Input: Organic extracts from a control standard soil (Lufa 2. 2) had negligible effects on expression of these genes, and similarly several pesticides had little effect on the expression of a constitutive myo-3:: GFP transgene.


Input: Both the P73 and P74 sites have been treated regularly with (undisclosed) pesticides, as permitted under EU regulations, though other (e. g. industrial) organic residues may also be present.


Input: Mineralocorticoid receptor antagonists and renal involvement in primary aldosteronism: opening of a new era.


Input: Primary aldosteronism (PA) is one of the commonest forms of curable hypertension, and use of the plasma aldosterone-to-renin ratio as a screening test has led to a more efficient identification of this condition.

aldosterone


Input: Both animal and human studies have indicated that PA is associated with a variety of cardiovascular and renal complications that reflect the capability of elevated aldosterone to induce tissue damage exceeding that induced by hypertension itself.

aldosterone


Input: Involvement of the kidney in PA is highly relevant because structural renal damage is associated with less favorable outcome, both in terms of blood pressure response to treatment and possibility to develop progressive renal failure.


Input: However, early involvement of the kidney in PA is characterized by functional changes that are largely reversible with treatment.


Input: Unilateral adrenalectomy or administration of mineralocorticoid receptor antagonists are the current options for treating an aldosterone-producing adenoma or idiopathic adrenal hyperplasia.

aldosterone


Input: Both treatments are effective in correcting hypertension and hypokalemia, and currently available information on their capability to prevent deterioration of renal function indicates that both surgery and medical treatment are of considerable value.


Input: Immune regulation toward immunomodulation for neuroprotection in glaucoma.


Input: Although the immune system functions to preserve and restore tissue homeostasis, accumulating risk factors, prolonged glial activation, and sustained release of pro-inflammatory mediators in glaucoma may lead to a failure in the regulation of stress-induced immune response, and innate immune cells, autoreactive T cells, autoantibodies, and excess complement attack may exhibit potent stimuli that harm retinal ganglion cell somas, axons, and synapses.


Input: Identification of the cellular and molecular components of immune response pathways can provide immunomodulatory treatment strategies to attenuate neuroinflammation, protect neural tissue from collateral injury, and enhance endogenous recovery processes.


Input: This review highlights the current knowledge of molecular mechanisms regulating neuroinflammation in glaucoma.


Input: Bis (12)-hupyridone, a novel acetylcholinesterase inhibitor, protects against glutamate-induced neuronal excitotoxicity via activating alpha 7 nicotinic acetylcholine receptor/phosphoinositide 3-kinase/Akt cascade.

Bis (12)-hupyridone

glutamate

acetylcholine

phosphoinositide


Input: Bis (12)-hupyridone (B12H), derived from the Chinese medicinal component huperzine A, was originally designed as a novel acetylcholinesterase (AChE) inhibitor.

Bis (12)-hupyridone

huperzine A


Input: In this paper, we report that B12H (24-h pretreatment) effectively blocked glutamate-induced neuronal excitotoxicity in cerebellar granule neurons (CGNs).

glutamate


Input: However, the huge discrepancy between the EC50 value and IC50 value of B12H, to protect against neuronal toxicity (0. 09 mu M) and to block the NMDA receptor (21. 8 mu M) respectively, suggests that the neuroprotection of B12H might be not primarily due to the blockade of the NMDA receptor.

NMDA

NMDA


Input: Pretreatment by specific antagonists of alpha7-nicotinic acetylcholine receptor (alpha 7nAChR), but not muscarinic acetylcholine receptor (mAChR) or alpha 4 beta 2nAChR, decreased the neuroprotection of B12H.

acetylcholine

acetylcholine


Input: The neuroprotection of B12H could also be abolished by the pretreatment of specific PI3-K inhibitors.


Input: Furthermore, B12H restored the suppressed activation of the Akt pathway caused by glutamate as evidenced by the decreased expressions of pSer473-Akt and pSer9-GSK3 beta.

glutamate


Input: All these results suggest that B12H substantially protected CGNs against glutamate-induced neuronal excitotoxicity via activating alpha 7nAChR/PI3-K/Akt cascade.

glutamate


Input: Ts6 and Ts2 from Tityus serrulatus venom induce inflammation by mechanisms dependent on lipid mediators and cytokine production.


Input: Inflammatory mediators are thought to be involved in the systemic and local immune response induced by the Tityus serrulatus scorpion envenomation.


Input: New functional aspects of lipid mediators have recently been described.


Input: Here, we examine the unreported role of lipid mediators in cell recruitment to the peritoneal cavity after an injection with Ts2 or Ts6 toxins isolated from the T. serrulatus scorpion venom.


Input: In this report, we demonstrate that following a single intraperitoneal (i. p.) injection of Ts2 or Ts6 (250 mu g/kg) in mice, there was an induction of leukocytosis with a predominance of neutrophils observed at 4, 24, 48 and 96 h.


Input: Moreover, total protein, leukotriene (LT) B (4), prostaglandin (PG) E (2) and pro-inflammatory cytokine levels were increased.

leukotriene (LT) B (4)

prostaglandin (PG) E (2)


Input: We also observed an increase of regulatory cytokines, including interleukin (IL)-10, after the Ts2 injection.


Input: Finally, we observed that Ts2 or Ts6 injection in 5-lipoxygenase (LO) deficient mice and in wild type (WT) 129sv mice pre-treated with LTs and PGs inhibitors (MK-886 and celecoxib, respectively) a reduction the influx of leukocytes occurs in comparison to WT.

celecoxib


Input: The recruitment of these cells demonstrated a phenotype characteristic of neutrophils, macrophages, CD4 and CD8 lymphocytes expressing GR1 +, F4/80 +, CD3 +/CD4 + and CD3 +/CD8 +, respectively.


Input: In conclusion, our data demonstrate that Ts2 and Ts6 induce inflammation by mechanisms dependent on lipid mediators and cytokine production.


Input: Ts2 may play a regulatory role whereas Ts6 exhibits pro-inflammatory activity exclusively.


Input: Xanthohumol induces phase II enzymes via Nrf2 in human hepatocytes in vitro.

Xanthohumol


Input: The aim of this study was to investigate whether xanthohumol may exert chemoprotective activity through the modulation of the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway in immortalized normal THLE-2 hepatocytes and a hepatocellular carcinoma HepG2 cell line.

xanthohumol


Input: Cells were incubated in the presence of xanthohumol and the activation of Nrf2 and expression of genes controlled by this transcription factor were evaluated.

xanthohumol


Input: Additionally, p53 level was assessed.


Input: Xanthohumol increased the expression and led to the activation of Nrf2 in both cell lines.

Xanthohumol


Input: However, in contrast to normal cells the expression of genes controlled by this transcription factor was not affected in HepG2 cells, except for GSTA and GSTP.


Input: Xanthohumol, beside the induction of GSTs and HO-1, significantly elevated NQO1 expression in concert with p53 level in normal hepatocytes.

Xanthohumol


Input: The activation of Nrf2 pathway and subsequently phase II enzymes in concert with p53 induction in normal hepatocytes may account for the molecular mechanism of the chemopreventive activity of xanthohumol.

xanthohumol


Input: On the other hand its cytotoxicity towards HCC cells shown in this study indicates that it may also be considered as potentially chemotherapeutic.


Input: Deriving an explicit hepatic clearance equation accounting for plasma protein binding and hepatocellular uptake.


Input: High throughput in vitro biochemical and cell-based assays have the promise to provide more mechanism-based assessments of the adverse effects of large numbers of chemicals.


Input: One of the most challenging hurdles for interpreting in vitro toxicity findings is the need for reverse dosimetry tools that estimate the exposures that will give concentrations in vivo similar to the active concentrations in vitro.


Input: Recent experience using IVIVE approaches to estimate in vivo pharmacokinetics (Wetmore et al., 2012) identified the need to develop a hepatic clearance equation that explicitly accounted for a broader set of protein binding and membrane transport processes and did not depend on a well-mixed description of the liver compartment.


Input: Here we derive an explicit steady-state hepatic clearance equation that includes these factors.


Input: In addition to the derivation, we provide simple computer code to calculate steady-state extraction for any combination of blood flow, membrane transport processes and plasma protein-chemical binding rates.


Input: This expanded equation provides a tool to estimate hepatic clearance for a more diverse array of compounds.


Input: Growth differentiation factor 15 stimulates rapamycin-sensitive ovarian cancer cell growth and invasion.

rapamycin


Input: Identification of novel molecular markers and therapeutic targets may improve survival rates for patients with ovarian cancer.


Input: In the current study, immunohistochemical (IHC) analysis of two human ovarian tumor tissue arrays showed high staining for GDF15 in a majority of tissues.


Input: Exogenous stimulation of ovarian cancer cell lines with recombinant human GDF15 (rhGDF15) or stable over-expression of a GDF15 expression plasmid promoted anchorage-independent growth, increased invasion, and up-regulation of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF).


Input: MMP inhibition suppressed GDF15-mediated invasion.


Input: In addition, IHC analysis of human ovarian tumor tissue arrays indicated that GDF15 expression correlated significantly with high MMP2 and MMP9 expression.


Input: Exogenous and endogenous GDF15 over-expression stimulated phosphorylation of p38, Erk1/2, and Akt.


Input: Pharmacologic inhibition of p38, MEK, or PI3K suppressed GDF15-stimulated growth.


Input: Further, proliferation, growth, and invasion of GDF15 stable clones were blocked by rapamycin.

rapamycin


Input: IHC analysis demonstrated significant correlation between GDF15 expression and phosphorylation of mTOR.


Input: Finally, knockdown of endogenous GDF15 or neutralization of secreted GDF15 suppressed invasion and growth of a GDF15-over-expressing ovarian cancer cell line.


Input: These data indicate that GDF15 over-expression, which occurred in a majority of human ovarian cancers, promoted rapamycin-sensitive invasion and growth of ovarian cancer cells.

rapamycin


Input: Inhibition of mTOR may be an effective therapeutic strategy for ovarian cancers that over-express GDF15.


Input: Future studies should examine GDF15 as a novel molecular target for blocking ovarian cancer progression.


Input: Solid-state dependent dissolution and oral bioavailability of piroxicam in rats.

piroxicam


Input: The aim of this study was to gain understanding about the effects of different solid-state forms of a poorly water-soluble piroxicam on drug dissolution and oral bioavailability in rats.

piroxicam


Input: Three different solid-state forms of piroxicam were studied: anhydrate I (AH), monohydrate (MH), and amorphous form in solid dispersion (SD).

piroxicam


Input: In addition, the effect of a new polymeric excipient Soluplus (R) (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) on oral bioavailability of piroxicam was investigated.

Soluplus

polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer

piroxicam


Input: Significant differences in the dissolution and oral bioavailability were found between the solid-state forms of piroxicam.

piroxicam


Input: Amorphous piroxicam in SD showed the fastest dissolution in vitro and a solid-state transformation to MH in the dissolution medium.

piroxicam


Input: Despite the presence of solid-state transformation, SD exhibited the highest rate and extent of oral absorption in rats.


Input: Oral bioavailability of other two solid-state forms decreased in the order AH and MH.


Input: The use of Soluplus (R) was found to enhance the dissolution and oral bioavailability of piroxicam in rats.

Soluplus

piroxicam


Input: The present study shows the importance of solid-state form selection for oral bioavailability of a poorly water-soluble drug.


Input: Fetal muscle-type nicotinic acetylcholine receptor activation in TE-671 cells and inhibition of fetal movement in a day 40 pregnant goat model by optical isomers of the piperidine alkaloid coniine.

acetylcholine

piperidine alkaloid coniine


Input: Coniine is an optically active toxic piperidine alkaloid and nicotinic acetylcholine receptor (nAChR) agonist found in poison hemlock (Conium maculatum L.).

Coniine

piperidine alkaloid

acetylcholine


Input: Coniine teratogenicity is hypothesized to be attributable to the binding, activation, and prolonged desensitization of fetal muscle-type nAChR, which results in the complete inhibition of fetal movement.

Coniine


Input: However, pharmacological evidence of coniine actions at fetal muscle-type nAChR is lacking.

coniine


Input: The present study compared (-)-coniine, (+)-coniine, and nicotine for the ability to inhibit fetal movement in a day 40 pregnant goat model and in TE-671 cells that express fetal muscle-type nAChR.

(-)-coniine

(+)-coniine

nicotine


Input: Furthermore, alpha-conotoxins (CTx) EI and GI were used to antagonize the actions of (+)-and (-)-coniine in TE-671 cells.

(+)-and (-)-coniine


Input: (-)-Coniine was more effective at eliciting electrical changes in TE-671 cells and inhibiting fetal movement than was (+)-coniine, suggesting stereoselectivity by the receptor.

(-)-Coniine

(+)-coniine


Input: The pyridine alkaloid nicotine did not inhibit fetal movement in a day 40 pregnant goat model, suggesting agonist specificity for the inhibition of fetal movement.

pyridine alkaloid nicotine


Input: Low concentrations of both CTxs potentiated the TE-671 cell response and higher concentrations of CTx EI, and GI antagonized the actions of both coniine enantiomers demonstrating concentration-dependent coagonism and selective antagonism.

coniine


Input: These results provide pharmacological evidence that the piperidine alkaloid coniine is acting at fetal muscle-type nAChR in a concentration-dependent manner.

piperidine alkaloid coniine


Input: Review and discussion of tubular biomarkers in the diagnosis and management of diabetic nephropathy.


Input: The prevalence of diabetic nephropathy has tremendously increased with the relentless rise in the incidence of diabetes over the last couple decades.


Input: Diabetic nephropathy is a leading cause of morbidity and mortality, and it invariably leads to an end-stage renal disease (ESRD).


Input: In an effort to delay the onset of ESRD systematic screening and appropriate management are needed to evaluate the progression of renal damage in diabetic nephropathy.


Input: The reliability of current tests in predicting the onset, progression and response to various regimens for diabetic nephropathy is still under debate; and it has engendered a search for more sensitive and specific urinary biomarkers, especially those reflective of tubular dysfunctions.


Input: It is well-known that there is a good correlation between the degree of damage to the tubulo-interstitial compartment and the deterioration of renal functions.


Input: In view of this, the utility of urinary biomarkers, reflective of tubular injury, reported in the literature is discussed in this brief review.


Input: Density functional conformational study of 2-O-sulfated 3, 6 anhydro-alpha-D-galactose and of neo-kappa-and iota-carrabiose molecules in gas phase and water.

2-O-sulfated 3, 6 anhydro-alpha-D-galactose

neo-kappa-and iota-carrabiose


Input: We examined the conformational preferences of the 2-O-sulfated-3, 6-alpha-D-anhydrogalactose (compound I) and two 1, 3 linked disaccharides constituting-kappa or iota-carrageenans using density functional and ab initio methods in gas phase and aqueous solution.

2-O-sulfated-3, 6-alpha-D-anhydrogalactose

disaccharides


Input: Systematic modifications of two torsion angles leading to 324 and 144 starting geometries for the compound I and each disaccharide were used to generate adiabatic maps using B3LYP/6-31G (d).

disaccharide


Input: The lower energy conformers were then fully optimized using B3LYP, B3PW91 and MP2 with several basis sets.


Input: Overall, we discuss the impact of full relaxation on the energy and structure of the dominant conformations, present the performance comparison with previous molecular mechanics calculations if available, and determine whether our results are impacted, when polarization and diffuse functions are added to the 6-31G (d) basis set, or when the MP2 level of theory is used.


Input: Effects of silver nanoparticles on the liver and hepatocytes in vitro.

silver


Input: With the increasing use and incorporation of nanoparticles (NPs) into consumer products, screening for potential toxicity is necessary to ensure customer safety.


Input: NPs have been shown to translocate to the bloodstream following inhalation and ingestion, and such studies demonstrate that the liver is an important organ for accumulation.


Input: Silver (Ag) NPs are highly relevant for human exposure due to their use in food contact materials, dietary supplements, and antibacterial wound treatments.

Silver

Ag


Input: Due to the large number of different NPs already used in various products and being developed for new applications, it is essential that relevant, quick, and cheap methods of in vitro risk assessment suitable for these new materials are established.


Input: Therefore, this study used a simple hepatocytes model combined with an in vivo injection model to simulate the passage of a small amount of NPs into the bloodstream following exposure, e. g., via ingestion or inhalation, and examined the potential of Ag NPs of 20 nm diameter to cause toxicity, inflammation, and oxidative stress in the liver following in vivo exposures of female Wistar rats via iv injection to 50 mu g of NPs and in vitro exposures using the human hepatocyte cell line C3A.

Ag


Input: We found that Ag NPs were highly cytotoxic to hepatocytes (LC (50) lactate dehydrogenase: 2. 5 mu g/cm (2)) and affected hepatocyte homeostasis by reducing albumin release.

Ag

lactate


Input: At sublethal concentrations with normal cell or tissue morphology, Ag NPs were detected in cytoplasm and nuclei of hepatocytes.

Ag


Input: We observed similar effects of Ag NPs on inflammatory mediator expression in vitro and in vivo with increase of interleukin-8 (IL-8)/macrophage inflammatory protein 2, IL-1RI, and tumor necrosis factor-alpha expression in both models and increased IL-8 protein release in vitro.

Ag


Input: This article presents evidence of the potential toxicity and inflammogenic potential of Ag NPs in the liver following ingestion.

Ag


Input: In addition, the similarities between in vitro and in vivo responses are striking and encouraging for future reduction, refinement, and replacement of animal studies by the use of hepatocyte cell lines in particle risk assessment.


Input: Comment on real-time observation on dynamic growth/dissolution of conductive filaments in oxide-electrolyte-based ReRAM.

oxide


Input: Filament formation and dissolution in the system Ag (Cu)/ZrO (2)/Pt were observed by Liu et al.

Ag (Cu)

ZrO (2)

Pt


Input: [Adv. Mater. 2012, 24, 1844].


Input: Their explanation of the phenomena is shown here to be inappropriate.


Input: Various situations, including the " bipolar electrode " shown in the figure, are considered and the difference between the behavior in electrochemical metallization memories (ECMs) and valence change memories (VCMs) outlined.


Input: Of crucial importance for distinguishing ECM from VCM behavior, that is, the effects of cation and anion migration, is the choice of the solid materials used to transport metal cations.


Input: A possible explanation of the phenomena is proposed.


Input: Extracellular loop II modulates GTP sensitivity of the prostaglandin EP3 receptor.

GTP

prostaglandin


Input: Unlike the majority of G protein-coupled receptors, the prostaglandin E (2) (PGE (2)) E-prostanoid 3 (EP3) receptor binds agonist with high affinity that is insensitive to the presence of guanosine 5 [prime]-O-(3-thio) triphosphate (GTP gamma S).

prostaglandin E (2)

PGE (2)

E-prostanoid

guanosine 5 [prime]-O-(3-thio) triphosphate

GTP gamma S


Input: We report the identification of mutations that confer GTP gamma S sensitivity to agonist binding.

GTP gamma S


Input: Seven point mutations were introduced into the conserved motif in the second extracellular loop (ECII) of EP3, resulting in acquisition of GTP-sensitive agonist binding.

GTP


Input: One receptor mutation W203A was studied in detail.


Input: Loss of agonist binding was observed on intact human embryonic kidney 293 cells expressing the W203A receptor, conditions where high GTP levels are present; however, high affinity binding [(3) H] PGE (2) was observed in broken cell preparations washed free of GTP.

GTP

[(3) H] PGE (2)

GTP


Input: The [(3) H] PGE (2) binding of W203A in broken cell membrane fractions was inhibited by addition of GTP gamma S (IC (50) 21 +/- 1. 8 nM).

[(3) H] PGE (2)

GTP gamma S


Input: Taken together, these results suggest that the wild-type EP3 receptor displays unusual characteristics of the complex coupled equilibria between agonist-receptor and receptor-G protein interaction.


Input: Moreover, mutation of ECII can alter this coupled equilibrium from GTP-insensitive agonist binding to more conventional GTP-sensitive binding.

GTP

GTP


Input: This suggests that for the mutant receptors, ECII plays a critical role in linking the agonist bound receptor conformation to the G protein nucleotide bound state.

nucleotide


Input: Mesoscopic model parametrization of hydrogen bonds and stacking interactions of RNA from melting temperatures.

hydrogen


Input: Information about molecular interactions in DNA can be obtained from experimental melting temperature data by using mesoscopic statistical physics models.


Input: Here, we extend the technique to RNA and show that the new parameters correctly reproduce known properties such as the stronger hydrogen bonds of AU base pairs.

hydrogen


Input: We also were able to calculate a complete set of elastic constants for all 10 irreducible combinations of nearest neighbours (NNs).


Input: We believe that this is particularly useful as experimentally derived information about RNA elasticity is relatively scarce.


Input: The melting temperature prediction using the present model improves over those from traditional NN model, providing thus an alternative way to calculate these temperatures for RNA.


Input: Additionally, we calculated the site-dependent base pair oscillation to explain why RNA shows larger oscillation amplitudes despite having stronger AU hydrogen bonds.

hydrogen


Input: Carbaryl exposure and recovery modify the interrenal and thyroidal activities and the mitochondria-rich cell function in the climbing perch Anabas testudineus Bloch.

Carbaryl


Input: We examined the effects of carbaryl (1-naphthyl methylcarbamate; sevin), a carbamate pesticide, on interrenal and thyroid activities and mitochondrial rich (MR) cell function in climbing perch to understand the physiological basis of toxicity acclimation in this fish to the chemical stressor.

carbaryl

1-naphthyl methylcarbamate

sevin

carbamate


Input: Carbaryl exposure (5-20 mg L (-1)) for 48 h increased cortisol and glucose, but decreased the T (3) level without affecting T (4) concentration in the plasma.

Carbaryl

cortisol

glucose


Input: These responses of the carbaryl-exposed fish were nullified and a rise in plasma T (4) occurred in these fish when they were kept for 96 h recovery in clean water.

carbaryl


Input: A tight plasma mineral control was indicated in the carbaryl-exposed fish as reflected by the unchanged plasma Na, K, Ca and inorganic phosphate levels.

carbaryl

K

Ca

phosphate


Input: The ouabain-sensitive Na (+), K (+)-ATPase activity showed an increase in the gills but the intestinal and renal tissues showed little response to carbaryl treatment.

ouabain

Na (+)

K (+)

carbaryl


Input: However, substantial increases in the intestinal and renal Na (+), K (+)-ATPase activities occurred in the recovery fish.

Na (+)

K (+)


Input: The MR cells in the branchial epithelia showed a strong Na (+), K (+)-ATPase immunoreactivity to carbaryl treatment indicating an activated MR cell function.

Na (+)

K (+)

carbaryl


Input: The numerical MR cell density remained unchanged, but stretching of secondary gill lamellae as part of gill remodeling occurred during carbaryl exposure.

carbaryl


Input: The increased surface of these lamellae with abundant MR cells as a result of its migration into the lamellar surface points to marked structural and functional modifications of these cells in the carbaryl-treated fish which is likely to a target for carbaryl action.

carbaryl

carbaryl


Input: The rise in plasma T (4) and the restoration of normal branchial epithelia in the recovery fish indicate a thyroidal involvement in the recovery response and survival.


Input: Our data thus provide evidence that carbaryl exposure and its recovery evoke interrenal and thyroid disruption in this fish leading to a modified osmotic response including an altered MR cell function.

carbaryl


Input: Liquid crystal pump.


Input: We report a dielectrically actuated liquid crystal (LC) pump.


Input: A small volume of LC forms a pillar-like droplet in a cylindrical hole which partially touches the bottom substrate with embedded interdigitated electrodes.


Input: By applying a voltage, the LC droplet can be largely stretched along the electrode direction by the generated dielectric force, which in turn exerts a pressure to displace a small volume of fluid on the opposite side of the chamber.


Input: Once the voltage is removed, the LC droplet returns to its initial state.


Input: The LC droplet with such a reciprocating movement behaves like a pump.


Input: In this work, the actuation mechanism of the LC pump is presented and the performance evaluated experimentally.


Input: Our LC pump has the following advantages: simple structure, easy fabrication, compact size, high precision, low power consumption, and relatively fast response time.


Input: It is promising for applications in lens actuators, biotechnology, drug delivery, and other lab-on-a-chip devices.


Input: Costs of living in metal polluted areas: respiration rate of the ground beetle Pterostichus oblongopunctatus from two gradients of metal pollution.


Input: To address the question about costs of living in polluted areas, biomarkers linked to metabolism were measured in Pterostichus oblongopunctatus (Coleoptera: Carabidae) collected along two metal-pollution gradients in the vicinity of the two largest Polish zinc smelters:' Boles l aw' and' Miasteczko S l a skie' in southern Poland.

zinc


Input: Both gradients covered a broad range of Zn and Cd concentrations in the humus layer (109-6151 and 1. 48-71. 4 mg kg (-1), respectively) and body metal concentrations increased with increasing soil metal concentrations.

Zn

Cd


Input: The whole-organism respiration rate was measured as oxygen consumption with Micro-Oxymax respirometer, and cellular energy consumption-as the activity of electron transport system, which is linked to cellular respiration rate.

oxygen


Input: The significant increase in the whole-organism respiration rate with the body metal concentration was found when taking into account other factors such as body mass, gradient (or year of sampling as the beetles were collected on the gradients in different years) and the interactions: body metal concentrations x collection date, body metal concentrations x body mass, and body mass x gradient/sampling year.


Input: However, no relationships between metal concentrations in soil or body metal concentrations and the whole-organism or cellular respiration rate could be detected when using mean values per site, underlining the crucial importance of incorporating individual variability in such analyses.


Input: The observed increase of the whole-organism respiration rate with increasing body contamination with metals suggests that P. oblongopunctatus incurs energetic expenditures resulting from the necessity to facilitate metal elimination or repair of toxicant-induced damage.


Input: Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation.

linaclotide


Input: Linaclotide, a potent guanylate cyclase C agonist, is a therapeutic peptide approved in the United States for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation.

Linaclotide

guanylate


Input: We present for the first time the metabolism, degradation, and disposition of linaclotide in animals and humans.

linaclotide


Input: We examined the metabolic stability of linaclotide in conditions that mimic the gastrointestinal tract and characterized the metabolite MM-419447 (CCEYCCNPACTGC), which contributes to the pharmacologic effects of linaclotide.

linaclotide

linaclotide


Input: Systemic exposure to these active peptides is low in rats and humans, and the low systemic and portal vein concentrations of linaclotide and MM-419447 observed in the rat confirmed both peptides are minimally absorbed after oral administration.

linaclotide


Input: Linaclotide is stable in the acidic environment of the stomach and is converted to MM-419447 in the small intestine.

Linaclotide


Input: The disulfide bonds of both peptides are reduced in the small intestine, where they are subsequently proteolyzed and degraded.

disulfide


Input: After oral administration of linaclotide, < 1% of the dose was excreted as active peptide in rat feces and a mean of 3-5% in human feces; in both cases MM-419447 was the predominant peptide recovered.

linaclotide


Input: MM-419447 exhibits high-affinity binding in vitro to T84 cells, resulting in a significant, concentration-dependent accumulation of intracellular cyclic guanosine-3', 5'-monophosphate (cGMP).

cyclic guanosine-3', 5'-monophosphate

cGMP


Input: In rat models of gastrointestinal function, orally dosed MM-419447 significantly increased fluid secretion into small intestinal loops, increased intraluminal cGMP, and caused a dose-dependent acceleration in gastrointestinal transit.

cGMP


Input: These results demonstrate the importance of the active metabolite in contributing to linaclotide' s pharmacology.

linaclotide


Input: Lanthanum (III) regulates the nitrogen assimilation in soybean seedlings under ultraviolet-B radiation.

Lanthanum (III)

nitrogen


Input: Ultraviolet-B (UV-B, 280-320 nm) radiation has seriously affected the growth of plants.


Input: Finding the technology/method to alleviate the damage of UV-B radiation has become a frontal topic in the field of environmental science.


Input: The pretreatment with rare earth elements (REEs) is an effective method, but the regulation mechanism of REEs is unknown.


Input: Here, the regulation effects of lanthanum (La (III)) on nitrogen assimilation in soybean seedlings (Glycine max L.) under ultraviolet-B radiation were investigated to elucidate the regulation mechanism of REEs on plants under UV-B radiation.

lanthanum

La (III)

nitrogen


Input: UV-B radiation led to the inhibition in the activities of the key enzymes (nitrate reductase, glutamine synthetase, glutamate synthase) in the nitrogen assimilation, the decrease in the contents of nitrate and soluble proteins, as well as the increase in the content of amino acid in soybean seedlings.

nitrate

glutamine

glutamate

nitrogen

nitrate

amino acid


Input: The change degree of UV-B radiation at the high level (0. 45 W m (-2)) was higher than that of UV-B radiation at the low level (0. 15 W m (-2)).


Input: The pretreatment with 20 mg L (-1) La (III) could alleviate the effects of UV-B radiation on the activities of nitrate reductase, glutamine synthetase, glutamate synthase, and glutamate dehydrogenase, promoting amino acid conversion and protein synthesis in soybean seedlings.

La (III)

nitrate

glutamine

glutamate

glutamate

amino acid


Input: The regulation effect of La (III) under UV-B radiation at the low level was better than that of UV-B radiation at the high level.

La (III)


Input: The results indicated that the pretreatment with 20 mg L (-1) La (III) could alleviate the inhibition of UV-B radiation on nitrogen assimilation in soybean seedlings.

La (III)

nitrogen


Input: Neutrophil and eosinophil granulocytes as key players in a mouse model of chemical-induced asthma.


Input: Diisocyanates are an important cause of chemical-induced occupational asthma.

Diisocyanates


Input: This type of immunologically mediated asthma is often characterized by a predominant granulocytic inflammation in the airways, rather than an infiltration by lymphocytes.


Input: We sought to determine the contribution of granulocytes in the outcome of chemical-induced asthma using general and specific leukocyte depletion strategies in an established mouse model of isocyanate asthma.

isocyanate


Input: On days 1 and 8, BALB/c mice received dermal applications with toluene-2, 4-diisocyanate (TDI) or vehicle (acetone olive oil), followed by two ip injections of cyclophosphamide (CP, days 11 and 13), or one iv injection of antigranulocyte receptor 1 (aGR1, day 13) monoclonal antibody (mAb), or two ip injections of Ly6G-specific mAb (1A8, days 13 and 14).

toluene-2, 4-diisocyanate

TDI

acetone

cyclophosphamide


Input: On day 15, the mice were challenged (oropharyngeal administration) with TDI or vehicle.

TDI


Input: The next day, we assessed methacholine airway hyperreactivity (AHR); bronchoalveolar lavage differential cell count; histopathology and total serum IgE; and auricular lymphocyte subpopulations and release of interleukin (IL)-2, IL-4, IL-10, IL-13, and gamma interferon by these lymphocytes.

methacholine


Input: CP depleted all leukocyte types and completely prevented AHR and airway inflammation.


Input: aGR1 depleted granulocytes and CD8 (+) lymphocytes, which resulted in a partial prevention in AHR but no decrease in airway inflammation.


Input: Depletion of Ly6G-positive granulocytes, i. e., both neutrophils and eosinophils, prevented AHR and lung epithelial damage and significantly reduced airway inflammation.


Input: Injection of aGR1 or 1A8 led to significantly changed cytokine release patterns in TDI-treated mice.

TDI


Input: Granulocytes, both neutrophils and eosinophils, are key cellular players in this model of chemical-induced asthma.


Input: Thermosensitive polymeric hydrogels as drug delivery systems.


Input: Thermosensitive hydrogels are very important biomaterials used in drug delivery systems (DDSs), which gained increasing attention of researchers.


Input: Thermosensitive hydrogels have great potential in various applications, such as drug delivery, cell encapsulation, tissue engineering, and etc.


Input: Especially, injectable thermosensitive hydrogels with lower sol-gel transition temperature around physiological temperature have been extensively studied.


Input: By in vivo injection, the hydrogels formed non-flowing gel at body temperature.


Input: Upon incorporation of pharmaceutical agents, the hydrogel systems could act as sustained drug release depot in situ.


Input: Injectable thermosensitive hydrogel systems have a number of advantages, including simplicity of drug formulation, protective environment for drugs, prolonged and localized drug delivery, and ease of application.


Input: The objective of this review is to summarize fundamentals, applications, and recent advances of injectable thermosensitive hydrogel as DDSs, including chitosan and related derivatives, poly (N-isopropylacrylamide)-based (PNIPAAM) copolymers, poly (ethylene oxide)/poly (propylene oxide) (PEO/PPO) copolymers and its derivatives, and poly (ethylene glycol)/biodegradable polyester copolymers.

poly (N-isopropylacrylamide)

PNIPAAM

poly (ethylene oxide)

poly (propylene oxide)

PEO

PPO

poly (ethylene glycol)

polyester


Input: New insights in the pathogenesis and treatment of normal tension glaucoma.


Input: Increased intraocular pressure (IOP) is a major risk factor for glaucomatous damage and reducing IOP improves prognosis.


Input: Nevertheless, there is little doubt that other risk factors besides IOP such as unstable ocular perfusion are involved.


Input: Blood flow is unstable if either the IOP fluctuates at a high level (or blood pressure fluctuates at a low level) or if the autoregulation of blood flow disturbed.


Input: A common cause for a disturbed OBF autoregulation is a primary vascular dysregulation (PVD) frequently observed in normal tension glaucoma patients.


Input: An unstable blood flow leads to recurrent mild reperfusion injury (chronic oxidative stress) affecting particularly the mitochondria of the optic nerve head.


Input: OBF regulation can be improved by magnesium, calcium channel blockers as well as with carbonic anhydrase inhibitors.

magnesium

calcium


Input: Upregulation of phagocyte-like NADPH oxidase by cytokines in pancreatic beta-cells: attenuation of oxidative and nitrosative stress by 2-bromopalmitate.

NADPH


Input: Phagocyte-like NADPH oxidase (Nox2) has been shown to play regulatory roles in the metabolic dysfunction of the islet beta-cell under the duress of glucolipotoxic conditions and exposure to proinflammatory cytokines.

NADPH


Input: However, the precise mechanisms underlying Nox2 activation by these stimuli remain less understood.


Input: To this end, we report a time-dependent phosphorylation of p47phox, a cytosolic subunit of Nox2, by cytomix (IL-1 beta + TNF alpha + IFN gamma) in insulin-secreting INS-1 832/13 cells.


Input: Furthermore, cytomix induced the expression of gp91phox, a membrane component of Nox2.


Input: 2-Bromopalmitate (2-BP), a known inhibitor of protein palmitoylation, markedly attenuated cytokine-induced, Nox2-mediated reactive oxygen species (ROS) generation and inducible nitric oxide synthase (iNOS)-mediated nitric oxide (NO) generation.

oxygen

nitric oxide

nitric oxide

NO


Input: However, 2-BP failed to exert any significant effects on cytomix-induced CHOP expression, a marker for endoplasmic reticulum stress.


Input: Together, our findings identify palmitoyltransferase as a target for inhibition of cytomix-induced oxidative (ROS generation) and nitrosative (NO generation) stress in the pancreatic beta-cell.

NO


Input: mTOR inhibition modulates epileptogenesis, seizures and depressive behavior in a genetic rat model of absence epilepsy.


Input: Several signaling pathways are believed to be involved in the epileptogenic process that triggers the subsequent changes in the brain causing epilepsy.


Input: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that in the brain, regulates several important physiological functions such as neuronal development and synaptic plasticity, and also seems to be involved in many pathologies, including epilepsy and psychiatric disorders.

rapamycin

serine

threonine


Input: Previous work in animal models of both genetic and acquired generalized convulsive epilepsies, has suggested that modulators of the mTOR signaling pathway may have beneficial neuroprotective and antiepileptogenic effects.


Input: Here, we investigated for the first time, the effect of some treatment schedules (i. e. early chronic, sub-chronic and acute) with the specific mTOR inhibitor rapamycin, on the development of absence seizures and seizure parameters as well as depressive-like behavior in WAG/Rij rats, a genetic model of absence epilepsy, epileptogenesis and mild-depression comorbidity.

rapamycin


Input: In addition, we studied the possible interaction between rapamycin treatment and the effects of bacterial lipopolysaccharide (LPS) endotoxin administration, which is known to aggravate absence seizures through generation of increased neuroinflammatory responses.

rapamycin


Input: We found that rapamycin (early chronic treatment for 17 weeks, starting at P45) exhibited clear antiepileptogenic properties also in this animal epilepsy model; however, this effect was accompanied by unexpected prodepressant effects.

rapamycin


Input: Both acute and sub-chronic (7 day) treatments also had anti-absence properties, but the sub-chronic treatment produced contrasting antidepressant properties in the WAG/Rij rats that were not seen in control Wistar rats.


Input: The rapamycin/LPS co-administration studies showed that rapamycin blocked or prevented the LPS-dependent increase in absence seizures, suggesting an anti-inflammatory-like protective action.

rapamycin

rapamycin


Input: In conclusion, we have demonstrated a novel antiepileptogenic effect of rapamycin in a well-established animal model of absence epilepsy, and we suggest that this effect may be mediated by the inhibition of inflammatory processes that are developed in the brain of these specific animals during epileptogenesis and during seizures.

rapamycin


Input: Our experiments here suggest new insights into this intriguing field, which deserves to be further explored.


Input: This article is part of the Special Issue entitled' New Targets and Approaches to the Treatment of Epilepsy'.


Input: The pyridyl group in ligand design for selective metal ion complexation and sensing.

pyridyl


Input: Factors in polypyridyl ligands that control their thermodynamic metal ion selectivity in aqueous solution, and their use in selective fluorescent sensing, are examined.

polypyridyl


Input: Preorganization of polypyridyl ligands ranging from bidentate to tetradentate by bridging benzo groups, as are present in 1, 10-phenanthroline (phen) compared to 2, 2'-bipyridyl (bpy), is discussed.

polypyridyl

benzo

1, 10-phenanthroline

phen

2, 2'-bipyridyl

bpy


Input: The role of solvation is considered in relation to the relative affinity of ligands containing pyridyl groups for divalent and trivalent metal ions in aqueous solution.

pyridyl


Input: The effects of steric clashes between H atoms on polypyridyl ligands in decreasing complex stability are evaluated, as well as the effect of chelate ring size on metal ion selectivity.

H

polypyridyl


Input: Phen ligands with other donor groups present at the 2 and 9 positions, such as alcohols, amides, carboxylates, and oximes are discussed.

Phen

alcohols

amides

carboxylates

oximes


Input: The design of pyridyl-based ligands for the separation of Am (III) from lanthanide (III) ions is considered, as well as ligands for the removal of metal ions such as Cu (II) or Zn (II) in neurological diseases such as Alzheimer' s.

pyridyl

Am (III)

lanthanide (III)

Cu (II)

Zn (II)


Input: The design of pyridyl-based fluorescent sensors for selective sensing of metal ions is examined in terms of the role of spin-orbit coupling constants (zeta), paramagnetism, and steric effects in the development of selective fluorescent sensors that operate via chelation enhanced fluorescence (CHEF).

pyridyl


Input: It is concluded that for lighter metal ions with smaller zeta values such as Zn (II) and Ca (II), and to a lesser extent Cd (II), that the CHEF effect can be achieved with pyridyl-containing fluorophores that coordinate directly to the metal ion.

Zn (II)

Ca (II)

Cd (II)

pyridyl


Input: The way in which steric effects can be used to decrease the CHEF effect in Zn (II) relative to Cd (II) to enable selective sensing of the latter is analyzed.

Zn (II)

Cd (II)


Input: For heavier metal ions such as Hg (II) and Pb (II), because of their large zeta values which quench fluorescence, it is concluded that the fluorophore should be tethered to the metal-binding part of the sensor, and prevented from binding to the metal ion by steric and electronic factors.

Hg (II)

Pb (II)


Input: How Hg (II) can quench the CHEF effect by pi-contact with fluorophores such as the anthracenyl group, which at first sight might not seem able to bond with metal ions, is examined.

Hg (II)

anthracenyl


Input: Positive selection within a diatom species acts on putative protein interactions and transcriptional regulation.


Input: Diatoms are the most species-rich group of microalgae, and their contribution to marine primary production is important on a global scale.


Input: Diatoms can form dense blooms through rapid asexual reproduction; mutations acquired and propagated during blooms likely provide the genetic, and thus phenotypic, variability upon which natural selection may act.


Input: Positive selection was tested using genome and transcriptome-wide pair-wise comparisons of homologs in three genera of diatoms (Pseudo-nitzschia, Ditylum, and Thalassiosira) that represent decreasing phylogenetic distances.


Input: The signal of positive selection was greatest between two strains of Thalassiosira pseudonana.


Input: Further testing among seven strains of T. pseudonana yielded 809 candidate genes of positive selection, which are 7% of the protein-coding genes.


Input: Orphan genes and genes encoding protein-binding domains and transcriptional regulators were enriched within the set of positively selected genes relative to the genome as a whole.


Input: Positively selected genes were linked to the potential selective pressures of nutrient limitation and sea surface temperature based on analysis of gene expression profiles and identification of positively selected genes in subsets of strains from locations with similar environmental conditions.


Input: The identification of positively selected genes presents an opportunity to test new hypotheses in natural populations and the laboratory that integrate selected genotypes in T. pseudonana with their associated phenotypes and selective forces.


Input: Negative regulation of inflammation by SIRT1.


Input: Sirtuin 1 (SIRT1), the mammalian Sir2 homologue, is a class III histone deacetylase shown to act on a wide range of histones and non-histone substrates.


Input: Numerous studies have demonstrated that SIRT1 regulates critical metabolic and physiological processes including senescence, stress resistance, metabolism and apoptosis.


Input: Recently, SIRT1 was also found to play an important role in modulating the development and progression of inflammation through deacetylating histones and critical transcription factor such as nuclear factor kappa B (NF-kappa B) and activator protein 1 (AP-1), thus leading to transcriptional repression of various inflammation-related genes.


Input: There is increasing evidence that reduction of SIRT1 levels is closely correlated with many inflammatory diseases while pharmacologic activation of SIRT1 would be a promising therapeutic strategy for inflammation-related diseases.


Input: Four disruptive strategies for removing drug discovery bottlenecks.


Input: Drug discovery is shifting focus from industry to outside partners and, in the process, creating new bottlenecks.


Input: Technologies like high throughput screening (HTS) have moved to a larger number of academic and institutional laboratories in the USA, with little coordination or consideration of the outputs and creating a translational gap.


Input: Although there have been collaborative public-private partnerships in Europe to share pharmaceutical data, the USA has seemingly lagged behind and this may hold it back.


Input: Sharing precompetitive data and models may accelerate discovery across the board, while finding the best collaborators, mining social media and mobile approaches to open drug discovery should be evaluated in our efforts to remove drug discovery bottlenecks.


Input: We describe four strategies to rectify the current unsustainable situation.


Input: Converging levels of analysis on a genomic hotspot for psychosis: insights from 22q11. 2 deletion syndrome.


Input: Schizophrenia is a devastating neurodevelopmental disorder that, despite extensive research, still poses a considerable challenge to attempts to unravel its heterogeneity, and the complex biochemical mechanisms by which it arises.


Input: While the majority of cases are of unknown etiology, accumulating evidence suggests that rare genetic mutations, such as 22q11. 2 Deletion Syndrome (22qDS), can play a significant role in predisposition to the illness.


Input: Up to 25% of individuals with 22qDS eventually develop schizophrenia; conversely, this deletion is estimated to account for 1-2% of schizophrenia cases overall.


Input: This locus of Chromosome 22q11. 2 contains genes that encode for proteins and enzymes involved in regulating neurotransmission, neuronal development, myelination, microRNA processing, and post-translational protein modifications.


Input: As a consequence of the deletion, affected individuals exhibit cognitive dysfunction, structural and functional brain abnormalities, and neurodevelopmental anomalies that parallel many of the phenotypic characteristics of schizophrenia.


Input: As an illustration of the value of rare, highly penetrant genetic subtypes for elucidating pathological mechanisms of complex neuropsychiatric disorders, we provide here an overview of the cellular, network, and systems-level anomalies found in 22qDS, and review the intriguing evidence for this disorder' s association with schizophrenia.


Input: This article is part of the Special Issue entitled' Neurodevelopmental Disorders'.


Input: Pharmacokinetic study of Growth Hormone-Releasing Peptide 6 (GHRP-6) in nine male healthy volunteers.

Growth Hormone-Releasing Peptide 6


Input: GHRP-6 is a growth hormone secretagogue that also enhances tissue viability in different organs.


Input: In the present work, we studied the pharmacokinetics of this short therapeutic hexapeptide (His-(D-Trp)-Ala-Trp-(D-Phe)-Lys-NH (2,) MW = 872. 44 Da) in nine male healthy volunteers after a single intravenous bolus administration of 100, 200 and 400 mu g/kg of body weight.

His-(D-Trp)-Ala-Trp-(D-Phe)-Lys-NH (2,)


Input: GHRP-6 was quantified in human plasma by a specific LC-MS method, previously developed and validated following FDA guidelines, using (13) C (3) Ala-GHRP-6 as internal standard (Gil et al., 2012, J. Pharm. Biomed. Anal. 60, 19-25).

(13) C (3) Ala-GHRP-6


Input: The Lower Limit of Quantification (5 ng/mL) was reached in all subjects at 12h post-administration, which was sufficient for modeling a pharmacokinetic profile including over 85% of the Area under the Curve (AUC).


Input: Disposition of GHRP-6 best fitted a bi-exponential function with R (2) higher than 0. 99, according to a mathematic modeling and confirmed by an Akaike index (AIC) lower than that of the corresponding one-compartment model for all subjects.


Input: Averaging all three dose levels, the distribution and elimination half-life of GHRP-6 were 7. 6 +/- 1. 9 min and 2. 5 +/- 1. 1h, respectively.


Input: These values are coherent with existing data for other drugs whose disposition also fits this model.


Input: Dose dependence analysis revealed a noticeable trend for AUC to increase proportionally with administered dose.


Input: Atypical GHRP-6 concentration spikes were observed during the elimination phase in four out of the nine subjects studied.


Input: Apoptosis initiation of beta-ionone in SGC-7901 gastric carcinoma cancer cells via a PI3K-AKT pathway.

beta-ionone


Input: beta-ionone has been shown to hold potent anti-proliferative and apoptosis induction properties in vitro and in vivo.

beta-ionone


Input: To investigate the effects of beta-ionone on apoptosis initiation and its possible mechanisms of action, we qualified cell apoptosis, proteins related to apoptosis and a phosphatidylinositol 3-kinase (PI3K)-AKT pathway in human gastric adenocarcinoma cancer SGC-7901 cells.

beta-ionone

phosphatidylinositol


Input: The results demonstrated that beta-ionone-induced apoptosis in a dose-dependent manner in SGC-7901 cells treated with beta-ionone (25, 50, 100 and 200 mu mol/L) for 24 h.

beta-ionone

beta-ionone


Input: beta-ionone was also shown to induce the expression of cleaved-caspase-3 and inhibit bcl-2 expression in SGC-7901 cells in a dose-dependent manner.

beta-ionone


Input: The significantly decreased levels of p-PI3K and p-AKT expression were observed in SGC-7901 cells after beta-ionone treatments in a time-and dose-dependent manner (P < 0. 01).

beta-ionone


Input: Thus, the apoptosis induction in SGC-7901 cells by beta-ionone may be regulated through a PI3K-AKT pathway.

beta-ionone


Input: These results demonstrate a potential mechanism by which beta-ionone to induce apoptosis initiation in SGC-7901 cells.

beta-ionone


Input: Enhanced carcinogenicity by coexposure to arsenic and iron and a novel remediation system for the elements in well drinking water.

arsenic

iron


Input: Various carcinomas including skin cancer are explosively increasing in arsenicosis patients who drink arsenic-polluted well water, especially in Bangladesh.

arsenicosis


Input: Although well drinking water in the cancer-prone areas contains various elements, very little is known about the effects of elements except arsenic on carcinogenicity.

arsenic


Input: In order to clarify the carcinogenic effects of coexposure to arsenic and iron, anchorage-independent growth and invasion in human untransformed HaCaT and transformed A431 keratinocytes were examined.

arsenic

iron


Input: Since the mean ratio of arsenic and iron in well water was 1: 10 in cancer-prone areas of Bangladesh, effects of 1 mu M arsenic and 10 mu M iron were investigated.

arsenic

iron

arsenic

iron


Input: Iron synergistically promoted arsenic-mediated anchorage-independent growth in untransformed and transformed keratinocytes.

Iron

arsenic


Input: Iron additionally increased invasion in both types of keratinocytes.

Iron


Input: Activities of c-SRC and ERK that regulate anchorage-independent growth and invasion were synergistically enhanced in both types of keratinocytes.


Input: Our results suggest that iron promotes arsenic-mediated transformation of untransformed keratinocytes and progression of transformed keratinocytes.

iron

arsenic


Input: We then developed a low-cost and high-performance adsorbent composed of a hydrotalcite-like compound for arsenic and iron.

hydrotalcite

arsenic

iron


Input: The adsorbent rapidly reduced concentrations of both elements from well drinking water in cancer-prone areas of Bangladesh to levels less than those in WHO health-based guidelines for drinking water.


Input: Thus, we not only demonstrated for the first time increased carcinogenicity by coexposure to arsenic and iron but also proposed a novel remediation system for well drinking water.

arsenic

iron


Input: The effect of oxygen heteroatoms on the single molecule conductance of saturated chains.

oxygen


Input: Single molecule conductance measurements on alkanedithiols and alkoxydithiols (dithiolated oligoethers) were performed using the STM-controlled break junction method in order to ascertain how the oxygen heteroatoms in saturated linear chains impact the molecular conductance.

alkanedithiols

alkoxydithiols

dithiolated oligoethers

oxygen


Input: The experimental results show that the difference in conductance increases with chain length, over the range studied.


Input: Comparisons with electronic structure calculations and previous work on alkanes indicate that the conductance of the oligoethers is lower than that of alkane chains with the same length.

alkanes

oligoethers

alkane


Input: Electronic structure calculations allow the difference in the conductance of these two families of molecules to be traced to differences in the spatial distribution of the molecular orbitals that contribute most to the conductance.


Input: A pathway analysis of the electronic coupling through the chain is used to explain how the difference in conductance between the alkane and oligoether molecules depends on the chain length.

alkane


Input: Efficacy of asiatic acid, a pentacyclic triterpene on attenuating the key enzymes activities of carbohydrate metabolism in streptozotocin-induced diabetic rats.

asiatic acid

pentacyclic triterpene

carbohydrate

streptozotocin


Input: Asiatic acid (AA), a triterpenoid derivative of Centella asiatica, has shown significant biological effects of antioxidant and anti-inflammatory activities.

Asiatic acid

triterpenoid


Input: Aim of this investigation was to evaluate the antihyperglycemic effect of AA on the activities of hepatic enzymes of carbohydrate metabolism in streptozotocin (STZ)-induced diabetic rats.

carbohydrate

streptozotocin

STZ


Input: To induce diabetes mellitus, rats were injected with streptozotocin intraperitoneally at a single dose of 40 mg/kg b. w.

streptozotocin


Input: Diabetic rats showed significant (p < 0. 05) increased in plasma glucose, glycosylated hemoglobin and significant (p < 0. 05) decreased in circulating insulin and hemoglobin.

glucose


Input: The altered activities of key enzymes such as glucose-6-phosphatase and fructose-1, 6-bisphosphatase of carbohydrate metabolism significantly (p < 0. 05) increased whereas hexokinase, pyruvate kinase, glucose-6-phosphate dehydrogenase and glycogen content significantly (p < 0. 05) decreased in the liver of diabetic rats and also increased activities of aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP).

glucose

fructose

carbohydrate

pyruvate

aspartate

alanine


Input: Oral administration of AA (5, 10 and 20 mg/kg b. w.) and glibenclamide (600 mu g/kg b. w.) to diabetic rats for 45 days prevented the above alteration and reverted to near normalcy.

glibenclamide


Input: Protection of body weight loss of diabetic rats by AA was also observed.


Input: No significant effect was observed in normal rats treated with AA (20 mg/kg b. w.).


Input: In this search, AA found to be potential bioactive compound to regulate the carbohydrate metabolism by modulating the key regulatory enzymes in diabetic rats.

carbohydrate


Input: These findings merit further research in this field.


Input: Mancozeb-induced behavioral deficits precede structural neural degeneration.

Mancozeb


Input: Manganese-containing fungicides like Mancozeb have been associated with neurodegenerative conditions like Parkinson' s disease.

Manganese

Mancozeb


Input: We examined the behavioral damage and differential neuronal vulnerability resulting from Mancozeb exposure using Caenorhabditis elegans, an important mid-trophic level soil organism that is also a powerful model for studying mechanisms of environmental pollutant-induced neurodegenerative disease.

Mancozeb


Input: The dopamine-mediated swim to crawl locomotory transition behavior is exquisitely vulnerable to Mancozeb, with functional impairment preceding markers of neuronal structural damage.

dopamine

Mancozeb


Input: The damage is partially rescued in mutants lacking the divalent metal transporter, SMF-1, demonstrating that some, but not all, of the damage is mediated by manganese.

manganese


Input: Increasing concentrations of Mancozeb recruit additional behavioral dysfunction, notably serotonin-mediated egg-laying behavior, but without evident serotonergic neuronal structural damage.

Mancozeb

serotonin


Input: Thus, measurements of behavioral dysfunction are a sensitive early marker of fungicide toxicity that could be exploited to examine further mechanisms of neuron damage and possible therapeutic interventions.


Input: These results also provide important insight into the consequences of fungicide use on the ecological behavior of nematodes.


Input: In vitro metabolism, permeation, and brain availability of six major boswellic acids from Boswellia serrata gum resins.

boswellic acids


Input: Boswellia serrata gum resin extracts (BSE) revealed potent anti-inflammatory actions in preclinical and clinical studies.


Input: In 2002 BSE was assigned an orphan drug status by the European Medicines Agency (EMA) for the treatment of peritumoral edema.


Input: In the past pharmacological effects of BSE were mainly attributed to 11-keto-beta-boswellic acid (KBA) and 3-acetyl-11-keto-beta-boswellic acid (AKBA).

11-keto-beta-boswellic acid

KBA

3-acetyl-11-keto-beta-boswellic acid

AKBA


Input: Therefore pharmacokinetic and pharmacodynamic studies focused mainly on these two boswellic acids (BAs).

boswellic acids


Input: However, other BAs, like beta-boswellic acid (beta BA), might also contribute to the anti-inflammatory actions of BSE.

beta-boswellic acid

beta BA


Input: Here, we determined the metabolic stability, permeability and brain availability of six major BAs, that is, KBA, AKBA, beta BA, 3-acetyl-beta-boswellic acid (A beta BA), alpha-boswellic acid (alpha BA), and 3-acetyl-alpha-boswellic acid (A alpha BA).

KBA

AKBA

beta BA

3-acetyl-beta-boswellic acid

A beta BA

alpha-boswellic acid

alpha BA

3-acetyl-alpha-boswellic acid

A alpha BA


Input: For permeability studies, the Caco-2 model was adapted to physiological conditions by the addition of bovine serum albumin (BSA) to the basolateral side and the use of modified fasted state simulated intestinal fluid (FaSSIF) on the apical side.


Input: Under these conditions the four BAs lacking the 11-keto moiety revealed moderate permeability.


Input: Furthermore the permeability of AKBA and KBA was improved compared to earlier studies.

AKBA

KBA


Input: In contrast to A alpha-and A beta BA, beta BA and alpha BA were intensively metabolized after incubation with human and rat liver microsomes.

A alpha-and A beta BA

beta BA

alpha BA


Input: Finally, the availability of all six major BAs could be confirmed in rat brain 8h after oral administration of 240mg/kg BSE to rats showing mean concentrations of 11. 6ng/g for KBA, 37. 5ng/g for AKBA, 485. 1ng/g for alpha BA, 1066. 6ng/g for beta BA, 43. 0ng/g for A alpha BA and 163. 7ng/g for A beta BA.

KBA

AKBA

alpha BA

beta BA

A alpha BA

A beta BA


Input: Possible ways of fagopyrin biosynthesis and production in buckwheat plants.

fagopyrin


Input: The present work extends knowledge about possible biosynthesis of fagopyrin in buckwheat plants by providing possible candidate genes for its biosynthesis and the role of type III polyketide synthases (PKSs).

fagopyrin


Input: Moreover, new information is presented about the possible connection between naphthodianthrones and phenolic biosynthesis.

naphthodianthrones

phenolic


Input: Possible regulation of fagopyrin biosynthesis and production under different growth conditions is also discussed.

fagopyrin


Input: Adolescent male rats are less sensitive than adults to the anxiogenic and serotonin-releasing effects of fenfluramine.

serotonin

fenfluramine


Input: Risk taking behavior increases during adolescence, which is also a critical period for the onset of drug abuse.


Input: The central serotonergic system matures during the adolescent period, and its immaturity during early adolescence may contribute to adolescent risk taking, as deficits in central serotonergic function have been associated with impulsivity, aggression, and risk taking.


Input: We investigated serotonergic modulation of behavior and presynaptic serotonergic function in adult (67-74 days old) and adolescent (28-34 days old) male rats.


Input: Fenfluramine (2 mg/kg, i. p.) produced greater anxiogenic effects in adult rats in both the light/dark and elevated plus maze tests for anxiety-like behavior, and stimulated greater increases in extracellular serotonin in the adult medial prefrontal cortex (mPFC) (1, 2. 5, and 10 mg/kg, i. p.).

Fenfluramine

serotonin


Input: Local infusion of 100 mM potassium chloride into the mPFC also stimulated greater serotonin efflux in adult rats.

potassium chloride

serotonin


Input: Adult rats had higher tissue serotonin content than adolescents in the prefrontal cortex, amygdala, and hippocampus, but the rate of serotonin synthesis was similar between age groups.

serotonin

serotonin


Input: Serotonin transporter (SERT) immunoreactivity and SERT radioligand binding were comparable between age groups in all three brain regions.

Serotonin


Input: These data suggest that lower tissue serotonin stores in adolescents limit fenfluramine-stimulated serotonin release and so contribute to the lesser anxiogenic effects of fenfluramine.

serotonin

fenfluramine

serotonin

fenfluramine


Input: Arsenic trioxide-induced hERG K (+) channel deficiency can be rescued by matrine and oxymatrine through up-regulating transcription factor Sp1 expression.

Arsenic trioxide

K (+)

matrine

oxymatrine


Input: The human ether-a-go-go-related gene (hERG) encodes the rapidly activating, delayed rectifier potassium channel (IKr) important for cardiac repolarization.

ether

potassium


Input: Dysfunction of the hERG channel can cause Long QT Syndrome (LQTS).


Input: A wide variety of structurally diverse therapeutic compounds reduce the hERG current by acute direct inhibition of the hERG current or/and selective disruption of hERG protein expression.


Input: Arsenic trioxide (As (2) O (3)), which is used to treat acute promyelocytic leukemia, can cause LQTS type 2 (LQT2) by reducing the hERG current through the diversion of hERG trafficking to the cytoplasmic membrane.

Arsenic trioxide

As (2) O (3)


Input: This cardiotoxicity limits its clinical applications.


Input: Our aim was to develop cardioprotective agents to decrease As (2) O (3)-induced cardiotoxicity.

As (2) O (3)


Input: We reported that superfusion of hERG-expressing HEK293 (hERG-HEK) cells with matrine (1, 10 mu M) increased the hERG current by promoting hERG channel activation.

matrine


Input: Long-term treatment with 1 mu M matrine or oxymatrine increased expression of the hERG protein and rescued the hERG surface expression disrupted by As (2) O (3).

matrine

oxymatrine

As (2) O (3)


Input: In addition, Matrine and oxymatrine significantly shortened action potential duration prolonged by As (2) O (3) in guinea pig ventricular myocytes.

Matrine

oxymatrine

As (2) O (3)


Input: These results were ascribed to the up-regulation of hERG at both mRNA and protein levels via an increase in the expression of transcription factor Sp1, an established transactivator of the hERG gene.


Input: Therefore, matrine and oxymatrine may have the potential to cure LQT2 as a potassium channel activator by promoting hERG channel activation and increasing hERG channel expression.

matrine

oxymatrine

potassium


Input: TNF-alpha-mediated NF-kappa B survival signaling impairment by cisplatin enhances JNK activation allowing synergistic apoptosis of renal proximal tubular cells.

cisplatin


Input: Cisplatin-induced nephrotoxicity is an important limiting factor for cisplatin use.

Cisplatin

cisplatin


Input: Tumor necrosis factor-alpha (TNF-alpha) is known to contribute to cisplatin-induced nephrotoxicity by inducing an inflammatory process aggravating the primary injury, thereby resulting in acute kidney injury (AKI).

cisplatin


Input: The present study investigates the pathways synergistically activated by cisplatin and TNF-alpha responsible for TNF-alpha-enhanced cisplatin-induced renal cell injury.

cisplatin

cisplatin


Input: To do so, immortalized renal proximal tubular epithelial cells (IM-PTECs) were co-treated with TNF-alpha and cisplatin.

cisplatin


Input: Under these conditions, cisplatin induced dose-dependent apoptosis in IM-PTECs, which was significantly enhanced by TNF-alpha.

cisplatin


Input: Transcriptomic analysis revealed that cisplatin inhibited the typical TNF-alpha response and cisplatin/TNF-alpha treatment up-regulated cell death pathways while it down-regulated survival pathways compared to cisplatin alone.

cisplatin

cisplatin

cisplatin


Input: In concordance, the gene expression levels of kidney injury markers combined with activation of specific inflammatory mediators were enhanced by cisplatin/TNF-alpha treatment, resembling the in vivo cisplatin-induced nephrotoxicity response.

cisplatin

cisplatin


Input: Furthermore, combined cisplatin/TNF-alpha treatment inhibited NF-kappa B nuclear translocation and NF-kappa B-mediated gene transcription leading to enhanced and prolonged JNK and c-Jun phosphorylation.

cisplatin


Input: JNK sustained activation further inhibited NF-kappa B signaling via a feedback loop mechanism.


Input: This led to an alteration in the transcription of the NF-kappa B-induced anti-apoptotic genes c-IAP2, Bcl-XL, Bruce and Bcl2 and pro-apoptotic genes Bfk and Xaf1 and consequently to sensitization of the IM-PTECs toward cisplatin/TNF-alpha-induced toxicity.

cisplatin


Input: In conclusion, our findings support a model whereby renal cells exposed to both cisplatin and TNF-alpha switch into a more pro-apoptotic and inflammatory program by altering their NF-kappa B/JNK/c-Jun balance.

cisplatin


Input: Ibandronate increases the expression of the pro-apoptotic gene FAS by epigenetic mechanisms in tumor cells.

Ibandronate


Input: There is growing evidence that aminobisphosphonates like ibandronate show anticancer activity by an unknown mechanism.

aminobisphosphonates

ibandronate


Input: Biochemically, they prevent posttranslational isoprenylation of small GTPases, thus inhibiting their activity.


Input: In tumor cells, activated RAS-GTPase, the founding member of the gene family, down-regulates the expression of the pro-apoptotic gene FAS via epigenetic DNA-methylation by DNMT1.


Input: We compared ibandronate treatment in neoplastic human U-2 osteosarcoma and in mouse CCL-51 breast cancer cells as well as in the immortalized non-neoplastic MC3T3-E1 osteoblastic cells.

ibandronate


Input: Ibandronate attenuated cell proliferation in all cell lines tested.

Ibandronate


Input: In the neoplastic cells we found up-regulation of caspases suggesting apoptosis.


Input: Further we found stimulation of FAS-expression as a result of epigenetic DNA demethylation that was due to down-regulation of DNMT1, which was rescued by re-isoprenylation by both geranylgeranyl-pyrophosphate and farnesylpyrophosphate.

geranylgeranyl-pyrophosphate

farnesylpyrophosphate


Input: In contrast, ibandronate did not affect FAS and DNMT1 expression in MC3T3-E1 non-neoplastic cells.

ibandronate


Input: Data suggest that bisphosphonates via modulation of the activity of small-GTPases induce apoptosis in neoplastic cells by DNA-CpG-demethylation and stimulation of FAS-expression.

bisphosphonates

CpG


Input: In conclusion the shown epigenetic mechanism underlying the anti-neoplastic activity of farnesyl-transferase-inhibition, also explains the clinical success of other drugs, which target this pathway.

farnesyl


Input: Interorgan metabolism of ornithine phenylacetate (OP)--a novel strategy for treatment of hyperammonemia.

ornithine phenylacetate


Input: Combined administration of ornithine and phenylacetate (OP) is proposed as a novel treatment of hyperammonemia and hepatic encephalopathy.

ornithine

phenylacetate


Input: Ornithine is believed to increase ammonia fixation into glutamine in muscle tissue and glutamine is subsequently thought to react with phenylacetate forming phenylacetylglutamine (PAGN) which is excreted in urine.

Ornithine

ammonia

glutamine

glutamine

phenylacetate

phenylacetylglutamine

PAGN


Input: The aim of the present study was to elucidate the interorgan metabolism of ornithine and ammonia in cirrhotic rats treated with OP in order to obtain an understanding of the underlying mechanisms of the beneficial effect of the treatment, which are largely unknown.

ornithine

ammonia


Input: Bile duct ligated cirrhotic rats and SHAM rats were treated with OP or saline for five days.


Input: [2, 5-(15) N] Ornithine or (15) NH (4) (+) were administered intravenously and the incorporation of (15) N in amino acids as well as the content of the amino acids were subsequently determined in plasma, skeletal muscle, liver and kidney.

[2, 5-(15) N] Ornithine

(15) NH (4) (+)

(15) N

amino acids

amino acids


Input: In BDL rats, OP treatment reduced arterial ammonia concentration and increased that of glutamine 30 min after the treatment but not after 15 h.

ammonia

glutamine


Input: OP treatment did not increase (15) N labeling in glutamine from [2, 5-(15) N] ornithine and (15) NH (4) (+) in skeletal muscle or liver.

(15) N

glutamine

[2, 5-(15) N] ornithine

(15) NH (4) (+)


Input: However, the extent of glutamine labeling from [2, 5-(15) N] ornithine or (15) NH (4) (+) was similar in arterial blood and liver and higher than that in skeletal muscle.

glutamine

[2, 5-(15) N] ornithine

(15) NH (4) (+)


Input: These findings suggest that the effect of OP was related to hepatic metabolism of ornithine.

ornithine


Input: PAGN could not be detected in urine or blood in any of the rats which may explain why OP treatment only reduced arterial ammonia transiently.

PAGN

ammonia


Input: Platelet-derived growth factor triggers PKA-mediated signalling by a redox-dependent mechanism in rat renal mesangial cells.


Input: Inflammatory glomerular kidney diseases are often accompanied with a massive production of reactive oxygen species (ROS) that affect the function of the glomerular filtration barrier and contribute to mesangiolysis via the induction of cell death in mesangial cells.

oxygen


Input: Intriguingly, ROS also trigger fine-tuned signalling processes that affect gene expression and cell proliferation or migration.


Input: To define such redox-driven signalling devices, a proteomics approach was performed to identify the formation of protein complexes induced by ROS.


Input: To this end, protein lysates of human podocytes were treated with or without hydrogen peroxide (250 mu M).

hydrogen peroxide


Input: Thereafter cell lysates were subjected to diagonal 2D gel electrophoresis and putative redox-affected proteins were analysed by MS/MS analysis.


Input: Among others, the regulatory subunit of protein kinase A (PKA) could be identified that forms homodimers under oxidative conditions.


Input: To evaluate whether ROS dependent dimerization of PKA also occurs in a more physiological setting, rat mesangial cells were treated with platelet-derived growth factor-BB (PDGF-BB) to induce ROS formation.


Input: This regimen resulted in a redox dependent dimerization of the R-subunits of PKA.


Input: To demonstrate whether PDGF-BB induced ROS formation affects PKA dependent pathways, the effects of PDGF-BB on phosphorylation of serine 157 of vasodilator stimulated protein (VASP) a classical target of PKA were analysed.

serine


Input: Interestingly PDGF-BB induced VASP phosphorylation in a ROS dependent manner but independent of changes in cAMP levels.

cAMP


Input: Taken together, we demonstrate a redox-mediated activation of PKA by PDGF-BB thus highlighting a physiological role of ROS as regulator of PKA activity in rat mesangial cells.


Input: Chloroacetic acid induced neuronal cells death through oxidative stress-mediated p38-MAPK activation pathway regulated mitochondria-dependent apoptotic signals.

Chloroacetic acid


Input: Chloroacetic acid (CA), a toxic chlorinated analog of acetic acid, is widely used in chemical industries as an herbicide, detergent, and disinfectant, and chemical intermediates that are formed during the synthesis of various products.

Chloroacetic acid

acetic acid


Input: In addition, CA has been found as a by-product of chlorination disinfection of drinking water.


Input: However, there is little known about neurotoxic injuries of CA on the mammalian, the toxic effects and molecular mechanisms of CA-induced neuronal cell injury are mostly unknown.


Input: In this study, we examined the cytotoxicity of CA on cultured Neuro-2a cells and investigated the possible mechanisms of CA-induced neurotoxicity.


Input: Treatment of Neuro-2a cells with CA significantly reduced the number of viable cells (in a dose-dependent manner with a range from 0. 1 to 3mM), increased the generation of ROS, and reduced the intracellular levels of glutathione depletion.

glutathione


Input: CA also increased the number of sub-G1 hypodiploid cells; increased mitochondrial dysfunction (loss of MMP, cytochrome c release, and accompanied by Bcl-2 and Mcl-1 down-regulation and Bax up-regulation), and activated the caspase cascades activations, which displayed features of mitochondria-dependent apoptosis pathway.


Input: These CA-induced apoptosis-related signals were markedly prevented by the antioxidant N-acetylcysteine (NAC).

N-acetylcysteine

NAC


Input: Moreover, CA activated the JNK and p38-MAPK pathways, but did not that ERK1/2 pathway, in treated Neuro-2a cells.


Input: Pretreatment with NAC and specific p38-MAPK inhibitor (SB203580), but not JNK inhibitor (SP600125) effectively abrogated the phosphorylation of p38-MAPK and attenuated the apoptotic signals (including: decrease in cytotoxicity, caspase-3/-7 activation, the cytosolic cytochrome c release, and the reversed alteration of Bcl-2 and Bax mRNA) in CA-treated Neuro-2a cells.

NAC


Input: Taken together, these data suggest that oxidative stress-induced p38-MAPK activated pathway-regulated mitochondria-dependent apoptosis plays an important role in CA-caused neuronal cell death.


Input: Bioassay-guided isolation of urease and alpha-chymotrypsin inhibitory constituents from the stems of Lawsonia alba Lam.


Input: (Henna).


Input: Seven constituents were isolated from the stems of Lawsonia alba Lam., following an activity-guided isolation, which include two new constituents, namely lawsorosemarinol (1) and lawsofructose (2), one known compound 2-(beta-d-glucopyranosyloxy)-1, 4-naphthoquinone (3) and four compounds, 4-hydroxy coumarine (4), 3-(4-hyroxyphenyl)-triacontyl-(Z)-propenoate (5), 3-(4-hydroxy-3-methoxyphenyl)-triacontyl-(Z)-propenoate (6) and 7-hydroxy-4-methyl coumarin (7) first time isolated from Lawsonia alba.

lawsorosemarinol

lawsofructose

2-(beta-d-glucopyranosyloxy)-1, 4-naphthoquinone

4-hydroxy coumarine

3-(4-hyroxyphenyl)-triacontyl-(Z)-propenoate

3-(4-hydroxy-3-methoxyphenyl)-triacontyl-(Z)-propenoate

7-hydroxy-4-methyl coumarin


Input: Their structure elucidation was based on spectroscopic data analyses.


Input: Compounds 3 and 7 showed a moderate inhibition of urease activity, while rest of them showed less than 50% inhibition.


Input: These compounds did not show any significant inhibition against alpha-chymotrypsin.


Input: Active self-healing encapsulation of vaccine antigens in PLGA microspheres.

PLGA


Input: Herein, we describe the detailed development of a simple and effective method to microencapsulate vaccine antigens in poly (lactic-co-glycolic acid) (PLGA) by simple mixing of preformed active self-microencapsulating (SM) PLGA microspheres in a low concentration aqueous antigen solution at modest temperature (10-38 degrees C).

poly (lactic-co-glycolic acid)

PLGA

PLGA


Input: Co-encapsulating protein-sorbing vaccine adjuvants and polymer plasticizers were used to " actively " load the protein in the polymer pores and facilitate polymer self-healing at a temperature > the hydrated polymer glass transition temperature, respectively.


Input: The microsphere formulation parameters and loading conditions to provide optimal active self-healing microencapsulation of vaccine antigens in PLGA was investigated.

PLGA


Input: Active self-healing encapsulation of two antigens, ovalbumin and tetanus toxoid (TT), in PLGA microspheres was adjusted by preparing blank microspheres containing different vaccine adjuvants (aluminum hydroxide (Al (OH) 3) or calcium phosphate).

PLGA

aluminum hydroxide

Al (OH) 3

calcium phosphate


Input: Active loading of vaccine antigen in Al (OH) 3-PLGA microspheres was found to: a) increase with an increasing loading of Al (OH) 3 (0. 88-3 wt.%) and addition of porosigen, b) decrease when the inner Al (OH) 3/trehalose phase to 1 mL outer oil phase and size of microspheres was respectively > 0. 2 mL and 63 mu m, and c) change negligibly by PLGA concentration and initial incubation (loading) temperature.

Al (OH) 3

PLGA

Al (OH) 3

Al (OH) 3

trehalose

PLGA


Input: Encapsulation of protein sorbing Al (OH) 3 in PLGA microspheres resulted in suppression of self-healing of PLGA pores, which was then overcome by improving polymer chain mobility, which in turn was accomplished by coincorporating hydrophobic plasticizers in PLGA.

Al (OH) 3

PLGA

PLGA

PLGA


Input: Active self-healing microencapsulation of manufacturing process-labile TT in PLGA was found to: a) obviate micronization-and organic solvent-induced TT degradation, b) improve antigen loading (1. 4-1. 8 wt.% TT) and encapsulation efficiency (~ 97%), c) provide nearly homogeneous distribution and stabilization of antigen in polymer, and d) provide improved in vitro controlled release of antigenic TT.

PLGA


Input: N-Arachidonyl glycine does not activate G protein-coupled receptor 18 signaling via canonical pathways.

N-Arachidonyl glycine


Input: Recent studies propose that N-arachidonyl glycine (NAGly), a carboxylic analogue of anandamide, is an endogenous ligand of the G alpha (i/o) protein-coupled receptor 18 (GPR18).

N-arachidonyl glycine

NAGly

carboxylic

anandamide


Input: However, a high-throughput beta-arrestin-based screen failed to detect activation of GPR18 by NAGly (Yin et al., 2009; JBC, 18: 12328).

NAGly


Input: To address this inconsistency, this study investigated GPR18 coupling in a native neuronal system with endogenous signaling pathways and effectors.


Input: GPR18 was heterologously expressed in rat sympathetic neurons, and the modulation of N-type (Ca (v) 2. 2) calcium channels was examined.

N

Ca

calcium


Input: Proper expression and trafficking of receptor were confirmed by the " rim-like " fluorescence of fluorescently tagged receptor and the positive staining of external hemagglutinin-tagged GPR18-expressing cells.


Input: Application of NAGly on GPR18-expressing neurons did not inhibit calcium currents but instead potentiated currents in a voltage-dependent manner, similar to what has previously been reported (Guo et al., 2008; J Neurophysiol, 100: 1147).

NAGly

calcium


Input: Other proposed agonists of GPR18, including anandamide and abnormal cannabidiol, also failed to induce inhibition of calcium currents.

anandamide

cannabidiol

calcium


Input: Mutants of GPR18, designed to constitutively activate receptors, did not tonically inhibit calcium currents, indicating a lack of GPR18 activation or coupling to endogenous G proteins.

calcium


Input: Other downstream effectors of G alpha (i/o)-coupled receptors, G protein-coupled inwardly rectifying potassium channels and adenylate cyclase, were not modulated by GPR18 signaling.

potassium

adenylate


Input: Furthermore, GPR18 did not couple to other G proteins tested: G alpha (s), G alpha (z), and G alpha (15).


Input: These results suggest NAGly is not an agonist for GPR18 or that GPR18 signaling involves noncanonical pathways not examined in these studies.

NAGly


Input: Effects of Korean red ginseng extracts on neural tube defects and impairment of social interaction induced by prenatal exposure to valproic acid.

valproic acid


Input: Ginseng is one of the most widely used medicinal plants, which belongs to the genus Panax.


Input: Compared to uncured white ginseng, red ginseng has been generally regarded to produce superior pharmacological effects with lesser side/adverse effects, which made it popular in a variety of formulation from tea to oriental medicine.


Input: Using the prenatal valproic acid (VPA)-injection model of autism spectrum disorder (ASD) in rats, which produces social impairrment and altered seizure susceptibility as in human ASD patients as well as mild neural tube defects like crooked tail phenotype, we examined whether chronic administration of red ginseng extract may rescue the social impairment and crooked tail phenotype in prenatally VPA-exposed rat offspring.

valproic acid

VPA

VPA


Input: VPA-induced impairment in social interactions tested using sociability and social preference paradigms as well as crooked tail phenotypes were significantly improved by administration of Korean red ginseng (KRG) in a dose dependent manner.

VPA


Input: Rat offspring prenatally exposed to VPA showed higher sensitivity to electric shock seizure and increased locomotor activity in open-field test.

VPA


Input: KRG treatment reversed abnormal locomotor activity and sensitivity to electric shock to control level.


Input: These results suggest that KRG may modulate neurobehavioral and structural organization of nervous system adversely affected by prenatal exposure to VPA.

VPA


Input: The crystal structure of human telomeric DNA complexed with berberine: an interesting case of stacked ligand to G-tetrad ratio higher than 1: 1.

berberine


Input: The first crystal structure of human telomeric DNA in complex with the natural alkaloid berberine, produced by different plant families and used in folk medicine for millennia, was solved by X-ray diffraction method.

berberine


Input: The G-quadruplex unit features all-parallel strands.


Input: The overall folding assumed by DNA is the same found in previously reported crystal structures.


Input: Similarly to previously reported structures the ligand molecules were found to be stacked onto the external 5' and 3'-end G-tetrads.


Input: However, the present crystal structure highlighted for the first time, the presence of two berberine molecules in the two binding sites, directly interacting with each tetrad.

berberine


Input: As a consequence, our structural data point out a 2: 1 ligand to G-tetrad molar ratio, which has never been reported before in a telomeric intramolecular quadruplex structure.


Input: Arsenic increases Pi-mediated vascular calcification and induces premature senescence in vascular smooth muscle cells.

Arsenic


Input: Several mechanisms have been proposed to explain the vascular toxicity of arsenic.

arsenic


Input: Some of them are described in this work, such as stress-induced premature senescence (SIPS), dedifferentiation, and medial vascular calcification, and they all affect vascular smooth muscle cells (VSMC).


Input: Rat aortic VSMC were treated with 1-100 micro M of either sodium arsenate (As (V)), sodium arsenite (As (III)), monomethylarsonic acid, or dimethylarsinic acid.

sodium arsenate

As (V)

sodium arsenite

As (III)

monomethylarsonic acid

dimethylarsinic acid


Input: None of the treatments induced VSMC calcification in the presence of 1mM inorganic phosphate (Pi), but 1 micro M As (III) did increase calcification when induced with 2. 5mM Pi.

phosphate

As (III)


Input: A lactate dehydrogenase assay revealed that this increase was explained by a rise in cytotoxicity due to simultaneous incubation with 1 micro M As (III) and 2. 5mM Pi.

lactate

As (III)


Input: This calcification increase was also observed in the aortas of a vascular calcification model: 5/6 nephrectomized rats fed with a high Pi diet and treated with vitamin D (3).

vitamin D (3)


Input: Several known mechanisms that might explain arsenic toxicity in our experimental model were discarded: apoptosis, oxidative stress, and inflammasome activation.

arsenic


Input: Nevertheless, both senescence-associated beta-galactosidase activity and p21 expression were increased by As (III), which reveals the induction of SIPS.

As (III)


Input: As (III) also caused dedifferentiation of VSMC, as shown by the reduced expression of the VSMC markers SM22 alpha and calponin.

As (III)


Input: Senescence and gene expression were also observed in the aortas of healthy rats treated with 50 ppm As (V) in drinking water for 1 month.

As (V)


Input: In conclusion, both premature senescence in aortic VSMC with phenotypic dedifferentiation and the increase of Pi-induced calcification are novel mechanisms of arsenic vasculotoxicity.

arsenic


Input: Consideration of rat chronic progressive nephropathy in regulatory evaluations for carcinogenicity.


Input: Chronic progressive nephropathy (CPN) is a spontaneous renal disease of rats which can be a serious confounder in toxicology studies.


Input: It is a progressive disease with known physiological factors that modify disease progression, such as high dietary protein.


Input: The weight of evidence supports an absence of a renal counterpart in humans.


Input: There is extensive evidence that advanced CPN, particularly end-stage kidney, is a risk factor for development of a background incidence of atypical tubule hyperplasia and renal tubule tumors (RTT).


Input: The likely cause underlying this association with tubule neoplasia is the long-term increased tubule cell proliferation that occurs throughout CPN progression.


Input: As a variety of chemicals are able to exacerbate CPN, there is a potential for those exacerbating the severity up to and including end-stage kidney to cause a marginal increase in RTT and their precursor lesions.


Input: Extensive statistical analysis of National Toxicology Program studies shows a strong correlation between high-grade CPN, especially end-stage CPN, and renal tumor development.


Input: CPN as a mode of action (MOA) for rat RTT has received attention from regulatory authorities only recently.


Input: In the absence of toxic effects elsewhere, this does not constitute a carcinogenic effect of the chemical but can be addressed through a proposed MOA approach for regulatory purposes to reach a decision that RTT, developing as a result of CPN exacerbation in rats, have no relevance for human risk assessment.


Input: Guidelines are proposed for evaluation of exacerbation of CPN and RTT as a valid MOA for a given chemical.


Input: Differential influences of ethanol on early exposure to racemic methylphenidate compared with dexmethylphenidate in humans.

ethanol

methylphenidate

dexmethylphenidate


Input: Enantioselective hydrolysis of oral racemic methylphenidate (dl-MPH) by carboxylesterase 1 (CES1) limits the absolute bioavailability of the pharmacologically active d-MPH isomer to approximately 30% and that of the inactive l-MPH to only 1-2%.

racemic methylphenidate

dl-MPH

d-MPH

l-MPH


Input: Coadministration of dl-MPH with ethanol results in elevated d-MPH plasma concentrations accompanied by CES1-mediated enantioselective transesterification of l-MPH to l-ethylphenidate (EPH).

dl-MPH

ethanol

d-MPH

l-MPH

l-ethylphenidate

EPH


Input: The present study tested the hypothesis that administration of the pure isomer dexmethylphenidate (d-MPH) will overcome the influence of ethanol on d-MPH absorption by eliminating competitive CES1-mediated presystemic metabolism of l-MPH to l-EPH.

dexmethylphenidate

d-MPH

ethanol

d-MPH

l-MPH

l-EPH


Input: Twenty-four healthy volunteers received dl-MPH (0. 3 mg/kg) or d-MPH (0. 15 mg/kg), with or without ethanol (0. 6 g/kg).

dl-MPH

d-MPH

ethanol


Input: During the absorption phase of dl-MPH, concomitant ethanol significantly elevated d-MPH plasma concentrations (44-99%; P < 0. 005).

dl-MPH

ethanol

d-MPH


Input: Furthermore, immediately following the ethanol drink the subjective effects of " high, " " good, " " like, " " stimulated, " and overall " effect " were significantly potentiated (P <= 0. 01).

ethanol


Input: Plasma l-EPH concentrations exceeded those of l-MPH.

l-EPH

l-MPH


Input: Ethanol combined with pure d-MPH did not elevate plasma d-MPH concentrations during the absorption phase, and the ethanol-induced potentiation of subjective effects was delayed relative to dl-MPH-ethanol.

Ethanol

d-MPH

d-MPH

ethanol

dl-MPH

ethanol


Input: These findings are consistent with l-MPH competitively inhibiting presystemic CES1 metabolism of d-MPH.

l-MPH

d-MPH


Input: Ethanol increased the d-MPH area under the curve (AUC) (0-inf) by 21% following dl-MPH (P < 0. 001) and 14% for d-MPH (P = 0. 001).

Ethanol

d-MPH

dl-MPH

d-MPH


Input: In men receiving d-MPH-ethanol, the d-MPH absorption partial AUC (0. 5-2 hours) was 2. 1 times greater and the time to maximum concentration (T (max)) occurred 1. 1 hours earlier than in women, consistent with an increased rate of d-MPH absorption reducing hepatic extraction.

d-MPH

ethanol

d-MPH

d-MPH


Input: More rapid absorption of d-MPH carries implications for increased abuse liability.

d-MPH


Input: Evolution and diversity of Arsenophonus endosymbionts in aphids.


Input: Endosymbiotic bacteria are important drivers of insect evolutionary ecology, acting both as partners that contribute to host adaptation and as subtle parasites that manipulate host reproduction.


Input: Among them, the genus Arsenophonus is emerging as one of the most widespread lineages.


Input: Its biology is, however, entirely unknown in most cases, and it is therefore unclear how infections spread through insect populations.


Input: Here we examine the incidence and evolutionary history of Arsenophonus in aphid populations from 86 species, characterizing the processes that shape their diversity.


Input: We identify aphids as harbouring an important diversity of Arsenophonus strains.


Input: Present in 7% of the sampled species, incidence was especially high in the Aphis genus with more than 31% of the infected species.


Input: Phylogenetic investigations revealed that these Arseno-phonus strains do not cluster within an aphid-specific clade but rather exhibit distinct evolutionary origins showing that they undergo repeated horizontal transfers (HT) between distantly related host species.


Input: Their diversity pattern strongly suggests that ecological interactions, such as plant mediation and parasitism, are major drivers for Arsenophonus dispersal, dictating global incidence across insect communities.


Input: Notably, plants hosting aphids may be important ecological arenas for global exchange of Arsenophonus, serving as reservoirs for HT.


Input: Methotrexate-conjugated and hyperbranched polyglycerol-grafted Fe 3 O 4 magnetic nanoparticles for targeted anticancer effects.

Methotrexate

polyglycerol

Fe 3 O 4


Input: Superparamagnetic nanoparticles grafted with hyperbranched polyglycerol (HPG) and conjugated with methotrexate (MTX) (MNP-g-HPG-MTX) were synthesized via a sol-gel reaction followed by thiol-ene click chemistry and esterification reaction.

polyglycerol

methotrexate

MTX

MTX

thiol-ene


Input: The successful grafting of MTX and HPG onto the nanoparticles was confirmed by X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FT-IR) spectroscopy, and UV-visible spectroscopy.

MTX


Input: The HPG-graft layer confers the magnetic nanoparticles with good dispersibility and stability in aqueous medium and macrophage-evasive property while the MTX acts as a chemotherapeutic drug as well as a tumor targeting ligand.

MTX


Input: The dose-dependent targeting and anticancer effect of the MNP-g-HPG-MTX nanoparticles were evaluated, and the results showed that depending on the amount of conjugated MTX and the concentration of the incubated nanoparticles, the uptake of MNP-g-HPG-MTX nanoparticles by human head and neck cancer (KB) cells can be eight times or more higher than those by 3T3 fibroblasts and RAW macrophages.

MTX

MTX

MTX


Input: As a result, the MNP-g-HPG-MTX nanoparticles are capable of killing ~ 50% of the KB cells while at the same time exhibiting low cytotoxicity towards 3T3 fibroblasts and RAW macrophages.

MTX


Input: Thus, such nanoparticles can potentially be used as active targeting anticancer agents.


Input: Promoting effect of polysaccharide isolated from Mori fructus on dendritic cell maturation.


Input: Maturation of dendritic cells (DCs) is usually attenuated in the tumor microenvironment, which is an important immunological problem in DC-based immunotherapy of cancer.


Input: In this study, we report the effect of a Mori fructus polysaccharide (MFP) on DC maturation.


Input: MFP was treated to DCs generated from mouse BM cells.


Input: MFP induced phenotypic maturation of DCs, as proven by the increased expression of CD40, CD80/86, and MHC-I/II molecules.


Input: MFP induced functional maturation of DCs, in that MFP increased the expression of IL-12, IL-1 beta, TNF-alpha, and IFN-beta, decreased antigen capture capacity, and enhanced allogenic T cell stimulation.


Input: MFP efficiently induced maturation of DCs from C3H/HeN mice having normal toll-like receptor4 (TLR4), but not DCs from C3H/HeJ mice having mutated TLR4, suggesting that TLR4 might be one of the membrane receptors of MFP.


Input: As a mechanism of action, MFP increased phosphorylation of mitogen-activated protein kinase (MAPKs), and nuclear translocation of NF-kappa B p65 subunit, which were important signal molecules downstream from TLR4.


Input: These data suggest that MFP induces DC maturation through TLR4 and MFP can be used as an adjuvant in DC-based cancer immunotherapy.


Input: The hypothalamus-adipose axis is a key target of developmental programming by maternal nutritional manipulation.


Input: Epidemiological studies initially demonstrated that maternal undernutrition leading to low birth weight may predispose for energy balance disorders throughout life.


Input: High birth weight due to maternal obesity or diabetes, inappropriate early post-natal nutrition and rapid catch-up growth may also sensitise to increased risk of obesity.


Input: As stated by the Developmental Origin of Health and Disease concept, the perinatal perturbation of foetus/neonate nutrient supply might be a crucial determinant of individual programming of body weight set point.


Input: The hypothalamus-adipose axis plays a pivotal role in the maintenance of energy homoeostasis controlling the nutritional status and energy storage level.


Input: The perinatal period largely corresponds to the period of brain maturation, neuronal differentiation and active adipogenesis in rodents.


Input: Numerous dams and/or foetus/neonate dietary manipulation models were developed to investigate the mechanisms underlying perinatal programming in rodents.


Input: These models showed several common offspring hypothalamic consequences such as impaired neurogenesis, neuronal functionality, nuclei structural organisation and feeding circuitry hardwiring.


Input: These alterations led to a persistent reprogrammed appetite system that favoured the orexigenic pathways, leptin/insulin resistance and hyperphagia.


Input: Impaired hypothalamic sympathetic outflow to adipose tissue and/or reduced innervation may also account for modified fat cell metabolism.