.


Input: Studies in Afabp (also known as Fabp4) knockout mice and AFABP inhibitor-treated animals suggest that total AFABP promotes insulin resistance, hypertriacylglycerolaemia and atherosclerosis by ligand/ligand delivery, as well as ligand-independent mechanisms.


Input: In contrast, the pathophysiological significance of circulating AFABP and the mechanisms leading to its release remain to be established.


Input: The current review summarises recent findings on the regulation and potential role of AFABP in metabolic and vascular disease.


Input: Magnesium sulfate treatment against sarin poisoning: dissociation between overt convulsions and recorded cortical seizure activity.

Magnesium sulfate

sarin


Input: Sarin, a potent organophosphate cholinesterase inhibitor, induces an array of toxic effects including convulsions.

Sarin

organophosphate


Input: Many antidotal treatments contain anticonvulsants to block seizure activity and the ensuing brain damage.


Input: Magnesium sulfate (MGS) is used to suppress eclamptic seizures in pregnant women with hypertension and was shown to block kainate-induced convulsions.

Magnesium sulfate

MGS

kainate


Input: Magnesium sulfate was evaluated herein as an anticonvulsant against sarin poisoning and its efficacy was compared with the potent anticonvulsants midazolam (MDZ) and caramiphen (CRM).

Magnesium sulfate

midazolam

MDZ

caramiphen

CRM


Input: Rats were exposed to a convulsant dose of sarin (96 mu g/kg, im) and 1 min later treated with the oxime TMB4 and atropine to increase survival.

sarin

oxime TMB4

atropine


Input: Five minutes after initiation of convulsions, MGS, CRM, or MDZ were administered.

MGS

CRM

MDZ


Input: Attenuation of tonic-clonic convulsions was observed following all these treatments.


Input: However, radio-telemetric electro-corticography (ECoG) monitoring demonstrated sustained seizure activity in MGS-injected animals while this activity was completely blocked by MDZ and CRM.

MGS

MDZ

CRM


Input: This disrupted brain activity was associated with marked increase in brain translocator protein levels, a marker for brain damage, measured 1 week following exposure.


Input: Additionally, histopathological analyses of MGS-treated group showed typical sarin-induced brain injury excluding the hippocampus that was partially protected.

MGS

sarin


Input: Our results clearly show that MGS demonstrated misleading features as an anticonvulsant against sarin-induced seizures.

MGS

sarin


Input: This stems from the dissociation observed between overt convulsions and seizure activity.


Input: Thus, the presence or absence of motor convulsions may be an unreliable indicator in the assessment of clinical status and in directing adequate antidotal treatments following exposure to nerve agents in battle field or terror attacks.


Input: Repeat oral dose toxicity studies of melamine in rats and monkeys.

melamine


Input: Melamine is an important and widely used organic industrial chemical.

Melamine


Input: Recently, clinical findings of renal failure and kidney stones in infants have been associated with ingestion of melamine-contaminated infant formula.

melamine


Input: To understand the toxicity and clinical outcome of melamine exposure, repeated oral dose studies in rats and monkeys were performed to characterize the subchronic toxicity of melamine.

melamine

melamine


Input: Assessment of toxicity was based on mortality, clinical signs, body weights, ophthalmic findings, clinical pathology, gross pathology, organ weights, and microscopic observations.


Input: The first rat study was intended to be a 14-day oral study followed by an 8-day recovery period.


Input: The dose levels were 140, 700, and 1, 400 mg/kg/day (lowered to 1, 000 mg/kg/day subsequently due to mortality).


Input: Oral administration of melamine at 700 mg/kg/day for 14 consecutive days in rats produced compound-related clinical signs (red urine), decreased body weights, and changes in clinical pathology (increased serum urea nitrogen and creatinine) and anatomical pathology (renal tubular cell debris, crystal deposition, and hyperactive regeneration of renal tubular epithelium).

melamine

urea nitrogen

creatinine


Input: The kidney was identified as the target organ.


Input: Oral administration at 1, 400 mg/kg/day (subsequently lowered to 1, 000 mg/kg/day) resulted in animal death and moribundity.


Input: There were no treatment-related findings in the 140 mg/kg/day group.


Input: There were no compound-related findings in the high-dose recovery animals.


Input: The second rat study was a 5-day oral toxicity study with genomic biomarkers assayed in the kidney tissues.


Input: At the top dose of 1, 050 mg/kg/day, similar clinical and anatomical pathology findings as described above were observed.


Input: The genes measured, Kim-1, Clu, Spp1, A2m, Lcn2, Tcfrsf12a, Gpnmb, and CD44, were significantly up-regulated (fivefold to 550-fold), while Tff3 was significantly down-regulated (fivefold).


Input: These results indicated that genomic markers could sensitively diagnose melamine-induced kidney injury.

melamine


Input: A 3-month oral study with 4-week recovery in monkeys was also conducted.


Input: In this monkey study, the animals were treated with melamine at doses of 60, 200, or 700 mg/kg/day.

melamine


Input: The administration of 700 mg/kg/day melamine by nasal-gastric gavage to monkeys resulted in test article-related clinical signs including turbid and whitish urine, urine crystals, red blood cell changes, increased serum alanine aminotransferase and kidney and/or liver weights, and microscopic findings including nephrotoxicity, pericarditis, and increased hematopoiesis.

melamine

alanine


Input: Nephrotoxicity was also noted at 200 mg/kg/day.


Input: It was concluded that the kidney is the primary target organ and the NOAEL was estimated to be 140 mg/kg/day in rats following a 14-day oral administration and 60 mg/kg/day in the monkey study.


Input: Claudin-3 and claudin-4 regulate sensitivity to cisplatin by controlling expression of the copper and cisplatin influx transporter CTR1.

cisplatin

copper

cisplatin


Input: Claudin-3 (CLDN3) and claudin-4 (CLDN4) are the major structural molecules that form tight junctions (TJs) between epithelial cells.


Input: We found that knockdown of the expression of either CLDN3 or CLDN4 produced marked changes in the phenotype of ovarian cancer cells, including an increase in resistance to cisplatin (cDDP).

cisplatin


Input: The effect of CLND3 and CLDN4 on cDDP cytotoxicity, cDDP cellular accumulation, and DNA adduct formation was compared in the CLDN3-and CLDN4-expressing parental human ovarian carcinoma 2008 cells and CLDN3 and CLDN4 knockdown sublines (CLDN3KD and CLDN4KD, respectively).


Input: Knockdown of CLDN3 or CLDN4 rendered human ovarian carcinoma 2008 cells resistant to cDDP in both in vitro culture and in vivo xenograft model.


Input: The net accumulation of platinum (Pt) and the Pt-DNA adduct levels were reduced in CLDN3KD and CLDN4KD cells.

platinum

Pt

Pt


Input: The endogenous mRNA levels of copper influx transporter CTR1 were found to be significantly reduced in the knockdown cells, and exogenous expression of CTR1 restored their sensitivity to cDDP.

copper


Input: Reexpression of an shRNAi-resistant CLDN3 or CLDN4 up-regulated CTR1 levels, reversed the cDDP resistance, and enhanced TJ formation in the knockdown cells.


Input: Baseline copper (Cu) level, Cu uptake, and Cu cytotoxicity were also reduced in CLDN3KD and CLDN4KD cells.

copper

Cu

Cu

Cu


Input: Cu-dependent tyrosinase activity was also markedly reduced in both types of CLDN knockdown cells when incubated with the substrate l-DOPA.

Cu

l-DOPA


Input: These results indicate that CLDN3 and CLDN4 affect sensitivity of the ovarian cancer cells to the cytotoxic effect of cDDP by regulating expression of the Cu transporter CTR1.

Cu


Input: Parallel changes in serotonin levels in brain and blood following acute administration of MDMA.

serotonin

MDMA


Input: Recent studies have demonstrated a similar acute effect of 3, 4-methylenedioxymethamphetamine (MDMA) in blood platelets and brain tissue via action on the serotonin transporter.

3, 4-methylenedioxymethamphetamine

MDMA

serotonin


Input: To investigate the validity of blood serotonin as a peripheral marker for central serotonin in this regard, we administered MDMA (20 mg/kg i. p.) to rats and observed a parallel decrease in serotonin levels in the frontal cortex and blood at 2 h (63% and 46% respectively) with some recovery evident at 8 h (42% and 38%) and more so at 18 h (19% and 24% below control levels).

serotonin

serotonin

MDMA

serotonin


Input: Administration of a tryptophan supplement (82. 5 mg/kg p. o.) to na i ve rats produced parallel increases in serotonin levels 2 h later in the frontal cortex (39%) and blood (26%).

tryptophan

serotonin


Input: Following MDMA administration, the same dose of tryptophan caused a smaller (26%) rise in brain serotonin whereas in blood it had no effect.

MDMA

tryptophan

serotonin


Input: We conclude that blood serotonin is a useful marker for brain serotonin levels in the rat following acute administration of MDMA and this finding highlights the possible use of platelet serotonin as a marker for brain serotonin in human studies involving MDMA.

serotonin

serotonin

MDMA

serotonin

serotonin

MDMA


Input: Multi-fuel driven Janus micromotors.


Input: Here the first example of a chemically powered micromotor that harvests its energy from the reactions of three different fuels is presented.


Input: The new Al/Pd Janus microspheres-prepared by depositing a Pd layer on one side of Al microparticles-are propelled efficiently by the thrust of hydrogen bubbles generated from different reactions of Al in strong acidic and alkaline environments, and by an oxygen bubble thrust produced at their partial Pd coating in hydrogen peroxide media.

Al

Pd

Pd

Al

hydrogen

Al

oxygen

Pd

hydrogen peroxide


Input: High speeds and long lifetimes of 200 mu m s (-1) and 8 min are achieved in strong alkaline media and acidic media, respectively.


Input: The ability to autonomously adapt to the presence of a new fuel (surrounding environment), without compromising the propulsion behavior is illustrated.


Input: These data also represent the first example of a chemically powered micromotor that propels autonomously and efficiently in alkaline environments (pH > 11) without additional fuels.


Input: The ability to use multiple fuel sources to power the same micromotor offers a broader scope of operation and considerable promise for diverse applications of micromotors in different chemical environments.


Input: INO-8875, a highly selective A1 adenosine receptor agonist: evaluation of chronotropic, dromotropic, and hemodynamic effects in rats.

adenosine


Input: Selective pharmacological activation of the adenosine 1 receptor (A (1) R) is a promising new approach to achieve a potent block of atrioventricular (A-V)-nodal conduction without significant cardiovascular side effects.

adenosine


Input: The purpose of the present study was to evaluate the cardiovascular profile of INO-8875, a highly selective A (1) R agonist, and to compare its properties with N-[3 (R)-tetrahydrofuranyl]-6-aminopurine riboside (CVT-510), which has already been shown to induce negative dromotropic effects with minimal cardiovascular side effects in animals and in clinical studies.

N-[3 (R)-tetrahydrofuranyl]-6-aminopurine riboside


Input: Dose-response experiments in the isolated hearts of rats were used to evaluate the functional selectivity of INO-8875 for the slowing of A-V-nodal conduction.


Input: Ventilated adult rats were used to study the effects of INO-8875, in vivo, on arterial blood pressure as well as on supraventricular electrophysiology.


Input: Ex vivo, INO-8875 (100 nM to 3 mu M) progressively prolonged A-V-nodal conduction without reducing left ventricular function or coronary resistance.


Input: In vivo, INO-8875 up to a dose of 50 mu g/kg did not reduce the carotid arterial blood pressure (n = 4).


Input: INO-8875 (1-50 mu g/kg) and CVT-510 (20 and 50 mu g/kg) both induced a dose-dependent decrease in heart rate and atrial refractoriness, as well as slowing of A-V-nodal conduction.


Input: However, compared with CVT-510, the activity of INO-8875 was more pronounced in A-V-nodal function.


Input: INO-8875 exhibited a greater duration of action, lasting up to 2. 5 hours post dosing, whereas the effects of CVT-510 dissipated over 1 hour.


Input: INO-8875 demonstrates functional properties of a highly selective A (1) R agonist.


Input: INO-8875 exhibits an increased dromotropic effect and greater duration of action compared with CVT-510.


Input: Molecular mechanisms associated with increased tolerance to the neonicotinoid insecticide imidacloprid in the dengue vector Aedes aegypti.

imidacloprid


Input: Mosquitoes are vectors of several major human diseases and their control is mainly based on the use of chemical insecticides.


Input: Resistance of mosquitoes to organochlorines, organophosphates, carbamates and pyrethroids led to a regain of interest for the use of neonicotinoid insecticides in vector control.

organochlorines

organophosphates

carbamates

pyrethroids


Input: The present study investigated the molecular basis of neonicotinoid resistance in the mosquito Aedes aegypti.


Input: A strain susceptible to insecticides was selected at the larval stage with imidacloprid.

imidacloprid


Input: After eight generations of selection, larvae of the selected strain (Imida-R) showed a 5. 4-fold increased tolerance to imidacloprid while adult tolerance level remained low.

imidacloprid


Input: Imida-R larvae showed significant cross-tolerance to other neonicotinoids but not to pyrethroids, organophosphates and carbamates.

pyrethroids

organophosphates

carbamates


Input: Transcriptome profiling identified 344 and 108 genes differentially transcribed in larvae and adults of the Imida-R strain compared to the parental strain.


Input: Most of these genes encode detoxification enzymes, cuticle proteins, hexamerins as well as other proteins involved in cell metabolism.


Input: Among detoxification enzymes, cytochrome P450 monooxygenases (CYPs) and glucosyl/glucuronosyl transferases (UDPGTs) were over-represented.


Input: Bioassays with enzyme inhibitors and biochemical assays confirmed the contribution of P450s with an increased capacity of the Imida-R microsomes to metabolize imidacloprid in presence of NADPH.

imidacloprid

NADPH


Input: Comparison of substrate recognition sites and imidacloprid docking models of six CYP6s over-transcribed in the Imida-R strain together with Bemisia tabaci CYP6CM1vQ and Drosophila melanogaster CYP6G1, both able to metabolize imidacloprid, suggested that CYP6BB2 and CYP6N12 are good candidates for imidacloprid metabolism in Ae. aegypti.

imidacloprid

imidacloprid

imidacloprid


Input: The present study revealed that imidacloprid tolerance in mosquitoes can arise after few generations of selection at the larval stage but does not lead to a significant tolerance of adults.

imidacloprid


Input: As in other insects, P450-mediated insecticide metabolism appears to play a major role in imidacloprid tolerance in mosquitoes.

imidacloprid


Input: Suppressive effect of accumulated aluminum trichloride on the hepatic microsomal cytochrome P450 enzyme system in rats.

aluminum trichloride


Input: Aluminum (Al) is a low toxicological metal and can accumulate in the liver.

Aluminum

Al


Input: The hepatic microsomal cytochrome P450 enzyme system (CYPS) plays important role in the transformation of the toxic materials.


Input: It is not clear if the CYPS is affected by Al exposure.

Al


Input: Thus, the aim of this study is to investigate the effects of aluminum trichloride (AlCl (3)) on CYPS in rats.

aluminum trichloride

AlCl (3)


Input: Forty male Wistar rats (5weeks old) weighing 110-120g were randomly allocated and orally exposed to 0, 64. 18, 128. 36 and 256. 72mg/kg body weight (BW) AlCl (3) in drinking water for 120days.

AlCl (3)


Input: The body weight (BW) of rats, hepatosomatic index (HSI), hepatic Al content, the concentrations of cytochrome P450 (CYP450), cytochrome B5 (B5), microsomal protein and the activities of NADPH-cytochrome c reductase (CR), aminopyrin N-demethylase (AND), erythromycin N-demethylase (ERND) and aniline-4-hydeoxylase (AH) were assessed at the end of the experiment.

Al

NADPH

aminopyrin N

aniline


Input: The results showed that the increase in Al concentration decreased BW, HIS, concentrations of CYP450, B5, microsomal protein and the activity of CR, AND, ERND and AH in hepatic microsomes.

Al


Input: The results revealed that exposure to AlCl (3) inhibited the microsomal CYP450 dependent enzyme system of liver.

AlCl (3)


Input: Our findings suggest that long term daily exposure of AlCl (3) exerts the suppressive effects and thus may cause dysfunction of hepatic CYP450 dependent enzyme system of rat.

AlCl (3)


Input: Metal distribution in tissues of free-range chickens near a lead-zinc mine in Kabwe, Zambia.

zinc


Input: Concentrations of Pb, Cd, and other metals in tissues of 17 free-range and 32 commercial broiler chickens from the Kabwe mining town in Zambia were determined.

Pb

Cd


Input: Mean concentrations of Pb and Cd exceeded maximum levels for human consumption in some organs including muscle (Pb only) in free-range chickens, in contrast to low levels in broiler chickens.

Pb

Cd

Pb


Input: Human consumers in Kabwe could be exposed to Pb and Cd in free-range chickens.

Pb

Cd


Input: The quest for probiotic effector molecules--unraveling strain specificity at the molecular level.


Input: Pharmaceutical agents are widely applied for the treatment of gastrointestinal (and systemic) disorders and their role as modulators of host cell responses is relatively well characterized.


Input: By contrast, we are only beginning to understand the molecular mechanisms by which health-promoting, probiotic bacteria act as host cell modulators.


Input: The last decade has seen a rapid development of the genomics field for the widely applied probiotic genus Lactobacillus, and nowadays dozens of full genome sequences are available, as well as sophisticated post genomic and genetic engineering tools.


Input: This development has enabled comparative (functional) genomics approaches to identify the bacterial effector molecules involved in molecular communication with the host system that may underlie the probiotic effects observed.


Input: These efforts can also be complemented with dedicated mutagenesis approaches to eliminate or alter these effector molecules, followed by assessment of the host interaction consequences thereof, allowing the elucidation of the molecular mechanisms involved in probiotic health effects.


Input: Many of these approaches have pinpointed that the Lactobacillus cell envelope contains several effector molecules that are pivotal in the direct signaling capacity of these bacteria that underlies their immunomodulatory effects, including lipoteichoic acid, peptidoglycan, and (glyco) proteins.


Input: Moreover, the cell envelope contains several compounds such as wall teichoic acid and capsular polysaccharides that may not be involved in direct signaling to the host cell, but still affect signaling through shielding of other bacterial effector molecules.


Input: Initial structural studies revealed subtle strain-and species-specific biochemical differences in the canonical cell envelope compounds that are involved in these host interactions.


Input: These biochemical variations include the degree and positioning of d-alanyl and glycosyl substitution in lipoteichoic acids, and acetylation of peptidoglycan.

d-alanyl

glycosyl


Input: Furthermore, specific peptides derived from peptidoglycan and envelope associated (glyco) proteins were recently identified as potent immunomodulators.


Input: The latter findings are exciting in the light of the possibility of more pharmacological application of these bioactive probiotic molecules, and especially cost-effective production and targeted delivery of bioactive peptides seems to emerge as a feasible strategy to harness this knowledge.


Input: Nano-graphene in biomedicine: theranostic applications.

graphene


Input: Owing to their unique physical and chemical properties, graphene and its derivatives such as graphene oxide (GO), reduced graphene oxide (RGO) and GO-nanocomposites have attracted tremendous interest in many different fields including biomedicine in recent years.

graphene

graphene oxide

reduced graphene oxide

RGO


Input: With every atom exposed on its surface, single-layered graphene shows ultra-high surface area available for efficient molecular loading and bioconjugation, and has been widely explored as novel nano-carriers for drug and gene delivery.

graphene


Input: Utilizing the intrinsic near-infrared (NIR) optical absorbance, in vivo graphene-based photothermal therapy has been realized, achieving excellent anti-tumor therapeutic efficacy in animal experiments.

graphene


Input: A variety of inorganic nanoparticles can be grown on the surface of nano-graphene, obtaining functional graphene-based nanocomposites with interesting optical and magnetic properties useful for multi-modal imaging and imaging-guided cancer therapy.

graphene

graphene


Input: Moreover, significant efforts have also been devoted to study the behaviors and toxicology of functionalized nano-graphene in animals.

graphene


Input: It has been uncovered that both surface chemistry and sizes play key roles in controlling the biodistribution, excretion, and toxicity of nano-graphene.

graphene


Input: Biocompatibly coated nano-graphene with ultra-small sizes can be cleared out from body after systemic administration, without rendering noticeable toxicity to the treated mice.

graphene


Input: In this review article, we will summarize the latest progress in this rapidly growing field, and discuss future prospects and challenges of using graphene-based materials for theranostic applications.

graphene


Input: Chronic PFOS exposures induce life stage-specific behavioral deficits in adult zebrafish and produce malformation and behavioral deficits in F1 offspring.

PFOS


Input: Perfluorooctane sulfonic acid (PFOS) is an organic contaminant that is ubiquitous in the environment.

Perfluorooctane sulfonic acid

PFOS


Input: Few studies have assessed the behavioral effects of chronic PFOS exposure in aquatic organisms.

PFOS


Input: The present study defined the behavioral effects of varying life span chronic exposures to PFOS in zebrafish.

PFOS


Input: Specifically, zebrafish were exposed to control or 0. 5 micro M PFOS during 1 to 20, 21 to 120, or 1 to 120 d postfertilization (dpf).

PFOS


Input: Exposure to PFOS impaired the adult zebrafish behavior mode under the tapping stimulus.

PFOS


Input: The movement speed of male and female fish exposed for 1 to 120 dpf was significantly increased compared with control before and after tapping, whereas in the groups exposed for 1 to 20 and 21 to 120 dpf, only the males exhibited elevated swim speed before tapping.


Input: Residues of PFOS in F1 embryos derived from parental exposure for 1 to 120 and 21 to 120 dpf were significantly higher than control, and F1 embryos in these two groups also showed high malformation and mortality.

PFOS


Input: The F1 larvae of parental fish exposed to PFOS for 1 to 20 or 21 to 120 dpf exhibited a higher swimming speed than control larvae in a light-to-dark behavior assessment test.

PFOS


Input: The F1 larvae derived from parental fish exposed to PFOS for 1 to 120 dpf showed a significantly lower speed in the light period and a higher speed in the dark period compared with controls.

PFOS


Input: Although there was little PFOS residue in embryos derived from the 1-to 20-dpf parental PFOS-exposed group, the adverse behavioral effects on both adult and F1 larvae indicate that exposure during the first 21 dpf induces long-term neurobehaviorial toxicity.

PFOS

PFOS


Input: The authors' findings demonstrate that chronic PFOS exposure during different life stages adversely affects adult behavior and F1 offspring morphology, behavior, and survival.

PFOS


Input: Defective neural crest migration revealed by a Zebrafish model of Alx1-related frontonasal dysplasia.


Input: Frontonasal dysplasia (FND) refers to a class of midline facial malformations caused by abnormal development of the facial primordia.


Input: The term encompasses a spectrum of severities but characteristic features include combinations of ocular hypertelorism, malformations of the nose and forehead and clefting of the facial midline.


Input: Several recent studies have drawn attention to the importance of Alx homeobox transcription factors during craniofacial development.


Input: Most notably, loss of Alx1 has devastating consequences resulting in severe orofacial clefting and extreme microphthalmia.


Input: In contrast, mutations of Alx3 or Alx4 cause milder forms of FND.


Input: Whilst Alx1, Alx3 and Alx4 are all known to be expressed in the facial mesenchyme of vertebrate embryos, little is known about the function of these proteins during development.


Input: Here, we report the establishment of a zebrafish model of Alx-related FND.


Input: Morpholino knock-down of zebrafish alx1 expression causes a profound craniofacial phenotype including loss of the facial cartilages and defective ocular development.


Input: We demonstrate for the first time that Alx1 plays a crucial role in regulating the migration of cranial neural crest (CNC) cells into the frontonasal primordia.


Input: Abnormal neural crest migration is coincident with aberrant expression of foxd3 and sox10, two genes previously suggested to play key roles during neural crest development, including migration, differentiation and the maintenance of progenitor cells.


Input: This novel function is specific to Alx1, and likely explains the marked clinical severity of Alx1 mutation within the spectrum of Alx-related FND.


Input: Mechanistic sediment quality guidelines based on contaminant bioavailability: equilibrium partitioning sediment benchmarks.


Input: Globally, estimated costs to manage (i. e., remediate and monitor) contaminated sediments are in the billions of U. S. dollars.


Input: Biologically based approaches for assessing the contaminated sediments which pose the greatest ecological risk range from toxicity testing to benthic community analysis.


Input: In addition, chemically based sediment quality guidelines (SQGs) provide a relatively inexpensive line of evidence for supporting these assessments.


Input: The present study summarizes a mechanistic SQG based on equilibrium partitioning (EqP), which uses the dissolved concentrations of contaminants in sediment interstitial waters as a surrogate for bioavailable contaminant concentrations.


Input: The EqP-based mechanistic SQGs are called equilibrium partitioning sediment benchmarks (ESBs).


Input: Sediment concentrations less than or equal to the ESB values are not expected to result in adverse effects and benthic organisms should be protected, while sediment concentrations above the ESB values may result in adverse effects to benthic organisms.


Input: In the present study, ESB values are reported for 34 polycyclic aromatic hydrocarbon, 32 other organic contaminants, and seven metals (cadmium, chromium, copper, nickel, lead, silver, zinc).

polycyclic aromatic hydrocarbon

cadmium

chromium

copper

nickel

silver

zinc


Input: Also included is an overview of EqP theory, ESB derivation, examples of applying ESB values, and considerations when using ESBs.


Input: The ESBs are intended as a complement to existing sediment-assessment tools, to assist in determining the extent of sediment contamination, to help identify chemicals causing toxicity, and to serve as targets for pollutant loading control measures.


Input: Exposures to 1, 3-dimethylamylamine-containing products reported to Texas poison centers.

1, 3-dimethylamylamine


Input: 1, 3-Dimethylamylamine (DMAA) is an ingredient in a number of weight loss and exercise performance enhancing products.

1, 3-Dimethylamylamine

DMAA


Input: However, information on the safety of DMAA-containing products is limited.

DMAA


Input: Exposures to DMAA-containing products reported to Texas poison centers during 2010-2011 were identified and selected factors were examined.

DMAA


Input: A total of 56 exposures were found, of which 75. 0% were reported during 2011.


Input: OxyElite Pro (TM) was the reported product in 80. 4% of the exposures.


Input: The patients were 51. 8% male and 55. 4% age <= 5 years.


Input: The patient was managed on site (such as at home) in 57. 1% of the cases, and the exposure was known or expected to result in an outcome that was classified as not serious in 80. 4%.


Input: The most frequently reported clinical effects were tachycardia (28. 6%), nausea (16. 1%), and vomiting (12. 5%).


Input: The most common treatments were dilution (41. 1%), food (19. 6%), and activated charcoal (14. 3%).

charcoal


Input: It should be noted that the adverse clinical effects may be due to other ingredients in the DMAA-containing products, such as caffeine.

DMAA

caffeine


Input: Emergency do not consume/do not use concentrations for blended phosphates in drinking water.

phosphates


Input: The U. S.


Input: Congress [PL 107-188] amended the Safe Drinking Water Act and required each community water system serving more than 3, 000 people to conduct vulnerability assessments.


Input: These assessments address potential circumstances that could compromise the safety and reliability of municipal water.


Input: The present evaluation concerns the concentrations of the blended phosphates (also known as polyphosphates, condensed complex phosphates, polyphosphate glassy balls, and pyrophosphates) intended to aid regulatory agencies in decisions to avoid contact with affected water.

phosphates

polyphosphates

phosphates

pyrophosphates


Input: Polyphosphates are direct food additives and they are used to treat municipal drinking water, but depending upon the concentration and duration of exposure these substances can induce chemical burns.

Polyphosphates


Input: Ingested polyphosphates are degraded by phosphatase enzymes to monophosphates, substances that are over-the-counter bowel purgatives.

polyphosphates

monophosphates


Input: High oral doses of the monophosphates can induce transient hyperphosphatemia in older and susceptible young people, which can lead to acute phosphate nephropathy.

monophosphates


Input: In some patients, the condition is fatal.


Input: Based on the acute diarrhea after the ingestion of a single oral dose of monobasic (NaH2PO (4)) and dibasic (Na2HPO (4)) monophosphates in adults, a do not consume concentration of 600 mg PO (4)/L can be derived.

NaH2PO (4)

Na2HPO (4)

monophosphates

PO (4)


Input: Based on mild local irritation after topical application of 1. 0% sodium metaphosphate [(NaPO (3)) 6 * H2O] to intact skin of sensitive volunteers, a do not use concentration of 8, 000 mg PO4/L can be assigned.

sodium metaphosphate

(NaPO (3)) 6 * H2O


Input: Given the lack of eye irritation in rabbits after direct instillation of 0. 2% (NaPO (3)) 6 * H2O, an acute ocular contact limit of 50 mg PO4/L serves as the overall do not use level.

(NaPO (3)) 6 * H2O


Input: TLR4 antagonist reduces early-stage atherosclerosis in diabetic apolipoprotein E-deficient mice.


Input: Although it has been reported that deficiency of toll-like receptor 4 (TLR4) is associated with reduced atherosclerosis in atherosclerosis-prone mice and attenuated pro-inflammatory state in diabetic mice, it remains undetermined whether treatment with a TLR4 antagonist reduces atherosclerosis in nondiabetic or diabetic mice that have TLR4 expression.


Input: In this study, we determined the effect of Rhodobacter sphaeroides lipopolysaccharide (Rs-LPS), an established TLR4 antagonist, on early-stage atherosclerosis in nondiabetic and streptozotocin-induced diabetic apolipoprotein E-deficient (Apoe (-/-)) mice.

streptozotocin


Input: Analysis of atherosclerotic lesions of both en face aortas and cross sections of aortic roots showed that administration of Rs-LPS in 14-week-old diabetic Apoe (-/-) mice for 10 weeks significantly reduced atherosclerotic lesions.


Input: Although atherosclerotic lesions in nondiabetic Apoe (-/-) mice appeared to be decreased by Rs-LPS treatment, the difference was not statistically significant.


Input: Metabolic study showed that Rs-LPS significantly lowered serum levels of cholesterol and triglycerides in nondiabetic mice but not in diabetic mice.

cholesterol

triglycerides


Input: Furthermore, immunohistochemistry studies showed that Rs-LPS inhibited the expression of interleukin 6 and matrix metalloproteinase-9 and reduced the content of monocytes and macrophages in atherosclerotic plaques.


Input: Taken together, this study demonstrated for the first time that TLR4 antagonist inhibited vascular inflammation and atherogenesis in diabetic Apoe (-/-) mice and lowered serum cholesterol and triglyceride levels in nondiabetic Apoe (-/-) mice.

cholesterol

triglyceride


Input: Progress in synthesis and antitumor activities of estradiol-linked platinum complex.

estradiol

platinum


Input: Platinum complexes such as cisplatin and caboplatin are widely used in cancer chemotherapy.

Platinum

cisplatin

caboplatin


Input: However, their clinical applications are substantially limited by unexpected toxic side effects.


Input: In this review, we discuss the current progress on the design and synthesis of estradiol-linked platinum complexes as the targeted antitumor drugs.

estradiol

platinum


Input: Many of them display a high antitumor activity against the growth of breast cancer cell lines in vitro.


Input: The estradiol-linked platinum complexes could be used as target therapeutics for breast cancer.

estradiol

platinum


Input: Antioxidant evaluation of heterocyclic compounds by cytokinesis-block micronucleus assay.


Input: This article summarizes the results of using cytokinesis-block micronucleus (CBMN) assay to evaluate the antioxidant potential of heterocyclic compounds.


Input: Most studies were carried out with naturally occurring heterocyclic compounds such as plant polyphenols: flavonoids, xanthones, coumarins, and ellagitannins, or plant derived products (juices, extracts, supplements) rich in bioactive heterocyclic compounds.

polyphenols

flavonoids

xanthones

coumarins

ellagitannins


Input: There are also some studies dealing with synthetic heterocyclic antioxidants.


Input: CBMN assay is an in vitro study that has been used to evaluate antioxidant and protective effects of heterocyclic compounds on induced chromosome aberration in human lymphocytes.


Input: FoxA1 corrupts the antiandrogenic effect of bicalutamide but only weakly attenuates the effect of MDV3100 (Enzalutamide (TM)).

bicalutamide

Enzalutamide


Input: Prostate cancer growth depends on androgens.

androgens


Input: Synthetic antiandrogens are used in the cancer treatment.


Input: However, antiandrogens, such as bicalutamide (BIC), have a mixed agonist/antagonist activity.

bicalutamide

BIC


Input: Here we compare the antiandrogenic capacity of BIC to a new antiandrogen, MDV3100 (MDV) or Enzalutamide (TM).

BIC

Enzalutamide


Input: By reconstitution of a hormone-regulated enhancer in Xenopus oocytes we show that both antagonists trigger the androgen receptor (AR) translocation to the nucleus, albeit with a reduced efficiency for MDV.

androgen


Input: Once in the nucleus, both AR-antagonist complexes can bind sequence specifically to DNA in vivo.


Input: The forkhead box transcription factor A (FoxA1) is a negative prognostic indicator for prostate cancer disease.


Input: FoxA1 expression presets the enhancer chromatin and makes the DNA more accessible for AR binding.


Input: In this context the BIC-AR antiandrogenic effect is seriously compromised as demonstrated by a significant chromatin remodeling and induction of a robust MMTV transcription whereas the MDV-AR complex displays a more persistent antagonistic character.

BIC


Input: Global slowing of network oscillations in mouse neocortex by diazepam.

diazepam


Input: Benzodiazepines have a broad spectrum of clinical applications including sedation, anti-anxiety, and anticonvulsive therapy.

Benzodiazepines


Input: At the cellular level, benzodiazepines are allosteric modulators of GABA (A) receptors; they increase the efficacy of inhibition in neuronal networks by prolonging the duration of inhibitory postsynaptic potentials.

benzodiazepines


Input: This mechanism of action predicts that benzodiazepines reduce the frequency of inhibition-driven network oscillations, consistent with observations from human and animal EEG.

benzodiazepines


Input: However, most of existing data are restricted to frequency bands below ~ 30 Hz.


Input: Recent data suggest that faster cortical network rhythms are critically involved in several behavioral and cognitive tasks.


Input: We therefore analyzed diazepam effects on a large range of cortical network oscillations in freely moving mice, including theta (4-12 Hz), gamma (40-100 Hz) and fast gamma (120-160 Hz) oscillations.

diazepam


Input: We also investigated diazepam effects over the coupling between theta phase and the amplitude fast oscillations.

diazepam


Input: We report that diazepam causes a global slowing of oscillatory activity in all frequency domains.

diazepam


Input: Oscillation power was changed differently for each frequency domain, with characteristic differences between active wakefulness, slow-wave sleep and REM sleep.


Input: Cross-frequency coupling strength, in contrast, was mostly unaffected by diazepam.

diazepam


Input: Such state-and frequency-dependent actions of benzodiazepines on cortical network oscillations may be relevant for their specific cognitive effects.

benzodiazepines


Input: They also underline the strong interaction between local network oscillations and global brain states.


Input: The role of oxygen during fracture healing.

oxygen


Input: Oxygen affects the activity of multiple skeletogenic cells and is involved in many processes that are important for fracture healing.

Oxygen


Input: However, the role of oxygen in fracture healing has not been fully studied.

oxygen


Input: Here we systematically examine the effects of oxygen tension on fracture healing and test the ability of hyperoxia to rescue healing defects in a mouse model of ischemic fracture healing.

oxygen


Input: Mice with tibia fracture were housed in custom-built gas chambers and groups breathed a constant atmosphere of 13% oxygen (hypoxia), 21% oxygen (normoxia), or 50% oxygen (hyperoxia).

oxygen

oxygen

oxygen


Input: The influx of inflammatory cells to the fracture site, stem cell differentiation, tissue vascularization, and fracture healing were analyzed.


Input: In addition, the efficacy of hyperoxia (50% oxygen) as a treatment regimen for fracture nonunion was tested.

oxygen


Input: Hypoxic animals had decreased tissue vascularity, decreased bone formation, and delayed callus remodeling.


Input: Hyperoxia increased tissue vascularization, altered fracture healing in un-complicated fractures, and improved bone repair in ischemia-induced delayed fracture union.


Input: However, neither hypoxia nor hyperoxia significantly altered chondrogenesis or osteogenesis during early stages of fracture healing, and infiltration of macrophages and neutrophils was not affected by environmental oxygen after bone injury.

oxygen


Input: In conclusion, our results indicate that environmental oxygen levels affect tissue vascularization and fracture healing, and that providing oxygen when fractures are accompanied by ischemia may be beneficial.

oxygen

oxygen


Input: Copy number variation in ACHE/EPHB4 (7q22) and in BCHE/MME (3q26) genes in sporadic breast cancer.


Input: Gene amplifications and deletions are common changes in human cancer cells.


Input: Previous studies indicate that the regions, where the ACHE (7q22) and BCHE (3q26. 1-q26. 2) genes are localized, are suffering such structural modifications in breast cancer.


Input: Therefore, the products of these genes, acetylcholinesterase and butyrylcholinesterase, respectively, are related to the process of cell differentiation and proliferation, as well as apoptosis.


Input: This study also included two other genes involved in tumorigenesis, the EPHB4 (7q22. 1) and MME (3q21-27).


Input: The aim of this study was to verify amplification and/or deletion in the ACHE, BCHE, EPHB4 and MME genes in 32 samples of sporadic breast cancer.


Input: The gene alterations were detected using real-time PCR and determined by relative quantification with the standard curve method.


Input: All samples presented genetic alterations, showing a higher tendency for amplification of the ACHE (62. 5% vs. 37. 5%; p > 0. 1) and EPHB4 (53. 13% vs. 46. 88%; p > 0. 5) genes, and for deletions of the BCHE and MME genes (56. 25% vs. 43. 75% for both; p > 0. 5).


Input: A positive correlation was found between alterations in ACHE-EPHB4 and BCHE-MME pairs (rs = 0. 5948; p = 0. 0004; rs = 0. 3581; p = 0. 0478, respectively) indicating that these changes comprise a wide region.


Input: In conclusion, the results suggest that these genomic regions may contain important genes for this pathology, such as the oncogenes MET (7q31) and PIK3CA (3q26), and thus being interesting targets for future studies in breast cancer research.


Input: Delivering the promise of miRNA cancer therapeutics.


Input: MicroRNAs (miRNAs) are pivotal post-transcriptional gene expression regulators.


Input: These endogenous small non-coding RNAs aberrantly expressed in cancer have significant roles in tumorigenesis and progression.


Input: Currently, miRNAs are being pursued as diagnostic and prognostic biomarkers, and as therapeutic tools in cancer.


Input: miRNA modulation provides the unique ability to fine-tune multiple genes simultaneously, thereby regulating relevant signaling pathways involved in cell differentiation, proliferation and survival.


Input: This unique miRNA feature shifts the traditional one drug one target paradigm to a novel one drug multiple targets paradigm.


Input: We herein review in vivo strategies of miRNA modulator (mimic and/or inhibitor) delivery in cancer models, a subject that remains the key challenge to the establishment of this novel class of RNA therapeutics.


Input: Inhalable highly concentrated itraconazole nanosuspension for the treatment of bronchopulmonary aspergillosis.

itraconazole


Input: Cystic fibrosis (CF) patients are suffering from multiple often chronic endobronchial infection.


Input: The stiff mucus in these patients represents a compartment, which cannot easily be reached by systemic treatment.


Input: While bacterial infections are now successfully treated with repeated inhalation of antibiotics such as tobramycine, 57% of CF patients are colonized by Aspergillus species.

tobramycine


Input: About 10-20% of colonized patients develop symptoms of allergic bronchopulmonary aspergillosis (ABPA).


Input: While current standard of treatment of ABPA in CF patients is to suppress the allergy related symptoms by administration of glucocorticoids, itraconazole (ITRA), administered orally at high doses, can alleviate the symptoms of ABPA.

itraconazole

ITRA


Input: However, no inhalable formulation of ITRA is available to enable local treatment of aspergillosis.

ITRA


Input: The aim of this study was to describe an aqueous nanosuspension of ITRA and to characterize the pharmacokinetics after single dose inhalation.

ITRA


Input: Using wet-milling with organic milling beads, a stable nanosuspension with particle size in the range of 200nm and an ITRA concentration of 20% (v/w) could be obtained, using polysorbate 80 at a concentration of 14% relative to ITRA.

ITRA

polysorbate 80

ITRA


Input: The suspension was stable if stored at 8 degrees C for 3 months without particle growth and could be nebulized using standard nebulizer technologies including mesh technology and pressured air nebulizers.


Input: A 10% suspension was well tolerated upon repeated dose inhalation once daily for 7 days at a predicted dose of 45mg/kg in rats.


Input: A single dose inhalation at a predicted dose of 22. 5mg/kg resulted in maximum lung tissue concentration of 21. 4 mu g/g tissue with a terminal half-life of 25. 4h.


Input: Serum concentrations were lower, with a maximum concentration of 104ng/ml at 4h after dosing and a terminal half-life of 10. 5h.


Input: The data indicate that ITRA nanosuspension represents an interesting formulation for inhaled administration in CF patients suffering from ABPA.

ITRA


Input: High and long lasting lung tissue concentrations well above the minimal inhibitory concentration of Aspergillus species enable once daily administration with minimal systemic exposure.


Input: Regulation of adenosine levels during cerebral ischemia.

adenosine


Input: Adenosine is a neuromodulator with its level increasing up to 100-fold during ischemic events, and attenuates the excitotoxic neuronal injury.

Adenosine


Input: Adenosine is produced both intracellularly and extracellularly, and nucleoside transport proteins transfer adenosine across plasma membranes.

Adenosine

nucleoside

adenosine


Input: Adenosine levels and receptor-mediated effects of adenosine are regulated by intracellular ATP consumption, cellular release of ATP, metabolism of extracellular ATP (and other adenine nucleotides), adenosine influx, adenosine efflux and adenosine metabolism.

Adenosine

adenosine

ATP

ATP

ATP

adenine nucleotides

adenosine

adenosine

adenosine


Input: Recent studies have used genetically modified mice to investigate the relative contributions of intra-and extracellular pathways for adenosine formation.

adenosine


Input: The importance of cortical or hippocampal neurons as a source or a sink of adenosine under basal and hypoxic/ischemic conditions was addressed through the use of transgenic mice expressing human equilibrative nucleoside transporter 1 (hENT1) under the control of a promoter for neuron-specific enolase.

adenosine

nucleoside


Input: From these studies, we conclude that ATP consumption within neurons is the primary source of adenosine in neuronal cultures, but not in hippocampal slices or in vivo mice exposed to ischemic conditions.

ATP

adenosine


Input: The toxicity of the N-hydroxy and 6-hydroxy metabolites of 3, 4-dichloropropionanilide does not depend on calcium release-activated calcium channel inhibition.

N-hydroxy

3, 4-dichloropropionanilide

calcium

calcium


Input: Each year ~ 1 billion kg of herbicides are used worldwide to control the unwanted growth of plants.


Input: In the United States, over a quarter of a billion kg of herbicides are used, representing 28% of worldwide use.


Input: (Kiely, T., Donaldson, D., and Grube, A. [2004]. Pesticide Industry Sales and Usage. 2000 and 2001 Market Estimates. Available at: http://www. epa. gov/pesticides/pestsales/01pestsales/market _ estimates2001. pdf. Accessed October 25, 2012.) Propanil (3, 4-dichloropropionanilide [DCPA]) is a commonly used herbicide in the United States, with 2-4 million kg applied annually to 2 million acres of crop land.

Propanil

3, 4-dichloropropionanilide

DCPA


Input: The immunomodulatory effects of DCPA have been well documented, but limited data are available on the effects of its metabolites.

DCPA


Input: (Salazar, K. D., Ustyugova, I. V., Brundage, K. M., Barnett, J. B., and Schafer, R. [2008]. A review of the immunotoxicity of the pesticide 3, 4-dichloropropionanalide. J. Toxicol. Environ. Health B Crit. Rev. 11, 630-645.) In mammals, hepatic enzymes metabolize DCPA, resulting in the production of 3, 4-dichloroaniline (DCA).

3, 4-dichloropropionanalide

DCPA

3, 4-dichloroaniline

DCA


Input: Further biotransformation of DCA leads to the production of 6-hydroxy-3, 4-dichloroaniline (6OH-DCA) and N-hydroxy-3, 4-dichloroaniline (NOH-DCA).

DCA

6-hydroxy-3, 4-dichloroaniline

N-hydroxy-3, 4-dichloroaniline

NOH-DCA


Input: We report, for the first time, the immunotoxic effects of DCPA metabolites on T-cell function.

DCPA


Input: Human Jurkat T cells were exposed to varying concentrations of DCPA or its metabolites and assayed for effects on T-cell function.

DCPA


Input: In addition, fluorine analogs of DCPA and DCA were investigated to determine the relative role of chlorine substituents on T-cell immunotoxicity.

fluorine

DCPA

DCA

chlorine


Input: Here we report that exposure of Jurkat T cells to DCPA and DCA alters IL-2 secretion, nuclear factor of activated T cells (NFAT) activity, and calcium influx.

DCPA

DCA

calcium


Input: However, exposure to 6OH-DCA and NOH-DCA reduces IL-2 secretion and NFAT activity but has no effect on calcium flux.

NOH-DCA

calcium


Input: When both chlorines in DCPA and DCA were substituted with fluorines all effects were abrogated.

chlorines

DCPA

DCA

fluorines


Input: Our data indicate that metabolites of DCPA have differential effects on T-cell function and the presence of chlorines plays an important role in eliciting these effects.

DCPA

chlorines


Input: Metabolism and quantification of [(18) F] DPA-714, a new TSPO positron emission tomography radioligand.

[(18) F] DPA-714


Input: [(18) F] DPA-714 [N, N-diethyl-2-(2-(4-(2 [(18) F]-fluoroethoxy) phenyl) 5, 7dimethylpyrazolo [1, 5a] pyrimidin-3-yl) acetamide] is a new radioligand currently used for imaging the 18-kDa translocator protein in animal models of neuroinflammation and recently in humans.

[(18) F] DPA-714

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


Input: The biodistribution by positron emission tomography (PET) in baboons and the in vitro and in vivo metabolism of [(18) F] DPA-714 were investigated in rats, baboons, and humans.

[(18) F] DPA-714


Input: Whole-body PET experiments showed a high uptake of radioactivity in the kidneys, heart, liver, and gallbladder.


Input: The liver was a major route of elimination of [(18) F] DPA-714, and urine was a route of excretion for radiometabolites.

[(18) F] DPA-714


Input: In rat and baboon plasma, high-performance liquid chromatography (HPLC) metabolic profiles showed three major radiometabolites accounting for 85% and 89% of total radioactivity at 120 minutes after injection, respectively.


Input: Rat microsomal incubations and analyses by liquid chromatography-mass spectrometry (LC-MS) identified seven metabolites, characterized as O-deethyl, hydroxyl, and N-deethyl derivatives of nonradioactive DPA-714, two of them having the same retention times than those detected in rat and baboon plasma.

O-deethyl

hydroxyl

N-deethyl


Input: The third plasma radiometabolite was suggested to be a carboxylic acid compound that accounted for 15% of the rat brain radioactivity.

carboxylic acid


Input: O-deethylation led to a nonradioactive compound and [(18) F] fluoroacetic acid.

O

[(18) F] fluoroacetic acid


Input: Human CYP3A4 and CYP2D6 were shown to be involved in the oxidation of the radioligand.


Input: Finally an easy, rapid, and accurate method--indispensable for PET quantitative clinical studies--for quantifying [(18) F] DPA-714 by solid-phase extraction was developed.

[(18) F] DPA-714


Input: In vivo, an extensive metabolism of [(18) F] DPA-714 was observed in rats and baboons, identified as [(18) F] deethyl, [(18) F] hydroxyl, and [(18) F] carboxylic acid derivatives of [(18) F] DPA-714.

[(18) F] DPA-714

[(18) F] deethyl

[(18) F] hydroxyl

[(18) F] carboxylic acid

[(18) F] DPA-714


Input: The main route of excretion of the unchanged radioligand in baboons was hepatobiliary while that of radiometabolites was the urinary system.


Input: Polymorphisms in the vitamin D receptor gene and risk of autoimmune thyroid diseases: a meta-analysis.

vitamin D


Input: Environmental and genetic factors are thought to be involved in the pathogenesis of autoimmune thyroid diseases (AITD), which include Graves' disease, Hashimoto' s thyroiditis.


Input: Polymorphisms of vitamin D receptor (VDR) were implicated in AITDs risk.

vitamin D


Input: To date, many studies have evaluated the association between a functional polymorphism in the VDR gene and AITDs risk; however, the result is still ambiguous and inconclusive.


Input: To address the association of VDR gene FokI (rs10735810), TaqI (rs731236), BsmI (rs1544410), and ApaI (rs7975232) polymorphisms with AITD risk by meta-analysis.


Input: By searching the relevant literature, a total of eight studies were identified and meta-analyzed.


Input: HWE for each study are checked.


Input: Crude odds ratios (OR) with 95% confidence intervals (CIs) were used to assess the strength of association in the allele polymorphism, codominant model, dominant model, and recessive model.


Input: The result indicates that the BsmI or TaqI polymorphisms is significantly associated with AITD risk (OR = 0. 801 95% CI 0. 705, 0. 910, Pz = 0. 001 for B vs. b; OR = 0. 854, 95% CI 0. 757, 0. 963, Pz = 0. 010 for t vs. T), while the ApaI or FokI polymorphism do not.


Input: In the subgroup analysis in Europeans, the decreased risk of AITD remained for the B or t variant.


Input: This gene-based analysis indicates that, based on current evidence from published studies, the cumulative effect of BsmI or TaqI polymorphisms in VDR is significantly associated with AITD.


Input: Optimization of CD4/gp120 inhibitors by thermodynamic-guided alanine-scanning mutagenesis.

alanine


Input: As protein/protein interactions usually trigger signalling processes, inhibitors of those interactions must preclude protein binding without eliciting the signalling process themselves.


Input: To accomplish those goals, small molecules need to target those protein residues that contribute the most to binding (binding hotspots) without disturbing those residues that initiate signalling processes (allosteric hotspots).


Input: The availability of a blueprint identifying binding and allosteric hotspots will significantly aid inhibitor design and optimization.


Input: In this study, we show that in some situations the blueprint can be constructed by combining the standard technique of alanine-scanning mutagenesis with isothermal titration calorimetry (ITC).

alanine


Input: We demonstrate the approach by developing the combined binding and allosteric hotspots blueprint for CD4/gp120, the initial interaction leading to HIV-1 cell infection.


Input: A major finding of these studies is that not all binding hotspots are allosteric hotspots opening the possibility for the rational design of inhibitors and antagonist or agonist modulators.


Input: Alanine scan of an immunosuppressive peptide (CP): analysis of structure-function relationships.

Alanine


Input: Core peptide is a hydrophobic peptide, the sequence of which is derived from the T-cell antigen receptor alpha-chain transmembrane region.


Input: Previous studies have shown that core peptide can inhibit T-cell-mediated immune responses both in vitro and in vivo.


Input: Here, we report the role each constituent amino acid plays within core peptide using an alanine scan and the amino acid effect on function using a biological antigen presentation assay.

amino acid

alanine

amino acid


Input: The biophysical behaviour of these analogues in model membranes was analysed using surface plasmon resonance studies and then binding correlated with T-cell function.


Input: Removal of any single hydrophobic amino acid between the two charged amino acids in core peptide (R, K) resulted in lower binding.

amino acid

amino acids


Input: Changing the overall net charge of core peptide, by removing either of the positively charged residues (R or K), had varying effects on peptide binding and IL-2 production.


Input: There was a direct correlation (rho = 0. 718) between peptide binding to model membranes and peptide ability to inhibit IL-2.


Input: Except for IL-2 inhibition, production of other T-cell cytokines such as GM-CSF, IFN-gamma, IL-1 alpha, IL-4, IL-5, IL-6, IL-10, IL-17 and T-cell antigen receptor alpha-chain was not detected using a fluorescent bead immunoassay.


Input: This study provides important structure-function relationships essential for further drug design.


Input: Anti-tumor necrosis factor treatment in cherubism--clinical, radiological and histological findings in two children.


Input: Cherubism is a rare and disfiguring genetic disorder with excessive bone resorption and multilocular lesions in the mandible and/or maxilla.


Input: The disease-causing gain-of-function mutations in the SH3-binding protein 2 (SH3BP2) gene result in increased myeloid cell responses to macrophage colony stimulating factor and RANK ligand, formation of hyperactive osteoclasts (giant cells), and hyper-reactive macrophages that produce excessive amounts of the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha).


Input: Recent findings in the cherubism mouse model suggest that TNF-alpha plays a major role in disease pathogenesis and that removal of TNF-alpha prevents development of the bone phenotype.


Input: We treated two children with cherubism with the TNF-alpha antagonist adalimumab for approximately 2. 5 years and collected extensive clinical, radiological and histological follow-up data during the treatment.


Input: Histologically the treatment resulted in a significant reduction in the number of multinucleated giant cells and TNF-alpha staining positivity in both patients.


Input: As evaluated by computed tomography and magnetic resonance imaging, the lesions in Patient 1 showed either moderate enlargement (mandibular symphysis) or remained stable (mandibular rami and body, the maxilla).


Input: In Patient 2, the lesions in mandibular symphysis showed enlargement during the first 8 months of treatment, and thereafter the lesions remained unchanged.


Input: Bone formation and resorption markers remained unaffected.


Input: The treatment was well tolerated.


Input: Based on our findings, TNF-alpha antagonist may decrease the formation of pathogenic giant cells, but does not result in lesion regression or prevent lesion expansion in active cherubism.


Input: TNF-alpha modulator treatment thus does not appear to provide sufficient amelioration for patients suffering from cherubism.


Input: Controlling enzymatic action in living cells with a kinase-inducible bimolecular switch.


Input: Molecular probes designed to monitor or perturb signaling events in living cells rely on engineered molecular switches.


Input: Here, we show that a kinase-inducible bimolecular switch comprising a kinase-specific substrate and a phosphoamino acid binding domain can be used for acute regulation of cellular events.

phosphoamino acid


Input: As a proof of concept, we employed a Protein Kinase A (PKA)-dependent switch and coupled it to a lipid phosphatase to manipulate the level of phosphatidylinositol 4, 5-bisphosphate (PI (4, 5) P (2)) in living cells.

phosphatidylinositol 4, 5-bisphosphate

PI (4, 5) P (2)


Input: PKA activation results in rapid degradation of PI (4, 5) P (2).

PI (4, 5) P (2)


Input: Conversely, when PKA is inhibited, dephosphorylation of the switch leads to the replenishment of PI (4, 5) P (2).

PI (4, 5) P (2)


Input: Thus, this strategy can be used for reversibly controlling enzymatic action in living cells.


Input: Furthermore, its genetic encodability and modular design should facilitate the adaptation of this approach to control different cellular activities as a function of phosphorylation-dependent input signals, thereby providing versatile tools for potentially perturbing or rewiring signaling pathways.


Input: Design, synthesis, and in vitro evaluation of new amphiphilic cyclodextrin-based nanoparticles for the incorporation and controlled release of acyclovir.

acyclovir


Input: Acyclovir possesses low solubility in water and in lipid bilayers, so that its dosage forms do not allow suitable drug levels at target sites following oral, local, or parenteral administration.

Acyclovir


Input: In order to improve this lack of solubility, new cyclodextrin-based amphiphilic derivatives have been designed to form nanoparticles, allowing the efficient encapsulation of this hydrophobic antiviral agent.


Input: The present work first describes the synthesis and characterization of five new O-2, O-3 permethylated O-6 alkylthio-and perfluoroalkyl-propanethio-amphiphilic beta-cyclodextrins.

O-2, O-3 permethylated O-6 alkylthio-and perfluoroalkyl-propanethio-amphiphilic beta-cyclodextrins


Input: These derivatives have been obtained with good overall yields.


Input: The capacity of these molecules to form nanoparticles in water and to encapsulate acyclovir has then been studied.

acyclovir


Input: The nanoparticles prepared from the new beta-cyclodextrin derivatives have been characterized by dynamic light scattering and have an average size of 120nm for the fluorinated derivatives and 220nm for the hydrogenated analogs.

beta-cyclodextrin


Input: They all allowed high loading and sustained release of acyclovir.

acyclovir


Input: Fingolimod protects cultured cortical neurons against excitotoxic death.

Fingolimod


Input: Fingolimod (FTY720), a novel drug approved for the treatment of relapsing-remitting multiple sclerosis, activates different sphingosine-1-phosphate receptor (S1PR) subtypes.

Fingolimod


Input: Its primary mechanism of action is to reduce the egress of T lymphocytes from secondary lymphoid organs, thus restraining neuroinflammation and autoimmunity.


Input: However, recent evidence suggests that the action of FTY720 involves S1PRs expressed by cells resident in the CNS, including neurons.


Input: Here, we examined the effect of FTY720, its active metabolite, FTY720-P, and sphingosine-1-phosphate (S1P) on neuronal viability using a classical in vitro model of excitotoxic neuronal death.


Input: Mixed cultures of mouse cortical cells were challenged with toxic concentrations of N-methyl-d-aspartate (NMDA) for 10 min, and neuronal death was assessed 20 h later.

N-methyl-d-aspartate

NMDA


Input: FTY720, FTY720-P, and S1P were all neuroprotective when applied 18-20 h prior to the NMDA pulse.

NMDA


Input: Neuroprotection was attenuated by pertussis toxin, and inhibited by the selective type-1 S1PR (S1P1R) antagonist, W146, and by inhibitors of the mitogen associated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PtdIns-3-K) pathways.

phosphatidylinositol


Input: Both FTY720 and FTY720-P retained their protective activity in pure cultures of mouse or rat cortical neurons.


Input: These data offer the first direct demonstration that FTY720 and its active metabolite protect neurons against excitotoxic death.


Input: In situ control of cell substrate microtopographies using photolabile hydrogels.


Input: Substratum topography can play a significant role in regulating cellular function and fate.


Input: To study cellular responses to biophysical cues, researchers have developed dynamic methods for controlling cell morphology; however, many of these platforms are limited to one transition between two predefined substratum topographies.


Input: To afford the user additional control over the presentation of microtopographic cues to cell populations, a photolabile, PEG-based hydrogel system is presented in which precisely engineered topographic cues can be formed in situ by controlled erosion.

PEG


Input: Here, the ability to produce precisely engineered static microtopographies in the hydrogel surface is first established.


Input: Human mesenchymal stem cell (hMSC) response to topographies with features of subcellular dimensions (~ 5 to 40 mu m) and with various aspect ratios increasing from 1: 1 to infinity (e. g., channels) are quantified, and the dynamic nature of the culture system is demonstrated by sequentially presenting a series of topographies through in situ modifications and quantifying reversible changes in cell morphology in response to substratum topographies altered in real time.


Input: Treadmill exercise promotes interleukin 15 expression in skeletal muscle and interleukin 15 receptor alpha expression in adipose tissue of high-fat diet rats.


Input: Interleukin 15 (IL-15) has recently been proposed as a myokine involved in regulating lipid metabolism.


Input: We investigated the effect of exercise training on IL-15 content in skeletal muscle and expression of IL-15 receptor (IL-15R) in adipose tissue of obese rats.


Input: After 12 weeks of a high-fat diet, obese rats underwent treadmill running at 26 m/min (60 min each, 5 days/week for 8 weeks).


Input: High-fat diet induced obesity, with increased body weight, body fat, and lipid profile.


Input: The level of IL-15 immunoreactivity (IL-15-ir) in plasma and gastrocnemius muscle was lower in obese than control rats, and the mRNA level of IL-15 in gastrocnemius muscle was markedly decreased.


Input: The mRNA and protein levels of IL-15R in adipose tissue were markedly lower in obese rats.


Input: Compared with sedentary obese rats, treadmill running showed decreased body weight and elevated mRNA expression of IL-15 in muscle and elevated IL-15-ir level in plasma and muscle.


Input: The mRNA and protein level of IL-15R were increased in adipose tissue in treadmill running obese rats.


Input: Our results showed that exercise training improve obesity and reversed the downregulation of the IL-15 in muscle and IL-15R in adipose tissue induced by high-fat diet.


Input: Hyaluronic acid modified mesoporous silica nanoparticles for targeted drug delivery to CD44-overexpressing cancer cells.

silica


Input: In this paper, a targeted drug delivery system has been developed based on hyaluronic acid (HA) modified mesoporous silica nanoparticles (MSNs).

silica


Input: HA-MSNs possess a specific affinity to CD44 over-expressed on the surface of a specific cancer cell line, HCT-116 (human colon cancer cells).


Input: The cellular uptake performance of fluorescently labelled MSNs with and without HA modification has been evaluated by confocal microscopy and fluorescence-activated cell sorter (FACS) analysis.


Input: Compared to bare MSNs, HA-MSNs exhibit a higher cellular uptake via HA receptor mediated endocytosis.


Input: An anticancer drug, doxorubicin hydrochloride (Dox), has been loaded into MSNs and HA-MSNs as drug delivery vehicles.

doxorubicin hydrochloride

Dox


Input: Dox loaded HA-MSNs show greater cytotoxicity to HCT-116 cells than free Dox and Dox-MSNs due to the enhanced cell internalization behavior of HA-MSNs.

Dox

Dox

Dox


Input: It is expected that HA-MSNs have a great potential in targeted delivery of anticancer drugs to CD44 over-expressing tumors.


Input: An in vitro model using the IPEC-J2 cell line for efficacy and drug interaction testing of mycotoxin detoxifying agents.


Input: An in vitro model simulating the intestinal barrier for efficacy and drug interaction testing of mycotoxin detoxifying agents was developed using Transwell (R) cell culture inserts.


Input: Intestinal porcine epithelial cells derived from the jejunum of piglets were exposed to DON and a mycotoxin binder (efficacy testing) or exposed to tylosin and a mycotoxin binder (drug interaction testing).

tylosin


Input: Active carbon and bentonite were used in the efficacy and drug interaction trials, respectively, to validate the developed model.

carbon

bentonite


Input: The evaluated parameters were passage of DON and tylosin through the epithelial monolayer, the integrity of the monolayer by measurements of the trans-epithelial electrical resistance and the viability of the monolayer using the neutral red assay.

DON

tylosin

neutral red


Input: In the efficacy model it was shown that active carbon effectively bound DON at both non-cytotoxic and cytotoxic concentrations of DON, respectively 0. 5 and 1 mu g/mL.

carbon

DON

DON


Input: Moreover, the negative effects of DON at cytotoxic concentrations on cellular viability and integrity were completely offset.

DON


Input: A commercially available modified gluco-mannan binder was also tested and it was able to partly reduce the negative effects on these latter parameter.


Input: Moreover, it reduced the transepithelial passage of DON with 37% to 57% compared to active carbon, at both cytotoxic and non-cytotoxic concentrations of DON.

DON

carbon

DON


Input: In our drug interaction model, the interaction between tylosin and mycotoxin binders was investigated as some authors suggest binding of macrolide antibiotics to bentonite clays.

tylosin

macrolide

bentonite


Input: Indeed, a bentonite clay showed decreased passage of tylosin through the epithelial monolayer, indicating binding of tylosin by bentonite.

bentonite

tylosin

tylosin

bentonite


Input: This indicates that the combined use of bentonite and tylosin in the feed could lead to therapy failure.

bentonite

tylosin


Input: The modified gluco-mannan binder did not alter the passage of tylosin significantly, indicating safe combined use.

tylosin


Input: Novel and de novo PHEX mutations in patients with hypophosphatemic rickets.


Input: X-linked hypophosphatemic rickets (XLH) is the most common inherited rickets.


Input: XLH is caused by inactivating mutations in the PHEX gene and is transmitted as an X-linked dominant disorder.


Input: We investigated PHEX mutation in 10 patients from 6 unrelated Turkish families by PCR-sequence analysis.


Input: Six different PHEX mutations were detected in the patients.


Input: Four of them were novel: c. 1217G > A (p. C406Y) in exon 11, c. 2078G > T (p. C693F) in exon 21, a splice donor site mutation in intron 13 (IVS13 + 1G > T), and a splice acceptor site mutation in intron 13 (IVS13-2A > G).


Input: De novo PHEX mutations were found exclusively in female patients from 4 families and inherited mutations were detected from remaining two families.


Input: The patients' phenotype was consistent with the loss of PHEX function.


Input: Literature review of 78 sporadic cases shows that de novo mutations are present in 83% female patients and female/male ratio is 5 to 1.


Input: One patient had biallilic PHEX mutations at c. 1735G > A (p. G579R) whereas her mother and two siblings carried a monoallelic mutation.


Input: The clinical and laboratory findings of the patient with biallilic PHEX mutation were similar to those with monoallelic mutation.


Input: The study shows that PHEX mutation is a common cause of either familial or sporadic hypophosphatemic rickets in Turkish population.


Input: Gene dosage effect is not observed.


Input: The frequent de novo mutations found in the female patients are likely resulting from mutagenesis of X chromosome in paternal germ cells.


Input: Ageing and gut microbes: perspectives for health maintenance and longevity.


Input: The ageing process affects the human gut microbiota phylogenetic composition and its interaction with the immune system.


Input: Age-related gut microbiota modifications are associated with immunosenescence and inflamm-ageing in a sort of self-sustaining loop, which allows the placement of gut microbiota unbalances among both the causes and the effects of the inflamm-ageing process.


Input: Even if, up to now, the link between gut microbiota and the ageing process is only partially understood, the gut ecosystem shows the potential to become a promising target for strategies able to contribute to the health status of older people.


Input: In this context, the consumption of pro/prebiotics may be useful in both prevention and treatment of age-related pathophysiological conditions, such as recovery and promotion of immune functions, i. e. adjuvant effect for influenza vaccine, and prevention and/or alleviation of common " winter diseases ", as well as constipation and Clostridium difficile-associated diarrhoea.


Input: Moreover, being involved in different mechanisms which concur in counteracting inflammation, such as down-regulation of inflammation-associated genes and improvement of colonic mucosa conditions, probiotics have the potentiality to be involved in the promotion of longevity.


Input: The arginine and GHRP-2 tests as alternatives to the insulin tolerance test for the diagnosis of adult GH deficiency in Japanese patients: a comparison.

arginine


Input: The arginine + GHRH test has been established as an alternative to the insulin tolerance test (ITT) for the diagnosis of adult GH deficiency (AGHD).

arginine


Input: However, the glucagon, arginine, and GH releasing peptide-2 (GHRP-2) test are recommended as alternatives in Japan.

arginine


Input: The objective of this study was to evaluate the arginine and GHRP-2 tests as alternatives to the ITT for the diagnosis of AGHD in a Japanese population.

arginine


Input: Three stimulation tests (ITT, arginine test, and GHRP-2 test) were conducted in 71 pre-operative adult patients with pituitary tumors (age, 18-65 years).

arginine


Input: The peak GH responses to each test were examined.


Input: The peak GH responses were significantly lower with the ARG test (median 4. 43 mu g/L) (p < 0. 0001) than with the ITT (median 9. 38 mu g/L), and the peak GH responses with the GHRP-2 test (median 28. 88 mu g/L) were higher (p < 0. 0001).

ARG


Input: However, among the AGHD patients, there was no significant difference between the peak GH responses to the ARG test and the ITT.

ARG


Input: The sensitivities and specificities of the ARG/GHRP-2 tests compared to the ITT for the diagnosis of severe AGHD (peak GH responses to ITT <= 1. 8 mu g/L) were 93. 8%/81. 3% and 85. 5%/94. 5%, respectively.

ARG


Input: The arginine and GHRP-2 stimulation tests are acceptable alternatives to the ITT for the diagnosis of AGHD in Japanese patients.

arginine


Input: The method and criterion for the diagnosis of AGHD should be reconsidered and adjusted to each population.