Input: The results reveal that the imidazole nitrogen atom of GlcNAcstatin has shown a better interaction with the active site of Clostridium perfringens in its protonated form, which is compatible with a substrate-assisted reaction mechanism involving two conserved aspartate residues (297 and 298).

imidazole nitrogen

GlcNAcstatin

aspartate


Input: Furthermore, the quantum mechanics/molecular mechanics-molecular dynamics simulations appointed a strong interaction between Asp401, Asp298, and Asp297 residues and the GlcNAcstatin inhibitor, which is in accordance with experimental data.

GlcNAcstatin


Input: Lastly, these results may contribute to understand the molecular mechanism of inhibition of Clostridium perfringens by GlcNAcstatin inhibitor and, consequently, this study might be useful to design new molecules with more interesting inhibitory activity.

GlcNAcstatin


Input: Methylparaben protects 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells and improved behavioral impairments in mouse model of Parkinson' s disease.

Methylparaben


Input: Parkinson' s disease (PD) is a progressive neurodegenerative disorder of unknown etiology.


Input: Considerable evidence suggests that free radical formation and oxidative stress might play an important role in the pathogenesis of PD.


Input: In the present investigation we evaluated the therapeutic potential of methylparaben (MP) a well known pharmaceutical preservative against 6-hydroxydopamine (6-OHDA) neurotoxicity in SH-SY5Y cells and in a mouse model of PD.

methylparaben


Input: At nanomolar concentrations MP (0. 01, 0. 1 and 1 nM) significantly attenuated the 6-OHDA-and hydrogen peroxide-induced cytotoxicity in SH-SY5Y cells.

hydrogen peroxide


Input: The reactive oxygen species generated by 6-OHDA in SH-SY5Y cells was also inhibited by MP in a concentration dependent fashion.

oxygen


Input: Further, intranigral damage induced by stereotaxically injecting 6-OHDA in mouse brain was significantly attenuated by MP treatment.


Input: MP (1, 10 or 50 mu g/kg, i. p.) prevented apomorphine-induced rotational behavior and significantly improved motor deficits in 6-OHDA-lesioned mice.

apomorphine


Input: The cognitive impairments as evaluated by passive avoidance and Y-maze task in mice were also attenuated by MP concentration dependently.


Input: Immunohistochemical analysis of substantia nigra in MP treated mice showed significantly higher number of surviving tyrosine hydroxylase positive cells.

tyrosine


Input: Furthermore, MP also suppressed the lipid peroxidation products in 6-OHDA-lesioned mouse brain tissues.


Input: Considering the results obtained, the marked neuroprotection exhibited by MP might be attributed to its potent antioxidant property.


Input: In conclusion, this study reports the neuroprotective properties of MP in experimental models of PD for the first time and can be developed as a potential therapeutic agent.


Input: A case study of real-time monitoring of solid-state phase transformations in acoustically levitated particles using near infrared and Raman spectroscopy.


Input: The objective of this study was to monitor the amorphous-to-crystalline solid-state phase transformation kinetics of the model drug ibuprofen with spectroscopic methods during acoustic levitation.

ibuprofen


Input: Chemical and physical information was obtained by real-time near infrared (NIRS) and Raman spectroscopy measurements.


Input: The recrystallisation kinetic parameters (overall recrystallisation rate constant beta and the time needed to reach 50% of the equilibrated level t (50)), were determined using a multivariate curve resolution approach.


Input: The acoustic levitation device coupled with non-invasive spectroscopy enabled monitoring of the recrystallisation process of the difficult-to-handle (adhesive) amorphous sample.


Input: The application of multivariate curve resolution enabled isolation of the underlying pure spectra, which corresponded well with the reference spectra of amorphous and crystalline ibuprofen.

ibuprofen


Input: The recrystallisation kinetic parameters were estimated from the recrystallisation profiles.


Input: While the empirical recrystallisation rate constant determined by NIR and Raman spectroscopy were comparable, the lag time for recrystallisation was significantly lower with Raman spectroscopy as compared to NIRS.


Input: This observation was explained by the high energy density of the Raman laser beam, which might have led to local heating effects of the sample and thus reduced the recrystallisation onset time.


Input: It was concluded that acoustic levitation with NIR and Raman spectroscopy combined with multivariate curve resolution allowed direct determination of the recrystallisation kinetics of amorphous drugs and thus is a promising technique for monitoring solid-state phase transformations of adhesive small-sized samples during the early phase of drug development.


Input: Cathepsin K knockout mitigates high-fat diet-induced cardiac hypertrophy and contractile dysfunction.


Input: The cysteine protease cathepsin K has been implicated in pathogenesis of cardiovascular disease.


Input: We hypothesized that ablation of cathepsin K protects against obesity-associated cardiac dysfunction.


Input: Wild-type mice fed a high-fat diet exhibited elevated heart weight, enlarged cardiomyocytes, increased left ventricular wall thickness, and decreased fractional shortening.


Input: All these changes were reconciled in cathepsin K knockout mice.


Input: Cathepsin K knockout partly reversed the impaired cardiomyocyte contractility and dysregulated calcium handling associated with high-fat diet.

calcium


Input: Additionally, cathepsin K knockout alleviated whole-body glucose intolerance and improved insulin-stimulated Akt phosphorylation in high-fat diet-fed mice.

glucose


Input: High-fat feeding increased the expression of cardiac hypertrophic proteins and apoptotic markers, which were inhibited by cathepsin K knockout.


Input: Furthermore, high-fat feeding resulted in cathepsin K release from lysosomes into the cytoplasm.


Input: In H9c2 myoblasts, silencing of cathepsin K inhibited palmitic acid-induced release of cytochrome c from mitochondria and expression of proapoptotic signaling molecules.

palmitic acid


Input: Collectively, our data indicate that cathepsin K contributes to the development of obesity-associated cardiac hypertrophy and may represent a potential target for the treatment to obesity-associated cardiac anomalies.


Input: Electric control of the giant Rashba effect in bulk GeTe.

GeTe


Input: Relativistic effects, including the Rashba effect, are increasingly seen as key ingredients in spintronics.


Input: A link between Rashba physics and the field of ferroelectrics is established by predicting giant Rashba spin-splitting in bulk GeTe (see the Figure showing the band-structure as well as in-plane and out-of-plane spin polarization for a constant energy cut).

GeTe


Input: Potentiation of sulfonylurea action by an EPAC-selective cAMP analog in INS-1 cells: comparison of tolbutamide and gliclazide and a potential role for EPAC activation of a 2-APB-sensitive Ca2 + influx.

sulfonylurea

cAMP

tolbutamide

gliclazide


Input: Tolbutamide and gliclazide block the K (ATP) channel K (ir) 6. 2/Sur1, causing membrane depolarization and stimulating insulin secretion in pancreatic beta cells.

Tolbutamide


Input: We examined the ability of the EPAC-selective cAMP analog 8-pCPT-2'-O-Me-cAMP-AM to potentiate the action of these drugs and the mechanism that might account for it.

cAMP


Input: Insulin secretion stimulated by both 200 mu M tolbutamide and 20 mu M gliclazide, concentrations that had equivalent effects on membrane potential, was inhibited by thapsigargin (1 mu M) or the L-type Ca (2 +) channel blocker nicardipine (2 mu M) and was potentiated by 8-pCPT-2'-O-Me-cAMP-AM at concentrations >= 2 mu M in INS-1 cells.

tolbutamide

gliclazide

thapsigargin

Ca (2 +)

nicardipine


Input: Ca (2 +) transients stimulated by either tolbutamide or gliclazide were inhibited by thapsigargin or nicardipine and were significantly potentiated by 8-pCPT-2'-O-Me-cAMP-AM at 5 mu M but not 1 mu M.

Ca (2 +)

tolbutamide

gliclazide

thapsigargin

nicardipine


Input: Both tolbutamide and gliclazide stimulated phospholipase C activity; however, only gliclazide did so independently of its activity at K (ATP) channels, and this activity was partially inhibited by pertussis toxin.

tolbutamide

gliclazide

gliclazide

K

ATP


Input: 8-pCPT-2'-O-Me-cAMP-AM alone (5 mu M) did not stimulate insulin secretion, but did increase intracellular Ca (2 +) concentration significantly, and this activity was inhibited by 25 mu M 2-aminoethoxydiphenylborate (2-APB) or the removal of extracellular Ca (2 +).

Ca (2 +)

Ca (2 +)


Input: 8-pCPT-2'-O-Me-cAMP-AM potentiation of insulin secretion stimulated by tolbutamide was markedly inhibited by 2-APB (25 mu M) and enhanced by the PKC inhibitor bisindolylmaleimide I (1 mu M).

tolbutamide

bisindolylmaleimide I


Input: Our data demonstrate that the actions of both tolbutamide and gliclazide are strongly potentiated by 8-pCPT-2'-O-Me-cAMP-AM, that gliclazide can stimulate phospholipase C activity via a partially pertussis toxin-sensitive mechanism, and that 8-pCPT-2'-O-Me-cAMP-AM potentiation of tolbutamide action may involve activation of a 2-APB-sensitive Ca (2 +) influx.

tolbutamide

gliclazide

gliclazide

Ca (2 +)


Input: ApoE derived from adipose tissue does not suppress atherosclerosis or correct hyperlipidemia in apoE knockout mice.


Input: The synthesis of apoE by adipocytes has profound effects on adipose tissue lipid flux and gene expression.


Input: Using adipose tissue transplantation from wild-type (WT) to apoE knockout (EKO) mice, we show that adipose tissue also contributes to circulating apoE.


Input: Different from circulating apoE produced by bone marrow transplantation (BMT), however, adipose tissue-derived apoE does not correct hyperlipidemia or suppress atherosclerosis.


Input: ApoE secreted by macrophages has a more acidic isoform distribution, and it increases binding of reconstituted VLDL particles to hepatocytes and fibroblasts more effectively than apoE secreted by adipocytes.


Input: The incremental binding can be entirely accounted for by binding to the LDL receptor.


Input: After BMT into EKO hosts, plasma cholesterol and macrophage-derived apoE are largely within IDL/LDL-and HDL-sized particles.

cholesterol


Input: After adipose tissue transplantation, most cholesterol and adipocyte apoE remain in VLDL.

cholesterol


Input: After BMT, circulating apoE no longer demonstrates predominance of acidic isoforms compared with that circulating after fat transplantation.


Input: In conclusion, fat transplantation provides circulating apoE levels similar to those provided by bone marrow transplantation, but it does not suppress hyperlipidemia or atherosclerosis.


Input: A potential mechanism contributing to this difference is differential binding to cell surface lipoprotein receptors.


Input: In vitro and in vivo approaches to study osteocyte biology.


Input: Osteocytes, the most abundant cell population of the bone lineage, have been a major focus in the bone research field in recent years.


Input: This population of cells that resides within mineralized matrix is now thought to be the mechanosensory cell in bone and plays major roles in the regulation of bone formation and resorption.


Input: Studies of osteocytes had been impaired by their location, resulting in numerous attempts to isolate primary osteocytes and to generate cell lines representative of the osteocytic phenotype.


Input: Progress has been achieved in recent years by utilizing in vivo genetic technology and generation of osteocyte directed transgenic and gene deficiency mouse models.


Input: We will provide an overview of the current in vitro and in vivo models utilized to study osteocyte biology.


Input: We discuss generation of osteocyte-like cell lines and isolation of primary osteocytes and summarize studies that have utilized these cellular models to understand the functional role of osteocytes.


Input: Approaches that attempt to selectively identify and isolate osteocytes using fluorescent protein reporters driven by regulatory elements of genes that are highly expressed in osteocytes will be discussed.


Input: In addition, recent in vivo studies utilizing overexpression or conditional deletion of various genes using dentin matrix protein (Dmp1) directed Cre recombinase are outlined.


Input: In conclusion, evaluation of the benefits and deficiencies of currently used cell lines/genetic models in understanding osteocyte biology underlines the current progress in this field.


Input: The future efforts will be directed towards developing novel in vitro and in vivo models that would additionally facilitate in understanding the multiple roles of osteocytes.


Input: This article is part of a Special Issue entitled " The Osteocyte ".


Input: Effects of conjugated linoleic acid supplementation and exercise on post-heparin lipoprotein lipase, butyrylcholinesterase, blood lipid profile and glucose metabolism in young men.

linoleic acid

glucose


Input: This study was designed to investigate the effects of conjugated linoleic acid (CLA) supplementation and endurance exercise training-induced changes on post-heparin lipoprotein lipase (PH-LPL) and butyrylcholinesterase (BChE) activities along with leptin, insulin and lipid levels in plasma by a randomized double blind experiment.

linoleic acid

CLA


Input: Eighteen sedentary male volunteers were randomly divided into CLA and Placebo (PLC) supplementation groups.

CLA


Input: Both groups underwent daily supplementation of either 3g CLA or 3g placebo for 30days, respectively, and performed exercise on a bicycle ergometer 3 times per week for 30-40min at 50% VO2 peak workload.

CLA


Input: For plasma glucose, insulin and leptin levels and BChE activity fasting blood was used.

glucose


Input: For PH-LPL measurements, blood was collected 15min after 50IU/kg iv heparin injection.


Input: In all groups, there is a statistically significant decrease in BChE (p = 0. 03, p = 0. 02) and leptin (p = 0. 002), insulin and HOMA-IR levels (p = 0. 02).


Input: Exercise with or without CLA supplementation decreased insulin levels and increased insulin sensitivity.

CLA


Input: PH-LPL activity was increased significantly in both groups, displaying increased fatty acid mobilization.


Input: We conclude that though CLA supplementation and exercise can affect these parameters, CLA is not more effective than exercise alone.

CLA

CLA


Input: Hence, a prolonged supplementation regime may be more effective.


Input: Taken together in our small study group, our findings display that BChE is a potential marker for synthetic function of liver, fat metabolism, an obesity marker, a function long overlooked.


Input: In vivo genotoxicity of methyleugenol in gpt delta transgenic rats following medium-term exposure.

methyleugenol


Input: Methyleugenol (MEG), which is commonly used as a fragrance and flavoring agent, has been shown to induce hepatocellular tumors in rodents.

Methyleugenol

MEG


Input: However, the role of genotoxicity as a possible mechanism of action is not fully understood even though the DNA-reactive metabolite of MEG has been identified.

MEG


Input: In this study, a gpt delta transgenic rat model was used to clarify whether genotoxic mechanisms are involved in MEG-induced hepatocarcinogenesis following medium-term exposure.

MEG


Input: F344 gpt delta rats were subjected to repeated oral administration of MEG at dosages of 0, 10, 30, or 100mg/kg (a carcinogenic dose) for 13 weeks.

MEG


Input: The relative weight of the liver of the male and female rats that were administered 100mg/kg MEG and the absolute weight of the liver of the male rats that were administered 100mg/kg MEG were significantly increased.

MEG

MEG


Input: In addition, the number and area of glutathione S-transferase placental form (GST-P) positive foci and proliferating cell nuclear antigen (PCNA) positive cell ratios in the hepatocytes were significantly increased in the male and female rats that were administered 100mg/kg MEG compared with the control animals.

glutathione S

MEG


Input: In the in vivo mutation assays, a significant increase in the gpt and Spi (-) mutant frequencies was observed in both sexes at the carcinogenic dose.


Input: These results suggest the possible participation of genotoxic mechanisms in MEG-induced hepatocarcinogenesis.

MEG


Input: Temperature controlled water/oil wettability of a surface fabricated by a block copolymer: application as a dual water/oil on-off switch.


Input: A temperature controlled dual water/oil on-off switch is achieved by using a PMMA-b-PNIPAAm block-copolymer coated mesh, determined by the conformational change of the PNIPAAm chain around the lower critical solution temperature (LCST) and also the cooperation between PNIPAAm and PMMA.

PMMA-b-PNIPAAm

PNIPAAm

PNIPAAm

PMMA


Input: Water can permeate through the BCP-coated mesh, and oil cannot below the LCST, whereas oil can and water cannot above the LCST.


Input: Resolving sub-molecular binding and electrical switching mechanisms of single proteins at electroactive conducting polymers.


Input: Polymer-based electrodes for interfacing biological tissues are becoming increasingly sophisticated.


Input: Their many functions place them at the cross-roads of electromaterials, biomaterials, and drug-delivery systems.


Input: For conducting polymers, the mechanism of conductivity requires doping with anionic molecules such as extracellular matrix molecules, a process that distinguishes them as biomaterials and provides a means to control interactions at the cellular-electrode interface.


Input: However, due to their complex structure, directly observing the selective binding of target molecules or proteins has so far eluded researchers.


Input: This situation is compounded by the polymer' s ability to adopt different electronic states that alter the polymer-dopant interactions.


Input: Here, the ability to resolve sub-molecular binding specificity between sulfate and carboxyl groups of dopants and heparin binding domains of human plasma fibronectin is demonstrated.

carboxyl


Input: The interaction exploits a form of biological' charge complementarity' to enable specificity.


Input: When an electrical signal is applied to the polymer, the specific interaction is switched to a non-specific, high-affinity binding state that can be reversibly controlled using electrochemical processes.


Input: Both the specific and non-specific interactions are integral for controlling protein conformation and dynamics.


Input: These details, which represent the first direct measurement of biomolecular recognition between a single protein and any type of organic conductor, give new molecular insight into controlling cellular interactions on these polymer surfaces.


Input: The iron chelator, deferasirox, as a novel strategy for cancer treatment: oral activity against human lung tumor xenografts and molecular mechanism of action.

iron

deferasirox


Input: Deferasirox is an orally effective iron (Fe) chelator currently used for the treatment of iron-overload disease and has been implemented as an alternative to the gold standard chelator, desferrioxamine (DFO).

Deferasirox

iron

Fe

iron

desferrioxamine

DFO


Input: Earlier studies demonstrated that DFO exhibits anticancer activity due to its ability to deplete cancer cells of iron.

DFO

iron


Input: In this investigation, we examined the in vitro and in vivo activity of deferasirox against cells from human solid tumors.


Input: To date, there have been no studies to investigate the effect of deferasirox on these types of tumors in vivo.

deferasirox


Input: Deferasirox demonstrated similar activity at inhibiting proliferation of DMS-53 lung carcinoma and SK-N-MC neuroepithelioma cell lines compared with DFO.

Deferasirox

DFO


Input: Furthermore, deferasirox was generally similar or slightly more effective than DFO at mobilizing cellular (59) Fe and inhibiting iron uptake from human transferrin depending on the cell type.

deferasirox

DFO

(59) Fe


Input: However, deferasirox potently inhibited DMS-53 xenograft growth in nude mice when given by oral gavage, with no marked alterations in normal tissue histology.

deferasirox


Input: To understand the antitumor activity of deferasirox, we investigated its effect on the expression of molecules that play key roles in metastasis, cell cycle control, and apoptosis.

deferasirox


Input: We demonstrated that deferasirox increased expression of the metastasis suppressor protein N-myc downstream-regulated gene 1 and upregulated the cyclin-dependent kinase inhibitor p21 (CIP1/WAF1) while decreasing cyclin D1 levels.

deferasirox


Input: Moreover, this agent increased the expression of apoptosis markers, including cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase 1.

poly (ADP-ribose)


Input: Collectively, we demonstrate that deferasirox is an orally effective antitumor agent against solid tumors.

deferasirox


Input: Nature of halogen bonding.

halogen


Input: A study based on the topological analysis of the Laplacian of the electron charge density and an energy decomposition analysis.


Input: In this work we investigate the nature of the Cl... N interactions in complexes formed between substituted ammonium [NHn (X3-n) (with n = 0, 1, 2, 3 and X =-CH3,-F] as Lewis bases and F-Cl molecule as Lewis acid.

Cl

N

NHn (X3-n)

F

Lewis bases

F

Cl

Lewis acid


Input: They have been chosen as a study case due to the wide range of variation of their binding energies, BEs.


Input: M o ller-Plesset [MP2/6-311 + + G (2d, 2p)] calculations show that the BEs for this set of complexes lie in the range from 1. 27 kcal/mol (in F-Cl... NF3) to 27. 62 kcal/mol [in F-Cl... N (CH3) 3].

F

Cl

F

Cl

N (CH3) 3


Input: The intermolecular distribution of the electronic charge density and their L (r) =-(1/4) nabla (2) rho (r) function have been investigated within the framework of the atoms in molecules (AIM) theory.


Input: The intermolecular interaction energy decomposition has also been analyzed using the reduced variational space (RVS) method.


Input: The topological analysis of the L (r) function reveals that the local topological properties measured at the (3, + 1) critical point [in L (r) topology] are good descriptors of the strength of the halogen bonding interactions.

halogen


Input: The results obtained from energy decomposition analysis indicate that electrostatic interactions play a key role in these halogen bonding interactions.

halogen


Input: These results allow us to establish that, when the halogen atom is bonded to a group with high electron-withdrawing capacity, the electrostatic interaction between the electron cloud of the Lewis base and the halogen atom unprotected nucleus of the Lewis acid produces the formation and determines the geometry of the halogen bonded complexes.

halogen

Lewis base

halogen

Lewis acid

halogen


Input: In addition, a good linear relationship has been established between: the natural logarithm of the BEs and the electrostatic interaction energy between electron charge distribution of N atom and nucleus of Cl atom, denoted as V e-n (N, Cl) within the AIM theory.

N

Cl

N

Cl


Input: Contamination, parasitism and condition of Anguilla anguilla in three Italian stocks.


Input: In conjunction with habitat loss and overfishing, pollution and parasitism are believed to be relevant causes of collapse of Anguilla, as these can affect eel swimming ability and the development of gonads and embryos.


Input: The present study investigated Persistent Organic Pollutant (POP) concentrations, infection levels of Anguillicoloides crassus, lipid content and gonad abnormalities in eels sampled in 2007-2008 in three Italian water bodies (Caprolace Lake, Lesina Lagoon and Tevere River) that vary in salinity, trophic condition, contamination level and fishing pressure.


Input: Our analysis revealed that low-to-moderate levels of contamination and parasitism were not associated with gonad abnormalities in Caprolace Lake and Lesina Lagoon.


Input: On the contrary, POP concentrations and abundances of swim bladder nematodes were remarkably high in eels from the heavily urbanized Tevere River and were associated with significant gonad and swim bladder alterations.


Input: Contamination and infestation levels were so high to potentially impair spawner successful migration and reproduction.


Input: POP concentrations in Tevere eels also exceeded levels considered safe for food consumption.


Input: Though marginally contaminated, eels from the oligotrophic Caprolace Lake were in critical health condition: their lipid reserve was so low as to be considered insufficient to sustain the energetic costs of the transoceanic migration.


Input: Lesina eel stock was the only one displaying relatively good quality but here spawner abundance is likely limited by overfishing.


Input: Our results suggest that multiple stressors may potentially affect eel reproductive success.


Input: More definitive studies are needed to assess whether health effects caused by these multiple stressors are additive, compensatory or synergistic.


Input: Induction of hepatic multidrug resistance-associated protein 3 by ethynylestradiol is independent of cholestasis and mediated by estrogen receptor.

ethynylestradiol

estrogen


Input: Multidrug resistance-associated protein 3 (Mrp3; Abcc3) expression and activity are up-regulated in rat liver after in vivo repeated administration of ethynylestradiol (EE), a cholestatic synthetic estrogen, whereas multidrug resistance-associated protein 2 (Mrp2) is down-regulated.

ethynylestradiol

estrogen


Input: This study was undertaken to determine whether Mrp3 induction results from a direct effect of EE, independent of accumulation of any endogenous common Mrp2/Mrp3 substrates resulting from cholestasis and the potential mediation of estrogen receptor (ER).

estrogen


Input: In in vivo studies, male rats were given a single, noncholestatic dose of EE (5 mg/kg s. c.), and basal bile flow and the biliary excretion rate of bile salts and glutathione were measured 5 hours later.

bile salts

glutathione


Input: This treatment increased Mrp3 mRNA by 4-fold, detected by real-time polymerase chain reaction, despite the absence of cholestasis.


Input: Primary culture of rat hepatocytes incubated with EE (1-10 micro M) for 5 hours exhibited a 3-fold increase in Mrp3 mRNA (10 micro M), consistent with in vivo findings.


Input: The increase in Mrp3 mRNA by EE was prevented by actinomycin D, indicating transcriptional regulation.

actinomycin D


Input: When hepatocytes were incubated with an ER antagonist [7 alpha, 17 beta-[9-[(4, 4, 5, 5, 5-Pentafluoropentyl) sulfinyl] nonyl] estra-1, 3, 5 (10)-triene-3, 17-diol (ICI182/780), 1 micro M], in addition to EE, induction of Mrp3 mRNA was abolished, implicating ER as a key mediator.

7 alpha, 17 beta-[9-[(4, 4, 5, 5, 5-Pentafluoropentyl) sulfinyl] nonyl] estra-1, 3, 5 (10)-triene-3, 17-diol


Input: EE induced an increase in ER-alpha phosphorylation at 30 minutes and expression of c-Jun, a well-known ER target gene, at 60 minutes, as detected by Western blotting of nuclear extracts.


Input: These increases were prevented by ICI182/780.


Input: In summary, EE increased the expression of hepatic Mrp3 transcriptionally and independently of any cholestatic manifestation and required participation of an ER, most likely ER-alpha, through its phosphorylation.


Input: Cell loss and autophagy in the extra-adrenal chromaffin organ of Zuckerkandl are regulated by glucocorticoid signalling.


Input: Neuroendocrine chromaffin cells exist in both intra-and extra-adrenal locations; the organ of Zuckerkandl (OZ) constitutes the largest accumulation of extra-adrenal chromaffin tissue in mammals.


Input: The OZ disappears postnatally by modes that are still enigmatic but can be maintained by treatment with glucocorticoids (GC).


Input: Whether the response to GC reflects a pharmacological or a physiological role of GC has not been clarified.


Input: Using mice with a conditional deletion of the GC-receptor (GR) gene restricted to cells expressing the dopamine beta-hydroxylase (DBH) gene [GR (fl/fl); DBHCre abbreviated (GR (DBHCre))], we now present the first evidence for a physiological role of GC signalling in the postnatal maintenance of the OZ: postnatal losses of OZ chromaffin cells in GR (DBHCre) mice are doubled compared to wild-type littermates.

dopamine


Input: We find that postnatal cell loss in the OZ starts at birth and is accompanied by autophagy.


Input: Electron microscopy reveals autophagic vacuoles and autophagolysosomes in chromaffin cells.


Input: Autophagy in OZ extra-adrenal chromaffin cells is confirmed by showing accumulation of p62 protein, which occurs, when autophagy is blocked by deleting the Atg5 gene (Atg5 (DBHCre) mice).


Input: Cathepsin-D, a lysosomal marker, is expressed in cells that surround chromaffin cells and are positive for the macrophage marker BM8.


Input: Macrophages are relatively more abundant in mice lacking the GR, indicating more robust elimination of degenerating chromaffin cells in GR (DBHCre) mice than in wild-type littermates.


Input: In summary, our results indicate that extra-adrenal chromaffin cells in the OZ show signs of autophagy, which accompany their postnatal numerical decline, a process that is controlled by GR signalling.


Input: Synergistic immunosuppressive effects of the mTOR inhibitor sirolimus and the phytochemical curcumin.

sirolimus

curcumin


Input: The immunosuppressant sirolimus and curcumin, the main principle of the turmeric spice, have shown antiproliferative effects on many human and not-human cell lines.

sirolimus

curcumin


Input: Whereas the antiproliferative effect of sirolimus is mainly mediated by inhibition of mTOR, curcumin is described to affect many molecular targets which makes it unpredictable to appraise if the effects of these both substances on cell proliferation and especially on immunosuppression are additive or synergistic.

sirolimus

curcumin


Input: To answer this question we investigated the interaction of both these substances on OKT3-induced human peripheral blood mononuclear cell (PBMC) proliferation.


Input: OKT3-induced human PBMC proliferation was determined by measuring (3) H-thymidine incorporation.

(3) H-thymidine


Input: Influence of curcumin on interleukin-2 (IL-2) release and I kappa B-phosphorylation in PBMC was determined by ELISA and western blot, respectively.

curcumin


Input: Curcumin-induced apoptosis and necrosis was analyzed by FACS analysis.

Curcumin


Input: Whereas curcumin completely inhibited OKT3-induced PBMC proliferation in a dose-dependent manner with an IC (50) of 2. 8 mu M, sirolimus could reduce PBMC proliferation dose-dependently only to a minimum of 28% at a concentration of 5 ng/ml (IC (50) 1. 1 ng/ml).

curcumin

sirolimus


Input: When curcumin was combined at concentrations of 1. 25-2. 5 mu M with sirolimus at concentrations from 0. 63 to 1. 25 ng/ml the effects were synergistic.

curcumin

sirolimus


Input: Combination of curcumin (1. 25-2. 5 mu M) with sirolimus (5 ng/ml) showed additive effects.

curcumin

sirolimus


Input: The effects after combination of curcumin at 5 mu M with each sirolimus concentration and sirolimus at 10 ng/ml with each curcumin concentration were presumably antagonistic.

curcumin

sirolimus

sirolimus

curcumin


Input: We conclude that the immunosuppressive effects of curcumin and sirolimus in low concentrations are synergistic in OKT3-activated PBMC.

curcumin

sirolimus


Input: Whether curcumin and sirolimus have also synergistic antiproliferative effects in tumor cells has to be shown in further experiments including animal models.

curcumin

sirolimus


Input: Patterned assembly of quantum dots onto surfaces modified with click microcontact printing.


Input: The self-assembly of CdSe quantum dots (QDs) onto a patterned silica surface generated from surface microcontact click printing is presented.


Input: The mechanically robust self-assembly process produces patterns of QDs which remain steadfast, even as subsequent reactions are performed on the substrate, demonstrating the utility and ease of this self-assembly process.


Input: Pluripotent stem cells escape from senescence-associated DNA methylation changes.


Input: Pluripotent stem cells evade replicative senescence, whereas other primary cells lose their proliferation and differentiation potential after a limited number of cell divisions, and this is accompanied by specific senescence-associated DNA methylation (SA-DNAm) changes.


Input: Here, we investigate SA-DNAm changes in mesenchymal stromal cells (MSC) upon long-term culture, irradiation-induced senescence, immortalization, and reprogramming into induced pluripotent stem cells (iPSC) using high-density HumanMethylation450 BeadChips.


Input: SA-DNAm changes are highly reproducible and they are enriched in intergenic and nonpromoter regions of developmental genes.


Input: Furthermore, SA-hypomethylation in particular appears to be associated with H3K9me3, H3K27me3, and Polycomb-group 2 target genes.


Input: We demonstrate that ionizing irradiation, although associated with a senescence phenotype, does not affect SA-DNAm.


Input: Furthermore, overexpression of the catalytic subunit of the human telomerase (TERT) or conditional immortalization with a doxycycline-inducible system (TERT and SV40-TAg) result in telomere extension, but do not prevent SA-DNAm.

doxycycline


Input: In contrast, we demonstrate that reprogramming into iPSC prevents almost the entire set of SA-DNAm changes.


Input: Our results indicate that long-term culture is associated with an epigenetically controlled process that stalls cells in a particular functional state, whereas irradiation-induced senescence and immortalization are not causally related to this process.


Input: Absence of SA-DNAm in pluripotent cells may play a central role for their escape from cellular senescence.


Input: Fungicide prochloraz and environmental pollutant dioxin induce the ABCG2 transporter in bovine mammary epithelial cells by the arylhydrocarbon receptor signaling pathway.

prochloraz

dioxin

arylhydrocarbon


Input: The molecular mechanisms by which environmental pollutants including 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) or widely used imidazole fungicide prochloraz display their toxic effects in vertebrates are still not well understood.

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

TCDD

imidazole

prochloraz


Input: Using computer analysis, we recently identified nuclear aryl hydrocarbon receptor (AhR) binding sites termed " dioxin response elements " (DREs) in the 5'-untranslated region (5'-UTR) of efflux transporter ABCG2 (Accession No. EU570105) from the bovine mammary gland.

aryl hydrocarbon

dioxin


Input: As these regulatory motifs mediate regulation of target genes by AhR agonists including TCDD and prochloraz, we have systematically investigated the effect of both contaminants on functional ABCG2 transport activity in primary bovine mammary epithelial cells.

TCDD

prochloraz


Input: TCDD or prochloraz doubled ABCG2-mediated Hoechst H33342 secretion.

TCDD

prochloraz

Hoechst H33342


Input: This effect was almost completely reversed by specific ABCG2 inhibitor Ko143.


Input: In further mechanistic studies, we showed that this induction was due to binding of activated AhR to DRE sequences in the ABCG2 5'-UTR.


Input: Receptor binding was significantly reduced by specific AhR antagonist salicyl amide.

salicyl amide


Input: Induction of AhR by TCDD and prochloraz resulted in a time-and dose-dependent increase of ABCG2 gene expression and transporter protein levels.

TCDD

prochloraz


Input: As ABCG2 represents the main mammary transporter for xenobiotics including drugs and toxins, exposure to prevalent AhR agonists may enhance transporter-mediated secretion of potential harmful compounds into milk.


Input: Through identification of mammary ABCG2 as a novel target gene of pesticide prochloraz and dioxin, our results may therefore help to improve the protection of breast-feeding infants and the consumer of dairy products.

prochloraz

dioxin


Input: Chlorine-enhanced surface mobility of Au (100).

Chlorine

Au


Input: Motivated by experimental studies of two-dimensional Ostwald ripening on Au (100) electrodes in chlorine-containing electrolytes, we have studied diffusion processes using density functional theory.

Au

chlorine


Input: We find that chlorine has a propensity to temporary form AuCl complexes, which diffuse significantly faster than gold adatoms.

chlorine

AuCl


Input: With and without chlorine, the lowest activation energy is found for the exchange mechanism.

chlorine


Input: Chlorine furthermore reduces the activation energy for the detachment from kink sites.

Chlorine


Input: Kinetic Monte Carlo simulations were performed on the basis of extensive density functional theory calculations.


Input: The island-decay rate obtained from these Monte Carlo simulations, as well as the decay rate obtained from the theoretical activation energies and frequency factors when inserted into analytical solutions for Ostwald ripening, are in agreement with experimental island-decay rates in chlorine-containing electrolytes.

chlorine


Input: Histone deacetylase 3 is required for maintenance of bone mass during aging.


Input: Histone deacetylase 3 (Hdac3) is a nuclear enzyme that removes acetyl groups from lysine residues in histones and other proteins to epigenetically regulate gene expression.

lysine


Input: Hdac3 interacts with bone-related transcription factors and co-factors such as Runx2 and Zfp521, and thus is poised to play a key role in the skeletal system.


Input: To understand the role of Hdac3 in osteoblasts and osteocytes, Hdac3 conditional knockout (CKO) mice were created with the osteocalcin (OCN) promoter driving Cre expression.


Input: Hdac3 CKO (OCN) mice were of normal size and weight, but progressively lost trabecular and cortical bone mass with age.


Input: The Hdac3 CKO (OCN) mice exhibited reduced cortical bone mineralization and material properties and suffered frequent fractures.


Input: Bone resorption was lower, not higher, in the Hdac3 CKO (OCN) mice, suggesting that primary defects in osteoblasts caused the reduced bone mass.


Input: Indeed, reductions in bone formation were observed.


Input: Osteoblasts and osteocytes from Hdac3 CKO (OCN) mice showed increased DNA damage and reduced functional activity in vivo and in vitro.


Input: Thus, Hdac3 expression in osteoblasts and osteocytes is essential for bone maintenance during aging.


Input: Zymosan induces NADPH oxidase activation in human neutrophils by inducing the phosphorylation of p47phox and the activation of Rac2: involvement of protein tyrosine kinases, PI3Kinase, PKC, ERK1/2 and p38MAPkinase.

NADPH

tyrosine


Input: Reactive oxygen species (ROS) production by the neutrophil NADPH oxidase plays a key role in host defense against pathogens, such as bacteria and fungi.

oxygen

NADPH


Input: Zymosan a cell-wall preparation from Saccharomyces cerevisiae is largely used to activate neutrophils in its opsonized form.


Input: In this study, we show that non-opsonized zymosan alone induced ROS production by human neutrophils.


Input: Zymosan-induced ROS production is higher than the formyl-methionyl-leucyl-phenylalanine (fMLF)-or the phorbol myristate acetate (PMA)-induced ROS production but is lower than the one induced by opsonized zymosan.

formyl-methionyl-leucyl-phenylalanine

fMLF

phorbol myristate acetate

PMA


Input: Most of the zymosan-induced ROS production is intracellular.


Input: Interestingly, zymosan induced the phosphorylation of the NADPH oxidase cytosolic component p47phox on several sites which are Ser315, Ser328 and Ser345.

NADPH


Input: Zymosan induced also the activation of the small G-protein Rac2.


Input: Phosphorylation of the p47phox as well as Rac2 activation were inhibited by genistein a broad range protein tyrosine kinase inhibitor and by wortmannin a PI3Kinase inhibitor.

genistein

tyrosine

wortmannin


Input: GF109203X a PKC inhibitor inhibited phosphorylation of p47phox on Ser315 and Ser328.


Input: SB203580 and UO126, inhibitors of p38MAPK and ERK1/2-pathway, respectively, inhibited phosphorylation of p47phox on Ser345.


Input: Zymosan-induced ROS production was completely inhibited by genistein and wortmannin and partially inhibited by SB203580, UO126 and GF109203X.

genistein

wortmannin


Input: These results show that zymosan alone is able to activate NADPH oxidase in human neutrophils via the phosphorylation of p47phox and Rac2 activation and that a protein tyrosine kinase, PI3Kinase, p38MAPK, ERK1/2 and PKC are involved in this process.

NADPH

tyrosine


Input: These pathways could be potential pharmacological targets to treat zymosan-and S. cerevisiae-induced inflammation.


Input: Solid dispersions for preparation of phototoxic supersaturated solutions for antimicrobial photodynamic therapy (aPDT): Studies on curcumin and curcuminoides L.

curcumin


Input: Curcumin is under investigation as a potential photosensitizer (PS) in antimicrobial photodynamic therapy (aPDT).

Curcumin


Input: The therapeutic potential of curcumin as a PS is limited by its low aqueous solubility, susceptibility to hydrolytic and photolytic degradation, and limited phototoxicity toward Gram negative (G-) bacteria.

curcumin


Input: Supersaturated solutions of curcumin have demonstrated high phototoxicity toward several species of Gram positive (G +) bacteria as well as the G-Escherichia (E) coli.

curcumin


Input: Thus, solid dispersions that can form supersaturated solutions of curcumin upon hydration may be beneficial in aPDT.

curcumin


Input: In the present study, solid dispersions of curcumin have been prepared through lyophilization of concentrated solutions obtained from dissolution of hydroxypropyl-beta-cyclodextrin (HP beta CD)-curcumin co-precipitates.

curcumin

hydroxypropyl-beta-cyclodextrin

HP beta CD

curcumin


Input: Hydroxypropyl methylcellulose (HPMC) was added to curcumin solutions prior to lyophilization.

Hydroxypropyl

curcumin


Input: The resulting lyophilizates were porous, amorphous and hydrated and dissolved rapidly in contact with a model physiological salt solution.


Input: The detected drug load of the lyophilizates was in the range 0. 5-1. 0% (w/w) and was dependent on the selected ratio between HP beta CD and curcumin in the co-precipitate.

HP beta CD

curcumin


Input: The lyophilizate with the highest drug load could easily be dissolved in aqueous medium to form curcumin solutions of relevant concentrations for aPDT (i. e., 10 mu M).

curcumin


Input: Selected solutions of the curcumin solid dispersions showed a pronounced decrease in curcumin concentration up to 90% after storage for 168h, which indicated that supersaturated curcumin solutions were initially formed upon dissolution of the lyophilizates.

curcumin

curcumin

curcumin


Input: Both freshly prepared and 2days old solutions of one selected curcumin lyophilizate induced significant inactivation of E. coli (~ 1% bacterial survival) after exposure to a light dose of only 5J/cm (2).

curcumin


Input: In vivo-in vitro comparison of acute respiratory tract toxicity using human 3D airway epithelial models and human A549 and murine 3T3 monolayer cell systems.


Input: The usefulness of in vitro systems to predict acute inhalation toxicity was investigated.


Input: Nineteen substances were tested in three-dimensional human airway epithelial models, EpiAirway (TM) and MucilAir (TM), and in A549 and 3T3 monolayer cell cultures.


Input: IC (50) values were compared to rat four-hour LC (50) values classified according to EPA and GHS hazard categories.


Input: Best results were achieved with a prediction model distinguishing toxic from non-toxic substances, with satisfactory specificities and sensitivities.


Input: Using a self-made four-level prediction model to classify substances into four in vitro hazard categories, in vivo-in vitro concordance was mediocre, but could be improved by excluding substances causing pulmonary edema and emphysema in vivo.


Input: None of the test systems was outstanding, and there was no evidence that tissue or monolayer systems using respiratory tract cells provide an added value.


Input: However, the test systems only reflected bronchiole epithelia and alveolar cells and investigated cytotoxicity.


Input: Effects occurring in other cells by other mechanisms could not be recognised.


Input: Further work should optimise test protocols and expand the set of substances tested to define applicability domains.


Input: In vivo respiratory toxicity data for in vitro comparisons should distinguish different modes of action, and their relevance for human health effects should be ensured.


Input: Nitrogen-containing bisphosphonates induce apoptosis of hematopoietic tumor cells via inhibition of Ras signaling pathways and Bim-mediated activation of the intrinsic apoptotic pathway.

Nitrogen

bisphosphonates


Input: Nitrogen-containing bisphosphonates (N-BPs) induce apoptosis in tumor cells by inhibiting the prenylation of small G-proteins.

Nitrogen

bisphosphonates

N

BPs


Input: However, the details of the apoptosis-inducing mechanism remain obscure.


Input: The present study showed that the induction of apoptosis by N-BPs in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of geranylgeranyl pyrophosphate (GGPP) biosynthesis.

N

BPs

geranylgeranyl pyrophosphate

GGPP


Input: Furthermore, N-BPs decreased the levels of phosphorylated extracellular signal-regulated kinase (ERK) and mTOR via suppression of Ras prenylation and enhanced Bim expression.

N

BPs


Input: The present results indicated that N-BPs induce apoptosis by decreasing the mitochondrial transmembrane potential, increasing the activation of caspase-9 and caspase-3, and enhancing Bim expression through inhibition of the Ras/MEK/ERK and Ras/mTOR pathways.

N

BPs


Input: The accumulation of N-BPs in bones suggests that they may act more effectively on tumors that have spread to bones or on Ras-variable tumors.

N

BPs


Input: This is the first study to show that the specific molecular pathways of N-BP-induced apoptosis.

N


Input: Changes in women' s feelings about their romantic relationships across the ovulatory cycle.


Input: According to the dual mating hypothesis, women possess two overlapping suites of mate-choice mechanisms: one leading to preferences for sexually desirable men who have high-fitness genes and one leading to preferences for men who are able to invest in a woman and her children.


Input: Evidence increasingly demonstrates that women' s preference for sexual desirability (but not investment attractiveness) increases when women are most fertile within the ovulatory cycle.


Input: Little is known, however, about the implications of these preference shifts for women' s relationships with their long-term partners.


Input: Using luteinizing hormone tests to verify ovulation, across two studies (Samples 1 and 2), we found that women whose partners were relatively low in sexual desirability felt less close to their partner (Samples 1 and 2) and were more critical of their partner' s faults (Sample 2) on high-fertility days of the cycle just prior to ovulation compared with low-fertility days of the cycle.


Input: Women whose partners were relatively high in sexual desirability felt closer to their partner (Sample 1) and more satisfied with their relationship (Sample 2) on high-than low-fertility days of the cycle.


Input: There were no such shifts in women' s commitment to their relationship.


Input: Therefore, partner sexual desirability predicts women' s high-fertility assessments of relationship quality but not their intentions to stay in their relationship, consistent with the dual mating hypothesis.


Input: These findings suggest that variations across the ovulation cycle in women' s reproductive hormones play an important role in relationship dynamics.


Input: Aryl hydrocarbon receptor-mediated disruption of contact inhibition is associated with connexin43 downregulation and inhibition of gap junctional intercellular communication.

Aryl hydrocarbon


Input: The aryl hydrocarbon receptor (AhR) contributes to the control of cell-to-cell communication, cell adhesion, migration or proliferation.

aryl hydrocarbon


Input: In the present study, we investigated the regulation of connexin43 (Cx43) and Cx43-mediated gap junctional intercellular communication (GJIC) during the AhR-dependent disruption of contact inhibition in non-tumorigenic liver epithelial cells.


Input: The contact inhibition of cell proliferation is a process restricting the cell division of confluent non-transformed cells, which is frequently abolished in cancer cells; however, the mechanisms contributing to its disruption are still only partially understood.


Input: Disruption of contact inhibition, which was induced by toxic AhR ligands 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) or polycyclic aromatic hydrocarbons in epithelial WB-F344 cells, reduced Cx43 protein levels, possibly via enhanced proteasomal degradation, significantly decreased the amount of gap junction plaques and downregulated GJIC, in an AhR-dependent manner.

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

TCDD

polycyclic aromatic hydrocarbons


Input: Although both intracellular and membrane Cx43 pools were markedly reduced in cells released from contact inhibition by TCDD, siRNA-mediated Cx43 knock-down was not sufficient to stimulate proliferation in contact-inhibited cells.

TCDD


Input: Our data suggest that downregulation of Cx43/GJIC in non-transformed epithelial cells is an inherent part of disruption of contact inhibition, which occurs at the post-transcriptional level.


Input: This process runs in parallel with alterations of other forms of cell-to-cell communication, thus suggesting that toxic AhR agonists may simultaneously abrogate contact inhibition and reduce GJIC, two essential mechanisms linked to deregulation of cell-to-cell communication during tumor promotion and progression.


Input: Actinin-4 in keratinocytes regulates motility via an effect on lamellipodia stability and matrix adhesions.


Input: During wound repair, epidermal cells at the edge of an injury establish front-rear polarity through orchestrated changes in their cytoskeleton and adhesion structures.


Input: The polarity and directed migration of such cells is determined by the assembly, extension, and stabilization of a lamellipodium.


Input: Actinin-4 associates with lamellipodia and has been implicated in regulating lamellipodial structure, function and assembly.


Input: To study the functions of actinin-4 in human keratinocytes, we used shRNA to generate knockdown cells and compared their motility behavior and matrix adhesion assembly to scrambled shRNA treated control keratinocytes.


Input: Actinin-4 knockdown keratinocytes lack polarity, assemble multiple lamellipodia with a 2 x increased area over controls, display reduced activity of the actin remodeling protein cofilin, and fail to migrate in a directional manner.


Input: This motility defect is rescued by plating knockdown cells on preformed laminin-332 matrix.


Input: In actinin-4-knockdown keratinocytes, focal contact area is increased by 25%, and hemidesmosome proteins are mislocalized.


Input: Specifically, alpha 6 beta 4 integrin localizes to large lamellipodial extensions, displays reduced dynamics, and fails to recruit its bullous pemphigoid antigen binding partners.


Input: Together, our data indicate a role for actinin-4 in regulating the steering mechanism of keratinocytes via profound effects on their matrix adhesion sites.


Input: PGC-1 alpha improves glucose homeostasis in skeletal muscle in an activity-dependent manner.

glucose


Input: Metabolic disorders are a major burden for public health systems globally.


Input: Regular exercise improves metabolic health.


Input: Pharmacological targeting of exercise mediators might facilitate physical activity or amplify the effects of exercise.


Input: The peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) largely mediates musculoskeletal adaptations to exercise, including lipid refueling, and thus constitutes such a putative target.


Input: Paradoxically, forced expression of PGC-1 alpha in muscle promotes diet-induced insulin resistance in sedentary animals.


Input: We show that elevated PGC-1 alpha in combination with exercise preferentially improves glucose homeostasis, increases Krebs cycle activity, and reduces the levels of acylcarnitines and sphingosine.

glucose

acylcarnitines

sphingosine


Input: Moreover, patterns of lipid partitioning are altered in favor of enhanced insulin sensitivity in response to combined PGC-1 alpha and exercise.


Input: Our findings reveal how physical activity improves glucose homeostasis.


Input: Furthermore, our data suggest that the combination of elevated muscle PGC-1 alpha and exercise constitutes a promising approach for the treatment of metabolic disorders.


Input: PAQR3 modulates insulin signaling by shunting phosphoinositide 3-kinase p110 alpha to the Golgi apparatus.


Input: Phosphoinositide 3-kinase (PI3K) mediates insulin actions by relaying signals from insulin receptors (IRs) to downstream targets.


Input: The p110 alpha catalytic subunit of class IA PI3K is the primary insulin-responsive PI3K implicated in insulin signaling.


Input: We demonstrate here a new mode of spatial regulation for the p110 alpha subunit of PI3K by PAQR3 that is exclusively localized in the Golgi apparatus.


Input: PAQR3 interacts with p110 alpha, and the intracellular targeting of p110 alpha to the Golgi apparatus is reduced by PAQR3 downregulation and increased by PAQR3 overexpression.


Input: Insulin-stimulated PI3K activity and phosphoinositide (3, 4, 5)-triphosphate production are enhanced by Paqr3 deletion and reduced by PAQR3 overexpression in hepatocytes.

phosphoinositide (3, 4, 5)-triphosphate


Input: Deletion of Paqr3 enhances insulin-stimulated phosphorylation of AKT and glycogen synthase kinase 3 beta, but not phosphorylation of IR and IR substrate-1 (IRS-1), in hepatocytes, mouse liver, and skeletal muscle.


Input: Insulin-stimulated GLUT4 translocation to the plasma membrane and glucose uptake are enhanced by Paqr3 ablation.

glucose


Input: Furthermore, PAQR3 interacts with the domain of p110 alpha involved in its binding with p85, the regulatory subunit of PI3K.


Input: Overexpression of PAQR3 dose-dependently reduces the interaction of p85 alpha with p110 alpha.


Input: Thus, PAQR3 negatively regulates insulin signaling by shunting cytosolic p110 alpha to the Golgi apparatus while competing with p85 subunit in forming a PI3K complex with p110 alpha.


Input: NADPH-cytochrome P450 oxidoreductase: roles in physiology, pharmacology, and toxicology.

NADPH


Input: This is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 2012 meeting in San Diego, California, on April 25, 2012.


Input: The symposium speakers summarized and critically evaluated our current understanding of the physiologic, pharmacological, and toxicological roles of NADPH-cytochrome P450 oxidoreductase (POR), a flavoprotein involved in electron transfer to microsomal cytochromes P450 (P450), cytochrome b (5), squalene mono-oxygenase, and heme oxygenase.

NADPH

squalene

heme


Input: Considerable insight has been derived from the development and characterization of mouse models with conditional Por deletion in particular tissues or partial suppression of POR expression in all tissues.


Input: Additional mouse models with global or conditional hepatic deletion of cytochrome b (5) are helping to clarify the P450 isoform-and substrate-specific influences of cytochrome b (5) on P450 electron transfer and catalytic function.


Input: This symposium also considered studies using siRNA to suppress POR expression in a hepatoma cell-culture model to explore the basis of the hepatic lipidosis phenotype observed in mice with conditional deletion of Por in liver.


Input: The symposium concluded with a strong translational perspective, relating the basic science of human POR structure and function to the impacts of POR genetic variation on human drug and steroid metabolism.

steroid


Input: Importance of UDP-glucuronosyltransferases 2A2 and 2A3 in tobacco carcinogen metabolism.

UDP


Input: UDP-glucuronosyltransferase A1 (UGT2A1) is expressed in the lung and exhibits activity against polycyclic aromatic hydrocarbons (PAHs), suggesting UGT2A1 involvement in the local metabolism of PAH tobacco carcinogens.

UDP

polycyclic aromatic hydrocarbons

PAHs

PAH


Input: The goal of the present study was to investigate the importance of two additional UGT2A enzymes, UGT2A2 and UGT2A3, in tobacco carcinogen metabolism.


Input: Real-time polymerase chain reaction suggested that wild-type UGT2A2 had the highest expression in the breast, followed by trachea > larynx > kidney.


Input: A novel splice variant of UGT2A2 lacking exon 3 (termed UGT2A2 Delta exon3) was investigated, with UGT2A2 Delta exon3 expression determined to be 25-50% that of wild-type UGT2A2 in all tissues examined.


Input: UGT2A3 was determined to be well expressed in the liver and colon, followed by pancreas > kidney > lung > tonsil > trachea > larynx.


Input: Cell homogenates prepared from human embryonic kidney (HEK) 293 cells overexpressing wild-type UGT2A2 (termed UGT2A2 _ i1) exhibited glucuronidation activity, as observed by reverse-phase ultra-pressure liquid chromatography, against 1-hydroxy-(OH)-pyrene, 1-naphthol, and hydroxylated benzo (a) pyrene metabolites, whereas homogenates prepared from HEK293 cells overexpressing UGT2A3 only showed activity against simple PAHs like 1-OH-pyrene and 1-naphthol.

hydroxylated benzo (a) pyrene

PAHs


Input: Activity assays showed the UGT2A2 Delta exon3 protein (termed UGT2A2 _ i2) exhibited no detectable glucuronidation activity against all substrates examined; however, coexpression studies suggested that UGT2A2 _ i2 negatively modulates UGT2A2 _ i1 activity.


Input: Both UGT2A2 and UGT2A3 exhibited no detectable activity against complex PAH proximate carcinogens, tobacco-specific nitrosamines, or heterocyclic amines.

PAH

nitrosamines

heterocyclic amines


Input: These data suggest that, although UGT2A1 is the only UGT2A enzyme active against PAH proximate carcinogens (including PAH diols), both UGTs 2A1 and 2A2 play an important role in the local detoxification of procarcinogenic monohydroxylated PAH metabolites.

PAH

PAH diols

monohydroxylated PAH


Input: Low-molecular-weight CXCR4 ligands with variable spacers.


Input: Low-molecular-weight CXCR4 ligands based on known lead compounds including the 14-mer peptide T140, the cyclic pentapeptide FC131, peptide mimetics, and dipicolylamine-containing compounds were designed and synthesized.

cyclic pentapeptide FC131

dipicolylamine


Input: Three types of aromatic spacers, 1, 4-phenylenedimethanamine, naphthalene-2, 6-diyldimethanamine, and [1, 1'-biphenyl]-4, 4'-diyldimethanamine, were used to build four pharmacophore groups.

1, 4-phenylenedimethanamine

naphthalene-2, 6-diyldimethanamine

[1, 1'-biphenyl]-4, 4'-diyldimethanamine


Input: As pharmacophore groups, 2-pyridylmethyl and 1-naphthylmethyl are present in all of the compounds, and several aromatic groups and a cationic group from 1-propylguanidine and 1, 1, 3, 3-tetramethyl-2-propylguanidine were also used.

1, 1, 3, 3-tetramethyl-2-propylguanidine


Input: Several compounds showed significant CXCR4 binding affinity, and zinc (II) complexation of bis (pyridin-2-ylmethyl) amine moieties resulted in a remarkable increase in CXCR4 binding affinity.

zinc (II)

bis (pyridin-2-ylmethyl) amine


Input: Lysine 48-linked polyubiquitination of organic anion transporter-1 is essential for its protein kinase C-regulated endocytosis.

Lysine


Input: Organic anion transporter-1 (OAT1) mediates the body' s disposition of a diverse array of environmental toxins and clinically important drugs.


Input: Therefore, understanding the regulation of this transporter has profound clinical significance.


Input: We had previously established that OAT1 undergoes constitutive internalization from and recycling back to the cell surface and that acute activation of protein kinase C (PKC) inhibits OAT1 activity by reducing OAT1 cell-surface expression through accelerating its internalization from cell surface to intracellular compartments.


Input: However, the underlying mechanisms are poorly understood.


Input: In the current study, we provide novel evidence that acute activation of PKC significantly enhances OAT1 ubiquitination both in vitro and ex vivo.


Input: We further show that ubiquitination of cell-surface OAT1 increases in cells transfected with dominant negative mutant of dynamin-2, a maneuver blocking OAT1 internalization, which suggests that OAT1 ubiquitination proceeds before OAT1 internalization.


Input: Mass spectroscopy has revealed that ubiquitination of OAT1 consists of polyubiquitin chains, primarily through lysine 48 linkage.

lysine


Input: Transfection of cells with the dominant negative mutant of ubiquitin Ub-K48R, which prevents the formation of Lys48-linked polyubiquitin chains, abolishes PKC-stimulated OAT1 ubiquitination and internalization.


Input: Together, our findings demonstrate for the first time that Lys48-linked polyubiquitination is essential for PKC-regulated OAT1 trafficking.


Input: ATP binding cassette transporters in two distinct compartments of the skin contribute to transdermal absorption of a typical substrate.

ATP


Input: The role of two ATP binding cassette transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), in transdermal absorption of a typical common substrate was examined in vivo.

ATP


Input: Skin and plasma concentrations of rhodamine123 (Rho123) after dermal application were reduced in P-gp knockout (mdr1a/1b-/-) mice and were below the detection limit in P-gp and BCRP triple-knockout (mdr1a/1b/bcrp-/-) mice.


Input: Lower epidermal-to-hypodermal permeation of Rho123 in mdr1a/1b/bcrp-/-mouse skin compared to the wild-type mouse skin was confirmed in an Ussing-type chamber experiment.


Input: The reduction in skin concentration after dermal application in mdr1a/1b/bcrp-/-mice was greater in the dermis than in the epidermis, suggesting functional expressions of these transporters in two distinct skin compartments.


Input: Coadministration of the inhibitor itraconazole reduced the skin and plasma concentrations of Rho123 in the wild-type mice, but not in mdr1a/1b/bcrp-/-mice, and a marked decrease of Rho123 concentration was seen in the dermis, demonstrating that the functional activities of these transporters can be modulated in vivo.

itraconazole


Input: On the other hand, the distribution of Rho123 after intravenous infusion was higher in mdr1a/1b/bcrp-/-mice than in the wild-type mice.


Input: This supports the occurrence of vectorial transport from the skin into systemic circulation, and is consistent with the immunohistochemical localization of P-gp and BCRP in mouse dermal endothelial cells.


Input: BCRP was immunohistochemically identified in human epidermis and dermal endothelial cells.


Input: Thus, our findings show that ABC transporters in different compartments of the skin contribute to transdermal absorption of a typical substrate in vivo and can be modulated by a specific inhibitor.


Input: These findings have implications for transdermal drug delivery.


Input: A-kinase-anchoring protein-Lbc anchors I kappa B kinase beta to support interleukin-6-mediated cardiomyocyte hypertrophy.


Input: In response to stress, the heart undergoes a pathological remodeling process associated with hypertrophy and the reexpression of a fetal gene program that ultimately causes cardiac dysfunction and heart failure.


Input: In this study, we show that A-kinase-anchoring protein (AKAP)-Lbc and the inhibitor of NF-kappa B kinase subunit beta (IKK beta) form a transduction complex in cardiomyocytes that controls the production of proinflammatory cytokines mediating cardiomyocyte hypertrophy.


Input: In particular, we can show that activation of IKK beta within the AKAP-Lbc complex promotes NF-kappa B-dependent production of interleukin-6 (IL-6), which in turn enhances fetal gene expression and cardiomyocyte growth.


Input: These findings provide a new mechanistic hypothesis explaining how hypertrophic signals are coordinated and conveyed to interleukin-mediated transcriptional reprogramming events in cardiomyocytes.


Input: Identification of Dlk1-Dio3 imprinted gene cluster noncoding RNAs as novel candidate biomarkers for liver tumor promotion.


Input: The molecular events during nongenotoxic carcinogenesis and their temporal order are poorly understood but thought to include long-lasting perturbations of gene expression.


Input: Here, we have investigated the temporal sequence of molecular and pathological perturbations at early stages of phenobarbital (PB) mediated liver tumor promotion in vivo.

phenobarbital


Input: Molecular profiling (mRNA, microRNA [miRNA], DNA methylation, and proteins) of mouse liver during 13 weeks of PB treatment revealed progressive increases in hepatic expression of long noncoding RNAs and miRNAs originating from the Dlk1-Dio3 imprinted gene cluster, a locus that has recently been associated with stem cell pluripotency in mice and various neoplasms in humans.


Input: PB induction of the Dlk1-Dio3 cluster noncoding RNA (ncRNA) Meg3 was localized to glutamine synthetase-positive hypertrophic perivenous hepatocytes, suggesting a role for beta-catenin signaling in the dysregulation of Dlk1-Dio3 ncRNAs.

glutamine


Input: The carcinogenic relevance of Dlk1-Dio3 locus ncRNA induction was further supported by in vivo genetic dependence on constitutive androstane receptor and beta-catenin pathways.

androstane


Input: Our data identify Dlk1-Dio3 ncRNAs as novel candidate early biomarkers for mouse liver tumor promotion and provide new opportunities for assessing the carcinogenic potential of novel compounds.


Input: Pharmacokinetic mechanism involved in the prolonged high retention of laninamivir in mouse respiratory tissues after intranasal administration of its prodrug laninamivir octanoate.

laninamivir

laninamivir octanoate


Input: Laninamivir octanoate (LO) (Inavir; Daiichi Sankyo, Japan) is an ester prodrug of the neuraminidase inhibitor laninamivir.

Laninamivir octanoate

Inavir

ester

laninamivir


Input: We previously reported that a prolonged high retention of laninamivir in mouse respiratory tissues was achieved by intranasal administration of LO.

laninamivir


Input: In this study, we evaluated intrapulmonary pharmacokinetics both in vivo and in vitro to investigate the potential mechanism involved in such a preferable retention.


Input: After intranasal administration of LO to mice (0. 5 mu mol/kg), the drug was distributed from the airway space into the lungs, and laninamivir remained in the lung at 24 hours postdose (2680 pmol/g), with a higher concentration than that in the epithelial lining fluid.

laninamivir


Input: The laninamivir was localized mainly on the epithelial cells of airway tracts, determined by microautoradiography using (14) C-labeled LO.

laninamivir

(14) C


Input: In mouse airway epithelial cells, the cellular uptake and hydrolysis of LO were observed over incubation time without any apparent saturation at the highest concentration tested (1000 mu M).


Input: Furthermore, after additional incubation in drug-free medium, the intracellular laninamivir was released very slowly into the medium with an estimate rate constant of 0. 0707 h (-1), which was regarded as a rate-limiting step in the cellular retention.

laninamivir


Input: These results demonstrated that the prolonged high retention of laninamivir in the respiratory tissues was attributed to a consecutive series of three steps: uptake of LO into the airway epithelial cells, hydrolysis of LO into laninamivir by intracellular esterase (s), and limited efflux of the generated laninamivir due to its poor membrane permeability.

laninamivir

laninamivir

laninamivir


Input: This prodrug approach could be useful for lung-targeting drug delivery.


Input: A metabolomic study reveals novel plasma lyso-Gb3 analogs as Fabry disease biomarkers.


Input: Fabry disease is an X-linked, multisystemic lysosomal storage disorder due to alpha-galactosidase A deficiency.


Input: It is characterized by the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb (3)), in biological fluids, vascular endothelium, heart, and kidneys.


Input: Treatment by enzyme replacement therapy has been shown to be beneficial in both males and females affected with the disease.


Input: In addition to Gb (3), increased concentrations of globotriaosylsphingosine (lyso-Gb (3)) have recently been reported in urine and plasma of Fabry patients.


Input: The overall objective of this metabolomic study was to identify and characterize new potential plasma biomarkers in treated and untreated males and females affected with Fabry disease which might better reflect disease severity and progression.


Input: We employed a time-of-flight mass spectrometry metabolomic approach using plasma samples of Fabry patients compared to age-matched controls.


Input: We found three new lyso-Gb (3) analogs in Fabry patients presenting m/z ratios at 802, 804, and 820.


Input: As previously detected by our group, we also found a m/z ratio of 784 corresponding to the lyso-Gb (3) molecule minus two hydrogen atoms.

hydrogen


Input: Using exact mass measurements and tandem mass spectrometry, we confirmed that these analogs result from modifications of the lyso-Gb (3) sphingosine moiety.


Input: We evaluated the relative plasma concentration by measuring area counts for each lyso-Gb (3) analog.


Input: None of these analogs was detected in the majority of healthy controls.


Input: The relative concentration of each analog was higher in males compared to female Fabry patients.


Input: We demonstrated that mass spectrometry combined to a metabolomic approach is a powerful tool to detect and identify new potential biomarkers.


Input: Pump-Probe Microscopy: Spatially Resolved Carrier Dynamics in ZnO Rods and the Influence of Optical Cavity Resonator Modes.

ZnO


Input: Femtosecond pump-probe microscopy is used to investigate the charge recombination dynamics at different points within a single needle-shaped ZnO rod.

ZnO


Input: Recombination in the tips of the rod occurs through an excitonic or electron-hole plasma state, taking place on a picosecond time scale.


Input: Photoexcitation in the larger diameter sections of the interior exhibit dramatically slower recombination that occurs primarily through defects sites, i. e., trap mediated recombination.


Input: Transient absorption imaging shows that the spatial variation in the dynamics is also influenced by the cavity resonances supported within the hexagonal cross section of the rod.


Input: Finite element simulations suggest that these optical resonator modes produce qualitatively different intensity patterns in the two different locations.


Input: Near the end of the rod, the intensity pattern has significant standing-wave character, which leads to the creation of photoexcited carriers in the core of the structure.


Input: The larger diameter regions, on the other hand, exhibit intensity distributions in which the whispering gallery (WG) mode character dominates.


Input: At these locations, the photoexcited carriers are produced in subsurface depletion zone, where the internal fields separate the electrons and holes and lead to a greater degree of trap recombination on longer time scales.


Input: Chemical profile and biological activities of Deguelia duckeana A. M. G.


Input: Azevedo (Fabaceae).


Input: Deguelia duckeana is popularly known as timb o and used by indigenous people as ictiotoxic.


Input: On account of there being no literature pertaining to the chemical profile or biological activity of this plant, the hexane, methanol and aqueous crude extracts from leaves, stems and roots were assayed that presented very high cytotoxic potential against Artemia salina, achieving 100% mortality in up to 5. 0 micro g mL (-1) concentration, but lower antioxidant potential on 2, 2-diphenyl-1-picryl-hydrazyl and Fe (3 +)/Phenanthroline assays.

hexane

methanol

2, 2-diphenyl-1-picryl-hydrazyl

Fe (3 +)

Phenanthroline


Input: The phytochemical analysis of crude extracts showed the presence of flavonoids and related compounds as major constituents as well as steroids in all of them, and tannins in polar extracts.

flavonoids

steroids

tannins


Input: All the extracts were assayed for antibacterial activity but only the hexane extract of stems showed moderate activity on Staphylococcus aureus, which was fractionated and yielded a mixture of 3, 5, 4'-trimethoxy-4-prenylstilbene, lonchocarpine, 4-hydroxylonchocarpine and derricidine, reported for the first time in D. duckeana and other fraction with beta-sitosterol and stigmasterol mixture.

hexane

3, 5, 4'-trimethoxy-4-prenylstilbene

lonchocarpine

derricidine

beta-sitosterol

stigmasterol


Input: Lipophilic stinging nettle extracts possess potent anti-inflammatory activity, are not cytotoxic and may be superior to traditional tinctures for treating inflammatory disorders.


Input: Extracts of four plant portions (roots, stems, leaves and flowers) of Urtica dioica (the stinging nettle) were prepared using accelerated solvent extraction (ASE) involving water, hexanes, methanol and dichloromethane.

hexanes

methanol

dichloromethane


Input: The extracts were evaluated for their anti-inflammatory and cytotoxic activities in an NF-kappa B luciferase and MTT assay using macrophage immune (RAW264. 7) cells.

MTT


Input: A standardized commercial ethanol extract of nettle leaves was also evaluated.

ethanol


Input: The methanolic extract of the flowering portions displayed significant anti-inflammatory activity on par with a standard compound celastrol (1) but were moderately cytotoxic.

celastrol


Input: Alternatively, the polar extracts (water, methanol, ethanol) of the roots, stems and leaves displayed moderate to weak anti-inflammatory activity, while the methanol and especially the water soluble extracts exhibited noticeable cytotoxicity.

methanol

ethanol

methanol


Input: In contrast, the lipophilic dichloromethane extracts of the roots, stems and leaves exhibited potent anti-inflammatory effects greater than or equal to 1 with minimal cytotoxicity to RAW264. 7 cells.

dichloromethane


Input: Collectively these results suggest that using lipophilic extracts of stinging nettle may be more effective than traditional tinctures (water, methanol, ethanol) in clinical evaluations for the treatment of inflammatory disorders especially arthritis.

methanol

ethanol


Input: A chemical investigation into the lipophilic extracts of stinging nettle to identify the bioactive compound (s) responsible for their observed anti-inflammatory activity is further warranted.


Input: GH improves spatial memory and reverses certain anabolic androgenic steroid-induced effects in intact rats.


Input: GH has previously been shown to promote cognitive functions in GH-deficient rodents.


Input: In this study we report the effects of GH on learning and memory in intact rats pretreated with the anabolic androgenic steroid nandrolone.

steroid nandrolone


Input: Male Wistar rats received nandrolone decanoate (15 mg/kg) or peanut oil every third day for 3 weeks and were subsequently treated with recombinant human GH (1. 0 IU/kg) or saline for 10 consecutive days.

nandrolone decanoate


Input: During the GH/saline treatment spatial learning and memory were tested in the Morris water maze (MWM).


Input: Also, plasma levels of IGF1 were assessed and the gene expression of the GH receptors (Ghr), Igf1 and Igf2, in hippocampus and frontal cortex was analyzed.


Input: The results demonstrated a significant positive effect of GH on memory functions and increased gene expression of Igf1 in the hippocampus was found in the animals treated with GH.


Input: In addition, GH was demonstrated to increase the body weight gain and was able to attenuate the reduced body weight seen in nandrolone-treated animals.

nandrolone


Input: In general, the rats treated with nandrolone alone did not exhibit any pronounced alteration in memory compared with controls in the MWM, and in many cases GH did not induce any alteration.

nandrolone


Input: Regarding target zone crossings, considered to be associated with spatial memory, the difference between GH-and steroid-treated animals was significant and administration of GH improved this parameter in the latter group.


Input: In conclusion, GH improves spatial memory in intact rats and can reverse certain effects induced by anabolic androgenic steroid.

steroid


Input: PET and SPECT tracers for glutamate receptors.

glutamate


Input: Radioligands for PET imaging of glutamate receptors will have the potential for studying neurological and neuropsychiatric disorders and their diagnosis and therapeutic intervention.

glutamate


Input: Glutamate is the major excitatory neurotransmitter in the brain and is implicated in the pathophysiology of many neurodegenerative and neuropsychiatric disorders.

Glutamate


Input: Glutamate and its receptors are potential targets in the treatment of these disorders.

Glutamate


Input: Glutamate signaling is mediated through ionotropic and metabotropic receptors.

Glutamate


Input: The abundant concentration of these receptors can facilitate their in vivo quantification using positron emission tomography (PET).


Input: Glutamate receptors are a potentially important set of targets for monitoring disease progression, for evaluating the effect of therapy and for new treatment development based on the quantification of receptor occupancy.

Glutamate


Input: Here, we review the PET and single-photon emission computed tomography (SPECT) radioligands that have been developed for imaging glutamate receptors in living brain.

glutamate


Input: The Online Protein Processing Resource (TOPPR): a database and analysis platform for protein processing events.


Input: We here present The Online Protein Processing Resource (TOPPR; http://iomics. ugent. be/toppr/), an online database that contains thousands of published proteolytically processed sites in human and mouse proteins.


Input: These cleavage events were identified with COmbinded FRActional DIagonal Chromatography proteomics technologies, and the resulting database is provided with full data provenance.


Input: Indeed, TOPPR provides an interactive visual display of the actual fragmentation mass spectrum that led to each identification of a reported processed site, complete with fragment ion annotations and search engine scores.


Input: Apart from warehousing and disseminating these data in an intuitive manner, TOPPR also provides an online analysis platform, including methods to analyze protease specificity and substrate-centric analyses.


Input: Concretely, TOPPR supports three ways to retrieve data: (i) the retrieval of all substrates for one or more cellular stimuli or assays; (ii) a substrate search by UniProtKB/Swiss-Prot accession number, entry name or description; and (iii) a motif search that retrieves substrates matching a user-defined protease specificity profile.


Input: The analysis of the substrates is supported through the presence of a variety of annotations, including predicted secondary structure, known domains and experimentally obtained 3D structure where available.


Input: Across substrates, substrate orthologs and conserved sequence stretches can also be shown, with iceLogo visualization provided for the latter.


Input: Silicon surface functionalization targeting Si-N linkages.

Silicon

Si-N


Input: Silicon substrates have been a fascinating topic of fundamental and applied research for well over 50 years.

Silicon


Input: They have attracted even more attention over the last couple of decades with advances in chemical functionalization that made oxide-free silicon surfaces a reality.

silicon


Input: Fundamentally new electronic properties and chemical reactivity became available, and the focus of chemical research turned more toward targeting specific chemical bonds and functionalities on silicon.

silicon


Input: Although thermodynamics clearly drives most processes under ambient conditions toward the formation of an oxide layer, kinetic control of the oxidation processes and thermodynamic tricks based on gaining stability of surface monolayers with high-density assembly have allowed for the formation of stable Si-C bonds and Si-O-C linkages on oxide-free silicon crystals.

Si-C

Si-O-C

silicon


Input: This feature article targets recent advances in making Si-N linkages on the same oxide-free single crystals.

Si-N


Input: It covers the range of chemical approaches to achieving this goal and offers possible chemistry that can take advantage of the systems produced.


Input: The present status of the field and the future directions of its development will be considered.


Input: Tanshinone derivatives: a patent review (January 2006-September 2012).

Tanshinone


Input: INTRODUCTION: Tanshinone IIA (TSIIA), cryptotanshinone and tanshinone I are major bioactive constituents of Danshen, a Chinese herbal medicine.

Tanshinone IIA

TSIIA

cryptotanshinone

tanshinone I


Input: Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of TSIIA and it is currently used for treating cardiovascular diseases in China.

Sodium tanshinone IIA sulfonate

STS

TSIIA


Input: AREAS COVERED: The article presents a review of the anti-atherosclerosis, cardioprotective effects, neuroprotection and anti-tumor activities of TSIIA and a review of patents on tanshinone derivatives from January 2006 to September 2012.

TSIIA

tanshinone


Input: EXPERT OPINION: Mechanistic studies have discovered that TSIIA modulates ion channels, kinases, hormone receptors, apoptosis proteins, growth factors, cytokines, microRNA, tumor suppressor and many other targets, revealing an intricate biological network modulated by TSIIA.

TSIIA

TSIIA


Input: Many patents have attempted to overcome the low water solubility of TSIIA and tanshinone I by attaching a polar substituent or by a prodrug strategy.

TSIIA

tanshinone I


Input: However, biological activities of these tanshinone derivatives need to be further evaluated.

tanshinone


Input: Given the extensive in vitro and in vivo biological activities of TSIIA, this compound is a promising candidate to be further developed as a novel therapeutics for treating atherosclerosis, cardiovascular diseases, neurodegenerative diseases and cancer.

TSIIA


Input: Kainate receptor signaling in pain pathways.

Kainate


Input: Receptors and channels that underlie nociceptive signaling constitute potential sites of intervention for treatment of chronic pain states.


Input: The kainate receptor family of glutamate-gated ion channels represents one such candidate set of molecules.

kainate

glutamate


Input: They have a prominent role in modulation of excitatory signaling between sensory and spinal cord neurons.


Input: Kainate receptors are also expressed throughout central pain neuraxis, where their functional contributions to neural integration are less clearly defined.

Kainate


Input: Pharmacological inhibition or genetic ablation of kainate receptor activity reduces pain behaviors in a number of animal models of chronic pain, and small clinical trials have been conducted using several orthosteric antagonists.

kainate


Input: This review will cover kainate receptor function and participation in pain signaling as well as the pharmacological studies supporting further consideration as potential targets for therapeutic development.

kainate


Input: Subacute effects of ecstasy on mood: an exploration of associated risk factors.

ecstasy


Input: Ecstasy use may result in lowered mood, anxiety or aggression in the days following use.

Ecstasy


Input: Yet, few studies have investigated what factors increase the risk of experiencing such symptoms.


Input: Ecstasy users (at least once in the last 12 months) who subsequently took ecstasy (n = 35) over the period of one week, were compared on measures of mood, sleep, stress and drug use, with those who abstained from ecstasy (n = 21) that week.

Ecstasy

ecstasy

ecstasy


Input: Measures were administered the week prior to ecstasy use and one and three days following use, or the equivalent day for abstainers.

ecstasy


Input: Mood symptoms were assessed using the Kessler-10 self-report psychological distress scale, a subjective mood rating (1-10), and using the depression, anxiety and hostility items from the clinician-rated Brief Psychiatric Rating Scale.


Input: Timeline Followback methods were used to collect information on drug use and life stress in the past month.


Input: Self-reported sleep quality was also assessed.


Input: Ecstasy use was not associated with subacute depressive, anxiety or aggressive symptoms.

Ecstasy


Input: Rather, lowered mood and increased psychological distress were associated with self-reported hours and quality of sleep obtained during the three-day follow-up.


Input: These findings highlight the importance of considering sleep disruption in understanding the short-term mood effects of ecstasy use.

ecstasy


Input: Simulated microgravity exposure modulates the phenotype of cultured vascular smooth muscle cells.


Input: Evidence from ground-based animal studies using tail-suspended hindlimb unloaded rats model has clearly demonstrated that simulated microgravity-induced smooth muscle cell phenotype conversion, a characteristic vascular structural and functional remodeling, may be one of the key contributors to postspaceflight orthostatic intolerance.


Input: However, the rats model involves multiple collective effects of microgravity including cephalic fluid shift and postural muscle unloading on smooth muscle cells (SMCs).


Input: It cannot isolate a single factor from the collective ones and therefore is not ideal to study the effects of gravitational vector alteration alone on SMCs.


Input: To test the hypothesis that gravitational vector alteration per se might affect smooth muscle cell phenotype, a roller culture apparatus was employed to expose cultured rat aortic smooth muscle cells (RASMCs) to simulated microgravity.


Input: Cell proliferation, cell cycle distribution, apoptosis, migration, and nitric oxide production rates were measured and compared between the control and the simulated microgravity groups.

nitric oxide


Input: Cell cytoskeleton reorganization induced by simulated microgravity was observed by confocal microscopy.


Input: Specific contractile and synthetic Gene expression at the mRNA level was quantified by reverse transcriptional polymerase chain reaction.


Input: It was observed that simulated microgravity suppressed RASMC proliferation and migration, enhanced cell apoptosis, stimulated NO release, and destroyed the original well-organized cytoskeleton.

NO


Input: Moreover, at the mRNA level, long-time exposure (>= 72 h) to simulated microgravity induced a contractile phenotype tendency by up-regulating smMHC expression.


Input: All these findings suggest that the phenotype modulation of vascular smooth muscle cells may be gravity dependent.


Input: Antiulcerogenic activities of the extracts and isolated flavonoids of Euphorbia cuneata Vahl.

flavonoids


Input: The total alcohol extracts of Euphorbia cuneata Vahl. (Euphorbiaceae) were screened for antiulcerogenic activity using an ethanol-induced ulcer model at doses of 125, 250 and 500 mg/kg.

alcohol

ethanol


Input: The extracts possessed antiulcerogenic activity in a dose-dependent manner.


Input: Four flavonoidal compounds were isolated and identified as naringenin, aromadendrin, apigenin and 4'-O-methoxy-luteolin-7-O-rhamnoglucoside, each demonstrating antiulcerogenic activity with curative ratios ranging from 75. 78% to 88. 23%.

flavonoidal

naringenin

aromadendrin

apigenin

4'-O-methoxy-luteolin-7-O-rhamnoglucoside


Input: In addition, the alcohol extracts and isolated compounds were shown to scavenge the 1, 1-diphenyl, 2-picrylhydrazyl radical by different ratio, with the most effective being 4'-O-methoxy-luteolin-7-O-rhamnoglucoside (91. 14%).

alcohol

1, 1-diphenyl, 2-picrylhydrazyl

4'-O-methoxy-luteolin-7-O-rhamnoglucoside


Input: The antioxidant activity of the alcohol extracts and the isolated compounds may explain the antiulcerogenic properties.

alcohol


Input: No side effects were observed on either liver or kidney functions.


Input: Effects of menstrual cycle phase on cocaine self-administration in rhesus macaques.

cocaine


Input: Epidemiological findings suggest that men and women vary in their pattern of cocaine use resulting in differences in cocaine dependence and relapse rates.

cocaine

cocaine


Input: Preclinical laboratory studies have demonstrated that female rodents are indeed more sensitive to cocaine' s reinforcing effects than males, with estrous cycle stage as a key determinant of this effect.

cocaine


Input: The current study sought to extend these findings to normally cycling female rhesus macaques, a species that shares a nearly identical menstrual cycle to humans.


Input: Dose-dependent intravenous cocaine self-administration (0. 0125, 0. 0250, and 0. 0500 mg/kg/infusion) using a progressive-ratio schedule of reinforcement was determined across the menstrual cycle.

cocaine


Input: The menstrual cycle was divided into 5 discrete phases-menses, follicular, periovulatory, luteal, and late luteal phases-verified by the onset of menses and plasma levels of estradiol and progesterone.

estradiol

progesterone


Input: Dependent variables including number of infusions self-administered per session, progressive ratio breakpoint, and cocaine intake were analyzed according to cocaine dose and menstrual cycle phase.

cocaine

cocaine


Input: Analysis of plasma hormone levels verified phase-dependent fluctuations of estradiol and progesterone, with estrogen levels peaking during the periovulatory phase, and progesterone peaking during the luteal phase.

estradiol

progesterone

estrogen

progesterone


Input: Progressive ratio breakpoint, infusions self-administered, and cocaine intake did not consistently vary based on menstrual cycle phase.

cocaine


Input: These findings demonstrate that under the current experimental parameters, the reinforcing effects of cocaine did not vary across the menstrual cycle in a systematic fashion in normally cycling rhesus macaques.

cocaine


Input: The catalytic competence of cytochrome P450 in the synthesis of serotonin from 5-methoxytryptamine in the brain: an in vitro study.

serotonin


Input: Brain serotonin has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs.

serotonin


Input: The aim of present study was to identify rat cytochrome P450 (CYP) isoforms which can catalyze the O-demethylation of 5-methoxytryptamine to serotonin, and to find out whether that alternative pathway of serotonin synthesis may take place in the brain.

O

serotonin

serotonin


Input: The study was conducted on cDNA-expressed CYPs (rat CYP1A1/2, 2A1/2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6), on rat brain and liver microsomes and on human liver microsomes (the wild-type CYP2D6 or the allelic variant 2D6 * 4 * 4).


Input: Of the rat CYP isoforms studied, CYP2D isoforms were the most efficient in catalyzing the O-demethylation of 5-methoxytryptamine to serotonin, but they were less effective than the human isoform CYP2D6.

Of

serotonin


Input: Microsomes from different brain regions were capable of metabolizing 5-methoxytryptamine to serotonin.

serotonin


Input: The reaction was inhibited by the specific CYP2D inhibitors quinine and fluoxetine.

quinine

fluoxetine


Input: Human liver microsomes of the wild-type CYP2D6 metabolized 5-methoxytryptamine to serotonin more effectively than did the defective CYP2D6 * 4 * 4 ones.

serotonin


Input: The obtained results indicate that rat brain CYP2D isoforms catalyze the formation of serotonin from 5-methoxytryptamine, and that the deficit or genetic defect of CYP2D may affect serotonin metabolism in the brain.

serotonin

serotonin


Input: The results are discussed in the context of their possible physiological and pharmacological significance in vivo.


Input: A novel furanoeremophilane with an unusual oxygen bridge from Senecio nemorensis.

furanoeremophilane

oxygen


Input: Two new furanoeremophilanes, 1 alpha, 6 alpha-epoxy-9-oxo-10 beta-hydroxyl-furanoeremophilane (1), and 9-oxo-1 alpha, 6 beta, 10 beta-trihydroxy-furanoeremophilane (2) were isolated from Senecio nemorensis.

furanoeremophilanes

1 alpha, 6 alpha-epoxy-9-oxo-10 beta-hydroxyl-furanoeremophilane

9-oxo-1 alpha, 6 beta, 10 beta-trihydroxy-furanoeremophilane


Input: Their structures were elucidated by spectroscopic methods and X-ray crystallography.


Input: This is the first report of the isolation of the C1-C6 oxygen bridge of furanoeremophilane.

C1-C6 oxygen

furanoeremophilane


Input: Their cytotoxic effects on BEL7402 and NF-KB cell lines were tested.


Input: The role of transient receptor potential A 1 (TRPA1) in the development and maintenance of carrageenan-induced hyperalgesia.


Input: Transient receptor potential ankyrin 1 (TRPA1) is a nonselective cation channel important in setting nociceptive threshold.


Input: It is expressed in nociceptive C-fibers and in non-neuronal cells involved in pro-inflammatory mediators' release.


Input: We asked whether TRPA1 contributes to carrageenan-induced hyperalgesia in rats, and if so, whether this contribution is mediated by mechanisms involved in inflammation such as cytokine release and neutrophil migration and/or by a direct sensitization of the primary afferent nociceptors.


Input: Pharmacological blockade of local TRPA1 by its selective antagonist HC 030031 prevented and reversed carrageenan-induced hyperalgesia, which was detected either by a mechanical or chemical (low dose of capsaicin) stimulus.

HC 030031

capsaicin


Input: However, it did not affect either carrageenan-induced cytokines expression or neutrophil migration.


Input: The neuronal TRPA1 gene silencing induced by intrathecal pre-treatment with antisense oligodoexynucleotide completely prevented carrageenan-induced hyperalgesia over 24 h and significantly reduced TRPA1 expression in the dorsal root ganglia cells (L5-6), which was not affected by carrageenan treatment.


Input: We conclude that TRPA1 plays an important role in the development and maintenance of carrageenan-induced inflammatory hyperalgesia by directly contributing to nociceptor excitability.


Input: Caffeine reduces cadmium accumulation in the organism and enhances the levels of antioxidant protein expression in the epididymis.

Caffeine

cadmium


Input: The aim of this study was to investigate the effects of caffeine (20 mg/L) intake on cadmium (15 mg/L) accumulation in the rat blood, testes, epididymis and prostate as well as cadmium-induced changes to the antioxidant defense system of the epididymis.

caffeine

cadmium

cadmium


Input: Caffeine reduced the cadmium concentration in all tissues analyzed.

Caffeine

cadmium


Input: Meanwhile, cadmium reduced catalase activity and increased superoxide dismutase (SOD) activity in the epididymis.

cadmium

superoxide


Input: Caffeine increased SOD activity, catalase and glutathione tissue expression and sustains the cadmium' s effect on catalase and GSP-Px activity.

Caffeine

glutathione

cadmium


Input: No differences in the expression of metallothionein and lipid peroxidation were observed among the different treatments in the epididymis.


Input: In conclusion, low doses of cadmium alter the antioxidant enzymatic profile of the epididymis, but not induced oxidative lipid damage.

cadmium


Input: Caffeine intake reduces overall cadmium accumulation in the organism and enhances the levels of antioxidant protein expression in the epididymis, thus exerting a protective effect against this metal.

Caffeine

cadmium


Input: Teratogenic effects of diabetic conditions in chick heart in ovo and in micromass culture may be prevented by addition of vitamin C and folic acid.

vitamin C

folic acid


Input: Maternal diseases like diabetes mellitus may cause developmental defects.


Input: Supplementation with folic acid and vitamin C during the periconceptional period has been shown to prevent some neural tube and congenital heart defects.

folic acid

vitamin C


Input: Hearts were dissected from 5 days-old White Leghorn chick embryos, the cells isolated and cultured in micromass under diabetic conditions, with and without folic acid and vitamin C.

folic acid

vitamin C


Input: Contractile activity, cell viability (resazurin reduction) and protein assays were performed.

resazurin


Input: Results indicated diabetic conditions reduced contractile activity and cell viability, whilst vitamin C (100 mu M) and folic acid (1 mM) administered concurrently significantly improved them to values comparable with the control.

vitamin C

folic acid


Input: Day 3 chick embryos in ovo were injected with glucose + hydroxybutyrate or a combination of these and vitamins.

glucose

hydroxybutyrate


Input: Diabetic conditions caused gross and histological malformations, but these effects were abrogated by vitamin supplement.


Input: Teratogenic effects on heart development could possibly be prevented by vitamin supplementation during pregnancy.


Input: Association of NDRG1 Gene Promoter Methylation with Reduced NDRG1 Expression in Gastric Cancer Cells and Tissue Specimens.


Input: NDRG1 (N-myc downstream-regulated gene 1) plays a role in cell differentiation and suppression of tumor metastasis.


Input: This study aims to determine the expression of NDRG1 mRNA and protein in gastric cancer cell lines and tissue specimens and then assess the possible cause of its aberrant expression.


Input: Six gastric cancer cell lines and 20 pairs of normal and gastric cancer tissue samples were used to assess NDRG1 expression using Real-time PCR and Western blot.