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Synthesis and cytotoxic evaluation of novel pyrimidine deoxyapiothionucleosides.

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The synthesis of novel pyrimidine deoxyapiothionucleosides of d- and l-series was realized following application of a versatile and high-yielding scheme, which utilized inexpensive l- and d-arabinose as starting materials, respectively, and which makes use of a regio- and stereo-selective Pummerer rearrangement reaction for the coupling of the nucleobase with the thiosugar moiety. Some of the targeted compounds have shown selective cytotoxic effects (with IC50<10μM) against specific cancer cell lines. All of the tested compounds had no cytotoxic effect on the normal cell line tested.

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Oxidative stress and MAPK involved into ATF2 expression in immortalized human urothelial cells treated by arsenic.

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ATF2 is a subfamily member of AP-1 and has an important role in cellular stress responses. ATF2 has been implicated in a transcriptional response leading to cell migration and malignant tumor progression. However, little is known about the effect of arsenic on expression of ATF2 and regulatory pathways in human urothelial cells. In this study, ATF2 expression was measured in NaAsO2-treated human uroepithelial cell line (SV-HUC-1) with 1, 2, 4, 8 and 10 μM concentrations in order to provide some basis data for the study on mechanism of bladder cancer induced by arsenic. We found that ATF2 expression levels at 2, 4, 8 and 10 μM arsenic-treated cells were significantly higher than those of control cells, and the strongest expression occurred in 4 μM NaAsO2-treated cells. Antioxidants (melatonin) and JNK or p38 inhibitors decreased significantly arsenic-induced ATF2 expression. Taken together, these data indicated that the increasing of ATF2 expression is mediated via oxidative stress induced by arsenic in SV-HUC-1 cells, and JNK or p38 rather than ERK is responsible for arsenic-induced ATF2 expression. ROS were also involved in arsenic induced the activation of JNK and p38 MAPK signaling pathway.

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Two Common Bean Genotypes with Contrasting Response to Phosphorus Deficiency Show Variations in the microRNA 399-Mediated PvPHO2 Regulation within the PvPHR1 Signaling Pathway.

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Widening the pH Activity Profile of a Fungal Laccase by Directed Evolution.

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Unnatural selection: A fungal laccase was tailored by directed evolution to be active at neutral/alkaline pH. After five generations, the final mutant showed a broader pH profile while retaining 50 to 80 % of its activity at neutral pH.

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An in Vivo Tagging Method Reveals that Ras Undergoes Sustained Activation upon Transglutaminase-Mediated Protein Serotonylation.

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Don't interrupt! Protein serotonylation has been implicated in living cells, yet its role remains poorly defined because of the lack of characterization tools. We synthesized a serotonin derivative to enable selective tagging of serotonylation and to investigate its effect on Ras; the latter displayed undisrupted interaction with Raf-1 at the Ras binding domain.

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A Surgical Model in Male Obese Rats Uncovers Protective Effects of Bile Acids Post-Bariatric Surgery.

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Bariatric surgery elevates serum bile acids. Conjugated bile acid administration, such as tauroursodeoxycholic acid (TUDCA), improves insulin sensitivity, while short-circuiting bile acid circulation through ileal interposition surgery in rats raises TUDCA levels. We hypothesized that bariatric surgery outcomes could be recapitulated by short-circuiting the normal entero-hepatic bile circulation. We established a model wherein male obese rats underwent either bile diversion (BD) or Sham (SH) surgery. The BD group had a catheter inserted into the common bile duct and its distal end anchored into the mid-distal jejunum for 4-5 weeks. Glucose tolerance, insulin and glucagon-like peptide-1 (GLP-1) response, hepatic steatosis and endoplasmic reticulum (ER) stress were measured. Rats' post-BD lost significantly more weight than the SH-rats. BD rats gained less fat mass post-surgery. BD rats had improved glucose tolerance, increased higher post-prandial GLP-1 response and serum bile acids but less liver steatosis. Serum bile acid levels including TUDCA concentrations were higher in BD compared to SH pair-fed rats. Fecal bile acid levels were not different. Liver ER stress (CHOP mRNA and pJNK protein) was decreased in BD rats. Bile acid gavage (TUDCA/UDCA) in diet-induced obese rats, elevated serum TUDCA and concomitantly reduced hepatic steatosis and ER stress (CHOP mRNA). These data demonstrate the ability of alterations in bile acids to recapitulate important metabolic improvements seen after bariatric surgery. Further, our work establishes a model for focused study of bile acids in the context of bariatric surgery that may lead to the identification of therapeutics for metabolic disease.

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Silver nanoparticles enhance Pseudomonas aeruginosa PAO1 biofilm detachment.

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Abstract Objectives: Silver nanoparticles (AgNPs) with a size ranging from 7 to 70 nm were synthesized using the ascorbic acid-citrate seed-mediated growth approach at room temperature. Methods: The 8 nm silver particles were prepared using gallic acid in alkaline conditions and used as seed to prepare AgNPs. Results: The presence of ascorbic acid and citrate allows the regulation of size and size distribution of the nanoparticles. The increase in free silver ion-to-seed ratio (Ag(+)/Ag(0)) resulted in changes of particle shape from spherical to pseudo-spherical and minor cylindrical shape. Further, a repetitive seeding approach resulted in the formation of pseudo-spherical particles with higher polydispersity index and minor distributions of tetrahedral particles. Citrate-capped AgNPs were stable and did not agglomerate upon centrifugation. The effect of AgNPs on biofilm reduction was evaluated using static culture on 96-well microtiter plates. Results showed that AgNPs with the smallest average diameter were most effective in the reduction of Pseudomonas aeruginosa biofilm colonies, which accounted for 90% of removal. Conclusion: The biofilm removal activities of the nanoparticles were found to be concentration-independent particularly for the concentration within the range of 80-200 µg/mL.

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Bacteriolysis by vancomycin-conjugated acryl nanoparticles and morphological component analysis.

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Abstract Nanoparticles are currently attracting considerable attention because of their ability to conjugate to various substances. As such, these nanoparticles can assist the transfer of the conjugated substance to target tissues where they are gradually released. In this study, vancomycin-conjugated nanoparticles (VCM NPs) were prepared. The antibacterial activity of VCM NPs was compared with that of VCM alone by exposure to vancomycin-resistant enterococci (VRE). The morphology of the cells was then analyzed by electron microscopy. VCM NPs were found to have more potent antibacterial activity against VRE compared to VCM alone, but the activity against vancomycin-sensitive enterococci (VSE) remained the same. The antibacterial activity of nanoparticles alone was the same against VSE and VRE. The nanoparticles were found to induce characteristic morphological changes in the bacteria based on scanning and transmission electron microscopy. The results suggest that the strong antibacterial activity of VCM NPs against VRE may be attributable not only to the well-known control release carrier property of the nanoparticles but to an additional mechanism that involves VCM NPs avoiding the drug resistant mechanism of VRE.

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Ingestion toxicity of three Lamiaceae essential oils incorporated in protein baits against the olive fruit fly, Bactrocera oleae (Rossi) (Diptera Tephritidae).

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The ingestion toxicity of three Lamiaceae essential oils (EOs) - Hyptis suaveolens, Rosmarinus officinalis and Lavandula angustifolia - incorporated in protein baits was evaluated against Bactrocera oleae, a worldwide pest of olive fruits. In laboratory conditions, all the tested EOs showed dose-dependent toxicity on B. oleae, with mortality rates ranging from 12% (EO concentration: 0.01% w:v) to 100% (EO concentration: 1.75% w:v). Semi-field results highlighted the toxicity of L. angustifolia and H. suaveolens EOs, which exerted more than 60% of flies mortality at a concentration of 1.75% (w:v). Gas Chromatography-Electron Impact Mass Spectrometry analyses of the three EOs showed that H. suaveolens EO was dominated by monoterpene and sesquiterpene hydrocarbons. Oxygenated monoterpenes were the main chemical class in R. officinalis and L. angustifolia EOs. Further research is needed to evaluate the efficacy of these EOs plus food bait against the olive fruit fly in the open field.

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Aberrant free radical biology is a unifying theme in the etiology and pathogenesis of major human diseases.

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The seemingly disparate areas of oxygen toxicity, radiation exposure, and aging are now recognized to share a common feature-the aberrant production and/or removal of biologically derived free radicals and other reactive oxygen and nitrogen species (ROS/RNS). Advances in our understanding of the effects of free radicals in biology and medicine have been, and continue to be, actively translated into clinically tractable diagnostic and therapeutic applications. This issue is dedicated to recent advances, both basic discoveries and clinical applications, in the field of free radicals in biology and medicine. As more is understood about the proximal biological targets of aberrantly produced or removed reactive species, their sensors, and effectors of compensatory response, a great deal more will be learned about the commonalities in mechanisms underlying seemingly disparate disease states. Together with this deeper understanding, opportunities will arise to devise rational therapeutic interventions to decrease the incidence and severity of these diseases and positively impact the human healthspan.

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Structural and Immunochemical Studies of the Lipopolysaccharide from the Fish Pathogen, Aeromonas bestiarum Strain K296, Serotype O18.

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Protective Effects of HemoHIM on Immune and Hematopoietic Systems Against γ-Irradiation.

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We examined the effect of HemoHIM on the protective efficacy of hematopoietic stem cells and on the recovery of immune cells against sublethal doses of ionizing radiation. Two-month-old mice were exposed to γ-rays at a dose of 8, 6.5, or 5 Gy for a30-day survival study, endogenous spleen colony formation, or other experiments, respectively. HemoHIM was injected intraperitoneally before and after irradiation. Our results showed that HemoHIM significantly decreased the mortality of sublethally irradiated mice. The HemoHIM administration decreased the apoptosis of bone marrow cells in irradiated mice. On the other hand, HemoHIM increased the formation of endogenous spleen colony in irradiated mice. In irradiated mice, the recovery of total leukocytes in the peripheral blood and lymphocytes in the spleen were enhanced significantly by HemoHIM. Moreover, the function of B cells, T cells, and NK cells regenerated in irradiated mice were significantly improved by the administration of HemoHIM. HemoHIM showed an ideal radioprotector for protecting hematopoietic stem cells and for accelerating the recovery of immune cells. We propose HemoHIM as a beneficial supplement drug during radiotherapy to alleviate adverse radiation-induced effects for cancer patients. Copyright © 2013 John Wiley & Sons, Ltd.

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Palbinone from Paeonia suffruticosa Protects Hepatic Cells via Up-regulation of Heme Oxygenase-1.

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Paeonia suffruticosa has been traditionally employed for vitalizing blood circulation and alleviating liver and inflammatory diseases. The pathways by which palbinone (PB) isolated from P. suffruticosa mediates heme oxygenase-1 (HO-1) induction were investigated using the specific inhibitors for PI3K and mitogen activated protein kinases pathways. The effect of PB-treatment on Nrf2 translocalization and HO-1-antioxidant response element (ARE) regulation was examined employing Western blot and luciferase assays. PB induced HO-1 expression via the activation of Nrf2 in the hepatic cells, and ARE-dependent genes were stimulated via the PB-mediated Nrf2 activation. PB-mediated HO-1 expression could be involved with PI3K/Akt and ERK1/2 pathways. Our study suggests the mechanism by which PB induces HO-1 expression in the hepatic cells. This might substantiate the traditional applications of P. suffruticosa for the treatment of oxidative stress-related diseases including oxidant and inflammatory-mediated vascular and liver diseases. Copyright © 2013 John Wiley & Sons, Ltd.

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Identification of candidate genes encoding an LDL-C QTL in baboons.

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Cardiovascular disease (CVD), the leading cause of death in developed countries and dyslipidemia, is a major risk factor for CVD. We previously identified a cluster of quantitative trait loci (QTL) on baboon chromosome 11 for multiple related quantitative traits for serum low-density lipoprotein cholesterol (LDL-C). Here we report differentially regulated hepatic genes that appear to encode an LDL-C QTL that influences LDL-C levels in baboons. We performed hepatic whole genome expression profiling for LDL-C discordant baboons fed a high-cholesterol, high-fat (HCHF) diet for 7 weeks. We detected expression of 117 genes within the QTL 2-LOD-support interval. Three genes were differentially expressed in low LDL-C responders and 8 in high LDL-C responders in response to a HCHF diet. Seven genes (ACVR1B, CALCOCO1, DGKA, ERBB3, KRT73, MYL6B, TENC1) showed discordant expression between low and high LDL-C responders. To prioritize candidate genes, we integrated miRNA and mRNA expression profiles using network tools and found that four candidates (ACVR1B, DGKA, ERBB3, TENC1) were miRNA targets and the miRNAs were inversely expressed to the target genes. Candidate gene expression was validated using QRT-PCR and Westerns. This study reveals candidate genes that influence variation in LDL-C in baboons and potential genetic mechanisms for further investigation.

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Macromolecular amplification of binding response in superaptamer hydrogels.

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It is becoming more important to detect ultralow concentrations of analytes for biomedical, environmental, and national security applications. Equally important is that new methods should be easy to use, inexpensive, portable, and if possible allow detection by the naked eye. By and large, detection of low concentrations of analytes cannot be achieved directly but requires signal amplification by catalysts, macromolecules, metal surfaces, or supramolecular aggregates. The rapidly progressing field of macromolecular signal amplification has been advanced using conjugated polymers, chirality in polymers, solvating polymers, and polymerization/depolymerization strategies. A new type of aptamer-based hydrogel with specific response to target proteins presented in this report demonstrates an additional category of macromolecular signal amplification. This superaptamer assembly provides the first example of using protein-specific aptamers to create volume-changing hydrogels with amplified response to the target protein. A remarkable aspect of these superaptamer hydrogels is that volume shrinking is visible to the naked eye down to femtomolar concentrations of protein. This extraordinary macromolecular amplification is attributed to a complex interplay between protein-aptamer supramolecular cross-links and the consequential reduction of excluded volume in the hydrogel. Specific recognition is even maintained in biological matrices such as urine and tears. Furthermore, the gels can be dried for long-term storage and regenerated for use without loss of activity. In practice, the ease of this biomarker detection method offers an alternative to traditional analytical techniques that require sophisticated instrumentation and highly trained personnel.

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Polyelectrolyte Multilayers Promote Stent-Mediated Delivery of DNA to Vascular Tissue.

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We report an approach to deliver DNA to vascular tissue in vivo using intravascular stents coated with degradable, DNA-containing polyelectrolyte multilayers (PEMs). Ionically cross-linked multilayers ∼120 nm thick were fabricated layer-by-layer on the surfaces of balloon-mounted stainless steel stents using plasmid DNA and a hydrolytically degradable poly(β-amino ester) (polymer 1). Characterization of stents coated using a fluorescently end-labeled analog of polymer 1 revealed film erosion to be uniform across the surfaces of the stents; differential stresses experienced upon balloon expansion did not lead to faster film erosion or dose dumping of DNA in areas near stent joints when stents were incubated in physiologically relevant media. The ability of film-coated stents to transfer DNA and transfect arterial tissue in vivo was then investigated in pigs and rabbits. Stents coated with films fabricated using fluorescently labeled DNA resulted in uniform transfer of DNA to sub-endothelial tissue in the arteries of pigs in patterns corresponding to the locations and geometries of stent struts. Stents coated with films fabricated using polymer 1 and plasmid DNA encoding EGFP resulted in expression of EGFP in the medial layers of stented tissue in both pigs and rabbits two days after implantation. The results of this study, combined with the modular and versatile nature of layer-by-layer assembly, provide a polymer-based platform that is well suited for fundamental studies of stent-mediated gene transfer. With further development, this approach could also prove useful for the design of nonviral, gene-based approaches for prevention of complications that arise from the implantation of stents and other implantable interventional devices.

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Kinase Scaffold Repurposing for Neglected Disease Drug Discovery: Discovery of an Efficacious, Lapatanib-Derived Lead Compound for Trypanosomiasis.

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Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei . Because drugs in use against HAT are toxic and require intravenous dosing, new drugs are needed. Initiating lead discovery campaigns by using chemical scaffolds from drugs approved for other indications can speed up drug discovery for neglected diseases. We demonstrated recently that the 4-anilinoquinazolines lapatinib (GW572016, 1) and canertinib (CI-1033) kill T. brucei with low micromolar EC50 values. We now report promising activity of analogues of 1, which provided an excellent starting point for optimization of the chemotype. Our compound optimization that has led to synthesis of several potent 4-anilinoquinazolines, including NEU617, 23a, a highly potent, orally bioavailable inhibitor of trypanosome replication. At the cellular level, 23a blocks duplication of the kinetoplast and arrests cytokinesis, making it a new chemical tool for studying regulation of the trypanosome cell cycle.

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Molecular Mechanisms in the Pyrolysis of Unsaturated Chlorinated Hydrocarbons: Formation of Benzene Rings Part II - Experimental and Kinetic Modeling Studies.

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The mechanism of formation of benzene rings during the pyrolysis of dichloro- and trichloroethylene has been investigated by the method of Laser Powered Homogeneous Pyrolysis coupled with product analysis by gas chromatography. Additionally, selected (co)-pyrolyses between the chlorinated ethylenes, CH2Cl2, C4Cl4, C4Cl6, and C2H2 have been performed to explicitly probe the roles of 2C3 and C4/C2 reaction pairs in aromatic growth. The presence of odd-carbon products in neat C4Cl6 pyrolyses indicates 2C3 processes are operative in these systems; however, comparison with product yields from C2HCl3 suggests C4/C2 processes dominate most other systems. This is further evidenced by an absence of C3 and other odd-carbon species in (co)-pyrolyses with dichloromethane which should seed C3-based growth. The reactions of perchlorinated C4 species C4Cl5, C4Cl3, and C4Cl4 with C2Cl2 were subsequently explored through extensive kinetic simulations of the possible reaction pathways based on previous kinetic models and the exhaustive quantum chemical investigations of our preceding work. The experimental and theoretical results strongly suggest that, at moderate temperatures, aromatic ring formation from chlorinated ethylenes normally follows a Diels-Alder coupling of C4 and C2 molecular units followed by internal shifts; the one exception is the C4Cl4 + C2Cl2 system, where steric factors lead to the formation of non-aromatic products. There is little evidence for radical-based routes in these systems.

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CH-01 is a hypoxia-activated prodrug that sensitizes cells to hypoxia/reoxygenation through inhibition of Chk1 and Aurora A.

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The increased resistance of hypoxic cells to all forms of cancer therapy presents a major barrier to the successful treatment of most solid tumors. Inhibition of the essential kinase, Checkpoint kinase 1 (Chk1) has been described as a promising cancer therapy for tumors with high levels of hypoxia-induced replication stress. However, as inhibition of Chk1 affects normal replication and induces DNA damage, these agents also have the potential to induce genomic instability and contribute to tumorigenesis. To overcome this problem, we have developed a bioreductive prodrug, which functions as a Chk1/Aurora A inhibitor specifically in hypoxic conditions. To achieve this activity, a key functionality on the Chk1 inhibitor (CH-01) is masked by a bioreductive group, rendering the compound inactive as a Chk1/Aurora A inhibitor. Reduction of the bioreductive group nitro moiety, under hypoxic conditions, reveals an electron-donating substituent that leads to fragmentation of the molecule, affording the active inhibitor. Most importantly, we show a significant loss of viability in cancer cell lines exposed to hypoxia in the presence of CH-01. This novel approach targets the most aggressive and therapy-resistant tumor fraction while protecting normal tissue from therapy-induced genomic instability.

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Toxicity study of isolated polypeptide from wool hydrolysate.

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The cytotoxicity of wool polypeptide has been evaluated by both cell and animal models. Wool was dissolved in sodium hydroxide solution, the pH value of the solution was adjusted to 5.55 and the precipitate was harvested as wool polypeptide. The spray-dried polypeptide was collected as powders and characterized by SEM, FTIR and TG-DSC. The cell culturing results showed that wool polypeptide had no obvious negative effect on cell viability in vitro. Both acute oral toxicity and subacute 30-day oral toxicology studies showed that wool polypeptide had no influence on body weight, feed consumption, blood chemistry, and hematology at any dose levels. There were no treatment related findings on gross or detailed necroscopy, organ weights, organ/body weight ratios and histology. Our study indicated the absence of toxicity in wool polypeptide and supported its safe use as a food ingredient or drug carrier.

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Açai (Euterpe oleracea Mart.) feeding attenuates dimethylhydrazine-induced rat colon carcinogenesis.

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This study investigated the protective effect of spray-dried açaí powder (AP) intake on colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH) in male Wistar rats. After 4weeks of DMH administrations, the groups were fed with standard diet, a diet containing 2.5% or 5.0% AP or a diet containing 0.2% N-acetylcysteine (NAC) for 10weeks, using aberrant crypt foci (ACF) as the endpoint. Additionally, two groups were fed with standard diet or a diet containing 5.0% AP for 20weeks, using colon tumors as the endpoint. In ACF assay, a reduction in the number of aberrant crypts (ACs) and ACF (1-3 AC) were observed in the groups fed with 5.0% AP (37% AC and 47% ACF inhibition, p=0.036) and 0.2% NAC (39% AC and 41% ACF inhibition, p=0.042). In tumor assay, a reduction in the number of invasive tumors (p<0.005) and tumor multiplicity (p=0.001) was observed in the group fed with 5.0% AP. Also, a reduction in tumor Ki-67 cell proliferation (p=0.003) and net growth index (p=0.001) was observed in the group fed with 5.0% AP. Therefore the findings of this study indicate that AP feeding may reduce the development of chemically-induced rat colon carcinogenesis.

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Connexin channel modulators and their mechanisms of action.

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Gap junction channels and hemichannels formed by the connexin family of proteins play important roles in many aspects of tissue homeostasis in the brain and in other organs. In addition, connexin channels have been proposed as pharmacological targets in the treatment of a number of human disorders. In this review, we describe the connexin-subtype selectivity and specificity of pharmacological agents that are commonly used to modulate connexin channels. We also highlight recent progress made towardtoward identifying new agents for connexin channels that act in a selective and specific manner. Finally, we discuss developing insights into possible mechanisms by which these agents modulate connexin channel function. This article is part of a Special Issue entitled 'Connexin based channels'.

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1,1-Difluoroethyl-substituted triazolothienopyrimidines as inhibitors of a human urea transport protein (UT-B): New analogs and binding model.

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The kidney urea transport protein UT-B is an attractive target for the development of small-molecule inhibitors with a novel diuretic ('urearetic') action. Previously, two compounds in the triazolothienopyrimidine scaffold (1a and 1c) were reported as UT-B inhibitors. Compound 1c incorporates a 1,1-difluoroethyl group, which affords improved microsomal stability when compared to the corresponding ethyl-substituted compound 1a. Here, a small focused library (4a-4f) was developed around lead inhibitor 1c to investigate the requirement of an amidine-linked thiophene in the inhibitor scaffold. Two compounds (4a and 4b) with nanomolar inhibitory potency (IC50≈40nM) were synthesized. Computational docking of lead structure 1c and 4a-4f into a homology model of the UT-B cytoplasmic surface suggested binding with the core heterocycle buried deep into the hydrophobic pore region of the protein.

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Greater impairment of postprandial triacylglycerol than glucose response in metabolic syndrome subjects with fasting hyperglycaemia.

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OBJECTIVE: Studies have started to question whether a specific component or combinations of metabolic syndrome (MetS) components may be more important in relation to cardiovascular disease risk. Our aim was to examine the impact of the presence of raised fasting glucose as a MetS component on postprandial lipaemia. METHODS: Men classified with the MetS underwent a sequential test meal investigation, in which blood samples were taken at regular intervals after a test breakfast (t=0 min) and lunch (t=330 min). Lipids, glucose and insulin were measured in the fasting and postprandial samples. RESULTS: MetS subjects with 3 or 4 components were subdivided into those without (n=34) and with (n=23) fasting hyperglycaemia (≥5.6mmol/l), irrespective of the combination of components. Fasting lipids and insulin were similar in the two groups, with glucose significantly higher in the men with glucose as a MetS component (P<0.001). Following the test meals, there were higher maximum concentration (maxC), area under the curve (AUC) and incremental AUC (P≤0.016) for the postprandial triacylglycerol (TAG) response in men with fasting hyperglycaemia. Greater glucose AUC (P<0.001) and insulin maxC (P=0.010) were also observed in these individuals after the test meals. Multiple regression analysis revealed fasting glucose to be an important predictor of the postprandial TAG and glucose response. CONCLUSION: Our data analysis has revealed a greater impairment of postprandial TAG than glucose response in MetS subjects with raised fasting glucose. The worsening of postprandial lipaemic control may contribute to the greater CVD risk reported in individuals with MetS component combinations which include hyperglycaemia.

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HIV Cure: Knocking on the Door.

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Although major advances in drug development and public health are helping to control the HIV/AIDS epidemic, there is a strong rationale for pursuing a more definitive cure. Several bold but unproven strategies for HIV eradication are reviewed in this issue of CPT, including novel drugs, gene therapy, and bone marrow transplantation (BMT). Early results, including one probable case of HIV eradication in a leukemia patient, are intriguing but raise many questions.

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New Diterpenes from a Godavari Mangrove, Ceriops decandra.

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Eleven new diterpenes, named decandrins A-K (1-11), including nine abietanes (1-9) and two podocarpanes (10-11), were isolated from the barks of an Indian mangrove, Ceriops decandra, collected in the mangrove swamp of Godavari estuary, Andhra Pradesh, together with four known abietanes. The structures of these compounds were established on the basis of spectroscopic data (new compounds) or comparison with data in the literature (known compounds). This is the first report of abietane and podocarpane diterpenoids from C. decandra.

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Spin-polarized transport through single-molecule magnet Mn6 complexes.

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The coherent transport properties of a device, constructed by sandwiching a Mn6 single-molecule magnet between two gold surfaces, are studied theoretically by using the non-equilibrium Green's function approach combined with density functional theory. Two spin states of such Mn6 complexes are explored, namely the ferromagnetically coupled configuration of the six Mn(III) cations, leading to the S = 12 ground state, and the low S = 4 spin state. For voltages up to 1 volt the S = 12 ground state shows a current one order of magnitude larger than that of the S = 4 state. Furthermore this is almost completely spin-polarized, since the Mn6 frontier molecular orbitals for S = 12 belong to the same spin manifold. As such the high-anisotropy Mn6 molecule appears as a promising candidate for implementing, at the single molecular level, both spin-switches and low-temperature spin-valves.

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Concentration and Strain Fields inside a Ag/Au Core-Shell Nanowire Studied by Coherent X-ray Diffraction.

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Three-dimensional coherent diffraction patterns of an isolated, single-crystalline Ag/Au core-shell nanowire were recorded at different X-ray beam energies close to the Au LIII absorption edge. Two-dimensional slices of the three-dimensional diffraction pattern, with the diffraction vector oriented perpendicular to the wire axis, were investigated in detail. In reciprocal space, facet streaks with thickness fringes were clearly observed in the two-dimensional diffraction patterns, from which the shape and size of the corresponding cross sections of the nanowire could be revealed. Comparison with simulated diffraction patterns exhibited the coherency strain field in the nanowire. During in situ annealing at temperatures which would lead to significant intermixing by volume diffusion in bulk material, according to literature data, a core-shell morphology was preserved; that is, intermixing in the nanowire was pronouncedly decelerated compared to bulk diffusion.

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Assessing the Accuracy and Performance of Implicit Solvent Models for Drug Molecules: Conformational Ensemble Approaches.

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The accuracy and performance of implicit solvent methods for solvation free energy calculations were assessed on a set of 20 neutral drug molecules. Molecular dynamics (MD) provided ensembles of conformations in water and water-saturated octanol. The solvation free energies were calculated by popular implicit solvent models based on quantum mechanical (QM) electronic densities (COSMO-RS, MST, SMD) as well as on molecular mechanical (MM) point-charge models (GB, PB). The performance of the implicit models was tested by a comparison with experimental water-octanol transfer free energies (ΔGow) by using single- and multiconformation approaches. MD simulations revealed difficulties in a priori estimation of the flexibility features of the solutes from simple structural descriptors, such as the number of rotatable bonds. An increasing accuracy of the calculated ΔGow was observed in the following order: GB1 ∼ PB < GB7 ≪ MST < SMD ∼ COSMO-RS with a clear distinction identified between MM- and QM-based models, although for the set excluding three largest molecules, the differences among COSMO-RS, MST, and SMD were negligible. It was shown that the single-conformation approach applied to crystal geometries provides a rather accurate estimate of ΔGow for rigid molecules yet fails completely for the flexible ones. The multiconformation approaches improved the performance, but only when the deformation contribution was ignored. It was revealed that for large-scale calculations on small molecules a recent GB model, GB7, provided a reasonable accuracy/speed ratio. In conclusion, the study contributes to the understanding of solvation free energy calculations for physical and medicinal chemistry applications.

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Three-dimensional plasmonic chiral tetramers assembled by DNA origami.

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Molecular chemistry offers a unique toolkit to draw inspiration for the design of artificial metamolecules. For a long time, optical circular dichroism has been exclusively the terrain of natural chiral molecules, which exhibit optical activity mainly in the UV spectral range, thus greatly hindering their significance for a broad range of applications. Here we demonstrate that circular dichroism can be generated with artificial plasmonic chiral nanostructures composed of the minimum number of spherical gold nanoparticles required for three-dimensional (3D) chirality. We utilize a rigid addressable DNA origami template to precisely organize four nominally identical gold nanoparticles into a three-dimensional asymmetric tetramer. Because of the chiral structural symmetry and the strong plasmonic resonant coupling between the gold nanoparticles, the 3D plasmonic assemblies undergo different interactions with left and right circularly polarized light, leading to pronounced circular dichroism. Our experimental results agree well with theoretical predictions. The simplicity of our structure geometry and, most importantly, the concept of resorting on biology to produce artificial photonic functionalities open a new pathway to designing smart artificial plasmonic nanostructures for large-scale production of optically active metamaterials.

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Demonstration of Efficient On-Chip Photon Transfer in Self-Assembled Optoplasmonic Networks.

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Plasmonic nanoantennas facilitate the manipulation of light fields on deeply sub-diffraction-limited length scales, but high dissipative losses in metals make new approaches for an efficient energy transfer in extended on-chip integrated plasmonic circuits mandatory. We demonstrate in this article efficient photon transfer in discrete optoplasmonic molecules comprising gold nanoparticle (NP) dimer antennas located in the evanescent field of a 2 μm diameter polystyrene bead, which served as an optical microcavity (OM). The optoplasmonic molecules were generated through a guided self-assembly strategy in which the OMs were immobilized in binding sites generated by quartz (SiO2) or silicon posts that contained plasmonic nanoantennas on their tips. Control of the post height facilitated an accurate positioning of the plasmonic antennas into the evanescent field of the whispering gallery modes located in the equatorial plane of the OM. Cy3 and Cy5.5 dyes were tethered to the plasmonic antennas through oligonucleotide spacers to act as on-chip light sources. The intensity of Cy3 was found to be increased relative to that of Cy5.5 in the vicinity of the plasmonic antennas where strongly enhanced electric field intensity and optical density of states selectively increase the excitation and emission rates of Cy3 due to spectral overlap with the plasmon. The fluorescent dyes preferentially emitted into the OM, which efficiently trapped and recirculated the photons. We experimentally determined a relative photon transfer efficiency of 44% in non-optimized self-assembled optoplasmonic molecules in this proof-of-principle study.

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The effect of inorganic salt type and concentration on hydrophilic drug loading into microspheres using the emulsion/solvent diffusion method.

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Abstract Aim: In order to avoid gastric irritation caused by tolmetin sodium (TS), gastro resistant Eudragit® S 100 microsphere formulations were prepared with the emulsion/solvent diffusion method. Materials: Considering the high water solubility of the TS molecule, the effects of the presence of inorganic salt (NaCl, NaBr and KH2PO4; 0.1 M and 1.0 M) in external phase and external phase pH on the encapsulation efficiency were evaluated. Results: Percentage yield value was found to vary between 55.8% and 72.1%. Improvement in encapsulation efficiency was determined by increasing concentrations of NaCl, NaBr and KH2PO4. The microspheres were observed to have a spherical shape and the measured particle size values varied between 52.1 and 81.5 µm. The released amounts of the drug were found to be low as the inorganic salt concentrations increased. Conclusion: Conclusively, drug release in stomach pH was significantly prevented by the microspheres prepared using Eudragit® S 100 polymer, and these formulations are considered to be a model for other orally administered drugs with similar problems.

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Development and in vitro evaluation of a nanoemulsion for transcutaneous delivery.

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Abstract Objective: The purpose of this study is to develop a nanoemulsion formulation for its use as a transcutaneous vaccine delivery system. Materials and methods: With bovine albumin-fluorescein isothiocyanate conjugate (FITC-BSA) as a vaccine model, formulations were selected with the construction of pseudo-ternary phase diagrams and a short-term stability study. The size of the emulsion droplets was furthered optimized with high-pressure homogenization. The optimized formulation was evaluated for its skin permeation efficiency. In vitro skin permeation studies were conducted with shaved BALB/c mice skin samples with a Franz diffusion cell system. Different drug concentrations were compared, and the effect of the nanoemulsion excipients on the permeation of the FITC-BSA was also studied. Results: The optimum homogenization regime was determined to be five passes at 20 000 psi, with no evidence of protein degradation during processing. With these conditions, the particle diameter was 85.2 nm ± 15.5 nm with a polydispersity index of 0.186 ± 0.026 and viscosity of 14.6 cP ± 1.2 cP. The optimized formulation proved stable for 1 year at 4 °C. In vitro skin diffusion studies show that the optimized formulation improves the permeation of FITC-BSA through skin with an enhancement ratio of 4.2 compared to a neat control solution. Finally, a comparison of the skin permeation of the nanoemulsion versus only the surfactant excipients resulted in a steady state flux of 23.44 μg/cm(2)/h for the nanoemulsion as opposed to 6.10 μg/cm(2)/h for the emulsifiers. Conclusion: A novel nanoemulsion with optimized physical characteristics and superior skin permeation compared to control solution was manufactured. The formulation proposed in this study has the flexibility for the incorporation of a variety of active ingredients and warrants further development as a transcutaneous vaccine delivery vehicle.

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Polymer-based protein engineering can rationally tune enzyme activity, pH-dependence, and stability.

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The attachment of inert polymers, such as polyethyleneglycol, to proteins has driven the emergence of a multibillion dollar biotechnology industry. In all cases, proteins have been stabilized or altered by covalently coupling the pre-existing polymer to the surface of the protein. This approach is inherently limited by a lack of exquisite control of polymer architecture, chain length, site and density of attachment. Using a novel water-soluble atom transfer radical polymerization initiator, we have grown temperature- and pH-responsive polymers from the surface of a model protein, the enzyme chymotrypsin. Poly(2-(dimethylamino)ethyl methacrylate) changes in conformation with altered temperature and pH. Growing the polymer from the surface of chymotrypsin we were able to demonstrate that changes in temperature or pH can change predictably the conformation of the polymer surrounding the enzyme, which in turn enabled the rational tailoring of enzyme activity and stability. Using what we now term "Polymer-Based Protein Engineering" we have increased the activity and stability of chymotrypsin by an order of magnitude at pH's where the enzyme is usually inactive or unstable.

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The Chemical constituents of the twigs of Ammopiptanthus nanus.

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Two new isoflavone glycosides, ammopiptanosides A and B, have been isolated from the 95% EtOH extract of the twigs of Ammopiptanthus nanus (M.Pop.) Cheng f., together with six known compounds, and their structures were characterized by spectroscopic methods and compared with the data in the literature.

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Sulfonated Polyaniline-Based Organic Electrodes for Controlled Electrical Stimulation of Human Osteosarcoma Cells.

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Electrically conducting polymers (CPs) were found to stimulate various cell types such as neurons, osteoblasts, and fibroblasts in both in vitro and in vivo studies. However, to our knowledge, no studies have been reported on the utility of CPs in stimulation of cancer or tumor cells in the literature. Here we report a facile fabrication method of self-doped sulfonated polyaniline (SPAN)-based interdigitated electrodes (IDEs) for controlled electrical stimulation of human osteosarcoma (HOS) cells. Increased degree of sulfonation was found to increase the SPAN conductivity, which in turn improved the cell attachment and cell growth without electrical stimulation. However, an enhanced cell growth was observed under controlled electrical (AC) stimulation at low applied voltage and frequency (≤800 mV and ≤1 kHz). The cell growth reached a maximum threshold at an applied voltage or frequency and beyond which pronounced cell death was observed. We believe that these organic electrodes may find utility in electrical stimulation of cancer or tumor cells for therapy and research and may also provide an alternative to the conventional metal-based electrodes.

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Three new triterpene glycosides from Ilex asprella.

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Three new sulfated triterpene glycosides, asprellanosides C-E (1-3), were isolated from the roots of Ilex asprella. Their structures were elucidated as 3β-[(2-O-sulfo-β-d-xylopyranosyl)oxy]urs-12,19(29)-diene-28-oic acid 28-β-d-glucopyranoside (1), 3β-[(2-O-sulfo-β-d-xylopyranosyl)oxy]urs-12,19-diene-28-oic acid 28-β-d-glucopyranoside (2), and 3β-[(2-O-sulfo-β-d-xylopyranosyl)oxy]urs-12,19-diene-28-oic acid (3) on the basis of the spectral and chemical methods.

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The potential of sarcospan in adhesion complex replacement therapeutics for the treatment of muscular dystrophy.

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Three adhesion complexes span the sarcolemma and facilitate critical connections between the extracellular matrix and the actin cytoskeleton: the dystrophin- and utrophin-glycoprotein complexes and α7β1 integrin. Loss of individual protein components results in a loss of the entire protein complex and muscular dystrophy. Muscular dystrophy is a progressive, lethal wasting disease characterized by repetitive cycles of myofiber degeneration and regeneration. Protein replacement therapy offers a promising approach for the treatment of muscular dystrophy. Recently, we demonstrated that sarcospan facilitates protein-protein interactions amongst the adhesion complexes and is an important therapeutic target. Here, we review current protein replacement strategies, discuss the potential benefits of sarcospan expression, and identify important experiments that must be addressed for sarcospan to move to the clinic. This article is protected by copyright. All rights reserved.

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Design, Synthesis and biological evaluation of catecholamine vehicle for studying dopaminergic system.

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Catecholamine mimetic EDTA-bis(tyramide) was synthesized and characterized by various spectroscopic techniques (NMR, Mass spectroscopy) and λem 310 nm for the excitation at 270 nm. Molecular docking studies were performed with Human Serum Albumin (HSA: PDB 1E78), showing binding pattern with amino acid residues Arg218, Arg222 and Lys444, identifies the ligand-HSA interaction for the transportation affinity of the ligand at the specific site of the target. Subsequently binding study with HSA at λex =350 nm found to be 5.847x10(4) M(-1) shows effective quenching effect. Additionally to go more insight AChE binding affinity was investigated, which shows 90% binding affinity for the 10 mM concentration. IC50 value was was found 18.60 μM for MAO-B inhibition. Finally, EDTA-bis(tyramide) labeled with (99m) Tc to investigate its in-vivo radiopharmaceutical efficiency, having 97% binding affinity with 98% radiochemical purity. In-vivo studies were carried out for (99m) Tc- EDTA-bis(tyramide) included blood kinetics showed a quick wash out from the circulation via renal route and biodistribution revealed that maximum%ID/g was found in kidney at 1h and its scintigraphy image shows 3.96% brain uptake with respect to whole body. This article is protected by copyright. All rights reserved.

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Discovery of a new bioactive molecule for neuroblastoma.

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Neuroblastoma, a common pediatric malignancy of neural crest origin, is unique in its wide spectrum of clinical and biological behavior, ranging from spontaneous regression or differentiation to rapid progression and metastasis. Overexpression of neurotrophin receptors of the tyrosine kinase (Trk) family has been identified as a major prognostic and biological factor for this disease. Novel molecules were selected using cheminformatics tools (SBVS & LBVS) and screened in cell-based assays to modulate Trk receptor activity. One compound (C390-0031) had a potent anti-proliferative activity in dose-response studies using neuroblastoma cell lines. The molecular effects of this molecule were further characterized by using cell-cycle and western blot analysis. Interestingly, despite the presence of the anchoring fragment to the Trk kinase domain composing its structure, this molecule does not inhibit TrkA like lestaurtinib, constituting a new chemical with a yet unknown mechanism of action. This article is protected by copyright. All rights reserved.

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Health benefits of seafood; Is it just the fatty acids?

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There is a considerable body of literature suggesting a wide range of health benefits associated with diets high in seafood. However, the demand for seafood across the world now exceeds that available from capture fisheries. This has created a rapidly increasing market for aquaculture products, the nutrient composition of which is dependent on feed composition. The use of fishmeal in this food chain does little to counteract the environmental impact of fisheries and so the on-going development of alternative sources is to be welcomed. Nevertheless, an in-depth understanding as to which nutrients in seafood provide benefit is required to permit the production of foods of maximal health benefit to humans. This paper reviews our current knowledge of the beneficial nutrient composition of seafood, in particular omega-3 fatty acids, selenium, taurine, vitamins D and B12, in the context of the development of environmentally sustainable aquaculture.

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Assessing caffeine intake in the United Kingdom diet.

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Caffeine occurs naturally in the leaves and seeds of many plants and is artificially added to some beverages. Consumption of caffeine has been linked to both positive and adverse health outcomes. We incorporated estimates of caffeine content (mg/100g or ml) of foods and drinks, taken from the published literature, to provide a preliminary estimate of caffeine intake for the UK population, based on data collected in the National Diet and Nutrition Survey 2008-10. Among consumers mean total caffeine intakes of adult men 19+ y were significantly greater than intakes by boys 4-10y and 11-18y (p<0.05), with the same age-related differences seen for females. 4.1% of men 19+ y and 3.8% of women 19+ y had caffeine intakes in excess of 300mg/d. The addition of caffeine to UK food composition databases will allow more detailed study of the health effects of caffeine consumption.

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Nutrients and bioactive compounds of Thai indigenous fruits.

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This study determined the nutritional potential of Thai indigenous fruits in terms of nutrients, bioactive compounds, and antioxidant activities. Three indigenous fruits were collected at two conservation areas in Kanchanaburi province, Thailand. The results showed that Phyllanthus emblica L. exhibited the highest levels of vitamin C (575±452mg/100g), total phenolics (TP) (3703±1244mGAE/100g), and antioxidant activities, as measured by DPPH, FRAP and ORAC assays. Compared to the other two fruits, Antidesma velutinosum Blume contained higher levels of most nutrients and dietary fibre (15.6±5.9g/100g), as well as carotenoids (335±98μg/100g) and phytosterols (22.1±3.9mg/100g). Spondias pinnata (L.f.) Kurz was high in total phenolics (3178±887mGAE/100g) and antioxidant activity. Moreover, high correlations were found between TP and antioxidant activities (r>0.9). These Thai indigenous fruits are potentially good sources of nutrients, bioactive compounds, and antioxidant activities. Conservation and utilisation should be promoted for food security and consumption as part of a healthy diet.

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Effect of different maize meal diets on growth and vitamin A: Case-study on chickens.

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South Africa embarked on mandatory vitamin and mineral fortification of wheat flour and maize meal in 2003 as part of a multi-faceted approach to alleviate malnutrition. However, it was reported, in 2008, that vitamin A deficiency increased despite the mandatory fortification programme. This motivates an investigation into the absorption of vitamin A as fortificant in the maize meal. Relative absorption, in chickens as the biological model, was determined by evaluating growth and vitamin A status. The weight, cumulative feed intake and liver retinol stores of chickens on different diets were measured over a 6week period. The fortified white maize meal diet was able to maintain the vitamin A status of the chickens. Poor absorption of the fortificant vitamin A is therefore not a constraint in combating vitamin A deficiency. It is in therefore also important to focus on the level of fortification delivered when consumed as a traditional prepared dish. In the traditional diet, maize porridge is often consumed with only a relish. The total fat content of the traditional meal is very low, lacking absorption enhancers.

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Voluntary food fortification with folic acid in Spain: Predicted contribution to children's dietary intakes as assessed with new food folate composition data.

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The Spanish market offers a significant number of folic acid (FA) voluntarily fortified foods. We analysed FA and (6S)-5-methyltetrahydrofolic acid ((6S)-5-CH3-H4PteGlu) content in ready-to-eat cereals (RTEC) (n=68) and cow's milk (n=25) by a previously validated affinity chromatography-HPLC method. Contribution to potential FA intakes for children aged 2-13years, was assessed using food consumption data from a representative nationwide study, folate Recommended Dietary Intakes (RDI), and Upper Levels (UL). Results showed that at all food fortification levels obtained, fortified products provided more than tenfold FA than (6S)-5-CH3-H4PteGlu. For RTEC, the high fortification level provided 6-21%, per serving, of RDI and ⩽32% of ULs at 90th percentile of RTEC consumption (P90). Milk products fortified at the higher level reached on average 54-136% of RDI per serving and only exceeded UL at P90 of milk consumption in children aged 2-5years.

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Data collection and assessment of commonly consumed foods and recipes in six geo-political zones in Nigeria: Important for the development of a National Food Composition Database and Dietary Assessment.

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A cross-sectional study was undertaken to collect and assess commonly consumed foods/recipes from the six geopolitical zones in Nigeria for the production of food composition database (FCDB) for dietary assessment. Communities used were selected using a multi-stage sampling plan. Focus group discussions, interviews, recipe documentation, food preparations and literature reviews were employed. Qualitative methods were used to analyse and present data. SWOT (strengths, weaknesses, opportunities, and threats) analysis was used to evaluate the project. A total of 322 recipes were collected out of which 110 were soups. Food consumption patterns across the geographical zones were found to be changing. Variations in recipes and methods of preparation of similar foods were observed. Factors to be considered in the development of a country-specific FCDB were identified. There were challenges with the use of values reported in literature for Nigerian foods. The study justifies the need for a country-specific FCDB that will include traditional recipes.

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Dietary fibre fractions in cereal foods measured by a new integrated AOAC method.

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The reliable determination of soluble, insoluble and total dietary fibre in baked goods and cereal flours is an important issue for research, nutritional labelling and marketing. We compared total dietary fibre (TDF) contents of selected cereal based foods determined by AOAC Method 991.43 and the new AOAC Method 2009.01. Fifteen bread and bakery products were included in the study. Our results showed that TDF values of cereal products determined by AOAC Method 2009.01 were always significantly higher than those determined by AOAC Method 991.43. This was explained by the inclusion of low molecular weight soluble fibre fractions and resistant starch fractions in the TDF measurement by AOAC 2009.01. This documents that nutritional labelling of cereal products poses the challenge how to update TDF data in nutrient databases in a reasonable time with an acceptable expenditure.

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Total nitrogen vs. amino-acid profile as indicator of protein content of beef.

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Biosynthetic conclusions from the functional dissection of oxygenases for biosynthesis of actinorhodin and related streptomyces antibiotics.

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Actinorhodin (ACT) produced by Streptomyces coelicolor A3(2) belongs to the benzoisochromanequinone (BIQ) class of antibiotics. ActVA-ORF5, a flavin-dependent monooxygenase (FMO) essential for ACT biosynthesis, forms a two-component enzyme system in combination with a flavin:NADH oxidoreductase, ActVB. The genes for homologous two-component FMOs are found in the biosynthetic gene clusters for two other BIQs, granaticin (GRA) and medermycin (MED), and a closely related antibiotic, alnumycin (ALN). Our functional analysis of these FMOs (ActVA-ORF5, Gra-ORF21, Med-ORF7, and AlnT) in S. coelicolor unambiguously demonstrated that ActVA-ORF5 and Gra-ORF21 are bifunctional and capable of both p-quinone formation at C-6 in the central ring and C-8 hydroxylation in the lateral ring, whereas Med-ORF7 catalyzes only p-quinone formation. No p-quinone formation on a BIQ substrate was observed for AlnT, which is involved in lateral p-quinone formation in ALN.

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2-(1H-Pyrazol-4-yl)acetic acids as CRTh2 antagonists.

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High throughput screening identified the pyrazole-4-acetic acid substructure as CRTh2 receptor antagonists. Optimisation of the compounds uncovered a tight SAR but also identified some low nanomolar inhibitors.

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Genome-wide Analysis Reveals TET- and TDG-Dependent 5-Methylcytosine Oxidation Dynamics.

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TET dioxygenases successively oxidize 5-methylcytosine (5mC) in mammalian genomes to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). 5fC/5caC can be excised and repaired to regenerate unmodified cytosines by thymine-DNA glycosylase (TDG) and base excision repair (BER) pathway, but it is unclear to what extent and at which part of the genome this active demethylation process takes place. Here, we have generated genome-wide distribution maps of 5hmC/5fC/5caC using modification-specific antibodies in wild-type and Tdg-deficient mouse embryonic stem cells (ESCs). In wild-type mouse ESCs, 5fC/5caC accumulates to detectable levels at major satellite repeats but not at nonrepetitive loci. In contrast, Tdg depletion in mouse ESCs causes marked accumulation of 5fC and 5caC at a large number of proximal and distal gene regulatory elements. Thus, these results reveal the genome-wide view of iterative 5mC oxidation dynamics and indicate that TET/TDG-dependent active DNA demethylation process occurs extensively in the mammalian genome.

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Synthesis and antiproliferative evaluation of piperazine-1-carbothiohydrazide derivatives of indolin-2-one.

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