Input: Previously, we reported the synthesis of amphiphilic polyvinyl alcohol and dextrin-based nanogel conjugates with the phosphorylated 5-FU nucleoside Floxuridine and demonstrated their enhanced activity against regular and drug-resistant cancers (T. H. Senanayake, G. Warren, S. V. Vinogradov, Novel anticancer polymeric conjugates of activated nucleoside analogs, Bioconjug. Chem. 22 (2011) 1983-1993).

polyvinyl alcohol

phosphorylated 5-FU nucleoside Floxuridine

nucleoside


Input: In this study, we synthesized and evaluated oral applications of nanogel conjugates of a protected Gemcitabine, the drug never used in oral therapies.

Gemcitabine


Input: These conjugates were able to quickly release an active form of the drug (Gemcitabine 5'-mono-, di-and triphosphates) by specific enzymatic activities, or slowly during hydrolysis.

Gemcitabine 5'-mono-, di-and triphosphates


Input: Gemcitabine conjugates demonstrated up to 127 times higher in vitro efficacy than the free drug against various cancer cells, including the lines resistant to nucleoside analogs.

Gemcitabine

nucleoside


Input: Surprisingly, these nanogel-drug conjugates were relatively stable in gastric conditions and able to actively penetrate through the gastrointestinal barrier based on permeability studies in Caco-2 cell model.


Input: In tumor xenograft models of several drug-resistant human cancers, we observed an efficient inhibition of tumor growth and extended the life-span of the animals by 3 times that of the control with orally treated Gemcitabine-or Floxuridine-nanogel conjugates.

Gemcitabine

Floxuridine


Input: Thus, we have demonstrated a potential of therapeutic nanogel conjugates with the activated and stabilized Gemcitabine as a successful oral drug form against Gemcitabine-resistant and other drug-resistant tumors.

Gemcitabine

Gemcitabine


Input: Design and synthesis of imidazole and triazole derivatives as Lp-PLA 2 inhibitors and the unexpected discovery of highly potent quaternary ammonium salts.

imidazole

triazole

quaternary ammonium salts


Input: New Lp-PLA (2) inhibitors were synthesized by the bioisosteric replacement of the amide group of Darapladib with an imidazole or a triazole.

amide

Darapladib

imidazole

triazole


Input: Unfortunately, the inhibitory activities of these derivatives were lower than that of Darapladib.

Darapladib


Input: But interestingly, a series of quaternary ammonium salts that were isolated as by-products during this synthetic work were found with high potency.

quaternary ammonium salts


Input: Of these by-products, compound 22c showed a similar profile to Darapladib both in vitro and in vivo.

Darapladib


Input: Synthesis and antibacterial activities of new piperidine substituted (5R)-[1, 2, 3] triazolylmethyl and (5R)-[(4-F-[1, 2, 3] triazolyl) methyl] oxazolidinones.

piperidine

(5R)-[1, 2, 3] triazolylmethyl and (5R)-[(4-F-[1, 2, 3] triazolyl) methyl] oxazolidinones


Input: A novel series of 5 (R)-[1, 2, 3] triazolylmethyl and (5R)-[(4-F-[1, 2, 3] triazolyl) methyl] oxazolidinones having various piperidine group were synthesized and evaluated antibacterial activity against clinically isolated resistant strains of Gram-positive and Gram-negative bacteria.

5 (R)-[1, 2, 3] triazolylmethyl and (5R)-[(4-F-[1, 2, 3] triazolyl) methyl] oxazolidinones

piperidine


Input: The compound 12a having exo-cyanoethylidene group in the 4-position of piperidine ring was found to be two to threefold more potent than the linezolid against penicillin-resistant Staphylococcus pneumonia and Staphylococcus agalactiae, and also exhibited reduced MAO-B inhibitory activity.

exo-cyanoethylidene

piperidine

linezolid

penicillin


Input: Integrated analysis of transcriptomics and metabonomics profiles in aflatoxin B1-induced hepatotoxicity in rat.

aflatoxin B1


Input: The aim of this work was to identify mechanisms and potential biomarkers for predicting the development and progression of aflatoxin B1 (AFB1)-induced acute hepatotoxicity.

aflatoxin B1


Input: In this study, microarray analysis and metabolites profiles were used to identify shifts in gene expression and metabolite levels associated with the affected physiological processes of rats treated with AFB1.


Input: Histopathological examinations and serum biochemical analysis were simultaneously performed; the results indicated that hepatotoxicity occurred in higher dosage groups.


Input: However, gene expression analysis and metabolite profiles are more sensitive than general toxicity studies for detecting AFB1-induced acute hepatotoxicity as the patterns of low-dose AFB1-treated rats in these two technique platforms were more similar to the rats in higher dosage groups than to the control rats.


Input: Integrated analysis of the results from general toxicity studies, transcriptomics and metabonomics profiles suggested that p53 signaling pathway induced by oxidative damage was the crucial step in AFB1-induced acute hepatotoxicity, whereas gluconeogenesis and lipid metabolism disorder were found to be the major metabolic effects after acute AFB1 exposure.


Input: The genes and metabolites significantly affected in common in rat liver or serum of three doses AFB1 treatments served as potential biomarkers for detecting AFB1-induced acute hepatotoxicity.


Input: QM/MM simulations of vibrational spectra of bacteriorhodopsin and channelrhodopsin-2.


Input: Channelrhodopsin-2 is a light-gated ion channel, which has been studied intensively over the last decade.


Input: Vibrational spectroscopic experiments started to shed light on the structural changes, that occur during the photocycle, especially in the hydrogen-bonded network surrounding the protonated D156 and C128-the DC gate.

hydrogen


Input: However, the interpretation of these experiments was only based on homology models.


Input: Since then, an X-ray structure and better computational models became available.


Input: In this article, we show that in combination with a recent reparametrization, the approximate DFT method, DFTB, is able to describe the effects of hydrogen bonding on the C [double bond, length as m-dash] O stretch vibration in carboxylic acids reliably and agrees well with full DFT results.

hydrogen

C

O

carboxylic acids


Input: We apply DFTB in a QM/MM framework to perform vibrational analysis of buried aspartic acids in bacteriorhodopsin and channelrhodopsin-2.

aspartic acids


Input: Using this approach, we can simulate the FTIR spectral difference between D115 in the dark-adapted and K states of bacteriorhodopsin.


Input: The FTIR experiments on the DC gate in channelrhodopsin-2 are well described using an indirect model, where D156 and C128 are bridged via a water molecule.


Input: Preparation and evaluation of sustained-release doxazosin mesylate pellets.

doxazosin mesylate


Input: Doxazosin mesylate (DXM) sustained release pellets were prepared by an extrusion-spheronization and fluid-bed coating technique.

Doxazosin mesylate

DXM


Input: The core pellets containing DXM were prepared by extrusion-spheronization technique, and coated by a fluid-bed coater to control the release of DXM.

DXM

DXM


Input: The factors affecting to properties of pellets, such as diluent content, type and coating level of coating agents and plasticizers were studied in the present study.


Input: Polymethacrylate derivatives (Eudragit (R) RS PO and RL PO) were used for coating agents, and polyethylene glycol 6000 (PEG 6000), triethyl citrate (TEC) and castor oil were as plasticizers.

Polymethacrylate

Eudragit

polyethylene glycol 6000

PEG 6000

triethyl citrate

TEC


Input: To evaluate the properties of prepared pellets, the size of prepared pellets was investigated by sieve analysis technique and the morphology of pellets was evaluated by scanning electron microscopy.


Input: Through the dissolution test, factors that have an effect on the dissolution of the drug were evaluated.


Input: As the content ratio of microcrystalline cellulose (MCC) had increased, the dissolution was proportionally sustained.


Input: Eudragit (R) RS PO had more marked sustaining effect on the dissolution rate than Eudragit (R) RL PO, and the effect was more pronounced with the increased coating level.

Eudragit

Eudragit


Input: PEG 6000 was an appropriate plasticizer for DXM pellets, and increasing the content of PEG 6000, was also slightly decreasing the dissolution rate.

PEG 6000

DXM

PEG 6000


Input: Nocapyrones H-J, 3, 6-Disubstituted alpha-Pyrones from the Marine Actinomycete Nocardiopsis sp.

Nocapyrones H-J

3, 6-Disubstituted alpha-Pyrones


Input: Three new 3, 6-disubstituted alpha-pyrones, nocapyrones H-J (1-3), were isolated from the marine actinomycete Nocardiopsis sp.

3, 6-disubstituted alpha-pyrones

nocapyrones H-J


Input: Their structures were assigned to be 3-alkylated 6-(1-methyl-1-propenyl)-2H-pyran-2-ones on the basis of UV, MS, NMR, and high resolution (HR)-FAB-MS analyses.

3-alkylated 6-(1-methyl-1-propenyl)-2H-pyran-2-ones


Input: Nocapyrone H (1) reduced the pro-inflammatory factor such as nitric oxide (NO), prostaglandin E2 (PGE2) and interleukin-1 beta (IL-1 beta).

Nocapyrone H

nitric oxide

NO

prostaglandin E2


Input: Moreover, nocapyrone H showed 5. 82% stronger inhibitory effect on NO production than chrysin at a concentration of 10 micro m in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells.

nocapyrone H

NO


Input: In vitro-in vivo correlation of the inhibition potency of sodium-glucose cotransporter inhibitors in rat: a pharmacokinetic and pharmacodynamic modeling approach.

sodium

glucose


Input: To evaluate the relationship between the in vitro and in vivo potency of sodium-glucose cotransporter (SGLT) inhibitors, a pharmacokinetic and pharmacodynamic (PK-PD) study was performed using normal rats.

sodium

glucose


Input: A highly selective SGLT2 inhibitor, tofogliflozin, and four other inhibitors with different in vitro inhibition potency to SGLT2 and selectivity toward SGLT2, versus SGLT1 were used as test compounds, and the time courses for urinary glucose excretion (UGE) and the plasma glucose and compound concentrations were monitored after administration of the compounds.

tofogliflozin

glucose

glucose


Input: A PK-PD analysis of the UGE caused by SGLT inhibition was performed on the basis of a nonlinear parallel tube model that took into consideration the consecutive reabsorption by different glucose transport properties of SGLT2 and SGLT1.

glucose


Input: The model adequately captured the time course of cumulative UGE caused by SGLT inhibition; then, the in vivo inhibition constants (Ki) of inhibitors for both SGLT1 and SGLT2 were estimated.


Input: The in vivo selectivity toward SGLT2 showed a good correlation with the in vitro data (r = 0. 985; P < 0. 05), with in vivo Ki values for SGLT2 in the range of 0. 3-3. 4-fold the in vitro data.


Input: This suggests that in vitro inhibition potency to both SGLT2 and SGLT1 is reflected in vivo.


Input: Furthermore, the complementary role of SGLT1 to SGLT2 and how selectivity toward SGLT2 affects the inhibitory potency for renal glucose reabsorption were discussed using the PK-PD model.

glucose


Input: SnO (2)-Based Nanomaterials: Synthesis and Application in Lithium-Ion Batteries.

SnO (2)

Lithium


Input: The development of new electrode materials for lithium-ion batteries (LIBs) has always been a focal area of materials science, as the current technology may not be able to meet the high energy demands for electronic devices with better performance.

lithium


Input: Among all the metal oxides, tin dioxide (SnO (2)) is regarded as a promising candidate to serve as the anode material for LIBs due to its high theoretical capacity.

metal oxides

tin dioxide

SnO (2)


Input: Here, a thorough survey is provided of the synthesis of SnO (2)-based nanomaterials with various structures and chemical compositions, and their application as negative electrodes for LIBs.

SnO (2)


Input: It covers SnO (2) with different morphologies ranging from 1D nanorods/nanowires/nanotubes, to 2D nanosheets, to 3D hollow nanostructures.

SnO (2)


Input: Nanocomposites consisting of SnO (2) and different carbonaceous supports, e. g., amorphous carbon, carbon nanotubes, graphene, are also investigated.

SnO (2)

carbonaceous

carbon

graphene


Input: The use of Sn-based nanomaterials as the anode material for LIBs will be briefly discussed as well.

Sn


Input: The aim of this review is to provide an in-depth and rational understanding such that the electrochemical properties of SnO (2)-based anodes can be effectively enhanced by making proper nanostructures with optimized chemical composition.

SnO (2)


Input: By focusing on SnO (2), the hope is that such concepts and strategies can be extended to other potential metal oxides, such as titanium dioxide or iron oxides, thus shedding some light on the future development of high-performance metal-oxide based negative electrodes for LIBs.

SnO (2)

metal oxides

titanium dioxide

iron oxides

metal-oxide


Input: Add-on therapy with the DPP-4 inhibitor sitagliptin improves glycemic control in insulin-treated Japanese patients with type 2 diabetes mellitus.

sitagliptin


Input: The effect of add-on therapy with sitagliptin on glycemic control was prospectively investigated in patients with type 2 diabetes mellitus (T2DM) receiving insulin alone or insulin combined with oral antidiabetic drugs.

sitagliptin


Input: Seventy-one patients were evaluated (38 men and 33 women aged 63. 9 +/- 10. 2 years).


Input: They were divided into three groups, which were 45 patients receiving premixed insulin twice daily, 15 patients receiving multiple daily insulin injections, and 11 patients receiving basal insulin with oral antidiabetic drugs (basal insulin therapy).


Input: Concomitant oral drugs included sulfonylureas, alpha-glucosidase inhibitors and metformin.

sulfonylureas

metformin


Input: The hemoglobin A1c (HbA1c) of all patients improved significantly from 8. 1 +/- 1. 2% to 7. 6 +/- 1. 1% after 12 weeks of add-on therapy with sitagliptin (p < 0. 01), and the insulin dosage was reduced from 27. 3 +/- 15. 8 U/day to 24. 5 +/- 16. 5 U/day (p < 0. 001).

sitagliptin


Input: Body weight did not change after the start of concomitant therapy and severe hypoglycemia was not observed.


Input: The baseline HbA1c and glycated albumin levels were identified as factors that predicted the response to add-on therapy with sitagliptin.

sitagliptin


Input: These findings suggest that add-on therapy with sitagliptin can be expected to achieve improvement of poor glycemic control irrespective of a patient' s demographic profile.

sitagliptin


Input: Stratified analysis based on the insulin regimen revealed a stronger antidiabetic effect and a high efficacy of sitagliptin when it was added to basal insulin therapy.

sitagliptin


Input: The results of this investigation confirmed that add-on therapy with sitagliptin to various insulin regimens could improve glycemic control without severe hypoglycemia and/or weight gain.

sitagliptin


Input: CYP21A2 Mutations in Women with Polycystic Ovary Syndrome (PCOS).


Input: The question of the contribution of CYP21A2 heterozygosity to the development of polycystic ovary syndrome (PCOS) has repeatedly been raised in the literature.


Input: The available data, however, do not offer a satisfactory answer.


Input: The discrepancy must be attributed, primarily, to the small number of subjects in the various studies, the type of selected phenotype, and the number of searched mutations.


Input: The aim of the study was to define the contribution of CYP21A2 heterozygous mutations to the pathogenesis of PCOS.


Input: We searched for 14 molecular defects of the CYP21A2 gene in 197 PCOS women, employing allele specific PCR.


Input: Androgen levels were determined at baseline by appropriate methodology in the follicular phase.

Androgen


Input: PCOS women with 17-hydroxyprogesterone (17OHP) basal values > 2 ng/ml and/or post-ACTH > 10 ng/ml were excluded.


Input: Appropriate controls were included.


Input: The frequency of the CYP21A2 heterozygous mutations in PCOS women and in controls was 7. 6% and 5. 9%, respectively [p-value (PCOS vs. controls): 0. 663].


Input: Homozygosity for CYP21A2 gene defects was not detected.


Input: In conclusion, the contribution of CYP21A2 heterozygous mutations to the pathogenesis of PCOS is not substantiated by our data.


Input: Moreover, 17-hydroxyprogesterone values of < 10 ng/ml post-ACTH exclude homozygosity of CYP21A2 mutations.


Input: Effectiveness of an educational intervention on prescription writing skill of preclerkship medical students in a problem-based learning curriculum.


Input: Medical school training for students in pharmacotherapy is suboptimal and junior doctors are not confident to prescribe drugs.


Input: This study evaluated the effectiveness of an optional educational intervention on prescribing skill of pre-clerkship medical students in a problem-based learning (PBL) program.


Input: Performance was assessed in seven end-unit objective structured practical examinations (OSPE).


Input: Physician-related prescription components (PRCs) and drug-related prescription components (DRCs) were assessed.


Input: The performance of students who attended the intervention sessions (attendees) and non-attendees was compared.


Input: Approximately half of the students attended the sessions.


Input: PRCs were written appropriately by most of the students.


Input: DRCs were written less competently by both attendees and non-attendees, specifically the dosage form, quantity to be dispensed and directions.


Input: Performance on individual DRCs was significantly better for attendees compared to non-attendees.


Input: The mean total score for all prescription components of attendees was significantly greater than that of non-attendees.


Input: The percentage of high achievers was significantly greater for attendees.


Input: A positive correlation was found between student attendance and the total score.


Input: An optional educational intervention during the preclerkship phase is an important determinant of prescribing performance of medical students.


Input: Reversible inhibition of human carboxylesterases by acyl glucuronides.

acyl glucuronides


Input: Carboxylesterases hydrolyze esters, amides, and thioesters to produce carboxylic acids and resulting alcohols, amines, and thiols, respectively.

esters

amides

thioesters

carboxylic acids

alcohols

amines

thiols


Input: Uridine 5'-diphosphate-glucuronosyltransferases are colocalized with carboxylesterases and have the potential to further metabolize carboxylic acids to acyl glucuronides, but it is currently unknown if acyl glucuronides, being esters, also interact with carboxylesterases.

Uridine 5'-diphosphate

carboxylic acids

acyl glucuronides

acyl glucuronides

esters


Input: Objective: This study explores the ability of acyl glucuronides to act as substrates or inhibitors of human carboxylesterases 1 (hCES1) and 2 (hCES2).

acyl glucuronides


Input: Methods: The stability of six acyl glucuronides in the presence of hCES1, hCES2, and buffer alone (100 mM potassium phosphate, pH 7. 4, 37 degrees C) were investigated.

acyl glucuronides

potassium phosphate


Input: Reversible inhibition of 4-nitrophenyl acetate hydrolysis by the acyl glucuronides was also studied.

4-nitrophenyl acetate

acyl glucuronides


Input: Diclofenac-beta-d-glucuronide was used to explore potential time-dependent inactivation.

Diclofenac-beta-d-glucuronide


Input: Results: The chemical stability half-life values for CGP 47292-beta-d-glucuronide, diclofenac-beta-d-glucuronide, (R)-naproxen-beta-d-glucuronide, (S)-naproxen-beta-d-glucuronide, ibuprofen-beta-d-glucuronide (racemic), clopidogrel-beta-d-glucuronide, and valproate-beta-d-glucuronide were found to be 0. 252, 0. 537, 0. 996, 1. 77, 3. 67, 5. 02, and 15. 2 hours, respectively.

CGP 47292-beta-d-glucuronide

diclofenac-beta-d-glucuronide

(R)-naproxen-beta-d-glucuronide

(S)-naproxen-beta-d-glucuronide

ibuprofen-beta-d-glucuronide (racemic)

clopidogrel-beta-d-glucuronide

valproate-beta-d-glucuronide


Input: Diclofenac-beta-d-glucuronide, clopidogrel-beta-d-glucuronide, ibuprofen-beta-d-glucuronide, (R)-naproxen-beta-d-glucuronide, and (S)-naproxen-beta-d-glucuronide selectively inhibited hCES1, with Ki values of 4. 32 +/- 0. 47, 24. 8 +/- 4. 2, 355 +/- 38, 468 +/- 21, 707 +/- 64 micro M, respectively, but did not significantly inhibit hCES2.

Diclofenac-beta-d-glucuronide

clopidogrel-beta-d-glucuronide

ibuprofen-beta-d-glucuronide

(R)-naproxen-beta-d-glucuronide

(S)-naproxen-beta-d-glucuronide


Input: Valproate-beta-d-glucuronide and CGP 47292-beta-d-glucuronide did not inhibit either hCES.

Valproate-beta-d-glucuronide

CGP 47292-beta-d-glucuronide


Input: Time-dependent inactivation of hCES1 by diclofenac-beta-d-glucuronide was not observed.

diclofenac-beta-d-glucuronide


Input: Lastly, both hCES1 and hCES2 were shown not to catalyze the hydrolysis of the acyl glucuronides studied.

acyl glucuronides


Input: Conclusion: Drug-drug interaction studies may be warranted for drugs that metabolize to acyl glucuronides due to the potential inhibition of hCESs.

acyl glucuronides


Input: Hepatic effects of ketamine administration for 2 weeks in rats.

ketamine


Input: The aim of the present study was to investigate the long-term and high-dose application of ketamine on the liver by employing histologic and biochemical methods.

ketamine


Input: A total of 30 male rats were randomly assigned to control and four treatment groups (n: 6).


Input: Saline for control group and different doses of ketamine for four treatment groups (40, 60, 80 and 100 mg kg (-1)) were administered intraperitoneal twice a day for 2 weeks.

ketamine


Input: Immunohistological staining, light and electron microscopy were used to study tissue specimens.


Input: Histopathological changes were more severe and diverse in groups 80 and 100 mg kg (-1) day (-1), and the least significant change was observed in groups 40 and 60 mg kg (-1) day (-1).


Input: The most important ultrastructural changes were seen in mitochondria and in the rough endoplasmic reticulum.


Input: The immunoreactivity of calcineurin was determined as different.


Input: Prolonged use of ketamine caused hepatocellualar toxicity and histological changes in hepatocytes in a dose-dependent manner in all experimental groups.

ketamine


Input: Cytotoxic activity of Guettarda pohliana M u ll.


Input: Arg.


Input: (Rubiaceae).


Input: The cytotoxic activity of crude extracts and their fractions from leaves and roots of G. pohliana was assessed against nine human cancer cell lines: melanoma (UACC-62), breast (MCF-7), breast expressing the multidrug resistance phenotype (NCI-ADR), lung (NCI-460), prostate (PCO-3), kidney (786-0), ovarian (OVCAR), colon (HT-29) and leukaemia (K-562).


Input: The hexane fraction from leaves (HL) and ethyl acetate (EAR), chloroform (CR) and hydromethanolic (HMR) fractions from roots were the most active fractions against K-562 with GI (50) values being lower than 1 mu g mL (-1).

hexane

ethyl acetate

chloroform


Input: Also, CR and HMR fractions were active against UACC-62 cell line in the same order of magnitude.


Input: The phytochemical study of the CR fraction allowed identifying the known iridoids secoxyloganin, sweroside and loganin.

iridoids secoxyloganin

sweroside

loganin


Input: Photoelectron and electron momentum spectroscopy of tetrahydrofuran from a molecular dynamical perspective.

tetrahydrofuran


Input: The results of experimental studies of the valence electronic structure of tetrahydrofuran employing He I photoelectron spectroscopy as well as Electron Momentum Spectroscopy (EMS) have been reinterpreted on the basis of Molecular Dynamical simulations employing the classical MM3 force field and large-scale quantum mechanical simulations employing Born-Oppenheimer Molecular Dynamics in conjunction with the dispersion corrected omega B97XD exchange-correlation functional.

tetrahydrofuran

He


Input: Analysis of the produced atomic trajectories demonstrates the importance of thermal deviations from the lowest energy path for pseudorotation, in the form of considerable variations of the ring-puckering amplitude.


Input: These deviations are found to have a significant influence on several outer-valence electron momentum distributions, as well as on the He I photoelectron spectrum.

He


Input: Azaspiracid-1 inhibits the maturation of cathepsin D in mammalian cells.


Input: Azaspiracid-1 (AZA-1) inhibits endocytosis, but the consequences of this alteration on cellular processes are unknown.


Input: We hypothesized that the inhibition of endocytosis is a key step of the mode of action of AZA-1, leading to perturbation of cellular processes dependent on proper functioning of endocytic machinery.


Input: We tested this working hypothesis by probing whether AZA-1 can alter the maturation of cathepsin D in MCF-7 epithelial cells, as a model system.


Input: We found that cell treatment with AZA-1 inhibited the conversion of 52 kDa procathepsin D into the mature 30 kDa protein.


Input: The effects induced by AZA-1 were similar to those elicited by chlorpromazine and other agents preventing proper maturation of lysosomal enzymes, indicating that the inhibition of endocytic transfer of proforms to late endosomes/lysosomess is responsible for the effect induced by the toxin.

chlorpromazine


Input: By immunofluorescence microscopy, we found no colocalization of cathepsin D and the early endosomal marker EEA-1 in control cells, where most of cathepsin D resides in late endosomes/lysosomes.


Input: Co-localization of cathepsin D and EEA-1 immunoreactivity, in turn, was found in cells exposed to AZA-1, indicating that the toxin blocks protein maturation at the early steps of endocytosis, causing accumulation of procathepsin D in early endosomes.


Input: The molecular alteration induced by AZA-1 involved both secreted and intracellular pools of procathepsin D, showing that the toxin effect does not result from a general impairment of vesicular trafficking but is the outcome of a perturbed centripetal process.


Input: Furthermore, AZA-1 was found to inhibit procathepsin D maturation also in normal fibroblasts, showing that this molecular response is induced by this toxin in different cell types.


Input: The data we obtained corroborated our hypothesis and provide a unified molecular frame for the mode of action of AZAs in animal models, involving a primary alteration of endocytic processes.

AZAs


Input: Controlled fabrication of hexagonally close-packed Langmuir-Blodgett silica particulate monolayers from binary surfactant and solvent systems.

silica


Input: We describe a controllable method to fabricate hexagonally close-packed Langmuir-Blodgett (LB) monolayers with stearic acid (SA) as co-surfactant and methanol as co-solvent.

stearic acid

methanol


Input: The optimal SA concentrations and volume ratios of chloroform to methanol are 0. 8 mg/mL and 3: 1 for particles of 140 nm, 0. 50 mg/mL and 4: 1 for particles of 300 nm, and 0. 05 mg/mL and 5: 1 for particles of 550 nm, respectively.

chloroform

methanol


Input: Additionally, SEM detections of the monolayers transferred at different surface pressures indicate that the monolayers deposited from the binary systems are more compressible.


Input: The experimental results indicate that the interparticle repulsions and particle-water interactions can be enhanced without decreasing the particle hydrophobicity by adding SA and methanol; thus, particulate monolayers with large hexagonally close-packed domains composed of small silica particles can be successfully fabricated using LB technique.

methanol

silica


Input: We propose that the enhanced interparticle repulsion is attributed to the Columbic repulsion resulting from the attachment of SA molecules to the CTAB modified particles around the three phase contact line.

CTAB


Input: Sesquiterpenes from the rhizomes of Curcuma heyneana.

Sesquiterpenes


Input: Four new germacranes [heyneanones A-D (1-4)], three new guaianes [4, 10-epizedoarondiol (5), 15-hydroxyprocurcumenol (6), 12-hydroxycurcumenol (7)], and two new spirolactones [curcumanolides C (8) and D (9)] were isolated from the rhizomes of Curcuma heyneana together with 13 known sesquiterpenes and two known labdane-type diterpenes.

germacranes

heyneanones A-D

guaianes

4, 10-epizedoarondiol

spirolactones

curcumanolides

sesquiterpenes

labdane

diterpenes


Input: Among the isolated compounds, heyneanone A (1), heyneanone C (3), 4, 10-epizedoarondiol (5), procurcumenol (16), aerugidiol (17), zerumin A (23), and (E)-15, 16-bisnorlabda-8 (17), 11-dien-13-one (24) inhibited protein tyrosine phosphatase 1B (PTP1B) with IC (50) values of 42. 5, 35. 2, 35. 1, 45. 6, 35. 7, 10. 4, and 14. 7 mu M, respectively.

heyneanone A

heyneanone C

4, 10-epizedoarondiol

procurcumenol

aerugidiol

zerumin A

(E)-15, 16-bisnorlabda-8 (17), 11-dien-13-one

tyrosine


Input: c (RGDfK) decorated micellar drug delivery system for intravesical instilled chemotherapy of superficial bladder cancer.


Input: The aim of this work was to develop a targeted drug delivery system with potentials for intravesical instilled chemotherapy of superficial bladder cancer.


Input: The amphiphilic diblock copolymer poly (epsilon-caprolactone)-b-poly (ethylene oxide) (PCL-b-PEO) was first conjugated with the cyclic (Arginine-Glycine-Aspartic acid-d-Phenylalanine-Lysine) (c (RGDfK)) and fluorescein isothiocyannate (FITC) via the functional terminal groups of hydrophilic block, and then assembled into micelles.

poly (epsilon-caprolactone)-b-poly (ethylene oxide)

PCL-b-PEO

cyclic (Arginine-Glycine-Aspartic acid-d-Phenylalanine-Lysine)

fluorescein isothiocyannate

FITC


Input: The interaction between micelles and various model cells was well studied by means of confocal laser scanning microscopy and flow cytometry.


Input: The c (RGDfK) on the surface of the micelle was confirmed by (1) H NMR analysis and cell affinity with human glioblastoma-astrocytoma cells (U87MG).

(1) H


Input: The cell viability of bladder cancer cells (T-24 cells) after incubation with doxorubicin (DOX) loaded polymeric micelles was evaluated by in vitro cytotoxicity assay.

doxorubicin

DOX


Input: The results revealed that c (RGDfK) modified micelles showed strong affinity to T-24 cells and strong inhibitory effect on the proliferation of T-24 cells when doxorubicin drug was loaded, indicating the high affinity of c (RGDfK) to bladder cancer cells.

doxorubicin


Input: The c (RGDfK) modified micelles assembled from PCL-b-PEO diblock copolymers developed in this study are of great potentials as nano-scaled drug delivery system for intravesical instilled chemotherapy of superficial bladder cancer.

PCL-b-PEO


Input: Prolyl-hydroxylase inhibition preserves endothelial cell function in a rat model of vascular ischemia reperfusion injury.

Prolyl


Input: Storage protocols of vascular grafts need further improvement against ischemia-reperfusion (IR) injury.


Input: Hypoxia elicits a variety of complex cellular responses by altering the activity of many signaling pathways, such as the oxygen-dependent prolyl-hyroxylase domain-containing enzyme (PHD).

oxygen

prolyl


Input: Reduction of PHD activity during hypoxia leads to stabilization and accumulation of hypoxia inducible factor (HIF) 1 alpha.


Input: We examined the effects of PHD inhibiton by dimethyloxalylglycine on the vasomotor responses of isolated rat aorta and aortic vascular smooth muscle cells (VSMCs) in a model of cold ischemia/warm reperfusion.

dimethyloxalylglycine


Input: Aortic segments underwent 24 hours of cold ischemic preservation in saline or DMOG (dimethyloxalylglycine)-supplemented saline solution.

DMOG

dimethyloxalylglycine


Input: We investigated endothelium-dependent and-independent vasorelaxations.


Input: To simulate IR injury, hypochlorite (NaOCl) was added during warm reperfusion.

hypochlorite

NaOCl


Input: VSMCs were incubated in NaCl or DMOG solution at 4 degrees C for 24 hours after the medium was changed for a supplied standard medium at 37 degrees C for 6 hours.

NaCl

DMOG


Input: Apoptosis was assessed using the TUNEL method.


Input: Gene expression analysis was performed using quantitative real-time polymerase chain reaction.


Input: Cold ischemic preservation and NaOCl induced severe endothelial dysfunction, which was significantly improved by DMOG supplementation (maximal relaxation of aortic segments to acetylcholine: control 95% +/- 1% versus NaOCl 44% +/- 4% versus DMOG 68% +/- 5%).

NaOCl

DMOG

acetylcholine

NaOCl

DMOG


Input: Number of TUNEL-positive cell nuclei was significantly higher in the NaOCl group, and DMOG treatment significantly decreased apoptosis.

NaOCl

DMOG


Input: Inducible heme-oxygenase 1 mRNA expressions were significantly higher in the DMOG group.

heme

DMOG


Input: Pharmacological modulation of oxygen sensing system by DMOG in an in vitro model of vascular IR effectively preserved endothelial function.

oxygen

DMOG


Input: Inhibition of PHDs could therefore be a new therapeutic avenue for protecting endothelium and vascular muscle cells against IR injury.


Input: Transport of A1 adenosine receptor agonist tecadenoson by human and mouse nucleoside transporters: evidence for blood-brain barrier transport by murine equilibrative nucleoside transporter 1 mENT1.

adenosine

tecadenoson

nucleoside

nucleoside


Input: The high density of A1 adenosine receptors in the brain results in significant potential for central nervous system (CNS)-related adverse effects with A1 agonists.

adenosine


Input: Tecadenoson is a selective A1 adenosine receptor agonist with close similarity to adenosine.

Tecadenoson

adenosine

adenosine


Input: We studied the binding and transmembrane transport of tecadenoson by recombinant human equilibrative nucleoside transporters (hENTs) hENT1 and hENT2, and human concentrative nucleoside transporters (hCNTs) hCNT1, hCNT2, and hCNT3 in vitro and by mouse mENT1 in vivo.

tecadenoson

nucleoside

nucleoside


Input: Binding affinities of the five recombinant human nucleoside transporters for tecadenoson differed (hENT1 > hCNT1 > hCNT3 > hENT2 > hCNT2), and tecadenoson was transported largely by hENT1.

nucleoside

tecadenoson

tecadenoson


Input: Pretreatment of mice with a phosphorylated prodrug of nitrobenzylmercaptopurine riboside, an inhibitor of mENT1, significantly decreased brain exposure to tecadenoson compared with that of the untreated (control) group, suggesting involvement of mENT1 in transport of tecadenoson across the blood-brain barrier (BBB).

nitrobenzylmercaptopurine

tecadenoson

tecadenoson


Input: In summary, ENT1 was shown to mediate the transport of tecadenoson in vitro with recombinant and native human protein and in vivo with mice.

tecadenoson


Input: The micromolar apparent Km value of tecadenoson for transport by native hENT1 in cultured cells suggests that hENT1 will not be saturated at clinically relevant (i. e., nanomolar) concentrations of tecadenoson, and that hENT1-mediated passage across the BBB may contribute to the adverse CNS effects observed in clinical trials.

tecadenoson

tecadenoson


Input: In contrast, in cases in which a CNS effect is desired, the present results illustrate that synthetic A1 agonists that are transported by hENT1 could be used to target CNS disorders because of enhanced delivery to the brain.


Input: Core oligosaccharide of Plesiomonas shigelloides PCM 2231 (Serotype O17) lipopolysaccharide--structural and serological analysis.


Input: The herein presented complete structure of the core oligosaccharide of lipopolysaccharide (LPS) P. shigelloides Polish Collection of Microorganisms (PCM) 2231 (serotype O17) was investigated by (1) H, (13) C NMR spectroscopy, mass spectrometry, chemical analyses and serological methods.

(1) H

(13) C


Input: The core oligosaccharide is composed of an undecasaccharide, which represents the second core type identified for P. shigelloides serotype O17 LPS.


Input: This structure is similar to that of the core oligosaccharide of P. shigelloides strains 302-73 (serotype O1) and 7-63 (serotype O17) and differs from these only by one sugar residue.

sugar


Input: Serological screening of 55 strains of P. shigelloides with the use of serum against identified core oligosaccharide conjugated with bovine serum albumin (BSA) indicated the presence of similar structures in the LPS core region of 28 O-serotypes.


Input: This observation suggests that the core oligosaccharide structure present in strain PCM 2231 could be the most common type among P. shigelloides lipopolysaccharides.


Input: New casbane diterpenoids from a South China Sea soft coral, Sinularia sp.

casbane diterpenoids


Input: Six new casbane diterpenoids, named as sinularcasbanes A-F (1-6), along with six known analogues 7-12, were isolated from a South China Sea soft coral, Sinularia sp.

casbane diterpenoids

sinularcasbanes A-F


Input: The structures of the new compounds were elucidated by extensive spectroscopic analysis and by comparison with data reported in the literature.


Input: All compounds were evaluated for their cytotoxicity against selected cancer cell lines and the inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in mouse peritoneal macrophages.

nitric oxide

NO


Input: The effect of magnetically induced linear aggregates on proton transverse relaxation rates of aqueous suspensions of polymer coated magnetic nanoparticles.


Input: It has been recently reported that for some suspensions of magnetic nanoparticles the transverse proton relaxation rate, R (2), is dependent on the time that the sample is exposed to an applied magnetic field.


Input: This time dependence has been linked to the formation of linear aggregates or chains in an applied magnetic field via numerical modeling.


Input: It is widely known that chain formation occurs in more concentrated ferrofluids systems and that this has an affect on the ferrofluid properties.


Input: In this work we examine the relationships between colloidal stability, the formation of these linear structures, and changes observed in the proton transverse relaxation rate of aqueous suspensions of magnetic particles.


Input: A series of iron oxide nanoparticles with varying stabilizing ligand brush lengths were synthesized.

iron oxide


Input: These systems were characterized with dynamic light scattering, transmission electron microscopy, dark-field optical microscopy, and proton transverse relaxation rate measurements.


Input: The dark field optical microscopy and R (2) measurements were made in similar magnetic fields over the same time scale so as to correlate the reduction of the transverse relaxivity with the formation of linear aggregates.


Input: Our results indicate that varying the ligand length has a direct effect on the colloidal arrangement of the system in a magnetic field, producing differences in the rate and size of chain formation, and hence systematic changes in transverse relaxation rates over time.


Input: With increasing ligand brush length, attractive inter-particle interactions are reduced, which results in slower aggregate formation and shorter linear aggregate length.


Input: These results have implications for the stabilization, characterization and potentially the toxicity of magnetic nanoparticle systems used in biomedical applications.


Input: Public health challenges and prospects for malaria control and elimination.


Input: The past decade witnessed unprecedented efforts to control malaria, including renewed political and financial commitment and increased availability of both old and new strategies and tools.


Input: However, malaria still represents a major health burden, particularly in Africa.


Input: Important challenges such as the fragility of many health systems, the rise of insecticide and drug resistance, and particularly the expected decline both in funding and in the coverage of key interventions if they are not replaced as needed, urgently need to be addressed.


Input: Further research and development is also becoming increasingly crucial.


Input: Among other needs, common methodologies for estimating and tracking the malaria burden, new strategies to measure transmission, better understanding of immunity, and increased knowledge of the mechanisms and effects of resistance to drugs and insecticides stand out.


Input: The ongoing efforts in research and development for new antimalarial drugs, more sensitive point-of-care rapid diagnostic tests and new insecticides need further innovation and substantial strengthening.


Input: Clearly, efforts should focus not only on Plasmodium falciparum but also and increasingly on Plasmodium vivax, the neglected human malaria parasite.


Input: Addressing these challenges in a comprehensive and timely way will allow us to sustain the gains made so far and make further progress in control and progressive elimination.


Input: Comparison of toxicity between the different-type TiO (2) nanowires in vivo and in vitro.

TiO (2)


Input: In this study, we compared their toxicity in vivo and in vitro based on the physicochemical properties of three different types of TiO (2) nanowires, H (2) Ti (3) O (7) nanowires (1HTO), hydrothermal treatment (2HTO), and calcination (3HTO) of 1HTO.

TiO (2)

H (2) Ti (3) O (7)


Input: The surface of 1HTO was smooth, and the surface of 2HTO was much rougher.


Input: The negative charge on the surface increased in the order of 2HTO, 3HTO, and 1HTO, whereas the surface area increased in the order of 3HTO, 1HTO, and 2HTO.


Input: The lung is a main exposure route of nanoparticles.


Input: On day 28 after a single instillation (1 mg/kg), three nanowires induced a Th2-type inflammatory response together with the relative increase in CD4 (+) T cells, especially by 2HTO.


Input: In vitro, three TiO (2) nanowires (10 mu g/ml) commonly induced the generation of cell debris in eight cell lines which may be the potential target organ of nanoparticles, especially by 2HTO.

TiO (2)


Input: It seemed that the generation of cell debris coincides with the increase in autophagosome-like vacuoles in the cytosol.


Input: In further study using BEAS-2B cells originated from the lung, the protein amount from cells exposed to 2HTO decreased more clearly although the generation of reactive oxygen species (ROS) was less compared to 1HTO and 3HTO.

oxygen


Input: Based on these results, we suggest that surface area may act as an important factor depends on the biological response by TiO (2) nanowires.

TiO (2)


Input: Furthermore, the increase in autophagosome-like vacuoles may be an important cause of cell death by nanoparticles with ROS.


Input: The effects of BMY-14802 against L-DOPA-and dopamine agonist-induced dyskinesia in the hemiparkinsonian rat.

L-DOPA

dopamine


Input: RATIONALE: L-DOPA continues to be the primary treatment for patients with Parkinson' s disease; however, the benefits of long-term treatment are often accompanied by debilitating side effects known as dyskinesias.

L-DOPA


Input: In recent years, several 5-HT (1A) receptor agonists have been found to reduce dyskinesia in clinical and experimental models of PD.


Input: The purported sigma-1 antagonist, BMY-14802 has been previously demonstrated to reduce L-DOPA induced dyskinesia in a 5-HT (1A) receptor dependent manner.

L-DOPA


Input: OBJECTIVE: In the present study, we extend these findings by examining the anti-dyskinetic potential of BMY-14802 against L-DOPA, the D (1) receptor agonist SKF81297 and the D (2) receptor agonist, quinpirole, in the hemi-parkinsonian rat model.

L-DOPA

quinpirole


Input: In addition, the receptor specificity of BMY-14802' s effects was evaluated using WAY-100635, a 5-HT (1A) receptor antagonist.


Input: RESULTS: Results confirmed the dose-dependent (20 > 10 > 5 mg/kg) anti-dyskinetic effects of BMY-14802 against L-DOPA with preservation of anti-parkinsonian efficacy at 10 mg/kg.

L-DOPA


Input: BMY-14802 at 10 and 20 mg/kg also reduced dyskinesia induced by both D (1) and D (2) receptor agonists.


Input: Additionally, BMY-14802' s anti-dyskinetic effects against L-DOPA, but not SKF81297 or quinpirole, were reversed by WAY-100635 (0. 5 mg/kg).

L-DOPA

quinpirole


Input: CONCLUSION: Collectively, these findings demonstrate that BMY-14802 provides anti-dyskinetic relief against L-DOPA and direct DA agonist in a preclinical model of PD, acting via multiple receptor systems and supports the utility of such compounds for the improved treatment of PD.

L-DOPA


Input: Contractile signaling pathways in mouse prostate smooth muscle.


Input: BACKGROUND: Prostate smooth muscle plays an important role in the physiological ejection of prostatic fluid and also in the pathogenesis of benign prostate hyperplasia.


Input: Although mouse is the best genetically engineered animal model to identify potential molecular targets for human diseases, only fragmentary information is available for basic mechanism of mouse prostate contraction.


Input: METHODS: Small smooth muscle tubular rings were excised from four mouse prostate lobes to measure their isometric contractions.


Input: High K (+), noradrenaline (NA), or acetylcholine (ACh) was applied with and without various antagonists and/or inhibitors to examine the contractile signaling pathways.

K (+)

noradrenaline

acetylcholine

ACh


Input: RESULTS: Maximum amplitude of agonist-induced contractions varied greatly with different lobes but not with different locations or orientations within each lobe.


Input: Both NA and ACh produced large contractions in ventral and dorsal rings, whereas only small contractions were elicited in lateral and anterior rings.

ACh


Input: Combination of alpha-1 and muscarinic antagonists suppressed K (+) depolarization-induced contraction potently in ventral rings, but slightly in anterior rings.

K (+)


Input: Blocking of either Ca (2 +)-release or Ca (2 +)-influx reduced agonist-induced contraction of ventral rings, however, a considerable amount of contractility remained even with both blockers.

Ca (2 +)

Ca (2 +)


Input: Inhibitors of ROCK and PKC partially inhibited NA-induced contractions, whereas a combination of Ca (2 +)-blockers and Ca (2 +)-sensitization inhibitors strongly suppressed the contraction.

Ca (2 +)

Ca (2 +)


Input: CONCLUSIONS: The ejection of prostatic fluid is differentially regulated in each prostate lobe.


Input: In ventral prostate smooth muscle, Ca (2 +)-release, Ca (2 +)-influx, and ROCK-and PKC-mediated Ca (2 +)-sensitizations are all involved in NA-induced contractions.

Ca (2 +)

Ca (2 +)

Ca (2 +)


Input: This finding is a useful step toward the understanding of the phenotypic changes in the smooth muscle of BPH prostate.


Input: Prostate (c) 2013 Wiley Periodicals, Inc.


Input: A mouse model of chronic prostatic inflammation using a human prostate cancer-derived isolate of Propionibacterium acnes.


Input: BACKGROUND: Prostatic inflammation has been linked to a number of prostatic diseases such as benign prostatic hyperplasia (BPH), prostatitis syndromes, and prostate cancer.


Input: Major unanswered questions include what pathogenic mechanisms, such as bacterial infections, may drive the accumulation of inflammatory infiltrates in the human prostate, and how inflammation might contribute to disease.


Input: To study this potential link in an in vivo system, we developed a mouse model of long-term bacteria-induced chronic inflammation of the prostate using a human prostatectomy-derived strain of Propionibacterium acnes.


Input: METHODS: C57BL/6J mice were inoculated, via urethral catheterization, with vehicle control or a prostatectomy-derived strain of P. acnes (PA2).


Input: Animals were assessed at 2 days, 1, 2, or 8 weeks post-inoculation via histology and immunohistochemistry (IHC).


Input: RESULTS: PA2 inoculation resulted in severe acute and chronic inflammation confined to the dorsal lobe of the prostate.


Input: Chronic inflammation persisted for at least 8 weeks post-inoculation.


Input: Inflammatory lesions were associated with an increase in the Ki-67 proliferative index, and diminished Nkx3. 1 and androgen receptor (AR) production.

androgen


Input: Interestingly, the observed response required live bacteria and both IHC and in situ hybridization assays for P. acnes indicated a potential intracellular presence of P. acnes in prostate epithelial cells.


Input: CONCLUSIONS: To our knowledge, this is the first mouse model of long-term prostatic inflammation induced by P. acnes, and more generally, any prostatectomy-derived bacterial isolate.


Input: This model may serve as a valuable preclinical model of chronic prostatic inflammation that can be used to mechanistically study the link between inflammation and prostatic disease.


Input: Prostate (c) 2013 Wiley Periodicals, Inc.


Input: Phosphodiesterase 4 inhibitors augment the ability of formoterol to enhance glucocorticoid-dependent gene transcription in human airway epithelial cells: a novel mechanism for the clinical efficacy of roflumilast in severe chronic obstructive pulmonary disease.

formoterol

roflumilast


Input: Post-hoc analysis of two phase III clinical studies found that the phosphodiesterase 4 (PDE4) inhibitor, roflumilast, reduced exacerbation frequency in patients with severe chronic obstructive pulmonary disease (COPD) who were taking inhaled corticosteroids (ICS) concomitantly, whereas patients not taking ICS derived no such benefit.

roflumilast


Input: In contrast, in two different trials also performed in patients with severe COPD, roflumilast reduced exacerbation rates in the absence of ICS, indicating that PDE4 inhibition alone is sufficient for therapeutic activity to be realized.

roflumilast


Input: Given that roflumilast is recommended as an " add-on " medication to patients with severe disease who will inevitably be taking a long-acting beta 2-adrenoceptor agonist (LABA)/ICS combination therapy, we tested the hypothesis that roflumilast augments the ability of glucocorticoids to induce genes with anti-inflammatory activity.

roflumilast

roflumilast


Input: Using a glucocorticoid response element (GRE) luciferase reporter transfected into human airway epithelial cells [both bronchial epithelium + adenovirus 12-SV40 hybrid (BEAS-2B) cells and primary cultures], roflumilast enhanced fluticasone propionate-induced GRE-dependent transcription.

roflumilast

fluticasone propionate


Input: Roflumilast also produced a sinistral displacement of the concentration-response curves that described the augmentation of GRE-dependent transcription by the LABA formoterol.

Roflumilast

formoterol


Input: In BEAS-2B cells and primary airway epithelia, roflumilast interacted with formoterol in a positive cooperative manner to enhance the expression of several glucocorticoid-inducible genes that have anti-inflammatory potential.

roflumilast

formoterol


Input: We suggest that the ability of roflumilast and formoterol to interact in this way supports the concept that these drugs together may impart clinical benefit beyond that achievable by an ICS alone, a PDE4 inhibitor alone, or an ICS/LABA combination therapy.

roflumilast

formoterol


Input: Roflumilast may, therefore, be especially effective in patients with severe COPD.

Roflumilast


Input: FOXO1 binds to the TAU5 motif and inhibits constitutively active androgen receptor splice variants.

androgen


Input: BACKGROUND: Aberrant activation of the androgen receptor (AR) is a major factor highly relevant to castration-resistant progression of prostate cancer (PCa).

androgen


Input: FOXO1, a key downstream effector of PTEN, inhibits androgen-independent activation of the AR.

androgen


Input: However, the underlying mechanism remains elusive.


Input: METHODS: The inhibitory effect of FOXO1 on full-length and constitutively active splice variants of the AR was examined by luciferase reporter assays and real-time reverse transcription polymerase chain reaction (RT-qPCR).


Input: In vitro protein binding assays and western blot analyses were used to determine the regions in FOXO1 and AR responsible for their interaction.


Input: RESULTS: We found that a putative transcription repression domain in the NH2-terminus of FOXO1 is dispensable for FOXO1 inhibition of the AR.


Input: In vitro protein binding assays showed that FOXO1 binds to the transcription activation unit 5 (TAU5) motif in the AR NH2-terminal domain (NTD), a region required for recruitment of p160 activators including SRC-1.


Input: Ectopic expression of SRC-1 augmented transcriptional activity of some, but not all AR splice variants examined.


Input: Forced expression of FOXO1 blocked the effect of SRC-1 on AR variants' transcriptional activity by decreasing the binding of SRC-1 to the AR NTD.


Input: Ectopic expression of FOXO1 inhibited expression of endogenous genes activated primarily by alternatively spliced AR variants in human castration-resistant PCa 22Rv1 cells.


Input: CONCLUSIONS: FOXO1 binds to the TAU5 motif in the AR NTD and inhibits ligand-independent activation of AR splice variants, suggesting the PTEN/FOXO1 pathway as a potential therapeutic target for inhibition of aberrant AR activation and castration-resistant PCa growth.


Input: Prostate (c) 2013 Wiley Periodicals, Inc.


Input: Development and characterization of an SMN2-based intermediate mouse model of Spinal Muscular Atrophy.


Input: Spinal Muscular Atrophy (SMA) is due to the loss of the survival motor neuron gene 1 (SMN1), resulting in motor neuron (MN) degeneration, muscle atrophy and loss of motor function.


Input: While SMN2 encodes a protein identical to SMN1, a single nucleotide difference in exon 7 causes most of the SMN2-derived transcripts to be alternatively spliced resulting in a truncated and unstable protein (SMN Delta 7).

nucleotide


Input: SMA patients retain at least one SMN2 copy, making it an important target for therapeutics.


Input: Many of the existing SMA models are very severe, with animals typically living less than 2 weeks.


Input: Here, we present a novel intermediate mouse model of SMA based upon the human genomic SMN2 gene.


Input: Genetically, this model is similar to the well-characterized SMN Delta 7 model; however, we have manipulated the SMN Delta 7 transgene to encode a modestly more functional protein referred to as SMN read-through (SMN (RT)).


Input: By introducing the SMN (RT) transgene onto the background of a severe mouse model of SMA (SMN2 (+/+); Smn (-/-)), disease severity was significantly decreased based upon a battery of phenotypic parameters, including MN pathology and a significant extension in survival.


Input: Importantly, there is not a full phenotypic correction, allowing for the examination of a broad range of therapeutics, including SMN2-dependent and SMN-independent pathways.


Input: This novel animal model serves as an important biological and therapeutic model for less severe forms of SMA and provides an in vivo validation of the SMN (RT) protein.


Input: Superatom paramagnetism enables gold nanocluster heating in applied radiofrequency fields.


Input: The Au102 (pMBA) 44 nanocluster becomes a superatom paramagnet after chemical oxidation.

Au102 (pMBA) 44


Input: Solutions of paramagnetic Au102 (pMBA) 44 heat in an oscillating magnetic field component of an RF field, but not in the electric component.

Au102 (pMBA) 44


Input: Combined, these experiments suggest that paramagnetic Au102 (pMBA) 44 heats through interactions of spin magnetic moment with an external oscillating magnetic field.

Au102 (pMBA) 44


Input: These results may clarify some current controversy regarding gold nanoparticle heating in radiofrequency fields.


Input: Signature of singlet open-shell character on the optically allowed singlet excitation energy and singlet-triplet energy gap.


Input: A signature of singlet open-shell character on the optically allowed singlet excitation energy and singlet-triplet energy gap is theoretically illuminated for open-shell singlet molecules.


Input: On the basis of a two-site diradical model with two electrons in two orbitals, the linear dependence of these excitation energies on the transfer integral, which is equivalent to the energy gap between the highest occupied (HOMO) and the lowest unoccupied (LUMO) molecular orbitals in the H u ckel theory, is found to be broken down in the high diradical character region due to an increase in electron correlation in the open-shell singlet ground state.


Input: A series of polyacenes shows the similar behavior of the optically allowed singlet excitation energies obtained by time-dependent spin-flip density functional theory calculations and experiments, which bears testimony to the singlet open-shell character in long polyacenes.

polyacenes


Input: High-resolution zero-field NMR J-spectroscopy of aromatic compounds.


Input: We report the acquisition and interpretation of nuclear magnetic resonance (NMR) J-spectra at zero magnetic field for a series of benzene derivatives, demonstrating the analytical capabilities of zero-field NMR.

benzene


Input: The zeroth-order spectral patterns do not overlap, which allows for straightforward determination of the spin interactions of substituent functional groups.


Input: Higher-order effects cause additional line splittings, revealing additional molecular information.


Input: We demonstrate resonance linewidths as narrow as 11 mHz, permitting resolution of minute frequency differences and precise determination of long-range J-couplings.


Input: The measurement of J-couplings with the high precision offered by zero-field NMR may allow further refinements in the determination of molecular structure and conformation.


Input: Solvent and pressure effects on the motions of encapsulated guests: tuning the flexibility of a supramolecular host.


Input: The supramolecular host assembly [Ga4L6] (12-) [1; L = 1, 5-bis (2, 3-dihydroxybenzamido) naphthalene] contains a flexible, hydrophobic interior cavity that can encapsulate cationic guest molecules and catalyze a variety of chemical transformations.

[Ga4L6] (12-)

1, 5-bis (2, 3-dihydroxybenzamido) naphthalene


Input: The Ar-CH2 bond rotational barrier for encapsulated ortho-substituted benzyl phosphonium guest molecules is sensitive to the size and shape of the host interior space.

ortho-substituted benzyl phosphonium


Input: Here we examine how changes in bulk solvent (water, methanol, or DMF) or applied pressure (up to 150 MPa) affect the rotational dynamics of encapsulated benzyl phosphonium guests, as a way to probe changes in host cavity size or flexibility.

methanol

DMF

benzyl phosphonium


Input: When host 1 is dissolved in organic solvents with large solvent internal pressures (d U/d V) T, we find that the free energy barrier to Ar-CH2 bond rotation increases by 1-2 kcal/mol, compared with that in aqueous solution.


Input: Likewise, when external pressure is applied to the host-guest complex in solution, the bond rotational rates for the encapsulated guests decrease.


Input: The magnitude of these rate changes and the volumes of activation obtained using either solvent internal pressure or applied external pressure are very similar.


Input: NOE distance measurements reveal shorter average host-guest distances (~ 0. 3 A) in organic versus aqueous solution.


Input: These experiments demonstrate that increasing solvent internal pressure or applied external pressure reduces the host cavity size or flexibility, resulting in more restricted motions for encapsulated guest molecules.


Input: Changing bulk solvent or external pressure might therefore be used to tune the physical properties or reactivity of guest molecules encapsulated in a flexible supramolecular host.


Input: Allometric scaling and prediction of concentration-time profiles of coagulation factors in humans from animals.


Input: Abstract 1.


Input: Allometric scaling is a useful tool in early drug development and can be used for the prediction of human pharmacokinetic (PK) parameters from animal PK parameters.


Input: The main objective of this work was to predict concentration-time profiles of coagulation factors in humans in a multi-compartment system using animal PK parameters.


Input: The prediction of concentration-time profiles in humans in a multi-compartment system was based on the predicted values of clearance and volumes of distribution (V (c), V (ss) and V (beta)) from animals.


Input: Five coagulation factors from the literature were chosen that were described by two-compartment model in both humans and animals.


Input: Clearance and volumes of distribution from animals were allometrically scaled to humans and then were used to predict concentration-time profiles in humans.


Input: The predicted concentration-time profile for a given coagulation factor was accurate for most of the time points.


Input: Percent prediction error range varied across coagulation factors.


Input: The prediction error > 50% was observed either at 1 or a maximum of two time points for a given drug.


Input: The study indicated that the allometric scaling can be useful in the prediction of concentration-time profiles of coagulation factors in humans from animals and may be helpful in designing a first-in-human study.


Input: ADME characterization in rats revealed immediate secretion of AZD7903 into the stomach after IV dosing.


Input: Abstract 1.


Input: The distribution of AZD7903 and/or its metabolites was studied in rats following a single p. o. or i. v. dose using quantitative whole-body autoradiography (QWBA).


Input: At 5 min after i. v. administration of the (14) C compound, high levels of radioactivity were observed in the fundus of the stomach compared to blood and plasma and the rest of the stomach, indicating an active secretion of (14) C material into the stomach.

(14) C

(14) C


Input: Also, excretion and pharmacokinetics were studied following p. o. and i. v. dosage in rats.


Input: The radioactivity was mainly excreted via feces, and even in i. v. administered bile-duct cannulated (BDC) animals a significant part of radioactivity (26% in males and 57% in females) was recovered in the feces in the form of parent compound and two minor metabolic products.


Input: The compound was well absorbed (F% 98 in males and 76 in females), and showed low clearance in plasma (0. 14 L/h/kg in males and 0. 03 L/h/kg in females) and low-intermediate Vd (ss) (0. 7 L/kg).


Input: Clear differences in metabolic pathways (qualitative) and rates (quantitative) and consequently in PK parameters between sexes were observed.


Input: In summary, the results indicate AZD7903 being substrate for a transporter protein and support the hypothesis that the differences in disposition between sexes are due to differences in metabolic pathways and rates.


Input: Metabolically obese status with normal weight is associated with both the prevalence and severity of angiographic coronary artery disease.


Input: OBJECTIVE: We evaluated prevalence and severity of angiographic coronary artery disease (CAD) according to groups by metabolically obese (MO) and/or weight status.


Input: MATERIAL/METHODS: Normal weight was defined as body mass index (BMI, kg/m (2)) < 25 and obesity was defined as BMI >= 25.


Input: The MO was determined using the National Cholesterol Education Program-Adult Treatment Panel III classification with Korean-specific cutoffs for abdominal obesity.

Cholesterol


Input: Therefore, a total of 856 subjects were categorized as follows: (1) metabolically healthy and normal weight (MHNW); (2) metabolically obese but normal weight (MONW); (3) metabolically healthy but obese (MHO); and (4) metabolically abnormally obese (MAO).


Input: The presence of obstructive lesion >= 50% of coronary artery was considered as an angiographic CAD and the Gensini scoring system was used for the severity.


Input: RESULTS: MONW or MO showed a higher prevalence of CAD than MHNW or non-MO after adjustment for age and sex, respectively (MONW, odds ratio [OR] = 1. 69, 95% confidence interval [CI]: 1. 13-2. 51 and MO, OR = 1. 44, 95% CI: 1. 09-1. 91).


Input: In subjects without diabetes mellitus (DM), MONW or MO showed a marginally higher prevalence of CAD (MONW, OR = 1. 58, 95% CI: 0. 96-2. 61 and MO, OR = 1. 41, 95% CI: 0. 96-2. 08).


Input: MONW was independently associated with a higher severity of angiographic CAD than MHNW after age, sex, glomerular filtration rate, smoking status, high sensitive C-reactive protein, and use of anti-platelet and anti-angina drugs (beta = 0. 118, P = 0. 005).


Input: And MO was associated with a higher severity of angiographic CAD than non-MO after adjustment for age and sex (beta = 0. 077, P = 0. 024).


Input: The above associations were also consistent in subjects without DM (MONW, beta = 0. 147, P = 0. 003 and MO, beta = 0. 129, P = 0. 005).


Input: CONCLUSIONS: MONW or MO is associated with both the prevalence and severity of angiographic CAD after adjustment for age and sex and MONW is independently associated with the severity of angiographic CAD irrespective of DM.


Input: Therefore, subjects with MO but normal weight (MONW) should be carefully examined for angiographic CAD.


Input: Quasiclassical trajectory and statistical quantum calculations for the C + OH --> CO + H reaction on the first excited 1 (2) A'' potential energy surface.

C

OH

CO

H


Input: We report quasiclassical trajectory dynamical calculations for the C ((3) P) + OH (X (2) Pi) --> CO (a (3) Pi) + H ((2) S) using a recently developed ab initio potential energy surface for the first electronic state of HCO of 1 (2) A'' symmetry.

C

OH

CO

H

HCO


Input: The dependence of integral cross sections on the collision energy was determined.


Input: Product energy and angular distributions have also been calculated.


Input: Integral cross sections show no energy threshold and decrease as the collision energy increases.


Input: The comparison with results obtained from a statistical quantum method seems to confirm that the reaction is mainly dominated by an indirect mechanism in which a long-lived intermediate complex is involved.


Input: Biotransformation pathways of biocides and pharmaceuticals in freshwater crustaceans based on structure elucidation of metabolites using high resolution mass spectrometry.


Input: So far, there is limited information on biotransformation mechanisms and products of polar contaminants in freshwater crustaceans.


Input: In the present study, metabolites of biocides and pharmaceuticals formed in Gammarus pulex and Daphnia magna were identified using liquid chromatography-high resolution mass spectrometry.


Input: Different confidence levels were assigned to the identification of metabolites without reference standards using a framework based on the background evidence used for structure elucidation.


Input: Twenty-five metabolites were tentatively identified for irgarol, terbutryn, tramadol, and venlafaxine in G. pulex (21 via oxidation and 4 via conjugation reactions) and 11 metabolites in D. magna (7 via oxidation and 4 via conjugation reactions), while no evidence of metabolites for clarithromycin and valsartan was found.

irgarol

terbutryn

tramadol

venlafaxine

clarithromycin

valsartan


Input: Of the 360 metabolites predicted for the four parent compounds using pathway prediction systems and expert knowledge, 23 products were true positives, while 2 identified metabolites were unexpected products.


Input: Observed oxidative reactions included N-and O-demethylation, hydroxylation, and N-oxidation.

N

O

N


Input: Glutathione conjugation of selected biocides followed by subsequent reactions forming cysteine conjugates was described for the first time in freshwater invertebrates.

Glutathione

cysteine


Input: Cloning, Characterization, and Sulfonamide and Thiol Inhibition Studies of an alpha-Carbonic Anhydrase from Trypanosoma cruzi, the Causative Agent of Chagas Disease.

Sulfonamide

Thiol


Input: An alpha-carbonic anhydrase (CA, EC 4. 2. 1. 1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease.


Input: The enzyme (TcCA) has a very high catalytic activity for the CO (2) hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle.

CO (2)


Input: A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1, 3, 4-thiadiazoles were investigated as TcCA inhibitors.

aromatic/heterocyclic sulfonamides

5-mercapto-1, 3, 4-thiadiazoles


Input: The aromatic sulfonamides were weak inhibitors (K (I) values of 192 nM to 84 mu M), whereas some heterocyclic compounds inhibited the enzyme with K (I) values in the range 61. 6-93. 6 nM.

aromatic sulfonamides


Input: The thiols were the most potent in vitro inhibitors (K (I) values of 21. 1-79. 0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo.

thiols


Input: Cell division: kinetochores SKAdaddle.


Input: Accurate chromosome segregation during cell division requires that kinetochores couple microtubule dynamics to chromosome movement.


Input: New research reveals that the kinetochore-associated Ska1 complex hangs on to depolymerizing microtubules and brings some important friends along for the ride.


Input: Improved intratumoral nanoparticle extravasation and penetration by mild hyperthermia.


Input: Accumulation of nanoparticles in solid tumors depends on their extravasation.


Input: However, vascular permeability is very heterogeneous within a tumor and among different tumor types, hampering efficient delivery.


Input: Local hyperthermia at a tumor can improve nanoparticle delivery by increasing tumor vasculature permeability, perfusion and interstitial fluid flow.


Input: The aim of this study is to investigate hyperthermia conditions required to improve tumor vasculature permeability, subsequent liposome extravasation and interstitial penetration in 4 tumor models.


Input: Tumors are implanted in dorsal skin flap window chambers and observed for liposome (~ 85 nm) accumulation by intravital confocal microscopy.


Input: Local hyperthermia at 41 degrees C for 30 min initiates liposome extravasation through permeable tumor vasculature in all 4 tumor models.


Input: A further increase in nanoparticle extravasation occurs while continuing heating to 1h, which is a clinically relevant duration.


Input: After hyperthermia, the tumor vasculature remains permeable for 8h.


Input: We visualize gaps in the endothelial lining of up to 10 mu m induced by HT.


Input: Liposomes extravasate through these gaps and penetrate into the interstitial space to at least 27. 5 mu m in radius from the vessel walls.


Input: Whole body optical imaging confirms HT induced extravasation while liposome extravasation was absent at normothermia.


Input: In conclusion, a thermal dose of 41 degrees C for 1h is effective to induce long-lasting permeable tumor vasculature for liposome extravasation and interstitial penetration.


Input: These findings hold promise for improved intratumoral drug delivery upon application of local mild hyperthermia prior to administration of nanoparticle-based drug delivery systems.


Input: Toxicological, toxicokinetic and gastroprotective evaluation of the benzaldehyde semicarbazone.

benzaldehyde semicarbazone


Input: Benzaldehyde semicarbazone (BS) has presented positive results in several pharmacological models, including anticonvulsivant and anti-inflammatory models.

Benzaldehyde semicarbazone


Input: The present study evaluated the preclinical toxicity (acute and subchronic), as well as the toxicokinetic and gastroprotective effects of BS against ethanol lesions.

ethanol


Input: Oral doses of 300 and 2000mg/kg were used in the preclinical acute toxicity study; 100, 200, and 300mg/kg were used in both the subchronic toxicity evaluation and the gastric study; and 300mg/kg was used in the toxicokinetic study.


Input: No impact from the dose of 300mg/kg could be identified; while, one animal died at 2000mg/kg in the acute toxicity test.


Input: In the subchronic toxicity test, changes in the biochemical parameters of the liver, as well as in the histopatological evaluation, demonstrated that BS is a hepatotoxic drug.


Input: BS proved to be effective for moderate and severe gastric lesions.


Input: In the toxicokinetics study, BS presented a low concentration and rapid plasma disappearance.


Input: Several results also indicate that BS is likely to be mostly eliminated from the liver and may well undergo a first-pass effect after oral absorption.


Input: It was impossible to estimate the noobserved-adverse-effect-levels (NOAEL) and lowest-observed-adverse-effect-levels (LOAEL) due to the presence of hepatotoxicity in all tested doses.


Input: Synthesis of Li-Mn-O mesocrystals with controlled crystal phases through topotactic transformation of MnCO 3.

Li

Mn

O

MnCO 3


Input: Mesocrystals of Li-Mn-O compounds, such as LiMn2O4, Li2MnO3, and LiMnO2-Li2MnO3, consisting of oriented nanoscale units were selectively produced under hydrothermal conditions from biomimetically prepared MnCO3 mesocrystals.

Li

Mn

O


Input: Topotactic transformation through the intermediate phase of Mn5O8 inheriting a hierarchical structure of the MnCO3 precursor was essential for the formation of the mesocrystal compounds.


Input: The crystal phases were successfully controlled by varying the conditions for the hydrothermal reactions.


Input: The Li-Mn-O mesocrystals have considerable potential as cathodes of Li-ion batteries.

Li

Mn

O

Li


Input: Time-of-flight magnetic flow cytometry in whole blood with integrated sample preparation.


Input: Rapid and specific rare cell detection for point-of-care testing requires an integration of the sample preparation for flow cytometry.


Input: To achieve such a challenging goal we have developed a magnetic flow cytometry technique which applies magnetophoresis to perform cell enrichment, focusing, and background elimination in a single step.


Input: Time-of-flight measurements are performed with integrated magnetic sensors to detect specifically cancer cells and cell diameters in whole blood.


Input: Ventral tegmental area GABA neurons and opiate motivation.

GABA


Input: RATIONALE: Past research has demonstrated that when an animal changes from a previously drug-naive to an opiate-dependent and withdrawn state, morphine' s motivational effects are switched from a tegmental pedunculopontine nucleus (TPP)-dependent to a dopamine-dependent pathway.

morphine

dopamine


Input: Interestingly, a corresponding change is observed in ventral tegmental area (VTA) GABA (A) receptors, which change from mediating hyperpolarization of VTA GABA neurons to mediating depolarization.

GABA

GABA


Input: OBJECTIVES: The present study investigated whether pharmacological manipulation of VTA GABA (A) receptor activity could directly influence the mechanisms underlying opiate motivation.

GABA


Input: RESULTS: Using an unbiased place conditioning procedure, we demonstrated that in Wistar rats, intra-VTA administration of furosemide, a Cl (-) cotransporter inhibitor, was able to promote a switch in the mechanisms underlying morphine' s motivational properties, one which is normally observed only after chronic opiate exposure.

furosemide

Cl (-)

morphine


Input: This behavioral switch was prevented by intra-VTA administration of acetazolamide, an inhibitor of the bicarbonate ion-producing carbonic anhydrase enzyme.

acetazolamide

bicarbonate


Input: Electrophysiological recordings of mouse VTA showed that furosemide reduced the sensitivity of VTA GABA neurons to inhibition by the GABA (A) receptor agonist muscimol, instead increasing the firing rate of a significant subset of these GABA neurons.

furosemide

GABA

GABA

muscimol

GABA


Input: CONCLUSIONS: Our results suggest that the carbonic anhydrase enzyme may constitute part of a common VTA GABA neuron-based biological pathway responsible for controlling the mechanisms underlying opiate motivation, supporting the hypothesis that VTA GABA (A) receptor hyperpolarization or depolarization is responsible for selecting TPP-or dopamine-dependent motivational outputs, respectively.

GABA

GABA

dopamine


Input: Effects of monocarboxylate transporter inhibition on the oral toxicokinetics/toxicodynamics of gamma-hydroxybutyrate and gamma-butyrolactone.

monocarboxylate

gamma-hydroxybutyrate

gamma-butyrolactone


Input: Respiratory depression and death secondary to respiratory arrest have occurred after oral overdoses of gamma-hydroxybutyrate (GHB) and its precursor gamma-butyrolactone (GBL).

gamma-hydroxybutyrate

GHB

gamma-butyrolactone

GBL


Input: GHB is a substrate for monocarboxylate transporters (MCTs), and increasing GHB renal clearance or decreasing GHB absorption via MCT inhibition represents a potential treatment strategy for GHB/GBL overdose.

GHB

monocarboxylate

GHB

GHB

GHB

GBL


Input: In these studies, GHB and GBL were administered in doses of 1. 92, 5. 77, and 14. 4 mmol/kg orally with and without MCT inhibition to determine effects of this treatment strategy on the oral toxicokinetics and toxicodynamics of GHB and GBL.

GHB

GBL

GHB

GBL


Input: The competitive MCT inhibitor l-lactate was administered by intravenous infusion starting 1 hour after GHB and GBL administration.

l-lactate

GHB

GBL


Input: Oral administration of l-lactate and the MCT inhibitor luteolin was also evaluated.

l-lactate


Input: Respiratory depression was measured using plethysmography.


Input: Intravenous l-lactate, but not oral treatments, significantly increased GHB renal and/or oral clearances.

l-lactate

GHB


Input: At the low dose of GHB and GBL, i. v. l-lactate increased GHB renal clearance.

GHB

GBL

l-lactate

GHB


Input: Due to the increased contribution of renal clearance to total clearance at the moderate dose, increased renal clearance translated to an increase in oral clearance.


Input: At the highest GHB dose, oral clearance was increased without a significant change in renal clearance.

GHB


Input: The lack of effect of i. v. l-lactate on renal clearance after a high oral GHB dose suggests possible effects of i. v. l-lactate on MCT-mediated absorption.

l-lactate

GHB

l-lactate


Input: The resulting increases in oral clearance improved respiratory depression.


Input: Intravenous l-lactate also reduced mortality with the high GBL dose.

l-lactate

GBL


Input: These data indicate i. v. l-lactate represents a potential treatment strategy in oral overdose of GHB and GBL.

l-lactate

GHB

GBL


Input: Antidepressant treatment and emotional processing: can we dissociate the roles of serotonin and noradrenaline?

serotonin

noradrenaline


Input: The ability to match individual patients to tailored treatments has the potential to greatly improve outcomes for individuals suffering from major depression.


Input: In particular, while the vast majority of antidepressant treatments affect either serotonin or noradrenaline or a combination of these two neurotransmitters, it is not known whether there are particular patients or symptom profiles which respond preferentially to the potentiation of serotonin over noradrenaline or vice versa.

serotonin

noradrenaline

serotonin

noradrenaline


Input: Experimental medicine models suggest that the primary mode of action of these treatments may be to remediate negative biases in emotional processing.


Input: Such models may provide a useful framework for interrogating the specific actions of antidepressants.


Input: Here, we therefore review evidence from studies examining the effects of drugs which potentiate serotonin, noradrenaline or a combination of both neurotransmitters on emotional processing.

serotonin

noradrenaline


Input: These results suggest that antidepressants targeting serotonin and noradrenaline may have some specific actions on emotion and reward processing which could be used to improve tailoring of treatment or to understand the effects of dual-reuptake inhibition.

serotonin

noradrenaline


Input: Specifically, serotonin may be particularly important in alleviating distress symptoms, while noradrenaline may be especially relevant to anhedonia.

serotonin

noradrenaline


Input: The data reviewed here also suggest that noradrenergic-based treatments may have earlier effects on emotional memory that those which affect serotonin.

serotonin


Input: GnRH pulse frequency-dependent stimulation of FSH beta transcription is mediated via activation of PKA and CREB.

GnRH


Input: Expression of pituitary FSH and LH, under the control of pulsatile GnRH, is essential for fertility.

GnRH


Input: cAMP response element-binding protein (CREB) has been implicated in the regulation of FSH beta gene expression, but the molecular mechanisms by which pulsatile GnRH regulates CREB activation remain poorly understood.

cAMP

GnRH


Input: We hypothesized that CREB is activated by a distinct signaling pathway in response to pulsatile GnRH in a frequency-dependent manner to dictate the FSH beta transcriptional response.

GnRH


Input: GnRH stimulation of CREB phosphorylation (pCREB) in the gonadotrope-derived L beta T2 cell line was attenuated by a protein kinase A (PKA) inhibitor, H89.

GnRH


Input: A dominant negative PKA (DNPKA) reduced GnRH-stimulated pCREB and markedly decreased GnRH stimulation of FSH beta mRNA and FSH beta LUC activity, but had little effect on LH beta LUC activity, indicating relative specificity of this pathway.

GnRH

GnRH


Input: In perifusion studies, FSH beta mRNA levels and FSH beta LUC activities were increased by pulsatile GnRH, with significantly greater increases at low compared with high pulse frequencies.

GnRH


Input: DNPKA markedly reduced these GnRH-stimulated FSH beta responses at both low and high pulse frequencies.

GnRH


Input: Correlating with FSH beta activation, both PKA activity and levels of pCREB were increased to a greater extent by low compared with high GnRH pulse frequencies, and the induction of pCREB was also attenuated by overexpression of DNPKA at both low and high pulse frequencies.

GnRH


Input: Taken together, these data indicate that a PKA-mediated signaling pathway mediates GnRH activation of CREB at low-pulse frequencies, playing a significant role in the decoding of the hypothalamic GnRH signal to result in frequency-dependent FSH beta activation.

GnRH

GnRH


Input: Regional Primary Care Team to Deliver Best-Practice Diabetes Care: A needs-driven health workforce model reflecting a biopsychosocial construct of health.


Input: OBJECTIVEBest-practice diabetes care can reduce the burden of diabetes and associated health care costs.


Input: But this requires access to a multidisciplinary team with the right skill mix.


Input: We applied a needs-driven evidence-based health workforce model to describe the primary care team required to support best practice diabetes care, paying particular attention to diverse clinic populations. RESEARCH DESIGN AND METHODSCare protocols, by number and duration of consultations, were derived for twenty distinct competencies based on clinical practice guidelines and structured input from a multidisciplinary clinical panel.


Input: This was combined with a previously estimated population profile of persons across 26 patient attributes (i. e., type of diabetes, complications, and threats to self-care) to estimate clinician contact hours by competency required to deliver best practice care in the study region. RESULTSA primary care team of 22. 1 full-time-equivalent (FTE) positions was needed to deliver best practice primary care to a catchment of 1, 000 persons with diabetes with the attributes of the Australian population.


Input: Competencies requiring greatest contact time were psychosocial issues and dietary advice at 3. 5 and 3. 3 FTE, respectively (1 FTE/~ 300 persons); home (district) nursing at 3. 2 FTE; and diabetes education at 2. 8 FTE.


Input: The annual cost of delivering care was estimated at just over 2, 000 Australian dollars (~ 2, 090 USD) (2012) per person with diabetes. CONCLUSIONSA needs-driven approach to primary care service planning identified a wider range of competencies in the diabetes primary and community care team than typically described.


Input: Access to psychosocial competences as well as medical management is required if clinical targets are to be met, especially in disadvantaged groups.


Input: Detectable subclinical myocardial necrosis is associated with cardiovascular risk in stable patients with diabetes.


Input: OBJECTIVE To investigate the relationship between different degrees of subclinical myocardial necrosis, glycemic control, and long-term adverse clinical outcomes within a stable patient population with diabetes mellitus.


Input: RESEARCH DESIGN AND METHODS We examined 1, 275 stable patients with diabetes mellitus undergoing elective diagnostic coronary angiography with cardiac troponin I (cTnI) levels below the diagnostic cut-off for defining myocardial infarction (MI) (< 0. 03 ng/mL).


Input: The relationship of subclinical myocardial necrosis (cTnI 0. 009-0. 029 ng/mL) with incident major adverse cardiovascular events (MACE; defined as any death, MI, or stroke) over 3 years of follow-up was examined.


Input: RESULTS Subclinical myocardial necrosis was observed in 22% of patients.


Input: A strong association was observed between the magnitude of subclinical myocardial necrosis and risk of 3-year incident MACE (hazard ratio, 1. 98; 95% confidence interval, 1. 48-2. 65; P < 0. 001) and remained statistically significant even after adjustment for traditional risk factors, high-sensitivity C-reactive protein, and creatinine clearance.


Input: Only a weak correlation was observed between the presence of subclinical myocardial necrosis and either glycemic control (r = 0. 06; P = 0. 044 for hemoglobin A1c versus cTnI) or insulin resistance (r = 0. 04; P = 0. 094 for glucose-to-insulin ratio versus cTnI).

glucose


Input: CONCLUSIONS The presence of detectable subclinical myocardial necrosis in stable patients with diabetes mellitus is associated with heightened long-term risk for MACE, independent of traditional risk factors and glycemic control.


Input: Removal of Duodenum Elicits GLP-1 Secretion.


Input: OBJECTIVETo evaluate the effect of removal of the duodenum on the complex interplay between incretins, insulin, and glucagon in nondiabetic subjects. RESEARCH DESIGN AND METHODSFor evaluation of hormonal secretion and insulin sensitivity, 10 overweight patients without type 2 diabetes (age 61 +/- 19. 3 years and BMI 27. 9 +/- 5. 3 kg/m (2)) underwent a mixed-meal test and a hyperinsulinemic-euglycemic clamp before and after pylorus-preserving pancreatoduodenectomy for ampulloma. RESULTSAll patients experienced a reduction in insulin (P = 0. 002), C-peptide (P = 0. 0002), and gastric inhibitory peptide (GIP) secretion (P = 0. 0004), while both fasting and postprandial glucose levels increased (P = 0. 0001); GLP-1 and glucagon responses to the mixed meal increased significantly after surgery (P = 0. 02 and 0. 031).

glucose


Input: While changes in GIP levels did not correlate with insulin, glucagon, and glucose levels, the increase in GLP-1 secretion was inversely related to the postsurgery decrease in insulin secretion (R (2) = 0. 56; P = 0. 012) but not to the increased glucagon secretion, which correlated inversely with the reduction of insulin (R (2) = 0. 46; P = 0. 03) and C-peptide (R (2) = 0. 37; P = 0. 04).

glucose


Input: Given that the remaining pancreas presumably has preserved intraislet anatomy, insulin secretory capacity, and alpha-and beta-cell interplay, our data suggest that the increased glucagon secretion is related to decreased systemic insulin. CONCLUSIONSPylorus-preserving pancreatoduodenectomy was associated with a decrease in GIP and a remarkable increase in GLP-1 levels, which was not translated into increased insulin secretion.


Input: Rather, the hypoinsulinemia may have caused an increase in glucagon secretion.


Input: Pharmacokinetic Interactions between Monoamine Oxidase A Inhibitor Harmaline and 5-Methoxy-N, N-Dimethyltryptamine, and the Impact of CYP2D6 Status.

Monoamine

Harmaline

5-Methoxy-N, N-Dimethyltryptamine


Input: 5-Methoxy-N, N-dimethyltryptamine (5-MeO-DMT or street name " 5-MEO ") is a newer designer drug belonging to a group of naturally occurring indolealkylamines.

5-Methoxy-N, N-dimethyltryptamine

indolealkylamines


Input: Our recent study has demonstrated that coadministration of monoamine oxidase A (MAO-A) inhibitor harmaline (5 mg/kg) increases systemic exposure to 5-MeO-DMT (2 mg/kg) and active metabolite bufotenine.

monoamine

harmaline


Input: This study is aimed at delineating harmaline and 5-MeO-DMT pharmacokinetic (PK) interactions at multiple dose levels, as well as the impact of CYP2D6 that affects harmaline PK and determines 5-MeO-DMT O-demethylation to produce bufotenine.

harmaline

harmaline

5-MeO-DMT O

bufotenine


Input: Our data revealed that inhibition of MAO-A-mediated metabolic elimination by harmaline (2, 5, and 15 mg/kg) led to a sharp increase in systemic and cerebral exposure to 5-MeO-DMT (2 and 10 mg/kg) at all dose combinations.

harmaline


Input: A more pronounced effect on 5-MeO-DMT PK was associated with greater exposure to harmaline in wild-type mice than CYP2D6-humanized (Tg-CYP2D6) mice.

harmaline


Input: Harmaline (5 mg/kg) also increased blood and brain bufotenine concentrations that were generally higher in Tg-CYP2D6 mice.

Harmaline

bufotenine


Input: Surprisingly, greater harmaline dose (15 mg/kg) reduced bufotenine levels.

harmaline

bufotenine


Input: The in vivo inhibitory effect of harmaline on CYP2D6-catalyzed bufotenine formation was confirmed by in vitro study using purified CYP2D6.

harmaline

bufotenine


Input: Given these findings, a unified PK model including the inhibition of MAO-A-and CYP2D6-catalyzed 5-MeO-DMT metabolism by harmaline was developed to describe blood harmaline, 5-MeO-DMT, and bufotenine PK profiles in both wild-type and Tg-CYP2D6 mouse models.

harmaline

harmaline

bufotenine


Input: This PK model may be further employed to predict harmaline and 5-MeO-DMT PK interactions at various doses, define the impact of CYP2D6 status, and drive harmaline-5-MeO-DMT pharmacodynamics.

harmaline

harmaline


Input: Hyperbranched Polyester Hydrogels with Controlled Drug Release and Cell Adhesion Properties.

Polyester


Input: Hyperbranched polyesters (HPE) have a high efficiency to encapsulate bioactive agents, including drugs, genes, and proteins, due to their globe-like nanostructure.

polyesters


Input: However, the use of these highly branched polymeric systems for tissue engineering applications has not been broadly investigated.


Input: Here, we report synthesis and characterization of photocrosslinkable HPE hydrogels with sustained drug release characteristics for cellular therapies.


Input: These HPE can encapsulate hydrophobic drug molecules within the HPE cavities due to the presence of a hydrophobic inner structure that is otherwise difficult to achieve in conventional hydrogels.


Input: The functionalization of HPE with photocrosslinkable acrylate moieties renders the formation of hydrogels with a highly porous interconnected structure and mechanically tough network.

acrylate


Input: The compressive modulus of HPE hydrogels was tunable by changing the crosslinking density.


Input: The feasibility of using these HPE networks for cellular therapies was investigated by evaluating cell adhesion, spreading, and proliferation on hydrogel surface.


Input: Highly crosslinked and mechanically stiff HPE hydrogels have higher cell adhesion, spreading, and proliferation compared to soft and complaint HPE hydrogels.


Input: Overall, we showed that hydrogels made from HPE could be used for biomedical applications that require spatial control of cell adhesion and controlled release of hydrophobic clues.


Input: One-pot, exchange-free, room-temperature synthesis of sub-10 nm aqueous, noninteracting, and stable zwitterated iron oxide nanoparticles.

zwitterated iron oxide


Input: Stable aqueous dispersions of superparamagnetic iron oxide nanoparticles were synthesized in one step in the presence of a zwitterionic siloxane as the stabilizing/capping/solubilizing ligand.

iron oxide

zwitterionic siloxane


Input: The hydrodynamic diameter of the particles was tuned by controlling the concentration of zwitterion siloxane, which ultimately yielded monodisperse nanoparticles small enough for renal filtration (< 6 nm diameter).

zwitterion siloxane


Input: The zwitterated nanoparticles were readily dispersed and stable in aqueous media in the pH range 6-9 but exhibited lower magnetization values than nonzwitterated materials due to amorphous content and spin canting, typical for particles of such size.


Input: Turbidimetry and light scattering studies revealed no interaction between the particles and proteins, suggesting the materials will circulate well in vivo.


Input: Tetracyclic diterpenoids with isomerized isospongian skeleton and labdane diterpenoids from the fruits of Amomum kravanh.

Tetracyclic diterpenoids

isospongian

labdane diterpenoids


Input: Four novel diterpenoids, including three tetracyclic diterpenes with isomerized isospongian skeletons, kravanhins A-C (1-3), and kravanhin D (4), and three new labdane diterpenes (5-7) were isolated from the fruits of Amomum kravanh.

diterpenoids

tetracyclic diterpenes

isospongian

kravanhins A-C

kravanhin D

labdane diterpenes


Input: Compounds 1-4 had unprecedented isospongian diterpene skeletons with a trans-anti-cis fused tricyclic ring system.

isospongian diterpene


Input: The structures of compounds 1-7 were established on the basis of extensive analysis of NMR spectra, CD, and X-ray crystallography.


Input: Compound 2 showed inhibitory activity on nitric oxide production in lipopolysaccharide-induced RAW264. 7 macrophages with an IC (50) value of 36. 2 mu M.

nitric oxide


Input: Methotrexate pharmacogenetics in rheumatoid arthritis: a status report.

Methotrexate


Input: Methotrexate (MTX), an antifolate drug, is the first-line disease-modifying agent for the treatment of rheumatoid arthritis (RA) worldwide.

Methotrexate

MTX


Input: MTX has excellent long-term efficacy, tolerability and safety.

MTX


Input: Early initiation of MTX in patients with RA controls joint destruction and slows progression of disease.

MTX


Input: However, the clinical response to MTX and frequency of adverse effects from the drug exhibit marked interpatient variability.

MTX


Input: Over the past decade, there has been a quest to identify genetic markers that reliably predict MTX efficacy and toxicity and help optimize MTX therapy in RA; that is, the field of MTX pharmacogenetics.

MTX

MTX

MTX


Input: This review will summarize key pharmacogenetic studies examining SNPs in the genes encoding enzymes in the MTX cellular pathway and their association with MTX response in RA.

MTX

MTX


Input: As evident from this review, MTX pharmacogenetics in RA remains a muddled field, mostly due to inconsistent results from several small underpowered studies.

MTX


Input: Reversible sol-to-gel transformation of uracil gelators: specific colorimetric and fluorimetric sensor for fluoride ions.

uracil

fluoride


Input: A new type of anthracene organogelator based on uracil was obtained using organic aromatic solvents, cyclohexane, DMSO, ethanol, and ethyl acetate.

anthracene

uracil

cyclohexane

DMSO

ethanol

ethyl acetate


Input: It was further characterized by field-emission scanning electron microscopy and transmission electron microscopy.


Input: Specifically, the resulting organogels were demonstrated to be promising colorimetric and fluorescent sensors toward fluoride ions with high sensitivity and selectivity, accompanying the disruption of the gelators.


Input: Spectroscopic study and (1) H NMR titration experiment revealed that the deprotonation of the hydrogen atom on the N position of uracil moiety by fluoride ions is responsible for the recognition events, evidenced by immediate transformation from the sol phase to the gel state upon adding a small amount of a proton solvent, methanol.

(1) H

hydrogen

N

uracil

fluoride

methanol


Input: The process is reversible, with zero loss in sensing activity and sol-to-gel transformation ability even after five runs.


Input: Statin intolerance: why and what to do-with a focus on diabetic people.


Input: The standards of medical care in diabetes recommend that statin therapy is added to lifestyle therapy for diabetic patients with overt cardiovascular disease (LDL cholesterol goal < 70 mg/dl), or without cardiovascular disease who are over the age of 40 years and who have one or more other cardiovascular disease risk factors (LDL cholesterol goal < 100 mg/dl).

cholesterol

cholesterol


Input: In order to reach strict LDL targets, high doses of statins may be required.


Input: However, the frequency of statin associated adverse effects and statin intolerance in clinical practice is high (up to 10-15% of statin users) especially at muscle level.


Input: The review overviews: 1) the known or hypothesised mechanisms through which causal and contributing factors are associated with adverse effects in diabetic people, and 2) the rationale of strategies for managing statin intolerant patients.


Input: Thymidylate kinase: an old topic brings new perspectives.

Thymidylate


Input: Thymidylate kinase (TMPK) is a key enzyme for pyrimidine synthesis that catalyzes the phosphorylation of thymidine 5'-monophosphate (dTMP) in the presence of ATP and Mg (2 +) to form thymidine 5'-diphosphate (dTDP), which is then converted to thymidine 5'-triphosphate (dTTP) by nucleoside-diphosphate kinase (NDK).

Thymidylate

pyrimidine

thymidine 5'-monophosphate

dTMP

ATP

Mg (2 +)

thymidine 5'-diphosphate

dTDP

thymidine 5'-triphosphate

dTTP

nucleoside-diphosphate


Input: TMPK has an important function in cell proliferation and its enzyme kinetics and related structures have been determined in various organisms.


Input: TMPK is well recognized as a potential drug target, with the most notable function being in the activation of anti-HIV nucleoside prodrugs.

nucleoside


Input: Recent studies have shown that TMPK is a validated target for antibiotic development against gram-positive bacterium of Staphylococcus aureus.


Input: In addition, inhibition of human TMPK increases the potential of anticancer agent doxorubicin toward colon cancer cells regardless of p53 status.

doxorubicin