Input: MeHg caused a significant increase in DA release that was both concentration-and time-dependent.

MeHg


Input: DA release was significantly increased by 2 micro M MeHg at 60min and by 5 micro M MeHg at 30min; 1 micro M MeHg was without effect.

MeHg

MeHg

MeHg


Input: Because DA release induced by 5 micro M MeHg was associated with a significant percentage of cell death at 60 and 120min, 2 micro M MeHg was chosen for further characterization of release mechanisms.

MeHg

MeHg


Input: MeHg-induced DA release was attenuated but not abolished in the absence of extracellular calcium, whereas the vesicular content depleting drug reserpine (50nM) abolished release.

MeHg

calcium


Input: Thus, MeHg-induced DA release requires vesicular exocytosis but not extracellular calcium.

MeHg

calcium


Input: MeHg also increased intracellular DA and the rate of DA storage utilization, suggesting a role for DA synthesis in MeHg-induced DA release.

MeHg

MeHg


Input: The tyrosine hydroxylase inhibitor alpha-methyltyrosine (300 micro M, 24h) completely abolished MeHg-induced DA release.

tyrosine

alpha-methyltyrosine

MeHg


Input: MeHg significantly increased DA precursor accumulation in cells treated with 3-hydroxybenzylhydrazine (10 micro M), revealing that MeHg increases tyrosine hydroxylase activity.

MeHg

MeHg

tyrosine


Input: Overall, these data demonstrate that MeHg facilitates DA synthesis, increases intracellular DA, and augments vesicular exocytosis.

MeHg


Input: Nfil3 is a glucocorticoid-regulated gene required for glucocorticoid-induced apoptosis in male murine T cells.


Input: Glucocorticoids (GCs) have essential roles in the regulation of development, integrated metabolism, and immune and neurological responses, and act primarily via the glucocorticoid receptor (GR).


Input: In most cells, GC treatment results in down-regulation of GR mRNA and protein levels via negative feedback mechanisms.


Input: However, in GC-treated thymocytes, GR protein levels are maintained at a high level, increasing sensitivity of thymocytes to GCs, resulting in apoptosis termed glucocorticoid-induced cell death (GICD).


Input: CD4 (+) CD8 (+) double-positive thymocytes and thymic natural killer T cells in particular are highly sensitive to GICD.


Input: Although GICD is exploited via the use of synthetic GC analogues in the treatment of hematopoietic malignancies, the intracellular molecular pathway of GICD is not well understood.


Input: To explore GICD in thymocytes, the authors performed whole genome expression microarray analysis in mouse GR exon 2 null vs wild-type thymus RNA 3 hours after dexamethasone treatment.


Input: Identified and validated direct GR targets included P21 and Bim, in addition to an important transcriptional regulator Nfil3, which previously has been associated with GICD and is essential for natural killer cell development in vivo.


Input: Immunostaining of NFIL3 in whole thymus localized NFIL3 primarily to the medullary region, and double labeling colocalized NFIL3 to apoptotic cells.


Input: In silico analysis revealed a putative GC response element 5 kb upstream of the Nfil3 promoter that is strongly conserved in the rat genome and was confirmed to bind GR by chromatin immunoprecipitation.


Input: The knockdown of Nfil3 mRNA levels to 20% of normal using specific small interfering RNAs abrogated GICD, indicating that NFIL3 is required for normal GICD in CTLL-2 T cells.


Input: Prescription of antiepileptics and the risk of road traffic crash.


Input: Studies assessing the impact of epilepsy and its medication on the risk of road traffic crashes have shown inconsistent results.


Input: The aim in this study was to assess this risk using French databases.


Input: Data from three French national databases were extracted and matched: the national health care insurance database, police reports, and the national police database of injurious crashes.


Input: Only antiepileptics prescribed predominantly in epilepsy were studied (phenobarbital, phenytoin, ethosuximide, valproic acid, vigabatrin, tiagabin, levitiracetam, zonisamide, and lacosamide).

phenobarbital

phenytoin

ethosuximide

valproic acid

vigabatrin

tiagabin

levitiracetam

zonisamide

lacosamide


Input: A case-control analysis comparing responsible and non-responsible drivers and a case-crossover analysis were performed.


Input: Drivers (72 685) involved in an injurious crash in France between July 2005 and May 2008, were included.


Input: Drivers exposed to prescribed antiepileptic medicines (n = 251) had an increased risk of being responsible for a crash (OR 1. 74 [1. 29-2. 34]).


Input: The association was also significant for the most severe epileptic patients (n = 99; OR = 2. 20 [1. 31-3. 69]).


Input: Case-crossover analysis found no association between crash risk and treatment prescription.


Input: Patients with prescription of antiepileptic drugs should be cautioned about their potential risk of road traffic crash.


Input: This risk is however more likely to be related to seizures than to the effect of antiepileptic medicines.


Input: Anti-inflammatory profile of paricalcitol in hemodialysis patients: a prospective, open-label, pilot study.

paricalcitol


Input: Inflammation is a strong predictor of increased morbidity and mortality in hemodialysis (HD) patients.


Input: Paricalcitol, a selective vitamin D receptor activator used for prevention and treatment of secondary hyperparathyroidism, has shown anti-inflammatory properties in experimental studies, although clinical data are scarce.

Paricalcitol

vitamin D


Input: In an open-label, prospective, single center, pilot study, 25 stable HD patients, previously receiving calcitriol, completed 12 weeks of therapy with oral paricalcitol.

calcitriol

paricalcitol


Input: Serum and peripheral blood mononuclear cell (PBMC) expression profiles of inflammatory cytokines were analyzed.


Input: Serum interleukin (IL)-1, IL-10, and IL-18 did not change, unlike high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-alpha), and IL-6, which experienced a significant mean percent decrease of 14. 3%, 4. 7%, and 5%, respectively.


Input: There was a significant reduction in the TNF-alpha/IL-10 and the IL-6/IL-10 ratios (P <. 05).


Input: Serum intact parathyroid hormone concentration experienced a mild but significant reduction.


Input: In addition, expression levels of TNF-alpha and IL-6 decreased by 19. 1% (P <. 01) and 17. 5% (P <. 001), respectively, whereas expression of IL-10 increased by 17. 7% (P <. 01) after treatment.


Input: In conclusion, paricalcitol administration to HD patients is associated with a beneficial effect on the inflammatory cytokine serum and gene expression profile of PBMC.

paricalcitol


Input: This effect may contribute to the survival benefits of paricalcitol observed in clinical studies.

paricalcitol


Input: Novel Insights into CB1 Cannabinoid Receptor Signaling: A Key Interaction Identified between the Extracellular-3 Loop and Transmembrane Helix 2.


Input: Activation of the cannabinoid CB1 receptor (CB1) is modulated by aspartate residue D2. 63 (176) in transmembrane helix (TMH) 2.

aspartate


Input: Interestingly, D2. 63 does not affect the affinity for ligand binding at the CB1 receptor.


Input: Studies in class A G protein-coupled receptors have suggested an ionic interaction between residues of TMH2 and 7.


Input: In this report, modeling studies identified residue K373 in the extracellular-3 (EC-3) loop in charged interactions with D2. 63.


Input: We investigated this possibility by performing reciprocal mutations and biochemical studies.


Input: D2. 63 (176) A, K373A, D2. 63 (176) A-K373A, and the reciprocal mutant with the interacting residues juxtaposed D2. 63 (176) K-K373D were characterized using radioligand binding and guanosine 5'-3-O-(thio) triphosphate functional assays.

guanosine 5'-3-O-(thio) triphosphate


Input: None of the mutations resulted in a significant change in the binding affinity of N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A) or (-)-3cis-[2-hydroxyl-4-(1, 1-dimethyl-heptyl) phenyl]-trans-4-[3-hydroxyl-propyl] cyclohexan-1-ol (CP55, 940).

N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride

(-)-3cis-[2-hydroxyl-4-(1, 1-dimethyl-heptyl) phenyl]-trans-4-[3-hydroxyl-propyl] cyclohexan-1-ol

CP55, 940


Input: Modeling studies indicated that binding-site interactions and energies of interaction for CP55, 940 were similar between wild-type and mutant receptors.

CP55, 940


Input: However, the signaling of CP55, 940, and (R)-(+)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl) methyl]-pyrrolo [1, 2, 3-de]-1, 4-benzoxazin-6-yl] (1-naphthalenyl)-methanone mesylate (WIN55, 212-2) was impaired at the D2. 63 (176) A-K373A and the single-alanine mutants.

CP55, 940

(R)-(+)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl) methyl]-pyrrolo [1, 2, 3-de]-1, 4-benzoxazin-6-yl] (1-naphthalenyl)-methanone mesylate

WIN55, 212-2

alanine


Input: In contrast, the reciprocal D2. 63 (176) K-K373D mutant regained function for both CP55, 940 and WIN55, 212-2.

CP55, 940

WIN55, 212-2


Input: Computational results indicate that the D2. 63 (176)-K373 ionic interaction strongly influences the conformation (s) of the EC-3 loop, providing a structure-based rationale for the importance of the EC-3 loop to signal transduction in CB1.


Input: The putative ionic interaction results in the EC-3 loop pulling over the top (extracellular side) of the receptor; this EC-3 loop conformation may serve protective and mechanistic roles.


Input: These results suggest that the ionic interaction between D2. 63 (176) and K373 is important for CB1 signal transduction.


Input: Theoretical Study on the Photodegradation Mechanism of Nona-BDEs in Methanol.

Nona-BDEs

Methanol


Input: Polybrominated diphenyl ethers (PBDEs) have received special environmental concern due to their potential toxicity to humans and wildlife worldwide, however, it is difficult to reveal their dominant photochemical degradation pathways by experiment.

Polybrominated diphenyl ethers

PBDEs


Input: We explored the reaction mechanisms of photochemical degradation-debromination of three nona-BDEs in methanol using theoretical calculations, in which time-dependent density functional theory (TDDFT) combined with the polarizable continuum (PCM) model is applied.

nona-BDEs

methanol


Input: The selectivity of debromination was studied, and the major octa-BDE products photochemically debrominated from nona-BDEs were identified.

octa-BDE

nona-BDEs


Input: We find that the debromination reaction results from the electronic transitions from pi to sigma * orbitals when nona-BDEs are exposed to UV-light in the sunlight region, at which point the two low-lying excited states for each nona-BDE are pi sigma * (5Br) and pi sigma * (4Br), which correlate to the sigma * orbitals located on the penta-Br and tetra-Br substituted phenyls, respectively.

nona-BDEs

nona-BDE

penta-Br

tetra-Br

phenyls


Input: Our calculations indicate that each nona-BDE may degrade to form three kinds of octa-BDE products via the pi sigma * (5Br) state, whereas only one kind of octa-BDEs can be formed via the pi sigma * (4Br) state.

nona-BDE

octa-BDE

octa-BDEs


Input: Our calculations can interpret the recent experiments successfully.


Input: Meal conditions affect the absorption of supplemental vitamin D (3) but not the plasma 25-hydroxyvitamin D response to supplementation.

vitamin D (3)

25-hydroxyvitamin D


Input: It is sometimes assumed that dietary fat is required for vitamin D absorption, although the impact of different amounts of dietary fat on vitamin D absorption is not established.

vitamin D

vitamin D


Input: This study was conducted to determine whether the presence of a meal and the fat content of the meal influences vitamin D absorption or the 25-hydroxyvitamin D (25OHD) response to supplemental vitamin D (3).

vitamin D

25-hydroxyvitamin D

vitamin D (3)


Input: Based on earlier studies in rats we postulated that absorption would be greatest in the low-fat meal group.


Input: Sixty two healthy older men and women were randomly assigned to one of three meal groups: no meal, high-fat meal or low-fat meal; each was given a monthly 50, 000 IU vitamin D (3) supplement with the test breakfast meal (or after a fast for the no-meal group) and followed for 90 days.

vitamin D (3)


Input: Plasma vitamin D (3) was measured by LC/MS before and 12 hrs after the first dose; plasma 25OHD was measured by radioimmunoassay at baseline and after 30 and 90 days.

vitamin D (3)


Input: The mean 12-hr increments in vitamin D (3), after adjusting for age and sex, were 200. 9 nmol/L in the no-meal group, 207. 4 nmol/L in the high-fat meal group, and 241. 1 nmol/L in the low-fat meal group (P = 0. 038), with the increase in the low-fat group being significantly greater than the increases in the other two groups.

vitamin D (3)


Input: However, increments in 25OHD levels at 30 and 90 days didn' t differ significantly in the three groups.


Input: We conclude that absorption was increased when a 50, 000 IU dose of vitamin D was taken with a low-fat meal, compared with a high-fat meal and no meal, but that the greater absorption didn' t result in higher plasma 25OHD levels in the low-fat meal group.

vitamin D


Input: (c) 2013 American Society for Bone and Mineral Research.


Input: Exendin-4, a GLP-1 receptor agonist, prevents osteopnia by promoting bone formation and suppressing bone resorption in aged ovariectomized rats.


Input: Osteoporosis mainly affects postmenopausal women and older men.


Input: Gastrointestinal hormones released after meal ingestion, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP)-2, have been shown to regulate bone turnover.

glucose


Input: However, whether GLP-1, another important gastrointestinal hormone, and its analogues also have anti-osteoporotic effects, especially in aged postmenopausal situation, is not confirmed yet.


Input: In the present study, we evaluated the effects of the GLP-1 receptor agonist exendin-4 on ovariectomy (OVX) induced osteoporosis in old rats.


Input: Twelve-month-old female Sprague-Dawley rats were subjected to OVX, and exendin-4 were administrated 4 weeks after the surgery and lasted for 16 weeks.


Input: Bone characters and related serum and gene biomarkers were analyzed.


Input: Sixteen weeks treatment of exendin-4 slowed down the body weight gain by decreasing fat mass and prevented the loss of bone mass in old OVX rats.


Input: Exendin-4 also enhanced the bone strength and prevented the deterioration of trabecular microarchitecture.


Input: Moreover, exendin-4 decreased urinary DPD/creatinine ratio and serum CTX-I and increased serum ALP, OC and P1NP levels, key biochemical markers of bone turnover.

creatinine


Input: Interestingly, gene expression results further showed that exendin-4 not only inhibited bone resorption by increasing OPG/RANKL ratio, but also promoted bone formation by increasing the expressions of OC, Col1, Runx2, and ALP, which exhibited dual regulatory effects on bone turnover as compared with previous anti-osteoporotic agents.


Input: In conclusion, these findings demonstrated for the first time the anti-osteoporotic effects of exendin-4 in old OVX rats and that it might be a potential candidate for treatment of aged postmenopausal osteoporosis.


Input: (c) 2013 American Society for Bone and Mineral Research.


Input: Nanoscale poling of polymer films.


Input: Spots of second harmonic generation (SHG) are produced from nanopatterned sub-micrometer areas of nonlinear polymer media.


Input: Information is written by using a biased-AFM tip, a highly nonlinear polymer (poly (methyl metha-acrylate)-co-Disperse Red 1), and a novel " floating-tip nanolithography " (FTN) technique.

poly (methyl metha-acrylate)

Disperse Red 1


Input: Dipoles are oriented and aligned at the nanoscale under the biased-AFM tip, resulting in SHG production.


Input: The information is storable over weeks.


Input: Interactive effects of contaminants and climate-related stressors: High temperature increases sensitivity to cadmium.

cadmium


Input: An emerging issue in environmental toxicology is in understanding how climate change will alter responses of organisms to chemical contaminants.


Input: The objective of the present study was to characterize the interactive effects of cadmium and elevated temperature on life-stage-specific responses in the freshwater snail Physa pomilia.

cadmium


Input: We exposed developing eggs, juveniles, and adults to Cd (5 micro g/L, 15 micro g/L, and 25 micro g/L for eggs, and 250 micro g/L for juveniles and adults) and 2 temperatures of 25 degrees C (control) and 35 degrees C (upper range of tolerance).

Cd


Input: In the absence of Cd, time to hatch was shorter at 35 degrees C compared with 25 degrees C, demonstrating a stimulatory effect of the higher temperature.

Cd


Input: However, when egg masses were reared at 35 degrees C and exposed to Cd, hatching success was significantly lower, and time-to-hatching was significantly longer.

Cd


Input: The effects of the higher temperature and Cd on newly hatched neonate survival were additive, except at the highest Cd concentration, at which effects of the 2 stressors were greater than additive.

Cd

Cd


Input: Overall, within the combined stressor treatments, adult snails generally survived significantly longer than did juvenile snails, and both were more tolerant than developing snails.


Input: Many climate projection models predict future increases in global temperatures.


Input: The present study shows that combined stressors may produce greater-than-additive effects, challenging predictive power.


Input: More studies are needed to better characterize the interactive effects of chemical contaminants and stressors related to climate change.


Input: Environ Toxicol Chem 2013; 32: 1337-1343.


Input: (c) 2013 SETAC.


Input: Dechlorane plus monoadducts in a lake ontario (Canada) food web and biotransformation by lake trout (Salvelinus namaycush) liver microsomes.

Dechlorane plus


Input: Compounds related to the high-production-volume flame retardant Dechlorane Plus (DP) were measured in a Lake Ontario food web located downstream of a DP manufacturing plant.

Dechlorane Plus


Input: These compounds, 1, 3-and 1, 5-DP-monoadducts (DPMA), are positional isomers and are thought to arise from the incomplete reaction of DP or impurities in the DP starting material during its manufacture.

1, 3-and 1, 5-DP


Input: The 1, 3-DPMA isomer was measured (0. 12-199 ng g (-1) lipid wt) in all trophic levels, whereas 1, 5-DPMA was measured only sporadically in the food web and was not detectable in the apex predator, lake trout (Salvelinus namaycush).


Input: Concentrations of DPMA isomers when detected in Lake Ontario biota were greater than that of total DP for all trophic levels.


Input: The prevalence of 1, 3-DPMA in the food web, and especially in lake trout, may be due to obstruction of the existing carbon double bond to enzyme attack, rendering it less readily metabolized.

carbon


Input: To examine this hypothesis, biotransformation kinetic experiments using in vitro lake trout liver microsomal exposures were performed.


Input: Zero-order depletion rate constants for 1, 3-and 1, 5-DPMA were 92. 2 and 134. 6 pmole h (-1), respectively, with corresponding half-lives of 2. 03 +/- 0. 14 h (1, 3-DPMA) and 1. 39 +/- 0. 09 h (1, 5-DPMA).


Input: Furthermore, the 1, 5-isomer was depleted to a greater extent than 1, 3-DPMA.


Input: Specific biotransformation products were not identified.


Input: These data support the hypothesis that 1, 5-DPMA is more readily metabolized than 1, 3-DPMA by lake trout.


Input: The present study also shows that the concentrations of these isomers, which the authors speculate might be unintended impurities or byproducts in some technical DP formulations, exceed that of the intended product in biota.


Input: Environ Toxicol Chem 2013; 32: 1376-1381.


Input: (c) 2013 SETAC.


Input: Addressable organic structure by anisotropic wetting.


Input: The anisotropic wetting of functional organic molecules on a patterned surface and the development of a photolithography-compatible method to fabricate addressable organic structures is reported.


Input: For example, DtCDQA is grown on a SiO2 surface with a Au prepattern, achieving a high resolution cross-over organic structure.

Au


Input: In vivo overexpression of tissue-nonspecific alkaline phosphatase increases skeletal mineralization and affects the phosphorylation status of osteopontin.


Input: Functional ablation of tissue-nonspecific alkaline phosphatase (TNAP) (Alpl (-/-) mice) leads to hypophosphatasia, characterized by rickets/osteomalacia attributable to elevated levels of extracellular inorganic pyrophosphate, a potent mineralization inhibitor.

pyrophosphate


Input: Osteopontin (OPN) is also elevated in the plasma and skeleton of Alpl (-/-) mice.


Input: Phosphorylated OPN is known to inhibit mineralization, however, the phosphorylation status of the increased OPN found in Alpl (-/-) mice is unknown.


Input: Here, we generated a transgenic mouse line expressing human TNAP under control of an osteoblast-specific Col1a1 promoter (Col1a1-Tnap).


Input: The transgene is expressed in osteoblasts, periosteum, and cortical bones, and plasma levels of TNAP in mice expressing Col1a1-Tnap are 10-20 times higher than those of wild-type mice.


Input: The Col1a1-Tnap animals are healthy and exhibit increased bone mineralization by microCT analysis.


Input: Crossbreeding of Col1a1-Tnap transgenic mice to Alpl (-/-) mice rescues the lethal hypophosphatasia phenotype characteristic of this disease model.


Input: Osteoblasts from [Col1a1-Tnap] mice mineralize better than non-transgenic controls and osteoblasts from [Col1a1-Tnap (+/-); Alpl (-/-)] mice are able to mineralize to the level of Alpl (+/-) heterozygous osteoblasts, while Alpl (-/-) osteoblasts show no mineralization.


Input: We found that the increased levels of OPN in bone tissue of Alpl (-/-) mice are comprised of phosphorylated forms of OPN while WT and [Col1a1-Tnap (+/-); Alpl (-/-)] mice had both phosphorylated and dephosphorylated forms of OPN.


Input: OPN from [Col1a1-Tnap] osteoblasts were more phosphorylated than non-transgenic control cells.


Input: Titanium dioxide-liquid chromatography and tandem mass spectrometry analysis revealed that OPN peptides derived from Alpl (-/-) bone and osteoblasts yielded a higher proportion of phosphorylated peptides than samples from WT mice, and at least two phosphopeptides, p (S (174) FQVS (178) DEQY (182) PDAT (186) DEDLT (191)) SHMK and FRIp (S (299) HELES (304) S (305) S (306) S (307)) EVN, with one non-localized site each, appear to be preferred sites of TNAP action on OPN.

Titanium dioxide


Input: Our data suggest that the pro-mineralization role of TNAP may be related not only to its accepted pyrophosphatase activity but also to its ability to modify the phosphorylation status of OPN.


Input: (c) 2013 American Society for Bone and Mineral Research.


Input: A liquid crystalline phase with uniform tilt, local polar order and capability of symmetry breaking.


Input: A new liquid crystalline (LC) phase with uniform tilt, local polar order and capability of symmetry breaking is found for a bent-core mesogen combining a 4-cyanoresorcinol unit with two azobenzene wings.

azobenzene


Input: The combination of local polar order and long range synclinic tilt in this SmCs PR phase leads, under special conditions, to macroscopic domains with opposite chirality, though the molecules themselves are achiral.


Input: Surface-confined electroactive molecules for multistate charge storage information.


Input: Bi-stable molecular systems with potential for applications in binary memory devices are raising great interest for device miniaturization.


Input: Particular appealing are those systems that operate with electrical inputs since they are compatible with existing electronic technologies.


Input: The processing of higher memory densities in these devices could be accomplished by increasing the number of memory states in each cell, although this strategy has not been much explored yet.


Input: Here we highlight the recent advances devoted to the fabrication of charge-storage molecular surface-confined devices exhibiting multiple states.


Input: Mainly, this goal has been realized immobilizing a variety (or a combination) of electroactive molecules on a surface, although alternative approaches employing non-electroactive systems have also been described.


Input: Undoubtedly, the use of molecules with chemically tunable properties and nanoscale dimensions are raising great hopes for the devices of the future in which molecules can bring new perspectives such as multistability.


Input: Formation of a polymer surface with a gradient of pore size using a microfluidic chip.


Input: Here we demonstrate the generation of polymer monolithic surfaces possessing a gradient of pore and polymer globule sizes from ~ 0. 1 to ~ 0. 5 mu m defined by the composition of two polymerization mixtures injected into a microfluidic chip.


Input: To generate the gradient, we used a PDMS microfluidic chip with a cascade micromixer with a subsequent reaction chamber for the formation of a continuous gradient film.

PDMS


Input: The micromixer has zigzag channels of 400 x 680 mu m (2) cross section and six cascades.


Input: The chip was used with a reversible bonding connection, realized by curing agent coating.


Input: After polymerization in the microfluidic chip the reversible bond was opened, resulting in a 450 mu m thick polymer film possessing the pore size gradient.


Input: The gradient formation in the microfluidic reaction chamber was studied using microscopic laser-induced fluorescence (mu LIF) and different model fluids.


Input: Formation of linear gradients was shown using the fluids of the same density by both diffusive mixing at flow rates of 0. 001 mL/min and in a convective mixing regime at flow rates of 20 mL/min.


Input: By using different density fluids, formation of a two-dimensional wedge-like gradient controlled by the density difference and orientation of the microfluidic chip was observed.


Input: Solubility-driven optimization of (pyridin-3-yl) benzoxazinyl-oxazolidinones leading to a promising antibacterial agent.

(pyridin-3-yl) benzoxazinyl-oxazolidinones


Input: The solubility-driven structural modification of (pyridin-3-yl) benzoxazinyl-oxazolidinones is described, which resulted in the development of a new series of benzoxazinyl-oxazolidinone analogues with high antibacterial activity against Gram-positive pathogens, including that against linezolid-resistant strains and low hERG inhibition.

(pyridin-3-yl) benzoxazinyl-oxazolidinones

benzoxazinyl-oxazolidinone

linezolid


Input: With regard to structure-activity relationship (SAR) trends among the various substituents on the pyridyl ring, relatively small and nonbasic substituents were preferable to sterically demanding or basic substituents.

pyridyl


Input: Oxazolidinone ring substitution on the pyridyl ring generated analogues with antibacterial activity superior to imidazolidinone ring.

Oxazolidinone

pyridyl

imidazolidinone


Input: Solubility was enhanced by the incorporation of polar groups, especially when compounds were converted to their prodrugs.


Input: Among the prodrugs, compound 85 exhibited excellent solubility and a good pharmacokinetic profile.


Input: In a MRSA systemic infection model, compound 85 displayed an ED50 = 5. 00 mg/kg, a potency that is 2-fold better than that of linezolid.

linezolid


Input: Transparent, Conductive, and Printable Composites Consisting of TEMPO-Oxidized Nanocellulose and Carbon Nanotube.

TEMPO

Carbon


Input: Ultrastrong, transparent, conductive and printable nanocomposites were successfully prepared by mixing single-walled carbon nanotubes (CNTs) with 2, 2, 6, 6-tetramethylpiperidine-1-oxyl (TEMPO)-oxidized cellulose nanofibrils (TOCNs) with abundant sodium carboxyl groups on the crystalline nanocellulose surfaces.

carbon

2, 2, 6, 6-tetramethylpiperidine-1-oxyl

TEMPO

sodium carboxyl


Input: The surface-anionic cellulose nanofibrils had reinforcing and nanodispersing effects on the CNTs both in water used as the dispersed medium and in the dried composite film, providing highly conductive and printable nanocomposites with a small amount of CNTs.


Input: TOCNs are therefore expected as an effective flexible matrix that can be used as an alternative to conventional polymers for various electrical materials, when nanocomposited with CNTs and also graphene.

graphene


Input: Our findings provide a promising route to realize green and flexible electronics.


Input: Plant development: brassinosteroids go out of bounds.

brassinosteroids


Input: Patterning in plants requires defining boundary domains that separate and organize the development of the neighboring organs.


Input: Two papers now show how the interplay between brassinosteroid phytohormones and frontier genes contributes to boundary formation in plants.

brassinosteroid


Input: Bortezomib enhances antigen-specific cytotoxic T cell responses against immune-resistant cancer cells generated by STAT3-ablated dendritic cells.

Bortezomib


Input: Dendritic cell (DC)-based vaccines have received attention as a new therapeutic modality against cancer.


Input: However, increased STAT3 activity in the tumor microenvironment makes DCs tolerogenic and suppresses their antitumor activity.


Input: In this study, we explored the effects of a combination treatment consisting of a proteasome inhibitor, bortezomib, and an antigen specific STAT3-ablated (STAT3 (-/-)) DC-based vaccine on the control of TC-1 (P3) tumors, a p53-degraded immune resistant cancer cells.

bortezomib


Input: We found that E7-antigen expressing STAT3 (-/-) DC (E7-DC-1STAT3 (-/-)) vaccination enhanced generation of E7-specific CD8 (+) T cells, but was not enough to control TC-1 (P3) cancer cells.


Input: Therefore, we investigated whether bortezomib could create a synergistic effect with E7-DC-1STAT3 (-/-) vaccination.

bortezomib


Input: We found that apoptosis via down-regulation of STAT3 and NF-kappa B and up-regulation of Fas and death receptor 5 (DR5) expression in TC-1 (P3) induced by bortezomib was independent of p53 status.

bortezomib


Input: We also observed that TC-1 (P3) cells pretreated with bortezomib had markedly enhanced anti-tumor effects on E7-specific CD8 (+) T cells through a Fas/DR5-mediated mechanism.

bortezomib


Input: In addition, TC-1 (P3) tumor-bearing mice treated with bortezomib prior to vaccination with E7-DC-1STAT3 (-/-) demonstrated enhanced generation of E7-specific CD8 (+) T cells and prolonged survival compared to those treated with monotherapy.

bortezomib


Input: These results suggest that the anti-tumor effects against a p53-degraded immune resistant variant generated by antigen-expressing STAT3-ablated mature DCs may be enhanced by bortezomib via death receptor-mediated apoptosis.

bortezomib


Input: Lecithin/chitosan controlled release nanopreparations of tamoxifen citrate: Loading, enzyme-trigger release and cell uptake.

Lecithin

tamoxifen citrate


Input: Tamoxifen citrate (TAM), an anticancer drug with amphiphilic properties, was loaded in lecithin/chitosan nanoparticles (LCN) with a view to oral administration.

Tamoxifen citrate

TAM

lecithin


Input: The influence of tamoxifen loading on the physico-chemical properties of nanoparticles was studied.

tamoxifen


Input: Size, surface charge and morphological properties of tamoxifen-loaded nanoparticles (LCN-TAM) were assessed.

tamoxifen

TAM


Input: The increase in the tamoxifen amount in the LCN-TAM preparation up to 60mg/100ml maintained the positive zeta potential value of about + 45mV.

tamoxifen

TAM


Input: A statistically significant decrease in particle size was observed for TAM amounts between 5 and 20mg.

TAM


Input: A strong influence of loaded tamoxifen on the structure of lecithin/chitosan nanoparticles was observed, supported by the quantification of free chitosan and morphological analysis.

tamoxifen

lecithin


Input: A loading of tamoxifen in nanoparticles of around 19% was obtained.

tamoxifen


Input: The release of the drug from the LCN-TAM colloidal dispersion was measured, showing that tamoxifen citrate was released very slowly in simulated gastro-intestinal fluids without enzymes.

TAM

tamoxifen citrate


Input: When enzymes able to dismantle the nanoparticle structure were added to the dissolution medium, drug release was triggered and continued in a prolonged manner.


Input: Tamoxifen-loaded nanoparticles showed cytotoxicity towards MCF-7 cells comparable to that obtained with tamoxifen citrate solution, but the rate of this toxic effect was dependent on drug release.

Tamoxifen

tamoxifen citrate


Input: Caco-2 cells, used as a model of the intestinal epithelium, were shown to take up the TAM loaded nanoparticles extensively.

TAM


Input: Estimation of the safe use concentrations of the preservative 1, 2-benzisothiazolin-3-one (BIT) in consumer cleaning products and sunscreens.

1, 2-benzisothiazolin-3-one

BIT


Input: 1, 2-Benzisothiazolin-3-one (BIT; CAS #2634-33-5) is a preservative used in consumer products.

1, 2-Benzisothiazolin-3-one

BIT


Input: Dermal exposure to BIT at sufficient dose and duration can produce skin sensitization and allergic contact dermatitis in animals and susceptible humans. The purpose of this study is to derive a maximal concentration of BIT in various consumer products that would result in exposures below the No Expected Sensitization Induction Level (NESIL), a dose below which skin sensitization should not occur.

BIT

BIT


Input: A screening level exposure estimate was performed for several product use scenarios with sunscreen, laundry detergent, dish soap, and spray cleaner.


Input: We calculated that BIT concentrations below the following concentrations of 0. 0075%, 0. 035%, 0. 035%, 0. 021% in sunscreen, laundry detergent, dish soap, and spray cleaner, respectively, are unlikely to induce skin sensitization.

BIT


Input: We completed a pilot study consisting of bulk sample analysis of one representative product from each category labelled as containing BIT, and found BIT concentrations of 0. 0009% and 0. 0027% for sunscreen and dish soap, respectively.

BIT

BIT


Input: BIT was not detected in the laundry detergent and spray cleaner products above the limit of detection of 0. 0006%.

BIT


Input: Based on publically available data for product formulations and our results, we were able to establish that cleaning products and sunscreens likely contain BIT at concentrations similar to or less than our calculated maximal safe concentrations and that exposures are unlikely to induce skin sensitization in most users.

BIT


Input: Biochemical properties and comparative pharmacology of a coagulant from Deinagkistrodon acutus snake venom.


Input: A number of snake venom thrombin-like enzymes (TLEs) have already been characterized.


Input: Some TLEs play significant roles in vessel injury hemostasis.


Input: A novel TLE (Agacutase) was purified from Deinagkistrodon acutus snake venom by the means of Sephadex G-75, DEAE-Sepharose FF, and Sephadex G-25 column chromatography.


Input: Structural analysis indicated that Agacutase is a single-chain glycoprotein with a molecular mass of 31, 084Da, isoelectric point of 4. 38, optimal activity at 37 degrees C and pH 6. 6, sugar content of 7. 6%.


Input: Its N-terminal 44 amino acid sequence was determined to be VIGGNECDTNEHRFLAAFFTSRPWIFQCAGTLIHEEWVLAAAHC, showing maximum identity of 80% with that of Dav-X protease.

N


Input: The Agacutase-induced clotting activity was not influenced by heparin, hirudin, or Dextran 40, but activated by Ca (2 +) and inhibited by PMSF or lactose, which suggests that Agacutase is a serine protease and the coagulation activity is independent of Thrombin.

Ca (2 +)

PMSF

lactose

serine


Input: Agacutase with arginine esterase activity specifically cleaves the alpha-chain of fibrinogen.


Input: Agacutase iv (0. 03-0. 12U/kg) shortened 16-68% of the rabbit blood clotting time.


Input: No significant influence was indicated on platelet, Factor II and XIII, or fibrinolytic system.


Input: It converts fibrinogen into the soluble fibrin that accelerates hemostasis at wound.


Input: Pharmacological comparison showed the hemostatic effect of Agacutase lasted 24h while Reptilase did 8h.


Input: Its maximum tolerated, abnormal toxicity, allergic, and hemorrhagin doses were 80U/kg, 1U, 2U, and 50U, respectively, whereas those of Reptilase or Agacutin were 35U/kg, 0. 25U, 0. 25U, and 0. 2U, respectively.


Input: The results indicated that Agacutase may be a predominant coagulant.


Input: Brain metastasis in pancreatic cancer.


Input: Pancreatic cancer is a fatal disease with a 5-year survival rate below 5%.


Input: Most patients are diagnosed at an advanced tumor stage and existence of distant metastases.


Input: However, involvement of the central nervous system is rare in pancreatic cancer.


Input: We retrospectively analyzed all cases of brain metastases in pancreatic cancer reported to date focusing on patient characteristics, clinical appearance, therapy and survival.


Input: Including our own, 12 cases of brain metastases originating from pancreatic cancer were identified.


Input: In three patients brain metastases were the first manifestation of pancreatic cancer.


Input: All other patients developed brain metastases during their clinical course.


Input: In most cases, the disease progressed rapidly and the patients died within weeks or months.


Input: However, two patients showed long-term survival.


Input: Of note, both patients received resection of the pancreatic cancer as well as curative resection of the metachronous brain metastases.


Input: Brain metastases in pancreatic cancer are a rare condition and usually predict a very poor prognosis.


Input: However, there is evidence that resection of brain metastases of pancreatic cancer can be immensely beneficial to patient' s survival, even with the chance for cure.


Input: Therefore, a surgical approach in metastatic pancreatic cancer should be considered in selective cases.


Input: Endothelial cell response to (co) polymer nanoparticles depending on the inflammatory environment and comonomer ratio.


Input: Endothelial cells lining the lumen of blood vessels serve as a physiological barrier controlling nanoparticle movement from the vasculature into the tissue.


Input: For exploring the effect of polymer hydrophilicity on nanoparticle interactions with human umbilical vein endothelial cells (HUVECs) in vitro, a series of monomodal poly [acrylonitrile-co-(N-vinylpyrrolidone)] model nanoparticles with increasing hydrophilicity as related to their increasing content (0-30mol.%) of N-vinylpyrrolidone (NVP) were synthesized by miniemulsion polymerization.

poly [acrylonitrile-co-(N-vinylpyrrolidone)]

N-vinylpyrrolidone

NVP


Input: Nanoparticles with a low NVP content were rapidly endocytized into all cells independent from the particle dose with toxic effects only observed at high particle concentrations, while only 10-30% of the cells incorporated particles with <= 20mol.% NVP.

NVP

NVP


Input: Since pathologies are often related to inflammation, an inflammatory HUVEC culture condition with IL-1 beta stimulation has been introduced and suggested to be widely applied for studying nanocarriers, since cellular uptake in this assay was clearly increased for NVP contents <= 20mol.%.

NVP


Input: Importantly, the secretion of functional biological mediators by HUVEC was not relevantly influenced by the nanoparticles for both homeostatic and inflammatory conditions.


Input: These findings may motivate concepts for nanocarriers specifically targeted to pathologic regions.


Input: Additionally, rapidly endocytized RhodaminB loaded particles with low NVP content may be explored for cell labeling and tracking.

RhodaminB

NVP


Input: Sources of secondary metabolite variation in Dysidea avara (Porifera: Demospongiae): the importance of having good neighbors.


Input: Several studies report temporal, geographical, and intra-individual variation in sponge metabolite yields.


Input: However, the internal and/or external factors that regulate the metabolite production remain poorly understood.


Input: Dysidea avara is a demosponge that produces sesquiterpenoids (avarol and derivatives) with interesting medical properties, which has prompted addressed studies to obtain enough amounts of these metabolites for research on drug discovery.

sesquiterpenoids

avarol


Input: Within this framework, specimens of Dysidea avara from a population of the Northwest Mediterranean were sampled and their secondary metabolites quantified to assess their variability and the possible relationship with external (seasonality, interactions with neighbors) and internal (reproductive stages) factors.


Input: The results show a variation of the amount of both avarol and its monoacetate derivative with time, with no clear relationship with seawater temperature.

avarol and its monoacetate


Input: A trade-off with sponge reproduction was not found either.


Input: However, our results showed for the first time that sponges are able to increase production or accumulation of secondary metabolites in their peripheral zone depending on the nature of their neighbors.


Input: This finding could explain part of the high variability in the amount of secondary metabolites usually found in chemical ecology studies on sponges and opens new biotechnological approaches to enhance the metabolite yield in sponge cultures.


Input: Murine oatp1a/1b uptake transporters control rosuvastatin systemic exposure without affecting its apparent liver exposure.

rosuvastatin


Input: Organic anion-transporting polypeptides (OATPs) mediate the liver uptake and hence plasma clearance of a broad range of drugs.


Input: For rosuvastatin, a cholesterol-lowering drug and OATP1A/1B substrate, the liver represents both its main therapeutic target and its primary clearance organ.

rosuvastatin

cholesterol


Input: Here we studied the impact of Oatp1a/1b uptake transporters on the pharmacokinetics of rosuvastatin using wild-type and Oatp1a/1b-null mice.

rosuvastatin


Input: After oral administration (15 mg/kg), intestinal absorption of rosuvastatin was not impaired in Oatp1a/1b-null mice, but systemic exposure (area under the curve) was 8-fold higher in these mice compared with wild-type.

rosuvastatin


Input: Although liver exposure was comparable between the two mouse strains (despite the increased blood exposure), the liver-to-blood ratios were markedly decreased (> 10-fold) in the absence of Oatp1a/1b transporters.


Input: After intravenous administration (5 mg/kg), systemic exposure was 3-fold higher in Oatp1a/1b-null mice than in the wild-type mice.


Input: Liver, small intestinal, and kidney exposure were slightly, but not significantly, increased in Oatp1a/1b-null mice.


Input: The biliary excretion of rosuvastatin was very fast, with 60% of the dose eliminated within 15 minutes after intravenous administration, and also not significantly altered in Oatp1a/1b-null mice.

rosuvastatin


Input: Rosuvastatin renal clearance, although still minor, was increased ~ 15-fold in Oatp1a/1b-null males, suggesting a role of Oatp1a1 in the renal reabsorption of rosuvastatin.

Rosuvastatin

rosuvastatin


Input: Absence of Oatp1a/1b uptake transporters increases the systemic exposure of rosuvastatin by reducing its hepatic extraction ratio.

rosuvastatin


Input: However, liver concentrations are not significantly affected, most likely due to the compensatory activity of high-capacity, low-affinity alternative uptake transporters at higher systemic rosuvastatin levels and the absence of efficient alternative rosuvastatin clearance mechanisms.

rosuvastatin

rosuvastatin


Input: Molecular mechanism regulating 24-hour rhythm of dopamine d3 receptor expression in mouse ventral striatum.

dopamine


Input: The dopamine D3 receptor (DRD3) in the ventral striatum is thought to influence motivation and motor functions.

dopamine


Input: Although the expression of DRD3 in the ventral striatum has been shown to exhibit 24-hour variations, the mechanisms underlying the variation remain obscure.


Input: Here, we demonstrated that molecular components of the circadian clock act as regulators that control the 24-hour variation in the expression of DRD3.


Input: The transcription of DRD3 was enhanced by the retinoic acid-related orphan receptor alpha (ROR alpha), and its activation was inhibited by the orphan receptor REV-ERB alpha, an endogenous antagonist of ROR alpha.

retinoic acid


Input: The serum or dexamethasone-induced oscillation in the expression of DRD3 in cells was abrogated by the downregulation or overexpression of REV-ERB alpha, suggesting that REV-ERB alpha functions as a regulator of DRD3 oscillations in the cellular autonomous clock.

dexamethasone


Input: Chromatin immunoprecipitation assays of the DRD3 promoter indicated that the binding of the REV-ERB alpha protein to the DRD3 promoter increased in the early dark phase.


Input: DRD3 protein expression varied with higher levels during the dark phase.


Input: Moreover, the effects of the DRD3 agonist 7-hydroxy-N, N-dipropyl-2-aminotetralin (7-OH-DPAT)-induced locomotor hypoactivity were significantly increased when DRD3 proteins were abundant.

7-hydroxy-N, N-dipropyl-2-aminotetralin


Input: These results suggest that ROR alpha and REV-ERB alpha consist of a reciprocating mechanism wherein ROR alpha upregulates the expression of DRD3, whereas REV-ERB alpha periodically suppresses the expression at the time of day when REV-ERB alpha is abundant.


Input: Our present findings revealed that a molecular link between the circadian clock and the function of DRD3 in the ventral striatum acts as a modulator of the pharmacological actions of DRD3 agonists/antagonists.


Input: Inflammation and immune system interactions in atherosclerosis.


Input: Cardiovascular disease (CVD) is the leading cause of mortality worldwide, accounting for 16. 7 million deaths each year.


Input: The underlying cause of the majority of CVD is atherosclerosis.


Input: In the past, atherosclerosis was considered to be the result of passive lipid accumulation in the vessel wall.


Input: Today' s picture is far more complex.


Input: Atherosclerosis is considered a chronic inflammatory disease that results in the formation of plaques in large and mid-sized arteries.


Input: Both cells of the innate and the adaptive immune system play a crucial role in its pathogenesis.


Input: By transforming immune cells into pro-and anti-inflammatory chemokine-and cytokine-producing units, and by guiding the interactions between the different immune cells, the immune system decisively influences the propensity of a given plaque to rupture and cause clinical symptoms like myocardial infarction and stroke.


Input: In this review, we give an overview on the newest insights in the role of different immune cells and subtypes in atherosclerosis.


Input: The metabolic effects of growth hormone in adipose tissue.


Input: There is a general consensus that a reduction in growth hormone (GH) secretion results in obesity.


Input: However, the pathophysiologic role of GH in the metabolism of lipids is yet to be fully understood.


Input: The major somatic targets of GH are bones and muscles, but GH stimulates lipolysis and seems to regulate lipid deposition in adipose tissue.


Input: Patients with isolated GH deficiency (GHD) have enlarged fat depots due to higher fat cell volume, but their fat cell numbers are lower than those of matched controls.


Input: The treatment of patients with GH results in a relative loss of body fat and shifts both fat cell number and fat cell volume toward normal, indicating an adipogenic effect of GH.


Input: Adults with GHD are characterized by perturbations in body composition, lipid metabolism, cardiovascular risk profile, and bone mineral density.


Input: It is well established that GHD is usually accompanied by an increase in fat accumulation; GH replacement in GHD results in the reduction of fat mass, particularly abdominal fat mass.


Input: In addition, abdominal obesity results in a secondary reduction in GH secretion that is reversible with weight loss.


Input: However, whereas GH replacement in patients with GHD leads to specific depletion of intra-abdominal fat, administering GH to obese individuals does not seem to result in a consistent reduction or redistribution of body fat.


Input: Although administering GH to obese non-GHD subjects has only led to equivocal results, more recent studies indicate that GH still remains a plausible metabolic candidate.


Input: A toxicokinetic model for thiamethoxam in rats: implications for higher-tier risk assessment.

thiamethoxam


Input: Risk assessment for mammals is currently based on external exposure measurements, but effects of toxicants are better correlated with the systemically available dose than with the external administered dose.


Input: So for risk assessment of pesticides, toxicokinetics should be interpreted in the context of potential exposure in the field taking account of the timescale of exposure and individual patterns of feeding.


Input: Internal concentration is the net result of absorption, distribution, metabolism and excretion (ADME).


Input: We present a case study for thiamethoxam to show how data from ADME study on rats can be used to parameterize a body burden model which predicts body residue levels after exposures to LD50 dose either as a bolus or eaten at different feeding rates.

thiamethoxam


Input: Kinetic parameters were determined in male and female rats after an intravenous and oral administration of (14) C labelled by fitting one-compartment models to measured pesticide concentrations in blood for each individual separately.

(14) C


Input: The concentration of thiamethoxam in blood over time correlated closely with concentrations in other tissues and so was considered representative of pesticide concentration in the whole body.

thiamethoxam


Input: Body burden model simulations showed that maximum body weight-normalized doses of thiamethoxam were lower if the same external dose was ingested normally than if it was force fed in a single bolus dose.

thiamethoxam


Input: This indicates lower risk to rats through dietary exposure than would be estimated from the bolus LD50.


Input: The importance of key questions that should be answered before using the body burden approach in risk assessment, data requirements and assumptions made in this study are discussed in detail.


Input: Design and evaluation of ondansetron liquid suppository for the treatment of emesis.

ondansetron


Input: The thermosensitive-mucoadhesive ondansetron liquid suppository (tmOLS) was developed to enhance patient compliance and bioavailability in high-risk patients receiving highly emetogenic therapy and having difficulty in swallowing, The thermosensitive-mucoadhesive liquid suppository bases were formulated using poloxamers (P407 and P188) and hydroxypropylmethyl cellulose (HPMC).

ondansetron

poloxamers

hydroxypropylmethyl


Input: The physicochemical properties of the liquid suppository bases were characterized by their gelation temperature, mucoadhesive force, rheological properties, and in vitro release.


Input: Rectal mucosal damage following rectal administration of tmOLS in rats was assessed using microscopy.


Input: Pharmacokinetic analyses were performed to compare tmOLS administered via the rectal route to ondansetron solution administered orally.

ondansetron


Input: The liquid suppository base of tmOLS contained P407, P188, and HPMC in the ratio 18: 20: 0. 8, was in the liquid state at room temperature, underwent gelation at body temperature.


Input: Area under the curve and half-life (t (1/2)) of ondansetron were significantly higher in the tmOLS-treated group, indicating that the formulation bypassed the first-pass metabolism and that it was released slowly from the tmOLS because of the formation of mucoadhesive gel state.

ondansetron


Input: Furthermore, the t (1/2) of tmOLS was two-fold that of the oral solution.


Input: Thus, tmOLS could be administered to patients who have difficulty in swallowing; however, adjustments in dosing interval may be needed.


Input: Gd-based Macromolecules and Nanoparticles as Magnetic Resonance Contrast Agents for Molecular Imaging.

Gd


Input: As we move towards an era of personalized medicine, molecular imaging contrast agents are likely to see an increasing presence in routine clinical practice.


Input: Magnetic resonance (MR) imaging has garnered particular interest as a platform for molecular imaging applications due its ability to monitor anatomical changes concomitant with physiologic and molecular changes.


Input: One promising new direction in the development of MR contrast agents involves the labeling and/or loading of nanoparticles with gadolinium (Gd).

gadolinium

Gd


Input: These nanoplatforms are capable of carrying large payloads of Gd, thus providing the requisite sensitivity to detect molecular signatures within disease pathologies.

Gd


Input: In this review, we discuss some of the progress that has recently been made in the development of Gd-based macromolecules and nanoparticles and outline some of the physical and chemical properties that will be important to incorporate into the next generation of contrast agents, including high Gd chelate stability, high " relaxivity per particle " and " relaxivity density ", and biodegradability.

Gd

Gd


Input: (89) Zr-PET Radiochemistry in the Development and Application of Therapeutic Monoclonal Antibodies and Other Biologicals.

(89) Zr


Input: Positron emission tomography with (89) Zr can be used to follow the behaviour of therapeutic monoclonal antibodies (mAbs) and other biologicals in vivo.

(89) Zr


Input: The favourable radiophysical characteristics of (89) Zr allow multiple days PET scanning after injection.

(89) Zr


Input: For the coupling of (89) Zr to proteins six desferrioxamine (DFO)-based bifunctional chelators have been described, five of which forming stable complexes in vivo.

(89) Zr

desferrioxamine

DFO


Input: Of the methods that give stable complexes three are based on random lysine modification of mAbs and two on site-specific engineering.

lysine


Input: Up to now only two methods, random lysine modification with N-suc-DFO or DFO-Bz-NCS, have been used in clinical studies.

lysine

N-suc-DFO

DFO-Bz-NCS


Input: In this review firstly aspects of the physicochemical properties and production of (89) Zr are emphasized as well as important items that have to be taken into account for current good manufacturing practice (cGMP) compliant production of (89) Zr-labeled proteins.

(89) Zr

(89) Zr


Input: Next, the different DFO-based conjugation strategies will be discussed with respect to synthesis, and their (pre) clinical evaluation particularly in the field of oncology.


Input: Chemistry and theranostic applications of radiolabeled nanoparticles for cardiovascular, oncological, and pulmonary research.


Input: Labeling nanoparticles with radionuclides has been widely used to form multifunctional and multivalency agents for various biomedical applications.


Input: A variety of nanostructures including inorganic, organic and lipid nanoparticles have been labeled with positron or gamma emitting radioisotopes through versatile radiochemistry in a number of disease models to track their in vivo fate, image biomarkers, and monitor treatment response.


Input: This review briefly summarizes the recent applications of nanoparticles labeled with radionuclides for oncological, cardiovascular, and pulmonary theranostics.


Input: TRP Channels as Targets for Therapeutic Intervention in Obesity: Focus on TRPV1 and TRPM5.


Input: The disease of obesity is one of the greatest healthcare challenges of our time.


Input: The increasing urgency for effective treatment is driving an intensive search for new targets for anti-obesity drug discovery.


Input: The TRP channel super family represents a class of proteins now recognized to serve many functions in physiology related to maintenance of health and the development of diseases.


Input: A few of these might offer new potential for therapeutic intervention in obesity.


Input: Among the TRP channels, TRPV1 appears most closely associated with body weight homeostasis through its influence on energy expenditure.


Input: TRPM5 has been thoroughly characterized as a critical component of taste signaling and recently has been implicated in insulin release.


Input: Because of its role in taste signaling, we argue that drugs designed to modulate TRPM5 could be useful in controlling energy consumption by impacting taste sensory signals.


Input: As drug targets for obesity, both TRPV1 and TRPM5 offer the advantage of operating in compartments that could limit drug distribution to the site of action.


Input: The potential for other TRP channels as anti-obesity drug targets also is discussed.


Input: Possible Involvement of TRP Channels in Cardiac Hypertrophy and Arrhythmia.


Input: Over the past 20 years, studies of transient receptor potential (TRP) channels have significantly extended our knowledge regarding the molecular basis of Ca2 + signals in cardiac myocytes.

Ca2 +


Input: The functional significance of cardiac TRP channels is likely connected to the alteration of membrane potential or Ca2 + entry into a noncontractile compartment, where gene expression responsible for various cardiac diseases is induced.

Ca2 +


Input: This review highlights some aspects of TRP channels with anticipated roles in cardiac disease.


Input: Evidence suggests that (a) increased activities of TRPC1, TRPC3, or TRPC6 are involved in the development of cardiac hypertrophy, where these TRPC channels act as unique sensors for a wide range of hypertrophic stimuli, and (b) mutations in TRPM4 are now recognized as causes of human cardiac conduction disorders.


Input: Ultimately, TRP channels may become novel pharmacological targets in the treatment of human cardiac disease.


Input: Transient receptor potential channels and dermatological disorders.


Input: Transient receptor potential (TRP) cation channels are an emerging field of research in dermatology.


Input: Beyond their classical role in skin sensory perception, TRPs are involved in various cutaneous functions that include keratinocyte differentiation, apoptosis and melanocyte pigmentation.


Input: In addition, they have a role as pharmacological targets in many inflammatory skin diseases including psoriasis, chronic itch, hair disorders and skin cancers.


Input: Moreover, mutations in TRPs have recently been related to rare skin conditions such as Olmsted syndrome.


Input: This review will cover the role of TRPs in dermatologic conditions with special emphasis on itch and skin inflammatory diseases.


Input: Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17 beta-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer.

indomethacin

17 beta-hydroxysteroid


Input: Castrate-resistant prostate cancer (CRPC) is a fatal, metastatic form of prostate cancer.


Input: CRPC is characterized by reactivation of the androgen axis due to changes in androgen receptor signaling and/or adaptive intratumoral androgen biosynthesis.

androgen

androgen

androgen


Input: AKR1C3 is upregulated in CRPC where it catalyzes the formation of potent androgens.

androgens


Input: This makes AKR1C3 a target for the treatment of CRPC.


Input: AKR1C3 inhibitors should not inhibit AKR1C1/AKR1C2, which inactivate 5 alpha-dihydrotestosterone.

5 alpha-dihydrotestosterone


Input: Indomethacin, used to inhibit cyclooxygenase, also inhibits AKR1C3 and displays selectivity over AKR1C1/AKR1C2.

Indomethacin


Input: Parallel synthetic strategies were used to generate libraries of indomethacin analogues, which exhibit reduced cyclooxygenase inhibitory activity but retain AKR1C3 inhibitory potency and selectivity.

indomethacin


Input: The lead compounds inhibited AKR1C3 with nanomolar potency, displayed > 100-fold selectivity over AKR1C1/AKR1C2, and blocked testosterone formation in LNCaP-AKR1C3 cells.

testosterone


Input: The AKR1C3. NADP (+). 2'-des-methyl-indomethacin crystal structure was determined, and it revealed a unique inhibitor binding mode.

NADP (+)


Input: The compounds reported are promising agents for the development of therapeutics for CRPC.


Input: Five new secondary metabolites from Monascus purpureus-fermented Hordeum vulgare and Sorghum bicolor.


Input: Long grains of Hordeum vulgare and Sorghum bicolor were individually fermented with Monascus purpureus MTCC 369 under solid state fermentation.


Input: The aqueous extract of Monascus which fermented H. vulgare and S. bicolor was found to contain five different new metabolites.


Input: Silica gel column chromatography of the aqueous extract with a linear gradient of ethyl acetate, acetonitrile and carbon tetrachloride (v/v) yielded five new metabolites named benzopranyl capriate (9H-1-isoprenyl-benzopyran-5-isopropanoic acid-6-ol-6-n-decanoate), shorghumoic acid (n-octadec-8, 11-dien-7 alpha-ol-1-oic acid) and sorghumflavin A (2-n-butyloxo-6-beta-hydroxy-7-beta-isoprenyl ankaflavin) from Monascus-fermented S. bicolor, while hordeumflavin B (2-n-undecanyloxo-7-beta-isoprenyl ankaflavin) and vulgaredilone (2-dodecanyl-7-beta isopranyl monoscodilone) from Monascus-fermented H. vulgare.

Silica gel

ethyl acetate

acetonitrile

carbon tetrachloride

benzopranyl capriate

9H-1-isoprenyl-benzopyran-5-isopropanoic acid-6-ol-6-n-decanoate

shorghumoic acid

n-octadec-8, 11-dien-7 alpha-ol-1-oic acid

sorghumflavin A

2-n-butyloxo-6-beta-hydroxy-7-beta-isoprenyl ankaflavin

hordeumflavin B

2-n-undecanyloxo-7-beta-isoprenyl ankaflavin

vulgaredilone

2-dodecanyl-7-beta isopranyl monoscodilone


Input: Development and characterization of monomeric N-end rule inhibitors through in vitro model substrates.


Input: In the N-end rule pathway, a set of N-terminal amino acids, called N-degrons, are recognized and ubiquitinated by the UBR proteins.

N

amino acids


Input: Here we examined various N-end rule inhibitors to identify essential structural components of the system.


Input: Our study using in vitro biochemical assay indicated that the l-conformation and protonated alpha-amino group of the first residue were critical for N-degrons to properly interact with the UBR proteins.

alpha-amino


Input: The monomeric molecules with minimum interacting motifs showed endopeptidase resistance and better inhibitory activities than traditional dipeptide inhibitors.


Input: Collectively, our study identifies a pharmacophore of N-end rule inhibitors, which provides a structural platform to improve the efficiency and druggable properties of inhibitors.


Input: Considering that the N-end rule has been implicated in many pathophysiological processes in cells, inhibitors of this pathway, such as p-chloroamphetamine, are potentially of clinical interest in a novel aspect of action mechanisms.

p-chloroamphetamine


Input: Montiporic acid D, a new polyacetylene carboxylic acid from scleractinian coral Montipora digitata.

Montiporic acid D

polyacetylene carboxylic acid


Input: A new polyacetylene carboxylic acid named montiporic acid D (1) was isolated along with a known polyacetylene alcohol, (Z)-13, 15-hexadecadien-2, 4-diyn-1-ol (2) from scleractinian coral Montipora digitata.

polyacetylene carboxylic acid

montiporic acid D

polyacetylene alcohol

(Z)-13, 15-hexadecadien-2, 4-diyn-1-ol


Input: The structures of compounds were determined by analyses of NMR and MS spectra.


Input: RNAi in Clinical Studies.


Input: RNA interference (RNAi) is an efficient process of posttranscriptional gene silencing.


Input: In recent years it has been developed into a new technology in biopharmaceutical fields of science.


Input: RNAi products include short interference RNA (siRNA) but also short hairpin RNA (shRNA), bifunctional short hairpin RNA (bi-shRNA) and microRNA (miRNA).


Input: They combine with homologous fragments of the mRNA and cause its degradation.


Input: It results in inhibition of protein synthesis, or in mutation in the gene encoding it.


Input: RNAi has been used in analysis of genomes and creation of new animal models to test drugs.


Input: From the pharmaceutical point of view, what is the most important is its therapeutic application.


Input: So far the basic and clinical research has been focused on the following targets: macular degeneration, cancer and antiviral therapy.


Input: But there are also reports on clinical trials in asthma, hypercholesterolemia and genetic diseases such as inherited skin disorders and amyloidosis.


Input: Among over 20 therapeutics that reached clinical trials, only few are still investigated.


Input: Another few are clinical candidates.


Input: The review focuses on RNAi products under clinical evaluation and their most promising new applications.


Input: Bisacylimidoselenocarbamates Cause G2/M Arrest Associated with the Modulation of CDK1 and Chk2 in Human Breast Cancer MCF-7 Cells.

Bisacylimidoselenocarbamates


Input: Bisacylimidoselenocarbamate derivatives (BSC) are potent anticancer agents with a strong cytotoxic activity against different types of tumour cells.

Bisacylimidoselenocarbamate

BSC


Input: Based in phosphatidylserine exposure on the cell membranes we show that BSC treatment resulted in enhanced cell death in leukaemia CCRF-CEM cells.

phosphatidylserine

BSC


Input: DNA fragmentation detection in breast adenocarcinoma MCF-7 cells showed that BSC triggered cell death is concentration and time dependent.

BSC


Input: We also show that two of these compounds, BSC 3g and 3n, cause cell-cycle arrest in the late G2/M in MCF-7 cells.

BSC


Input: Consistent with this, a reduction in CDK1 and CDK2 expression with no change in cyclin A an B1 was observed in this cell line.


Input: Activation of caspase-2 was also detected.


Input: However, the involvement of the caspase-dependent pathway in the process of cell death induced by either BSC 3g or 3n is discarded since cell death could not be prevented by pretreatment with the pancaspase inhibitor z-VAD-fmk.

BSC

z-VAD-fmk


Input: Moreover, since reduced levels of p21CIP1 and Chk2 proteins but no change in p53 levels could be detected in MCF-7 cells after BSC 3g or 3n treatment our results suggest that BSC treated cells die from lethal mitosis.

BSC

BSC


Input: Immunophilins are Involved in the Altered Platelet Aggregation Observed in Patients with Type 2 Diabetes Mellitus.


Input: Platelet hyperaggregability might contribute to vascular complications associated with type 2 diabetes mellitus (DM2). Experimental evidence supports a direct link between altered Ca2 + entry and hyperaggregability in DM2 patients.

Ca2 +


Input: Objectives: We aimed to investigate whether altered immunophilin expression and function are involved in the abnormal Ca2 + entry observed in platelets from DM2 patients.

Ca2 +


Input: Results: Inhibition of immunophilins by tacrolimus (FK506) and sirolimus (rapamycin) reduced Ca2 + entry in platelets from healthy donors and DM2 patients.

tacrolimus

sirolimus

rapamycin

Ca2 +


Input: Similarly, immunophilin inhibitors reduced platelet degranulation in both healthy and DM2 subjects.


Input: Nevertheless, alpha-granule secretion reduction was greater than that observed for dense granules in platelets from DM2 patients.


Input: However, no difference was observed in the inhibition of secretion in platelets from healthy subjects.


Input: Additionally, altered expression of FK506 binding protein-52 (FKBP52) and coupling to Ca (2 +) channels were found in platelets from DM2 patients compared to healthy subjects.

Ca (2 +)


Input: Finally, reduction in platelet function from healthy subjects and DM2 patients in the presence of immunophilin antagonists was observed, being this dysfunction more evident in platelets from DM2 patients.


Input: Conclusions: We suggest that, among others, FKBP52 expression and function are altered in platelets from DM2 patients, contributing to the altered Ca (2 +) entry and hyperaggregability in these cells.

Ca (2 +)


Input: Aminophosphonate metal complexes of biomedical potential.

Aminophosphonate


Input: Metals and their complexes with organic ligands have an important role in biochemical systems such as enzymatic catalysis, metal ion transfer across the cell membranes, treatment of malignancy, rheumatoid arthritis, ulcer and other types of diseases.


Input: Special attention is directed to metal complexes with ligands which are important in biological systems, as their incorporation into metallo-organic compounds offers much scope for design of potential metal-based agents that provide new opportunities in the medicinal chemistry.


Input: In view of this, derivatives of aminophosphonic acids, owing to their broad spectrum of biological activities and wide range of applications in the medicinal and agrochemical fields, are very attractive metal-ligand agents that might form biomedical important metal complexes.

aminophosphonic acids


Input: Thus, a number of aminophosphonate complexes of platinum group metals have been found to possess remarkable antitumor activity while complexes of some other transition and rare-earth metals like technetium, rhenium, samarium and gadolinium have been used either as therapeutic and diagnostic radiopharmaceuticals or as magnetic resonance imaging (MRI) contrast agents.

aminophosphonate

platinum

technetium

rhenium

samarium

gadolinium


Input: In addition, the high phosphonate affinity towards bone and other calcified tissues may be utilized for the drug targeting based on synthesis of metal complexes linked to bioactive carrier systems, affording better modalities of attack to the site of pathology.

phosphonate


Input: In this review article, aminophosphonate metal-based compounds with potential biomedical applications are described.

aminophosphonate


Input: Ab initio MRCI + Q study on low-lying states of CS including spin-orbit coupling.


Input: Carbon monosulfide (CS), which plays an important role in a variety of research fields, has long received considerable interest.

Carbon monosulfide

CS


Input: Due to its transient nature and large state density, the electronic states of CS have not been well understood, especially the interactions between different states.

CS


Input: In this paper, we performed a detail ab initio study on the low-lying electronic states of CS by means of the internally contracted multireference configuration interaction method (including Davidson correction) with scalar relativistic correction using the Douglas-Kroll-Hess Hamiltonian.

CS


Input: We focused on the spin-orbit coupling of the states via the state interaction method with the full Breit-Pauli Hamiltonian.


Input: The potential energy curves (PECs) of 18 Lambda-S states correlated with the lowest dissociation limit of the CS molecule were calculated, as well as those of 50 Omega states generated from the Lambda-S states.

CS


Input: The spectroscopic constants of the bound states were obtained, which are in good agreement with previous available experimental and theoretical results.


Input: The state perturbations of the a (3) Pi and A (1) Pi states with other low-lying electronic states are discussed in detail, based on the calculated spin-orbit matrix as well as the PECs of the Omega states.


Input: Avoided crossing in the states of CS was indicated when spin-orbit coupling was taken into account.

CS


Input: Finally, the allowed transition dipole moments as well as the lifetimes of the five lowest vibrational states of the A (1) Pi 1, A' (1) Sigma (+) 0 (+) and a (3) Pi i states were obtained.


Input: Structural and mechanistic principles of intramembrane proteolysis--lessons from rhomboids.


Input: Intramembrane proteases cleave membrane proteins in their transmembrane helices to regulate a wide range of biological processes.


Input: They catalyse hydrolytic reactions within the hydrophobic environment of lipid membranes where water is normally excluded.


Input: How?


Input: Do the different classes of intramembrane proteases share any mechanistic principles?


Input: In this review these questions will be discussed in view of the crystal structures of prokaryotic members of the three known catalytic types of intramembrane proteases published over the past 7 years.


Input: Rhomboids, the intramembrane serine proteases that are the best understood family, will be the initial area of focus, and the principles that have arisen from a number of structural and biochemical studies will be considered.


Input: The site-2 metalloprotease and GXGD-type aspartyl protease structures will then be discussed, with parallels drawn and differences highlighted between these enzymes and the rhomboids.


Input: Despite the significant advances achieved so far, to obtain a detailed understanding of the mechanism of any intramembrane protease, high-resolution structural information on the substrate-enzyme complex is required.


Input: This remains a major challenge for the field.


Input: Reduction of dNTP levels enhances DNA replication fidelity in vivo.

dNTP


Input: ATP is the most important energy source for the maintenance and growth of living cells.

ATP


Input: Here we report that the impairment of the aerobic respiratory chain by inactivation of the ndh gene, or the inhibition of glycolysis with arsenate, both of which reduce intracellular ATP, result in a significant decrease in spontaneous mutagenesis in Escherichia coli.

arsenate

ATP


Input: The genetic analyses and mutation spectra in the ndh strain revealed that the decrease in spontaneous mutagenesis resulted from an enhanced accuracy of the replicative DNA polymerase.


Input: Quantification of the dNTP content in the ndh mutant cells and in the arsenate-treated cells showed reduction of the dNTP pool, which could explain the observed broad antimutator effects.

dNTP

arsenate

dNTP


Input: In conclusion, our work indicates that the cellular energy supply could affect spontaneous mutation rates and that a reduction of the dNTP levels can be antimutagenic.

dNTP


Input: Identification and characterization of small molecule inhibitors of signal transducer and activator of transcription 3 (STAT3) signaling pathway by virtual screening.


Input: Inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling pathway has been considered a novel therapeutic strategy to treat human cancers that harbor aberrantly-active STAT3.


Input: In this study, a series of small molecules were identified as novel inhibitors of STAT3 signaling pathway through virtual screening.


Input: A tricyclic scaffold containing compound, 6, was identified as an inhibitor of IL-6/STAT3 signaling with an IC50 of 26. 68 mu M.


Input: In addition, this compound inhibited Tyr705 phosphorylation of STAT3 and had no obvious effect on upstream tyrosine kinases.

tyrosine


Input: Thus, compound 6 is a potential lead structure and valuable for further drug development.


Input: Synthesis and photochemical behavior of coumarin-caged cholesterol.

coumarin

cholesterol


Input: The syntheses of three coumarin-caged cholesterols are reported that contain the 6-diethylaminocoumarin (DEACM), 6-bromo-7-hydroxycoumarin (BHC) and 6-bromo-7-methoxycoumarin (BMCM) photocleavable groups.

coumarin

cholesterols

DEACM

BHC

BMCM


Input: Upon photolysis, the best caged derivative was found to be BHC-cholesterol whose quantum yield was determined to be 0. 032 at 350 nm.

BHC

cholesterol


Input: Dynamic readers for 5-(hydroxy) methylcytosine and its oxidized derivatives.

5-(hydroxy) methylcytosine


Input: Tet proteins oxidize 5-methylcytosine (mC) to generate 5-hydroxymethyl (hmC), 5-formyl (fC), and 5-carboxylcytosine (caC).

hmC

caC


Input: The exact function of these oxidative cytosine bases remains elusive.

cytosine


Input: We applied quantitative mass-spectrometry-based proteomics to identify readers for mC and hmC in mouse embryonic stem cells (mESC), neuronal progenitor cells (NPC), and adult mouse brain tissue.

hmC


Input: Readers for these modifications are only partially overlapping, and some readers, such as Rfx proteins, display strong specificity.


Input: Interactions are dynamic during differentiation, as for example evidenced by the mESC-specific binding of Klf4 to mC and the NPC-specific binding of Uhrf2 to hmC, suggesting specific biological roles for mC and hmC.

hmC

hmC


Input: Oxidized derivatives of mC recruit distinct transcription regulators as well as a large number of DNA repair proteins in mouse ES cells, implicating the DNA damage response as a major player in active DNA demethylation.


Input: Euryspongins A-C, three new unique sesquiterpenes from a marine sponge Euryspongia sp.

Euryspongins A-C

sesquiterpenes


Input: Three new unique sesquiterpenes, euryspongins A-C (1-3), were isolated from a marine sponge Euryspongia sp. collected at Iriomote Island, Okinawa, Japan.

sesquiterpenes

euryspongins A-C


Input: Compound 1 possessed a bicyclic furanosesquiterpene structure with six-and eight-membered rings, whereas compounds 2 and 3 had an alpha, beta-unsaturated-gamma-lactone ring instead of the furan ring in 1.

bicyclic furanosesquiterpene

alpha, beta-unsaturated-gamma-lactone

furan


Input: Only five natural products in this class have been reported, and compounds 1-3 are the sixth-eighth examples of natural products.


Input: Compounds 1-3 had no inhibition effect against PTP1B, an important target enzyme for the treatment of diabetes, while the dehydro derivative of 1 [dehydroeuryspongin A (4)] exhibited inhibitory activity (IC (50) = 3. 6 mu M).

dehydroeuryspongin A


Input: Mucous hypersecretion and relationship to cough.


Input: A variety of foreign " invaders " such as viruses, bacteria and other particulates e. g., cigarette smoke, are inhaled, deposit on the airway surface and invade the " host. " Mucins produced by the surface airway epithelium and by the submucosal glands are secreted into the airway lumen.


Input: Deposited particulates adhere to the mucus and are cleared via mucociliary transport and via cough.


Input: Mucins are major constituents of mucus, which is important in the clearance of inhaled materials.


Input: Normally, secreted mucus is cleared without symptoms or interference with lung function.


Input: However, in obstructive airway diseases such as COPD, asthma, and cystic fibrosis, excessive mucus is produced.


Input: Because of the prominence of mucous hypersecretion as a cause of cough, this discussion focuses on mechanisms regulating normal production of mucins and the mechanisms underlying exaggerated mucin secretion in chronic obstructive airway diseases.


Input: Mucins are produced by airway epithelial cells via a cascade of signals (the Epidermal Growth Factor Cascade) and secreted on the luminal epithelial surface, often in response to the deposition of inhaled irritants.


Input: Normally, only minimal amounts of mucins are secreted, which assist in clearance of the inhaled particulates.


Input: However, in disease, additional pathways are induced via positive feedback systems, which lead to mucous hypersecretion.


Input: In the large conducting airways, where cough receptors are concentrated, mucous hypersecretion causes stimulation of neural receptors that result in cough.


Input: However, in small airways (e. g., bronchioles), because of their small diameters, mucous hypersecretion leads to plugging of the airways.


Input: Because there are so many small airways, their plugging is difficult to detect early, and this locus is known as a " silent zone. " In chronic obstructive airway diseases, plugging of small airways may persist and increase over time, finally resulting in severe airway obstruction.


Input: Different obstructive airway diseases induce inflammatory signaling (including mucous hypersecretion) via different stimuli, but often via similar signaling pathways.


Input: Application of present knowledge of signaling that occurs with mucous hypersecretion can lead to novel therapies for hypersecretion and cough induced in conducting airways and could prevent plugging in small airways that can lead to clinical deterioration and death.


Input: Interaction of 17 beta-estradiol and ketoconazole on endocrine function in goldfish (Carassius auratus).

17 beta-estradiol

ketoconazole


Input: An understanding of the effects of toxic mixtures of endocrine disrupting chemicals (EDCs) on aquatic organisms is challenging as these organisms are exposed to multiple classes of contaminants in their natural habitat.


Input: The aim of the present study was to evaluate the interactions of two classes of EDCs, 17 beta-estradiol (E2) and ketoconazole (KTC), on endocrine function in male goldfish (Carassius auratus), including vitellogenesis, metabolic capability and serum steroid synthesis.

17 beta-estradiol

ketoconazole

KTC


Input: Changes in vitellogenin (VTG) concentration, liver 7-ethoxyresorufin-O-deethylase (EROD) activity and circulating serum E2 level were examined.

O


Input: The expression of related genes was also determined using quantitative real-time polymerase chain reaction.


Input: Exposure to E2 caused a significant increase in VTG concentrations which corresponded with the gene expression of VTG and estrogen receptor (ER) in males, which were further elevated after combined exposure to E2 and KTC, indicative of a synergetic relationship.

estrogen

KTC


Input: Exposure to E2 also resulted in a distinct increase in serum steroid biosynthesis and associated cytochrome P450 (CYP) aromatase expression after 10 days.

steroid


Input: However, these changes were inhibited by the presence of KTC, which acted as a steroidogenic inhibitor in fish.

KTC


Input: Moreover, KTC significantly decreased liver EROD activity and increased the related gene expression of CYP1A.

KTC


Input: However, these KTC-mediated metabolic reactions in goldfish were up-regulated following exposure to KTC in combination with E2.

KTC

KTC


Input: These findings reveal complex interactions on endocrine functions in male goldfish when exposed to multiple contaminations and may provide a better understanding of the effects of toxic mixtures.


Input: New 2-benzylsulfanyl-nicotinic acid based 1, 3, 4-oxadiazoles: Their synthesis and biological evaluation.

2-benzylsulfanyl-nicotinic acid

1, 3, 4-oxadiazoles


Input: A novel series of 5-(2-benzylsulfanyl-pyridin-3-yl)-2-(substituted)-sulfanyl-1, 3, 4-oxadiazoles 6a-j were synthesized from key intermediate 5-(2-benzylsulfanyl-pyridin-3-yl)-3H-[1, 3, 4] oxadiazole-2-thione 5.

5-(2-benzylsulfanyl-pyridin-3-yl)-2-(substituted)-sulfanyl-1, 3, 4-oxadiazoles

5-(2-benzylsulfanyl-pyridin-3-yl)-3H-[1, 3, 4] oxadiazole-2-thione


Input: Nucleophilic substitution reactions with different electrophiles (E +), such as haloacetate and haloalkyl groups, were performed to get target compounds 6a-j.

haloacetate

haloalkyl


Input: Compounds were characterized by NMR, mass, IR spectra and C, H, N analyses.

Compounds

H

N


Input: All compounds were evaluated for their antimicrobial and antimycobacterial activities; selected analogs were screened for their anticancer activity on 60 tumor cell lines at single dose 1. 00 (-5) M.


Input: Unfortunately, none of the compounds showed a significant antitumor activity on 60 human tumor cell lines.


Input: However, compounds 6g and 6f with benzothiazole moiety (12. 5 and 25 mu g/ml) showed promising activity against Escherichia coli compared to ampicillin; compounds 6d, 6j bearing triazole and morpholine, respectively, showed promising antitubercular activity (25 mu g/ml) compared to rifampicin.

benzothiazole

ampicillin

triazole

morpholine

rifampicin


Input: Structural Characterization of an LPA1 Second Extracellular Loop Mimetic with a Self-Assembling Coiled-Coil Folding Constraint.


Input: G protein-coupled receptor (GPCR) structures are of interest as a means to understand biological signal transduction and as tools for therapeutic discovery.


Input: The growing number of GPCR crystal structures demonstrates that the extracellular loops (EL) connecting the membrane-spanning helices show tremendous structural variability relative to the more structurally-conserved seven transmembrane alpha-helical domains.


Input: The EL of the LPA (1) receptor have not yet been conclusively resolved, and bear limited sequence identity to known structures.

LPA


Input: This study involved development of a peptide to characterize the intrinsic structure of the LPA (1) GPCR second EL.

LPA


Input: The loop was embedded between two helices that assemble into a coiled-coil, which served as a receptor-mimetic folding constraint (LPA (1)-CC-EL2 peptide).

LPA


Input: The ensemble of structures from multi-dimensional NMR experiments demonstrated that a robust coiled-coil formed without noticeable deformation due to the EL2 sequence.


Input: In contrast, the EL2 sequence showed well-defined structure only near its C-terminal residues.

C


Input: The NMR ensemble was combined with a computational model of the LPA (1) receptor that had previously been validated.

LPA


Input: The resulting hybrid models were evaluated using docking.


Input: Nine different hybrid models interacted with LPA 18: 1 as expected, based on prior mutagenesis studies, and one was additionally consistent with antagonist affinity trends.

LPA


Input: Chemical Inhibitors and microRNAs (miRNA) Targeting the Mammalian Target of Rapamycin (mTOR) Pathway: Potential for Novel Anticancer Therapeutics.

Rapamycin


Input: The mammalian target of rapamycin (mTOR) is a critical regulator of many fundamental features in response to upstream cellular signals, such as growth factors, energy, stress and nutrients, controlling cell growth, proliferation and metabolism through two complexes, mTORC1 and mTORC2.

rapamycin


Input: Dysregulation of mTOR signalling often occurs in a variety of human malignant diseases making it a crucial and validated target in the treatment of cancer.


Input: Tumour cells have shown high susceptibility to mTOR inhibitors.


Input: Rapamycin and its derivatives (rapalogs) have been tested in clinical trials in several tumour types and found to be effective as anticancer agents in patients with advanced cancers.

Rapamycin


Input: To block mTOR function, they form a complex with FKBP12 and then bind the FRB domain of mTOR.


Input: Furthermore, a new generation of mTOR inhibitors targeting ATP-binding in the catalytic site of mTOR showed potent and more selective inhibition.

ATP


Input: More recently, microRNAs (miRNA) have emerged as modulators of biological pathways that are essential in cancer initiation, development and progression.


Input: Evidence collected to date shows that miRNAs may function as tumour suppressors or oncogenes in several human neoplasms.


Input: The mTOR pathway is a promising target by miRNAs for anticancer therapy.


Input: Extensive studies have indicated that regulation of the mTOR pathway by miRNAs plays a major role in cancer progression, indicating a novel way to investigate the tumorigenesis and therapy of cancer.


Input: Here, we summarize current findings of the role of mTOR inhibitors and miRNAs in carcinogenesis through targeting mTOR signalling pathways and determine their potential as novel anti-cancer therapeutics.


Input: Amelioration of Hypoglycemia via Somatostatin Receptor Type 2 Antagonism in Recurrently Hypoglycemic Diabetic Rats.

Somatostatin


Input: Selective antagonism of somatostatin receptor type 2 (SSTR2-) normalizes glucagon and corticosterone responses to hypoglycemic clamp in diabetic rats.

somatostatin

corticosterone


Input: The purpose of this study is to determine if SSTR2 antagonism (SSTR2a) ameliorates hypoglycemia in response to overinsulinization in diabetic rats previously exposed to recurrent hypoglycemia.


Input: Streptozotocin-diabetic rats (n = 19), previously subjected to 5 hypoglycemia events over 3 days, received an i. v. insulin bolus (10 U/kg) + insulin infusion (50 mU/kg/min) until hypoglycemia ensued (<= 3. 9 mM) (Expt-D1).

Streptozotocin


Input: The next day (Expt-D2), rats were allocated to receive either placebo treatment (n = 7) or SSTR2a infusion (3000 nmol/kg/min, n = 12) 60-min prior to same insulin regimen.


Input: On Expt-D1, all rats developed hypoglycemia by ~ 90 minutes, while on Expt-D2 hypoglycemia was attenuated with SSTR2a treatment (nadir = 3. 7 +/- 0. 3 mM vs. 2. 7 +/- 0. 3 mM in SSTR2a and controls, p < 0. 01).


Input: Glucagon response to hypoglycemia on Expt-D2 deteriorated by 20-fold in the placebo group (P < 0. 001) but improved in the SSTR2a group (3-fold increase in AUC, P < 0. 001).


Input: Corticosterone response deteriorated in the placebo treated rats on Expt-D2 but increased 2-fold in the SSTR2a group.

Corticosterone


Input: Catecholamine responses were not affected by antagonism.

Catecholamine


Input: Thus, SSTR2 antagonism following recurrent hypoglycemia improves the glucagon and corticosterone responses and largely ameliorates insulin-induced hypoglycemia in diabetic rats.

corticosterone


Input: TCF7L2 Variation and Proliferative Diabetic Retinopathy.


Input: Proliferative diabetic retinopathy (PDR) is the most severe vision-threatening complication of diabetes.


Input: To investigated genetic association between TCF7L2 and PDR in Caucasian type 2 diabetes mellitus (T2DM) and its functional consequences, 383 T2DM patients with PDR (T2DM-PDR) and 756 T2DM patients without diabetic retinopathy (T2DM-no DR) were genotyped with rs7903146 in TCF7L2.


Input: We found that risk allele (T) frequency of rs7903146 was significantly higher in T2DM-PDR patients (allelic P = 2. 52E-04).


Input: In lymphoblastoid cells induced to undergo endoplasmic reticulum (ER) stress by treatment of tunicamycin, higher fold change of TCF7L2 and VEGFA mRNA levels were observed in rs7903146-TT cells than that in rs7903146-CC cells (P = 0. 02 for TCF7L2; P = 0. 004 for VEGFA), suggesting ER stress plays a role in PDR pathogenesis.

tunicamycin


Input: Silencing TCF7L2 resulted in decreased mRNA levels of both TCF7L2 and VEGFA (P < 0. 001).


Input: Retinas of oxygen-induced retinopathy (OIR) mice (a model for PDR) had higher TCF7L2 and VEGFA mRNA levels than controls (P = 2. 9E-04 for TCF7L2; P = 1. 9E-07 for VEGFA).

oxygen


Input: Together, our study showed that TCF7L2-rs7903146 is associated with PDR in Caucasian T2DM and suggested TCF7L2 promoted pathological retinal neovascularization via ER stress-dependent upregulation of VEGFA.


Input: From SNP to Transcriptional Mechanism: A Model for FRMD3 in Diabetic Nephropathy.


Input: Genome wide association studies (GWAS) have proven to be highly effective at defining causal relationships between single nucleotide polymorphisms (SNP) and clinical phenotypes in complex diseases.

nucleotide


Input: Establishing a mechanistic link between a non-coding SNP and the clinical outcome is a significant hurdle in translating associations into biological insight.


Input: We demonstrate an approach to assess the functional context of a diabetic nephropathy (DN) associated SNP located in the promoter region of the gene FRMD3.


Input: The approach integrates pathway analyses with transcriptional regulatory pattern based promoter modeling and allows the identification of a transcriptional framework impacted by the DN-associated SNP in the FRMD3 promoter.


Input: This framework provides a testable hypothesis for mechanisms of genomic variation and transcriptional regulation in the context of DN.


Input: Our model proposes a possible transcriptional link through which the polymorphism in the FRMD3 promoter could influence transcriptional regulation within the bone morphogenetic protein (BMP) signaling pathway.


Input: These findings provide the rationale to interrogate the biological link between FRMD3 and the BMP pathway, and serve as an example of functional genomics-based hypothesis generation.


Input: Botulinum toxins: Mechanisms of action, antinociception and clinical applications.


Input: Botulinum toxin (BoNT) is a potent neurotoxin that is produced by the gram-positive, spore-forming, anaerobic bacterium, Clostridum botulinum.


Input: There are 7 known immunologically distinct serotypes of BoNT: types A, B, C1, D, E, F, and G.


Input: Clostridum neurotoxins are produced as a single inactive polypeptide chain of 150kDa, which is cleaved by tissue proteinases into an active di-chain molecule: a heavy chain (H) of ~ 100kDa and a light chain (L) of ~ 50kDa held together by a single disulfide bond.

disulfide


Input: Each serotype demonstrates its own varied mechanisms of action and duration of effect.


Input: The heavy chain of each BoNT serotype binds to its specific neuronal ecto-acceptor, whereby, membrane translocation and endocytosis by intracellular synaptic vesicles occurs.


Input: The light chain acts to cleave SNAP-25, which inhibits synaptic exocytosis, and therefore, disables neural transmission.


Input: The action of BoNT to block the release of acetylcholine botulinum toxin at the neuromuscular junction is best understood, however, most experts acknowledge that this effect alone appears inadequate to explain the entirety of the neurotoxin' s apparent analgesic activity.

acetylcholine


Input: Consequently, scientific and clinical evidence has emerged that suggests multiple antinociceptive mechanisms for botulinum toxins in a variety of painful disorders, including: chronic musculoskeletal, neurological, pelvic, perineal, osteoarticular, and some headache conditions.


Input: Tryptophan hydroxylase-2: An emerging therapeutic target for stress disorders.

Tryptophan


Input: Serotonin (5-HT) has been long recognized to modulate the stress response, and dysfunction of 5-HT has been implicated in numerous stress disorders.

Serotonin


Input: Accordingly, the 5-HT system has been targeted for the treatment of stress disorders.


Input: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT synthesis, and the recent identification of a second, neuron-specific TPH isoform (TPH2) opened up a new area of research.

Tryptophan


Input: With a decade of extensive investigation, it is now recognized that: (1) TPH2 exhibits a highly flexible gene expression that is modulated by an increasing number of internal and external environmental factors including the biological clock, stressors, endogenous hormones, and antidepressant therapies; and (2) genetically determined TPH2 activity is linked to a growing body of stress-related neuronal correlates and behavioral traits.


Input: These findings reveal an active role of TPH2 in the stress response and provide new insights into the long recognized but not yet fully understood 5-HT-stress interaction.


Input: As a major modulator of 5-HT neurotransmission and the stress response, TPH2 is of both pathophysiological and pharmacological significance, and is emerging as a new therapeutic target for the treatment of stress disorders.


Input: Given that numerous antidepressant therapies influence TPH2 gene expression, TPH2 is already inadvertently targeted for the treatment of stress disorders.


Input: With increased understanding of the regulation of TPH2 activity we can now purposely utilize TPH2 as a target to develop new or optimize current therapies, which are expected to greatly improve the prevention and treatment of a wide variety of stress disorders.


Input: Activation of beta-catenin/TCF targets following loss of the tumor suppressor SNF5.


Input: The SWI/SNF chromatin remodeling complex is a master regulator of developmental cell-fate decisions, although the key target pathways are poorly characterized.


Input: Here, we interrogated the contribution of the SWI/SNF subunit and tumor suppressor SNF5 to the regulation of developmental pathways using conditional mouse and cell culture models.


Input: We find that loss of SNF5 phenocopies beta-catenin hyperactivation and that SNF5 is essential for regulating Wnt/beta-catenin pathway target expression.


Input: These data provide insight into chromatin-based mechanisms that underlie developmental regulation and elucidate the emerging theme that mutation of this tumor suppressor complex can activate developmental pathways by uncoupling them from upstream control. Oncogene advance online publication, 25 February 2013; doi: 10. 1038/onc. 2013. 37.


Input: The (R)-omeprazole hydroxylation index reflects CYP2C19 activity in healthy Japanese volunteers.

(R)-omeprazole


Input: PURPOSE: Omeprazole has (R)-and (S)-enantiomers, which exhibit different pharmacokinetics (PK) among patients with cytochrome P450 (CYP) 2C19 genotype groups.

Omeprazole


Input: The aim of this study was to investigate whether the 1-point, 4-h postdose (R)-omeprazole hydroxylation index (HI) of racemic omeprazole reflects the three CYP2C19 genotype groups in Japanese individuals.

(R)-omeprazole

racemic omeprazole


Input: METHODS: Ninety healthy Japanese individuals were enrolled and classified into the three different CYP2C19 genotype groups: homozygous extensive metabolizers (hmEMs; n = 34), heterozygous EMs (htEMs; n = 44), and poor metabolizers (PMs; n = 12).


Input: Blood samples were drawn 4 h after the intake of an oral dose of omeprazole 40 mg, and plasma levels of omeprazole and its metabolites were analyzed by high-performance liquid chromatography (HPLC) using a chiral column.

omeprazole

omeprazole


Input: RESULTS: Mean plasma concentrations of (R)-and (S)-omeprazole in PMs were significantly higher than those in hmEMs and htEMs, and similar results were obtained in the case of omeprazole sulfone.

(R)-and (S)-omeprazole

omeprazole sulfone


Input: Additionally, there was a significant difference in plasma concentrations of (R)-5-hydroxyomeprazole among CYP2C19 genotype groups, whereas no significant differences were observed in that of (S)-5-hydroxyomeprazole.


Input: Similarly, (R)-omeprazole HI in hmEMs, htEMs, and PMs were 5. 6, 3. 1, and 0. 3, respectively, which were significantly different, but no significant difference was present in the (S)-omeprazole HI.

(R)-omeprazole

(S)-omeprazole