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Genetic correlate of cognitive training response in schizophrenia.

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Hepatic ATGL knockdown uncouples glucose intolerance from liver TAG accumulation.

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Adipose triglyceride lipase (ATGL) is the predominant triacylglycerol (TAG) hydrolase in mammals; however, the tissue-specific effects of ATGL outside of adipose tissue have not been well characterized. Hence, we tested the contribution of hepatic ATGL on mediating glucose tolerance and insulin action. Glucose or insulin tolerance tests and insulin signaling were performed in C57BL/6 mice administered control (nongene specific shRNA) or Atgl shRNA adenoviruses. Glucose and lipid metabolism assays were conducted in primary hepatocytes isolated from mice transduced with control or Atgl shRNA adenoviruses. Knocking down hepatic ATGL completely abrogated the increase in serum insulin following either 1 or 12 wk of feeding a high-fat (HF) diet despite higher hepatic TAG content. Glucose tolerance tests demonstrated that ATGL knockdown normalized glucose tolerance in HF-diet-fed mice. The observed improvements in glucose tolerance were present despite unaltered hepatic insulin signaling and increased liver TAG. Mice with suppressed hepatic ATGL had reduced hepatic glucose production in vivo, and hepatocytes isolated from Atgl shRNA-treated mice displayed a 26% decrease in glucose production and a 38% increase in glucose oxidation compared to control cells. Taken together, these data suggest that hepatic ATGL knockdown enhances glucose tolerance by increasing hepatic glucose utilization and uncouples impairments in insulin action from hepatic TAG accumulation.

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Inference on population histories by approximating infinite alleles diffusion.

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Reconstruction of the past is an important task of evolutionary biology. It takes place at different points in a hierarchy of molecular variation, including genes, individuals, populations, and species. Statistical inference about population histories has recently received considerable attention, following the development of computational tools to provide tractable approaches to this very challenging problem. Here, we introduce a likelihood-based approach which generalizes a recently developed model for random fluctuations in allele frequencies based on an approximation to the neutral Wright-Fisher diffusion. Our new framework approximates the infinite alleles Wright-Fisher model and uses an implementation with an adaptive Markov chain Monte Carlo algorithm. The method is especially well suited to data sets harboring large population samples and relatively few loci for which other likelihood-based models are currently computationally intractable. Using our model, we reconstruct the global population history of a major human pathogen, Streptococcus pneumoniae. The results illustrate the potential to reach important biological insights to an evolutionary process by a population genetics approach, which can appropriately accommodate very large population samples.

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Crosslinked linear polyethylenimine enhances delivery of DNA to the cytoplasm.

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Crosslinked polyethylenimines (PEIs) have been frequently examined over the past decade since they can maintain the transfection efficiency of commercially available, 25k branched PEI, but exhibit less cytotoxicity. The argument is often made that the degradability of such polymers, generally synthesized with either disulfide or hydrolytically degradable crosslinkers, is critical to the high efficiency and low toxicity of the system. In this work, we present a crosslinked linear PEI (xLPEI) system in which either disulfide-responsive or non-degradable linkages are incorporated. As with previous systems, strong transfection efficiency in comparison with commercial standards was achieved with low cytotoxicity. However, these properties were shown to be present when either the degradable or non-degradable crosslinker was used. Uncomplexed polymer was demonstrated to be the critical factor determining transfection efficiency for these polymers, mediating efficient endosomal escape without signs of cell membrane damage. While several crosslinked PEI systems in the literature have demonstrated the effect of the disulfide moiety, this work demonstrates that disulfide-mediated unpackaging may not be as important as conventionally thought for some PEI systems.

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Molecular phylogeny of North American Branchiobdellida (Annelida: Clitellata).

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Branchiobdellidans, or crayfish worms, are ectosymbiotic clitellate annelids associated primarily with freshwater crayfishes. The main objectives of our study were to infer a molecular phylogeny for the North American Branchiobdellida, examine its congruence with morphology-based hypotheses of relationships at the subfamily and genus level, and use our dataset to assess consistency of GenBank-archived branchiobdellidan sequences. We used nucleotide sequence data from two mtDNA genes (COI and 16S rDNA) and three nuclear genes (28S rDNA, 18S rDNA, and ITS1) to estimate phylogenetic relationships among 47 described and one undescribed species of Branchiobdellida. We recovered a monophyletic branchiobdellidan clade with generally short branch lengths, suggesting that a large portion of the taxon has likely undergone a recent and rapid radiation in North America. Results from our phylogenetic analyses indicate that current taxonomic groupings are largely unsupported by the molecular data. All four subfamilies are either paraphyletic or polyphyletic, and only three of seven sampled non-monotypic genera were monophyletic. We found a high rate (49%) of inconsistency in GenBank-archived sequences, over 70% of which can be attributed to field- or laboratory-based error.

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Evidence for substrate-dependent inhibition profiles for human liver aldehyde oxidase.

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The goal of this study was to provide a reasonable assessment of how probe substrate selection may impact the results of in vitro aldehyde oxidase (AO) inhibition experiments. Here, we used a previously studied set of seven known AO inhibitors to probe the inhibition profile of a pharmacologically relevant substrate N-[(2-dimethylamino)ethyl]acridine-4-carboxamide (DACA). DACA oxidation in human liver cytosol was characterized with a measured V(max) of 2.3 ± 0.08 nmol product · min(-1) · mg(-1) and a K(m) of 6.3 ± 0.8 µM. The K(ii) and K(is) values describing the inhibition of DACA oxidation by the panel of seven inhibitors were tabulated and compared with previous findings with phthalazine as the substrate. In every case, the inhibition profile shifted to a much less uncompetitive mode of inhibition for DACA relative to phthalazine. With the exception of one inhibitor, raloxifene, this change in inhibition profile seems to be a result of a decrease in the uncompetitive mode of inhibition (an affected K(ii) value), whereas the competitive mode (K(is)) seems to be relatively consistent between substrates. Raloxifene was found to inhibit competitively when using DACA as a probe, and a previous report showed that raloxifene inhibited uncompetitively with other substrates. The relevance of these data to the mechanistic understanding of aldehyde oxidase inhibition and potential implications on drug-drug interactions is discussed. Overall, it appears that the choice in substrate may be critical when conducting mechanistic inhibition or in vitro drug-drug interactions prediction studies with AO.

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Dual imaging and photoactivated nanoprobe for controlled cell tracking.

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A photoactivated nanoprobe for cell labeling and tracking is demonstrated. The nanoprobe enables all targeted cells to be imaged (at 680 nm) as well as specific cells to be photoactivated using 405 nm light. Photoactivated cells can then be tracked (at 525 nm) spatiotemporally in a separate channel over prolonged periods.

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Comparison of emetic potencies of the 8-ketotrichothecenes deoxynivalenol, 15-acetyldeoxynivalenol, 3-acetyldeoxynivalenol, fusarenon X, and nivalenol.

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Although the acute toxic effects of trichothecene mycotoxin deoxynivalenol (DON or vomitoxin), a known cause of human food poisoning, have been well characterized in several animal species, much less is known about closely related 8-ketotrichothecenes that similarly occur in cereal grains colonized by toxigenic fusaria. To address this, we compared potencies of DON, 15-acetyldeoxynivalenol (15-ADON), 3-acetyldeoxynivalenol (3-ADON), fusarenon X (FX), and nivalenol (NIV) in the mink emesis model following intraperitoneal (ip) and oral administration. All five congeners dose-dependently induced emesis by both administration methods. With increasing doses, there were marked decreases in latency to emesis with corresponding increases in emesis duration and number of emetic events. The effective doses resulting in emetic events in 50% of the animals for ip exposure to DON, 15-ADON, 3-ADON, FX, and NIV were 80, 170, 180, 70, and 60 µg/kg bw, respectively, and for oral exposure, they were 30, 40, 290, 30, and 250 µg/kg bw, respectively. The emetic potency of DON determined here was comparable to that reported in analogous studies conducted in pigs and dogs, suggesting that the mink is a suitable small animal model for investigating acute trichothecene toxicity. The use of a mouse pica model, based on the consumption of kaolin, was also evaluated as a possible surrogate for studying emesis but was found unsuitable. From a public health perspective, comparative emetic potency data derived from small animal models such as the mink should be useful for establishing toxic equivalency factors for DON and other trichothecenes.

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SiC-CNT composite prepared by electrophoretic codeposition and the polymer infiltration and pyrolysis process.

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The paper reports on the successful anodic codeposition of submicrometer SiC powder and multiwalled carbon nanotubes from aqueous suspensions to form SiC-CNT composites. On the basis of the comprehensive analysis of the aqueous suspensions with different pHs, solids contents, and CNT contents, optimal conditions for deposition were determined. Besides having the necessary high absolute value of the ζ-potential, the suspensions that resulted in firm deposits were characterized by limited conductivity (<1 mS/cm). Lowering of suspension conductivity was achieved either by dilution of the suspension or by dialysis of the as-received CNT suspension with high intrinsic conductivity. Selected SiC-CNT deposits were further densified by use of the polymer infiltration and pyrolysis process.

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Three-finger toxins, a deadly weapon of elapid venom--milestones of discovery.

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Three-finger toxins (TFTs) are the main venom components of snakes from Elapidae family. Amino acid sequences of more than five hundreds TFTs are determined; these toxins form one of the largest protein families present in snake venoms. The first TFT α-bungarotoxin was isolated almost half a century ago and so far it remains a valuable tool in the study of nicotinic acetylcholine receptors. TFTs possess diverse biological activities; for example, α-neurotoxins bind specifically with high affinity to nicotinic acetylcholine receptors, while cytotoxins induce non-specific lysis in great variety of cells. These toxins are widely used as instruments in different branches of life sciences. In this review the main landmarks in TFT study are considered. These are the discovery and isolation of TFTs, determination of their structure and mode of action as well as evolution and relationship within the family.

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Bioconversion of quercetin and rutin and the cytotoxicity activities of the transformed products.

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Quercetin and rutin are well-know flavonoids. In spite of this, the comprehension of their metabolism is still incomplete. In this work, the cytotoxic activity of quercetin and rutin and its metabolites produced by metabolism of filamentous fungi was investigated. Flavonoids metabolism was monitored by HPLC and LC-MS. Both flavonoids were extensively metabolized. Quercetin was converted into metabolite methylquercetin (2) and quercetin glucuronide (3) and rutin into metabolite rutin sulphate (5), methylrutin (6) and rutin glucuronide (7). Cytotoxic effects of rutin, quercetin and its metabolites were measured by MTT tetrazolium reduction test and the trypan blue exclusion assay on HL-60 leukemic cells. The results showed similar concentration-dependent cytotoxic effect for rutin and rutin sulphate (5), while no cytotoxic effect was detected with the metabolites 6 and 7. In relation to the quercetin and its metabolites the results showed that all compounds have a similar concentration-dependent inhibitory effect on HL-60 cells. These findings corroborate the literature, showing that bioconversion is a useful strategy for production of biological active metabolites.

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Selective inhibitory effects of mollugin on CYP1A2 in human liver microsomes.

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A 90-day feeding study of glyphosate-tolerant maize with the G2-aroA gene in Sprague-Dawley rats.

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Maize is not only a staple food crop but also an important raw material for feed and industry; however, the threat of weeds leads to a serious decline in its output and quality. The G2-aroA gene confers glyphosate herbicide tolerance to crops. In this study, the food safety of genetically modified (GM), glyphosate-tolerant maize with the G2-aroA gene was evaluated in a 90-day feeding study in Sprague-Dawley (SD) rats. Maize grain from GM or non-GM isogenic control lines were separately formulated into rodent diets at concentrations of 12.5% (low level), 25% (middle level), and 50% (high level). An additional group of rats were fed a commercialized diet as a control. The toxicological response variables, including body weights, food consumption, serum biochemistry, hematology, and absolute and relative organ weights, were compared between rats fed GM maize and those fed non-GM maize after consumption of test diets for 90days. In addition, gross and microscopic pathology were conducted among treatment groups. No adverse effects related to the consumption of GM maize were detected in the subchronic feeding study. These results indicated that the GM glyphosate-tolerant maize was as safe and nutritious as conventional maize.

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Characterization of acetylcholinesterase in Hong Kong oyster (Crassostrea hongkongensis) from South China Sea.

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Acetylcholinesterase (AChE) activity has been used to evaluate the exposure of mollusk bivalves to organophosphates, carbamate pesticides, and heavy metals. Crassostrea hongkongensis is a Hong Kong endemic oyster, and has a high commercial value along the coastal area of South China. The use of this species as a bio-indicator of the marine environment, and the use of AChE activity measurements in tissues of C. hongkongensis require prior characterization of AChE in this species. Here, we report that gill tissue contains the highest AChE activity in C. hongkongensis, and that the molecular form of AChE is most likely to be a dimeric form. In addition, the effect of the pesticide acephate on AChE activity in the gill of C. hongkongensis was analyzed, and the mean inhibition concentration (IC50) value was determined. This study suggests that AChE activity in the gill tissue of C. hongkongensis might be used as a biomarker in monitoring organophosphate contamination in the marine fauna of South China.

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-116A and K BCHE gene variants associated with obesity and hypertriglyceridemia in adolescents from Southern Brazil.

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Butyrylcholinesterase (BChE) has been associated to body mass index (BMI), weight, cholesterol and triglyceride levels. -116A (rs1126680) and K (A539T, 1615A, rs1803274) BCHE gene variants had previously been associated to BChE activity, weight and BMI variance in adults. The present study examined -116A and K variants, BChE activity, anthropometric and biochemical variables associated with obesity in adolescents (120 obese and 150 non-obese from Curitiba, Brazil). Both -116A and K variants were found with significantly lower frequencies (p<0.05) in obese adolescents when compared with non-obese adolescents and with the general population. Mean BChE activity (KU/L) was significantly higher in obese adolescents when compared with non-obese adolescents and with the general population. Analyzing only the obese adolescents, it was found that carriers of the -116A variant showed lower BChE activity and higher triglyceride levels than homozygotes for the usual allele. Indeed, obese carriers of the -116A variant had triglyceride levels considered high according to reference values for serum triglycerides in Brazilian adolescents. These results show: (1) a protective effect of -116A and K variants on juvenile obesity risk, suggesting a role for the BCHE gene on juvenile onset obesity different from that observed on adult onset obesity and (2) an association of the -116A variant with hypertriglyceridemia in obese adolescents probably because of its effect on lowering BChE activity and consequently diminishing the enzyme capability of maintaining homeostasis on lipid metabolism during the metabolic stress caused by obesity.

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Plants as a source of butyrylcholinesterase variants designed for enhanced cocaine hydrolase activity.

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Cocaine addiction affects millions of people with disastrous personal and social consequences. Cocaine is one of the most reinforcing of all drugs of abuse, and even those who undergo rehabilitation and experience long periods of abstinence have more than 80% chance of relapse. Yet there is no FDA-approved treatment to decrease the likelihood of relapse in rehabilitated addicts. Recent studies, however, have demonstrated a promising potential treatment option with the help of the serum enzyme butyrylcholinesterase (BChE), which is capable of breaking down naturally occurring (-)-cocaine before the drug can influence the reward centers of the brain or affect other areas of the body. This activity of wild-type (WT) BChE, however, is relatively low. This prompted the design of variants of BChE which exhibit significantly improved catalytic activity against (-)-cocaine. Plants are a promising means to produce large amounts of these cocaine hydrolase variants of BChE, cheaply, safely with no concerns regarding human pathogens and functionally equivalent to enzymes derived from other sources. Here, in expressing cocaine-hydrolyzing mutants of BChE in Nicotiana benthamiana using the MagnICON virus-assisted transient expression system, and in reporting their initial biochemical analysis, we provide proof-of-principle that plants can express engineered BChE proteins with desired properties.

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Experimental tooth movement-induced osteoclast activation is regulated by sympathetic signaling.

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Experimental tooth movement (ETM) changes the distribution of sensory nerve fibers in periodontal ligament and the bone architecture through the stimulation of bone remodeling. As the sympathetic nervous system is involved in bone remodeling, we examined whether ETM is controlled by sympathetic signaling or not. In male mice, elastic rubber was inserted between upper left first molar (M1) and second molar (M2) for 3 or 5 days. Nerve fibers immunoreactive for not only sensory neuromarkers, such as calcitonin gene-related peptide (CGRP), but also sympathetic neuromarkers, such as tyrosine hydroxylase (TH) and neuropeptide Y (NPY) were increased in the periodontal ligament during ETM. To elucidate the effect of the sympathetic signal mediated by ETM, mice were intraperitoneally injected with a β-antagonist, propranolol (PRO: 20 μg/g/day), or a β-agonist, isoproterenol (ISO: 5 μg/g/day) from 7 days before ETM. PRO treatment suppressed the amount of tooth movement by 12.9% in 3-day ETM and by 32.2% in 5-day ETM compared with vehicle treatment. On the other hand, ISO treatment increased it. Furthermore, ETM remarkably increased the osteoclast number on the bone surface (alveolar socket) (Oc.N/BS) in all drug treatments. PRO treatment suppressed Oc.N/BS by 39.4% in 3-day ETM, while ISO treatment increased it by 32.1% in 3-day ETM compared with vehicle treatment. Chemical sympathectomy using 6-hydroxydopamine (6-OHDA: 250 μg/g) showed results similar to those for PRO treatment in terms of both the amount of tooth movement and osteoclast parameters. Our data showed that blockade of sympathetic signaling inhibited the tooth movement and osteoclast increase induced by ETM, and stimulation of sympathetic signaling accelerated these responses. These data suggest that the mechano-adaptive response induced by ETM is controlled by sympathetic signaling through osteoclast activation.

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Chronic toxicity of tire and road wear particles to water- and sediment-dwelling organisms.

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Tire and road wear particles (TRWP) consist of a complex mixture of rubber, and pavement released from tires during use on road surfaces. Subsequent transport of the TRWP into freshwater sediments has raised some concern about the potential adverse effects on aquatic organisms. Previous studies have shown some potential for toxicity for tread particles, however, toxicity studies of TRWP collected from a road simulator system revealed no acute toxicity to green algae, daphnids, or fathead minnows at concentrations up to 10,000 mg/kg under conditions representative of receiving water bodies. In this study, the chronic toxicity of TRWP was evaluated in four aquatic species. Test animals were exposed to whole sediment spiked with TRWP at concentrations up to 10,000 mg/kg sediment or elutriates from spiked sediment. Exposure to TRWP spiked sediment caused mild growth inhibition in Chironomus dilutus but had no adverse effect on growth or reproduction in Hyalella azteca. Exposure to TRWP elutriates resulted in slightly diminished survival in larval Pimephales promelas but had no adverse effect on growth or reproduction in Ceriodaphnia dubia. No other endpoints in these species were affected. These results, together with previous studies demonstrating no acute toxicity of TRWP, indicate that under typical exposure conditions TRWP in sediments pose a low risk of toxicity to aquatic organisms.

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Levothyroxine replacement therapy with vitamin E supplementation prevents oxidative stress and cognitive deficit in experimental hypothyroidism.

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Hypothyroidism has a variety of adverse effects on cognitive function. The treatment of levothyroxine alone cannot restore cognitive defects of hypothyroid patients. Antioxidant vitamin E supplementation could be useful in disturbances which are associated with oxidative stress and could effectively slow the progression of Alzheimer disease. Thus, the purpose of this study was to evaluate oxidative stress status of the serum and hippocampus in hypothyroidism and to examine the effects of levothyroxine replacement therapy with vitamin E supplementation on cognitive deficit. Sprague-Dawley rats were randomly divided into five groups: control group, PTU group, PTU + Vit E group, PTU + L-T4 group, and PTU + L-T4 + Vit E group. Serum and hippocampus malondialdehyde (MDA) levels were determined using the thiobarbituric-acid reactive substances method. Serum and hippocampus superoxide dismutase (SOD) levels were determined by measuring its ability to inhibit the photoreduction of nitroblue tetrazolium. Learning and memory was assessed by Morris water maze test. In the present study, we found that the rats of PTU + Vit E group spent less time to find the platform on days 2, 3, 4, and 5 than the PTU group. Moreover, the rats of PTU + L-T4 + Vit E group spent less time to find the platform on days 4 and 5 than the PTU + L-T4 group. The time spent in the target quadrants was measured in the probe test and no difference was observed in all groups. Oxidative damage has been observed in the serum and hippocampus of hypothyroidism rat. SOD levels of serum and hippocampus tissue were significantly increased and MDA levels were significantly decreased in the PTU + Vit E and PTU + L-T4 + Vit E groups than the PTU and PTU + L-T4 groups. Therefore, these findings indicate that levothyroxine replacement therapy with vitamin E supplementation may ameliorate cognitive deficit in PTU-induced hypothyroidism through the decrease of oxidative stress status.

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Gold nanoprisms as optoacoustic signal nanoamplifiers for in vivo bioimaging of gastrointestinal cancers.

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Early detection of cancer greatly increases the chances of a simpler and more effective treatment. Traditional imaging techniques are often limited by shallow penetration, low sensitivity, low specificity, poor spatial resolution or the use of ionizing radiation. Hybrid modalities, like optoacoustic imaging, an emerging molecular imaging modality, contribute to improving most of these limitations. However, this imaging method is hindered by relatively low signal contrast. Here, gold nanoprisms (AuNPrs) are used as signal amplifiers in multispectral optoacoustic tomography (MSOT) to visualize gastrointestinal cancer. PEGylated AuNPrs are successfully internalized by HT-29 gastrointestinal cancer cells in vitro. Moreover, the particles show good biocompatibility and exhibit a surface plasmon band centered at 830 nm, a suitable wavelength for optoacoustic imaging purposes. These findings extend well to an in vivo setting, in which mice are injected with PEGylated AuNPrs in order to visualize tumor angiogenesis in gastrointestinal cancer cells. Overall, both our in vitro and in vivo results show that PEGylated AuNPrs have the capacity to penetrate tumors and provide a high-resolution signal amplifier for optoacoustic imaging. The combination of PEGylated AuNPrs and MSOT represents a significant advance for the in vivo imaging of cancers.

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Arterial stiffness is inversely related to plasma adiponectin levels in young normotensive patients with type 1 diabetes.

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OBJECTIVE This study investigated the association between arterial stiffness and plasma adiponectin in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS Participants were normotensive patients with type 1 diabetes who were up to age 40 years. Subjects on statins with macrovascular disease or overt nephropathy were excluded. Large artery stiffness was assessed by measurement of carotid-femoral pulse wave velocity (PWV), whereas plasma adiponectin was measured by radioimmunoassay. RESULTS Data from 80 patients (age 27.1 ± 6.1 years, BMI 24.2 ± 3.1 kg/m(2), HbA(1c) 7.5 ± 1.6%, 39 men, adiponectin 13.9 ± 6.7 μg/mL, and PWV 5.6 ± 0.9 m/s) were analyzed. Log adiponectin inversely correlated with age-adjusted PWV (r = -0.291, P = 0.009) and waist circumference (r = -0.427, P < 0.001). In a fully adjusted model, age, expiration/inspiration index, and log adiponectin were independently associated with PWV, explaining 39.6% of its variance. CONCLUSIONS Arterial stiffness is inversely related to adiponectin concentration in young patients with type 1 diabetes without major complications.

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Effect of ifenprodil on GluN1/GluN2B N-methyl-D-aspartate receptor gating.

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Ifenprodil is an allosteric inhibitor of GluN1/GluN2B N-methyl-D-aspartate receptors. Despite its widespread use as a prototype for drug development and a subtype-selective tool for physiologic experiments, its precise effect on GluN1/GluN2B gating is yet to be fully understood. Interestingly, recent crystallographic evidence identified that ifenprodil, unlike zinc, binds at the interface of the GluN1/GluN2B amino terminal domain dimer by an induced-fit mechanism. To delineate the effect of this unique binding on GluN1/GluN2B receptor gating, we recorded steady-state currents from cell-attached and outside-out patches. At pH 7.9 in cell-attached patches, ifenprodil increased the occupancy of the long-lived shut conformations, thereby reducing the open probability of the receptor with no change in the mean open time. In addition, ifenprodil selectively affected the area of shut time constants, but not the time constants themselves. Kinetic analyses suggested that ifenprodil prevents the transition of the receptor to an open state and increases its dwell time in an intrinsically occurring closed conformation or desensitized state. We found distinct differences in the action of ifenprodil at GluN1/GluN2B in comparison with previous studies on the effect of zinc on GluN1/GluN2A gating, which may arise due to their unique binding sites. Our data also uncover the potential pH-dependent action of ifenprodil on gating. At a low pH (pH 7.4), but not pH 7.9, ifenprodil reduces the mean open time of GluN1/GluN2B receptors, which may be responsible for its usefulness as a context-dependent inhibitor in conditions like ischemia and stroke, when the pH of the extracellular milieu becomes acidic.

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Developmental immunotoxicity of ethanol in an extended one-generation reproductive toxicity study.

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The susceptibility of developing immune system to chemical disruption warrants the assessment of immune parameters in reproductive and developmental testing protocols. In this study, a wide range of immune endpoints was included in an extended one-generation reproduction toxicity study (EOGRTS) design to determine the relative sensitivity of immune and developmental parameters to ethanol (EtOH), a well-known developmental toxicant with immunomodulatory properties. Adult Wistar rats were exposed to EtOH via drinking water (0, 1.5, 4, 6.5, 9, 11.5 and 14 % (w/v EtOH)) during premating, mating, gestation and lactation and continuation of exposure of the F(1) from weaning until killed. Immune assessments were performed at postnatal days (PNDs) 21, 42 and 70. Keyhole limpet hemocyanin (KLH)-specific immune responses were evaluated following subcutaneous immunizations on PNDs 21 and 35. EtOH exposure affected innate as well as adaptive immune responses. The most sensitive immune parameters included white blood cell subpopulations, ConA-stimulated splenocyte proliferation, LPS-induced NO and TNF-α production by adherent splenocytes and KLH-specific immune responses. Most parameters showed recovery after cessation of EtOH exposure after weaning in the 14 % exposure group. However, effects on LPS-induced NO and TNF-α production by adherent splenocytes and KLH-specific parameters persisted until PND 70. The results demonstrate the relative sensitivity to EtOH of especially functional immune parameters and confirm the added value of immune parameters in the EOGRTS. Furthermore, this study identified an expanded KLH-specific parameter set and LPS-induced NO and TNF-α production by adherent splenocytes as valuable parameters that can provide additional information on functional immune effects.

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Lack of enantioselectivity in the SULT1A3-catalyzed sulfoconjugation of normetanephrine enantiomers: an in vitro and computational study.

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(1R)-Normetanephrine is the natural stereoisomeric substrate for sulfotransferase 1A3 (SULT1A3)-catalyzed sulfonation. Nothing appears known on the enantioselectivity of the reaction despite its potential significance in the metabolism of adrenergic amines and in clinical biochemistry. We confronted the kinetic parameters of the sulfoconjugation of synthetic (1R)-normetanephrine and (1S)-normetanephrine by recombinant human SULT1A3 to a docking model of each normetanephrine enantiomer with SULT1A3 and the 3'-phosphoadenosine-5'-phosphosulfate cofactor on the basis of molecular modeling and molecular dynamics simulations of the stability of the complexes. The K(M), V(max), and k(cat) values for the sulfonation of (1R)-normetanephrine, (1S)-normetanephrine, and racemic normetanephrine were similar. In silico models were consistent with these findings as they showed that the binding modes of the two enantiomers were almost identical. In conclusion, SULT1A3 is not substrate-enantioselective toward normetanephrine, an unexpected finding explainable by a mutual adaptability between the ligands and SULT1A3 through an "induced-fit model" in the catalytic pocket.

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Bonding and electronic transport properties of fullerene and fullerene derivatives in break-junction geometries.

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Fullerenes are considered anchoring groups for molecular electronics due to a large contact area and their affinity for noble metals. The conductances of fullerene-terminated molecules, however, are found to be even lower than for thiol termination. The effects of weak molecule-metal coupling and symmetry breaking are studied by transport measurements of C(60) and functionalized C(60). The results demonstrate highy efficient contacts between Au and C(60), despite of deposition from solution.

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Ocular perfusion pressure and ocular blood flow in glaucoma.

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Glaucoma is a progressive optic neuropathy of unknown origin. It has been hypothesized that a vascular component is involved in glaucoma pathophysiology. This hypothesis has gained support from studies showing that reduced ocular perfusion pressure is a risk factor for the disease. The exact nature of the involvement is, however, still a matter of debate. Based on recent evidence we propose a model including primary and secondary insults in glaucoma. The primary insult appears to happen at the optic nerve head. Increased intraocular pressure and ischemia at the post-laminar optic nerve head affects retinal ganglion cell axons. Modulating factors are the biomechanical properties of the tissues and cerebrospinal fluid pressure. After this primary insult retinal ganglion cells function at a reduced energy level and are sensitive to secondary insults. These secondary insults may happen if ocular perfusion pressure falls below the lower limit of autoregulation or if neurovascular coupling fails. Evidence for both faulty autoregulation and reduced hyperemic response to neuronal stimulation has been provided in glaucoma patients. The mechanisms appear to involve vascular endothelial dysfunction and impaired astrocyte-vessel signaling. A more detailed understanding of these pathways is required to direct neuroprotective strategies via the neurovascular pathway.

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The long road of research on snake venom serine proteinases.

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It has long been recognized that snake venom serine proteinases (SVSPs) affect various physiological functions including blood coagulation, fibrinolysis, blood pressure and platelet aggregation. Therefore, SVSPs have been used as refined tools to study molecular mechanisms involved in the activation of key factors that control hemostasis and as therapeutic agents in various thrombotic and hemostatic conditions. The aim of this review is to highlight the state of our knowledge on the advances made in SVSP research since the 18th century. It includes the personal accounts of some distinguished scientists that addressed specific problems and contributed to advance the field.

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A brief review of the scientific history of several lesser-known snake venom proteins: l-amino acid oxidases, hyaluronidases and phosphodiesterases.

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When considering the proteins and toxins in snake venom one's thoughts generally migrate to the proteinases, neurotoxins and phospholipases since these families of proteins are comprised by many of the toxins found in venom. However as modern proteomic and transcriptomic venom research has abundantly shown snake venoms are complex and containing numerous families of protein beyond the "big three". In this brief review we will discuss three of the lesser discussed proteins typically found in snake venoms: l-amino acid oxidases (LAAO); hyaluronidases and phosphodiesterases. These proteins have long been known to be part of many venoms' proteomes with reports appearing in the literature as early as 1944 for LAAO, 1947 for hyaluronidase (spreading factor), and 1932 for venom phosphodiesterase. These are more or less contemporary with the first reports (circa 1950) on snake venom proteases. Thus, the relatively modest literature on these snake venom proteins stems not from lack of early discovery but rather more likely to their ostensibly minor role in snake venom pathophysiology. In this review we will provide an overview of the experimental history of these venom proteins, their biochemical and structural features and their role in snake venom toxinology with the aim of bringing a fuller, more comprehensive, understanding of the history of laboratory research on snake venoms. In addition, there are some comments on these proteins from investigators who were actively engaged in their investigation.

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Functional and structural interaction of (-)-reboxetine with the human α4β2 nicotinic acetylcholine receptor.

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The interaction of the selective norepinephrine reuptake inhibitor (-)-reboxetine with the human α4β2 nicotinic acetylcholine receptor (nAChR) in different conformational states was studied by several functional and structural approaches. Patch-clamp and Ca(2+)-influx results indicate that (-)-reboxetine does not activate hα4β2 nAChRs via interaction with the orthosteric sites, but inhibits agonist-induced hα4β2 activation by a noncompetitive mechanism. Consistently, the results from the electrophysiology-based functional approach suggest that (-)-reboxetine may act via open channel block; therefore, it is capable of producing a use-dependent type of inhibition of the hα4β2 nAChR function. We tested whether (-)-reboxetine binds to the luminal [(3)H]imipramine site. The results indicate that, although (-)-reboxetine binds with low affinity to this site, it discriminates between the resting and desensitized hα4β2 nAChR ion channels. Patch-clamp results also indicate that (-)-reboxetine progressively inhibits the hα4β2 nAChR with two-fold higher potency at the end of one-second application of agonist, compared with the peak current. The molecular docking studies show that (-)-reboxetine blocks the ion channel at the level of the imipramine locus, between M2 rings 6' and 14'. In addition, we found a (-)-reboxetine conformer that docks in the helix bundle of the α4 subunit, near the middle region. According to molecular dynamics simulations, (-)-reboxetine binding is stable for both sites, albeit less stable than imipramine. The interaction of these drugs with the helix bundle might alter allostericaly the functionality of the channel. In conclusion, the clinical action of (-)-reboxetine may be produced (at least partially) by its inhibitory action on hα4β2 nAChRs.

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Proteins with an alpha/beta hydrolase fold: Relationships between subfamilies in an ever-growing superfamily.

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Alpha/beta hydrolases function as hydrolases, lyases, transferases, hormone precursors or transporters, chaperones or routers of other proteins. The amount of structural and functional available data related to this protein superfamily expands exponentially, as does the number of proteins classified as alpha/beta hydrolases despite poor sequence similarity and lack of experimental data. However the superfamily can be rationally divided according to sequence or structural homologies, leading to subfamilies of proteins with potentially similar functions. Since the discovery of proteins homologous to cholinesterases but devoid of enzymatic activity (e.g., the neuroligins), divergent functions have been ascribed to members of other subfamilies (e.g., lipases, dipeptidylaminopeptidase IV, etc.). To study the potentially moonlighting properties of alpha/beta hydrolases, the ESTHER database (for ESTerase and alpha/beta Hydrolase Enzymes and Relatives; http://bioweb.ensam.inra.fr/esther), which collects, organizes and disseminates structural and functional information related to alpha/beta hydrolases, has been updated with new tools and the web server interface has been upgraded. A new Overall Table along with a new Tree based on HMM models has been included to tentatively group subfamilies. These tools provide starting points for phylogenetic studies aimed at pinpointing the origin of duplications leading to paralogous genes (e.g., acetylcholinesterase versus butyrylcholinesterase, or neuroligin versus carboxylesterase). Another of our goals is to implement new tools to distinguish catalytically active enzymes from non-catalytic proteins in poorly studied or annotated subfamilies.

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Enantioselective apoptosis induction in histiocytic lymphoma cells and acute promyelocytic leukemia cells.

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The aim of this study was to identify valproic acid (VPA) analogs with a broad spectrum of anti-cancer activities and an increased apoptosis-inducing potential compared with the parent VPA, which is enrolled as histone deacetylase (HDAC) inhibitor in a large number of clinical trials. We identified a chiral VPA derivative, (S)-2-pentyl-4-pentynoic acid, previously characterized as HDAC inhibitor that induced massive programmed cell death in a strongly enantioselective manner in U937 histiocytic lymphoma cells and NB4 acute promyelocytic leukemia cells. By performing fluorescence-activated cell sorting and Western blotting analyses, we established that enantiomer (S)-2-pentyl-4-pentynoic acid has higher apoptosis-inducing potential than VPA itself. The optic antipode (R)-2-pentyl-4-pentynoic acid and VPA caused under the same conditions only a weak growth inhibition without inducing cell differentiation and apoptosis. (S)-2-pentyl-4-pentynoic acid is more apoptogenic than VPA and displays enantioselective anti-cancer properties that warrant further research regarding the mechanistic basis of its activity and its potential use in cancer therapy.

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Influence of pH, light cycle, and temperature on ecotoxicity of four sulfonylurea herbicides towards Lemna gibba.

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In chemical regulation, e.g. the EU Water Framework Directive, REACH, or the Pesticide Directive, standardized ecotoxicological tests are applied to evaluate and rank the hazard of compounds and for deriving environmental quality standards (EQS). Standardized test methods prescribe fixed testing conditions e.g. specific temperature, pH, light intensity etc. However, environmental conditions under which the organisms live are rarely identical to the standard conditions. Thus, the ecotoxicity of compounds found in standard test is not only a function of the compounds inherent physico-chemical properties but is also affected by test conditions. It is therefore important to study the effect of changes in test conditions in order to get reliable input ecotoxicity data for assessing the potential risk posed by a compound. The objective of this study was to investigate the implications of changing test conditions on the toxicity of four sulfonylurea herbicides (SUs). The toxicity of the four SUs towards Lemna gibba was investigated at three pH levels (6, 7.5 and 9), at two temperatures (15 and 24 °C) and two light regimes (continuous and 12:12 h light:dark cycle) The EC50 increased twofold to tenfold for the four SUs when pH was increased from 6 to 9. Decreasing the temperature from 24 to 15 °C or introducing a dark:light cycle did not cause any trends in changes in toxicity. The results show that test conditions can have an effect on the toxicity and this should be considered when the standard test results are used for derivation of EQS.

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Nondestructive indices of mercury exposure in three species of turtles occupying different trophic niches downstream from a former chloralkali facility.

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Turtles are useful for studying bioaccumulative pollutants such as mercury (Hg) because they have long life spans and feed at trophic levels that result in high exposure to anthropogenic chemicals. We compared total Hg concentrations in blood and toenails of three species of turtles (Chelydra serpentina, Sternotherus odoratus, and Graptemys geographica) with different feeding ecologies from locations up- and downstream of a superfund site in Virginia, USA. Mercury concentrations in turtle tissues were low at the reference site (average ± 1SE: blood = 48 ± 6 ng g(-1); nail = 2,464 ± 339 ng g(-1) FW) but rose near the contamination source to concentrations among the highest ever reported in turtles [up to 1,800 ng g(-1) (blood) and 42,250 ng g(-1) (nail) FW]. Tissue concentrations remained elevated ~130 km downstream from the source compared to reference concentrations. Tissue Hg concentrations were higher for C. serpentina and S. odoratus than G. geographica, consistent with the feeding ecology and our stable isotope (δ(13)C and δ(15)N) analyses of these species. In addition, we suggest that toenails were a better indication of Hg exposure than blood, probably because this keratinized tissue represents integrated exposure over time. Our results demonstrate that downstream transport of Hg from point sources can persist over vast expanses of river thereby posing potential exposure risks to turtles, but relative exposure varies with trophic level. In addition, our study identifies turtle toenails as a simple, cost-efficient, and minimally invasive tissue for conservation-minded sampling of these long-lived vertebrates.

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Comparative analysis of the protective effects of caffeic acid phenethyl ester (CAPE) on pulmonary contusion lung oxidative stress and serum copper and zinc levels in experimental rat model.

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The aim of this study was to investigate the effects of caffeic acid phenethyl ester (CAPE) in the lungs by biochemical and histopathological analyses in an experimental isolated lung contusion model. Eighty-one male Sprague-Dawley rats were used. The animals were divided randomly into four groups: group 1 (n = 9) was defined as without contusion and without CAPE injection. Group 2 (n = 9) was defined as CAPE 10 μmol/kg injection without lung contusion. Group 3 (n = 36) was defined as contusion without CAPE-administrated group which consisted of four subgroups that were created according to analysis between days 0, 1, 2, and 3. Group 4 (n = 27) was defined as CAPE 10 μmol/kg administrated after contusion group divided into three subgroups according to analysis on days 1, 2, and 3. CAPE 10 μmol/kg was injected intraperitoneally 30 min after trauma and on days 1 and 2. Blood samples were obtained to measure catalase (CAT) and superoxide dismutase (SOD) activities and level of malondialdehyde (MDA) and for blood gas analysis. Trace elements such as zinc and copper were measured in serum. The lung tissue was also removed for histopathological examination. Isolated lung contusion increased serum and tissue SOD and CAT activities and MDA levels (p < 0.05). Both serum and tissue SOD, MDA, and CAT levels on day 3 were lower in group 4 compared to group 3 (p < 0.05). Further, the levels of SOD, MDA, and CAT in group 4 were similar compared to group 1 (p > 0.05). CAPE also had a significant beneficial effect on blood gases (p < 0.05). Both serum zinc and copper levels were (p < 0.05) influenced by the administration of CAPE. Histopathological examination revealed lower scores in group 4 compared to group 3 (p < 0.05) and no significant differences compared to group 1 (p > 0.05). CAPE appears to be effective in protecting against severe oxidative stress and tissue damage caused by pulmonary contusion in an experimental setting. Therefore, we conclude that administration of CAPE may be used for a variety of conditions associated with pulmonary contusion. Clinical use of CAPE may have the advantage of prevention of pulmonary contusion.

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Carboxylesterases are uniquely expressed among tissues and regulated by nuclear hormone receptors in the mouse.

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Carboxylesterases (CES) are a well recognized, yet incompletely characterized family of proteins that catalyze neutral lipid hydrolysis. Some CES have well-defined roles in xenobiotic clearance, pharmacologic prodrug activation, and narcotic detoxification. In addition, emerging evidence suggests other CES may have roles in lipid metabolism. Humans have six CES genes, whereas mice have 20 Ces genes grouped into five isoenzyme classes. Perhaps due to the high sequence similarity shared by the mouse Ces genes, the tissue-specific distribution of expression for these enzymes has not been fully addressed. Therefore, we performed studies to provide a comprehensive tissue distribution analysis of mouse Ces mRNAs. These data demonstrated that while the mouse Ces family 1 is highly expressed in liver and family 2 in intestine, many Ces genes have a wide and unique tissue distribution defined by relative mRNA levels. Furthermore, evaluating Ces gene expression in response to pharmacologic activation of lipid- and xenobiotic-sensing nuclear hormone receptors showed differential regulation. Finally, specific shifts in Ces gene expression were seen in peritoneal macrophages following lipopolysaccharide treatment and in a steatotic liver model induced by high-fat feeding, two model systems relevant to disease. Overall these data show that each mouse Ces gene has its own distinctive tissue expression pattern and suggest that some CES may have tissue-specific roles in lipid metabolism and xenobiotic clearance.

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DCPIB, the proposed selective blocker of volume-regulated anion channels, inhibits several glutamate transport pathways in glial cells.

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4-(2-Butyl-6,7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid (DCPIB) was identified as the selective blocker of volume-regulated anion channels (VRAC). VRAC are permeable to small inorganic and organic anions, including the excitatory neurotransmitter glutamate. In recent years DCPIB has been increasingly used for probing the physiologic and pathologic roles of VRAC and was found to potently suppress pathologic glutamate release in cerebral ischemia. Because ischemic glutamate release can be mediated by a plethora of mechanisms, in this study we explored the selectivity of DCPIB toward the majority of previously identified glutamate transporters and permeability pathways. l-[(3)H]glutamate, d-[(3)H]aspartate, and l-[(14)C]cystine were used to trace amino acid release and uptake. We found that in addition to its well-characterized effect on VRAC, DCPIB potently inhibited glutamate release via connexin hemichannels and glutamate uptake via the glutamate transporter GLT-1 in rat glial cells. In contrast, DCPIB had no direct effect on vesicular glutamate release from rat brain synaptosomes or the cystine/glutamate exchange in astrocytes. The compound did not affect the astrocytic glutamate transporter GLAST, nor did it block glutamate release via the P2X(7)/pannexin permeability pathway. The ability of DCPIB to directly block connexin hemichannels was confirmed using a gene-specific siRNA knockdown approach. Overall, our data demonstrate that DCPIB influences several glutamate transport pathways and that its effects on VRAC in vivo should be verified using additional pharmacological controls.

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Molecular mechanism aspect of ER stress in Alzheimer's disease: current approaches and future strategies.

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by progressive loss of memory and cognitive impairment. Aggregation of amyloid-β (Aβ) peptides is the crucial factor in the onset of AD. The toxic Aβ peptides Aβ40 and Aβ42 are produced from the Aβ precursor protein (APP), a transmembrane protein which is folded and modified in endoplasmic reticulum (ER). ER is the main organelle for the synthesis and processing of nearly all proteins as well as the main cellular source of Ca2+. Under stress conditions, three main ER pathways including inositol-requiring enzyme 1, protein kinase RNA-like ER kinase, and activating transcription factor 6 become activated causing the accumulation of unfolded or misfolded proteins within ER lumen. These pathways manage the stress by regulating the expression of chaperones and enzymes involved in protein folding. Several studies have reported the dysfunction of these stress-sensing pathways in pathological conditions, including neurodegenerative diseases. Recent studies have proposed that neuronal death in AD arises from dysfunction of the ER. Here, we will review recent research findings on the interaction between ER and mitochondria, and its effect on apoptotic pathways. We further provide insights into studies which suggest the role of ER in animal and/or cellular models of AD. Therapeutic strategies that modulate ER could represent a promising approach for prevention or treatment of AD.

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Phenolic profiles of cultivated, in vitro cultured and commercial samples of Melissa officinalis L. infusions.

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Melissa officinalis L. (lemon balm) is normally consumed as an infusion and presents therapeutic properties, such as sedative, carminative and antispasmodic, also being included in some pharmaceutical preparations. The phenolic profiles of different samples of lemon balm, prepared as infusions, were evaluated by HPLC-DAD-ESI/MS. The profiles were compared in order to understand the differences between cultivated, in vitro cultured and commercial (bags and granulated) samples. All the samples showed a similar phenolic profile, presenting differences only in the quantities found of each compound. Rosmarinic acid was the most abundant compound, being higher in commercial samples, especially in tea bag sample (55.68mg/g of infusion) and lower in in vitro cultured sample (15.46mg/g). Moreover, dimers, trimers and tetramers of caffeic acid were identified and quantified for the first time in lemon balm. Only one flavonoid, luteolin-3'-O-glucuronide was found in all the samples, ranging from 8.43mg/g in commercial granulate sample to 1.22mg/g in in vitro cultured sample. Overall, cultivated and in vitro cultured samples presented the lowest amounts of phenolic compounds (59.59 and 30.21mg/g, respectively); otherwise, commercial samples showed the highest contents (109.24mg/g for tea bag and 101.03mg/g for granulate sample). The present study shows that infusion of lemon balm can be a source of phenolic compounds, known for their bioactive effects.

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SB365, Pulsatilla saponin D suppresses the proliferation of human colon cancer cells and induces apoptosis by modulating the AKT/mTOR signalling pathway.

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Pulsatilla koreana has been used as a traditional medicine for the treatment of several diseases. The purpose of this study was to determine if SB365, Pulsatilla saponin D isolated from the root of P. koreana inhibits the progression of colon cancer. We found that SB365 strongly suppressed the growth and proliferation of colon cancer cells and induced their apoptosis. Also, SB365 showed anti-angiogenic activity by decreasing the expression of HIF-1α and VEGF. These results were confirmed by an in vivo study showing that SB365 significantly inhibited tumor growth by the induction of apoptosis and inhibition of angiogenesis with stronger anticancer activity than 5-FU. When further examined for its anticancer mechanism, SB365 effectively suppressed the AKT/mTOR pathway both in vitro and in vivo. Taken together, our study demonstrated that SB365 inhibits the AKT/mTOR pathway, leading to the suppression of tumor growth and angiogenesis together with induction of apoptosis. Therefore, SB365 is a good candidate as a natural product for use in the treatment of colon cancer.

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Studies on the antioxidant potential of flavones of Allium vineale isolated from its water-soluble fraction.

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The aim of this work was to examine the chemical constituents and antioxidant potential of water-soluble fractions from the commonly consumed vegetable, Allium vineale. The water-soluble fraction, containing phenolic compounds, was extracted with ethyl acetate to obtain flavonoids which were separated and purified by repeated column chromatography over Sephadex LH-20, RP C18 and silica gel. The isolated compounds were identified according to their physicochemical properties and spectral data (UV, HPLC-TOF/MS, (1)H NMR, (13)C NMR and 2D NMR). Three flavonoids were isolated and identified as chrysoeriol-7-O-[2″-O-E-feruloyl]-β-d-glucoside (1), chrysoeriol (2), and isorhamnetin-3-β-d-glucoside (3). Antioxidant studies of the aqueous extract and three isolated compounds, 1, 2, 3, were undertaken and they were found to have significant antioxidant activity. Antioxidant activities were evaluated for total antioxidant activity by the ferric thiocyanate method, ferric ion (Fe(3+)) reducing antioxidant power assay (FRAP), ferrous ion (Fe(2+)) metal chelating activity, and DPPH free radical-scavenging activity. The water-soluble ethyl acetate and methanol extraction methods were also compared using HPLC-TOF/MS.

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Proteomic evaluation of myofibrillar carbonylation in chilled fish mince and its inhibition by catechin.

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The present study investigates the susceptibility of individual myofibrillar proteins from mackerel (Scomber scombrus) mince to undergo carbonylation reactions during chilled storage, and the antioxidant capacity of (+)-catechin to prevent oxidative processes of proteins. The carbonylation of each particular protein was quantified by combining the labelling of protein carbonyls by fluorescein-5-thiosemicarbazide (FTSC) with 1-D or 2-D gel electrophoresis. Alpha skeletal actin, glycogen phosphorylase, unnamed protein product (UNP) similar to enolase, pyruvate kinase, isoforms of creatine kinase, aldolase A and an isoform of glyceraldehyde 3-phosphate dehydrogenase (G3PDH) showed elevated oxidation in chilled non-supplemented mince. Myosin heavy chain (MHC) was not carbonylated in chilled muscle, but an extensive MHC degradation was observed in those samples. The supplementation of catechin reduced protein oxidation and lipid oxidation in a concentration-dependent manner: control>25>100≈200ppm. Therefore, the highest catechin concentrations (100 and 200ppm) exhibited the strongest antioxidant activity. Catechin (200ppm) reduced significantly carbonylation of protein spots identified as glycogen phosphorylase, pyruvate kinase muscle isozyme, isoforms of creatine kinase. Conversely, catechin was ineffective to inhibit the oxidation of actin and UNP similar to enolase. These results draw attention to the inefficiency of catechin to prevent actin oxidation, in contrast to the extremely high efficiency of catechin in inhibiting oxidation of lipids and other proteins.

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Can the dietary element content of virgin argan oils really be used for adulteration detection?

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Levels of eight dietary elements were assessed by ICP-AES in virgin edible and beauty argan oil samples prepared from four remote locations of the argan forest, and over a three-year period. The data showed sufficiently little variability to assess that all argan oil samples present, in terms of dietary elements, a similar composition, independently from the tree location within the argan forest. Therefore, adulteration detection by trace element analysis in edible and beauty argan oil is a method that can be generalised.

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Genistein and dicarboximide fungicides in infant formulae from the EU market.

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A method based on ultrasonic extraction and purification by solid phase extraction followed by LC-MS/MS and GC-MS analysis was developed for the determination of genistein, genistin, iprodione, vinclozolin and procymidone in infant powdered formulas. The method was tested for different formulations: milk, soy and hypoallergenic, and was applied to European pooled samples. Spike recoveries ranged from 53.1% to 91.5% and the relative standard deviation values for repeatability ranged from 9.6% to 17.7%, except for iprodione in milk formula (22.3%). None of the fungicides were found in the European pooled formulae, while genistein was found at 9.7μg/g in soy formula and the concentration of genistin, its β-glycosylated form, was respectively 31.4ng/g and 476ng/g in milk and soy formula.

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Sugar metabolism in relation to chilling tolerance of loquat fruit.

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The relationship between chilling injury and sugar metabolism was investigated in loquat fruit stored at 1°C for 35days. No symptoms of chilling injury occurred in the fruit, of 'Ninghaibai' cultivar, during the whole storage whereas, in 'Dahongpao' fruit, severe chilling symptoms were observed after 20days of storage at 1°C. 'Ninghaibai' fruit had higher levels of glucose and fructose and higher activities of sucrose hydrolyzing enzymes, such as sucrose synthase-cleavage and invertase, than had 'Dahongpao'. Furthermore, the chilling resistant 'Ninghaibai' fruit also showed higher activities of hexokinase and fructokinase, involved in hexose phoshorylation and sugar signal generation. These results suggest that the higher content of hexoses and activities of hexose sensors were likely part of the mechanism for chilling tolerance of loquat fruit.

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GABA shunt and polyamine degradation pathway on γ-aminobutyric acid accumulation in germinating fava bean (Vicia faba L.) under hypoxia.

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GABA shunt and polyamine degradation pathway on γ-aminobutyric acid (GABA) accumulation in germinating fava bean under hypoxia was investigated. GABA content, GAD and DAO activity were significantly increased under hypoxia treatment. Glu and polyamine contents enhanced largely and thus supplied as sufficient substrates for GABA formation. In contrast, GABA content decreased, mainly in the embryo, after removing the hypoxia stress. DAO activity, Glu and polyamines contents decreased, while an increment of GAD activity was observed. This indicated that GAD activity can be not only regulated by hypoxia, but by the rapid growth of embryo after the recovery from hypoxia stress. When treated with AG, DAO activity was almost inhibited completely, and the GABA content decreased by 32.96% and 32.07% after treated for 3 and 5 days, respectively. Hence, it can be inferred that about 30% of GABA formed in germinating fava bean under hypoxia was supplied by polyamine degradation pathway.

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Soymilk phenolic compounds, isoflavones and antioxidant activity as affected by in vitro gastrointestinal digestion.

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The aim of this research was to evaluate changes in the phenolic compounds, isoflavones and antioxidant activity of soymilk following in vitro gastrointestinal digestion (including dialysis). Gastric digestion significantly influenced the release of bioactive substances from the soymilk matrix, increasing the concentration of total phenolic components (35% as the sum of individuals and 14% by Folin-Ciocalteu [F-C] method), total isoflavone content (22%) and total antioxidant activity (76%). The concentration of all those compounds was reduced significantly in the duodenal fraction in comparison to gastric digestion and their lowest concentration was observed in the dialysed fraction, where phenolic acids were not detected. The bioaccessibility of soymilk phenolic compounds was 15% as the sum of individuals and 20% by F-C assay; isoflavones 36% and constituents with antioxidant activity 27%. Results suggest that most of these compounds were sufficiently available to be absorbed and could contribute health benefits.

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Pre-bottling use of dehydrated waste grape skins to improve colour, phenolic and aroma composition of red wines.

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Different dehydrated waste grape skins from the juice industry were added into aged and young red wines as an innovative way of compensating for colour loss before bottling. After addition of grape skins, colour intensity of wines increased a mean 11% and a maximum of 31% with predominance of the red component. Total polyphenols mean increase was 10% with a maximum value of 20%. Analysis of low molecular weight phenolic compounds by HPLC-DAD showed a significant (p<0.05) content increase of the bioactive compounds gallic acid, (+)-catechin, (-)-epicatechin, and (E)-resveratrol. Anthocyanins content also increased at an average of 50mg/l. The volatile profile of wines analysed by SBSE-GC-MS was only moderately influenced by the treatments. Mixtures of dehydrated waste grape skins were useful to improve the colour and polyphenol profile of red wines, considering them a useful tool for correcting colour loss before bottling.

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Light exposure during storage preserving soluble sugar and l-ascorbic acid content of minimally processed romaine lettuce (Lactuca sativa L.var. longifolia).

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Minimally processed romaine lettuce (MPRL) leaves were stored in light condition (2500lux) or darkness at 4°C for 7d. Light exposure significantly delayed the degradation of chlorophyll and decrease of glucose, reducing sugar, and sucrose content, and thus preserved more total soluble solid (TSS) content at the end of storage in comparison with darkness. While, it did not influenced starch content that progressively decreased over time. The l-ascorbic acid (AA) accumulated in light-stored leaves, but deteriorated in dark-stored leaves during storage. The dehydroascorbic acid (DHA) increased in all leaves stored in both light and dark condition, of which light condition resulted in less DHA than darkness. In addition, the fresh weight loss and dry matter significantly increased and these increases were accelerated by light exposure. Conclusively, light exposure in applied intensity effectively alleviated MPRL quality deterioration by delaying the decreases of pigments, soluble sugar, TSS content and accumulating AA.

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The role of personalized medicine in identifying appropriate candidates for menopausal estrogen therapy.

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Menopausal estrogen therapy has a complex balance of benefits and risks and is no longer routinely recommended for the majority of women during or after the transition to menopause. Recent findings from the Women's Health Initiative (WHI) and other studies suggest that a woman's clinical and biological characteristics may modify her health outcomes on hormone therapy (HT) and that some women may be more appropriate candidates for therapy than others. An emerging body of evidence suggests that it may be possible to identify women who are more likely to have favorable outcomes and less likely to have adverse events on HT, as well as to tailor the optimal dose, formulation, and route of delivery of treatment, by the use of individual risk stratification and a personalized approach. Several clinical characteristics that have been proposed for this purpose include a woman's age, time since menopause, symptom severity, baseline vascular health, risk for breast cancer, biomarker levels, and genetic predisposition. The underlying rationale for personalized medicine, that each person has a unique biologic profile that can help to guide the choice of therapy, applies well to HT decision making and holds promise for improved treatment efficacy and safety. This report, which focuses on vascular health, reviews the evidence on the role of such markers in tailoring the use of hormone therapy to appropriate candidates, with the ultimate goal of developing a personalized risk:benefit prediction model that takes into account clinical and genetic factors, "patient-centered" outcomes including sense of well being and quality of life, and other variables. The proposed personalized approach to HT decision making has the potential to improve the quality of health care.

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Reversal of dopamine D2 agonist-induced inhibition of ventral tegmental area neurons by Gq-linked neurotransmitters is dependent on protein kinase C, G protein-coupled receptor kinase, and dynamin.

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Dopaminergic neurons of the ventral tegmental area are important components of brain pathways related to addiction. Prolonged exposure of these neurons to moderate concentrations of dopamine (DA) decreases their sensitivity to inhibition by DA, a process called DA-inhibition reversal (DIR). DIR is mediated by phospholipase C and conventional subtype of protein kinase C (cPKC) through concurrent stimulation of D2 and D1-like DA receptors, or by D2 stimulation concurrent with activation of 5-HT(2) or neurotensin receptors. In the present study, we further characterized this phenomenon by use of extracellular recordings in brain slices to examine whether DIR is linked to G protein-coupled receptor kinase-2 (GRK2) or dynamin by assessing DIR in the presence of antagonists of these enzymes. DIR was blocked by β-ARK1 inhibitor, which inhibits GRK2, and by dynasore, which blocks dynamin. Reversal of inhibition by D2 agonist quinpirole was produced by serotonin (50 µM) and by neurotensin (5-10 nM). Serotonin-induced or neurotensin-induced reversal was blocked by β-ARK1 inhibitor, dynasore, or cPKC antagonist 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4c]carbazole-12-propanenitrile (Gö6976). This further characterization of DIR indicates that cPKC, GRK2, and dynamin play important roles in the desensitization of D2 receptors. As drugs of abuse produce persistent increases in DA concentration in the ventral tegmental area, reduction of D2 receptor sensitivity as a result of drug abuse may be a critical factor in the processes of addiction.

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A comparative analysis of computational approaches to relative protein quantification using peptide peak intensities in label-free LC-MS proteomics experiments.

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Liquid chromatography coupled with mass spectrometry (LC-MS) is widely used to identify and quantify peptides in complex biological samples. In particular, label-free shotgun proteomics is highly effective for the identification of peptides and subsequently obtaining a global protein profile of a sample. As a result, this approach is widely used for discovery studies. Typically, the objective of these discovery studies is to identify proteins that are affected by some condition of interest (e.g. disease, exposure). However, for complex biological samples, label-free LC-MS proteomics experiments measure peptides and do not directly yield protein quantities. Thus, protein quantification must be inferred from one or more measured peptides. In recent years, many computational approaches to relative protein quantification of label-free LC-MS data have been published. In this review, we examine the most commonly employed quantification approaches to relative protein abundance from peak intensity values, evaluate their individual merits, and discuss challenges in the use of the various computational approaches.

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