Input: The flexibility may occur in the positioning of the transcription bubble prior to RNA synthesis and may reflect bubble expansion (" scrunching ") or bubble contraction (" unscrunching ").


Input: Here, we assess the presence of dynamic flexibility in RP (o) with single-molecule FRET (F o rster resonance energy transfer).


Input: We obtain experimental evidence for dynamic flexibility in RP (o) using different FRET rulers and labeling positions.


Input: An analysis of FRET distributions of RP (o) using burst variance analysis reveals conformational fluctuations in RP (o) in the millisecond timescale.


Input: Further experiments using subsets of nucleotides and DNA mutations allowed us to reprogram the transcription start sites, in a way that can be described by repositioning of the single-stranded transcription bubble relative to the RNAP active site within RP (o).


Input: Our study marks the first experimental observation of conformational dynamics in the transcription bubble of RP (o) and indicates that DNA dynamics within the bubble affect the search for transcription start sites.


Input: The use of Reamer Irrigator Aspirator (RIA) autograft harvest in the treatment of critical-sized iliac wing defects in sheep: investigation of dexamethasone and beta-tricalcium phosphate augmentation.

dexamethasone

beta-tricalcium phosphate


Input: Bone grafts are commonly used for the treatment of segmental bone defects and fracture non-unions.


Input: Recently, osseous particles obtained during intermedullary canal reaming (using a Reamer-Irrigator-Aspirator (RIA) device) have been evaluated as graft material during in vitro and clinical studies.


Input: The aim of this study was to evaluate and quantify new bone formation after implantation of bone graft material obtained after reaming of the tibia in a bilateral critical-sized iliac wing defect in sheep and to investigate the effect of the augmentation of this graft.


Input: A reamer bone graft alone, or after short term incubation in a dexamethasone enriched solution, and a reamer graft collected using beta-tricalcium phosphate (beta-TCP) granules in the filter of the RIA collection device were compared to autologous iliac wing graft.

dexamethasone

beta-tricalcium phosphate

beta-TCP


Input: In addition, reamer graft was combined with the cellular fraction collected from the irrigation fluid with and without short-term incubation in a dexamethasone enriched solution.

dexamethasone


Input: It was hypothesized that the amount of physical bone in the reamer bone graft groups would be higher than the amount in the autologous iliac wing graft group and that augmentation of a reamer bone graft would increase bone formation.


Input: Three months after implantation, the amount of new bone formation (as percentage of the total defect volume) in the defects was evaluated ex-vivo by means of micro-CT and histomorphometry.


Input: The mean amount of bone in the autologous iliac wing graft group was 17. 7% and 16. 8% for micro-CT and histomorphometry, respectively.


Input: The mean amount of bone in all reamer graft groups ranged between 20. 4-29. 2% (micro-CT) and 17. 0-25. 4% (histomorphometry).


Input: Reamer graft collected using beta-TCP granules (29. 2 +/- 1. 7%) in the filter produced a significantly higher amount of bone in comparison to an autologous iliac wing graft evaluated by micro-CT.

beta-TCP


Input: RIA bone grafts added a small increase in bone volume to the 3month graft volume in this preclinical sheep model.


Input: The current model does not support the use of short-term high concentration dexamethasone for augmentation of a graft volume.

dexamethasone


Input: If avoidance of an iliac wing graft is desirable, or a reaming procedure is required, then a RIA graft or RIA graft plus beta-TCP granules are as good as the current gold standard for this model.

beta-TCP


Input: Pharmacokinetics explain in vivo/in vitro discrepancies of carcinogen-induced gene expression alterations in rat liver and cultivated hepatocytes.


Input: Cultivated hepatocytes represent a well-established in vitro system.


Input: However, the applicability of hepatocytes in toxicogenomics is still controversially discussed.


Input: Recently, an in vivo/in vitro discrepancy has been described, whereby the non-genotoxic rat liver carcinogen methapyrilene alters the expression of the metabolizing genes SULT1A1 and ABAT, as well as the DNA damage response gene GADD34 in vitro, but not in vivo.

methapyrilene


Input: If the collagen sandwich cultures of hepatocytes really produce false-positive data, this would compromise its application in toxicogenomics.


Input: To revisit the putative in vivo/in vitro discrepancy, we first analyzed and modeled methapyrilene concentrations in the portal vein of rats.

methapyrilene


Input: The relatively short half-life of 2. 8 h implies a rapid decrease in orally administered methapyrilene in vivo below concentrations that can cause gene expression alterations.

methapyrilene


Input: This corresponded to the time-dependent alteration levels of GADD34, ABAT and SULT1A1 RNA in the liver: RNA levels are altered 1, 6 and 12 h after methapyrilene administration, but return to control levels after 24 and 72 h.

methapyrilene


Input: In contrast, methapyrilene concentrations in the culture medium supernatant of primary rat hepatocyte cultures decreased slowly.

methapyrilene


Input: This explains why GADD34, ABAT and SULT1A1 were still deregulated after 24 h exposure in vitro, but not in vivo.


Input: It should also be considered that the earliest analyzed time point in the previous in vivo studies was 24 h after methapyrilene administration.

methapyrilene


Input: In conclusion, previously observed in vitro/in vivo discrepancy can be explained by different pharmacokinetics present in vitro and in vivo.


Input: When the in vivo half-life is short, levels of some initially altered genes may have returned to control levels already 24 h after administration.


Input: New targets for the antitumor activity of gambogic acid in hematologic malignancies.

gambogic acid


Input: Gambogic acid (GA) is the main active ingredient of gamboge, a brownish to orange dry resin secreted from Garcinia hanburyi, a plant that is widely distributed in nature.

Gambogic acid


Input: Recent in vitro and in vivo studies have demonstrated that GA exerts potent antitumor effects against solid tumors of various derivations, and its antitumor mechanisms have been thoroughly investigated.


Input: On the other hand, normal cells remain relatively resistant to GA, indicating a therapeutic window.


Input: GA is currently in clinical trials in China.


Input: Over the last decade, our laboratory demonstrates that GA exhibits potent anticancer activities against hematological malignancies.


Input: This review focuses on the new mechanisms through which GA inhibits proliferation and induces apoptosis in malignant hematological cells.


Input: These include the regulation of expression and intracellular positioning of nucleoporin and nucleophosmin; downregulation of steroid receptor coactivator-3 (SRC-3) and its downstream proteins; upregulation of death inducer-obliterator (DIO-1); downregulation of HERG potassium channel; as well as induction of reactive oxygen species (ROS) accumulation.

steroid

potassium

oxygen


Input: Synthesis of spirolactone-type diterpenoid derivatives from kaurene-type oridonin with improved antiproliferative effects and their apoptosis-inducing activity in human hepatoma Bel-7402 cells.

spirolactone

diterpenoid

kaurene

oridonin


Input: A series of novel spirolactone-type diterpenoid derivatives of oridonin (12a-j) were designed and synthesized.

spirolactone

diterpenoid

oridonin


Input: All the target compounds showed improved anti-proliferative activity against a panel of human cancer cell lines and the most effective compound 12j was more potent than positive control Taxol in K562 and Bel-7402 cells with IC (50) values of 0. 39 mu M and 1. 39 mu M, respectively.


Input: The cellular mechanisms showed that compound 12j induced apoptosis at low micromolar concentrations in human hepatoma Bel-7402 cells.


Input: These results demonstrate that the spirolactone-type diterpenoid derivatives of oridonin have optimized growth inhibitory activity against cancer cells and interesting apoptosis-inducing ability.

spirolactone

diterpenoid

oridonin


Input: Effects of water restriction on reproductive physiology and affiliative behavior in an opportunistically-breeding and monogamous songbird, the zebra finch.


Input: Wild zebra finches form long-term monogamous pair-bonds that are actively maintained year-round, even when not in breeding condition.


Input: These desert finches are opportunistic breeders, and breeding is highly influenced by unpredictable rainfall.


Input: Their high levels of affiliation and complex breeding patterns make zebra finches an excellent model in which to study the endocrine regulation of affiliation.


Input: Here, we compared zebra finch pairs that were provided with water ad libitum (control) or water restricted.


Input: We examined (1) reproductive physiology, (2) pair-maintenance behaviors in several contexts, and (3) circulating and brain steroid levels.

steroid


Input: In females, water restriction profoundly reduced largest ovarian follicle size, ovary size, oviduct size, and egg laying.


Input: In males, water restriction had no effect on testes size but decreased systemic testosterone levels.

testosterone


Input: However, in the hypothalamus, local testosterone and estradiol levels were unaffected by water restriction in both sexes.

testosterone

estradiol


Input: Systemic and local levels of the androgen precursor dehydroepiandrosterone (DHEA) were also unaffected by water restriction.

androgen

dehydroepiandrosterone

DHEA


Input: Lastly, in three different behavioral paradigms, we examined a variety of pair-maintenance behaviors, and none were reduced by water restriction.


Input: Taken together, these correlational data are consistent with the hypothesis that local production of sex steroids in the brain promotes the expression of pair-maintenance behaviors in non-breeding zebra finches.

steroids


Input: Trichothecene toxicity in eukaryotes: cellular and molecular mechanisms in plants and animals.

Trichothecene


Input: Trichothecenes are sesquiterpenoid mycotoxins commonly found as contaminants in cereal grains and are a major health and food safety concern due to their toxicity to humans and farm animals.

Trichothecenes

sesquiterpenoid mycotoxins


Input: Trichothecenes are predominantly produced by the phytopathogenic Fusarium fungus, and in plants they act as a virulence factor aiding the spread of the fungus during disease development.

Trichothecenes


Input: Known for their inhibitory effect on eukaryotic protein synthesis, trichothecenes also induce oxidative stress, DNA damage and cell cycle arrest and affect cell membrane integrity and function in eukaryotic cells.

trichothecenes


Input: In animals, trichothecenes can be either immunostimulatory or immunosuppressive and induce apoptosis via mitochondria-mediated or-independent pathway.

trichothecenes


Input: In plants, trichothecenes induce programmed cell death via production of reactive oxygen species.

trichothecenes


Input: Recent advances in molecular techniques have led to the elucidation of signal transduction pathways that manifest trichothecene toxicity in eukaryotes.

trichothecene


Input: In animals, trichothecenes induce mitogen-activated protein kinase (MAPK) signalling cascades via ribotoxic stress response and/or endoplasmic reticulum stress response.

trichothecenes


Input: The upstream signalling events that lead to the activation trichothecene-induced ribotoxic stress response are discussed.

trichothecene


Input: In plants, trichothecenes exhibit elicitor-like activity leading to the inductions MAPKs and genes involved in oxidative stress, cell death and plant defence response.

trichothecenes


Input: Trichothecenes might also modulate hormone-mediated defence signalling and abiotic stress signalling in plants.

Trichothecenes


Input: Cationic nanoparticles disrupt cellular signaling in a cholesterol dependent manner.

cholesterol


Input: In this study, we investigate the interaction of charged polystyrene particles with respiratory epithelial cells.

polystyrene


Input: Experiments were designed to reveal the effect of cellular interaction with particles of varying size and charge and how such interactions could alter cytokine induced cellular processes.


Input: A549 cells, containing a stably transfected Interleukin-8 (IL-8) Luciferase promoter construct, were cultured in the presence of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and polystyrene particles for 4. 5h.

polystyrene


Input: Several endpoints were measured: IL-8 gene expression, IL-6 protein, IL-8 protein, and NF-k B translocation.


Input: At 4. 5h, cellular viability was maintained for the particle exposed cells.


Input: Interestingly, we found that only the cationic nanoparticles have the ability to disrupt the TNF-alpha stimulated cellular signaling by reducing the IL-8 promoter activity, IL-6 and IL-8 protein.


Input: Cationic nanoparticles reduce these processes through interfering with NF-kappa B translocation.


Input: However, the activity of the cationic nanoparticles on the IL-8 promoter and NF-kappa B translocation is lost when cholesterol is depleted from A549 cells before particle exposure, which suggests that cationic nanoparticles rely on membrane cholesterol integrity to disrupt cellular signaling.

cholesterol

cholesterol


Input: Fecal microbiota composition differs between children with beta-cell autoimmunity and those without.


Input: The role of the intestinal microbiota as a regulator of autoimmune diabetes in animal models is well-established, but data on human type 1 diabetes are tentative and based on studies including only a few study subjects.


Input: To exclude secondary effects of diabetes and HLA risk genotype on gut microbiota, we compared the intestinal microbiota composition in children with at least two diabetes-associated autoantibodies (n = 18) with autoantibody-negative children matched for age, sex, early feeding history, and HLA risk genotype using pyrosequencing.


Input: Principal component analysis indicated that a low abundance of lactate-producing and butyrate-producing species was associated with beta-cell autoimmunity.

lactate

butyrate


Input: In addition, a dearth of the two most dominant Bifidobacterium species, Bifidobacterium adolescentis and Bifidobacterium pseudocatenulatum, and an increased abundance of the Bacteroides genus were observed in the children with beta-cell autoimmunity.


Input: We did not find increased fecal calprotectin or IgA as marker of inflammation in children with beta-cell autoimmunity.


Input: Functional studies related to the observed alterations in the gut microbiome are warranted because the low abundance of bifidobacteria and butyrate-producing species could adversely affect the intestinal epithelial barrier function and inflammation, whereas the apparent importance of the Bacteroides genus in development of type 1 diabetes is insufficiently understood.

butyrate


Input: EphA5-EphrinA5 interactions within the ventromedial hypothalamus influence counterregulatory hormone release and local glutamine/glutamate balance during hypoglycemia.

glutamine

glutamate


Input: Activation of beta-cell EphA5 receptors by its ligand ephrinA5 from adjacent beta-cells has been reported to decrease insulin secretion during hypoglycemia.


Input: Given the similarities between islet and ventromedial hypothalamus (VMH) glucose sensing, we tested the hypothesis that the EphA5/ephrinA5 system might function within the VMH during hypoglycemia to stimulate counterregulatory hormone release as well.

glucose


Input: Counterregulatory responses and glutamine/glutamate concentrations in the VMH were assessed during a hyperinsulinemic-hypoglycemic glucose clamp study in chronically catheterized awake male Sprague-Dawley rats that received an acute VMH microinjection of ephrinA5-Fc, chronic VMH knockdown, or overexpression of ephrinA5 using an adenoassociated viral construct.

glutamine

glutamate

glucose


Input: Local stimulation of VMH EphA5 receptors by ephrinA5-Fc or ephrinA5 overexpression increased, whereas knockdown of VMH ephrinA5 reduced counterregulatory responses during hypoglycemia.


Input: Overexpression of VMH ephrinA5 transiently increased local glutamate concentrations, whereas ephrinA5 knockdown produced profound suppression of VMH interstitial fluid glutamine concentrations in the basal state and during hypoglycemia.

glutamate

glutamine


Input: Changes in ephrinA5/EphA5 interactions within the VMH, a key brain glucose-sensing region, act in concert with islets to restore glucose homeostasis during acute hypoglycemia, and its effect on counterregulation may be mediated by changes in glutamate/glutamine cycling.

glucose

glucose

glutamate

glutamine


Input: Electrical Stimuli Release ATP to Increase GLUT4 Translocation and Glucose Uptake via PI3K gamma-Akt-AS160 in Skeletal Muscle Cells.

ATP

Glucose


Input: Skeletal muscle glucose uptake in response to exercise is preserved in insulin-resistant conditions, but the signals involved are debated.

glucose


Input: ATP is released from skeletal muscle by contractile activity and can autocrinely signal through purinergic receptors, and we hypothesized it may influence glucose uptake.

ATP

glucose


Input: Electrical stimulation, ATP, and insulin each increased fluorescent 2-NBD-Glucose (2-NBDG) uptake in primary myotubes, but only electrical stimulation and ATP-dependent 2-NBDG uptake were inhibited by adenosine-phosphate phosphatase and by purinergic receptor blockade (suramin).

ATP

ATP

adenosine-phosphate

suramin


Input: Electrical stimulation transiently elevated extracellular ATP and caused Akt phosphorylation that was additive to insulin and inhibited by suramin.

ATP

suramin


Input: Exogenous ATP transiently activated Akt and, inhibiting phosphatidylinositol 3-kinase (PI3K) or Akt as well as dominant-negative Akt mutant, reduced ATP-dependent 2-NBDG uptake and Akt phosphorylation.

ATP

ATP


Input: ATP-dependent 2-NBDG uptake was also inhibited by the G protein beta gamma subunit-interacting peptide beta ark-ct and by the phosphatidylinositol 3-kinase-gamma (PI3K gamma) inhibitor AS605240.

ATP


Input: ATP caused translocation of GLUT4myc-eGFP to the cell surface, mechanistically mediated by increased exocytosis involving AS160/Rab8A reduced by dominant-negative Akt or PI3K gamma kinase-dead mutants, and potentiated by myristoylated PI3K gamma.

ATP


Input: ATP stimulated 2-NBDG uptake in normal and insulin-resistant adult muscle fibers, resembling the reported effect of exercise.

ATP


Input: Hence, the ATP-induced pathway may be tapped to bypass insulin resistance.

ATP


Input: Permanent Neonatal Diabetes in INSC94Y Transgenic Pigs.


Input: Mutations in the insulin (INS) gene may cause permanent neonatal diabetes mellitus (PNDM).


Input: Ins2 mutant mouse models provided important insights into the disease mechanisms of PNDM but have limitations for translational research.


Input: To establish a large animal model of PNDM, we generated INS (C94Y) transgenic pigs.


Input: A line expressing high levels of INS (C94Y) mRNA (70-86% of wild-type INS transcripts) exhibited elevated blood glucose soon after birth but unaltered beta-cell mass at the age of 8 days.

glucose


Input: At 4. 5 months, INS (C94Y) transgenic pigs exhibited 41% reduced body weight, 72% decreased beta-cell mass (-53% relative to body weight), and 60% lower fasting insulin levels compared with littermate controls.


Input: beta-cells of INS (C94Y) transgenic pigs showed a marked reduction of insulin secretory granules and severe dilation of the endoplasmic reticulum.


Input: Cataract development was already visible in 8-day-old INS (C94Y) transgenic pigs and became more severe with increasing age.


Input: Diabetes-associated pathological alterations of kidney and nervous tissue were not detected during the observation period of 1 year.


Input: The stable diabetic phenotype and its rescue by insulin treatment make the INS (C94Y) transgenic pig an attractive model for insulin supplementation and islet transplantation trials, and for studying developmental consequences of maternal diabetes mellitus.


Input: Nogo-a downregulation improves insulin secretion in mice.


Input: Type 2 diabetes (T2D) is characterized by beta-cell dysfunction and the subsequent depletion of insulin production, usually in a context of increased peripheral insulin resistance.


Input: T2D patients are routinely treated with oral antidiabetic agents such as sulfonylureas or dipeptidyl peptidase-4 antagonists, which promote glucose-and incretin-dependent insulin secretion, respectively.

sulfonylureas

glucose


Input: Interestingly, insulin secretion may also be induced by neural stimulation.


Input: Here we report the expression of Nogo-A in beta-cells.


Input: Nogo-A is a membrane protein that inhibits neurite outgrowth and cell migration in the central nervous system.


Input: We observed that Nogo-A-deficient mice display improved insulin secretion and glucose clearance.

glucose


Input: This was associated with a stronger parasympathetic input and higher sensitivity of beta-cells to the cholinergic analog carbachol.

carbachol


Input: Insulin secretion was also improved in diabetic db/db mice treated with neutralizing antibody against Nogo-A.


Input: Together, these findings suggest that promoting the vagal stimulation of insulin secretion through the selective inhibition of Nogo-A could be a novel therapeutic approach in T2D.


Input: In vitro cytotoxicity and genotoxicity studies of titanium dioxide (TiO2) nanoparticles in Chinese hamster lung fibroblast cells.

titanium dioxide


Input: There are increasing safety concerns about the development and abundant use of nanoparticles.


Input: The unique physical and chemical characteristics of titanium dioxide (TiO2) nanoparticles result in different chemical and biological activities compared to their larger micron-sized counterparts, and can subsequently play an important role in influencing toxicity.

titanium dioxide


Input: Therefore, our objective was to investigate the cytotoxicity and genotoxicity of commercially available TiO2 nanoparticles with respect to their selected physicochemical properties, as well as the role of surface coating of these nanoparticles.


Input: While all types of tested TiO2 samples decrease cell viability in a mass-based concentration-and size-dependent manner, the polyacrylate-coated nano-TiO2 product was only cytotoxic at higher concentrations.

polyacrylate


Input: A similar pattern of response was observed for induction of apoptosis/necrosis, and no DNA damage was detected in the polyacrylate-coated nano-TiO2 model.

polyacrylate


Input: Given the increasing production of TiO2 nanoparticles, toxicological studies should take into account the physiochemical properties of these nanoparticles that may help researchers to develop new nanoparticles with minimum toxicity.


Input: A novel stimuli-synchronized alloy-treated matrix for space-defined gastrointestinal delivery of mesalamine in the Large White pig model.

mesalamine


Input: The study focussed on designing a Stimuli-Synchronized Matrix (SSM) for space-defined colonic delivery of the anti-inflammatory drug mesalamine.

mesalamine


Input: The configured matrix provided time-independent delivery and stimuli targeting.


Input: Formulations were optimized according to a Box-Behnken experimental design that constituted mesalamine-loaded BaSO4-crosslinked chitosan dispersed within a pectin, carboxymethylcellulose and xanthan gum complex.

mesalamine


Input: The complex was compressed into matrices and subsequently alloy-treated with pectin and ethylcellulose.


Input: In vitro drug release was determined in the presence and absence of colonic enzymes and the mean dissolution time was used for formulation optimization.


Input: To mechanistically elucidate the synchronous catalytic action of the enzymes pectinase and glucosidase on the matrix, computer-aided 3D modelling of active fractions of the enzyme-substrate complexes was generated to predict the orientation of residues affecting the substrate domain.


Input: Drug release profiles revealed distinct colonic enzyme responsiveness with fractions of 0. 402 and 0. 152 of mesalamine released in the presence and absence of enzymes, respectively after 24h.

mesalamine


Input: The commercial comparator product showed irreproducible release profiles over the same period (SD = 0. 550) compared to the SSM formulation (SD = 0. 037).


Input: FTIR spectra of alloy-treated matrices showed no peaks from 1589 to 1512cm (-1) after colonic enzyme exposure.


Input: With increasing enzyme exposure there were also no peaks between 1646 and 1132cm (-1).


Input: This indicated polymeric enzyme cleavage for controlled and space-defined release of mesalamine.

mesalamine


Input: Plasma concentration profiles in the Large White pig model produced a Cmax of 3. 77 +/- 1. 375 mu g/mL compared to 10. 604 +/- 2. 846 mu g/mL for the comparator formulation.


Input: The SSM formulation proved superior over the comparator product by providing superiorly controlled enzyme-responsive colonic drug delivery.


Input: Discriminative stimulus effects of the GABAB receptor-positive modulator rac-BHFF: comparison with GABAB receptor agonists and drugs of abuse.

rac-BHFF


Input: GABA (B) receptor-positive modulators are thought to have advantages as potential medications for anxiety, depression, and drug addiction.

GABA


Input: They may have fewer side effects than GABA (B) receptor agonists, because selective enhancement of activated receptors could have effects different from nonselective activation of all receptors.

GABA


Input: To examine this, pigeons were trained to discriminate the GABA (B) receptor-positive modulator (R, S)-5, 7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) from its vehicle.

GABA

(R, S)-5, 7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one

rac-BHFF


Input: The discriminative stimulus effects of rac-BHFF were not mimicked by the GABA (B) receptor agonists baclofen and gamma-hydroxybutyrate (GHB), not by diazepam, and not by alcohol, cocaine, and nicotine, whose self-administration has been reported to be attenuated by GABA (B) receptor-positive modulators.

rac-BHFF

GABA

baclofen

gamma-hydroxybutyrate

GHB

diazepam

alcohol

cocaine

nicotine

GABA


Input: The discriminative stimulus effects of rac-BHFF were not antagonized by the GABA (B) receptor antagonist 3-aminopropyl (diethoxymethyl) phosphinic acid (CGP35348) but were attenuated by the less efficacious GABA (B) receptor-positive modulator 2, 6-di-tert-butyl-4-(3-hydroxy-2, 2-dimethylpropyl) phenol (CGP7930), suggesting the possibility that rac-BHFF produces its discriminative stimulus effects by directly activating GABA (B2) subunits of GABA (B) receptors.

rac-BHFF

GABA

3-aminopropyl (diethoxymethyl) phosphinic acid

GABA

2, 6-di-tert-butyl-4-(3-hydroxy-2, 2-dimethylpropyl) phenol

rac-BHFF

GABA

GABA


Input: At a dose 10-fold lower than the training dose, rac-BHFF enhanced the discriminative stimulus effects of baclofen, but not of GHB.

rac-BHFF

baclofen

GHB


Input: This study provides evidence that the effects of GABA (B) receptor-positive modulators are not identical to those of GABA (B) receptor agonists.

GABA

GABA


Input: In addition, the results suggest that positive modulation of GABA (B) receptors does not produce discriminative stimulus effects similar to those of benzodiazepines, alcohol, cocaine, and nicotine.

GABA

benzodiazepines

alcohol

cocaine

nicotine


Input: Finally, the finding that rac-BHFF enhanced effects of baclofen but not of GHB is consistent with converging evidence that the populations of GABA (B) receptors mediating the effects of baclofen and GHB are not identical.

rac-BHFF

baclofen

GHB

GABA

baclofen

GHB


Input: Biocompatibility and levofloxacin delivery of mesoporous materials.

levofloxacin


Input: A comparative study of mesoporous matrices designed for both drug-loading methods, impregnation (IP) and surfactant-assisted drug loading (also denoted as one-pot, OP), has been carried out evaluating their physicochemical characteristics, cell response, drug delivery profiles, and antibacterial activity.


Input: Surfactant-free (calcined) and surfactant-templated (non-calcined) mesoporous silica have been used as IP and OP starting matrices, respectively.

silica


Input: Both non-calcined and calcined matrices do not exert any cytotoxic effect on osteoblasts.


Input: However, non-calcined matrices induce on fibroblasts a significant proliferation delay with morphological alterations and dose-dependent increases in fibroblast size, internal complexity, and intracellular calcium content but without cell lysis and apoptosis.

calcium


Input: Residual ethanol and the surface silanol groups in these non-calcined matrices are involved in the observed fibroblast changes.

ethanol

silanol


Input: Finally, both IP and OP matrices have been loaded with levofloxacin to compare them as drug delivery systems.

levofloxacin


Input: Both IP and OP matrices exhibit similar in vitro levofloxacin release profiles, showing an initial fast delivery followed by a sustained release during long time periods.

levofloxacin


Input: These profiles and the antimicrobial activity results suggest the use of these IP and OP matrices as local drug delivery systems in the osteomyelitis and other bone infection treatments.


Input: The COP9 signalosome interacts with and regulates interferon regulatory factor 5 protein stability.


Input: The transcription factor interferon regulatory factor 5 (IRF5) exerts crucial functions in the regulation of host immunity against extracellular pathogens, DNA damage-induced apoptosis, death receptor signaling, and macrophage polarization.


Input: Tight regulation of IRF5 is thus warranted for an efficient response toward extracellular stressors and for limiting autoimmune and inflammatory responses.


Input: Here we report that the COP9 signalosome (CSN), a general modulator of diverse cellular and developmental processes, associates constitutively with IRF5 and promotes its protein stability.


Input: The constitutive CSN/IRF5 interaction was identified using proteomics and confirmed by endogenous immunoprecipitations.


Input: The CSN/IRF5 interaction occurred on the carboxyl and amino termini of IRF5; a single internal deletion from amino acids 455 to 466 (Delta 455-466) was found to significantly reduce IRF5 protein stability.

carboxyl

amino

amino acids


Input: CSN subunit 3 (CSN3) was identified as a direct interacting partner of IRF5, and knockdown of this subunit with small interfering RNAs resulted in enhanced degradation.


Input: Degradation was further augmented by knockdown of CSN1 and CSN3 together.


Input: The ubiquitin E1 inhibitor UBEI-41 or the proteasome inhibitor MG132 prevented IRF5 degradation, supporting the idea that its stability is regulated by the ubiquitin-proteasome system.


Input: Importantly, activation of IRF5 by the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resulted in enhanced degradation via loss of the CSN/IRF5 interaction.


Input: This study defines CSN to be a new interacting partner of IRF5 that controls its stability.


Input: Osteoblast lineage-specific effects of notch activation in the skeleton.


Input: Transgenic overexpression of the Notch1 intracellular domain inhibits osteoblast differentiation and causes osteopenia, and inactivation of Notch1 and Notch2 increases bone volume transiently and induces osteoblastic differentiation.


Input: However, the biology of Notch is cell-context-dependent, and consequences of Notch activation in cells of the osteoblastic lineage at various stages of differentiation and in osteocytes have not been defined.


Input: For this purpose, Rosa (Notch) mice, where a loxP-flanked STOP cassette placed between the Rosa26 promoter and the NICD coding sequence, were crossed with transgenics expressing the Cre recombinase under the control of the Osterix (Osx), Osteocalcin (Oc), Collagen 1a1 (Col2. 3), or Dentin matrix protein1 (Dmp1) promoters.


Input: At 1 month, Osx-Cre; Rosa (Notch) and Oc-Cre; Rosa (Notch) mice exhibited osteopenia due to impaired bone formation.


Input: In contrast, Col2. 3-Cre; Rosa (Notch) and Dmp1-Cre; Rosa (Notch) exhibited increased femoral trabecular bone volume due to a decrease in osteoclast number and eroded surface.


Input: In the four lines studied, cortical bone was either not present, was porous, or had the appearance of trabecular bone.


Input: Oc-Cre; Rosa (Notch) and Col2. 3-Cre; Rosa (Notch) mice exhibited early lethality so that their adult phenotype was not established.


Input: At 3 months, Osx-Cre; Rosa (Notch) and Dmp1-Cre; Rosa (Notch) mice displayed increased bone volume, and increased osteoblasts although calcein-demeclocycline labels were diffuse and fragmented, indicating abnormal bone formation.

calcein


Input: In conclusion, Notch effects in the skeleton are cell-context-dependent.


Input: When expressed in immature osteoblasts, Notch arrests their differentiation, causing osteopenia, and when expressed in osteocytes, it causes an initial suppression of bone resorption and increased bone volume, a phenotype that evolves as the mice mature.


Input: RNA dimerization plays a role in ribosomal frameshifting of the SARS coronavirus.


Input: Messenger RNA encoded signals that are involved in programmed-1 ribosomal frameshifting (-1 PRF) are typically two-stemmed hairpin (H)-type pseudoknots (pks).


Input: We previously described an unusual three-stemmed pseudoknot from the severe acute respiratory syndrome (SARS) coronavirus (CoV) that stimulated-1 PRF.


Input: The conserved existence of a third stem-loop suggested an important hitherto unknown function.


Input: Here we present new information describing structure and function of the third stem of the SARS pseudoknot.


Input: We uncovered RNA dimerization through a palindromic sequence embedded in the SARS-CoV Stem 3.


Input: Further in vitro analysis revealed that SARS-CoV RNA dimers assemble through' kissing' loop-loop interactions.


Input: We also show that loop-loop kissing complex formation becomes more efficient at physiological temperature and in the presence of magnesium.

magnesium


Input: When the palindromic sequence was mutated, in vitro RNA dimerization was abolished, and frameshifting was reduced from 15 to 5. 7%.


Input: Furthermore, the inability to dimerize caused by the silent codon change in Stem 3 of SARS-CoV changed the viral growth kinetics and affected the levels of genomic and subgenomic RNA in infected cells.


Input: These results suggest that the homodimeric RNA complex formed by the SARS pseudoknot occurs in the cellular environment and that loop-loop kissing interactions involving Stem 3 modulate-1 PRF and play a role in subgenomic and full-length RNA synthesis.


Input: Survey of recent literature related to the biologically active 4 (3H)-quinazolinones containing fused heterocycles.

4 (3H)-quinazolinones


Input: The present review focuses on the synthesis and biological evaluation of polycyclic 4 (3H)-quinazolinones containing fused aromatic or heteroaromatic rings.

polycyclic 4 (3H)-quinazolinones


Input: The first part of the review is related to compounds with ring fused to the pyrimidine part of the quinazoline core.

pyrimidine

quinazoline


Input: Most of the quinazolinone alkaloids belong to this class of molecules.

quinazolinone alkaloids


Input: The second part presents molecules bearing extra ring (s) fused to the benzo moiety of the quinazolinone skeleton.

benzo

quinazolinone


Input: Their structural diversity opens new fields in the search of active molecules.


Input: Deregulation of HOX B13 expression in urinary bladder cancer progression.


Input: Urinary bladder cancer is a common malignancy in industrialized countries.


Input: More than 90% of bladder cancer originates in the transitional cells.


Input: Bladder transitional cancer prognosis is, according to the most recent definition related to the level of tumor infiltration, characterized by two main phenotypes, Non Muscle Invasive Bladder Transitional Cancer (NMIBC) and Muscle Invasive Bladder Transitional Cancer (MIBC).


Input: The genetic profile and the clinical course of the two subtypes are completely different, however among NMIBC the prognosis is not completely predictable, since 20% of the cases experience a relapse, even in the form of MIBC.


Input: It has recently been reported that the chromosomal region 12q13-15, containing crucial cancer genes such as MDM2, CDK4, GLI and an entire cluster of HOX genes, is amplified in bladder cancer.


Input: HOX genes codify for transcriptionl factor, involved in embryonal development and cancer progression, with main nuclear expression.


Input: Particularly it was also described the strong involvement of HOX B13 in several tumors of urogenital system.


Input: In this study we have been investigated, by immunohistochemisty and quantitative Real Time PCR, the HOX B13 expression in bladder cancer evolution and progression, evaluating its ability to discriminate between NMIBC and MBCI phenotypes.


Input: Cytoplasmic HOX B13 delocalization significantly relates with muscle invasion (p 0. 004).


Input: In addition in the series of NMIBC nuclear HOX B13 expression loss is significantly associated to shorter disease free survival (p-value = 0. 038) defining a potential prognostic role.


Input: Overexpression of HOX B13 in more aggressive phenotype is also demonstrate at gene level by quantitative RT-PCR.


Input: The de-regulation and delocalization of HOX B13 in urinary bladder cancer supports again the important role of HOX genes in tumor evolution and represents a starting point to establish an integrated analysis, in which HOX genes represent important prognostic and predictive markers for bladder cancer.


Input: Display of amino groups on substrate surfaces by simple dip-coating of methacrylate-based polymers and its application to DNA immobilization.

amino

methacrylate


Input: The implementation of a reactive functional group onto a material surface is of great importance.


Input: Reactive functional groups (e. g., an amino group and a hydroxyl group) are usually hydrophilic, which makes it difficult to display them on a dry polymer surface.

amino

hydroxyl


Input: We here propose a novel method for displaying amino groups on the surfaces of polymeric substrates through dip-coating of a methacrylate-based copolymer.

amino

methacrylate


Input: We synthesized copolymers composed of methyl methacrylate and 2-aminoethyl methacrylate with different protecting groups or ion-complexes on their amino groups, then dip-coated the copolymers onto a poly (methyl methacrylate) (PMMA) substrate.

methyl methacrylate

2-aminoethyl methacrylate

amino

poly (methyl methacrylate)

PMMA


Input: Evaluation using a cleavable fluorescent compound, which was synthesized in the present study to quantify a small amount (pmol/cm (2)) of amino groups on a solid surface, revealed that the protection of amino groups affected their surface segregation in the copolymer coating.

amino

amino


Input: p-Toluenesulfonate ion-complex and tert-butoxycarbonyl (Boc) protection of amino groups were found to effectively display amino groups on the surface (more than 70 pmol/cm (2)).

p-Toluenesulfonate

tert-butoxycarbonyl

Boc

amino

amino


Input: The density of amino groups displayed on a surface can be easily controlled by mixing the copolymer and PMMA before dip-coating.

amino

PMMA


Input: Dip-coating of the copolymer with Boc protection on various polymeric substrates also successfully displayed amino groups on their surfaces.

Boc

amino


Input: Finally, we demonstrated that the amino groups displayed can be utilized for the immobilization of a DNA oligonucleotide on a substrate surface.

amino


Input: Kinetics of the reaction of crystal violet with hydroxide ion in the critical solution of 2-butoxyethanol + water.

crystal violet

hydroxide


Input: The kinetics of alkaline fading of crystal violet (CV) has been studied by UV spectrophotometry and microcalorimetry in the critical binary solution of 2-butoxyethanol + water at the initial reaction stage and various temperatures.

crystal violet


Input: It was found that the first-order rate constants obtained from these two methods are well accorded with each other, and the temperature dependence of the rate constant obeyed the Arrhenius equation in a temperature region far from the critical point.


Input: The critical slowing down was detected by both methods near the critical point.


Input: A simple empirical crossover model was proposed and used to analyze the experimental data to obtain the critical exponents, which were 0. 158 +/- 0. 013 and 0. 133 +/- 0. 012 from UV spectrophotometry and microcalorimetry, respectively, and the former was in good agreement with the theoretical prediction of 0. 151.


Input: The slight lower value derived from microcalorimetry was attributed to the stirring in the microcalorimeter, which weakened the critical reduction of the diffusion coefficient.


Input: Spatial variation of available electronic excitations within individual quantum dots.


Input: Quantum dots (QDs) allow for manipulation of the position and energy levels of electrons at sub-10 nm length scales through control of material chemistry, size, and shape.


Input: It is known from optical studies that the bandgap of semiconductor QDs increases as their size decreases due to the narrowing of the quantum confinement potential.


Input: The mechanism of quantum confinement also indicates that the localized properties within individual QDs should depend on their shape in addition to their size, but direct observations of this effect have proven challenging due to the limited spatial resolution of measurement techniques at this scale and the ability to remove contributions from the surroundings.


Input: Here we present experimental evidence of spatial variations in the lowest available electron transition energy within a series of single electrically isolated QDs due to a dome-shaped geometry, measured using electron energy-loss spectroscopy in a (scanning) transmission electron microscope [(S) TEM-EELS].


Input: We observe a consistent increase in the energy onset of electronic excitations from the lateral center of the dot toward the edges, which we attribute purely to shape.


Input: This trend is in qualitative agreement with a simple quantum simulation of the local density of states in a dome-shaped QD.


Input: PGRMC2, a yet uncharacterized protein with potential as tumor suppressor, migration inhibitor, and regulator of cytochrome P450 enzyme activity.


Input: PGRMC2 (progesterone receptor membrane component 2) is highly homologous if compared with PGRMC1, a cytochrome-related protein, which is induced in several cancers and linked to cell growth in these cancers.


Input: Further it seems to be involved in progesterone signalling and cytochrome P450 binding.

progesterone


Input: For PGRMC2 only sparse information is available.


Input: Recent data show that PGRMC1 and 2 share several similar characteristics, but there are also important differences in expression and function of the both proteins.


Input: Several findings point to the fact that PGRMC2 might play a role in cancer as well.


Input: The protein influences the migration rate of ovarian cancer cells and a loss of PGRMC2 might result in higher metastasis rates.


Input: In contrast to PGRMC1 it seems more likely to act as a tumor suppressor than a promoter.


Input: Altered PGRMC2 expression was further detected in the context of term and preterm labour, though the implications of this finding are currently unknown and need further examination.


Input: PGRMC2 further might play a role in gynaecologic diseases like preterm labour and endometriosis.


Input: PGRMC2 shares the cellular localisation and the ability to bind cytochrome enzymes with PGRMC1.


Input: Further the protein was shown to influence the activity of CYP3A4.


Input: In conclusion, though not much is known about PGRMC2 so far, it deserves further examination as data point to a role of PGRMC2 as tumor suppressor, migration inhibitor and regulator of cytochrome P450 proteins.


Input: PXR-mediated P-glycoprotein induction by small molecule tyrosine kinase inhibitors.

tyrosine


Input: The rapid development of drug resistance as a result of exposure to small molecule tyrosine kinase inhibitors (TKIs) is an important drawback to the successful use of these agents in the clinic.

tyrosine


Input: Although one of the most established mechanisms by which cells acquire drug resistance to anticancer drugs is the up regulation of drug efflux transporters such as P-glycoprotein (PGP), it is currently still unknown whether TKIs have the propensity to induce PGP.


Input: The effect of TKIs on the protein expression and activity of PGP was assessed after treatment of LS180 cells with clinically relevant concentrations of the TKIs.


Input: In addition, the involvement of the nuclear pregnane X receptor (PXR), a known regulator of PGP expression, was determined.

pregnane


Input: At least five out of the nine tested TKIs (erlotinib, gefitinib, nilotinib, sorafenib, vandetanib) were able to induce the expression of PGP within 48 h in LS180 cells.

erlotinib

gefitinib

nilotinib

sorafenib

vandetanib


Input: Accordingly, these TKIs were also shown to affect the accumulation of a P-glycoprotein specific probe substrate.


Input: Furthermore, we showed that the pregnane X receptor (PXR), which is an important regulator of PGP induction, is involved in the upregulation of PGP protein expression following exposure to these TKIs.

pregnane


Input: Our data show that PXR-mediated upregulation of PGP expression by TKIs might be a possible mechanism underlying acquired drug resistance in cancer cells.


Input: Development of a dry, stable and inhalable acyl-homoserine-lactone-acylase powder formulation for the treatment of pulmonary Pseudomonas aeruginosa infections.

acyl-homoserine-lactone


Input: In the lungs of cystic fibrosis (CF) patients, Pseudomonas aeruginosa commonly causes chronic infections.


Input: It has been shown that the P. aeruginosa quorum sensing (QS) system controls the expression of virulence factors during invasion and infection to host cells.


Input: PvdQ is an acyl-homoserine lactone (AHL) acylase able to degrade the signal molecule of P. aeruginosa QS.

acyl-homoserine lactone

AHL


Input: The role of PvdQ in inhibiting the QS and its successive virulence determinants has been established in in vitro as well as in in vivo, the latter in a Caenorabdhitis elegans model.


Input: For the treatment of pulmonary P. aeruginosa infections, we propose that PvdQ can be best administered directly to the lungs of the patients as a dry powder because this is expected to give specific advantages in delivery as compared to nebulizing.


Input: Therefore in this study we investigated the production of a PvdQ powder by spray-freeze drying using mannitol, trehalose and inulin as excipient.

mannitol

trehalose


Input: The activity of PvdQ in the powder was determined immediately after production and after subsequent storage during 4 weeks at 20 degrees C and 55 degrees C.


Input: We found that the enzymatic activity of PvdQ is fully maintained during spray-freeze drying using mannitol, trehalose or inulin as excipient.

mannitol

trehalose


Input: However, mannitol was not able to stabilize the protein during storage, while PvdQ incorporated in trehalose or inulin was fully stabilized even during storage at 55 degrees C for at least 4 weeks.

mannitol

trehalose


Input: The poor stabilizing capacities of mannitol during storage could be related to its crystalline nature while the excellent stabilizing capacities of trehalose and inulin during storage could be related to their amorphous nature.

mannitol

trehalose


Input: The trehalose and inulin-based particles consisted of porous spheres with a volume average aerodynamical diameter of ~ 1. 8 mu m implying that they are suitable for pulmonary delivery.

trehalose


Input: This is the first study in which an AHL-degrading enzyme is processed into spray-freeze-dried powder suitable for inhalation.

AHL


Input: (R)-beta-lysine-modified elongation factor P functions in translation elongation.

(R)-beta-lysine


Input: Post-translational modification of bacterial elongation factor P (EF-P) with (R)-beta-lysine at a conserved lysine residue activates the protein in vivo and increases puromycin reactivity of the ribosome in vitro.

(R)-beta-lysine


Input: The additional hydroxylation of EF-P at the same lysine residue by the YfcM protein has also recently been described.

lysine


Input: The roles of modified and unmodified EF-P during different steps in translation, and how this correlates to its physiological role in the cell, have recently been linked to the synthesis of polyproline stretches in proteins.

polyproline


Input: Polysome analysis indicated that EF-P functions in translation elongation, rather than initiation as proposed previously.


Input: This was further supported by the inability of EF-P to enhance the rate of formation of fMet-Lys or fMet-Phe, indicating that the role of EF-P is not to specifically stimulate formation of the first peptide bond.

fMet-Lys

fMet-Phe


Input: Investigation of hydroxyl-(beta)-lysyl-EF-P showed 30% increased puromycin reactivity but no differences in dipeptide synthesis rates when compared with the beta-lysylated form.

hydroxyl-(beta)-lysyl

puromycin


Input: Unlike disruption of the other genes required for EF-P modification, deletion of yfcM had no phenotypic consequences in Salmonella.


Input: Taken together, our findings indicate that EF-P functions in translation elongation, a role critically dependent on post-translational beta-lysylation but not hydroxylation.


Input: Biomarkers of toluene exposure in rats: mercapturic acids versus traditional indicators (urinary hippuric acid and o-cresol and blood toluene).

toluene

mercapturic acids

hippuric acid

o-cresol

toluene


Input: Abstract 1.


Input: Toluene (TOL) is a neurotoxic, ototoxic and reprotoxic solvent which is metabolized via the glutathione pathway, producing benzylmercapturic, o-, m-and p-toluylmercapturic acids (MAs).

Toluene

TOL

glutathione

benzylmercapturic, o-, m-and p-toluylmercapturic acids

MAs


Input: These metabolites could be useful as biomarkers of TOL exposure.

TOL


Input: The aims of this study were (1) to provide data on MAs excretion in rat urine following TOL exposure by inhalation, (2) to compare them to data from traditional TOL biomarkers, i. e. TOL in blood (Tol-B), and urinary hippuric acid (HA) and o-cresol (oCre) and (3) to establish a relationship between these different indicators and the airborne TOL concentration (Tol-A).

MAs

TOL

TOL

TOL

Tol

hippuric acid

o-cresol

oCre

TOL

Tol


Input: Sprague-Dawley rats were exposed to a range of TOL concentrations.

TOL


Input: Blood and urine were collected and analyzed to determine biomarker levels.


Input: Levels of the four MAs correlate strongly with Tol-A (comparable to the correlation with Tol-B).

MAs

Tol

Tol


Input: MAs are thus clearly superior to oCre and HA as potential markers of exposure to TOL.

MAs

oCre

TOL


Input: Evolving therapeutic targets in ischemic stroke: a concise review.


Input: Ischemic stroke is the leading cause of mortality and morbidity worldwide for which the assemblage of therapeutic interventions has remained outstandingly limited.


Input: Several new insights into the causes of neuronal death during ischemic event have led to the identification of some important novel targets for intervention.


Input: This article highlights some of the promising protein targets, which are in the validation process and have the potential to get translated into viable neurotherapeutics against ischemic stroke.


Input: Treatment of estrogen receptor-positive breast cancer.

estrogen


Input: Estrogen receptor (ER) expression is the main indicator of potential responses to endocrine therapy (ET), and approximately 70% of human breast cancers (BCs) are hormone-dependent and ER-positive.

Estrogen


Input: The introduction of adjuvant systemic therapy led to a significant improvement in post-surgical survival and a reduction in disease relapse, especially in women with early BC and those with ER + tumors, who may receive ET alone or in combination with cytotoxic therapy.


Input: Adjuvant ET currently consists of (i) ovarian suppression, (ii) selective estrogen receptor modulators (SERMs) and down-regulators, and (iii) aromatase inhibitors (AIs).

estrogen


Input: In patients with ER + tumors pharmacologic ovary suppression with gonadotropin-releasing hormone agonists in combination with standard adjuvant therapy is generally more effective than adjuvant chemotherapy alone.

gonadotropin-releasing hormone


Input: Tamoxifen is the best established SERM, has favorable effects on BC control and bone metabolism, but also has adverse effects due to its estrogenic activity in other tissues.

Tamoxifen


Input: For these reasons, other SERMs have been developed.


Input: Fulvestrant is an ER down-regulator with several potential advantages over SERMs, including a 100-fold increase in its affinity for ER compared with tamoxifen and no estrogen-like activity in the uterus.

Fulvestrant

tamoxifen

estrogen


Input: The inhibition of the aromatase system with third-generation AIs is associated with improved survival in patients with advanced BC compared with SERMs.


Input: In postmenopausal patients with ER + BC adjuvant treatment with AIs should be performed, either as sequential treatment after tamoxifen or as upfront therapy.

tamoxifen


Input: Studies evaluating the role of AIs as first-line therapy are ongoing and the results are encouraging.


Input: Targeted approaches to triple-negative breast cancer: current practice and future directions.


Input: Triple-negative breast cancer (TNBC), that is breast cancer which stains negatively at immunohistochemistry for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2), comprises a particularly aggressive subtype of breast cancer, with high rate of early local and distant relapse.

estrogen

progesterone


Input: TNBC have demonstrated sensitivity to cytotoxic treatment regimens, but in the absence of HER2, ER and PR there is no benefit from hormonal therapy or trastuzumab.


Input: The lack of known specific molecular targets has promoted abundant research in order to find possible " vulnerabilities " in TNBC and the evaluation of novel biomarkers overcoming the traditional approach based on hormonal receptors and HER2-targeted therapy is one of the priorities in breast cancer research.


Input: Drugs under investigation can be broadly subdivided into four groups: (1) Agents that create DNA damage (i. e. cisplatin, cyclophosphamide); (2) Agents that inhibit poly (ADP-ribose) polymerase (PARP); (3) Tyrosin-kinase inhibitors and monoclonal antibodies; (4) Agents that inhibit downstream signals.

cisplatin

cyclophosphamide

poly (ADP-ribose)

Tyrosin


Input: Several preclinical and early phase clinical trials for the treatment or management of patients with triple-negative breast tumors are underway.


Input: Nonetheless, so far the major issue to deal with when trying to provide evidence for TNBC is the small numbers of the sample in the clinical studies and the retrospective nature of most of them.


Input: Future large studies could help in defining optimal treatment strategies for TNBC, both in the advanced setting as well as in the (neo) adjuvant setting.


Input: Entry inhibitors directed towards glycoprotein gp120: an overview on a promising target for HIV-1 therapy.


Input: In spite of the unquestionable positive impact of HAART in the treatment of HIV infection, the discovery and development of novel agents directed towards other targets of the replicative cycle of the virus that differ from those targeted by the clinically approved drugs, emerges nowadays as an imperative need.


Input: The blockade of HIV entry is a highly promising strategy against the pathogen and glycoprotein gp120 is a central actor in this process.


Input: This review discusses the current status in the research of anti-HIV agents targeting specifically the envelope protein gp120.


Input: The diverse approaches devoted to the achievement of therapeutic agents against gp120 currently under study are organized and analyzed critically according to their specific mechanism of inhibition and structural features.


Input: Identification of novel androgen receptor antagonists using structure-and ligand-based methods.

androgen


Input: Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer (PCa).

Androgen


Input: The AR hormone-binding site (HBS) is intensively studied and represents the target area for current antiandrogens including Bicalutamide and structurally related Enzalutamide.

Bicalutamide

Enzalutamide


Input: As resistance to antiandrogens invariably emerges in advanced prostate cancer, there exists a high medical need for the identification and development of novel AR antagonists of different chemotypes.


Input: Given the wealth of structural information on the AR in complex with a variety of ligands, we have applied an integrated structure-and ligand-based virtual screening methodology to identify novel AR antagonists.


Input: Virtual hits generated by a consensus voting approach were experimentally evaluated and resulted in the discovery of a number of structurally diverse submicromolar antagonists of the AR.


Input: In particular, one identified compound demonstrated anti-AR potency in vitro that is comparable to the clinically used Bicalutamide.


Input: These results set a ground for the development of novel classes of PCa drugs that are structurally different from current AR antagonists.


Input: Structure-based design, synthesis and evaluation of novel anthra [1, 2-d] imidazole-6, 11-dione derivatives as telomerase inhibitors and potential for cancer polypharmacology.

anthra [1, 2-d] imidazole-6, 11-dione


Input: A series of anthra [1, 2-d] imidazole-6, 11-dione derivatives were synthesized and evaluated for telomerase inhibition, hTERT expression and suppression of cancer cell growth in vitro.

anthra [1, 2-d] imidazole-6, 11-dione


Input: All of the compounds tested, except for compounds 4, 7, 16, 24, 27 and 28 were selected by the NCI screening system.


Input: Among them, compounds 16, 39, and 40 repressed hTERT expression without greatly affecting cell growth, suggesting for the selectivity toward hTERT expression.


Input: Taken together, our findings indicated that the analysis of cytotoxicity and telomerase inhibition might provide information applicable for further developing potential telomerase and polypharmacological targeting strategy.


Input: Synthesis and biological activity against Trypanosoma cruzi of substituted 1, 4-naphthoquinones.

1, 4-naphthoquinones


Input: The discovery and development of essential drugs for Chagas disease is a major concern worldwide.


Input: New substituted 1, 4-naphthoquinones were synthesized and tested against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease.

1, 4-naphthoquinones


Input: These products exhibited substantial activity against T. cruzi, especially 2-((8E, 11Z)-heptadeca-8, 11-dienyl)-3-hydroxynaphthalene-1, 4-dione (9) with IC (50) of 7. 8 mu M.

2-((8E, 11Z)-heptadeca-8, 11-dienyl)-3-hydroxynaphthalene-1, 4-dione


Input: Synthesis and Biological Evaluation of [1, 2, 4] Triazolo [3, 4-a] phthalazine and Tetrazolo [5, 1-a] phthalazine Derivatives Bearing Substituted Benzylpiperazine Moieties as Positive Inotropic Agents.

[1, 2, 4] Triazolo [3, 4-a] phthalazine

Tetrazolo [5, 1-a] phthalazine

Benzylpiperazine


Input: Two series of [1, 2, 4] triazolo [3, 4-a] phthalazine and tetrazolo [5, 1-a] phthalazine derivatives bearing substituted benzylpiperazine moieties have been synthesized and evaluated for their positive inotropic activity by measuring left atrium stroke volume on isolated rabbit heart preparations.

[1, 2, 4] triazolo [3, 4-a] phthalazine

tetrazolo [5, 1-a] phthalazine

benzylpiperazine


Input: The majority of the derivatives exhibited better in vitro activity than the existing drug, milrinone, and 6-((4-(4-methoxyphenyl) piperazin-1-yl) methyl) tetrazolo [5, 1-a] phthalazine.

milrinone

6-((4-(4-methoxyphenyl) piperazin-1-yl) methyl) tetrazolo [5, 1-a] phthalazine


Input: 8 m in particular was identified as the most potent with an increased stroke volume of 12. 02 +/- 0. 20% (milrinone: 2. 46 +/- 0. 07%) at a concentration of 3 x 10 (-5) m.

milrinone


Input: The chronotropic effects of the compounds that exhibited good potency were also evaluated.


Input: Combined effects of the herbicide terbuthylazine and temperature on different flagellates from the Northern Adriatic Sea.

terbuthylazine


Input: The triazinic herbicide terbuthylazine (TBA) is becoming an emergent contaminant in Italian rivers and in coastal and groundwater.

terbuthylazine

TBA


Input: A preliminary analysis of the sensitivity of marine flagellates to TBA was performed by monitoring the photosynthetic efficiency of nine species (belonging to the Dinophyceae or Raphidophyceae class) isolated from the Adriatic Sea.

TBA


Input: Different sensitivity levels for each flagellate were observed and the most sensitive microalgae, based on PSII inhibition, were: Gonyaulax spinifera > Fibrocapsa japonica > Lingulodinium polyedrum while the most resistant were two species belonging to the Prorocentrum genus.


Input: Then the response of two microalgae to drivers, such as temperature and terbuthylazine, applied in combination was also investigated.

terbuthylazine


Input: Two potentially toxic flagellates, Prorocentrum minimum and G. spinifera, were exposed, under different temperature conditions (15, 20 and 25 degrees C), to TBA concentrations that did not completely affect PSII.

TBA


Input: For both flagellates, effects of TBA on algal growth, measured through cell density and carbon analysis, as well as on the photosynthetic activity are reported.

TBA

carbon


Input: All parameters analyzed showed a negative effect of TBA from the exponential phase.

TBA


Input: TBA effect on algal growth was significantly enhanced at the optimal temperature conditions (20 and 25 degrees C), while no difference between control and herbicide treatments were detected for G. spinifera grown at 15 degrees C, which represented a stress condition for this species.

TBA


Input: The maximum inhibition of photosynthetic efficiency was found at 20 degrees C for both organisms.


Input: Both flagellates increased cell carbon and nitrogen content in herbicide treatments compared to the control, except G. spinifera grown at 15 degrees C.

carbon

nitrogen


Input: Chlorophyll-a production was increased only in G. spinifera exposed to 5 mu g L (-1) of TBA and the effect was enhanced with the increase of temperature.

Chlorophyll-a

TBA


Input: Herbicide-induced variations in cellular components determined changes in cellular carbon: nitrogen (C: N) and chlorophyll: carbon (Chl: C) ratios.

carbon

nitrogen

C

N

chlorophyll

carbon

Chl

C


Input: The C: N ratio decreased in both species, while only G. spinifera showed an increase in the Chl: C ratio at all temperature conditions.

C

N

Chl

C


Input: In response to TBA exposure G. spinifera increased extracellular polysaccharides release at 20 and 25 degrees C, while no difference was reported for P. minimum.

TBA


Input: Changes in nutrient uptake rates were also observed for P. minimum.


Input: Nitrate and phosphate uptake significantly increased in the presence of TBA and this response was enhanced at 25 degrees C, while nitrate uptake increased in G. spinifera only when grown at 25 degrees C.

Nitrate

phosphate

TBA

nitrate


Input: As for growth rates, the observed changes in intracellular component contents increased at optimal temperature conditions.


Input: In this work it is shown that temperature conditions can have an important role on the effect of terbuthylazine on algal growth and on the physiological responses of different species.

terbuthylazine


Input: Furthermore, the algal resistance and recovery can be dependent on nutrient availability.


Input: Mode of action of human pharmaceuticals in fish: the effects of the 5-alpha-reductase inhibitor, dutasteride, on reproduction as a case study.

dutasteride


Input: In recent years, a growing number of human pharmaceuticals have been detected in the aquatic environment, generally at low concentrations (sub-ng/L-low mu g/L).


Input: In most cases, these compounds are characterised by highly specific modes of action, and the evolutionary conservation of drug targets in wildlife species suggests the possibility that pharmaceuticals present in the environment may cause toxicological effects by acting through the same targets as they do in humans.


Input: Our research addressed the question of whether or not dutasteride, a pharmaceutical used to treat benign prostatic hyperplasia, may cause adverse effects in a teleost fish, the fathead minnow (Pimephales promelas), by inhibiting the activity of both isoforms of 5 alpha-reductase (5 alpha R), the enzyme that converts testosterone into dihydrotestosterone (DHT).

dutasteride

testosterone

dihydrotestosterone

DHT


Input: Mammalian pharmacological and toxicological information were used to guide the experimental design and the selection of relevant endpoints, according to the so-called " read-across approach ", suggesting that dutasteride may affect male fertility and steroid hormone dynamics.

dutasteride

steroid hormone


Input: Therefore, a 21-day reproduction study was conducted to determine the effects of dutasteride (10, 32 and 100 mu g/L) on fish reproduction.

dutasteride


Input: Exposure to dutasteride significantly reduced fecundity of fish and affected several aspects of reproductive endocrine functions in both males and females.

dutasteride


Input: However, none of the observed adverse effects occurred at concentrations of exposure lower than 32 mu g/L; this, together with the low volume of drug prescribed every year (10. 34 kg in the UK in 2011), and the extremely low predicted environmental concentration (0. 03 ng/L), suggest that, at present, the potential presence of dutasteride in the environment does not represent a threat to wild fish populations.

dutasteride


Input: Evaluation of zebra mussels (Dreissena polymorpha) as biomonitors of mercury contamination in aquatic ecosystems.

mercury


Input: Zebra mussels have invaded many lakes in the United States and could be a useful tool for monitoring responses of aquatic biota to changes in mercury loading.

mercury


Input: The goal of the present study was to evaluate zebra mussels for use as a biomonitor of mercury contamination by comparing zebra mussel mercury concentrations between a lake with only indirect atmospheric mercury contamination (Otisco Lake, NY, USA) and a lake that was directly contaminated by mercury discharges (Onondaga Lake, NY, USA).

mercury

mercury

mercury

mercury


Input: Zebra mussels were sampled in both the spring and fall of 2004 and 2005.


Input: Total mercury (THg) concentrations in zebra mussels were approximately seven times greater in Onondaga Lake than in Otisco Lake, and water column mercury concentrations differed by an order of magnitude between the two lakes.

mercury

mercury


Input: Seasonal differences resulted in significantly higher zebra mussel THg concentrations during the fall for both lakes.


Input: There was also significant variation among different sampling sites in Onondaga Lake.


Input: Mussel methylmercury concentrations averaged 53% of THg concentrations but were highly variable.

methylmercury


Input: Strong relationships between water column THg and zebra mussel THg suggest that zebra mussels are a good indicator of aquatic mercury concentrations and could be used as an effective biomonitor of mercury contamination in aquatic ecosystems.

mercury

mercury


Input: Estrogenic effects along the river Saale.


Input: Sediments along the river Saale, one of the main tributaries of the river Elbe, were characterized with the yeast estrogen screen to elucidate possible sources of endocrine-disrupting compounds that might contribute to the downstream contamination of the river Elbe.

estrogen


Input: At two sampling sites, elevated levels of estrogenic activity up to 55, 000 ng ethinylestradiol equivalents per kilogram sediment dry weight were detected in the respective sediment extracts.

ethinylestradiol


Input: Aliquots of the sediment extracts were analyzed for 4-nonylphenols and natural steroidal estrogens as possible candidates with an estrogenic potential.

steroidal estrogens


Input: The maximal concentrations of 4-iso-nonylphenol and estrone were 115 mg/kg dry weight and 20 micro g/kg dry weight at the sampling site Luppe, which showed in accordance the highest biological activity.

estrone


Input: Under consideration of compound concentration and compound specific estrogenic activity the 4-iso-nonylphenols contributed most to the observed estrogenic effect.


Input: A strong correlation between the measured estrogenic activity and the concentration of the sediment-associated 4-iso-nonylphenol underlines the relevance of this compound class as a xenoestrogen in the catchment area of the river Saale.


Input: Persistence of the tricyclic antidepressant drugs amitriptyline and nortriptyline in agriculture soils.

amitriptyline

nortriptyline


Input: Amitriptyline and nortriptyline are widely used tricyclic antidepressant drugs.

Amitriptyline

nortriptyline


Input: They have been detected in wastewater, surface runoff, and effluents from sewage treatment plants.


Input: As such, they could potentially reach agriculture land through the application of municipal biosolids or reclaimed water.


Input: In the absence of data on their fate in the environment, the persistence and dissipation pathways of radiolabeled amitriptyline were determined in three agriculture soils varying widely in texture and chemical properties (loam soil, clay loam soil, and sandy loam soil).

amitriptyline


Input: Tritiated amitriptyline was added to laboratory microcosms containing soils, and the metabolism of the extractable (3) H was monitored during incubation at 30 degrees C.

Tritiated amitriptyline

(3) H


Input: The total solvent extractable radioactivity decreased in all three soils with times to dissipate 50% of material (DT50) ranging from 34. 1 +/- 3. 2 (loam soil) to 85. 3 +/- 3. 2 d (sandy soil).


Input: Nortriptyline (N-desmethyl amitriptyline) and amitriptyline-N-oxide were identified as major transformation products in all three soils by high performance liquid chromatography with photodiode array detector and time-of-flight mass spectrometry (HPLC-TOF-MS/UV).

Nortriptyline

N-desmethyl amitriptyline

amitriptyline-N-oxide


Input: The addition of liquid municipal biosolids to the loam soil had no effect on the dissipation of amitriptyline.

amitriptyline


Input: The persistence of nortriptyline was evaluated in the loam soil.

nortriptyline


Input: The DT50 of nortriptyline was 40. 5 +/- 3. 2 d estimated with HPLC-TOF-MS/UV.

nortriptyline


Input: Approximately 10% of added nortriptyline was converted to hydroxylated products after 50 d of incubation.

nortriptyline


Input: In summary, amitriptyline persisted in agricultural soils with major dissipation mechanisms, including forming nonextractable residues and producing various transformation products including the psychoactive drug nortriptyline.

amitriptyline

nortriptyline


Input: Mercury in the seafood and human exposure in coastal area of Guangdong province, South China.

Mercury


Input: Consumption of fish and aquatic products is considered to be the main pathway of human exposure to methylmercury (MeHg).

methylmercury

MeHg


Input: To assess human health risk through seafood consumption in a coastal area of Guangdong Province, South China, a total of 518 seafood samples (including fish, shrimp, crabs, and mollusks) were collected from 11 coastal cities for total mercury (THg) analysis.

mercury


Input: The THg concentrations varied significantly among different seafood groups and ranged from 0. 11 to 317 ng/g (with a mean of 37. 2 ng/g).


Input: The THg concentrations were relatively low compared with fish from Europe and North America, and no samples exceeded the national limit recommended by the Standardization Administration of China (0. 5 ng/g wet wt).


Input: The ecological functional groups and cultured styles have significant effects on THg concentrations in the fish tissue.


Input: The median of probable daily intakes (PDIs) of MeHg via seafood consumption ranged from 42. 6 to 71. 4 ng/g for different age groups, with fish contributing the major portion (84%).

MeHg


Input: The results indicated potential health risks associated with seafood consumption for the general population in the coastal area of Guangdong Province, South China.


Input: A carbon nanotube synapse with dynamic logic and learning.

carbon


Input: A carbon nanotube (CNT) synapse emulates a biological synapse with its dynamic logic, learning, and memory functions induced by the interactions between CNTs and hydrogen ions in an electrochemical cell.

carbon

hydrogen


Input: A circuit of CNT synapses operates with extremely low-energy consumption and could potentially emulate the functions of the neuronal network.


Input: Hydrosoluble benzo [e] pyridoindolones as potent inhibitors of aurora kinases.

benzo [e] pyridoindolones


Input: Aurora kinases play an essential role in mitotic progression and are potentially druggable targets in cancer therapy.


Input: We identified benzo [e] pyridoindoles (BePI) as powerful aurora kinase inhibitors.

benzo [e] pyridoindoles

BePI


Input: Their efficiency was demonstrated both in enzymatic inhibition studies and in cell culture assays.


Input: New BePI molecules were synthesized, and a structure-activity relationship study was conducted with the aim of improving the activity and solubility of the lead compound.

BePI


Input: Tetracyclic BePI derivatives are characterized by a particular curved shape, and the presence of an oxo group on the pyridine ring was found to be required for aurora kinase B inhibition.

Tetracyclic BePI

oxo

pyridine


Input: New hydrosoluble benzo [e] pyridoindolones were subsequently designed, and their efficacy was tested by a combination of cell-cycle analysis and time-lapse experiments in live cells.

benzo [e] pyridoindolones


Input: The most active BePI derivative, 13 b, inhibited the cell cycle, drove cells to polyploidy, and eventually induced apoptosis.

BePI


Input: It exhibited high antiproliferative activity in HeLa cells with an IC (50) value of 63 nM.


Input: Relative to compounds tested in clinical trials, this antiproliferative potency places 13 b among the top 10 aurora kinase inhibitors.


Input: Our results justify further in vivo evaluation in preclinical animal models of cancer.


Input: Practical synthesis of (20S)-10-(3-aminopropyloxy)-7-ethylcamptothecin, a water-soluble analogue of camptothecin.

(20S)-10-(3-aminopropyloxy)-7-ethylcamptothecin

camptothecin


Input: A robust, practical synthesis of (20S)-10-(3-aminopropyloxy)-7-ethylcamptothecin (T-2513, 5), which is a water-soluble analogue of camptothecin, has been developed.

(20S)-10-(3-aminopropyloxy)-7-ethylcamptothecin

camptothecin


Input: The key step in this synthesis is a highly diastereoselective ethylation at the C20 position by using N-arylsulfonyl-(R)-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid ester as a chiral auxiliary, which affords the key intermediate ethyl-(S)-2-acyloxy-2-(6-cyano-5-oxo-1, 2, 3, 5-tetrahydroindolizin-7-yl) butanoate (8k) in 93% yield and 87% de.

N-arylsulfonyl-(R)-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid ester

ethyl-(S)-2-acyloxy-2-(6-cyano-5-oxo-1, 2, 3, 5-tetrahydroindolizin-7-yl) butanoate


Input: Optically pure compound 8k was obtained by a single recrystallization from acetone and its further elaboration through Friedlander condensation afforded compound 5.

acetone


Input: This synthesis does not require any chromatographic purification steps and can provide compound 5 on a multi-gram scale in 6. 3% overall yield (16 steps).


Input: Self-assembled BolA-like amphiphilic peptides as viral-mimetic gene vectors for cancer cell targeted gene delivery.


Input: In this study, two types of BolA-like amphiphilic peptides with dual ligands comprising a tumor-targeting moiety of RGD sequence and a cell-penetrating moiety of R8 sequence are designed and synthesized as gene vectors.


Input: The BolA-structural peptide carriers can self-assemble into spherical nanoparticles with a hydrophilic core and shell, which are similar to the viral capsid and can bind plasmid DNA in an aqueous medium to form viral-mimetic complexes.


Input: It is found that the BolA-like dual ligands system exhibits significantly enhanced gene expression in both HeLa and 293T cell lines, as compared with poly (ethylenimine) PEI.

poly (ethylenimine) PEI


Input: These BolA-like amphiphilic peptides are promising in clinical trials of gene therapy.


Input: New cyclomyrsinol diterpenes from Euphorbia aellenii with their immunomodulatory effects.

cyclomyrsinol diterpenes


Input: Chloroform-acetone extract of the aerial parts of Euphorbia aellenii Rech.

Chloroform

acetone


Input: f.


Input: (Euphorbiaceae) was investigated for its diterpenoidal constituents.

diterpenoidal


Input: This led to the isolation of two new and one known cyclomyrsinol-type diterpenes 1-3.

cyclomyrsinol

diterpenes


Input: The structures were elucidated on the basis of 1D and 2D (1) H and (13) C NMR techniques, and in vitro immunomodulatory activity was evaluated by standard proliferation of human peripheral blood lymphocytes.

(1) H

(13) C


Input: Results showed that all the three compounds were found to inhibit lymphocyte proliferation significantly (p < 0. 05) at 50 mu g/ml concentration.


Input: Among them, compound 2 showed more activity against phytohemagglutinin-activated T-cell proliferation with an IC (50) of 40. 4 +/- 9. 35 mu g/ml.


Input: Fusion of bolaamphiphile micelles: a method to prepare stable supported biomimetic membranes.


Input: Supported biomimetic membranes (SBMs) on solid substrates have been commonly prepared from vesicle-forming double-tail lipids, such as zwitterionic phospholipids, using the method of vesicle fusion.


Input: Here we report on the preparation of SBMs on silica surfaces via a similar process of " micelle fusion " from a cationic single-tail bolaamphiphile GLH-20 that forms spherical and elongated thread-like micelles in solution.

silica


Input: We demonstrate that, in contrast to zwitterionic phospholipids, GLH-20 self-assembles into a stable contiguous SBM at both low and high ionic strengths.


Input: The cationic charge of GLH-20 promotes the formation of a stable SBM through enhanced double-layer interactions with the negatively charged silica surface.

silica


Input: It is also shown that spinach aquaporin PM-28 was successfully incorporated within bolaamphiphile SBM in a manner similar to SBMs prepared by vesicle/proteoliposome fusion; thereby the inherent curvature of the micelle surface does not inhibit protein reconstitution.


Input: The results suggest that SBMs based on charged bolaamphiphiles might be an attractive platform for applications such as water purification and biosensors, where the stability and low defect rate of SBMs in diverse conditions are crucial for achieving desired performance.


Input: Distinct and opposing roles for Rab27a/Mlph/MyoVa and Rab27b/Munc13-4 in mast cell secretion.


Input: Mediator release from mast cells is a critical step in allergic and inflammatory disease.


Input: However, the processes regulating the latter stages of granule release are yet to be fully understood.


Input: Rab27 small GTPases regulate release of secretory lysosomes in a variety of cells, including mast cell granules.


Input: In the present study, using murine bone marrow-derived mast cells (BMMC) from Rab27-deficient mutant mice, we found that, in contrast to Rab27b, Rab27a primarily plays an inhibitory role in regulating degranulation.


Input: Immunofluorescence analysis revealed that resting Rab27a-deficient (ashen) BMMCs display abnormal cortical F-actin distribution.


Input: Actin disassembly prior to IgE cross-linking increased wild-type BMMC secretion to ashen levels, suggesting that changes in the integrity of cortical F-actin underlie the ashen phenotype.


Input: Comparison of the secretory impairment of Rab27b knockout and Rab27a/b double knockout BMMCs highlighted a secondary positive role for Rab27a in enhancing degranulation.


Input: Rab27 is known to interact with actin via its effectors melanophilin (Mlph) and myosin Va (MyoVa) in other cell types.


Input: To better understand the differing roles of Rab27 proteins, we analysed the secretory phenotype of BMMCs derived from mice lacking Rab27 effector proteins.


Input: These experiments revealed that the phenotype of BMMCs deficient in Mlph (leaden) and BMMCs deficient in MyoVa (dilute) resembles the hyper-secretion of ashen BMMCs, while Munc13-4-deficient (jinx) BMMCs phenocopy the Rab27b knockout and double Rab27a/b knockout secretory impairment.


Input: We conclude that Rab27a and Rab27b regulate distinct steps in the BMMC degranulation pathway, with Rab27a/Mlph/MyoVa regulating cortical actin stability upstream of Rab27a/b/Munc13-4-dependent granule exocytosis.


Input: A class of 5-nitro-2-furancarboxylamides with potent trypanocidal activity against Trypanosoma brucei in vitro.


Input: Recently, the World Health Organization approved the nifurtimox-eflornithine combination therapy for the treatment of human African trypanosomiasis, renewing interest in nitroheterocycle therapies for this and associated diseases.

nifurtimox

eflornithine


Input: In this study, we have synthesized a series of novel 5-nitro-2-furancarboxylamides that show potent trypanocidal activity, ~ 1000-fold more potent than nifurtimox against in vitro Trypanosoma brucei with very low cytotoxicity against human HeLa cells.

nifurtimox


Input: More importantly, the most potent analogue showed very limited cross-resistance to nifurtimox-resistant cells and vice versa.

nifurtimox


Input: This implies that our novel, relatively easy to synthesize and therefore cheap, 5-nitro-2-furancarboxylamides are targeting a different, but still essential, biochemical process to those targeted by nifurtimox or its metabolites in the parasites.

nifurtimox


Input: The significant increase in potency (smaller dose probably required) has the potential for greatly reducing unwanted side effects and also reducing the likelihood of drug resistance.


Input: Collectively, these findings have important implications for the future therapeutic treatment of African sleeping sickness.


Input: Thyroid hormone replacement therapy attenuates the decline of renal function in chronic kidney disease patients with subclinical hypothyroidism.

Thyroid hormone


Input: Background: Subclinical hypothyroidism (SH) is not a rare condition in females, the elderly, or patients with chronic kidney disease (CKD).


Input: Even though previous studies have demonstrated that thyroid hormone replacement therapy (THRT) improved cardiac function and dyslipidemia in patients with subclinical hypothyroidism, it remains unclear as to whether THRT can improve renal function in CKD patients with SH.

thyroid hormone


Input: This study investigated the impact of THRT on changes in estimated glomerular filtration rates (eGFR) in this patient population.


Input: Methods: A total of 113 CKD patients with SH who were treated with L-thyroxine and had eGFR available for at least 24 months before and after THRT were enrolled between January 2005 and December 2011.

L-thyroxine


Input: A linear mixed model was used to compare patients' clinical and biochemical parameters at various time points.


Input: The slope of the decline in eGFR over time, both before and after THRT, was also calculated and compared using a linear mixed model.


Input: Results: The mean age of the study participants was 63. 2 +/- 12. 7 years, and 36 patients (31. 9%) were male.


Input: The mean follow-up duration before and after THRT was 28. 6 +/- 4. 5 and 30. 6 +/- 6. 4 months, respectively.


Input: At 24-months of THRT, TSH levels were significantly reduced [8. 86 (0. 49) vs. 1. 41 (0. 73) <F06D> IU/mL, P < 0. 001], but there were no significant changes in T3 and fT4 concentrations.


Input: Serum albumin, calcium, phosphate, cholesterol, and triglyceride levels were also comparable after THRT.

calcium

phosphate

cholesterol

triglyceride


Input: The rates of decline in eGFR were significantly attenuated by THRT [-4. 31 (0. 51) vs.-1. 08 (0. 36) mL/min/year/1. 73 m2, P < 0. 001] even after adjustment for age, gender, diabetes, mean arterial pressure, serum albumin, cholesterol, and triglyceride concentrations (P < 0. 001).

cholesterol

triglyceride


Input: Conclusion: THRT attenuated the rate of decline in renal function in CKD patients with SH, suggesting that THRT may delay reaching end-stage renal disease in these patients.


Input: Two [4Fe-4S] clusters containing radical SAM enzyme SkfB catalyze thioether bond formation during the maturation of the sporulation killing factor.

thioether


Input: The sporulation killing factor (SKF) is a 26-residue ribosomally assembled and posttranslationally modified sactipeptide.


Input: It is produced by Bacillus subtilis 168 and plays a key role in its sporulation.


Input: Like all sactipeptides, SKF contains a thioether bond, which links the cysteine residue Cys4 with the alpha-carbon of the methionine residue Met12.

thioether

cysteine

alpha-carbon

methionine


Input: In this study we demonstrate that this bond is generated by the two [4Fe-4S] clusters containing radical SAM enzyme SkfB, which is encoded in the skf operon.

SAM


Input: By mutational analysis of both cluster-binding sites, we were able to postulate a mechanism for thioether generation which is in agreement with that of AlbA.


Input: Furthermore, we were able to show that thioether bond formation is specific toward hydrophobic amino acids at the acceptor site.

thioether

amino acids


Input: Additionally we demonstrate that generation of the thioether linkage is leader-peptide-dependent, suggesting that this reaction is the first step in SKF maturation.

thioether


Input: Structure-based investigation of rat aldehyde oxidase inhibition by flavonoids.

aldehyde

flavonoids


Input: Abstract 1.


Input: Flavonoids are a group of polyphenolic plant metabolites most commonly known for their antioxidant activities.

Flavonoids

polyphenolic


Input: They also show inhibitory activities on molybdo-flavoenzymes family of enzymes which are involved in biotransformation of some exogenous and endogenous chemicals.


Input: Most notably, aldehyde oxidase (AO), a member of this family, is responsible for metabolism of some therapeutic agents.

aldehyde


Input: On the other hand, there are some therapeutics which inhibit AO.


Input: As flavonoids are ubiquitous in human diet and have potential to interact with AO, it is important to investigate their effects at the molecular details.

flavonoids


Input: The inhibitory effects of 15 flavonoids on the activity of rat liver AO were assessed.

flavonoids


Input: Quantitative structure-activity relationship studies were performed using genetic algorithm coupled partial least square and stepwise multiple linear regression methods to elucidate the important structural properties responsible for the observed inhibitory effects.


Input: To further understand the mode of interaction between these flavonoids and AO, a homology model of the enzyme was built and flavonoids were docked into its active site.

flavonoids

flavonoids


Input: The most important amino acids involved in the interactions were identified.

amino acids


Input: Quercetin, myricetin and genistein were the most potent inhibitors establishing favorable interactions with the enzyme.

Quercetin

myricetin

genistein


Input: However, the glycosylated flavonoids showed relatively weaker inhibition which may be attributed to their hindered binding into the active site of AO by bulky sugar groups.

glycosylated flavonoids

sugar


Input: Aaptamine derivatives from the Indonesian sponge Aaptos suberitoides.

Aaptamine


Input: Four new aaptamine derivatives (1-4) along with aaptamine (5) and three related compounds (6-8) were isolated from the ethanol extract of the sponge Aaptos suberitoides collected in Indonesia.

aaptamine

aaptamine

ethanol


Input: The structures of the new compounds were unambiguously determined by one-and two-dimensional NMR and by HRESIMS measurements.


Input: Compounds 3, 5, and 6 showed cytotoxic activity against the murine lymphoma L5178Y cell line, with IC (50) values ranging from 0. 9 to 8. 3 mu M.


Input: Why is quercetin a better antioxidant than taxifolin?

quercetin

taxifolin


Input: Theoretical study of mechanisms involving activated forms.


Input: The stronger antioxidant capacity of the flavonoid quercetin (Q) compared with taxifolin (dihydroquercetin, T) has been the subject of previous experimental and theoretical studies.

quercetin

taxifolin

dihydroquercetin


Input: Theoretical work has focused on the analysis of hydrogen bond dissociation energies (BDE) of the OH phenolic groups, but consider mechanisms that only involve the transfer of one hydrogen atom.

hydrogen

OH phenolic

hydrogen


Input: In the present work we consider other mechanisms involving a second hydrogen transfer in reactions with free radicals.

hydrogen


Input: The relative stability of the radicals formed after the first hydrogen transfer reaction is considered in discussing the antioxidant activity of Q and T.

hydrogen


Input: In terms of global and local theoretical reactivity descriptors, we propose that the radical arising from Q should be more persistent in the environment and with the capability to react with a second radical by hydrogen transfer, proton transfer and electron transfer mechanisms.

hydrogen


Input: These mechanisms could be responsible of the stronger antioxidant capacity of Q.


Input: Modulation of esterified drug metabolism by tanshinones from Salvia miltiorrhiza (" Danshen ").


Input: The roots of Salvia miltiorrhiza (" Danshen ") are used in traditional Chinese medicine for the treatment of numerous ailments including cardiovascular disease, hypertension, and ischemic stroke.


Input: Extracts of S. miltiorrhiza roots in the formulation " Compound Danshen Dripping Pill " are undergoing clinical trials in the United States.


Input: To date, the active components of this material have not been conclusively identified.


Input: We have determined that S. miltiorrhiza roots contain potent human carboxylesterase (CE) inhibitors, due to the presence of tanshinones.


Input: K (i) values in the nM range were determined for inhibition of both the liver and intestinal CEs.


Input: As CEs hydrolyze clinically used drugs, the ability of tanshinones and S. miltiorrhiza root extracts to modulate the metabolism of the anticancer prodrug irinotecan (CPT-11) was assessed.

irinotecan


Input: Our results indicate that marked inhibition of human CEs occurs following incubation with both pure compounds and crude material and that drug hydrolysis is significantly reduced.


Input: Consequently, a reduction in the cytotoxicity of irinotecan is observed following dosing with either purified tanshinones or S. miltiorrhiza root extracts.


Input: It is concluded that remedies containing tanshinones should be avoided when individuals are taking esterified agents and that patients should be warned of the potential drug-drug interaction that may occur with this material.


Input: Multifunctional mesoporous nanocomposites with magnetic, optical, and sensing features: synthesis, characterization, and their oxygen-sensing performance.

oxygen


Input: In this paper, the fabrication, characterization, and application in oxygen sensing are reported for a novel multifunctional nanomaterial of [Ru (bpy) (2) phen-MMS] (bpy, 2, 2'-bipyridyl; phen, phenathrolin) which was simply prepared by covalently grafting the ruthenium (II) polypyridyl compounds into the channels of magnetic mesoporous silica nanocomposites (MMS).

oxygen

Ru (bpy) (2) phen

bpy

2, 2'-bipyridyl

phen

phenathrolin

ruthenium (II) polypyridyl

silica


Input: Scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, N (2) adsorption-desorption, a superconducting quantum interference device, UV-vis spectroscopy, and photoluminescence spectra were used to characterize the samples.


Input: The well-designed multifunctional nanocomposites show superparamagnetic behavior and ordered mesoporous characteristics and exhibit a strong red-orange metal-to-ligand charge transfer emission.


Input: In addition, the obtained nanocomposites give high performance in oxygen sensing with high sensitivity (I (0)/I (100) = 5. 2), good Stern-Volmer characteristics (R (2) = 0. 9995), and short response/recovery times (t v = 6 s and t ^ = 12 s).

oxygen


Input: The magnetic, mesoporous, luminescent, and oxygen-sensing properties of this multifunctional nanostructure make it hold great promise as a novel multifunctional oxygen-sensing system for chemical/biosensor.

oxygen

oxygen


Input: Lipofection and nucleofection of substrate plasmid can generate widely different readings of DNA end-joining efficiency in different cell lines.


Input: In vivo plasmid end-joining assays are valuable tools for dissecting important qualitative and quantitative aspects of non-homologous end-joining (NHEJ)--a key mechanism for the repair of DNA double-strand breaks (DSBs) in higher eukaryotes.


Input: They enable the use of defined DNA ends as substrates for end-joining and the analysis by sequencing of the resulting junctions to identify the repair pathways engaged.


Input: Yet, plasmid assays have generated divergent results of end-joining capacity in the same DSB repair mutants when used under different conditions, which implies contributions from undefined and therefore uncontrolled parameters.


Input: To help standardize these assays, we searched for parameters underpinning these variations and identified transfection method as an important determinant.


Input: Here, we compare a lipid-based transfection method, lipofection, with an electroporation method, nucleofection, and find large, unanticipated and cell line-dependent differences in percent end-joining without recognizable trends.


Input: For example, in rodent cells, transfection using lipofection gives nearly WT end-joining in DNA-PKcs mutants and only mildly inhibited end-joining in Lig4 and Ku mutants.


Input: In contrast, transfection using nucleofection shows marked end-joining inhibition in all NHEJ mutants tested as compared to the WT.


Input: In human HCT116 cells, end-joining after nucleofection is strongly suppressed even in the WT and the differences to the mutants are small.


Input: After lipofection, in contrast, end-joining is high in WT cells and markedly suppressed in the mutants.


Input: We conclude that better understanding and control of the physicochemical/biological and analytical parameters underpinning these differences will be required to generate with plasmid assays results with quantitative power comparable to that of well-established methods of DSB analysis such as pulsed-field gel electrophoresis or gamma-H2AX foci scoring.


Input: Until then, caution is needed in the interpretation of the results obtained-particularly with reference to pathway efficiency and residual damage-and confirmation of critical results with alternative transfection approaches is advisable.


Input: Development of an in vitro skin sensitization test based on ROS production in THP-1 cells.


Input: Recently, it has been reported that reactive oxygen species (ROS) produced by contact allergens can affect dendritic cell migration and contact hypersensitivity.

oxygen


Input: The aim of the present study was to develop a new in vitro assay that could predict the skin sensitizing potential of chemicals by measuring ROS production in THP-1 (human monocytic leukemia cell line) cells.


Input: THP-1 cells were pre-loaded with a ROS sensitive fluorescent dye, 5-(and 6-)-chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H2DCFDA), for 15min, then incubated with test chemicals for 30min.

5-(and 6-)-chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate

acetyl ester


Input: The fluorescence intensity was measured by flow cytometry.


Input: For the skin sensitizers, 25 out of 30 induced over a 2-fold ROS production at more than 90% of cell viability.


Input: In contrast, increases were only seen in 4 out of 20 non-sensitizers.


Input: The overall accuracy for the local lymph node assay (LLNA) was 82% for 50 chemicals tested.


Input: A correlation was found between the estimated concentration showing 2-fold ROS production in the ROS assay and the EC3 values (estimated concentration required to induce positive response) of the LLNA.


Input: These results indicated that the THP-1 cell-based ROS assay was a rapid and highly sensitive detection system able to predict skin sensitizing potentials and potency of chemicals.


Input: Role for membrane remodeling in cell death: implication for health and disease.


Input: Recently it has become clear that exposure to xenobiotics may result in various forms of cell death; not only passive cell deaths like necrosis, or programmed cell deaths such as apoptosis, but also regulated necrosis, autophagy, senescence, or mitotic catastrophe.


Input: Complex cell signaling networks influence the processing of cell death.


Input: Furthermore, recent research has revealed early complex molecular interactions between organelles prior to the final triggering of cell death.


Input: The plasma membrane may play an important role in the early cell death signaling events.