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Medicines Combinations Options and Regulatory Hurdles.

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The number of fixed dose combinations (FDC) on the market is increasing. However, both regulatory guidelines and the evidence for better effectiveness of fixed dose combinations are not established yet. These aspects were the topic for a recent EUFEPS workshop in Copenhagen. The discussion confirms the presence of hurdles and recommendations to further progress and alleviate the problems. The general conclusion was: Refinement of general systems pharmacology tools for identification of key molecular targets in disease development; Precompetitive methodologies and technologies designed for (co-) development of FDCs; Simulation and modeling algorithms applied on pharmacodynamics (synergy), pharmacokinetics and safety; New formulations of FDCs of solid, liquid or inhalation forms; Prospective clinical studies for measuring the efficacy and effectiveness of use of drug-drug combinations in elderly.

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Cyclooxygenase activity contributes to the monoaminergic damage caused by serial exposure to stress and methamphetamine.

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Methamphetamine (Meth) is a widely abused psychostimulant that causes long-term dopamine (DA) and serotonin (5-HT) depletions. Stress and Meth abuse are comorbid events in society and stress exacerbates Meth-induced monoaminergic terminal damage. Stress is also known to produce neuroinflammation. This study examined the role of the neuroinflammatory mediator, cyclooxygenase (COX), in the depletions of monoamines caused by serial exposure to chronic unpredictable stress (CUS) and Meth. CUS produced an increase in COX-2 protein expression and enhanced Meth-induced monoaminergic depletions in the striatum and hippocampus. The enhanced DA and 5-HT depletions in the striatum, but not the hippocampus, were prevented by pretreatment with COX inhibitor, ketoprofen, during stress or during Meth; however, ketoprofen did not attenuate the monoaminergic damage caused by Meth alone. The COX-dependent enhancement by stress of Meth-induced monoaminergic depletions was independent of hyperthermia, as ketoprofen did not attenuate Meth-induced hyperthermia. In addition, the EP1 receptor antagonist, SC-51089, did not attenuate DA or 5-HT depletions caused by stress and Meth. These findings illustrate that COX activity, but not activation of the EP1 receptor, is responsible for the potentiation of Meth-induced damage to striatal monoamine terminals by stress and suggests the use of anti-inflammatory drugs for mitigating the neurotoxic effects associated with the combination of stress and Meth.

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Upregulation of the dorsal raphe nucleus-prefrontal cortex serotonin system by chronic treatment with escitalopram in hyposerotonergic Wistar-Kyoto rats.

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Wistar-Kyoto (WKY) rats are sensitive to chronic stressors and exhibit depression-like behavior. Dorsal raphe nucleus (DRN) serotonin (5-HT) neurons projecting to the prefrontal cortex (PFC) comprise the important neurocircuitry underlying the pathophysiology of depression. To evaluate the DRN-PFC 5-HT system in WKY rats, we examined the effects of escitalopram (ESCIT) on the extracellular 5-HT level in comparison with Wistar rats using dual-probe microdialysis. The basal levels of 5-HT in the DRN, but not in the PFC, in WKY rats was reduced as low as 30% of Wistar rats. Responses of 5-HT in the DRN and PFC to ESCIT administered systemically and locally were attenuated in WKY rats. Feedback inhibition of DRN 5-HT release induced by ESCIT into the PFC was also attenuated in WKY rats. Chronic ESCIT induced upregulation of the DRN-PFC 5-HT system in WKY rats, with increases in basal 5-HT in the DRN, responsiveness to ESCIT in the DRN and PFC, and feedback inhibition, whereas downregulation of these effects was induced in Wistar rats. Thus, the WKY rat is an animal model of depression with low activity of the DRN-PFC 5HT system. The finding that chronic ESCIT upregulates the 5-HT system in hyposerotonergic WKY rats may contribute to improved understanding of mechanisms of action of antidepressants, especially in depression with 5-HT deficiency.

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Bioconcentration of chromium in edible mushrooms: influence of environmental and genetic factors.

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Chromium concentrations were determined in 167 samples of wild edible mushrooms, collected from three different sites (urban, traffic and pastureland areas) in Lugo (NW Spain). The hymenophore (H) and the rest of the fruiting body (RFB) were analysed separately. The analyses were performed using inductively coupled plasma optical emission spectrometry (ICP-OES). The highest mean chromium levels (mg/kg dry weight) of 3.5 and 8.0, 4.5 and 6.2, and 6.2 and 4.3 were found in Lycoperdon utriforme, Coprinus comatus and Agaricus campestris in H and RFB, respectively. The highest concentrations of chromium were observed in terrestrial saprophytic species in relation to mycorrhizal species. With respect to the underlying substrates, chromium concentration was lowest in the pastureland area (24.6 mg/kg dw). All mushroom species were bioexclusors of chromium (BCF<1) with statistically significant differences (p<0.001). The consumption of mushrooms harvested from the areas investigated poses no toxicological risk to human health due to chromium.

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Synthetic pathway to 22,23-dioxocholestanic chain derivatives and their usefulness for obtaining brassinosteroid analogues.

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Recognizing the functionality of the pentacyclic steroidal derivative 7a as important synthon to obtain new brassinosteroid analogs, we have accomplished the derivatization of hecogenin, a sapogenin from the 25R serie containing a carbonyl group at C-12, to a 22,23-dioxocholestanic chain derivative. Starting from hecogenin acetate (5a) or hecogenin tosylate (5b), we obtained two pentacyclic derivatives (7a and 7b) which were subjected to an oxidation reaction on the double bond at C-12(23) to obtain a 22,23-dioxocholestanic chain, with the regeneration of the carbonyl group at C-12. Reduction of the carbonyl groups lead to the 20-epi-12,23-dihydroxy-22-oxo system 11a-b. The absolute configuration of compound 11a was established by X-ray diffraction analysis.

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Evolution of Manduca sexta hornworms and relatives: Biogeographical analysis reveals an ancestral center of diversification in Central America.

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The hawkmoth genus Manduca is a diverse group of very large, conspicuous moths that has served as an important model across many biological disciplines. Two species in particular, the tobacco hornworm (Manduca sexta) and the tomato hornworm (Manduca quinquemaculatus) have been researched extensively. Studies across biological fields have referred to these two species as being closely related or even sister species, but the extent to which these two model organisms are related remains largely unknown. We conducted a comprehensive multi-gene phylogenetic analysis of Manduca, based on both an ML and Bayesian framework, which resulted in a monophyletic Manduca but only when two other genera, Dolba and Euryglottis are included. We tentatively conclude that the sister group to Manduca sexta comprises the Caribbean M. afflicta and M. johanni, and the sister lineage to this clade includes M. quinquemaculatus and the Hawaiian M. blackburni. Thus, M. sexta and M. quinquemaculatus are closely related, but are not sister species. Biogeographical analyses reveal an ancestral center of diversification in Central America, and Manduca appears to have subsequently colonized North and South America. Our phylogeny provides an important foundation for comparative studies of two model organisms and their relatives.

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Designing, structural elucidation, comparison of DNA binding, cleavage, radical scavenging activity and anticancer activity of copper(I) complex with 5-dimethyl-2-phenyl-4-[(pyridin-2-ylmethylene)-amino]-1,2-dihydro-pyrazol-3-one Schiff base ligand.

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A novel copper(I) Schiff base complex has been synthesized and fully characterized by spectral, analytical and structural modes. Single crystal X-ray diffraction studies revealed that the copper(I) complex [CuCl(PPh3)L] has a distorted tetrahedral geometry around the central copper(I) ion. The interaction of the ligand and the complex with CT-DNA has been explored by absorption titration method which revealed that the compounds could interact with CT-DNA through intercalation. A gel electrophoresis assay demonstrated the ability of the complex to cleave the pBR322 DNA. The antioxidative properties showed that the copper(I) complex has a strong radical-scavenging potency than ligands. Further the cytotoxic effect of the compounds examined on cancerous cell lines showed that the complex exhibited substantial anticancer activity.

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Synthesis and biological evaluation of novel phosphatidylinositol 3-kinase inhibitors: Solubilized 4-substituted benzimidazole analogs of 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).

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A range of 4-substituted derivatives of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) were prepared in a search for more soluble analogs. 4-Aminoalkoxy substituents provided the most potent derivatives, with the 4-O(CH2)3NMe2 analog (compound 14) being identified as displaying the best overall activity in combination with good aqueous solubility (25 mg/mL for the hydrochloride salt). This compound was tested in a U87MG xenograft model, but displayed less potency than ZSTK474 as a result of an unfavorable pharmacokinetic profile.

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Nitroimidazolyl hydrazones are better amoebicides than their cyclized 1,3,4-oxadiazoline analogues: In vitro studies and Lipophilic efficiency analysis.

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Two series of compounds with hydrazone derivatives (HZ1-HZl2, series 1) and oxadiazoline derivatives (OZ1-OZ12, series 2) of the 2-methyl-5-nitro-1H-imidazole scaffold were designed and synthesized. Physicochemical properties and Lipophilic efficiency (LipE) analysis predicted higher intrinsic quality of the acylhydrazone derivatives (series 1) than their corresponding oxadiazoline analogues (series 2). In vitro antiamoebic results supported the above findings and validated that the acylhydrazone derivatives (HZ1-HZl2) show better activity than the oxadiazoline derivatives (OZ1-OZ12). MTT assay, using HepG2 cell line, revealed noncytotoxic nature of the compounds. The most promising results were observed for compounds HZ5 (IC50 = 0.96 μM) and HZ9 (IC50 = 0.81 μM) both in silico and in vitro. Analysis of the Lipophilic efficiency (LipE) of the compounds provided new insight for the design of potent and selective amoebicides.

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Enmein-type diterpenoid analogs from natural kaurene-type oridonin: Synthesis and their antitumor biological evaluation.

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A series of enmein-type diterpenoid analogs (11-20) derived from natural kaurene-type diterpenoid oridonin were synthesized and biologically evaluated. All target compounds showed improved anti-proliferative activities against four human cancer cell lines compared with natural oridonin and parent compound 10. Some compounds were more potent than positive control Taxol. Furthermore, mechanistic investigation showed that the representative compound 17 affected cell cycle and induced apoptosis at low micro-molar level in human hepatoma Bel-7402 cells, via an oxidative stress triggered mitochondria-related caspase-dependent pathway.

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Siah2 regulates tight junction integrity and cell polarity through control of ASPP2 stability.

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Changes in cell adhesion and polarity are closely associated with epithelial cell transformation and metastatic capacity. The tumor suppressor protein ASPP (Apoptosis-Stimulating Proteins of p53) 2 has been implicated in control of cell adhesion and polarity through its effect on the PAR complex. Here we demonstrate that under hypoxic conditions, the ubiquitin ligase Siah (seven in absentia homolog)2 controls ASPP2 availability, with concomitant effect on epithelial cell polarity. LC-MS/MS analysis identified ASPP2 and ASPP1 as Siah2-interacting proteins. Biochemical analysis confirmed this interaction and mapped degron motifs within ASPP2, which are required for Siah2-mediated ubiquitination and proteasomal-dependent degradation. Inhibition of Siah2 expression increases ASPP2 levels and enhances ASPP2-dependent maintenance of tight junction (TJ) integrity, and polarized architecture in three dimensional (3D) organotypic culture. Conversely, increase of Siah2 expression under hypoxia decreases ASPP2 levels and the formation of apical polarity in 3D culture. In all, our studies demonstrate the role of Siah2 in regulation of TJ integrity and cell polarity under hypoxia, through its regulation of ASPP2 stability.Oncogene advance online publication, 6 May 2013; doi:10.1038/onc.2013.149.

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The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample.

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RATIONALE: To improve outcomes for patients undergoing extinction-based therapies (e.g., exposure therapy) for anxiety disorders such as post-traumatic stress disorder (PTSD), there has been interest in identifying pharmaceutical compounds that might facilitate fear extinction learning and recall. Oxytocin (OT) is a mammalian neuropeptide that modulates activation of fear extinction-based neural circuits and fear responses. Little is known, however, about the effects of OT treatment on conditioned fear responding and extinction in humans. OBJECTIVES: The purpose of the present study was to assess the effects of OT in a fear-potentiated startle task of fear conditioning and extinction. METHODS: A double-blind, placebo-controlled study of 44 healthy human participants was conducted. Participants underwent a conditioned fear acquisition procedure, after which they were randomized to treatment group and delivered OT (24 IU) or placebo via intranasal (IN) spray. Forty-five minutes after treatment, participants underwent extinction training. Twenty-four hours later, subjects were tested for extinction recall. RESULTS: Relative to placebo, the OT group showed increased fear-potentiated startle responding during the earliest stage of extinction training relative to placebo; however, all treatment groups showed the same level of reduced responding by the end of extinction training. Twenty-four hours later, the OT group showed significantly higher recall of extinction relative to placebo. CONCLUSIONS: The current study provides preliminary evidence that OT may facilitate fear extinction recall in humans. These results support further study of OT as a potential adjunctive treatment for extinction-based therapies in fear-related disorders.

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Greater risk sensitivity of dorsolateral prefrontal cortex in young smokers than in nonsmokers.

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RATIONALE: Despite a national reduction in the prevalence of cigarette smoking, ~19 % of the adult US population persists in this behavior, with the highest prevalence among 18-25-year-olds. Given that the choice to smoke imposes a known health risk, clarification of brain function related to decision-making, particularly involving risk-taking, in smokers may inform prevention and smoking cessation strategies. OBJECTIVES: This study aimed to compare brain function related to decision-making in young smokers and nonsmokers. METHODS: The Balloon Analogue Risk Task (BART) is a computerized risky decision-making task in which participants pump virtual balloons, each pump associated with an incremental increase in potential payoff on a given trial but also with greater risk of balloon explosion and loss of payoff. We used this task to compare brain activation associated with risky decision-making in smokers (n = 18) and nonsmokers (n = 25), while they performed the BART during functional magnetic resonance imaging (fMRI). The participants were young men and women, 17-21 years of age. RESULTS: Risk level (number of pumps) modulated brain activation in the right dorsolateral and ventrolateral prefrontal cortices more in smokers than in nonsmokers, and smoking severity (Heaviness of Smoking Index) was positively related to this modulation in an adjacent frontal region. CONCLUSIONS: Given evidence for involvement of the right dorsolateral and ventrolateral prefrontal cortices in inhibitory control, these findings suggest that young smokers have a different contribution of prefrontal cortical substrates to risky decision-making than nonsmokers. Future studies are warranted to determine whether the observed neurobiological differences precede or result from smoking.

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Measuring nanoparticle flow with the image structure function.

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We present a technique to measure the velocity and flow profiles of a nanofluid in a microfluidic channel. Importantly, we extract the flow velocity from a series of standard brightfield images without employing particle tracking or laser-enhanced methods. Our analysis retrieves the flow information from the image structure function of sub-diffraction limited nanoparticles in suspension. We are able to spatially resolve the flow velocity and map out the parabolic flow profile across the width of a microfluidic channel.

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Role of quercetin in cadmium-induced oxidative stress, neuronal damage, and apoptosis in rats.

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The present study was carried out to evaluate the neuroprotective effect of quercetin (QE) in protecting the cadmium (Cd)-induced neuronal injury in frontal cortex of rats. A total of 30 adult male Sprague-Dawley rats were randomly divided into three groups of 10 animals each: control, Cd treated and Cd treated with QE. The Cd-treated group was injected subcutaneously with cadmium chloride (CdCl2) dissolved in saline at a dose of 2 ml/kg/day for 30 days, resulting in a dosage of 1 mg/kg Cd. The rats in QE-treated groups were given QE (15 mg/kg body weight) once a day intraperitoneally starting 2 days prior to Cd injection, during the study period. Rats were sacrificed at the end of the study and the frontal cortex tissues were removed for biochemical and histopathological investigation. To date, there is no available information on the effect of QE on neuronal injury after Cd exposure. Rats intoxicated with Cd for 30 days, significantly increased tissue malondialdehyde (MDA) levels and significantly decreased enzymatic antioxidants superoxide dismutase, glutathione peroxidase and catalase in the frontal cortex tissue. Administration of QE with Cd significantly diminished the levels of MDA and significantly elevated the levels of enzymatic antioxidants in the frontal cortex tissue. The histopathological studies in the brain of rats also supported that QE markedly reduced the Cd-induced histopathological changes and well preserved the normal histological architecture of the frontal cortex tissue. The caspase-3 immunopositivity was increased in degenerating neurons of the Cd group. Treatment with QE markedly reduced the immunoreactivity of degenerating neurons. In conclusion, the results of the current study suggest that QE may be beneficial in combating the Cd-induced neurotoxicity in the brain of rats. We believe that further preclinical research into the utility of QE may indicate its usefulness as a potential treatment for neurodegeneration after Cd exposure in rats.

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Differential regulation of Arabidopsis plastid gene expression and RNA editing in non-photosynthetic tissues.

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RNA editing is one of the post-transcriptional processes that commonly occur in plant plastids and mitochondria. In Arabidopsis, 34 C-to-U RNA editing events, affecting transcripts of 18 plastid genes, have been identified. Here, we examined the editing and expression of these transcripts in different organs, and in green and non-green seedlings (etiolated, cia5-2, ispF and ispG albino mutants, lincomycin-, and norflurazon-treated). The editing efficiency of Arabidopsis plastid transcripts varies from site to site, and may be specifically regulated in different tissues. Steady state levels of plastid transcripts are low or undetectable in etiolated seedlings, but most editing sites are edited with efficiencies similar to those observed in green seedlings. By contrast, the editing of some sites is completely lost or significantly reduced in other non-green tissues; for instance, the editing of ndhB-149, ndhB-1255, and ndhD-2 is completely lost in roots and in lincomycin-treated seedlings. The editing of ndhD-2 is also completely lost in albino mutants and norflurazon-treated seedlings. However, matK-640 is completely edited, and accD-794, atpF-92, psbE-214, psbF-77, psbZ-50, and rps14-50 are completely or highly edited in both green and non-green tissues. In addition, the expression of nucleus-encoded RNA polymerase dependent transcripts is specifically induced by lincomycin, and the splicing of ndhB transcripts is significantly reduced in the albino mutants and inhibitor-treated seedlings. Our results indicate that plastid gene expression, and the splicing and editing of plastid transcripts are specifically and differentially regulated in various types of non-green tissues.

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Analysis of the inhibitory activity of Abeliophyllum distichum leaf constituents against aldose reductase by using high-speed counter current chromatography.

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We isolated five phenolic glycosides (acteoside, eutigoside B, isoacteoside, rutin and cornoside) from Abeliophyllum distichum leaves by high-speed counter current chromatography (HSCCC) using a solvent system of ethyl acetate:n-butanol:water (8:0.7:5). We determined the purity of the 5 compounds by high-performance liquid chromatography, and confirmed their chemical structures by using nuclear magnetic resonance data. We examined the inhibitory effect of these compounds on rat lens aldose reductase. Among these compounds, acteoside (1) showed the most potent inhibitory effect, with an IC50 value of 1.39 μM. The inhibitory effect of 1 was 5.0 times greater than that of quercetin (7.05 μM), which was used as a positive control. These results suggest that acteoside may be a promising agent for the prevention or treatment of diabetic complications. Moreover, HSCCC is a promising method for the isolation and purification of biologically active compounds from natural products.

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Understanding the Cost-Effectiveness of Influenza Vaccination in Children: Methodological Choices and Seasonal Variability.

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BACKGROUND: The universal vaccination of children for influenza has recently been recommended in the UK and is being considered in other developed countries. OBJECTIVES: The aim of this study was to explore the potential costs and benefits of childhood influenza vaccination to gain a better understanding of the key drivers of cost-effectiveness. METHODS: As our case study we examined the cost-effectiveness of vaccination in Australian schoolchildren using an age-stratified Susceptible Exposed Infectious Recovered model. RESULTS: The results of this study highlight the critical role that methodological choices play in determining the cost-effectiveness of influenza vaccination. These choices include decisions about the structure of the model (including/excluding herd immunity) and what costs and benefits to include in the analysis. In scenarios where herd protection was included we estimated that the program was likely to be cost-effective. The study also illustrates the importance of the inherent seasonal variability of influenza, which can produce counter-intuitive results, with low transmission seasons being easier to control by vaccination but resulting in fewer benefits. CONCLUSIONS: Universal childhood influenza vaccination is likely to be cost-effective if a substantial herd protection effect can be achieved by the program. However, it is important that decision makers understand the role of seasonal variability and the impact of alternative methodological choices in economic evaluations of influenza vaccination.

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The bacterial translocon SecYEG opens upon ribosome binding.

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In cotranslational translocation, the ribosome funnel and the channel of the protein translocation complex SecYEG are aligned. For the nascent chain to enter the channel immediately after synthesis, a yet unidentified signal triggers displacement of the SecYEG sealing plug from the pore. Here we show that ribosome binding to the resting SecYEG channel triggers this conformational transition. The purified and reconstituted SecYEG channel opens to form a large ion-conducting channel which has the conductivity of the plug deletion mutant. The number of ion conducting channels inserted into the planar bilayer per fusion event roughly equals the number of SecYEG channels counted by fluorescence correlation spectroscopy in a single proteoliposome. Thus, the open probability of the channel must be close to unity. To prevent the otherwise lethal proton leak, a closed post-translational conformation of the SecYEG complex bound to a ribosome must exist.

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Gain-of-function mutations in transient receptor potential C6 (TRPC6) activate extracellular-signal-regulated kinases Erk1/2.

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Gain-of-function mutations in the canonical transient receptor potential 6 (TRPC6) gene are a cause of autosomal dominant focal segmental glomerulosclerosis (FSGS4). The mechanisms whereby abnormal TRPC6 activity results in proteinuria remain unknown. The Erk1/2 MAP kinases are activated in glomeruli and podocytes in several proteinuric disease models. We therefore examined whether FSGS-associated mutations in TRPC6 result in activation of these kinases. In 293T cells and cultured podocytes, overexpression of gain-of-function TRPC6 mutants resulted in increased Erk1/2 phosphorylation, an effect dependent upon channel function. Pharmacologic inhibitor studies implicated several signaling mediators, including calmodulin and calcineurin, supporting the importance of TRPC6-mediated calcium influx in this process. Through media transfer experiments, we uncovered two distinct mechanisms for Erk activation by mutant TRPC6, a cell autonomous, EGFR-independent mechanism and a cell non-autonomous mechanism involving metalloprotease-mediated release of a presumed EGFR ligand. The inhibitors KN-92 and H89 were able to block both pathways in mutant TRPC6 expressing cells, as well as the prolonged elevation of intracellular calcium levels upon carbachol stimulation seen in these cells. However, these effects appear independent of their effects on CaMKII and PKA, respectively. Phosphorylation of T70, S282 and Y31/Y285 were not necessary for Erk activation by mutant TRPC6, though a phosphomimetic TRPC6 S282E mutant was capable of Erk activation. Taken together, these results identify two pathways downstream of mutant TRPC6 leading to Erk activation that may play a role in the development of FSGS.

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