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Sample records for activity markedly attenuated

  1. Activities across Nation Mark National Chemistry Week.

    ERIC Educational Resources Information Center

    Carpenter, Ernest, Ed.; And Others

    1989-01-01

    Describes national and local activities done during National Chemistry Week including chemistry demonstrations, shopping center exhibits, contests, and museum exhibits. Discusses the supplementary material about chemistry in selected editions of 16 newspapers, "Solution for the Future." Presents many pictures showing those activities. (YP)

  2. A robust activity marking system for exploring active neuronal ensembles

    PubMed Central

    Sørensen, Andreas T; Cooper, Yonatan A; Baratta, Michael V; Weng, Feng-Ju; Zhang, Yuxiang; Ramamoorthi, Kartik; Fropf, Robin; LaVerriere, Emily; Xue, Jian; Young, Andrew; Schneider, Colleen; Gøtzsche, Casper René; Hemberg, Martin; Yin, Jerry CP; Maier, Steven F; Lin, Yingxi

    2016-01-01

    Understanding how the brain captures transient experience and converts it into long lasting changes in neural circuits requires the identification and investigation of the specific ensembles of neurons that are responsible for the encoding of each experience. We have developed a Robust Activity Marking (RAM) system that allows for the identification and interrogation of ensembles of neurons. The RAM system provides unprecedented high sensitivity and selectivity through the use of an optimized synthetic activity-regulated promoter that is strongly induced by neuronal activity and a modified Tet-Off system that achieves improved temporal control. Due to its compact design, RAM can be packaged into a single adeno-associated virus (AAV), providing great versatility and ease of use, including application to mice, rats, flies, and potentially many other species. Cre-dependent RAM, CRAM, allows for the study of active ensembles of a specific cell type and anatomical connectivity, further expanding the RAM system’s versatility. DOI: http://dx.doi.org/10.7554/eLife.13918.001 PMID:27661450

  3. Organ inflammation in porcine Escherichia coli sepsis is markedly attenuated by combined inhibition of C5 and CD14.

    PubMed

    Egge, Kjetil H; Thorgersen, Ebbe B; Pischke, Søren E; Lindstad, Julie K; Pharo, Anne; Bongoni, Anjan K; Rieben, Robert; Nunn, Miles A; Barratt-Due, Andreas; Mollnes, Tom E

    2015-08-01

    Sepsis is an infection-induced systemic inflammatory syndrome, potentially causing organ failure. We previously showed attenuating effects on inflammation, thrombogenicity and haemodynamics by inhibiting the Toll-like receptor co-factor CD14 and complement factor C5 in a porcine Escherichia coli-induced sepsis model. The present study explored the effect on organ inflammation in these pigs. Tissue samples were examined from the combined treatment group (n = 8), the positive (n = 8) and negative (n = 6) control groups after 4h of sepsis. Inflammatory biomarkers were measured using ELISA, multiplex and qPCR analysis. Combined inhibition of C5 and CD14 markedly attenuated IL-1β by 31-66% (P < 0.05) and IL-6 by 54-96% (P < 0.01) in liver, kidney, lung and spleen; IL-8 by 65-100% in kidney, lung, spleen, and heart (P < 0.05) and MCP-1 by 46-69% in liver, kidney, spleen and heart (P < 0.05). Combined inhibition significantly attenuated tissue factor mRNA upregulation in spleen (P < 0.05) and IP-10 mRNA upregulation in four out of five organs. Finally, C5aR mRNA downregulation was prevented in heart and kidney (P < 0.05). Combined inhibition of C5 and CD14 thus markedly attenuated inflammatory responses in all organs examined. The anti-inflammatory effects observed in lung and heart may explain the delayed haemodynamic disturbances observed in septic pigs receiving combined inhibition of C5 and CD14. PMID:25956456

  4. Absence of canonical active chromatin marks in developmentally regulated genes

    PubMed Central

    Ruiz-Romero, Marina; Corominas, Montserrat; Guigó, Roderic

    2015-01-01

    The interplay of active and repressive histone modifications is assumed to play a key role in the regulation of gene expression. In contrast to this generally accepted view, we show that transcription of genes temporally regulated during fly and worm development occurs in the absence of canonically active histone modifications. Conversely, strong chromatin marking is related to transcriptional and post-transcriptional stability, an association that we also observe in mammals. Our results support a model in which chromatin marking is associated to stable production of RNA, while unmarked chromatin would permit rapid gene activation and de-activation during development. In this case, regulation by transcription factors would play a comparatively more important regulatory role. PMID:26280901

  5. Pentoxifylline attenuates neutrophil activation in experimental endotoxemia in chimpanzees.

    PubMed

    van Leenen, D; van der Poll, T; Levi, M; ten Cate, H; van Deventer, S J; Hack, C E; Aarden, L A; ten Cate, J W

    1993-08-15

    Costimulation of neutrophils and cytokines may play an important role in organ injury in sepsis. Pentoxifylline inhibits various neutrophil functions in vitro, and attenuates endotoxin-induced production of TNF in both in vitro and in vivo models. To assess the effect of pentoxifylline on neutrophil activation in endotoxemia, nine adult chimpanzees (Pan troglodytes) were i.v. injected with saline (n = 2), Escherichia coli endotoxin (4 ng/kg; n = 4), or E. coli endotoxin (4 ng/kg) in combination with pentoxifylline (500 mg/3 h, starting 30 min before the endotoxin injection; n = 3). Serial blood samples were obtained for measurements of leukocyte counts and the granulocytic proteinases elastase complexed with alpha 1-antitrypsin and lactoferrin, and cytokines during the next 5 h. No changes were observed in the saline-treated chimpanzees. Endotoxin induced a marked leukocytosis and neutrophilia, which were slightly reduced by pentoxifylline. In contrast, pentoxifylline almost completely prevented endotoxin-induced neutrophil degranulation: peak elastase-alpha 1-antitrypsin was 164 +/- 21 ng/ml (mean +/- SE) after endotoxin alone, vs 71 +/- 7 ng/ml after endotoxin with pentoxifylline (t = 3 h; p < 0.05); peak lactoferrin was 329 +/- 15 and 182 +/- 5 ng/ml, respectively (t = 5 h; p < 0.05). Pentoxifylline also inhibited the endotoxin-induced release of TNF (271 +/- 26 vs 55 +/- 23 pg/ml at t = 1.5 h; p < 0.05) and IL-6 (225 +/- 42 vs 73 +/- 25 pg/ml at t = 2 h; p < 0.05). IL-8 release was not significantly inhibited by pentoxifylline. In none of the animals activation of the C system could be detected. We conclude that pentoxifylline attenuates neutrophil activation in endotoxemia in chimpanzees, probably in part by inhibiting the release of TNF.

  6. Source term attenuation by water in the Mark I boiling water reactor drywell

    SciTech Connect

    Powers, D.A.

    1993-09-01

    Mechanistic models of aerosol decontamination by an overlying water pool during core debris/concrete interactions and spray removal of aerosols from a Mark I drywell atmosphere are developed. Eighteen uncertain features of the pool decontamination model and 19 uncertain features of the model for the rate coefficient of spray removal of aerosols are identified. Ranges for values of parameters that characterize these uncertain features of the models are established. Probability density functions for values within these ranges are assigned according to a set of rules. A Monte Carlo uncertainty analysis of the decontamination factor produced by water pools 30 and 50 cm deep and subcooled 0--70 K is performed. An uncertainty analysis for the rate constant of spray removal of aerosols is done for water fluxes of 0.25, 0.01, and 0.001 cm{sup 3} H{sub 2}O/cm{sup 2}-s and decontamination factors of 1.1, 2, 3.3, 10, 100, and 1000.

  7. Active attenuation of propeller blade passage noise

    NASA Technical Reports Server (NTRS)

    Zalas, J. M.; Tichy, J.

    1984-01-01

    Acoustic measurements are presented to show that active cancellation can be used to achieve significant reduction of blade passage noise in a turboprop cabin. Simultaneous suppression of all blade passage frequencies was attained. The spatial volume over which cancellation occurred, however, is limited. Acoustic intensity maps are presented to show that the acoustic input to the fuselage was sufficiently non-localized so as to require more judicious selection of cancellation speaker location.

  8. Hydrocarbon Deposition Attenuates Osteoblast Activity on Titanium

    PubMed Central

    Hayashi, R.; Ueno, T.; Migita, S.; Tsutsumi, Y.; Doi, H.; Ogawa, T.; Hanawa, T.; Wakabayashi, N.

    2014-01-01

    Although the reported percentage of bone-implant contact is far lower than 100%, the cause of such low levels of bone formation has rarely been investigated. This study tested the negative biological effect of hydrocarbon deposition onto titanium surfaces, which has been reported to be inevitable. Osteogenic MC3T3-E1 cells were cultured on titanium disks on which the carbon concentration was experimentally regulated to achieve carbon/titanium (C/Ti) ratios of 0.3, 0.7, and 1.0. Initial cellular activities such as cell attachment and cell spreading were concentration-dependently suppressed by the amount of carbon on the titanium surface. The osteoblastic functions of alkaline phosphatase activity and calcium mineralization were also reduced by more than 40% on the C/Ti (1.0) surface. These results indicate that osteoblast activity is influenced by the degree of hydrocarbon contamination on titanium implants and suggest that hydrocarbon decomposition before implant placement may increase the biocompatibility of titanium. PMID:24868012

  9. Activating and Attenuating the Amicoumacin Antibiotics.

    PubMed

    Park, Hyun Bong; Perez, Corey E; Perry, Elena Kim; Crawford, Jason M

    2016-01-01

    The amicoumacins belong to a class of dihydroisocoumarin natural products and display antibacterial, antifungal, anticancer, and anti-inflammatory activities. Amicoumacins are the pro-drug activation products of a bacterial nonribosomal peptide-polyketide hybrid biosynthetic pathway and have been isolated from Gram-positive Bacillus and Nocardia species. Here, we report the stimulation of a "cryptic" amicoumacin pathway in the entomopathogenic Gram-negative bacterium Xenorhabdus bovienii, a strain not previously known to produce amicoumacins. X. bovienii participates in a multi-lateral symbiosis where it is pathogenic to insects and mutualistic to its Steinernema nematode host. Waxmoth larvae are common prey of the X. bovienii-Steinernema pair. Employing a medium designed to mimic the amino acid content of the waxmoth circulatory fluid led to the detection and characterization of amicoumacins in X. bovienii. The chemical structures of the amicoumacins were supported by 2D-NMR, HR-ESI-QTOF-MS, tandem MS, and polarimeter spectral data. A comparative gene cluster analysis of the identified X. bovienii amicoumacin pathway to that of the Bacillus subtilis amicoumacin pathway and the structurally-related Xenorhabdus nematophila xenocoumacin pathway is presented. The X. bovienii pathway encodes an acetyltransferase not found in the other reported pathways, which leads to a series of N-acetyl-amicoumacins that lack antibacterial activity. N-acetylation of amicoumacin was validated through in vitro protein biochemical studies, and the impact of N-acylation on amicoumacin's mode of action was examined through ribosomal structural analyses. PMID:27347911

  10. N6-Methyldeoxyadenosine Marks Active Transcription Start Sites in Chlamydomonas

    PubMed Central

    Chen, Kai; Deng, Xin; Yu, Miao; Han, Dali; Hao, Ziyang; Liu, Jianzhao; Lu, Xingyu; Dore, Louis C; Weng, Xiaocheng; Ji, Quanjiang; Mets, Laurens; He, Chuan

    2015-01-01

    SUMMARY N6-methyldeoxyadenosine (6mA or m6A) is a DNA modification preserved in prokaryotes to eukaryotes. It is widespread in bacteria, and functions in DNA mismatch repair, chromosome segregation, and virulence regulation. In contrast, the distribution and function of 6mA in eukaryotes have been unclear. Here we present a comprehensive analysis of the 6mA landscape in the genome of Chlamydomonas using new sequencing approaches. We identified the 6mA modification in 84% of genes in Chlamydomonas. We found that 6mA mainly locates at ApT dinucleotides around transcription start sites (TSS) with a bimodal distribution, and appears to mark active genes. A periodic pattern of 6mA deposition was also observed at base resolution, which is associated with nucleosome distribution near the TSS, suggesting a possible role in nucleosome positioning. The new genome-wide mapping of 6mA and its unique distribution in the Chlamydomonas genome suggest potential regulatory roles of 6mA in gene expression in eukaryotic organisms. PMID:25936837

  11. Active sound attenuation across a double wall structure

    NASA Technical Reports Server (NTRS)

    Grosveld, Ferdinand W.; Shepherd, Kevin P.

    1991-01-01

    The possibility of achieving significant local and global sound attenuation across a flat double wall is demonstrated. It is also shown that sound can be prevented from entering the interior of a cabinlike environment. The approach used is unlike established active noise control techniques.

  12. Activating and Attenuating the Amicoumacin Antibiotics

    PubMed Central

    Park, Hyun Bong; Perez, Corey E.; Perry, Elena Kim; Crawford, Jason M.

    2016-01-01

    The amicoumacins belong to a class of dihydroisocoumarin natural products and display antibacterial, antifungal, anticancer, and anti-inflammatory activities. Amicoumacins are the pro-drug activation products of a bacterial nonribosomal peptide-polyketide hybrid biosynthetic pathway and have been isolated from Gram-positive Bacillus and Nocardia species. Here, we report the stimulation of a “cryptic” amicoumacin pathway in the entomopathogenic Gram-negative bacterium Xenorhabdus bovienii, a strain not previously known to produce amicoumacins. X. bovienii participates in a multi-lateral symbiosis where it is pathogenic to insects and mutualistic to its Steinernema nematode host. Waxmoth larvae are common prey of the X. bovienii-Steinernema pair. Employing a medium designed to mimic the amino acid content of the waxmoth circulatory fluid led to the detection and characterization of amicoumacins in X. bovienii. The chemical structures of the amicoumacins were supported by 2D-NMR, HR-ESI-QTOF-MS, tandem MS, and polarimeter spectral data. A comparative gene cluster analysis of the identified X. bovienii amicoumacin pathway to that of the Bacillus subtilis amicoumacin pathway and the structurally-related Xenorhabdus nematophila xenocoumacin pathway is presented. The X. bovienii pathway encodes an acetyltransferase not found in the other reported pathways, which leads to a series of N-acetyl-amicoumacins that lack antibacterial activity. N-acetylation of amicoumacin was validated through in vitro protein biochemical studies, and the impact of N-acylation on amicoumacin’s mode of action was examined through ribosomal structural analyses. PMID:27347911

  13. Stimulant-induced dopamine increases are markedly blunted in active cocaine abusers.

    PubMed

    Volkow, N D; Tomasi, D; Wang, G-J; Logan, J; Alexoff, D L; Jayne, M; Fowler, J S; Wong, C; Yin, P; Du, C

    2014-09-01

    Dopamine signaling in nucleus accumbens is essential for cocaine reward. Interestingly, imaging studies have reported blunted dopamine increases in striatum (assessed as reduced binding of [(11)C]raclopride to D2/D3 receptors) in detoxified cocaine abusers. Here, we evaluate whether the blunted dopamine response reflected the effects of detoxification and the lack of cocaine-cues during stimulant exposure. For this purpose we studied 62 participants (43 non-detoxified cocaine abusers and 19 controls) using positron emission tomography and [(11)C]raclopride (radioligand sensitive to endogenous dopamine) to measure dopamine increases induced by intravenous methylphenidate and in 24 of the cocaine abusers, we also compared dopamine increases when methylphenidate was administered concomitantly with a cocaine cue-video versus a neutral-video. In controls, methylphenidate increased dopamine in dorsal (effect size 1.4; P<0.001) and ventral striatum (location of accumbens) (effect size 0.89; P<0.001), but in cocaine abusers methylphenidate's effects did not differ from placebo and were similar whether cocaine-cues were present or not. In cocaine abusers despite the markedly attenuated dopaminergic effects, the methylphenidate-induced changes in ventral striatum were associated with intense drug craving. Our findings are consistent with markedly reduced signaling through D2 receptors during intoxication in active cocaine abusers regardless of cues exposure, which might contribute to compulsive drug use. PMID:24912491

  14. Stimulant-induced dopamine increases are markedly blunted in active cocaine abusers

    PubMed Central

    Volkow, ND; Tomasi, D; Wang, G-J; Logan, J; Alexoff, DL; Jayne, M; Fowler, JS; Wong, C; Yin, P; Du, C

    2016-01-01

    Dopamine signaling in nucleus accumbens is essential for cocaine reward. Interestingly, imaging studies have reported blunted dopamine increases in striatum (assessed as reduced binding of [11C]raclopride to D2/D3 receptors) in detoxified cocaine abusers. Here, we evaluate whether the blunted dopamine response reflected the effects of detoxification and the lack of cocaine-cues during stimulant exposure. For this purpose we studied 62 participants (43 non-detoxified cocaine abusers and 19 controls) using positron emission tomography and [11C]raclopride (radioligand sensitive to endogenous dopamine) to measure dopamine increases induced by intravenous methylphenidate and in 24 of the cocaine abusers, we also compared dopamine increases when methylphenidate was administered concomitantly with a cocaine cue-video versus a neutral-video. In controls, methylphenidate increased dopamine in dorsal (effect size 1.4; P < 0.001) and ventral striatum (location of accumbens) (effect size 0.89; P < 0.001), but in cocaine abusers methylphenidate’s effects did not differ from placebo and were similar whether cocaine-cues were present or not. In cocaine abusers despite the markedly attenuated dopaminergic effects, the methylphenidate-induced changes in ventral striatum were associated with intense drug craving. Our findings are consistent with markedly reduced signaling through D2 receptors during intoxication in active cocaine abusers regardless of cues exposure, which might contribute to compulsive drug use. PMID:24912491

  15. Adrenergic activation attenuates astrocyte swelling induced by hypotonicity and neurotrauma.

    PubMed

    Vardjan, Nina; Horvat, Anemari; Anderson, Jamie E; Yu, Dou; Croom, Deborah; Zeng, Xiang; Lužnik, Zala; Kreft, Marko; Teng, Yang D; Kirov, Sergei A; Zorec, Robert

    2016-06-01

    Edema in the central nervous system can rapidly result in life-threatening complications. Vasogenic edema is clinically manageable, but there is no established medical treatment for cytotoxic edema, which affects astrocytes and is a primary trigger of acute post-traumatic neuronal death. To test the hypothesis that adrenergic receptor agonists, including the stress stimulus epinephrine protects neural parenchyma from damage, we characterized its effects on hypotonicity-induced cellular edema in cortical astrocytes by in vivo and in vitro imaging. After epinephrine administration, hypotonicity-induced swelling of astrocytes was markedly reduced and cytosolic 3'-5'-cyclic adenosine monophosphate (cAMP) was increased, as shown by a fluorescence resonance energy transfer nanosensor. Although, the kinetics of epinephrine-induced cAMP signaling was slowed in primary cortical astrocytes exposed to hypotonicity, the swelling reduction by epinephrine was associated with an attenuated hypotonicity-induced cytosolic Ca(2+) excitability, which may be the key to prevent astrocyte swelling. Furthermore, in a rat model of spinal cord injury, epinephrine applied locally markedly reduced neural edema around the contusion epicenter. These findings reveal new targets for the treatment of cellular edema in the central nervous system. PMID:27018061

  16. Detailed analysis of the promoter activity of an attenuated lentivirus.

    PubMed

    Blatti-Cardinaux, Laure; Sanjosé, Leticia; Zahno, Marie-Luise; Zanoni, Reto; Reina, Ramses; Bertoni, Giuseppe

    2016-07-01

    In spite of an eradication campaign that eliminated clinical cases of caprine arthritis encephalitis virus-induced arthritis in the Swiss goat population, seroconversions are still observed. In the affected flocks, viruses belonging mainly to the small ruminant lentivirus A4 subtype are regularly isolated. These viruses are considered attenuated, except in the mammary gland, where high viral loads and histopathological lesions have been observed. We previously characterized and sequenced such field isolates, detecting several potentially attenuating mutations in their LTR. Here we present a detailed analysis of the promoter activity of these genetic elements, which was comparable to those of virulent isolates. An AP-1 binding site was shown to be crucial for promoter activity in reporter gene assays and also in the context of a replicating molecular clone. Other sites, such as AML(vis) and a conserved E-box, appeared to be less crucial. Analysis of a unique AP-4 site showed a clear discrepancy between results obtained with reporter gene assays and those with mutated viruses. Within the limits of this in vitro study, we did not find evidence pointing to the LTR as the genetic correlate of attenuation for these viruses. Finally, the limited replication of SRLV A4 in mammary cell culture could not explain the suggested mammary tropism. In contrast, and in view of the abundance of macrophages in the mammary gland, it is the striking replication capacity of SRLV A4 in these cells, unaffected by all LTR mutations tested, which may explain the apparent mammary tropism of these viruses.

  17. Detailed analysis of the promoter activity of an attenuated lentivirus.

    PubMed

    Blatti-Cardinaux, Laure; Sanjosé, Leticia; Zahno, Marie-Luise; Zanoni, Reto; Reina, Ramses; Bertoni, Giuseppe

    2016-07-01

    In spite of an eradication campaign that eliminated clinical cases of caprine arthritis encephalitis virus-induced arthritis in the Swiss goat population, seroconversions are still observed. In the affected flocks, viruses belonging mainly to the small ruminant lentivirus A4 subtype are regularly isolated. These viruses are considered attenuated, except in the mammary gland, where high viral loads and histopathological lesions have been observed. We previously characterized and sequenced such field isolates, detecting several potentially attenuating mutations in their LTR. Here we present a detailed analysis of the promoter activity of these genetic elements, which was comparable to those of virulent isolates. An AP-1 binding site was shown to be crucial for promoter activity in reporter gene assays and also in the context of a replicating molecular clone. Other sites, such as AML(vis) and a conserved E-box, appeared to be less crucial. Analysis of a unique AP-4 site showed a clear discrepancy between results obtained with reporter gene assays and those with mutated viruses. Within the limits of this in vitro study, we did not find evidence pointing to the LTR as the genetic correlate of attenuation for these viruses. Finally, the limited replication of SRLV A4 in mammary cell culture could not explain the suggested mammary tropism. In contrast, and in view of the abundance of macrophages in the mammary gland, it is the striking replication capacity of SRLV A4 in these cells, unaffected by all LTR mutations tested, which may explain the apparent mammary tropism of these viruses. PMID:27114068

  18. Active Attenuation of Acoustic Noise Using Adaptive Armax Control.

    NASA Astrophysics Data System (ADS)

    Swanson, David Carl

    An adaptive auxiliary input autoregressive moving average (ARMAX) control system using the recursive least -squares lattice for system identification is developed for active control of dynamic systems. The closed-loop adaptive ARMAX control system is applied to active acoustic noise reduction in three-dimensional spaces. The structure of the ARMAX system is compared to that for duct cancellation systems, model-reference control systems, and the general field solution and is seen as a reasonable approach for active field control in the general case. The ARMAX system is derived for multiple inputs and outputs where the measured outputs are to be driven to desired waveforms with least -squares error using a multi-channel ARMAX lattice for recursive system identification. A significant reduction in complexity is obtained by neglecting the ARMAX zeros for the special case of active attenuation of non-dispersive acoustic waves. It is shown that using the least-squares lattice requires fewer multiplies, divides, additions, and subtractions than the recursive least-squares algorithm which is based on the matrix inversion lemma. Computational complexity is seen as an important issue in the application of adaptive ARMAX systems to active field control because the system must control relatively higher numbers of modes and frequencies in real time than are seen in industrial process plants for which the adaptive ARMAX systems were first developed using recursive least squares. Convergence requirements using the lattice system identification algorithm are the same as that for the recursive least squares algorithm in adaptive ARMAX system and are verified in numerical simulations using known ARMAX parameters. A real-time simulation of active attenuation of acoustic noise is presented using the blade-excited harmonics from a small axial flow fan. The adaptive ARMAX controller provides active attenuation for correlated spectral peaks but not for uncorrelated noise from turbulence

  19. Active damping performance of the KAGRA seismic attenuation system prototype

    NASA Astrophysics Data System (ADS)

    Fujii, Yoshinori; Sekiguchi, Takanori; Takahashi, Ryutaro; Aso, Yoichi; Barton, Mark; Erasmo Peña Arellano, Fabián; Shoda, Ayaka; Akutsu, Tomotada; Miyakawa, Osamu; Kamiizumi, Masahiro; Ishizaki, Hideharu; Tatsumi, Daisuke; Hirata, Naoatsu; Hayama, Kazuhiro; Okutomi, Koki; Miyamoto, Takahiro; Ishizuka, Hideki; DeSalvo, Riccardo; Flaminio, Raffaele

    2016-05-01

    The Large-scale Cryogenic Gravitational wave Telescope (formerly LCGT now KAGRA) is presently under construction in Japan. This May we assembled a prototype of the seismic attenuation system (SAS) for the beam splitter and the signal recycling mirrors of KAGRA, which we call Type-B SAS, and evaluated its performance at NAOJ (Mitaka, Toyko). We investigated its frequency response, active damping performance, vibration isolation performance and long-term stability both in and out of vacuum. From the frequency response test and the active damping performance test, we confirmed that the SAS worked as we designed and that all mechanical resonances which could disturb lock acquisition and observation are damped within 1 minute, which is required for KAGRA, by the active controls.

  20. Intermittent fasting attenuates inflammasome activity in ischemic stroke.

    PubMed

    Fann, David Yang-Wei; Santro, Tomislav; Manzanero, Silvia; Widiapradja, Alexander; Cheng, Yi-Lin; Lee, Seung-Yoon; Chunduri, Prasad; Jo, Dong-Gyu; Stranahan, Alexis M; Mattson, Mark P; Arumugam, Thiruma V

    2014-07-01

    Recent findings have revealed a novel inflammatory mechanism that contributes to tissue injury in cerebral ischemia mediated by multi-protein complexes termed inflammasomes. Intermittent fasting (IF) can decrease the levels of pro-inflammatory cytokines in the periphery and brain. Here we investigated the impact of IF (16h of food deprivation daily) for 4months on NLRP1 and NLRP3 inflammasome activities following cerebral ischemia. Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion (I/R). IF decreased the activation of NF-κB and MAPK signaling pathways, the expression of NLRP1 and NLRP3 inflammasome proteins, and both IL-1β and IL-18 in the ischemic brain tissue. These findings demonstrate that IF can attenuate the inflammatory response and tissue damage following ischemic stroke by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. PMID:24805069

  1. Human Erythropoietin Dimers with Markedly Enhanced in vivo Activity

    NASA Astrophysics Data System (ADS)

    Sytkowski, Arthur J.; Dotimas Lunn, Elizabeth; Davis, Kerry Lynn; Feldman, Laurie; Siekman, Suvia

    1998-02-01

    Human erythropoietin, a widely used and important therapeutic glycoprotein, has a relatively short plasma half-life due to clearance by glomerular filtration as well as by other mechanisms. We hypothesized that an erythropoietin species with a larger molecular size would exhibit an increased plasma half-life and, potentially, an enhanced biological activity. We now report the production of biologically active erythropoietin dimers and trimers by chemical crosslinking of the conventional monomeric form. We imparted free sulfhydryl residues to a pool of erythropoietin monomer by chemical modification. A second pool was reacted with another modifying reagent to yield monomer with male-imido groups. Upon mixing these two pools, covalently linked dimers and trimers were formed that were biologically active in vitro. The plasma half-life of erythropoietin dimers in rabbits was >24 h compared with 4 h for the monomers. Importantly, erythropoietin dimers were biologically active in vivo as shown by their ability to increase the hematocrits of mice when injected subcutaneously. In addition, the dimers exhibited >26-fold higher activity in vivo than did the monomers and were very effective after only one dose. Dimeric and other oligomeric forms of Epo may have an important role in therapy.

  2. INDIRECT MEASUREMENT OF BIOLOGICAL ACTIVITY TO MONITOR NATURAL ATTENUATION

    EPA Science Inventory

    The remediation of ground water contamination by natural attenuation, specifically biodegradation, requires continual monitoring. This research is aimed at improving methods for evaluating the long-term performance of Monitored Natural Attenuation (MNA), specifically changes in ...

  3. A "Marked Success": Physical Activity at Miss White's School

    ERIC Educational Resources Information Center

    Morice, Linda C.

    2008-01-01

    This article examines the career of Flora White, who operated a school for girls in Concord, Massachusetts (USA) from 1897 to 1914. The school promoted individualised learning and physical activity for young women. Its programme of female exercise and sports ran counter to prevailing scholarly, medical, and popular opinion in the US. White faced…

  4. Development of attenuated baroreflexes in obese Zucker rats coincides with impaired activation of nucleus tractus solitarius

    PubMed Central

    Guimaraes, Priscila S.; Huber, Domitila A.; Campagnole-Santos, Maria J.

    2014-01-01

    Adult obese Zucker rats (OZR; >12 wk) develop elevated sympathetic nerve activity (SNA) and mean arterial pressure (MAP) with impaired baroreflexes compared with adult lean Zucker rats (LZR) and juvenile OZR (6–7 wk). In adult OZR, baroreceptor afferent nerves respond normally to changes in MAP, whereas electrical stimulation of baroreceptor afferent fibers produces smaller reductions in SNA and MAP compared with LZR. We hypothesized that impaired baroreflexes in OZR are linked to reduced activation of brain stem sites that mediate baroreflexes. In conscious adult rats, a hydralazine (HDZ)-induced reduction in MAP evoked tachycardia that was initially blunted in OZR, but equivalent to LZR within 5 min. In agreement, HDZ-induced expression of c-Fos in the rostral ventrolateral medulla (RVLM) was comparable between groups. In contrast, phenylephrine (PE)-induced rise in MAP evoked markedly attenuated bradycardia with dramatically reduced c-Fos expression in the nucleus tractus solitarius (NTS) of adult OZR compared with LZR. However, in juvenile rats, PE-induced hypertension evoked comparable bradycardia in OZR and LZR with similar or augmented c-Fos expression in NTS of the OZR. In urethane-anesthetized rats, microinjections of glutamate into NTS evoked equivalent decreases in SNA, heart rate (HR), and MAP in juvenile OZR and LZR, but attenuated decreases in SNA and MAP in adult OZR. In contrast, microinjections of glutamate into the caudal ventrolateral medulla, a target of barosensitive NTS neurons, evoked comparable decreases in SNA, HR, and MAP in adult OZR and LZR. These data suggest that OZR develop impaired glutamatergic activation of the NTS, which likely contributes to attenuated baroreflexes in adult OZR. PMID:24573182

  5. Development of attenuated baroreflexes in obese Zucker rats coincides with impaired activation of nucleus tractus solitarius.

    PubMed

    Guimaraes, Priscila S; Huber, Domitila A; Campagnole-Santos, Maria J; Schreihofer, Ann M

    2014-05-01

    Adult obese Zucker rats (OZR; >12 wk) develop elevated sympathetic nerve activity (SNA) and mean arterial pressure (MAP) with impaired baroreflexes compared with adult lean Zucker rats (LZR) and juvenile OZR (6-7 wk). In adult OZR, baroreceptor afferent nerves respond normally to changes in MAP, whereas electrical stimulation of baroreceptor afferent fibers produces smaller reductions in SNA and MAP compared with LZR. We hypothesized that impaired baroreflexes in OZR are linked to reduced activation of brain stem sites that mediate baroreflexes. In conscious adult rats, a hydralazine (HDZ)-induced reduction in MAP evoked tachycardia that was initially blunted in OZR, but equivalent to LZR within 5 min. In agreement, HDZ-induced expression of c-Fos in the rostral ventrolateral medulla (RVLM) was comparable between groups. In contrast, phenylephrine (PE)-induced rise in MAP evoked markedly attenuated bradycardia with dramatically reduced c-Fos expression in the nucleus tractus solitarius (NTS) of adult OZR compared with LZR. However, in juvenile rats, PE-induced hypertension evoked comparable bradycardia in OZR and LZR with similar or augmented c-Fos expression in NTS of the OZR. In urethane-anesthetized rats, microinjections of glutamate into NTS evoked equivalent decreases in SNA, heart rate (HR), and MAP in juvenile OZR and LZR, but attenuated decreases in SNA and MAP in adult OZR. In contrast, microinjections of glutamate into the caudal ventrolateral medulla, a target of barosensitive NTS neurons, evoked comparable decreases in SNA, HR, and MAP in adult OZR and LZR. These data suggest that OZR develop impaired glutamatergic activation of the NTS, which likely contributes to attenuated baroreflexes in adult OZR.

  6. Baroreceptor activation attenuates attentional effects on pain-evoked potentials.

    PubMed

    Gray, Marcus A; Minati, Ludovico; Paoletti, Giulia; Critchley, Hugo D

    2010-12-01

    Focused attention typically enhances neural nociceptive responses, reflected electroencephalographically as increased amplitude of pain-evoked event-related potentials (ERPs). Additionally, pain-evoked ERPs are attenuated by hypertension and baroreceptor activity, through as yet unclear mechanisms. There is indirect evidence that these two effects may interact, suggesting that baroreceptor-related modulation of nociception is more than a low-level gating phenomenon. To address this hypothesis, we explored in a group of healthy participants the combined effects of cue-induced expectancy and baroreceptor activity on the amplitude of pain-evoked ERPs. Brief nociceptive skin stimuli were delivered during a simple visual task; half were preceded by a visual forewarning cue, and half were unpredictable. Nociceptive stimuli were timed to coincide either with systole (maximum activation of cardiac baroreceptors) or with diastole (minimum baroreceptor activation). We observed a strong interaction between expectancy and cardiac timing for the amplitude of the P2 ERP component; no effects were observed for the N2 component. Cued stimuli were associated with larger P2 amplitude, but this effect was abolished for stimuli presented during baroreceptor activation. No cardiac timing effect was observed for un-cued stimuli. Taken together, these findings suggest a close integration of cognitive-affective aspects of expectancy and baroreceptor influences on pain, and as such may cast further light on mechanisms underlying mental and physiological contributions to clinical pain.

  7. Attenuation of synaptic toxicity and MARK4/PAR1-mediated Tau phosphorylation by methylene blue for Alzheimer’s disease treatment

    PubMed Central

    Sun, Wenchao; Lee, Seongsoo; Huang, Xiaoran; Liu, Song; Inayathullah, Mohammed; Kim, Kwang-Min; Tang, Hongxiang; Ashford, J. Wesson; Rajadas, Jayakumar

    2016-01-01

    Alzheimer’s disease (AD) is a neurodegenerative disease characterized by genotypic and phenotypic heterogeneity. Critical components of the two AD pathological pathways, Aβ-amyloidosis and Tauopathy, have been considered as therapeutic targets. Among them, much effort is focused on aberrant Tau phosphorylation and targeting Tau-phosphorylating kinases. Methylene blue (MB), a phenothiazine dye that crosses the blood-brain barrier, has been shown to hit multiple molecular targets involved in AD and have beneficial effects in clinical studies. Here we present evidence that microtubule affinity-regulating kinase (MARK4) is a novel target of MB. MB partially rescued the synaptic toxicity in Drosophila larva overexpressing PAR1 (MARK analog). In 293T culture, MB decreased MARK4-mediated Tau phosphorylation in a dose dependent manner. Further studies revealed a two-fold mechanism by MB including down-regulation of MARK4 protein level through ubiquitin-proteasome pathway and inhibition of MARK4 kinase activity in vitro. This study highlights the importance of MARK4 as a viable target for Tauopathy and provides fresh insight into the complex mechanism used by MB to treat AD. PMID:27708431

  8. Resveratrol attenuates hypoxia-induced neurotoxicity through inhibiting microglial activation.

    PubMed

    Zhang, Qun; Yuan, Lin; Zhang, Qingrui; Gao, Yan; Liu, Guangheng; Xiu, Meng; Wei, Xiang; Wang, Zhen; Liu, Dexiang

    2015-09-01

    Resveratrol is a natural polyphenol enriched in Polygonum cuspidatum and has been found to afford neuroprotective effects against neuroinflammation in the brain. Activated microglia can secrete various pro-inflammatory cytokines and neurotoxic mediators, which may contribute to hypoxic brain injuries. The aim of this study is to investigate the potential role of resveratrol in attenuating hypoxia-induced neurotoxicity via its anti-inflammatory actions through in vitro models of the BV-2 microglial cell line and primary microglia. We found that resveratrol significantly inhibited hypoxia-induced microglial activation and reduced subsequent release of pro-inflammatory factors. In addition, resveratrol inhibited the hypoxia-induced degradation of IκB-alpha and phosphorylation of p65 NF-κB protein. Hypoxia-induced ERK1/2 and JNK phosphorylation was also strongly inhibited by resveratrol, whereas resveratrol had no effect on hypoxia-stimulated p38 MAPK phosphorylation. Importantly, treating primary cortical neurons with conditioned medium (CM) from hypoxia-stimulated microglia induced neuronal apoptosis, which was reversed by CM co-treated with resveratrol. Taken together, resveratrol exerts neuroprotection against hypoxia-induced neurotoxicity through its anti-inflammatory effects in microglia. These effects were mediated, at least in part, by suppressing the activation of NF-ĸB, ERK and JNK MAPK signaling pathways. PMID:26225925

  9. Fractalkine Attenuates Microglial Cell Activation Induced by Prenatal Stress

    PubMed Central

    Ślusarczyk, Joanna; Trojan, Ewa; Głombik, Katarzyna; Chamera, Katarzyna; Roman, Adam; Budziszewska, Bogusława; Basta-Kaim, Agnieszka

    2016-01-01

    The potential contribution of inflammation to the development of neuropsychiatric diseases has recently received substantial attention. In the brain, the main immune cells are the microglia. As they are the main source of inflammatory factors, it is plausible that the regulation of their activation may be a potential therapeutic target. Fractalkine (CX3CL1) and its receptor CX3CR1 play a crucial role in the control of the biological activity of the microglia. In the present study, using microglial cultures we investigated whether fractalkine is able to reverse changes in microglia caused by a prenatal stress procedure. Our study found that the microglia do not express fractalkine. Prenatal stress decreases the expression of the fractalkine receptor, which in turn is enhanced by the administration of exogenous fractalkine. Moreover, treatment with fractalkine diminishes the prenatal stress-induced overproduction of proinflammatory factors such as IL-1β, IL-18, IL-6, TNF-α, CCL2, or NO in the microglial cells derived from prenatally stressed newborns. In conclusion, the present results revealed that the pathological activation of microglia in prenatally stressed newborns may be attenuated by fractalkine administration. Therefore, understanding of the role of the CX3CL1-CX3CR1 system may help to elucidate the mechanisms underlying the neuron-microglia interaction and its role in pathological conditions in the brain. PMID:27239349

  10. NSAIDs attenuate hyperalgesia induced by TRP channel activation

    PubMed Central

    Nozadze, Ivliane; Tsiklauri, Nana; Gurtskaia, Gulnaz; Tsagareli, Merab G.

    2016-01-01

    Transient receptor potential (TRP) cation channels have been extensively investigated as targets for analgesic drug discovery. Because some non-steroidal anti-inflammatory drugs (NSAIDs) are structural analogs of prostaglandins (mediators of inflammation) and NSAIDs attenuate heat nociception and mechanical allodynia in models of inflammatory and neuropathic pain, we examined three widely used NSAIDs (diclofenac, ketorolac, and xefocam) on the activation of TRPA1 and TRPV1 channels using thermal paw withdrawal (Hargreaves) test and mechanical paw withdrawal (von Frey) test in male rats. Thermal withdrawal latencies and mechanical thresholds for both hind paws were obtained with 5, 15, 30, 45, 60, and 120 min intraplantar post-injection of TRPA1 agonizts, allyl isothiocyanate (AITC) (a natural compound of mustard oil) and cinnamaldehyde (CA), and TRPV1 agonist capsaicin or vehicle. Twenty minutes prior to the start of the experiment with TRP agonizts, diclofenac, ketorolac or xefocam were pre-injected in the same hindpaw and animals were examined by these two tests. After pretreatment of all three NSAIDs in the ipsilateral (injected) hindpaw that produced strong antinociceptive effects, AITC, CA, and capsaicin caused significant decreases in latency of the thermal withdrawal reflex compared with vehicle or the contralateral hindpaw. The same findings were observed for the paw withdrawal threshold. In approximately 30 min the effects of CA, AITC, and capsaicin returned to baseline. The data are different from our previous evidence, where TRPA1 agonizts AITC and CA and TRPV1 agonist capsaicin produced hyperalgesia for nearly 2 h and resulted in facilitation of these withdrawal reflexes (Tsagareli et al., 2010, 2013). Thus, our data showing that NSAIDs suppress thermal and mechanical hyperalgesia following TRP activation could presumably due to inactivation or desensitization of TRPA1 and TRPV1 channels by NSAIDs. PMID:26909384

  11. Endogenous n-3 Polyunsaturated Fatty Acids Attenuate T Cell-Mediated Hepatitis via Autophagy Activation.

    PubMed

    Li, Yanli; Tang, Yuan; Wang, Shoujie; Zhou, Jing; Zhou, Jia; Lu, Xiao; Bai, Xiaochun; Wang, Xiang-Yang; Chen, Zhengliang; Zuo, Daming

    2016-01-01

    Omega-3 polyunsaturated fatty acids (n-3 PUFAs) exert anti-inflammatory effects in several liver disorders, including cirrhosis, acute liver failure, and fatty liver disease. To date, little is known about their role in immune-mediated liver diseases. In this study, we used fat-1 transgenic mice rich in endogenous n-3 PUFAs to examine the role of n-3 PUFAs in immune-mediated liver injury. Concanavalin A (Con A) was administered intravenously to wild-type (WT) and fat-1 transgenic mice to induce T cell-mediated hepatitis. Reduced liver damage was shown in Con A-administrated fat-1 transgenic mice, as evidenced by decreased mortality, attenuated hepatic necrosis, lessened serum alanine aminotransferase activity, and inhibited production of pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-17A, and IFN-γ). In vivo and in vitro studies demonstrated that n-3 PUFAs significantly inhibited the activation of hepatic T cells and the differentiation of Th1 cells after Con A challenge. Further studies showed that n-3 PUFAs markedly increased autophagy level in Con A-treated fat-1 T cells compared with the WT counterparts. Blocking hepatic autophagy activity with chloroquine diminished the differences in T cell activation and liver injury between Con A-injected WT and fat-1 transgenic mice. We conclude that n-3 PUFAs limit Con A-induced hepatitis via an autophagy-dependent mechanism and could be exploited as a new therapeutic approach for autoimmune hepatitis.

  12. Endogenous n-3 Polyunsaturated Fatty Acids Attenuate T Cell-Mediated Hepatitis via Autophagy Activation

    PubMed Central

    Li, Yanli; Tang, Yuan; Wang, Shoujie; Zhou, Jing; Zhou, Jia; Lu, Xiao; Bai, Xiaochun; Wang, Xiang-Yang; Chen, Zhengliang; Zuo, Daming

    2016-01-01

    Omega-3 polyunsaturated fatty acids (n-3 PUFAs) exert anti-inflammatory effects in several liver disorders, including cirrhosis, acute liver failure, and fatty liver disease. To date, little is known about their role in immune-mediated liver diseases. In this study, we used fat-1 transgenic mice rich in endogenous n-3 PUFAs to examine the role of n-3 PUFAs in immune-mediated liver injury. Concanavalin A (Con A) was administered intravenously to wild-type (WT) and fat-1 transgenic mice to induce T cell-mediated hepatitis. Reduced liver damage was shown in Con A-administrated fat-1 transgenic mice, as evidenced by decreased mortality, attenuated hepatic necrosis, lessened serum alanine aminotransferase activity, and inhibited production of pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-17A, and IFN-γ). In vivo and in vitro studies demonstrated that n-3 PUFAs significantly inhibited the activation of hepatic T cells and the differentiation of Th1 cells after Con A challenge. Further studies showed that n-3 PUFAs markedly increased autophagy level in Con A-treated fat-1 T cells compared with the WT counterparts. Blocking hepatic autophagy activity with chloroquine diminished the differences in T cell activation and liver injury between Con A-injected WT and fat-1 transgenic mice. We conclude that n-3 PUFAs limit Con A-induced hepatitis via an autophagy-dependent mechanism and could be exploited as a new therapeutic approach for autoimmune hepatitis.

  13. Absence of canonical marks of active chromatin in developmentally regulated genes.

    PubMed

    Pérez-Lluch, Sílvia; Blanco, Enrique; Tilgner, Hagen; Curado, Joao; Ruiz-Romero, Marina; Corominas, Montserrat; Guigó, Roderic

    2015-10-01

    The interplay of active and repressive histone modifications is assumed to have a key role in the regulation of gene expression. In contrast to this generally accepted view, we show that the transcription of genes temporally regulated during fly and worm development occurs in the absence of canonically active histone modifications. Conversely, strong chromatin marking is related to transcriptional and post-transcriptional stability, an association that we also observe in mammals. Our results support a model in which chromatin marking is associated with the stable production of RNA, whereas unmarked chromatin would permit rapid gene activation and deactivation during development. In the latter case, regulation by transcription factors would have a comparatively more important regulatory role than chromatin marks.

  14. Nrf2 activation attenuates both orthodontic tooth movement and relapse.

    PubMed

    Kanzaki, H; Shinohara, F; Itohiya-Kasuya, K; Ishikawa, M; Nakamura, Y

    2015-06-01

    During orthodontic tooth movement, osteoclasts resorb the alveolar bone at the compress side of periodontium. Reactive oxygen species (ROS) works as intracellular signaling molecules of RANKL during osteoclastogenesis, although ROS has cytotoxicity against cells such as lipid oxidation. To deal with oxidative stress, cells have a defense system that is scavenging ROS by augmented antioxidative stress enzymes via transcriptional regulation with nuclear factor E2-related factor 2 (Nrf2). Previously, we reported that augmented antioxidative stress enzymes by Nrf2-gene transfer inhibited bone destruction. In the present study, we examined the effects of Nrf2 activation on osteoclastogenesis and, thereby, orthodontic tooth movement and orthodontic relapse. Mouse macrophage cell line RAW264.7 cells were used as osteoclast progenitor cells and stimulated with recombinant RANKL (100 ng/mL) with or without Nrf2 activator sulforaphane (SFN) and epigallocatechin gallate (EGCG) or ROS scavenger catechin. Osteoclastogenesis, resorption activity, and osteoclast marker gene expression were examined. Intracellular ROS was analyzed by flow cytometry. Maxillary first molars of C57BL6 male mice were moved palatally with 0.012-inch NiTi wire (100-mN force); SFN or EGCG was injected into the palatal gingiva once a week; and phosphate buffered saline was injected on the contralateral side. Tooth movement was monitored using a stone model with precise impression, and the amount of the tooth movement was compared among groups. SFN and EGCG significantly, but catechin weakly, inhibited RANKL-mediated osteoclastogenesis in vitro. Western blot analysis revealed that SFN and EGCG augmented the nuclear translocation of Nrf2 and the expression of anti-oxidative stress enzymes such as HO-1, although catechin did not. SFN and EGCG significantly, but catechin weakly, attenuated the intracellular ROS. Finally, animal experiment revealed that both SFN and EGCG successfully inhibited the orthodontic

  15. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees.

    PubMed

    van der Poll, T; Levi, M; Hack, C E; ten Cate, H; van Deventer, S J; Eerenberg, A J; de Groot, E R; Jansen, J; Gallati, H; Büller, H R

    1994-04-01

    The role of interleukin 6 (IL-6) in the toxic sequelae of sepsis is controversial. To assess the part of IL-6 in inflammatory responses to endotoxin, we investigated eight chimpanzees after either a bolus intravenous injection of Escherichia coli endotoxin (n = 4; 4 ng/kg) or after the same dose of endotoxin with a simultaneous bolus intravenous injection of an anti-IL-6 mAb (30 mg; n = 4). Anti-IL-6 did not affect the induction of the cytokine network (tumor necrosis factor [TNF], soluble TNF receptors types I and II, and IL-8) by endotoxin, nor did it influence the occurrence of a neutrophilic leukocytosis and neutrophil degranulation, as monitored by the measurement of elastase-alpha 1-antitrypsin complexes. In contrast, anti-IL-6 markedly attenuated endotoxin-induced activation of coagulation, monitored with the plasma levels of the prothrombin fragment F1+2 and thrombin-antithrombin III complexes, whereas activation of fibrinolysis, determined with the plasma concentrations of plasmin-alpha 2-antiplasmin complexes, remained unaltered. We conclude that IL-6 does not have a feedback effect on the release of other cytokines after injection of endotoxin, and that it is not involved in endotoxin-induced neutrophilia or neutrophil degranulation. IL-6 is, however, an important intermediate factor in activation of coagulation in low grade endotoxemia in chimpanzees.

  16. Survival and Activity of lux-Marked Aeromonas salmonicida in Seawater

    PubMed Central

    Ferguson, Y.; Glover, L. A.; McGillivray, D. M.; Prosser, J. I.

    1995-01-01

    The fish pathogen Aeromonas salmonicida was chromosomally marked with genes encoding bacterial luciferase, luxAB, isolated from Vibrio fischeri, resulting in constitutive luciferase production. During exponential growth in liquid batch culture, luminescence was directly proportional to biomass concentration, and luminometry provided a lower detection limit of approximately 10(sup3) cells ml(sup-1), 1 order of magnitude more sensitive than enzyme-linked immunosorbent assay detection. In sterile seawater at 4(deg)C, lux-marked A. salmonicida entered a dormant, nonculturable state and population activity decreased rapidly. The activity per viable cell, however, increased by day 4, indicating that a proportion of the population remained active and culturable. Putative dormant cells were not resuscitated after the addition of a range of substrates. PMID:16535133

  17. The contribution of activated processes to Q. [stress corrosion cracking in seismic wave attenuation

    NASA Technical Reports Server (NTRS)

    Spetzler, H. A.; Getting, I. C.; Swanson, P. L.

    1980-01-01

    The possible role of activated processes in seismic attenuation is investigated. In this study, a solid is modeled by a parallel and series configuration of dashpots and springs. The contribution of stress and temperature activated processes to the long term dissipative behavior of this system is analyzed. Data from brittle rock deformation experiments suggest that one such process, stress corrosion cracking, may make a significant contribution to the attenuation factor, Q, especially for long period oscillations under significant tectonic stress.

  18. Two-dimensional seismic attenuation images of Stromboli Island using active data

    NASA Astrophysics Data System (ADS)

    Prudencio, J.; Del Pezzo, E.; Ibáñez, J. M.; Giampiccolo, E.; Patané, D.

    2015-03-01

    In this work we present intrinsic and scattering seismic attenuation 2-D images of Stromboli Volcano. We used 21,953 waveforms from air gun shots fired by an oceanographic vessel and recorded at 33 inland and 10 ocean bottom seismometer seismic stations. Coda wave envelopes of the filtered seismic traces were fitted to the energy transport equation in the diffusion approximation, obtaining a couple of separate Qi and Qs in six frequency bands. Using numerically estimated sensitivity kernels for coda waves, separate images of each quality factor were produced. Results appear stable and robust. They show that scattering attenuation prevails over intrinsic attenuation. The scattering pattern shows a strong concordance with the tectonic lineaments in the area, while an area of high total attenuation coincides with the zone where most of the volcanic activity occurs. Our results provide evidence that the most important attenuation effects in volcanic areas are associated with the presence of geological heterogeneities.

  19. A triterpene saponin from Tribulus terrestris attenuates apoptosis in cardiocyte via activating PKC signalling transduction pathway.

    PubMed

    Sun, Wei; Li, Hong; Yang, Shi-Jie

    2008-01-01

    The present study was conducted to examine the role of hecogenin-3-O-beta-D-glucopyranosyl(1-->4)-beta-D-galactopyranoside (1), which is a triterpene saponin of Tribulus terrestris in cardiocytes during chemical hypoxia-ischaemia in vitro. Neonatal rat ventricular myocytes were isolated by collagenase digestion and treated with NaCN for 12 h. Cell apoptosis was defined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) and flow cytometry. [Ca(2+)] was measured by confocal microscopy. There was a marked increase in the expression of the anti-apoptotic protein, Bcl-2, by NaCN. This change was increased by the saponin 1. PKCepsilon protein contents were increased in the cardiocyte membrane fraction in response to NaCN. PKCepsilon activation was augmented by the saponin 1. Inhibition of PKCepsilon with inhibitory peptide prevented Bcl-2 expression. Moreover, the saponin attenuated the apoptosis in cardiocyte in response to NaCN. It is therefore suggested that the saponin 1 may play a role in cardiocyte survival via PKCepsilon and Bcl-2.

  20. Joint reconstruction of activity and attenuation map using LM SPECT emission data

    NASA Astrophysics Data System (ADS)

    Jha, Abhinav K.; Clarkson, Eric; Kupinski, Matthew A.; Barrett, Harrison H.

    2013-03-01

    Attenuation and scatter correction in single photon emission computed tomography (SPECT) imaging often requires a computed tomography (CT) scan to compute the attenuation map of the patient. This results in increased radiation dose for the patient, and also has other disadvantages such as increased costs and hardware complexity. Attenuation in SPECT is a direct consequence of Compton scattering, and therefore, if the scattered photon data can give information about the attenuation map, then the CT scan may not be required. In this paper, we investigate the possibility of joint reconstruction of the activity and attenuation map using list- mode (LM) SPECT emission data, including the scattered-photon data. We propose a path-based formalism to process scattered-photon data. Following this, we derive analytic expressions to compute the Craḿer-Rao bound (CRB) of the activity and attenuation map estimates, using which, we can explore the fundamental limit of information-retrieval capacity from LM SPECT emission data. We then suggest a maximum-likelihood (ML) scheme that uses the LM emission data to jointly reconstruct the activity and attenuation map. We also propose an expectation-maximization (EM) algorithm to compute the ML solution.

  1. Endogenous n-3 Polyunsaturated Fatty Acids Attenuate T Cell-Mediated Hepatitis via Autophagy Activation.

    PubMed

    Li, Yanli; Tang, Yuan; Wang, Shoujie; Zhou, Jing; Zhou, Jia; Lu, Xiao; Bai, Xiaochun; Wang, Xiang-Yang; Chen, Zhengliang; Zuo, Daming

    2016-01-01

    Omega-3 polyunsaturated fatty acids (n-3 PUFAs) exert anti-inflammatory effects in several liver disorders, including cirrhosis, acute liver failure, and fatty liver disease. To date, little is known about their role in immune-mediated liver diseases. In this study, we used fat-1 transgenic mice rich in endogenous n-3 PUFAs to examine the role of n-3 PUFAs in immune-mediated liver injury. Concanavalin A (Con A) was administered intravenously to wild-type (WT) and fat-1 transgenic mice to induce T cell-mediated hepatitis. Reduced liver damage was shown in Con A-administrated fat-1 transgenic mice, as evidenced by decreased mortality, attenuated hepatic necrosis, lessened serum alanine aminotransferase activity, and inhibited production of pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-17A, and IFN-γ). In vivo and in vitro studies demonstrated that n-3 PUFAs significantly inhibited the activation of hepatic T cells and the differentiation of Th1 cells after Con A challenge. Further studies showed that n-3 PUFAs markedly increased autophagy level in Con A-treated fat-1 T cells compared with the WT counterparts. Blocking hepatic autophagy activity with chloroquine diminished the differences in T cell activation and liver injury between Con A-injected WT and fat-1 transgenic mice. We conclude that n-3 PUFAs limit Con A-induced hepatitis via an autophagy-dependent mechanism and could be exploited as a new therapeutic approach for autoimmune hepatitis. PMID:27679638

  2. Endogenous n-3 Polyunsaturated Fatty Acids Attenuate T Cell-Mediated Hepatitis via Autophagy Activation

    PubMed Central

    Li, Yanli; Tang, Yuan; Wang, Shoujie; Zhou, Jing; Zhou, Jia; Lu, Xiao; Bai, Xiaochun; Wang, Xiang-Yang; Chen, Zhengliang; Zuo, Daming

    2016-01-01

    Omega-3 polyunsaturated fatty acids (n-3 PUFAs) exert anti-inflammatory effects in several liver disorders, including cirrhosis, acute liver failure, and fatty liver disease. To date, little is known about their role in immune-mediated liver diseases. In this study, we used fat-1 transgenic mice rich in endogenous n-3 PUFAs to examine the role of n-3 PUFAs in immune-mediated liver injury. Concanavalin A (Con A) was administered intravenously to wild-type (WT) and fat-1 transgenic mice to induce T cell-mediated hepatitis. Reduced liver damage was shown in Con A-administrated fat-1 transgenic mice, as evidenced by decreased mortality, attenuated hepatic necrosis, lessened serum alanine aminotransferase activity, and inhibited production of pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-17A, and IFN-γ). In vivo and in vitro studies demonstrated that n-3 PUFAs significantly inhibited the activation of hepatic T cells and the differentiation of Th1 cells after Con A challenge. Further studies showed that n-3 PUFAs markedly increased autophagy level in Con A-treated fat-1 T cells compared with the WT counterparts. Blocking hepatic autophagy activity with chloroquine diminished the differences in T cell activation and liver injury between Con A-injected WT and fat-1 transgenic mice. We conclude that n-3 PUFAs limit Con A-induced hepatitis via an autophagy-dependent mechanism and could be exploited as a new therapeutic approach for autoimmune hepatitis. PMID:27679638

  3. Clusterless Decoding of Position From Multiunit Activity Using A Marked Point Process Filter

    PubMed Central

    Deng, Xinyi; Liu, Daniel F.; Kay, Kenneth; Frank, Loren M.; Eden, Uri T.

    2016-01-01

    Point process filters have been applied successfully to decode neural signals and track neural dynamics. Traditionally, these methods assume that multiunit spiking activity has already been correctly spike-sorted. As a result, these methods are not appropriate for situations where sorting cannot be performed with high precision such as real-time decoding for brain-computer interfaces. As the unsupervised spike-sorting problem remains unsolved, we took an alternative approach that takes advantage of recent insights about clusterless decoding. Here we present a new point process decoding algorithm that does not require multiunit signals to be sorted into individual units. We use the theory of marked point processes to construct a function that characterizes the relationship between a covariate of interest (in this case, the location of a rat on a track) and features of the spike waveforms. In our example, we use tetrode recordings, and the marks represent a four-dimensional vector of the maximum amplitudes of the spike waveform on each of the four electrodes. In general, the marks may represent any features of the spike waveform. We then use Bayes’ rule to estimate spatial location from hippocampal neural activity. We validate our approach with a simulation study and with experimental data recorded in the hippocampus of a rat moving through a linear environment. Our decoding algorithm accurately reconstructs the rat’s position from unsorted multiunit spiking activity. We then compare the quality of our decoding algorithm to that of a traditional spike-sorting and decoding algorithm. Our analyses show that the proposed decoding algorithm performs equivalently or better than algorithms based on sorted single-unit activity. These results provide a path toward accurate real-time decoding of spiking patterns that could be used to carry out content-specific manipulations of population activity in hippocampus or elsewhere in the brain. PMID:25973549

  4. Attenuation Properties of Fontainebleau Sandstone During True-Triaxial Deformation using Active and Passive Ultrasonics

    NASA Astrophysics Data System (ADS)

    Goodfellow, S. D.; Tisato, N.; Ghofranitabari, M.; Nasseri, M. H. B.; Young, R. P.

    2015-11-01

    Active and passive ultrasonic methods were used to study the evolution of attenuation properties in a sample of Fontainebleau sandstone during true-triaxial deformation. A cubic sample of Fontainebleau sandstone (80 mm × 80 mm × 80 mm) was deformed under true-triaxial stresses until failure. From the stress state: σ _3 = 5 MPa and σ _1 = σ _2 = 35 MPa, σ _1 was increased at a constant displacement rate until the specimen failed. Acoustic emission (AE) activity was monitored by 18 piezoelectric sensors and bandpass filtered between 100 kHz and 1 MHz. A source location analysis was performed on discrete AE data harvested from the continuous record where 48,502 events were locatable inside the sample volume. AE sensors were sequentially pulsed during periodic P-wave surveys among 135 raypaths. Analytical solutions for Biot, squirt flow, viscous shear, and scattering attenuation were used to discuss to observed attenuation at various stages of the experiment. We concluded that initial attenuation anisotropy was stress induced and resulted from friction and squirt flow. Later attenuation of the high-frequency spectrum was attributed to scattering as a result of the formation of large macroscopic vertical fractures. Passive (AE) ultrasonic data produced similar information to that from active data but with enhanced temporal and spacial resolution.

  5. Vibration attenuation of aircraft structures utilizing active materials

    NASA Astrophysics Data System (ADS)

    Agnes, Gregory S.; Whitehouse, Stephen R.; Mackaman, John R.

    1993-09-01

    The need for active vibration control for airborne laser systems was demonstrated during the late 1970s by the Airborne Laser Laboratory. Other possible applications include sonic fatigue alleviation, reduction of buffet induced fatigue, vibration control for embedded antennae, and active aeroelastic control. The purpose of this paper is to present an overview of active vibration control technology and its application to aircraft. Classification of classic aircraft vibration problems and currently available solutions are used to provide a framework for the study. Current solutions are classified as being either passive or active and by the methodology (modal modification or addition) used to reduce vibration. Possible applications for this technology in aircraft vibration control are presented within this framework to demonstrate the increased versatility active materials technologies provide the designer. An in- depth study of an active pylon to reduce wing/store vibration is presented as an example. Finally, perceived gaps in the existing technology base are identified and both on-going and future research plans in these areas are discussed.

  6. Curcumin attenuates diet-induced hepatic steatosis by activating AMP-activated protein kinase.

    PubMed

    Um, Min Young; Hwang, Kwang Hyun; Ahn, Jiyun; Ha, Tae Youl

    2013-09-01

    Curcumin is a well-known component of traditional turmeric (Curcuma longa), which has been reported to prevent obesity and diabetes. However, the effect of curcumin on hepatic lipid metabolism remains unclear. The aim of this study was to examine the effects of curcumin on hepatic steatosis in high-fat/cholesterol diet (HFD)-induced obese mice. Male C57BL/6J mice were fed a normal diet (ND), HFD or HFD with 0.15% curcumin (HFD+C) for 11 weeks. We found that curcumin significantly lowered the body-weight and adipose tissue weight of mice in the HFD+C group compared with the findings for the HFD group (p < 0.05). The levels of total cholesterol, fasting glucose and insulin in serum were decreased, and HFD-induced impairment of insulin sensitivity was improved by curcumin supplementation (p < 0.05). Curcumin protected against the development of hepatic steatosis by reducing hepatic fat accumulation. Moreover, curcumin activated AMP-activated protein kinase (AMPK) and elevated the gene expression of peroxisome proliferator-activated receptor alpha. By contrast, curcumin suppressed the HFD-mediated increases in sterol regulatory element-binding protein-1, acetyl-CoA carboxylase 1, fatty acid synthase and cluster of differentiation 36 expression. Taken together, these findings indicate that curcumin attenuates HFD-induced hepatic steatosis by regulating hepatic lipid metabolism via AMPK activation, suggesting its use as a therapeutic for hepatic steatosis.

  7. Ghrelin Inhibits Oligodendrocyte Cell Death by Attenuating Microglial Activation

    PubMed Central

    Lee, Jee Youn

    2014-01-01

    Background Recently, we reported the antiapoptotic effect of ghrelin in spinal cord injury-induced apoptotic cell death of oligodendrocytes. However, how ghrelin inhibits oligodendrocytes apoptosis, is still unknown. Therefore, in the present study, we examined whether ghrelin inhibits microglia activation and thereby inhibits oligodendrocyte apoptosis. Methods Using total cell extracts prepared from BV-2 cells activated by lipopolysaccharide (LPS) with or without ghrelin, the levels of p-p38 phosphor-p38 mitogen-activated protein kinase (p-p38MAPK), phospho-c-Jun N-terminal kinase (pJNK), p-c-Jun, and pro-nerve growth factor (proNGF) were examined by Western blot analysis. Reactive oxygen species (ROS) production was investigated by using dichlorodihydrofluorescein diacetate. To examine the effect of ghrelin on oligodendrocyte cell death, oligodendrocytes were cocultured in transwell chambers of 24-well plates with LPS-stimulated BV-2 cells. After 48 hours incubation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and terminal deoxynucleotidyl transferase 2'-deoxyuridine, 5'-triphosphate nick end labeling staining were assessed. Results Ghrelin treatment significantly decreased levels of p-p38MAPK, p-JNK, p-c-Jun, and proNGF in LPS-stimulated BV-2 cells. ROS production increased in LPS-stimulated BV-2 cells was also significantly inhibited by ghrelin treatment. In addition, ghrelin significantly inhibited oligodendrocyte cell death when cocultured with LPS-stimulated BV-2 cells. Conclusion Ghrelin inhibits oligodendrocyte cell death by decreasing proNGF and ROS production as well as p38MAPK and JNK activation in activated microglia as an anti-inflammatory hormone. PMID:25309797

  8. Autophagy activation attenuates renal ischemia-reperfusion injury in rats

    PubMed Central

    Zhang, Ya-Li; Cui, Li-Yan; Yang, Shuo

    2015-01-01

    Ischemia-reperfusion (I/R) injury is a leading cause of acute kidney injury (AKI), which is a common clinical complication but lacks effective therapies. This study investigated the role of autophagy in renal I/R injury and explored potential mechanisms in an established rat renal I/R injury model. Forty male Wistar rats were randomly divided into four groups: Sham, I/R, I/R pretreated with 3-methyladenine (3-MA, autophagy inhibitor), or I/R pretreated with rapamycin (autophagy activator). All rats were subjected to clamping of the left renal pedicle for 45 min after right nephrectomy, followed by 24 h of reperfusion. The Sham group underwent the surgical procedure without ischemia. 3-MA and rapamycin were injected 15 min before ischemia. Renal function was indicated by blood urea nitrogen and serum creatinine. Tissue samples from the kidneys were scored histopathologically. Autophagy was indicated by light chain 3 (LC3), Beclin-1, and p62 levels and the number of autophagic vacuoles. Apoptosis was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method and expression of caspase-3. Autophagy was activated after renal I/R injury. Inhibition of autophagy by 3-MA before I/R aggravated renal injury, with worsened renal function, higher renal tissue injury scores, and more tubular apoptosis. In contrast, rapamycin pretreatment ameliorated renal injury, with improved renal function, lower renal tissue injury scores, and inhibited apoptosis based on fewer TUNEL-positive cells and lower caspase-3 expression. Our results demonstrate that autophagy could be activated during I/R injury and play a protective role in renal I/R injury. The mechanisms were involved in the regulation of several autophagy and apoptosis-related genes. Furthermore, autophagy activator may be a promising therapy for I/R injury and AKI in the future. PMID:25898836

  9. Spatial distribution of intrinsic and scattering seismic attenuation in active volcanic islands - II: Deception Island images

    NASA Astrophysics Data System (ADS)

    Prudencio, Janire; Ibáñez, Jesús M.; García-Yeguas, Araceli; Del Pezzo, Edoardo; Posadas, Antonio M.

    2013-12-01

    In this work, we present regional maps of the inverse intrinsic quality factor (Qi-1), the inverse scattering quality factor (Qs-1) and total inverse quality factor (Qt-1) for the volcanic environment of Deception Island (Antarctica). Our attenuation study is based on diffusion approximation, which permits us to obtain the attenuation coefficients for every single couple source-receiver separately. The data set used in this research is derived from an active seismic experiment using more than 5200 offshore shots (air guns) recorded at 32 onshore seismic stations and four ocean bottom seismometers. To arrive at a regional distribution of these values, we used a new mapping technique based on a Gaussian space probability function. This approach led us to create `2-D probabilistic maps' of values of intrinsic and scattering seismic attenuation. The 2-D tomographic images confirm the existence of a high attenuation body below an inner bay of Deception Island. This structure, previously observed in 2-D and 3-D velocity tomography of the region, is associated with a massive magma reservoir. Magnetotelluric studies reach a similar interpretation of this strong anomaly. Additionally, we observed areas with lower attenuation effects that bear correlation with consolidated structures described in other studies and associated with the crystalline basement of the area. Our calculations of the transport mean-free path and absorption length for intrinsic attenuation gave respective values of ≈ 950 m and 5 km, which are lower than the values obtained in tectonic regions or volcanic areas such as Tenerife Island. However, as observed in other volcanic regions, our results indicate that scattering effects dominate strongly over the intrinsic attenuation.

  10. Ubiquitin in the activation and attenuation of innate antiviral immunity

    PubMed Central

    Heaton, Steven M.

    2016-01-01

    Viral infection activates danger signals that are transmitted via the retinoic acid–inducible gene 1–like receptor (RLR), nucleotide-binding oligomerization domain-like receptor (NLR), and Toll-like receptor (TLR) protein signaling cascades. This places host cells in an antiviral posture by up-regulating antiviral cytokines including type-I interferon (IFN-I). Ubiquitin modifications and cross-talk between proteins within these signaling cascades potentiate IFN-I expression, and inversely, a growing number of viruses are found to weaponize the ubiquitin modification system to suppress IFN-I. Here we review how host- and virus-directed ubiquitin modification of proteins in the RLR, NLR, and TLR antiviral signaling cascades modulate IFN-I expression. PMID:26712804

  11. Inhibition of NF-κB activity in the hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by modulating cytokines and attenuating oxidative stress

    SciTech Connect

    Yu, Xiao-Jing; Zhang, Dong-Mei; Jia, Lin-Lin; Qi, Jie; Song, Xin-Ai; Tan, Hong; Cui, Wei; Chen, Wensheng; Zhu, Guo-Qing; Qin, Da-Nian; Kang, Yu-Ming

    2015-05-01

    We hypothesized that chronic inhibition of NF-κB activity in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), attenuating nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase in the PVN of young spontaneously hypertensive rats (SHR). Young normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusions with NF–κB inhibitor pyrrolidine dithiocarbamate (PDTC) or vehicle for 4 weeks. SHR rats had higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, cardiomyocyte diameters of the left cardiac ventricle, and mRNA expressions of cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC). These SHR rats had higher PVN levels of proinflammatory cytokines (PICs), reactive oxygen species (ROS), the chemokine monocyte chemoattractant protein-1 (MCP-1), NAD(P)H oxidase activity, mRNA expression of NOX-2 and NOX-4, and lower PVN IL-10, and higher plasma levels of PICs and NE, and lower plasma IL-10. PVN infusion of NF-κB inhibitor PDTC attenuated all these changes. These findings suggest that NF-κB activation in the PVN increases sympathoexcitation and hypertensive response, which are associated with the increases of PICs and oxidative stress in the PVN; PVN inhibition of NF-κB activity attenuates PICs and oxidative stress in the PVN, thereby attenuates hypertension and cardiac hypertrophy. - Highlights: • Spontaneously hypertensive rats exhibit neurohormonal excitation in the PVN. • PVN inhibition of NF-κB attenuates hypertension-induced cardiac hypertrophy. • PVN inhibition of NF-κB attenuates hypertension-induced neurohormonal excitation. • PVN inhibition of NF-κB attenuates hypertension-induced imbalance of cytokines

  12. Morphine attenuates cholinergic nerve activity in human isolated colonic muscle.

    PubMed Central

    Burleigh, D. E.; Trout, S. J.

    1986-01-01

    The action of morphine on cholinergic nerves in human sigmoid taenia coli muscle strips (taenia) was investigated using a radiolabelling technique. Basal release of tritiated material from taenia was increased by electrical field stimulation (EFS). This increase was tetrodotoxin (3.14 microM)-sensitive and calcium-dependent. Analysis of basal and stimulated release of tritiated material indicated that evoked release (i.e. stimulated minus basal) is almost entirely due to an increase in [3H]-acetylcholine ([3H]-ACh) output. Evoked release of [3H]-ACh was dependent on the current strength and could be greatly reduced by exposing taenia to hemicholinium (34.8, 87.0 microM) before and during incubation with [3H]-choline (4 microCi ml-1, 15 Ci mmol-1). Spontaneous activity, muscle tone and the motor response of taenia to EFS were unaffected by morphine. Evoked, but not basal, release of tritiated material was inhibited by morphine (1.32-13.20 microM) in a concentration-dependent manner. The inhibition of release was frequency-dependent and naloxone (0.28 microM)-sensitive. The possible relationship between the effects of morphine on cholinergic nerves in taenia muscle and its actions in vivo are discussed. PMID:2873856

  13. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

    SciTech Connect

    Wu, Weibin; Zhu, Bo; Peng, Xiaomin; Zhou, Meiling; Jia, Dongwei; Gu, Jianxin

    2014-01-03

    Highlights: •FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. •Activation of FXR attenuated alcohol-induced liver injury and steatosis. •Activation of FXR attenuated cholestasis and oxidative stress in mouse liver. -- Abstract: Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients.

  14. Korean Red Ginseng attenuates ethanol-induced steatosis and oxidative stress via AMPK/Sirt1 activation

    PubMed Central

    Han, Jae Yun; Lee, Sangkyu; Yang, Ji Hye; Kim, Sunju; Sim, Juhee; Kim, Mi Gwang; Jeong, Tae Cheon; Ku, Sae Kwang; Cho, Il Je; Ki, Sung Hwan

    2014-01-01

    Background Alcoholic steatosis is the earliest and most common liver disease, and may precede the onset of more severe forms of liver injury. Methods The effect of Korean Red Ginseng extract (RGE) was tested in two murine models of ethanol (EtOH)-feeding and EtOH-treated hepatocytes. Results Blood biochemistry analysis demonstrated that RGE treatment improved liver function. Histopathology and measurement of hepatic triglyceride content verified the ability of RGE to inhibit fat accumulation. Consistent with this, RGE administration downregulated hepatic lipogenic gene induction and restored hepatic lipolytic gene repression by EtOH. The role of oxidative stress in the pathogenesis of alcoholic liver diseases is well established. Treatment with RGE attenuated EtOH-induced cytochrome P450 2E1, 4-hydroxynonenal, and nitrotyrosine levels. Alcohol consumption also decreased phosphorylation of adenosine monophosphate-activated protein kinase, which was restored by RGE. Moreover, RGE markedly inhibited fat accumulation in EtOH-treated hepatocytes, which correlated with a decrease in sterol regulatory element-binding protein-1 and a commensurate increase in sirtuin 1 and peroxisome proliferator-activated receptor-α expression. Interestingly, the ginsenosides Rb2 and Rd, but not Rb1, significantly inhibited fat accumulation in hepatocytes. Conclusion These results demonstrate that RGE and its ginsenoside components inhibit alcoholic steatosis and liver injury by adenosine monophosphate-activated protein kinase/sirtuin 1 activation both in vivo and in vitro, suggesting that RGE may have a potential to treat alcoholic liver disease. PMID:26045683

  15. Helping behavior induced by empathic concern attenuates anterior cingulate activation in response to others' distress.

    PubMed

    Kawamichi, Hiroaki; Yoshihara, Kazufumi; Sugawara, Sho K; Matsunaga, Masahiro; Makita, Kai; Hamano, Yuki H; Tanabe, Hiroki C; Sadato, Norihiro

    2016-01-01

    Helping behavior is motivated by empathic concern for others in distress. Although empathic concern is pervasive in daily life, its neural mechanisms remain unclear. Empathic concern involves the suppression of the emotional response to others' distress, which occurs when individuals distance themselves emotionally from the distressed individual. We hypothesized that helping behavior induced by empathic concern, accompanied by perspective-taking, would attenuate the neural activation representing aversive feelings. We also predicted reward system activation due to the positive feeling resulting from helping behavior. Participant underwent functional magnetic resonance imaging while playing a virtual ball-toss game. In some blocks ("concern condition"), one player ("isolated player") did not receive ball-tosses from other players. In this condition, participants increased ball-tosses to the isolated player (helping behavior). Participants then evaluated the improved enjoyment of the isolated player resulting from their helping behavior. Anterior cingulate activation during the concern condition was attenuated by the evaluation of the effect of helping behavior. The right temporoparietal junction, which is involved in perspective-taking and the dorsal striatum, part of the reward system, were also activated during the concern condition. These results suggest that humans can attenuate affective arousal by anticipating the positive outcome of empathic concern through perspective-taking. PMID:26032190

  16. Helping behavior induced by empathic concern attenuates anterior cingulate activation in response to others' distress.

    PubMed

    Kawamichi, Hiroaki; Yoshihara, Kazufumi; Sugawara, Sho K; Matsunaga, Masahiro; Makita, Kai; Hamano, Yuki H; Tanabe, Hiroki C; Sadato, Norihiro

    2016-01-01

    Helping behavior is motivated by empathic concern for others in distress. Although empathic concern is pervasive in daily life, its neural mechanisms remain unclear. Empathic concern involves the suppression of the emotional response to others' distress, which occurs when individuals distance themselves emotionally from the distressed individual. We hypothesized that helping behavior induced by empathic concern, accompanied by perspective-taking, would attenuate the neural activation representing aversive feelings. We also predicted reward system activation due to the positive feeling resulting from helping behavior. Participant underwent functional magnetic resonance imaging while playing a virtual ball-toss game. In some blocks ("concern condition"), one player ("isolated player") did not receive ball-tosses from other players. In this condition, participants increased ball-tosses to the isolated player (helping behavior). Participants then evaluated the improved enjoyment of the isolated player resulting from their helping behavior. Anterior cingulate activation during the concern condition was attenuated by the evaluation of the effect of helping behavior. The right temporoparietal junction, which is involved in perspective-taking and the dorsal striatum, part of the reward system, were also activated during the concern condition. These results suggest that humans can attenuate affective arousal by anticipating the positive outcome of empathic concern through perspective-taking.

  17. Neuroprotective Effect of 6-Paradol in Focal Cerebral Ischemia Involves the Attenuation of Neuroinflammatory Responses in Activated Microglia

    PubMed Central

    Park, Sung Hyuk; Chun, Kwang-Hoon; Kim, Sun Yeou; Shin, Dong Yun; Choi, Ji Woong

    2015-01-01

    Paradols are non-pungent and biotransformed metabolites of shogaols and reduce inflammatory responses as well as oxidative stress as shogaols. Recently, shogaol has been noted to possess therapeutic potential against several central nervous system (CNS) disorders, including cerebral ischemia, by reducing neuroinflammation in microglia. Therefore, paradol could be used to improve neuroinflammation-associated CNS disorders. Here, we synthesized paradol derivatives (2- to 10-paradols). Through the initial screening for anti-inflammatory activities using lipopolysaccharide (LPS)-stimulated BV2 microglia, 6-paradol was chosen to be the most effective compound without cytotoxicity. Pretreatment with 6-paradol reduced neuroinflammatory responses in LPS-stimulated BV2 microglia by a concentration-dependent manner, which includes reduced NO production by inhibiting iNOS upregulation and lowered secretion of proinflammatory cytokines (IL-6 and TNF-α). To pursue whether the beneficial in vitro effects of 6-paradol leads towards in vivo therapeutic effects on transient focal cerebral ischemia characterized by neuroinflammation, we employed middle cerebral artery occlusion (MCAO)/reperfusion (M/R). Administration of 6-paradol immediately after reperfusion significantly reduced brain damage in M/R-challenged mice as assessed by brain infarction, neurological deficit, and neural cell survival and death. Furthermore, as observed in cultured microglia, 6-paradol administration markedly reduced neuroinflammation in M/R-challenged brains by attenuating microglial activation and reducing the number of cells expressing iNOS and TNF-α, both of which are known to be produced in microglia following M/R challenge. Collectively, this study provides evidences that 6-paradol effectively protects brain after cerebral ischemia, likely by attenuating neuroinflammation in microglia, suggesting it as a potential therapeutic agent to treat cerebral ischemia. PMID:25789481

  18. Active vibration attenuating seat suspension for an armored helicopter crew seat

    NASA Astrophysics Data System (ADS)

    Sztein, Pablo Javier

    An Active Vibration Attenuating Seat Suspension (AVASS) for an MH-60S helicopter crew seat is designed to protect the occupants from harmful whole-body vibration (WBV). Magnetorheological (MR) suspension units are designed, fabricated and installed in a helicopter crew seat. These MR isolators are built to work in series with existing Variable Load Energy Absorbers (VLEAs), have minimal increase in weight, and maintain crashworthiness for the seat system. Refinements are discussed, based on testing, to minimize friction observed in the system. These refinements include the addition of roller bearings to replace friction bearings in the existing seat. Additionally, semi-active control of the MR dampers is achieved using special purpose built custom electronics integrated into the seat system. Experimental testing shows that an MH-60S retrofitted with AVASS provides up to 70.65% more vibration attenuation than the existing seat configuration as well as up to 81.1% reduction in vibration from the floor.

  19. Attenuation of microglial and neuronal activation in the brain by ICV minocycline following myocardial infarction.

    PubMed

    Dworak, Melissa; Stebbing, Martin; Kompa, Andrew R; Rana, Indrajeetsinh; Krum, Henry; Badoer, Emilio

    2014-10-01

    Following myocardial infarction, microglia, the immune cells in the central nervous system, become activated in the hypothalamic paraventricular nucleus (PVN) suggesting inflammation in this nucleus. Little is known about other brain nuclei. In the present study, we investigated whether the rostral ventrolateral medulla (RVLM), the nucleus tractus solitarius (NTS) and the periaqueductal grey (PAG), regions known to have important cardiovascular regulatory functions, also show increased microglial activation and whether this coincides with increased neuronal activity. We also investigated whether minocycline inhibited microglial activation and whether this also affected neuronal activity and cardiac function. Compared to controls there was a significant increase in the proportion of activated microglia and neuronal activation in the PVN, RVLM, NTS and PAG, 12weeks following myocardial infarction (P<0.001). Intracebroventricular infusion of minocycline (beginning one week prior to infarction) significantly attenuated the increase in microglial activation by at least 50% in the PVN, RVLM, PAG and NTS, and neuronal activation was significantly reduced by 50% in the PVN and virtually abolished in the PAG, RVLM and NTS. Cardiac function (percent fractional shortening) was significantly reduced by 55% following myocardial infarction but this was not ameliorated by minocycline treatment. The results suggest that following myocardial infarction, inflammation occurs in brain nuclei that play key roles in cardiovascular regulation and that attenuation of this inflammation may not be sufficient to ameliorate cardiac function.

  20. In-stream attenuation of neuro-active pharmaceuticals and their metabolites

    USGS Publications Warehouse

    Writer, Jeffrey; Antweiler, Ronald C.; Ferrar, Imma; Ryan, Joseph N.; Thurman, Michael

    2013-01-01

    In-stream attenuation was determined for 14 neuro-active pharmaceuticals and associated metabolites. Lagrangian sampling, which follows a parcel of water as it moves downstream, was used to link hydrological and chemical transformation processes. Wastewater loading of neuro-active compounds varied considerably over a span of several hours, and thus a sampling regime was used to verify that the Lagrangian parcel was being sampled and a mechanism was developed to correct measured concentrations if it was not. In-stream attenuation over the 5.4-km evaluated reach could be modeled as pseudo-first-order decay for 11 of the 14 evaluated neuro-active pharmaceutical compounds, illustrating the capacity of streams to reduce conveyance of neuro-active compounds downstream. Fluoxetine and N-desmethyl citalopram were the most rapidly attenuated compounds (t1/2 = 3.6 ± 0.3 h, 4.0 ± 0.2 h, respectively). Lamotrigine, 10,11,-dihydro-10,11,-dihydroxy-carbamazepine, and carbamazepine were the most persistent (t1/2 = 12 ± 2.0 h, 12 ± 2.6 h, 21 ± 4.5 h, respectively). Parent compounds (e.g., buproprion, carbamazepine, lamotrigine) generally were more persistent relative to their metabolites. Several compounds (citalopram, venlafaxine, O-desmethyl-venlafaxine) were not attenuated. It was postulated that the primary mechanism of removal for these compounds was interaction with bed sediments and stream biofilms, based on measured concentrations in stream biofilms and a column experiment using stream sediments.

  1. Adenosine triphosphate attenuates renal sympathetic nerve activity through left ventricular chemosensitive receptors.

    PubMed

    Taneyama, C; Benson, K T; Hild, P G; Goto, H

    1997-02-01

    We previously reported that ATP, but not adenosine, administered i.v. attenuates the baroreflex-mediated increase in sympathetic nerve activity in response to arterial hypotension by a vagal afferent mechanism. It was not elucidated in that study which vagal afferent endings are involved. Mongrel dogs were anesthetized with alpha-chloralose, thoracotomy was performed and a 27-gauge hypodermic needle was inserted into the left circumflex coronary artery. The left renal sympathetic nerves were isolated and placed on a bipolar silver electrode for measurement of renal sympathetic nerve activity (RSNA). Dose-response effects of intracoronary or i.v. infusion of ATP (100, 200 or 400 microg/kg/min) on RSNA and mean arterial pressure were studied in neuraxis-intact and cervically vagotomized dogs. RSNA was increased dose-dependently with decreasing mean arterial pressure during the i.v. ATP infusion. Elevation of RSNA was attenuated by higher intracoronary ATP infusion rates, despite the fact that mean arterial pressure was decreased dose-dependently. Left ventricular end-diastolic pressure, however, remained unchanged. This suppression of RSNA by the intracoronary ATP infusion was completely abolished by bilateral cervical vagotomy. Our data suggest that ATP attenuates reflex increases in sympathetic nerve activity by possibly stimulating ventricular chemoreceptors with cardiac vagal afferents. PMID:9023265

  2. Sirtinol Inhibits Neutrophil Elastase Activity and Attenuates Lipopolysaccharide-Mediated Acute Lung Injury in Mice

    PubMed Central

    Tsai, Yung-Fong; Yu, Huang-Ping; Chang, Wen-Yi; Liu, Fu-Chao; Huang, Zhen-Cheng; Hwang, Tsong-Long

    2015-01-01

    Enhanced activity of neutrophil elastase leads to a protease–antiprotease imbalance, and plays an essential pathogenic role in acute lung injury (ALI) and acute respiratory distress syndrome. We assayed the pharmacological effects and mechanisms of the action of sirtinol in human neutrophils, and in neutrophil elastase (HNE)-induced paw edema and lipopolysaccharide (LPS)-mediated ALI in mice. Sirtinol significantly inhibited the activity of HNE from human neutrophils in response to various stimulators. The inhibitory effects on HNE activity were not mediated through protein kinase A, calcium, extracellular-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, Akt, or Src family kinases. Analysis of enzymatic activities showed that sirtinol inhibited HNE activity in a concentration-dependent manner. These results demonstrate that sirtinol does not affect neutrophil function and is an HNE inhibitor. In addition, administration of sirtinol significantly inhibited HNE-induced paw edema, and attenuated the myeloperoxidase activity and reduced pulmonary wet/dry weight ratio in the LPS-induced ALI mouse model. Our study indicates that sirtinol has anti-inflammatory effects through direct inhibition of HNE activity and attenuates HNE-induced and LPS-mediated tissue or organ injury in vivo. Sirtinol is a novel HNE inhibitor and may have the potential for clinical application in the treatment of inflammatory lung diseases. PMID:25666548

  3. Donepezil attenuates high glucose-accelerated senescence in human umbilical vein endothelial cells through SIRT1 activation.

    PubMed

    Zhang, Tao; Tian, Feng; Wang, Jing; Zhou, Shanshan; Dong, Xueqing; Guo, Kai; Jing, Jing; Zhou, Ying; Chen, Yundai

    2015-09-01

    Cellular senescence of endothelial cells is a damage and stress response which induces pro-inflammatory, pro-atherosclerotic, and pro-thrombotic phenotypes. Donepezil is a drug used for the treatment of mild to moderate dementia of the Alzheimer's disease (AD). The aim of the present study was to investigate the attenuation of endothelial cell senescence by donepezil and to explore the mechanisms underlying the anti-aging effects of donepezil. Our results indicated that high glucose (HG) markedly decreased cell viability of human umbilical vein endothelial cells (HUVECs), and this phenomenon was reversed by treatment with donepezil. Importantly, our results displayed that the frequency of senescent (SA-ß-gal-positive) cells and the expression level of senescence genes (PAI-1 and p21) were significantly higher in the HG group compared with the normal glucose (NG) group, and these changes were blocked by treatment with donepezil. Also, our results showed that donepezil inhibits the generation of reactive oxygen species (ROS), which promotes cellular senescence. Pretreatment with nicotinamide (NAM), a sirtuin 1 (SIRT1) inhibitor, inhibited the reduction in senescence associated with donepezil. Indeed, our results indicated that donepezil increased the SIRT1 enzyme activity. Therefore, these results show that donepezil delays cellular senescence that is promoted under HG condition via activation of SIRT1.

  4. Brain tumor specifies intermediate progenitor cell identity by attenuating β-catenin/Armadillo activity

    PubMed Central

    Komori, Hideyuki; Xiao, Qi; McCartney, Brooke M.; Lee, Cheng-Yu

    2014-01-01

    During asymmetric stem cell division, both the daughter stem cell and the presumptive intermediate progenitor cell inherit cytoplasm from their parental stem cell. Thus, proper specification of intermediate progenitor cell identity requires an efficient mechanism to rapidly extinguish the activity of self-renewal factors, but the mechanisms remain unknown in most stem cell lineages. During asymmetric division of a type II neural stem cell (neuroblast) in the Drosophila larval brain, the Brain tumor (Brat) protein segregates unequally into the immature intermediate neural progenitor (INP), where it specifies INP identity by attenuating the function of the self-renewal factor Klumpfuss (Klu), but the mechanisms are not understood. Here, we report that Brat specifies INP identity through its N-terminal B-boxes via a novel mechanism that is independent of asymmetric protein segregation. Brat-mediated specification of INP identity is critically dependent on the function of the Wnt destruction complex, which attenuates the activity of β-catenin/Armadillo (Arm) in immature INPs. Aberrantly increasing Arm activity in immature INPs further exacerbates the defects in the specification of INP identity and enhances the supernumerary neuroblast mutant phenotype in brat mutant brains. By contrast, reducing Arm activity in immature INPs suppresses supernumerary neuroblast formation in brat mutant brains. Finally, reducing Arm activity also strongly suppresses supernumerary neuroblasts induced by overexpression of klu. Thus, the Brat-dependent mechanism extinguishes the function of the self-renewal factor Klu in the presumptive intermediate progenitor cell by attenuating Arm activity, balancing stem cell maintenance and progenitor cell specification. PMID:24257623

  5. Predicting trace organic compound attenuation with spectroscopic parameters in powdered activated carbon processes.

    PubMed

    Ziska, Austin D; Park, Minkyu; Anumol, Tarun; Snyder, Shane A

    2016-08-01

    The removal of trace organic compounds (TOrCs) is of growing interest in water research and society. Powdered activated carbon (PAC) has been proven to be an effective method of removal for TOrCs in water, with the degree of effectiveness depending on dosage, contact time, and activated carbon type. In this study, the attenuation of TOrCs in three different secondary wastewater effluents using four PAC materials was studied in order to elucidate the effectiveness and efficacy of PAC for TOrC removal. With the notable exception of hydrochlorothiazide, all 14 TOrC indicators tested in this study exhibited a positive correlation of removal rate with their log Dow values, demonstrating that the main adsorption mechanism was hydrophobic interaction. As a predictive model, the modified Chick-Watson model, often used for the prediction of microorganism inactivation by disinfectants, was applied. The applied model exhibited good predictive power for TOrC attenuation by PAC in wastewater. In addition, surrogate models based upon spectroscopic measurements including UV absorbance at 254 nm and total fluorescence were applied to predict TOrC removal by PAC. The surrogate model was found to provide an excellent prediction of TOrC attenuation for all combinations of water quality and PAC type included in this study. The success of spectrometric parameters as surrogates in predicting TOrC attenuation by PAC are particularly useful because of their potential application in real-time on-line sensor monitoring and process control at full-scale water treatment plants, which could lead to significantly reduced operator response times and PAC operational optimization. PMID:27174829

  6. Hormetic Effect of Berberine Attenuates the Anticancer Activity of Chemotherapeutic Agents.

    PubMed

    Bao, Jiaolin; Huang, Borong; Zou, Lidi; Chen, Shenghui; Zhang, Chao; Zhang, Yulin; Chen, Meiwan; Wan, Jian-Bo; Su, Huanxing; Wang, Yitao; He, Chengwei

    2015-01-01

    Hormesis is a phenomenon of biphasic dose response characterized by exhibiting stimulatory or beneficial effects at low doses and inhibitory or toxic effects at high doses. Increasing numbers of chemicals of various types have been shown to induce apparent hormetic effect on cancer cells. However, the underlying significance and mechanisms remain to be elucidated. Berberine, one of the major active components of Rhizoma coptidis, has been manifested with notable anticancer activities. This study aims to investigate the hormetic effect of berberine and its influence on the anticancer activities of chemotherapeutic agents. Our results demonstrated that berberine at low dose range (1.25 ~ 5 μM) promoted cell proliferation to 112% ~170% of the untreated control in various cancer cells, while berberine at high dose rage (10 ~ 80 μM) inhibited cell proliferation. Further, we observed that co-treatment with low dose berberine could significantly attenuate the anticancer activity of chemotherapeutic agents, including fluorouracil (5-FU), camptothecin (CPT), and paclitaxel (TAX). The hormetic effect and thereby the attenuated anticancer activity of chemotherapeutic drugs by berberine may attributable to the activated protective stress response in cancer cells triggered by berberine, as evidenced by up-regulated MAPK/ERK1/2 and PI3K/AKT signaling pathways. These results provided important information to understand the potential side effects of hormesis, and suggested cautious application of natural compounds and relevant herbs in adjuvant treatment of cancer. PMID:26421434

  7. PARP-1 Inhibition Attenuates Neuronal Loss, Microglia Activation and Neurological Deficits after Traumatic Brain Injury

    PubMed Central

    Loane, David J.; Zhao, Zaorui; Kabadi, Shruti V.; Hanscom, Marie; Byrnes, Kimberly R.; Faden, Alan I.

    2014-01-01

    Abstract Traumatic brain injury (TBI) causes neuronal cell death as well as microglial activation and related neurotoxicity that contribute to subsequent neurological dysfunction. Poly (ADP-ribose) polymerase (PARP-1) induces neuronal cell death through activation of caspase-independent mechanisms, including release of apoptosis inducing factor (AIF), and microglial activation. Administration of PJ34, a selective PARP-1 inhibitor, reduced cell death of primary cortical neurons exposed to N-Methyl-N'-Nitro-N-Nitrosoguanidine (MNNG), a potent inducer of AIF-dependent cell death. PJ34 also attenuated lipopolysaccharide and interferon-γ-induced activation of BV2 or primary microglia, limiting NF-κB activity and iNOS expression as well as decreasing generation of reactive oxygen species and TNFα. Systemic administration of PJ34 starting as late as 24 h after controlled cortical impact resulted in improved motor function recovery in mice with TBI. Stereological analysis demonstrated that PJ34 treatment reduced the lesion volume, attenuated neuronal cell loss in the cortex and thalamus, and reduced microglial activation in the TBI cortex. PJ34 treatment did not improve cognitive performance in a Morris water maze test or reduce neuronal cell loss in the hippocampus. Overall, our data indicate that PJ34 has a significant, albeit selective, neuroprotective effect after experimental TBI, and its therapeutic effect may be from multipotential actions on neuronal cell death and neuroinflammatory pathways. PMID:24476502

  8. Hormetic Effect of Berberine Attenuates the Anticancer Activity of Chemotherapeutic Agents.

    PubMed

    Bao, Jiaolin; Huang, Borong; Zou, Lidi; Chen, Shenghui; Zhang, Chao; Zhang, Yulin; Chen, Meiwan; Wan, Jian-Bo; Su, Huanxing; Wang, Yitao; He, Chengwei

    2015-01-01

    Hormesis is a phenomenon of biphasic dose response characterized by exhibiting stimulatory or beneficial effects at low doses and inhibitory or toxic effects at high doses. Increasing numbers of chemicals of various types have been shown to induce apparent hormetic effect on cancer cells. However, the underlying significance and mechanisms remain to be elucidated. Berberine, one of the major active components of Rhizoma coptidis, has been manifested with notable anticancer activities. This study aims to investigate the hormetic effect of berberine and its influence on the anticancer activities of chemotherapeutic agents. Our results demonstrated that berberine at low dose range (1.25 ~ 5 μM) promoted cell proliferation to 112% ~170% of the untreated control in various cancer cells, while berberine at high dose rage (10 ~ 80 μM) inhibited cell proliferation. Further, we observed that co-treatment with low dose berberine could significantly attenuate the anticancer activity of chemotherapeutic agents, including fluorouracil (5-FU), camptothecin (CPT), and paclitaxel (TAX). The hormetic effect and thereby the attenuated anticancer activity of chemotherapeutic drugs by berberine may attributable to the activated protective stress response in cancer cells triggered by berberine, as evidenced by up-regulated MAPK/ERK1/2 and PI3K/AKT signaling pathways. These results provided important information to understand the potential side effects of hormesis, and suggested cautious application of natural compounds and relevant herbs in adjuvant treatment of cancer.

  9. Brazilian Red Propolis Attenuates Inflammatory Signaling Cascade in LPS-Activated Macrophages

    PubMed Central

    Bueno-Silva, Bruno; Kawamoto, Dione; Ando-Suguimoto, Ellen S.; Alencar, Severino M.; Rosalen, Pedro L.; Mayer, Marcia P. A.

    2015-01-01

    Although previous studies suggested an anti-inflammatory property of Brazilian red propolis (BRP), the mechanisms involved in the anti-inflammatory effects of BRP and its activity on macrophages were still not elucidated. This study aimed to evaluate whether BRP attenuates the inflammatory effect of LPS on macrophages and to investigate its underlying mechanisms. BRP was added to RAW 264.7 murine macrophages after activation with LPS. NO production, cell viability, cytokines profile were evaluated. Activation of inflammatory signaling pathways and macrophage polarization were determined by RT-qPCR and Western blot. BRP at 50 μg/ml inhibited NO production by 78% without affecting cell viability. Cd80 and Cd86 were upregulated whereas mrc1 was down regulated by BRP indicating macrophage polarization at M1. BRP attenuated the production of pro-inflammatory mediators IL-12, GM-CSF, IFN-Ɣ, IL-1β in cell supernatants although levels of TNF- α and IL-6 were slightly increased after BRP treatment. Levels of IL-4, IL-10 and TGF-β were also reduced by BRP. BRP significantly reduced the up-regulation promoted by LPS of transcription of genes in inflammatory signaling (Pdk1, Pak1, Nfkb1, Mtcp1, Gsk3b, Fos and Elk1) and of Il1β and Il1f9 (fold-change rate > 5), which were further confirmed by the inhibition of NF-κB and MAPK signaling pathways. Furthermore, the upstream adaptor MyD88 adaptor-like (Mal), also known as TIRAP, involved in TLR2 and TLR4 signaling, was down- regulated in BRP treated LPS-activated macrophages. Given that BRP inhibited multiple signaling pathways in macrophages involved in the inflammatory process activated by LPS, our data indicated that BRP is a noteworthy food-source for the discovery of new bioactive compounds and a potential candidate to attenuate exhacerbated inflammatory diseases. PMID:26660901

  10. Deep Brain Stimulation of the Nucleus Accumbens Shell Attenuates Cocaine Reinstatement through Local and Antidromic Activation

    PubMed Central

    White, Samantha L.; Hopkins, Thomas J.; Guercio, Leonardo A.; Espallergues, Julie; Berton, Olivier; Schmidt, Heath D.; Pierce, R. Christopher

    2013-01-01

    Accumbal deep brain stimulation (DBS) is a promising therapeutic modality for the treatment of addiction. Here, we demonstrate that DBS in the nucleus accumbens shell, but not the core, attenuates cocaine priming-induced reinstatement of drug seeking, an animal model of relapse, in male Sprague Dawley rats. Next, we compared DBS of the shell with pharmacological inactivation. Results indicated that inactivation using reagents that influenced (lidocaine) or spared (GABA receptor agonists) fibers of passage blocked cocaine reinstatement when administered into the core but not the shell. It seems unlikely, therefore, that intrashell DBS influences cocaine reinstatement by inactivating this nucleus or the fibers coursing through it. To examine potential circuit-wide changes, c-Fos immunohistochemistry was used to examine neuronal activation following DBS of the nucleus accumbens shell. Intrashell DBS increased c-Fos induction at the site of stimulation as well as in the infralimbic cortex, but had no effect on the dorsal striatum, prelimbic cortex, or ventral pallidum. Recent evidence indicates that accumbens DBS antidromically stimulates axon terminals, which ultimately activates GABAergic interneurons in cortical areas that send afferents to the shell. To test this hypothesis, GABA receptor agonists (baclofen/muscimol) were microinjected into the anterior cingulate, and prelimbic or infralimbic cortices before cocaine reinstatement. Pharmacological inactivation of all three medial prefrontal cortical subregions attenuated the reinstatement of cocaine seeking. These results are consistent with DBS of the accumbens shell attenuating cocaine reinstatement via local activation and/or activation of GABAergic interneurons in the medial prefrontal cortex via antidromic stimulation of cortico-accumbal afferents. PMID:24005296

  11. Deep brain stimulation of the nucleus accumbens shell attenuates cocaine reinstatement through local and antidromic activation.

    PubMed

    Vassoler, Fair M; White, Samantha L; Hopkins, Thomas J; Guercio, Leonardo A; Espallergues, Julie; Berton, Olivier; Schmidt, Heath D; Pierce, R Christopher

    2013-09-01

    Accumbal deep brain stimulation (DBS) is a promising therapeutic modality for the treatment of addiction. Here, we demonstrate that DBS in the nucleus accumbens shell, but not the core, attenuates cocaine priming-induced reinstatement of drug seeking, an animal model of relapse, in male Sprague Dawley rats. Next, we compared DBS of the shell with pharmacological inactivation. Results indicated that inactivation using reagents that influenced (lidocaine) or spared (GABA receptor agonists) fibers of passage blocked cocaine reinstatement when administered into the core but not the shell. It seems unlikely, therefore, that intrashell DBS influences cocaine reinstatement by inactivating this nucleus or the fibers coursing through it. To examine potential circuit-wide changes, c-Fos immunohistochemistry was used to examine neuronal activation following DBS of the nucleus accumbens shell. Intrashell DBS increased c-Fos induction at the site of stimulation as well as in the infralimbic cortex, but had no effect on the dorsal striatum, prelimbic cortex, or ventral pallidum. Recent evidence indicates that accumbens DBS antidromically stimulates axon terminals, which ultimately activates GABAergic interneurons in cortical areas that send afferents to the shell. To test this hypothesis, GABA receptor agonists (baclofen/muscimol) were microinjected into the anterior cingulate, and prelimbic or infralimbic cortices before cocaine reinstatement. Pharmacological inactivation of all three medial prefrontal cortical subregions attenuated the reinstatement of cocaine seeking. These results are consistent with DBS of the accumbens shell attenuating cocaine reinstatement via local activation and/or activation of GABAergic interneurons in the medial prefrontal cortex via antidromic stimulation of cortico-accumbal afferents. PMID:24005296

  12. Effects of various midsole densities of basketball shoes on impact attenuation during landing activities.

    PubMed

    Zhang, Songning; Clowers, Kurt; Kohstall, Charles; Yu, Yeon-Joo

    2005-02-01

    The purpose of this study was to examine effects of shoe midsole densities and mechanical demands (landing heights) on impact shock attenuation and lower extremity biomechanics during a landing activity. Nine healthy male college athletes performed 5 trials of step-off landing in each of 9 test conditions, i.e., a combination of landings in shoes of 3 midsole densities (soft, normal, hard) from each of 3 landing potential energy (PE) levels (low, median, high). Ground reaction forces (GRF), accelerations (ACC) of the tibia and forehead, and sagittal kinematic data were sampled simultaneously. A 3 x 3 two-way (surface x height) repeated-measures analysis of variance (ANOVA) was performed on selected kinematic, ACC, and GRF variables; a 3 x 3 x 3 three-way (surface x height x joint) ANOVA was performed on variables related to eccentric muscular work. The GRF results showed that the forefoot peak GRF in the normal and hard midsoles was significantly greater than the soft midsole at the low and median PEs. Rearfoot peak GRF was significantly greater for the hard midsole than for the soft and normal midsoles at the median and high PEs, respectively. The peak head and tibia peak ACC were also attenuated in similar fashion. Kinematic variables did not vary significantly across different midsoles, nor did energy absorbed through lower extremity extensors in response to the increased shoe stiffness. Knee joint extensors were shown to be dominant in attenuating the forefoot impact force across the landing heights. The results showed limited evidence of impact-attenuating benefits of the soft midsole in the basketball shoes.

  13. Astragaloside IV attenuates apoptosis of hypertrophic cardiomyocyte through inhibiting oxidative stress and calpain-1 activation.

    PubMed

    Mei, Meng; Tang, Futian; Lu, Meili; He, Xin; Wang, Hongxin; Hou, Xuwei; Hu, Jin; Xu, Chonghua; Han, Ronghui

    2015-11-01

    Calpain-1 activation and oxidative stress are two critical factors contributing to apoptosis of hypertrophic cardiomyocyte. Astragaloside IV (ASIV) exhibits protective effect against various heart diseases. The present study was designed to investigate whether the inhibitory effect of ASIV on isoproterenol (ISO)-induced apoptosis of hypertrophic cardiomyocyte was associated with the anti-oxidation and calpain-1 inhibition. Hypertrophy, apoptosis, mitochondrial oxidative stress and calpain-1 expression were measured in the heart tissue of Sprague-Dawley (SD) rats and H9C2 cells treated with ISO alone or combination with ASIV. The results showed that ASIV attenuated apoptotic rate, increased Bcl-2 expression, decreased Bax expression, ameliorated the integrity of mitochondrial structure and improved mitochondrial membrane potential (MMP). Moreover, ASIV combination reduced both calpain-1 protein expression and calpain activity, down-regulated mitochondrial NOX4 (mito-NOX4) expression, increased activity of mitochondrial superoxide dismutase (mito-SOD) and mitochondrial catalase (mito-CAT) compared to ISO treated alone. The results suggested that ASIV exerted anti-apoptosis effect on ISO-induced hypertrophic cardiomyocyte by attenuating oxidative stress and calpain-1 activation. PMID:26433482

  14. Evodiamine Attenuates PDGF-BB-Induced Migration of Rat Vascular Smooth Muscle Cells through Activating PPARγ.

    PubMed

    Ge, Xie; Chen, Siyu; Liu, Mei; Liang, Tingming; Liu, Chang

    2015-11-26

    The uncontrolled migration of vascular smooth muscle cells (VSMCs) into the intima is a critical process in the development of atherosclerosis. Evodiamine, an indole alkaloid extracted from the Chinese medicine evodia, has been shown to inhibit tumor cell invasion and protect the cardiovascular system, but its effects on VSMCs remain unknown. In the present study, we investigated the inhibitory effects of evodiamine on the platelet-derived growth factor-BB (PDGF-BB)-induced VSMC migration using wound healing and transwell assays, and assessed its role in decreasing the protein levels of matrix metalloproteinases and cell adhesion molecules. More importantly, we found that evodiamine activated the expression and nuclear translocation of peroxisome proliferator-activated receptor γ (PPARγ). Inhibition of PPARγ activity by using its antagonist T0070907 and its specific siRNA oligonucleotides significantly attenuated the inhibitory effects of evodiamine on VSMC migration. Taken together, our results indicate a promising anti-atherogenic effect of evodiamine through attenuation of VSMC migration by activating PPARγ.

  15. Low Dose Nicotine Attenuates Aβ Neurotoxicity through Activation Early Growth Response Gene 1 Pathway

    PubMed Central

    Zhang, Jie; Qiu, Jinhua; Du, Guicheng; Qiao, Zhiliang; Jin, Guanghui; Gao, Fengguang; Zhang, Qiqing

    2015-01-01

    Epidemiological studies indicate that smoking is negatively correlated with the incidence and development of Alzheimer's disease (AD). Nicotine was reported to be the active factor. However, the detailed mechanisms still remain to be fully elucidated. Early growth response gene 1 (EGR-1) plays important roles in several important biological processes such as promoting cell growth, differentiation, anti oxidative stress, and apoptosis, but few in the pathogenesis of AD. In the present study, we show that nicotine can activate the MAPK/ERK/EGR-1 signaling pathway partially through α7 nAChR. In addition, the up-regulation of EGR-1 by nicotine can also increase the phosphorylation of CyclinD1 which contributes to the attenuation of amyloid-β (Aβ25–35) -induced neurotoxicity. Although nicotine and Aβ25–35 can activate EGR-1, the expression of EGR-1 is down-regulated following treatment with nicotine and Aβ25–35. This study demonstrates that low dose nicotine attenuates Aβ25–35-induced neurotoxicity in vitro and in vivo through activating EGR-1 pathway. PMID:25815723

  16. Hydroxysafflor yellow A attenuates ischemia/reperfusion-induced liver injury by suppressing macrophage activation

    PubMed Central

    Jiang, Shujun; Shi, Zhen; Li, Changyong; Ma, Chunlei; Bai, Xianyong; Wang, Chaoyun

    2014-01-01

    Hydroxysafflor yellow A (HSYA), a major constituent in the hydrophilic fraction of the safflower plant, can retard the progress of hepatic fibrosis. However, the anti-inflammatory properties and the underlying mechanisms of HSYA on I/R-induced acute liver injury are unknown. Inhibiting macrophage activation is a potential strategy to treat liver ischemia/reperfusion (I/R) injury. In this study, we investigated the therapeutic effect of HSYA on liver I/R injury and the direct effect of HSYA on macrophage activation following inflammatory conditions. The therapeutic effects of HSYA on I/R injury were tested in vivo using a mouse model of segmental (70%) hepatic ischemia. The mechanisms of HSYA were examined in vitro by evaluating migration and the cytokine expression profile of the macrophage cell line RAW264.7 exposed to acute hypoxia and reoxygenation (H/R). Results showed that mice pretreated with HSYA had reduced serum transaminase levels, attenuated inflammation and necrosis, reduced expression of inflammatory cytokines, and less macrophage recruitment following segmental hepatic ischemia. In vitro HSYA pretreated RAW264.7 macrophages displayed reduced migratory response and produced less inflammatory cytokines. In addition, HSYA pretreatment down-regulated the expression of matrix matalloproteinase-9 and reactive oxygen species, and inhibited NF-κB activation and P38 phosphorylation in RAW264.7 cells. Thus, these data suggest that HSYA can reduce I/R-induced acute liver injury by directly attenuating macrophage activation under inflammatory conditions. PMID:24966974

  17. Dynamic changes of integrated backscatter, attenuation coefficient and bubble activities during high-intensity focused ultrasound (HIFU) treatment.

    PubMed

    Zhang, Siyuan; Wan, Mingxi; Zhong, Hui; Xu, Cheng; Liao, Zhenzhong; Liu, Huanqing; Wang, Supin

    2009-11-01

    This paper simultaneously investigated the transient characteristics of integrated backscatter (IBS), attenuation coefficient and bubble activities as time traces before, during and after HIFU treatment, with different HIFU parameters (acoustic power and duty cycle) in both transparent tissue-mimicking phantoms and freshly excised bovine livers. These dynamic changes of acoustic parameters and bubble activities were correlated with the visualization of lesion development selected from photos, conventional B-mode ultrasound images and differential IBS images over the whole procedure of HIFU treatment. Two-dimensional radiofrequency (RF) data were acquired by a modified diagnostic ultrasound scanner to estimate the changes of mean IBS and attenuation coefficient averaged in the lesion region, and to construct the differential IBS images and B-mode ultrasound images simultaneously. Bubble activities over the whole procedure of HIFU treatment were investigated by the passive cavitation detection (PCD) method and the changes in subharmonic and broadband noise were correlated with the transient characteristics of IBS and attenuation coefficient. When HIFU was switched on, IBS and attenuation coefficient increased with the appearance of bubble clouds in the B-mode and differential IBS image. At the same time, the level of subharmonic and broadband noise rose abruptly. Then, there was an initial decrease in the attenuation coefficient, followed by an increase when at lower HIFU power. As the lesion appeared, IBS and attenuation coefficient both increased rapidly to a value twice that of normal. Then the changes in IBS and attenuation coefficient showed more complex patterns, but still showed a slower trend of increases with lesion development. Violent bubble activities were visible in the gel and were evident as strongly echogenic regions in the differential IBS images and B-mode images simultaneously. This was detected by a dramatic high level of subharmonic and broadband

  18. Dynamic changes of integrated backscatter, attenuation coefficient and bubble activities during high-intensity focused ultrasound (HIFU) treatment.

    PubMed

    Zhang, Siyuan; Wan, Mingxi; Zhong, Hui; Xu, Cheng; Liao, Zhenzhong; Liu, Huanqing; Wang, Supin

    2009-11-01

    This paper simultaneously investigated the transient characteristics of integrated backscatter (IBS), attenuation coefficient and bubble activities as time traces before, during and after HIFU treatment, with different HIFU parameters (acoustic power and duty cycle) in both transparent tissue-mimicking phantoms and freshly excised bovine livers. These dynamic changes of acoustic parameters and bubble activities were correlated with the visualization of lesion development selected from photos, conventional B-mode ultrasound images and differential IBS images over the whole procedure of HIFU treatment. Two-dimensional radiofrequency (RF) data were acquired by a modified diagnostic ultrasound scanner to estimate the changes of mean IBS and attenuation coefficient averaged in the lesion region, and to construct the differential IBS images and B-mode ultrasound images simultaneously. Bubble activities over the whole procedure of HIFU treatment were investigated by the passive cavitation detection (PCD) method and the changes in subharmonic and broadband noise were correlated with the transient characteristics of IBS and attenuation coefficient. When HIFU was switched on, IBS and attenuation coefficient increased with the appearance of bubble clouds in the B-mode and differential IBS image. At the same time, the level of subharmonic and broadband noise rose abruptly. Then, there was an initial decrease in the attenuation coefficient, followed by an increase when at lower HIFU power. As the lesion appeared, IBS and attenuation coefficient both increased rapidly to a value twice that of normal. Then the changes in IBS and attenuation coefficient showed more complex patterns, but still showed a slower trend of increases with lesion development. Violent bubble activities were visible in the gel and were evident as strongly echogenic regions in the differential IBS images and B-mode images simultaneously. This was detected by a dramatic high level of subharmonic and broadband

  19. Minocycline attenuates pain by inhibiting spinal microglia activation in diabetic rats.

    PubMed

    Sun, Jin-Shan; Yang, Yu-Jie; Zhang, Yong-Zhen; Huang, Wen; Li, Zhao-Shen; Zhang, Yong

    2015-08-01

    The mechanisms associated with diabetes-induced neuropathic pain are complex and poorly understood. In order to understand the involvement of spinal microglia activity in diabetic pain, the present study investigated whether minocycline treatment is able to attenuate diabetic pain using a rat model. Diabetes was induced using a single intraperitoneal injection of streptozotocin (STZ). Minocycline was then intrathecally administered to the rats. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were tested weekly. The expression of OX-42, Iba-1, phospho-p38 mitogen-activated protein kinase (MAPK), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and inducible nitric oxide synthase (iNOS), were examined in the spinal cord in order to evaluate the activation of microglia. The present study demonstrated that rats with STZ-induced diabetes exhibited increased mean plasma glucose concentration, decreased mean body weight and significant pain hypersensitivity compared with control rats. PWT and PWL values of rats with STZ-induced diabetes increased following treatment with minocycline. No differences were observed in expression levels of the microglial activity markers (OX-42, Iba-1 and phospho-p38 MAPK) between rats with STZ-induced diabetes and control rats. However, TNF-α, IL-1β and iNOS expression levels were higher in rats with STZ-induced diabetes compared with control rats. Following treatment with minocycline markers of microglial activation, including cytokines and iNOS, were downregulated in rats with STZ-induced diabetes. The results of the present study indicated that minocycline treatment may inhibit spinal microglial activation and attenuate diabetic pain in rats with STZ-induced diabetes.

  20. Alpha 1 Antitrypsin Inhibits Dendritic Cell Activation and Attenuates Nephritis in a Mouse Model of Lupus.

    PubMed

    Elshikha, Ahmed S; Lu, Yuanqing; Chen, Mong-Jen; Akbar, Mohammad; Zeumer, Leilani; Ritter, Andrea; Elghamry, Hanaa; Mahdi, Mahmoud A; Morel, Laurence; Song, Sihong

    2016-01-01

    Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution and considerable mortality and morbidity. Although the pathogenesis of this disease remains elusive, over-reactive dendritic cells (DCs) play a critical role in the disease development. It has been shown that human alpha-1 antitrypsin (hAAT) has protective effects in type 1 diabetes and rheumatoid arthritis mouse models. In the present study, we tested the effect of AAT on DC differentiation and functions, as well as its protective effect in a lupus-prone mouse model. We showed that hAAT treatment significantly inhibited LPS (TLR4 agonist) and CpG (TLR9 agonist) -induced bone-marrow (BM)-derived conventional and plasmacytoid DC (cDC and pDC) activation and reduced the production of inflammatory cytokines including IFN-I, TNF-α and IL-1β. In MRL/lpr mice, hAAT treatment significantly reduced BM-derived DC differentiation, serum autoantibody levels, and importantly attenuated renal pathology. Our results for the first time demonstrate that hAAT inhibits DC activation and function, and it also attenuates autoimmunity and renal damage in the MRL/lpr lupus model. These results imply that hAAT has a therapeutic potential for the treatment of SLE in humans. PMID:27232337

  1. LXW7 ameliorates focal cerebral ischemia injury and attenuates inflammatory responses in activated microglia in rats

    PubMed Central

    Fang, T.; Zhou, D.; Lu, L.; Tong, X.; Wu, J.; Yi, L.

    2016-01-01

    Inflammation plays a pivotal role in ischemic stroke, when activated microglia release excessive pro-inflammatory mediators. The inhibition of integrin αvβ3 improves outcomes in rat focal cerebral ischemia models. However, the mechanisms by which microglia are neuroprotective remain unclear. This study evaluated whether post-ischemic treatment with another integrin αvβ3 inhibitor, the cyclic arginine-glycine-aspartic acid (RGD) peptide-cGRGDdvc (LXW7), alleviates cerebral ischemic injury. The anti-inflammatory effect of LXW7 in activated microglia within rat focal cerebral ischemia models was examined. A total of 108 Sprague-Dawley rats (250–280 g) were subjected to middle cerebral artery occlusion (MCAO). After 2 h, the rats were given an intravenous injection of LXW7 (100 μg/kg) or phosphate-buffered saline (PBS). Neurological scores, infarct volumes, brain water content (BWC) and histology alterations were determined. The expressions of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β)], and Iba1-positive activated microglia, within peri-ischemic brain tissue, were assessed with ELISA, western blot and immunofluorescence staining. Infarct volumes and BWC were significantly lower in LXW7-treated rats compared to those in the MCAO + PBS (control) group. The LXW7 treatment lowered the expression of pro-inflammatory cytokines. There was a reduction of Iba1-positive activated microglia, and the TNF-α and IL-1β expressions were attenuated. However, there was no difference in the Zea Longa scores between the ischemia and LXW7 groups. The results suggest that LXW7 protected against focal cerebral ischemia and attenuated inflammation in activated microglia. LXW7 may be neuroprotective during acute MCAO-induced brain damage and microglia-related neurodegenerative diseases. PMID:27533766

  2. Stimulation of Brain AMP-Activated Protein Kinase Attenuates Inflammation and Acute Lung Injury in Sepsis

    PubMed Central

    Mulchandani, Nikhil; Yang, Weng-Lang; Khan, Mohammad Moshahid; Zhang, Fangming; Marambaud, Philippe; Nicastro, Jeffrey; Coppa, Gene F; Wang, Ping

    2015-01-01

    Sepsis and septic shock are enormous public health problems with astronomical financial repercussions on health systems worldwide. The central nervous system (CNS) is closely intertwined in the septic process but the underlying mechanism is still obscure. AMP-activated protein kinase (AMPK) is a ubiquitous energy sensor enzyme and plays a key role in regulation of energy homeostasis and cell survival. In this study, we hypothesized that activation of AMPK in the brain would attenuate inflammatory responses in sepsis, particularly in the lungs. Adult C57BL/6 male mice were treated with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR, 20 ng), an AMPK activator, or vehicle (normal saline) by intracerebroventricular (ICV) injection, followed by cecal ligation and puncture (CLP) at 30 min post-ICV. The septic mice treated with AICAR exhibited elevated phosphorylation of AMPKα in the brain along with reduced serum levels of aspartate aminotransferase, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), compared with the vehicle. Similarly, the expressions of TNF-α, IL-1β, keratinocyte-derived chemokine and macrophage inflammatory protein-2 as well as myeloperoxidase activity in the lungs of AICAR-treated mice were significantly reduced. Moreover, histological findings in the lungs showed improvement of morphologic features and reduction of apoptosis with AICAR treatment. We further found that the beneficial effects of AICAR on septic mice were diminished in AMPKα2 deficient mice, showing that AMPK mediates these effects. In conclusion, our findings reveal a new functional role of activating AMPK in the CNS to attenuate inflammatory responses and acute lung injury in sepsis. PMID:26252187

  3. Intrathecal Injection of Resveratrol Attenuates Burn Injury Pain by Activating Spinal Sirtuin 1

    PubMed Central

    Cheng, Wei; Wang, Jin-Feng; Yang, Cong-Xian; Wu, Liang; Yin, Qin; Liu, He; Fu, Zhi-Jian

    2016-01-01

    Objective: The present study sought to detect spinal sirtuin 1 (SIRT1) and acetylation of histone H3 (Ac-H3) expression in rats with burn injury pain (BIP model). Procedures and Results: A BIP model was first established. BIP rats showed lower paw withdrawal threshold (PWT) from day 1, which persisted for 21 days following the burn injury. Spinal SIRT1/Ac-H3 expression increased following burn injury. The intrathecal use of resveratrol increased PWT and SIRT1 expression but induced down-regulation of Ac-H3 expression. We first demonstrated that the inhibition of SIRT1 significantly induced mechanical allodynia in naïve rats. The preinjection of SIRT1 inhibitor partly antagonized the analgesic effects of resveratrol in BIP rats. Conclusion: Inhibition of SIRT1 produces pain facilitation in the naïve rats. The expression of spinal SIRT1 increased after burn injury in the BIP model. The activation of spinal SIRT1 might mediate the resveratrol-induced analgesic effects. SUMMARY Burn injury resulted in pain facilitationResveratrol attenuates pain facilitation induced by burn injuryIntrathecal injection of resveratrol attenuates burn injury pain by increasing spinal sirtuin 1 (SIRT1) expressionInhibition of SIRT1 by selisistat, an SIRT1 inhibitor attenuated analgesic effects of resveratrol Abbreviations used: SIRT1: Sirtuin 1, Ac-H3: Acetylation of histone H3, SD: Sprague-Dawley, EX527: Selisistat, an SIRT1 inhibitor, BIP: Burn injury pain, DMSO: Dimethyl sulfoxide, PWTs: Paw withdrawal thresholds PMID:27279707

  4. Impact attenuation during weight bearing activities in barefoot vs. shod conditions: a systematic review.

    PubMed

    Fong Yan, Alycia; Sinclair, Peter J; Hiller, Claire; Wegener, Caleb; Smith, Richard M

    2013-06-01

    Although it could be perceived that there is extensive research on the impact attenuation characteristics of shoes, the approach and findings of researchers in this area are varied. This review aimed to clarify the effect of shoes on impact attenuation to the foot and lower leg and was limited to those studies that compared the shoe condition(s) with barefoot. A systematic search of the literature yielded 26 studies that investigated vertical ground reaction force, axial tibial acceleration, loading rate and local plantar pressures. Meta-analyses of the effect of shoes on each variable during walking and running were performed using the inverse variance technique. Variables were collected at their peak or at the impact transient, but when grouped together as previous comparisons have done, shoes reduced local plantar pressure and tibial acceleration, but did not affect vertical force or loading rate for walking. During running, shoes reduced tibial acceleration but did not affect loading rate or vertical force. Further meta-analyses were performed, isolating shoe type and when the measurements were collected. Athletic shoes reduced peak vertical force during walking, but increased vertical force at the impact transient and no change occurred for the other variables. During running, athletic shoes reduced loading rate but did not affect vertical force. The range of variables examined and variety of measurements used appears to be a reason for the discrepancies across the literature. The impact attenuating effect of shoes has potentially both adverse and beneficial effects depending on the variable and activity under investigation. PMID:23245643

  5. Electrical stimulation of dorsal root entry zone attenuates wide-dynamic range neuronal activity in rats

    PubMed Central

    Yang, Fei; Zhang, Chen; Xu, Qian; Tiwari, Vinod; He, Shao-Qiu; Wang, Yun; Dong, Xinzhong; Vera-Portocarrero, Louis P.; Wacnik, Paul W.; Raja, Srinivasa N.; Guan, Yun

    2014-01-01

    Objectives Recent clinical studies suggest that neurostimulation at the dorsal root entry zone (DREZ) may alleviate neuropathic pain. However, the mechanisms of action for this therapeutic effect are unclear. Here, we examined whether DREZ stimulation inhibits spinal wide-dynamic-range (WDR) neuronal activity in nerve-injured rats. Materials and Methods We conducted in vivo extracellular single-unit recordings of WDR neurons in rats after an L5 spinal nerve ligation (SNL) or sham surgery. We set bipolar electrical stimulation (50 Hz, 0.2 ms, 5 min) of the DREZ at the intensity that activated only Aα/β-fibers by measuring the lowest current at which DREZ stimulation evoked a peak antidromic sciatic Aα/β-compound action potential without inducing an Aδ/C-compound action potential (i.e., Ab1). Results The elevated spontaneous activity rate of WDR neurons in SNL rats [n=25; data combined from day 14–16 (n = 15) and day 45–75 post-SNL groups (n=10)] was significantly decreased from the pre-stimulation level (p<0.01) at 0–15 min and 30–45 min post-stimulation. In both sham-operated (n=8) and nerve-injured rats, DREZ stimulation attenuated the C-component, but not A-component, of the WDR neuronal response to graded intracutaneous electrical stimuli (0.1–10 mA, 2 ms) applied to the skin receptive field. Further, DREZ stimulation blocked windup (a short form of neuronal sensitization) to repetitive noxious stimuli (0.5 Hz) at 0–15 min in all groups (p<0.05). Conclusions Attenuation of WDR neuronal activity may contribute to DREZ stimulation-induced analgesia. This finding supports the notion that DREZ may be a useful target for neuromodulatory control of pain. PMID:25308522

  6. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates postincisional pain by regulating macrophage polarization

    SciTech Connect

    Hasegawa-Moriyama, Maiko; Ohnou, Tetsuya; Godai, Kohei; Kurimoto, Tae; Nakama, Mayo; Kanmura, Yuichi

    2012-09-14

    Highlights: Black-Right-Pointing-Pointer Rosiglitazone attenuated postincisional pain. Black-Right-Pointing-Pointer Rosiglitazone alters macrophage polarization to F4/80{sup +}CD206{sup +} M2 macrophages at the incisional sites. Black-Right-Pointing-Pointer Transplantation of rosiglitazone-treated macrophages produced analgesic effects. -- Abstract: Acute inflammation triggered by macrophage infiltration to injured tissue promotes wound repair and may induce pain hypersensitivity. Peroxisome proliferator-activated receptor {gamma} (PPAR){gamma} signaling is known to regulate heterogeneity of macrophages, which are often referred to as classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages have considerable antimicrobial activity and produce a wide variety of proinflammatory cytokines. In contrast, M2 macrophages are involved in anti-inflammatory and homeostatic functions linked to wound healing and tissue repair. Although it has been suggested that PPAR{gamma} agonists attenuate pain hypersensitivity, the molecular mechanism of macrophage-mediated effects of PPAR{gamma} signaling on pain development has not been explored. In this study, we investigated the link between the phenotype switching of macrophage polarization induced by PPAR{gamma} signaling and the development of acute pain hypersensitivity. Local administration of rosiglitazone significantly ameliorated hypersensitivity to heat and mechanical stimuli, and paw swelling. Consistent with the down-regulation of nuclear factor {kappa}B (NF{kappa}B) phosphorylation by rosiglitazone at the incisional sites, the number of F4/80{sup +}iNOS{sup +} M1 macrophages was decreased whereas numbers of F4/80{sup +}CD206{sup +} M2 macrophages were increased in rosiglitazone-treated incisional sites 24 h after the procedure. In addition, gene induction of anti-inflammatory M2-macrophage-associated markers such as arginase1, FIZZ1 and interleukin (IL)-10 were significantly increased, whereas

  7. Thermodynamics of tryptophan-mediated activation of the trp RNA-binding attenuation protein.

    PubMed

    McElroy, Craig A; Manfredo, Amanda; Gollnick, Paul; Foster, Mark P

    2006-06-27

    The trp RNA-binding attenuation protein (TRAP) functions in many bacilli to control the expression of the tryptophan biosynthesis genes. Transcription of the trp operon is controlled by TRAP through an attenuation mechanism, in which competition between two alternative secondary-structural elements in the 5' leader sequence of the nascent mRNA is influenced by tryptophan-dependent binding of TRAP to the RNA. Previously, NMR studies of the undecamer (11-mer) suggested that tryptophan-dependent control of RNA binding by TRAP is accomplished through ligand-induced changes in protein dynamics. We now present further insights into this ligand-coupled event from hydrogen/deuterium (H/D) exchange analysis, differential scanning calorimetry (DSC), and isothermal titration calorimetry (ITC). Scanning calorimetry showed tryptophan dissociation to be independent of global protein unfolding, while analysis of the temperature dependence of the binding enthalpy by ITC revealed a negative heat capacity change larger than expected from surface burial, a hallmark of binding-coupled processes. Analysis of this excess heat capacity change using parameters derived from protein folding studies corresponds to the ordering of 17-24 residues per monomer of TRAP upon tryptophan binding. This result is in agreement with qualitative analysis of residue-specific broadening observed in TROSY NMR spectra of the 91 kDa oligomer. Implications for the mechanism of ligand-mediated TRAP activation through a shift in a preexisting conformational equilibrium and an induced-fit conformational change are discussed. PMID:16784236

  8. Guggulsterone attenuates cerulein-induced acute pancreatitis via inhibition of ERK and JNK activation.

    PubMed

    Kim, Dong-Goo; Bae, Gi-Sang; Choi, Sun-Bok; Jo, Il-Joo; Shin, Joon-Yeon; Lee, Sung-Kon; Kim, Myoung-Jin; Kim, Min-Jun; Jeong, Hyun-Woo; Choi, Chang-Min; Seo, Seung-Hee; Choo, Gab-Chul; Seo, Sang-Wan; Song, Ho-Joon; Park, Sung-Joo

    2015-05-01

    Guggulsterone (GS), a plant steroid and a compound found at high levels in Commiphora myrrha, exhibits anti-inflammatory, anti-cancer, and cholesterol-lowering effects. However, the potential of GS to ameliorate acute pancreatitis (AP) is unknown. The aim of this study was to evaluate the effects of GS on cerulein-induced AP. AP was induced by intraperitoneally injecting supramaximal concentrations of the stable cholecystokinin analog cerulein (50 μg/kg) hourly for 6 h. In the GS-treated group, GS was administered intraperitoneally (10, 25, or 50mg/kg) 1 h before the first cerulein injection. Mice were sacrificed 6 h after the final cerulein injection. Blood samples were collected to measure serum lipase levels and evaluate cytokine production. The pancreas and lung were rapidly removed for morphologic and histological examinations, flow cytometry analysis, myeloperoxidase (MPO) assay, and real-time reverse transcription-polymerase chain reaction analysis. Pre-treatment with GS attenuated cerulein-induced histological damage, reduced pancreas weight/body weight ratio, decreased serum lipase levels, inhibited infiltrations of macrophages and neutrophils, and suppressed cytokine production. Additionally, GS treatment suppressed the activation of extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) in the pancreas in cerulein-induced pancreatitis. In conclusion, our results suggest that GS attenuates AP via deactivation of ERK and JNK.

  9. Ligand activation of cannabinoid receptors attenuates hypertrophy of neonatal rat cardiomyocytes.

    PubMed

    Lu, Yan; Akinwumi, Bolanle C; Shao, Zongjun; Anderson, Hope D

    2014-11-01

    : Endocannabinoids are bioactive amides, esters, and ethers of long-chain polyunsaturated fatty acids. Evidence suggests that activation of the endocannabinoid pathway offers cardioprotection against myocardial ischemia, arrhythmias, and endothelial dysfunction of coronary arteries. As cardiac hypertrophy is a convergence point of risk factors for heart failure, we determined a role for endocannabinoids in attenuating endothelin-1-induced hypertrophy and probed the signaling pathways involved. The cannabinoid receptor ligand anandamide and its metabolically stable analog, R-methanandamide, suppressed hypertrophic indicators including cardiomyocyte enlargement and fetal gene activation (ie, the brain natriuretic peptide gene) elicited by endothelin-1 in isolated neonatal rat ventricular myocytes. The ability of R-methanandamide to suppress myocyte enlargement and fetal gene activation was mediated by CB2 and CB1 receptors, respectively. Accordingly, a CB2-selective agonist, JWH-133, prevented only myocyte enlargement but not brain natriuretic peptide gene activation. A CB1/CB2 dual agonist with limited brain penetration, CB-13, inhibited both hypertrophic indicators. CB-13 activated AMP-activated protein kinase (AMPK) and, in an AMPK-dependent manner, endothelial nitric oxide synthase (eNOS). Disruption of AMPK signaling, using compound C or short hairpinRNA knockdown, and eNOS inhibition using L-NIO abolished the antihypertrophic actions of CB-13. In conclusion, CB-13 inhibits cardiomyocyte hypertrophy through AMPK-eNOS signaling and may represent a novel therapeutic approach to cardioprotection. PMID:24979612

  10. Tau phosphorylation at Alzheimer's disease-related Ser356 contributes to tau stabilization when PAR-1/MARK activity is elevated.

    PubMed

    Ando, Kanae; Oka, Mikiko; Ohtake, Yosuke; Hayashishita, Motoki; Shimizu, Sawako; Hisanaga, Shin-Ichi; Iijima, Koichi M

    2016-09-16

    Abnormal phosphorylation of the microtubule-associated protein tau is observed in many neurodegenerative diseases, including Alzheimer's disease (AD). AD-related phosphorylation of two tau residues, Ser262 and Ser356, by PAR-1/MARK stabilizes tau in the initial phase of mismetabolism, leading to subsequent phosphorylation events, accumulation, and toxicity. However, the relative contribution of phosphorylation at each of these sites to tau stabilization has not yet been elucidated. In a Drosophila model of human tau toxicity, we found that tau was phosphorylated at Ser262, but not at Ser356, and that blocking Ser262 phosphorylation decreased total tau levels. By contrast, when PAR-1 was co-overexpressed with tau, tau was hyperphosphorylated at both Ser262 and Ser356. Under these conditions, the protein levels of tau were significantly elevated, and prevention of tau phosphorylation at both residues was necessary to completely suppress this elevation. These results suggest that tau phosphorylation at Ser262 plays the predominant role in tau stabilization when PAR-1/MARK activity is normal, whereas Ser356 phosphorylation begins to contribute to this process when PAR-1/MARK activity is abnormally elevated, as in diseased brains.

  11. Tau phosphorylation at Alzheimer's disease-related Ser356 contributes to tau stabilization when PAR-1/MARK activity is elevated.

    PubMed

    Ando, Kanae; Oka, Mikiko; Ohtake, Yosuke; Hayashishita, Motoki; Shimizu, Sawako; Hisanaga, Shin-Ichi; Iijima, Koichi M

    2016-09-16

    Abnormal phosphorylation of the microtubule-associated protein tau is observed in many neurodegenerative diseases, including Alzheimer's disease (AD). AD-related phosphorylation of two tau residues, Ser262 and Ser356, by PAR-1/MARK stabilizes tau in the initial phase of mismetabolism, leading to subsequent phosphorylation events, accumulation, and toxicity. However, the relative contribution of phosphorylation at each of these sites to tau stabilization has not yet been elucidated. In a Drosophila model of human tau toxicity, we found that tau was phosphorylated at Ser262, but not at Ser356, and that blocking Ser262 phosphorylation decreased total tau levels. By contrast, when PAR-1 was co-overexpressed with tau, tau was hyperphosphorylated at both Ser262 and Ser356. Under these conditions, the protein levels of tau were significantly elevated, and prevention of tau phosphorylation at both residues was necessary to completely suppress this elevation. These results suggest that tau phosphorylation at Ser262 plays the predominant role in tau stabilization when PAR-1/MARK activity is normal, whereas Ser356 phosphorylation begins to contribute to this process when PAR-1/MARK activity is abnormally elevated, as in diseased brains. PMID:27520376

  12. Meclozine Facilitates Proliferation and Differentiation of Chondrocytes by Attenuating Abnormally Activated FGFR3 Signaling in Achondroplasia

    PubMed Central

    Matsushita, Masaki; Kitoh, Hiroshi; Ohkawara, Bisei; Mishima, Kenichi; Kaneko, Hiroshi; Ito, Mikako; Masuda, Akio; Ishiguro, Naoki; Ohno, Kinji

    2013-01-01

    Achondroplasia (ACH) is one of the most common skeletal dysplasias with short stature caused by gain-of-function mutations in FGFR3 encoding the fibroblast growth factor receptor 3. We used the drug repositioning strategy to identify an FDA-approved drug that suppresses abnormally activated FGFR3 signaling in ACH. We found that meclozine, an anti-histamine drug that has long been used for motion sickness, facilitates chondrocyte proliferation and mitigates loss of extracellular matrix in FGF2-treated rat chondrosarcoma (RCS) cells. Meclozine also ameliorated abnormally suppressed proliferation of human chondrosarcoma (HCS-2/8) cells that were infected with lentivirus expressing constitutively active mutants of FGFR3-K650E causing thanatophoric dysplasia, FGFR3-K650M causing SADDAN, and FGFR3-G380R causing ACH. Similarly, meclozine alleviated abnormally suppressed differentiation of ATDC5 chondrogenic cells expressing FGFR3-K650E and -G380R in micromass culture. We also confirmed that meclozine alleviates FGF2-mediated longitudinal growth inhibition of embryonic tibia in bone explant culture. Interestingly, meclozine enhanced growth of embryonic tibia in explant culture even in the absence of FGF2 treatment. Analyses of intracellular FGFR3 signaling disclosed that meclozine downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells. Similarly, meclozine enhanced proliferation of RCS cells expressing constitutively active mutants of MEK and RAF but not of ERK, which suggests that meclozine downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation. We used the C-natriuretic peptide (CNP) as a potent inhibitor of the FGFR3 signaling throughout our experiments, and found that meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling. We propose that meclozine is a potential therapeutic agent for treating ACH and other FGFR3-related skeletal dysplasias. PMID:24324705

  13. Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia.

    PubMed

    Matsushita, Masaki; Kitoh, Hiroshi; Ohkawara, Bisei; Mishima, Kenichi; Kaneko, Hiroshi; Ito, Mikako; Masuda, Akio; Ishiguro, Naoki; Ohno, Kinji

    2013-01-01

    Achondroplasia (ACH) is one of the most common skeletal dysplasias with short stature caused by gain-of-function mutations in FGFR3 encoding the fibroblast growth factor receptor 3. We used the drug repositioning strategy to identify an FDA-approved drug that suppresses abnormally activated FGFR3 signaling in ACH. We found that meclozine, an anti-histamine drug that has long been used for motion sickness, facilitates chondrocyte proliferation and mitigates loss of extracellular matrix in FGF2-treated rat chondrosarcoma (RCS) cells. Meclozine also ameliorated abnormally suppressed proliferation of human chondrosarcoma (HCS-2/8) cells that were infected with lentivirus expressing constitutively active mutants of FGFR3-K650E causing thanatophoric dysplasia, FGFR3-K650M causing SADDAN, and FGFR3-G380R causing ACH. Similarly, meclozine alleviated abnormally suppressed differentiation of ATDC5 chondrogenic cells expressing FGFR3-K650E and -G380R in micromass culture. We also confirmed that meclozine alleviates FGF2-mediated longitudinal growth inhibition of embryonic tibia in bone explant culture. Interestingly, meclozine enhanced growth of embryonic tibia in explant culture even in the absence of FGF2 treatment. Analyses of intracellular FGFR3 signaling disclosed that meclozine downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells. Similarly, meclozine enhanced proliferation of RCS cells expressing constitutively active mutants of MEK and RAF but not of ERK, which suggests that meclozine downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation. We used the C-natriuretic peptide (CNP) as a potent inhibitor of the FGFR3 signaling throughout our experiments, and found that meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling. We propose that meclozine is a potential therapeutic agent for treating ACH and other FGFR3-related skeletal dysplasias. PMID:24324705

  14. Netrin-1 Abrogates Ischemia Reperfusion-induced Cardiac Mitochondrial Dysfunction via Nitric Oxide-dependent Attenuation of NOX4 Activation and Recoupling of NOS

    PubMed Central

    Siu, Kin Lung; Lotz, Christopher; Ping, Peipei; Cai, Hua

    2014-01-01

    Despite an established role of mitochondrial dysfunction in cardiac ischemia reperfusion (I/R) injury, the upstream activators have remained incompletely defined. We have recently identified an innovative role of exogenously applied netrin-1 in cardioprotection, which is mediated by increased nitric oxide (NO) bioavailability. Here, we tested the hypothesis that this “pharmacological” treatment of netrin-1 preserves mitochondrial function via novel mechanisms that are NO dependent. Freshly isolated C57BL6 mouse hearts were perfused using a Langendorff system, and subjected to a 20 min global ischemia/60 min reperfusion, in the presence or absence of netrin-1. I/R induced marked increases in infarct size, total superoxide and hydrogen peroxide production, activity and protein abundance of NADPH oxidase (NOX) isoform 4 (NOX4), as well as impaired mitochondrial integrity and function, all of which were attenuated by netrin-1. This protective effect of netrin-1 is attributed to cGMP, a downstream effector of NO. The protein levels of NOX1 and NOX2 were however unaffected, and infarct size from NOX1 and NOX2 knockouts were not different from wild type animals. Scavenging of NO with PTIO reversed inhibitory effects of netrin-1 on NOX4, while NO donor attenuated NOX4 protein abundance. In vivo NOX4 RNAi, or sepiapterin perfusion, resulted in recoupling of NOS, decreased infarct size, and blockade of dysfunctional mitochondrial swelling and mitochondrial superoxide production. These data demonstrate that netrin-1 induces cardioprotection through inhibition of NOX4 activity, which leads to recoupling of NOS, augmented NO bioavailability, reduction in oxidative stress, and ultimately preservation of mitochondrial function. The NO-dependent NOX4 inhibition connects with our previously established pathway of DCC/ERK1/2/eNOS/NO/DCC feed-forward mechanism, to maintain NOS in the coupling state to attenuate oxidative stress to preserve mitochondrial function. These findings

  15. Compound K Attenuates the Development of Atherosclerosis in ApoE−/− Mice via LXRα Activation

    PubMed Central

    Zhou, Li; Zheng, Yu; Li, Zhuoying; Bao, Lingxia; Dou, Yin; Tang, Yuan; Zhang, Jianxiang; Zhou, Jianzhi; Liu, Ya; Jia, Yi; Li, Xiaohui

    2016-01-01

    Background: Atherosclerosis is a fundamental pathological process responded to some serious cardiovascular events. Although the cholesterol-lowering drugs are widely prescribed for atherosclerosis therapy, it is still the leading cause of death in the developed world. Here we measured the effects of compound K in atherosclerosis formation and investigated the probably mechanisms of the anti-antherosclerosis roles of compound K. Methods: We treated the atherosclerotic model animals (apoE−/− mice on western diet) with compound K and measured the size of atherosclerotic lesions, inflammatory cytokine levels and serum lipid profile. Peritoneal macrophages were collected in vitro for the foam cell and inflammasome experiments. Results: Our results show that treatment with compound K dose-dependently attenuates the formation of atherosclerotic plaques by 55% through activation of reverse cholesterol transport pathway, reduction of systemic inflammatory cytokines and inhibition of local inflammasome activity. Compound K increases the cholesterol efflux of macrophage-derived foam cells, and reduces the inflammasome activity in cholesterol crystal stimulated macrophages. The activation of LXRα may contribute to the athero-protective effects of compound K. Conclusion: These observations provide evidence for an athero-protective effect of compound K via LXRα activation, and support its further evaluation as a potential effective modulator for the prevention and treatment of atherosclerosis. PMID:27399689

  16. Physical activity attenuates age-related biomarker alterations in preclinical AD

    PubMed Central

    Schultz, Stephanie A.; Oh, Jennifer M.; Larson, Jordan; Edwards, Dorothy; Cook, Dane; Koscik, Rebecca; Gallagher, Catherine L.; Dowling, N.M.; Carlsson, Cynthia M.; Bendlin, Barbara B.; LaRue, Asenath; Rowley, Howard A.; Christian, Brad T.; Asthana, Sanjay; Hermann, Bruce P.; Johnson, Sterling C.; Sager, Mark A.

    2014-01-01

    Objective: To examine whether engagement in physical activity might favorably alter the age-dependent evolution of Alzheimer disease (AD)-related brain and cognitive changes in a cohort of at-risk, late-middle-aged adults. Methods: Three hundred seventeen enrollees in the Wisconsin Registry for Alzheimer's Prevention underwent T1 MRI; a subset also underwent 11C-Pittsburgh compound B–PET (n = 186) and 18F-fluorodeoxyglucose–PET (n = 152) imaging. Participants' responses on a self-report measure of current physical activity were used to classify them as either physically active or physically inactive based on American Heart Association guidelines. They also completed a comprehensive neuropsychological battery. Covariate-adjusted regression analyses were used to test whether the adverse effect of age on imaging and cognitive biomarkers was modified by physical activity. Results: There were significant age × physical activity interactions for β-amyloid burden (p = 0.014), glucose metabolism (p = 0.015), and hippocampal volume (p = 0.025) such that, with advancing age, physically active individuals exhibited a lesser degree of biomarker alterations compared with the physically inactive. Similar age × physical activity interactions were also observed on cognitive domains of Immediate Memory (p = 0.042) and Visuospatial Ability (p = 0.016). In addition, the physically active group had higher scores on Speed and Flexibility (p = 0.002) compared with the inactive group. Conclusions: In a middle-aged, at-risk cohort, a physically active lifestyle is associated with an attenuation of the deleterious influence of age on key biomarkers of AD pathophysiology. However, because our observational, cross-sectional design cannot establish causality, randomized controlled trials/longitudinal studies will be necessary for determining whether midlife participation in structured physical exercise forestalls the development of AD and related disorders in later life. PMID:25298312

  17. Postnatal growth hormone deficiency in growing rats causes marked decline in the activity of spinal cord acetylcholinesterase but not butyrylcholinesterase.

    PubMed

    Koohestani, Faezeh; Brown, Chester M; Meisami, Esmail

    2012-11-01

    The effects of growth hormone (GH) deficiency on the developmental changes in the abundance and activity of cholinesterase enzymes were studied in the developing spinal cord (SC) of postnatal rats by measuring the specific activity of acetylcholinesterase (AChE), a marker for cholinergic neurons and their synaptic compartments, and butyrylcholinesterase (BuChE), a marker for glial cells and neurovascular cells. Specific activities of these two enzymes were measured in SC tissue of 21- and 90 day-old (P21, weaning age; P90, young adulthood) GH deficient spontaneous dwarf (SpDwf) mutant rats which lack anterior pituitary and circulating plasma GH, and were compared with SC tissue of normal age-matched control animals. Assays were carried out for AChE and BuChE activity in the presence of their specific chemical inhibitors, BW284C51 and iso-OMPA, respectively. Results revealed that mean AChE activity was markedly and significantly reduced [28% at P21, 49% at P90, (p<0.01)] in the SC of GH deficient rats compared to age-matched controls. GH deficiency had a higher and more significant effect on AChE activity of the older (P90) rats than the younger ones (P21) ones. In contrast, BuChE activity in SC showed no significant changes in GH deficient rats at either of the two ages studied. Results imply that, in the absence of pituitary GH, the postnatal proliferation of cholinergic synapses in the rat SC, a CNS structure, where AChE activity is abundant, is markedly reduced during both the pre- and postweaning periods; more so in the postweaning than preweaning ages. In contrast, the absence of any effects on BuChE activity implies that GH does not affect the development of non-neuronal elements, e.g., glia, as much as the neuronal and synaptic compartments of the developing rat SC. PMID:22922167

  18. Postnatal growth hormone deficiency in growing rats causes marked decline in the activity of spinal cord acetylcholinesterase but not butyrylcholinesterase.

    PubMed

    Koohestani, Faezeh; Brown, Chester M; Meisami, Esmail

    2012-11-01

    The effects of growth hormone (GH) deficiency on the developmental changes in the abundance and activity of cholinesterase enzymes were studied in the developing spinal cord (SC) of postnatal rats by measuring the specific activity of acetylcholinesterase (AChE), a marker for cholinergic neurons and their synaptic compartments, and butyrylcholinesterase (BuChE), a marker for glial cells and neurovascular cells. Specific activities of these two enzymes were measured in SC tissue of 21- and 90 day-old (P21, weaning age; P90, young adulthood) GH deficient spontaneous dwarf (SpDwf) mutant rats which lack anterior pituitary and circulating plasma GH, and were compared with SC tissue of normal age-matched control animals. Assays were carried out for AChE and BuChE activity in the presence of their specific chemical inhibitors, BW284C51 and iso-OMPA, respectively. Results revealed that mean AChE activity was markedly and significantly reduced [28% at P21, 49% at P90, (p<0.01)] in the SC of GH deficient rats compared to age-matched controls. GH deficiency had a higher and more significant effect on AChE activity of the older (P90) rats than the younger ones (P21) ones. In contrast, BuChE activity in SC showed no significant changes in GH deficient rats at either of the two ages studied. Results imply that, in the absence of pituitary GH, the postnatal proliferation of cholinergic synapses in the rat SC, a CNS structure, where AChE activity is abundant, is markedly reduced during both the pre- and postweaning periods; more so in the postweaning than preweaning ages. In contrast, the absence of any effects on BuChE activity implies that GH does not affect the development of non-neuronal elements, e.g., glia, as much as the neuronal and synaptic compartments of the developing rat SC.

  19. Rational Attenuation of a Morbillivirus by Modulating the Activity of the RNA-Dependent RNA Polymerase

    PubMed Central

    Brown, David D.; Rima, Bertus K.; Allen, Ingrid V.; Baron, Michael D.; Banyard, Ashley C.; Barrett, Thomas; Duprex, W. Paul

    2005-01-01

    Negative-strand RNA viruses encode a single RNA-dependent RNA polymerase (RdRp) which transcribes and replicates the genome. The open reading frame encoding the RdRp from a virulent wild-type strain of rinderpest virus (RPV) was inserted into an expression plasmid. Sequences encoding enhanced green fluorescent protein (EGFP) were inserted into a variable hinge of the RdRp. The resulting polymerase was autofluorescent, and its activity in the replication/transcription of a synthetic minigenome was reduced. We investigated the potential of using this approach to rationally attenuate a virus by inserting the DNA sequences encoding the modified RdRp into a full-length anti-genome plasmid from which a virulent virus (rRPVKO) can be rescued. A recombinant virus, rRPVKOL-RRegfpR, which grew at an indistinguishable rate and to an identical titer as rRPVKO in vitro, was rescued. Fluorescently tagged polymerase was visible in large cytoplasmic inclusions and beneath the cell membrane. Subcutaneous injection of 104 TCID50 of the rRPVKO parental recombinant virus into cattle leads to severe disease symptoms (leukopenia/diarrhea and pyrexia) and death by 9 days postinfection. Animals infected with rRPVKOL-RRegfpR exhibited transient leukopenia and mild pyrexia, and the only noticeable clinical signs were moderate reddening of one eye and a slight ocular-nasal discharge. Viruses that expressed the modified polymerase were isolated from peripheral blood lymphocytes and eye swabs. This demonstrates that a virulent morbillivirus can be attenuated in a single step solely by modulating RdRp activity and that there is not necessarily a correlation between virus growth in vitro and in vivo. PMID:16254367

  20. Rapamycin attenuates mitochondrial dysfunction via activation of mitophagy in experimental ischemic stroke

    SciTech Connect

    Li, Qiang; Zhang, Ting; Wang, Jixian; Zhang, Zhijun; Zhai, Yu; Yang, Guo-Yuan; Sun, Xiaojiang

    2014-02-07

    Highlights: • Rapamycin enhances mitophagy via increasing p62 translocation to the mitochondria. • Rapamycin attenuates brain ischemic damage and improves mitochondrial function. • The protection of rapamycin to mitochondrial is linked to enhanced mitophagy. - Abstract: Rapamycin has been demonstrated to exhibit neuroprotective functions via the activation of autophagy in a cerebral ischemia model. However, the involvement of mitophagy in this process and its contribution to the protection of mitochondrial function remains unknown. The present study explored the characteristics of mitophagy after cerebral ischemia and the effect of rapamycin on mitochondrial function. Male Sprague–Dawley rats underwent transient middle cerebral artery occlusion (tMCAO). Neurological deficits scores; infarct volumes; mitophagy morphology; and the levels of malondialdehyde (MDA), adenosine triphosphate (ATP) and mitochondrial membrane potentials (Δψm) were examined. The expression of LC3, Beclin-1 and p62 in the mitochondrial fraction combined with transmission electronic microscopy were used to explore mitophagic activity after ischemia. We also blocked autophagosome formation using 3-methyladenine (3-MA) to check the linkage between the mitochondrial protective effect of rapamycin and enhanced mitophagy. We observed that rapamycin significantly enhanced mitophagy, as evidenced by the increase in LC3-II and Beclin-1 expression in the mitochondria and p62 translocation to the mitochondria. Rapamycin reduced infarct volume, improved neurological outcomes and inhibited mitochondrial dysfunction compared with the control animals (p < 0.05). However, these protective effects were reversed by 3-methyladenine treatment after rapamycin. The present study indicates that rapamycin treatment attenuates mitochondrial dysfunction following cerebral ischemia, which is linked to enhanced mitophagy.

  1. Rational attenuation of a morbillivirus by modulating the activity of the RNA-dependent RNA polymerase.

    PubMed

    Brown, David D; Rima, Bertus K; Allen, Ingrid V; Baron, Michael D; Banyard, Ashley C; Barrett, Thomas; Duprex, W Paul

    2005-11-01

    Negative-strand RNA viruses encode a single RNA-dependent RNA polymerase (RdRp) which transcribes and replicates the genome. The open reading frame encoding the RdRp from a virulent wild-type strain of rinderpest virus (RPV) was inserted into an expression plasmid. Sequences encoding enhanced green fluorescent protein (EGFP) were inserted into a variable hinge of the RdRp. The resulting polymerase was autofluorescent, and its activity in the replication/transcription of a synthetic minigenome was reduced. We investigated the potential of using this approach to rationally attenuate a virus by inserting the DNA sequences encoding the modified RdRp into a full-length anti-genome plasmid from which a virulent virus (rRPV(KO)) can be rescued. A recombinant virus, rRPV(KO)L-RRegfpR, which grew at an indistinguishable rate and to an identical titer as rRPV(KO) in vitro, was rescued. Fluorescently tagged polymerase was visible in large cytoplasmic inclusions and beneath the cell membrane. Subcutaneous injection of 10(4) TCID(50) of the rRPV(KO) parental recombinant virus into cattle leads to severe disease symptoms (leukopenia/diarrhea and pyrexia) and death by 9 days postinfection. Animals infected with rRPV(KO)L-RRegfpR exhibited transient leukopenia and mild pyrexia, and the only noticeable clinical signs were moderate reddening of one eye and a slight ocular-nasal discharge. Viruses that expressed the modified polymerase were isolated from peripheral blood lymphocytes and eye swabs. This demonstrates that a virulent morbillivirus can be attenuated in a single step solely by modulating RdRp activity and that there is not necessarily a correlation between virus growth in vitro and in vivo.

  2. Marking Time

    ERIC Educational Resources Information Center

    Foster, Colin

    2011-01-01

    Teachers say that they would gladly teach a day in the classroom if at the end of the day they could leave and have no marking. There is a common staffroom perception that mathematics teachers have it easy when it comes to marking. In arts subjects, setting an essay can be a fairly straightforward matter--a one-line question may suffice--but…

  3. Amiloride lowers blood pressure and attenuates urine plasminogen activation in patients with treatment-resistant hypertension.

    PubMed

    Oxlund, Christina S; Buhl, Kristian B; Jacobsen, Ib A; Hansen, Mie R; Gram, Jeppe; Henriksen, Jan Erik; Schousboe, Karoline; Tarnow, Lise; Jensen, Boye L

    2014-12-01

    In conditions with albuminuria, plasminogen is aberrantly filtered across the glomerular barrier and activated along the tubular system to plasmin. In the collecting duct, plasmin activates epithelial sodium channels (ENaC) proteolytically. Hyperactivity of ENaC could link microalbuminuria/proteinuria to resistant hypertension. Amiloride, an ENaC inhibitor, inhibits urokinase-type plasminogen activator. We hypothesized that amiloride (1) reduces blood pressure (BP); (2) attenuates plasminogen-to-plasmin activation; and (3) inhibits urine urokinase-type plasminogen activator in patients with resistant hypertension and type 2 diabetes mellitus (T2DM).In an open-label, non-randomized, 8-week intervention study, a cohort (n = 80) of patients with resistant hypertension and T2DM were included. Amiloride (5 mg/d) was added to previous triple antihypertensive treatment (including a diuretic and an inhibitor of the renin-angiotensin-aldosterone system) and increased to 10 mg if BP control was not achieved at 4 weeks. Complete dataset for urine analysis was available in 60 patients. Systolic and diastolic BP measured by ambulatory BP monitoring and office monitoring were significantly reduced. Average daytime BP was reduced by 6.3/3.0 mm Hg. Seven of 80 cases (9%) discontinued amiloride due to hyperkalemia >5.5 mol/L, the most frequent adverse event. Urinary plasmin(ogen) and albumin excretions were significantly reduced after amiloride treatment (P < .0001). Urokinase activity was detectable in macroalbuminuric urine, with a tendency toward reduction in activity after amiloride treatment. Amiloride lowers BP, urine plasminogen excretion and activation, and albumin/creatinine ratio, and is a relevant add-on medication for the treatment of resistant hypertension in patients with T2DM and microalbuminuria.

  4. Active thermography and post-processing image enhancement for recovering of abraded and paint-covered alphanumeric identification marks

    NASA Astrophysics Data System (ADS)

    Montanini, R.; Quattrocchi, A.; Piccolo, S. A.

    2016-09-01

    Alphanumeric marking is a common technique employed in industrial applications for identification of products. However, the realised mark can undergo deterioration, either by extensive use or voluntary deletion (e.g. removal of identification numbers of weapons or vehicles). For recovery of the lost data many destructive or non-destructive techniques have been endeavoured so far, which however present several restrictions. In this paper, active infrared thermography has been exploited for the first time in order to assess its effectiveness in restoring paint covered and abraded labels made by means of different manufacturing processes (laser, dot peen, impact, cold press and scribe). Optical excitation of the target surface has been achieved using pulse (PT), lock-in (LT) and step heating (SHT) thermography. Raw infrared images were analysed with a dedicated image processing software originally developed in Matlab™, exploiting several methods, which include thermographic signal reconstruction (TSR), guided filtering (GF), block guided filtering (BGF) and logarithmic transformation (LN). Proper image processing of the raw infrared images resulted in superior contrast and enhanced readability. In particular, for deeply abraded marks, good outcomes have been obtained by application of logarithmic transformation to raw PT images and block guided filtering to raw phase LT images. With PT and LT it was relatively easy to recover labels covered by paint, with the latter one providing better thermal contrast for all the examined targets. Step heating thermography never led to adequate label identification instead.

  5. A non canonical subtilase attenuates the transcriptional activation of defence responses in Arabidopsis thaliana

    PubMed Central

    Serrano, Irene; Buscaill, Pierre; Audran, Corinne; Pouzet, Cécile; Jauneau, Alain; Rivas, Susana

    2016-01-01

    Proteases play crucial physiological functions in all organisms by controlling the lifetime of proteins. Here, we identified an atypical protease of the subtilase family [SBT5.2(b)] that attenuates the transcriptional activation of plant defence independently of its protease activity. The SBT5.2 gene produces two distinct transcripts encoding a canonical secreted subtilase [SBT5.2(a)] and an intracellular protein [SBT5.2(b)]. Concomitant to SBT5.2(a) downregulation, SBT5.2(b) expression is induced after bacterial inoculation. SBT5.2(b) localizes to endosomes where it interacts with and retains the defence-related transcription factor MYB30. Nuclear exclusion of MYB30 results in its reduced transcriptional activation and, thus, suppressed resistance. sbt5.2 mutants, with abolished SBT5.2(a) and SBT5.2(b) expression, display enhanced defence that is suppressed in a myb30 mutant background. Moreover, overexpression of SBT5.2(b), but not SBT5.2(a), in sbt5.2 plants reverts the phenotypes displayed by sbt5.2 mutants. Overall, we uncover a regulatory mode of the transcriptional activation of defence responses previously undescribed in eukaryotes. DOI: http://dx.doi.org/10.7554/eLife.19755.001 PMID:27685353

  6. Inhibition of classical complement activation attenuates liver ischaemia and reperfusion injury in a rat model.

    PubMed

    Heijnen, B H M; Straatsburg, I H; Padilla, N D; Van Mierlo, G J; Hack, C E; Van Gulik, T M

    2006-01-01

    Activation of the complement system contributes to the pathogenesis of ischaemia/reperfusion (I/R) injury. We evaluated inhibition of the classical pathway of complement using C1-inhibitor (C1-inh) in a model of 70% partial liver I/R injury in male Wistar rats (n = 35). C1-inh was administered at 100, 200 or 400 IU/kg bodyweight, 5 min before 60 min ischaemia (pre-I) or 5 min before 24 h reperfusion (end-I). One hundred IU/kg bodyweight significantly reduced the increase of plasma levels of activated C4 as compared to albumin-treated control rats and attenuated the increase of alanine aminotransferase (ALT). These effects were not better with higher doses of C1-inh. Administration of C1-inh pre-I resulted in lower ALT levels and higher bile secretion after 24 h of reperfusion than administration at end-I. Immunohistochemical assessment indicated that activated C3, the membrane attack complex C5b9 and C-reactive protein (CRP) colocalized in hepatocytes within midzonal areas, suggesting CRP is a mediator of I/R-induced, classical complement activation in rats. Pre-ischaemic administration of C1-inh is an effective pharmacological intervention to protect against liver I/R injury.

  7. Ulinastatin attenuates pulmonary endothelial glycocalyx damage and inhibits endothelial heparanase activity in LPS-induced ARDS.

    PubMed

    Wang, Lipeng; Huang, Xiao; Kong, Guiqing; Xu, Haixiao; Li, Jiankui; Hao, Dong; Wang, Tao; Han, Shasha; Han, Chunlei; Sun, Yeying; Liu, Xiangyong; Wang, Xiaozhi

    2016-09-16

    Acute respiratory distress syndrome (ARDS) is a syndrome of acute respiratory failure characterized by major pathologic mechanisms of increased microvascular permeability and inflammation. The glycocalyx lines on the endothelial surface, which determines the vascular permeability, and heparanase play pivotal roles in the degradation of heparan sulfate (HS). HS is the major component of the glycocalyx. The aim of this study is to examine the effects of Ulinastatin (UTI) on vascular permeability and pulmonary endothelial glycocalyx dysfunction induced by lipopolysaccharide (LPS). In our study, C57BL/6 mice and human umbilical vein endothelial cells were stimulated with LPS to induce injury models. After 6 h of LPS stimulation, pulmonary pathological changes, pulmonary edema, and vascular permeability were notably attenuated by UTI. UTI inhibited LPS-induced endothelial glycocalyx destruction and significantly decreased the production of HS as determined by ELISA and immunofluorescence. UTI also reduced the active form of heparanase (50 kDa) expression and heparanase activity. Moreover, lysosome pH was investigated because heparanase (65 kDa) can be reduced easily in its active form at 50 kDa in a low pH environment within lysosome. Results showed that UTI could inhibit LPS-induced pH elevation in lysosome. In conclusion, UTI protects pulmonary endothelial glycocalyx integrity and inhibits heparanase activity during LPS-induced ARDS.

  8. Attachment-security priming attenuates amygdala activation to social and linguistic threat.

    PubMed

    Norman, Luke; Lawrence, Natalia; Iles, Andrew; Benattayallah, Abdelmalek; Karl, Anke

    2015-06-01

    A predominant expectation that social relationships with others are safe (a secure attachment style), has been linked with reduced threat-related amygdala activation. Experimental priming of mental representations of attachment security can modulate neural responding, but the effects of attachment-security priming on threat-related amygdala activation remains untested. Using functional magnetic resonance imaging, the present study examined the effects of trait and primed attachment security on amygdala reactivity to threatening stimuli in an emotional faces and a linguistic dot-probe task in 42 healthy participants. Trait attachment anxiety and attachment avoidance were positively correlated with amygdala activation to threatening faces in the control group, but not in the attachment primed group. Furthermore, participants who received attachment-security priming showed attenuated amygdala activation in both the emotional faces and dot-probe tasks. The current findings demonstrate that variation in state and trait attachment security modulates amygdala reactivity to threat. These findings support the potential use of attachment security-boosting methods as interventions and suggest a neural mechanism for the protective effect of social bonds in anxiety disorders.

  9. Implementation of natural attenuation at a JP-4 jet fuel release after active remediation.

    PubMed

    Cho, J S; Wilson, J T; DiGiulio, D C; Vardy, J A; Choi, W

    1997-01-01

    After eighteen months of active remediation at a JP-4 jet-fuel spill, a residual of unremediated hydrocarbon remained. Further site characterization was conducted to evaluate the contribution of natural attenuation to control exposure to hazards associated with the residual contamination in the subsurface. Activities included the detailed characterization of ground-water flow through the spill; the distribution of fuel contaminants in groundwater; and the analysis of soluble electron acceptors moving into the spill from upgradient. These activities allowed a rigorous evaluation of the transport of contaminants from the spill to the receptor of groundwater, the Pasquotank River. The transport of dissolved contaminants of concern, that is benzene, toluene, ethyl benzene, xylene isomers (BTEX) and methyl-tertiary-butyl ether (MTBE), into the river from the source area was controlled by equilibrium dissolution from the fuel spill to the adjacent groundwater, diffusion in groundwater from the spill to permeable layers in the aquifer, and advective transport in the permeable layers. The estimated yearly loading of BTEX compounds and MTBE into the receptor was trivial even without considering biological degradation. The biodegradation of hydrocarbon dissolved in groundwater through aerobic respiration, denitrification, sulfate reduction, and iron reduction was estimated from changes in ground-water chemistry along the flow path. The concentrations of target components in permanent monitoring wells continue to decline over time. Long term monitoring will ensure that the plume is under control, and no further active remediation is required.

  10. Mark4 promotes oxidative stress and inflammation via binding to PPARγ and activating NF-κB pathway in mice adipocytes

    PubMed Central

    Liu, Zhenjiang; Gan, Lu; Chen, Yizhe; Luo, Dan; Zhang, Zhenzhen; Cao, Weina; Zhou, Zhongjie; Lin, Xueting; Sun, Chao

    2016-01-01

    MAP/Microtubule affinity-regulating kinase 4 (Mark4) plays an important role in the regulation of microtubule organization, adipogenesis and apoptosis. However, the role of Mark4 plays in oxidative stress and inflammation are poorly understood. In this study, we found Mark4 was induced by high fat diet (HFD) while PPARγ was elevated significantly in mice adipocytes. Further analyses revealed Mark4 impaired mitochondrial oxidative respiration and increased reactive oxygen species (ROS) production. At same time, the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) were greatly reduced. By treating cells with H2O2 and vitamin E (VE), Mark4 accentuated oxidative stress along with increased mRNA level of inflammatory factor interleukin-6 (IL-6) and decreased leptin mRNA. Furthermore, we found PPARγ bind to Mark4 promoter region and inhibited Mark4 expression. We showed PPARγ interacted with Mark4 and inhibited the stimulating effect of Mark4 on oxidative stress and inflammation. Finally, we demonstrated that the IKKα/NF-κB signal pathway was involved in Mark4 induced oxidative stress and inflammation, while PTDC, a special inhibitor of NF-κB signal pathway, reduced oxidative stress and inflammation. Thus, our study indicated that Mark4 was a potential drug target for treating metabolic diseases. PMID:26888669

  11. Long-lived activation products in TRIGA Mark II research reactor concrete shield: calculation and experiment

    NASA Astrophysics Data System (ADS)

    Žagar, Tomaž; Božič, Matjaž; Ravnik, Matjaž

    2004-12-01

    In this paper, a process of long-lived activity determination in research reactor concrete shielding is presented. The described process is a combination of experiment and calculations. Samples of original heavy reactor concrete containing mineral barite were irradiated inside the reactor shielding to measure its long-lived induced radioactivity. The most active long-lived (γ emitting) radioactive nuclides in the concrete were found to be 133Ba, 60Co and 152Eu. Neutron flux, activation rates and concrete activity were calculated for actual shield geometry for different irradiation and cooling times using TORT and ORIGEN codes. Experimental results of flux and activity measurements showed good agreement with the results of calculations. Volume of activated concrete waste after reactor decommissioning was estimated for particular case of Jožef Stefan Institute TRIGA reactor. It was observed that the clearance levels of some important long-lived isotopes typical for barite concrete (e.g. 133Ba, 41Ca) are not included in the IAEA and EU basic safety standards.

  12. Macrophage response to bacteria: induction of marked secretory and cellular activities by lipoteichoic acids.

    PubMed Central

    Keller, R; Fischer, W; Keist, R; Bassetti, S

    1992-01-01

    Lipoteichoic acids (LTAs) from various bacterial species, including Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Enterococcus faecalis, and Listeria monocytogenes, were examined for the ability to induce secretory and cellular responses in a pure population of bone marrow-derived mononuclear phagocytes. Some of the highly purified LTAs, in particular LTAs from Bacillus subtilis, S. pyogenes, E. faecalis, and Enterococcus hirae, were able to affect each of the macrophage parameters measured, i.e., reductive capacity, secretion of tumor necrosis factor and nitrite, and tumoricidal activity. As after stimulation with whole organisms or other bacterial products, secretion of tumor necrosis factor induced by these LTAs reached its maximum within the first few hours of the interaction, while secretion of nitrite and tumoricidal activity required 24 to 36 h for full expression. Other purified LTAs, i.e., LTAs from Streptococcus sanguis, S. pneumoniae, and L. monocytogenes, as well as lipomannan from Micrococcus luteus affected only some of these parameters, while native LTA from S. aureus was inactive. There was no obvious correlation between biological activity and chain length, kind of glycosyl substituents, glycolipid structures, or fatty acid composition of LTAs. Deacylation of LTAs resulted in a complete loss of activity, and deacylated LTAs did not impair the activity of their acylated counterparts, suggesting that acyl chains may be essential for binding of LTA to the cell surface. The results demonstrate that some LTA species are potent inducers of macrophage secretory and cellular activities. PMID:1500175

  13. Music Attenuated a Decrease in Parasympathetic Nervous System Activity after Exercise

    PubMed Central

    Miura, Misa; Ito, Osamu; Kohzuki, Masahiro

    2016-01-01

    Music and exercise can both affect autonomic nervous system activity. However, the effects of the combination of music and exercise on autonomic activity are poorly understood. Additionally, it remains unknown whether music affects post-exercise orthostatic tolerance. The aim of this study was to evaluate the effects of music on autonomic nervous system activity in orthostatic tolerance after exercise. Twenty-six healthy graduate students participated in four sessions in a random order on four separate days: a sedentary session, a music session, a bicycling session, and a bicycling with music session. Participants were asked to listen to their favorite music and to exercise on a cycle ergometer. We evaluated autonomic nervous system activity before and after each session using frequency analysis of heart rate variability. High frequency power, an index of parasympathetic nervous system activity, was significantly increased in the music session. Heart rate was increased, and high frequency power was decreased, in the bicycling session. There was no significant difference in high frequency power before and after the bicycling with music session, although heart rate was significantly increased. Additionally, both music and exercise did not significantly affect heart rate, systolic blood pressure or also heart rate variability indices in the orthostatic test. These data suggest that music increased parasympathetic activity and attenuated the exercise-induced decrease in parasympathetic activity without altering the orthostatic tolerance after exercise. Therefore, music may be an effective approach for improving post-exercise parasympathetic reactivation, resulting in a faster recovery and a reduction in cardiac stress after exercise. PMID:26840532

  14. Music Attenuated a Decrease in Parasympathetic Nervous System Activity after Exercise.

    PubMed

    Jia, Tiantian; Ogawa, Yoshiko; Miura, Misa; Ito, Osamu; Kohzuki, Masahiro

    2016-01-01

    Music and exercise can both affect autonomic nervous system activity. However, the effects of the combination of music and exercise on autonomic activity are poorly understood. Additionally, it remains unknown whether music affects post-exercise orthostatic tolerance. The aim of this study was to evaluate the effects of music on autonomic nervous system activity in orthostatic tolerance after exercise. Twenty-six healthy graduate students participated in four sessions in a random order on four separate days: a sedentary session, a music session, a bicycling session, and a bicycling with music session. Participants were asked to listen to their favorite music and to exercise on a cycle ergometer. We evaluated autonomic nervous system activity before and after each session using frequency analysis of heart rate variability. High frequency power, an index of parasympathetic nervous system activity, was significantly increased in the music session. Heart rate was increased, and high frequency power was decreased, in the bicycling session. There was no significant difference in high frequency power before and after the bicycling with music session, although heart rate was significantly increased. Additionally, both music and exercise did not significantly affect heart rate, systolic blood pressure or also heart rate variability indices in the orthostatic test. These data suggest that music increased parasympathetic activity and attenuated the exercise-induced decrease in parasympathetic activity without altering the orthostatic tolerance after exercise. Therefore, music may be an effective approach for improving post-exercise parasympathetic reactivation, resulting in a faster recovery and a reduction in cardiac stress after exercise.

  15. Activation of Toll-like receptor 9 attenuates unilateral ureteral obstruction-induced renal fibrosis

    PubMed Central

    Xin, Bing-mu; Wang, Xiao-xing; Jin, Wen; Yan, Hui-min; Cui, Bing; Zhang, Xiao-wei; Hua, Fang; Yang, Hong-zhen; Hu, Zhuo-wei

    2010-01-01

    Aim: To study whether activation of TLR9 by CpG-ODN would protect against and/or reverse renal fibrosis. Methods: Animals were treated with CpG-ODN before or after undergoing a unilateral ureteral obstruction (UUO) procedure. The interstitial fibrotic lesions of obstructed kidneys were evaluated using histology and immunohistostaining. The Th2-type cytokine profile and the expression and activity of sma and mad related protein (Smad)3, signal transducers and activators of transcription (Stat)3, extracellular regulated protein kinases (ERK), and p38 kinase were determined using RT-PCR or Western blot. Results: The obstructed kidneys displayed a significant increase in interstitial fibrosis, an infiltration of macrophages in the interstitium, and an enhanced expression of Th2 cytokines. Prophylactic application of CpG-ODN (40 μg/kg every 3 days from 2 h before UUO until the 14th day after UUO) suppressed the expression of α-smooth muscle actin, collagen deposition, and hydroxyproline in the UUO kidneys of rats. Moreover, CpG-ODN not only decreased the infiltration of macrophages but also inhibited the expression of chemokines CCL2 and CCL5, the Th2 cytokine IL-13, and the profibrogenic cytokines transforming growth factor (TGF)-β1 and plasminogen activator inhibitor (PAI)-1 in UUO kidneys of rats. Importantly, therapeutic administration of CpG-ODN (10 μg/mouse, ip, every 3 days from the 4th day to 21st day after UUO) reversed the established renal fibrosis, which was accompanied by significant reductions in the activity of ERK, Smad3, and Stat3 and an increase in the activity of p38 kinase. Conclusion: The activation of TLR9 by CpG-ODN attenuates UUO-induced renal fibrosis by reversing an immunosuppressive microenvironment in the fibrotic renal tissue, which might be a novel therapeutic strategy against fibrotic renal diseases. PMID:21113175

  16. Human Defensin 5 Disulfide Array Mutants: Disulfide Bond Deletion Attenuates Antibacterial Activity Against Staphylococcus aureus

    PubMed Central

    Wanniarachchi, Yoshitha A.; Kaczmarek, Piotr; Wan, Andrea; Nolan, Elizabeth M.

    2011-01-01

    Human α-defensin 5 (HD5, HD5ox to specify the oxidized and disulfide linked form) is a 32-residue cysteine-rich host-defense peptide, expressed and released by small intestinal Paneth cells, that exhibits antibacterial activity against a number of Gram-negative and –positive bacterial strains. To ascertain the contributions of its disulfide array to structure, antimicrobial activity, and proteolytic stability, a series of HD5 double mutant peptides where pairs of cysteine residues corresponding to native disulfide linkages (Cys3—Cys31, Cys5—Cys20, Cys10—Cys30) were mutated to Ser or Ala residues were overexpressed in E. coli, purified and characterized. A hexa mutant peptide, HD5[Serhexa], where all six native Cys residues are replaced by Ser residues was also evaluated. Removal of a single native S—S linkage influences oxidative folding and regioisomerization, antibacterial activity, Gram-negative bacterial membrane permeabilization, and proteolytic stability. Whereas the majority of the HD5 mutant peptides show low-micromolar activity against Gram-negative E. coli ATCC 25922 in colony counting assays, the wild-type disulfide array is essential for low-micromolar activity against Gram-positive S. aureus ATCC 25923. Removal of a single disulfide bond attenuates the activity observed for HD5ox against this Gram-positive bacterial strain. This observation supports the notion that the HD5ox mechanism of antibacterial action differs for Gram-negative and Gram-positive species (Wei, G.; de Leeuw, E., Pazgier, M., Yuan, W., Zou, G., Wang, J., Ericksen, B., Lu, W.-Y.; Lehrer, R. I.; Lu, W. (2009) J. Biol. Chem. 284, 29180-29192), and that the native disulfide array is a requirement for its activity against S. aureus. PMID:21861459

  17. Physical Activity Attenuates the Effect of Low Birth Weight on Insulin Resistance in Adolescents

    PubMed Central

    Ortega, Francisco B.; Ruiz, Jonatan R.; Hurtig-Wennlöf, Anita; Meirhaeghe, Aline; González-Gross, Marcela; Moreno, Luis A.; Molnar, Dénes; Kafatos, Anthony; Gottrand, Frederic; Widhalm, Kurt; Labayen, Idoia; Sjöström, Michael

    2011-01-01

    OBJECTIVE To examine whether physical activity influences the association between birth weight and insulin resistance in adolescents. RESEARCH DESIGN AND METHODS The study comprised adolescents who participated in two cross-sectional studies: the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study (n = 520, mean age = 14.6 years) and the Swedish part of the European Youth Heart Study (EYHS) (n = 269, mean age = 15.6 years). Participants had valid data on birth weight (parental recall), BMI, sexual maturation, maternal education, breastfeeding, physical activity (accelerometry, counts/minute), fasting glucose, and insulin. Insulin resistance was assessed by homeostasis model assessment–insulin resistance (HOMA-IR). Maternal education level and breastfeeding duration were reported by the mothers. RESULTS There was a significant interaction of physical activity in the association between birth weight and HOMA-IR (logarithmically transformed) in both the HELENA study and the EYHS (P = 0.05 and P = 0.03, respectively), after adjusting for sex, age, sexual maturation, BMI, maternal education level, and breastfeeding duration. Stratified analyses by physical activity levels (below/above median) showed a borderline inverse association between birth weight and HOMA-IR in the low-active group (standardized β = −0.094, P = 0.09, and standardized β = −0.156, P = 0.06, for HELENA and EYHS, respectively), whereas no evidence of association was found in the high-active group (standardized β = −0.031, P = 0.62, and standardized β = 0.053, P = 0.55, for HELENA and EYHS, respectively). CONCLUSIONS Higher levels of physical activity may attenuate the adverse effects of low birth weight on insulin sensitivity in adolescents. More observational data, from larger and more powerful studies, are required to test these findings. PMID:21752955

  18. A Drosophila Reporter for the Translational Activation of ATF4 Marks Stressed Cells during Development.

    PubMed

    Kang, Kwonyoon; Ryoo, Hyung Don; Park, Jung-Eun; Yoon, Jee-Hyun; Kang, Min-Ji

    2015-01-01

    Eukaryotic cells have evolved signaling pathways that help to restore cellular homeostasis in response to various physiological or pathological conditions. ATF4 is a transcription factor whose mRNA translation is stimulated in response to stress-activated eIF2alpha kinases. Established conditions that activate eIF2alpha phosphorylation and ATF4 translation include excessive stress in the endoplasmic reticulum (ER) and amino acid deprivation. ATF4 is activated through a unique translational activation mechanism that involves multiple upstream open reading frames (uORFs) in the 5'-untranslated region (UTR), which is conserved from yeast to mammals. Taking advantage of this, we developed a translational activation reporter of ATF4 in Drosophila, in which the dsRed reporter coding sequence was placed downstream of the Drosophila ATF4 5' UTR. This reporter remained inactive in most tissues under normal conditions, but showed dsRed expression when starved, or when challenged with conditions that imposed ER stress. In normally developing flies, a small number of cell types showed reporter expression even without exogenous stress, which included the salivary gland, gut, the male reproductive organ, and the photoreceptor cells, suggestive of inherent stress during the normal development of these cell types. These results establish a new tool to study ATF4-mediated stress response in Drosophila development and disease.

  19. Liver glutamine synthetase activity is markedly reduced in chronic ethanol-fed micropigs

    SciTech Connect

    Olin, K.L.; Zidenberg-Cherr, S.; Villanueva, J.; Halsted, C.H.; Keen, C.L. )

    1992-02-26

    The authors have reported that chronic ethanol (Et) feeding in the micropig results in changes in antioxidant defense including reductions in liver CuZnSOD and GSHPX activities, in vitamin E and A levels, and increases in liver MnSOD activity. Despite these alterations, liver mitochondria (mit) and microsome (mic) TBARS were lower in Et-fed than control (C) pigs. The significance of lower TBARS is unclear since the saturated to PUFA ratio was higher in mit and mic from Et than from C pigs. Thus in the current study they measured a non-lipid target of oxidative damage. Glutamine synthetase (GS) activity was measured as this protein is an excellent marker for oxidative damage due to the sensitivity of histidine residues to free radicals at the active site. Micropigs were fed high PUFA diets containing 40% of kcals as either Et or cornstarch (C) and 34% of kcals as corn oil. After 12 mo pigs were killed and livers removed. Fatty infiltration, inflammation and necrosis were observed in livers from Et pigs by 5 mo; collagen infiltration was apparent in 2 pigs by 12 mo. Et pigs had GS activities that were 90% lower than C pigs. The finding that liver Mn levels were higher in Et than in C pigs suggests that the low GS activity is not due to a reduction in Mn availability, although a shift in the distribution of Mn from GS to MnSOD may be involved. These data support the idea that chronic Et feeding is associated with oxidative damage and underscore the need to evaluate non-lipid targets as markers for oxidative damage.

  20. PERK Activation Promotes Medulloblastoma Tumorigenesis by Attenuating Premalignant Granule Cell Precursor Apoptosis.

    PubMed

    Ho, Yeung; Li, Xiting; Jamison, Stephanie; Harding, Heather P; McKinnon, Peter J; Ron, David; Lin, Wensheng

    2016-07-01

    Evidence suggests that activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum stress negatively or positively influences cell transformation by regulating apoptosis. Patched1 heterozygous deficient (Ptch1(+/-)) mice reproduce human Gorlin's syndrome and are regarded as the best animal model to study tumorigenesis of the sonic hedgehog subgroup of medulloblastomas. It is believed that medulloblastomas in Ptch1(+/-) mice results from the transformation of granule cell precursors (GCPs) in the developing cerebellum. Here, we determined the role of PERK signaling on medulloblastoma tumorigenesis by assessing its effects on premalignant GCPs and tumor cells. We found that PERK signaling was activated in both premalignant GCPs in young Ptch1(+/-) mice and medulloblastoma cells in adult mice. We demonstrated that PERK haploinsufficiency reduced the incidence of medulloblastomas in Ptch1(+/-) mice. Interestingly, PERK haploinsufficiency enhanced apoptosis of premalignant GCPs in young Ptch1(+/-) mice but had no significant effect on medulloblastoma cells in adult mice. Moreover, we showed that the PERK pathway was activated in medulloblastomas in humans. These results suggest that PERK signaling promotes medulloblastoma tumorigenesis by attenuating apoptosis of premalignant GCPs during the course of malignant transformation. PMID:27181404

  1. Inactivation of MARK4, an AMP-activated protein kinase (AMPK)-related kinase, leads to insulin hypersensitivity and resistance to diet-induced obesity.

    PubMed

    Sun, Chao; Tian, Liang; Nie, Jia; Zhang, Hai; Han, Xiao; Shi, Yuguang

    2012-11-01

    MARK4, also known as Par-1d/MarkL1, is a member of the AMP-activated protein kinase (AMPK)-related family of kinases, which are implicated in the regulation of dynamic biological functions, including glucose and energy homeostasis. However, the physiological function of MARK4 in mammals remains elusive. Here, we investigated a role for MARK4 in regulating energy homeostasis by generating mice with targeted inactivation of the mark4 gene. We show that MARK4 deficiency in mice caused hyperphagia, hyperactivity, and hypermetabolism, leading to protection from diet-induced obesity and its related metabolic complications through up-regulation of brown fat activity. Consequently, MARK4 deficiency mitigated insulin resistance associated with diet-induced obesity by dramatically enhancing insulin-stimulated AKT phosphorylation in major metabolic tissues. Ablation of MARK4 also significantly improved glucose homeostasis by up-regulating the activity and expression of AMPK kinase in key metabolic tissues. Taken together, these data identify a key role of MARK4 in energy metabolism, implicating the kinase as a novel drug target for the treatment of obesity and type 2 diabetes. PMID:22992738

  2. Inhibition of biomaterial-induced complement activation attenuates the inflammatory host response to implantation

    PubMed Central

    Kourtzelis, Ioannis; Rafail, Stavros; DeAngelis, Robert A.; Foukas, Periklis G.; Ricklin, Daniel; Lambris, John D.

    2013-01-01

    Although complement is a known contributor to biomaterial-induced complications, pathological implications and therapeutic options remain to be explored. Here we investigated the involvement of complement in the inflammatory response to polypropylene meshes commonly used for hernia repair. In vitro assays revealed deposition of complement activation fragments on the mesh after incubation in plasma. Moreover, significant mesh-induced complement and granulocyte activation was observed in plasma and leukocyte preparations, respectively. Pretreatment of plasma with the complement inhibitor compstatin reduced opsonization >2-fold, and compstatin and a C5a receptor antagonist (C5aRa) impaired granulocyte activation by 50 and 67%, respectively. We established a clinically relevant mouse model of implantation and could confirm deposition of C3 activation fragments on mesh implants in vivo using immunofluorescence. In meshes extracted after subcutaneous or peritoneal implantation, the amount of immune cell infiltrate in mice deficient in key complement components (C3, C5aR), or treated with C5aRa, was approximately half of that observed in wild-type littermates or mice treated with inactive C5aRa, respectively. Our data suggest that implantation of a widely used surgical mesh triggers the formation of an inflammatory cell microenvironment at the implant site through complement activation, and indicates a path for the therapeutic modulation of implant-related complications.—Kourtzelis, I., Rafail, S., DeAngelis, R. A., Foukas, P. G., Ricklin, D., Lambris, J. D. Inhibition of biomaterial-induced complement activation attenuates the inflammatory host response to implantation. PMID:23558338

  3. PHARMACOLOGICAL SIRT1 ACTIVATION IMPROVES MORTALITY AND MARKEDLY ALTERS TRANSCRIPTIONAL PROFILES THAT ACCOMPANY EXPERIMENTAL SEPSIS.

    PubMed

    Opal, Steven M; Ellis, James L; Suri, Vipin; Freudenberg, Johannes M; Vlasuk, George P; Li, Yong; Chahin, Abdullah B; Palardy, John E; Parejo, Nicholas; Yamamoto, Michelle; Chahin, Abdulrahman; Kessimian, Noubar

    2016-04-01

    The sirtuin family consists of seven NAD+-dependent enzymes affecting a broad array of regulatory protein networks by primarily catalyzing the deacetylation of key lysine residues in regulatory proteins. The enzymatic activity of SIRT1 can be enhanced by small molecule activators known as SIRT1 activator compounds (STACs). We tested the therapeutic potential of the STAC SRT3025 in two preclinical models of severe infection, the murine cecal ligation and puncture (CLP) model to induce peritonitis and intratracheal installation of Streptococcus pneumoniae to induce severe bacterial pneumonia. SRT3025 provided significant survival benefits over vehicle control in both the peritonitis and pneumococcal pneumonia models when administered with appropriate antimicrobial agents. The survival benefit of SRT3025 in the CLP model was absent in SIRT1 knockout showing the SIRT1 dependency of SRT3025's effects. SRT3025 administration promoted bacterial clearance and significantly reduced inflammatory cytokines from the lungs of animals challenged with S. pneumoniae. SRT3025 treatment was also accompanied by striking changes in the transcription profiles in multiple inflammatory and metabolic pathways in liver, spleen, small bowel, and lung tissue. Remarkably, these organ-specific changes in the transcriptome analyses were similar following CLP or pneumococcal challenge despite different sets of pathogens at disparate sites of infection. Pharmacologic activation of SIRT1 modulates the innate host response and could represent a novel treatment strategy for severe infection. PMID:26974318

  4. PHARMACOLOGICAL SIRT1 ACTIVATION IMPROVES MORTALITY AND MARKEDLY ALTERS TRANSCRIPTIONAL PROFILES THAT ACCOMPANY EXPERIMENTAL SEPSIS.

    PubMed

    Opal, Steven M; Ellis, James L; Suri, Vipin; Freudenberg, Johannes M; Vlasuk, George P; Li, Yong; Chahin, Abdullah B; Palardy, John E; Parejo, Nicholas; Yamamoto, Michelle; Chahin, Abdulrahman; Kessimian, Noubar

    2016-04-01

    The sirtuin family consists of seven NAD+-dependent enzymes affecting a broad array of regulatory protein networks by primarily catalyzing the deacetylation of key lysine residues in regulatory proteins. The enzymatic activity of SIRT1 can be enhanced by small molecule activators known as SIRT1 activator compounds (STACs). We tested the therapeutic potential of the STAC SRT3025 in two preclinical models of severe infection, the murine cecal ligation and puncture (CLP) model to induce peritonitis and intratracheal installation of Streptococcus pneumoniae to induce severe bacterial pneumonia. SRT3025 provided significant survival benefits over vehicle control in both the peritonitis and pneumococcal pneumonia models when administered with appropriate antimicrobial agents. The survival benefit of SRT3025 in the CLP model was absent in SIRT1 knockout showing the SIRT1 dependency of SRT3025's effects. SRT3025 administration promoted bacterial clearance and significantly reduced inflammatory cytokines from the lungs of animals challenged with S. pneumoniae. SRT3025 treatment was also accompanied by striking changes in the transcription profiles in multiple inflammatory and metabolic pathways in liver, spleen, small bowel, and lung tissue. Remarkably, these organ-specific changes in the transcriptome analyses were similar following CLP or pneumococcal challenge despite different sets of pathogens at disparate sites of infection. Pharmacologic activation of SIRT1 modulates the innate host response and could represent a novel treatment strategy for severe infection.

  5. Antifungal Imidazole-Decorated Cationic Amphiphiles with Markedly Low Hemolytic Activity.

    PubMed

    Benhamou, Raphael I; Steinbuch, Kfir B; Fridman, Micha

    2016-08-01

    Herein we report that an imidazole-decorated cationic amphiphile derived from the pseudo-disaccharide nebramine has potent antifungal activity against strains of Candida glabrata pathogens. In combination with the natural bis-benzylisoquinoline alkaloid tetrandrine the reported antifungal cationic amphiphile demonstrated synergistic antifungal activity against Candida albicans pathogens. This unique membrane disruptor caused no detectible mammalian red blood cell hemolysis at concentrations up to more than two orders of magnitude greater than its minimal inhibitory concentrations against the tested C. glabrata strains. We provide evidence that potency against C. glabrata may be associated with differences between the drug efflux pumps of C. albicans and C. glabrata. Imidazole decorated-cationic amphiphiles show promise for the development of less toxic membrane-disrupting antifungal drugs and drug combinations. PMID:27258738

  6. Matrine attenuates focal cerebral ischemic injury by improving antioxidant activity and inhibiting apoptosis in mice

    PubMed Central

    ZHAO, PENG; ZHOU, RU; ZHU, XIAO-YUN; HAO, YIN-JU; LI, NAN; WANG, JIE; NIU, YANG; SUN, TAO; LI, YU-XIANG; YU, JIAN-QIANG

    2015-01-01

    Matrine, an active constituent of the Chinese herb, Sophora flavescens Ait., and it is known for its antioxidant, anti-inflammatory and antitumor activities. It has been demonstrated that matrine exerts protective effects against heart failure by decreasing the expression of caspase-3 and Bax, and increasing Bcl-2 levels. In this study, we aimed to determine whether these protective effects of matrine can be applied to cerebral ischemia. Following 7 successive days of treatment with matrine (7.5, 15 and 30 mg/kg) and nimodipine (1 mg/kg) by intraperitoneal injection, male Institute of Cancer Research (ICR) mice were subjected to middle cerebral artery occlusion (MCAO). Following reperfusion, the neurobehavioral score and brain infarct volume were estimated, and morphological changes were analyzed by hematoxylin and eosin (H&E) staining and electron microscopy. The percentage of apoptotic neurons was determined by flow cytometry. The levels of oxidative stress were assessed by measuring the levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), and the total antioxidant capacity (T-AOC). Western blot analysis and immunofluorescence staining were used to examine the expression of the apoptosis-related proteins, caspase-3, Bax and Bcl-2. Our results revealed that pre-treatment with matrine significantly decreased the infarct volume and improved the neurological scores. Matrine also reduced the percentage of apoptotic neurons and relieved neuronal morphological damage. Furthermore, matrine markedly decreased the MDA levels, and increased SOD, GSH-Px and CAT activity, and T-AOC. Western blot analysis and immunofluorescence staining revealed a marked decrease in caspase-3 expression and an increase in the Bcl-2/Bax ratio in the group pre-treated with matrine (30 mg/kg) as compared with the vehicle-treated group. The findings of the present study demonstrate that matrine exerts neuroprotective effects against

  7. Matrine attenuates focal cerebral ischemic injury by improving antioxidant activity and inhibiting apoptosis in mice.

    PubMed

    Zhao, Peng; Zhou, Ru; Zhu, Xiao-Yun; Hao, Yin-Ju; Li, Nan; Wang, Jie; Niu, Yang; Sun, Tao; Li, Yu-Xiang; Yu, Jian-Qiang

    2015-09-01

    Matrine, an active constituent of the Chinese herb, Sophora flavescens Ait., and it is known for its antioxidant, anti-inflammatory and antitumor activities. It has been demonstrated that matrine exerts protective effects against heart failure by decreasing the expression of caspase-3 and Bax, and increasing Bcl‑2 levels. In this study, we aimed to determine whether these protective effects of matrine can be applied to cerebral ischemia. Following 7 successive days of treatment with matrine (7.5, 15 and 30 mg/kg) and nimodipine (1 mg/kg) by intraperitoneal injection, male Institute of Cancer Research (ICR) mice were subjected to middle cerebral artery occlusion (MCAO). Following reperfusion, the neurobehavioral score and brain infarct volume were estimated, and morphological changes were analyzed by hematoxylin and eosin (H&E) staining and electron microscopy. The percentage of apoptotic neurons was determined by flow cytometry. The levels of oxidative stress were assessed by measuring the levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), and the total antioxidant capacity (T-AOC). Western blot analysis and immunofluorescence staining were used to examine the expression of the apoptosis-related proteins, caspase-3, Bax and Bcl-2. Our results revealed that pre-treatment with matrine significantly decreased the infarct volume and improved the neurological scores. Matrine also reduced the percentage of apoptotic neurons and relieved neuronal morphological damage. Furthermore, matrine markedly decreased the MDA levels, and increased SOD, GSH-Px and CAT activity, and T-AOC. Western blot analysis and immunofluorescence staining revealed a marked decrease in caspase-3 expression and an increase in the Bcl-2/Bax ratio in the group pre-treated with matrine (30 mg/kg) as compared with the vehicle-treated group. The findings of the present study demonstrate that matrine exerts neuroprotective effects against

  8. Matrine attenuates focal cerebral ischemic injury by improving antioxidant activity and inhibiting apoptosis in mice.

    PubMed

    Zhao, Peng; Zhou, Ru; Zhu, Xiao-Yun; Hao, Yin-Ju; Li, Nan; Wang, Jie; Niu, Yang; Sun, Tao; Li, Yu-Xiang; Yu, Jian-Qiang

    2015-09-01

    Matrine, an active constituent of the Chinese herb, Sophora flavescens Ait., and it is known for its antioxidant, anti-inflammatory and antitumor activities. It has been demonstrated that matrine exerts protective effects against heart failure by decreasing the expression of caspase-3 and Bax, and increasing Bcl‑2 levels. In this study, we aimed to determine whether these protective effects of matrine can be applied to cerebral ischemia. Following 7 successive days of treatment with matrine (7.5, 15 and 30 mg/kg) and nimodipine (1 mg/kg) by intraperitoneal injection, male Institute of Cancer Research (ICR) mice were subjected to middle cerebral artery occlusion (MCAO). Following reperfusion, the neurobehavioral score and brain infarct volume were estimated, and morphological changes were analyzed by hematoxylin and eosin (H&E) staining and electron microscopy. The percentage of apoptotic neurons was determined by flow cytometry. The levels of oxidative stress were assessed by measuring the levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), and the total antioxidant capacity (T-AOC). Western blot analysis and immunofluorescence staining were used to examine the expression of the apoptosis-related proteins, caspase-3, Bax and Bcl-2. Our results revealed that pre-treatment with matrine significantly decreased the infarct volume and improved the neurological scores. Matrine also reduced the percentage of apoptotic neurons and relieved neuronal morphological damage. Furthermore, matrine markedly decreased the MDA levels, and increased SOD, GSH-Px and CAT activity, and T-AOC. Western blot analysis and immunofluorescence staining revealed a marked decrease in caspase-3 expression and an increase in the Bcl-2/Bax ratio in the group pre-treated with matrine (30 mg/kg) as compared with the vehicle-treated group. The findings of the present study demonstrate that matrine exerts neuroprotective effects against

  9. Intracellular Modulation, Extracellular Disposal and Serum Increase of MiR-150 Mark Lymphocyte Activation

    PubMed Central

    de Candia, Paola; Torri, Anna; Gorletta, Tatiana; Fedeli, Maya; Bulgheroni, Elisabetta; Cheroni, Cristina; Marabita, Francesco; Crosti, Mariacristina; Moro, Monica; Pariani, Elena; Romanò, Luisa; Esposito, Susanna; Mosca, Fabio; Rossetti, Grazisa; Rossi, Riccardo L.; Geginat, Jens; Casorati, Giulia; Dellabona, Paolo; Pagani, Massimiliano; Abrignani, Sergio

    2013-01-01

    Activated lymphocytes release nano-sized vesicles (exosomes) containing microRNAs that can be monitored in the bloodstream. We asked whether elicitation of immune responses is followed by release of lymphocyte-specific microRNAs. We found that, upon activation in vitro, human and mouse lymphocytes down-modulate intracellular miR-150 and accumulate it in exosomes. In vivo, miR-150 levels increased significantly in serum of humans immunized with flu vaccines and in mice immunized with ovalbumin, and this increase correlated with elevation of antibody titers. Immunization of immune-deficient mice, lacking MHCII, resulted neither in antibody production nor in elevation of circulating miR-150. This study provides proof of concept that serum microRNAs can be detected, with minimally invasive procedure, as biomarkers of vaccination and more in general of adaptive immune responses. Furthermore, the prompt reduction of intracellular level of miR-150, a key regulator of mRNAs critical for lymphocyte differentiation and functions, linked to its release in the external milieu suggests that the selective extracellular disposal of microRNAs can be a rapid way to regulate gene expression during lymphocyte activation. PMID:24205408

  10. Repetitive cryotherapy attenuates the in vitro and in vivo mononuclear cell activation response.

    PubMed

    Lindsay, Angus; Othman, Mohd Izani; Prebble, Hannah; Davies, Sian; Gieseg, Steven P

    2016-07-01

    What is the central question of this study? Acute and repetitive cryotherapy are routinely used to accelerate postexercise recovery, although the effect on resident immune cells and repetitive exposure has largely been unexplored and neglected. What is the main finding and its importance? Using blood-derived mononuclear cells and semi-professional mixed martial artists, we show that acute and repetitive cryotherapy reduces the in vitro and in vivo T-cell and monocyte activation response whilst remaining independent of the physical performance of elite athletes. We investigated the effect of repetitive cryotherapy on the in vitro (cold exposure) and in vivo (cold water immersion) activation of blood-derived mononuclear cells following high-intensity exercise. Single and repeated cold exposure (5°C) of a mixed cell culture (T cells and monocytes) was investigated using in vitro tissue culture experimentation for total neopterin production (neopterin plus 7,8-dihydroneopterin). Fourteen elite mixed martial art fighters were also randomly assigned to either a cold water immersion (15 min at 10°C) or passive recovery protocol, which they completed three times per week during a 6 week training camp. Urine was collected and analysed for neopterin and total neopterin three times per week, and perceived soreness, fatigue, physical performance (broad jump, push-ups and pull-ups) and training performance were also assessed. Single and repetitive cold exposure significantly (P < 0.001) reduced total neopterin production from the mixed cell culture, whereas cold water immersion significantly (P < 0.05) attenuated urinary neopterin and total neopterin during the training camp without having any effect on physical performance parameters. Soreness and fatigue showed little variation between the groups, whereas training session performance was significantly (P < 0.05) elevated in the cold water immersion group. The data suggest that acute and repetitive cryotherapy

  11. Repetitive cryotherapy attenuates the in vitro and in vivo mononuclear cell activation response.

    PubMed

    Lindsay, Angus; Othman, Mohd Izani; Prebble, Hannah; Davies, Sian; Gieseg, Steven P

    2016-07-01

    What is the central question of this study? Acute and repetitive cryotherapy are routinely used to accelerate postexercise recovery, although the effect on resident immune cells and repetitive exposure has largely been unexplored and neglected. What is the main finding and its importance? Using blood-derived mononuclear cells and semi-professional mixed martial artists, we show that acute and repetitive cryotherapy reduces the in vitro and in vivo T-cell and monocyte activation response whilst remaining independent of the physical performance of elite athletes. We investigated the effect of repetitive cryotherapy on the in vitro (cold exposure) and in vivo (cold water immersion) activation of blood-derived mononuclear cells following high-intensity exercise. Single and repeated cold exposure (5°C) of a mixed cell culture (T cells and monocytes) was investigated using in vitro tissue culture experimentation for total neopterin production (neopterin plus 7,8-dihydroneopterin). Fourteen elite mixed martial art fighters were also randomly assigned to either a cold water immersion (15 min at 10°C) or passive recovery protocol, which they completed three times per week during a 6 week training camp. Urine was collected and analysed for neopterin and total neopterin three times per week, and perceived soreness, fatigue, physical performance (broad jump, push-ups and pull-ups) and training performance were also assessed. Single and repetitive cold exposure significantly (P < 0.001) reduced total neopterin production from the mixed cell culture, whereas cold water immersion significantly (P < 0.05) attenuated urinary neopterin and total neopterin during the training camp without having any effect on physical performance parameters. Soreness and fatigue showed little variation between the groups, whereas training session performance was significantly (P < 0.05) elevated in the cold water immersion group. The data suggest that acute and repetitive cryotherapy

  12. Paclitaxel attenuates renal interstitial fibroblast activation and interstitial fibrosis by inhibiting STAT3 signaling

    PubMed Central

    Zhang, Lei; Xu, Xuan; Yang, Ruhao; Chen, Jingwen; Wang, Shixuan; Yang, Junqin; Xiang, Xudong; He, Zhibiao; Zhao, Yu; Dong, Zheng; Zhang, Dongshan

    2015-01-01

    Recent studies have demonstrated that paclitaxel might inhibit renal fibrosis. However, the underlying molecular mechanism remains unclear. In this study, we hypothesized that low-dose paclitaxel may block the STAT3 (signal transducer and activator of transcription 3) signaling to attenuate fibrosis in a mouse model with unilateral ureteral obstruction. Both NRK-49F cells and mice with unilateral ureteral obstruction were treated with paclitaxel. The results showed that paclitaxel treatment resulted in a dose- and time-dependent decrease in tyrosine-phosphorylated STAT3, and inhibited the expression of fibronectin, alpha-smooth muscle actin (α-SMA), and collagen I in cultured NRK-49F cells. S3I-201, an STAT3 inhibitor, also suppressed the expression of fibronectin, α-SMA, and collagen I in cultured NRK-49F cells. Mechanistically, paclitaxel treatment blocked the STAT3 activity by disrupting the association of STAT3 with tubulin and inhibiting STAT3 nucleus translocation. Furthermore, paclitaxel also ameliorated renal fibrosis by down-regulating the expression of fibronectin, α-SMA, and collagen I, and suppressed the infiltration of macrophages and production of TNF-α, IL-1β, TGF-β, and ICAM-1 (intercellular adhesion molecule 1) by inhibition of STAT3 activity in obstructive nephropathy. These results suggest that paclitaxel may block the STAT3 activity by disrupting the association of STAT3 with tubulin and inhibiting STAT3 nucleus translocation, consequently leading to the suppression of renal interstitial fibroblast activation and the development of renal fibrosis, and inhibition of proinflammatory cytokine production. PMID:25931810

  13. Pulmonary C-fiber activation attenuates respiratory-related tongue movements.

    PubMed

    Lee, Kun-Ze; Fuller, David D; Hwang, Ji-Chuu

    2012-11-01

    The functional impact of pulmonary C-fiber activation on upper airway biomechanics has not been evaluated. Here, we tested the hypothesis that pulmonary C-fiber activation alters the respiratory-related control of tongue movements. The force produced by tongue movements was quantified in spontaneously breathing, anesthetized adult rats before and after stimulation of pulmonary C fibers via intrajugular delivery of capsaicin (0.625 and 1.25 μg/kg). Brief occlusion of the trachea was used to increase the respiratory drive to the tongue muscles, and hypoglossal (XII) nerve branches were selectively sectioned to denervate the protrusive and retrusive tongue musculature. Tracheal occlusion triggered inspiratory-related tongue retrusion in rats with XII nerves intact or following section of the medial XII nerve branch, which innervates the genioglossus muscle. Inspiratory-related tongue protrusion was only observed after section of the lateral XII branch, which innervates the primary tongue retrusor muscles. The tension produced by inspiratory-related tongue movement was significantly attenuated by capsaicin, but tongue movements remained retrusive, unless the medial XII branch was sectioned. Capsaicin also significantly delayed the onset of tongue movements such that tongue forces could not be detected until after onset of the inspiratory diaphragm activity. We conclude that altered neural drive to the tongue muscles following pulmonary C-fiber activation has a functionally significant effect on tongue movements. The diminished tongue force and delay in the onset of tongue movements following pulmonary C-fiber activation are potentially unfavorable for upper airway patency. PMID:22936725

  14. Controllable attenuators

    NASA Astrophysics Data System (ADS)

    Krylov, G. M.; Khoniak, E. I.; Tynynyka, A. N.; Iliushenko, V. N.; Sikolenko, S. F.

    Methods for the synthesis of controllable attenuators and their implementations are examined. In particular, attention is given to the general properties of controllable attenuators, control elements, types of controllable attenuators and methods of their analysis, and synthesis of the control characteristic of attenuators. The discussion also covers the efficiency of attenuator control, the use of transmission line segments in wide-band controllable attenuators, and attenuators with a discretely controlled transmission coefficient.

  15. Oral intake of curcumin markedly activated CYP 3A4: in vivo and ex-vivo studies.

    PubMed

    Hsieh, Yow-Wen; Huang, Ching-Ya; Yang, Shih-Ying; Peng, Yu-Hsuan; Yu, Chung-Ping; Chao, Pei-Dawn Lee; Hou, Yu-Chi

    2014-10-10

    Curcumin, a specific secondary metabolite of Curcuma species, has potentials for a variety of beneficial health effects. It is nowadays used as a dietary supplement. Everolimus (EVL) is an immunosuppressant indicated for allograft rejection and cancer therapy, but with narrow therapeutic window. EVL is a substrate of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). This study investigated the effect of coadministration of curcumin on the pharmacokinetics of EVL in rats and the underlying mechanisms. EVL (0.5 mg/kg) was orally administered without and with 50 and 100 mg/kg of curcumin, respectively, in rats. Blood samples were collected at specific time points and EVL concentrations in blood were determined by QMS immunoassay. The underlying mechanisms were evaluated using cell model and recombinant CYP 3A4 isozyme. The results indicated that 50 and 100 mg/kg of curcumin significantly decreased the AUC0-540 of EVL by 70.6% and 71.5%, respectively, and both dosages reduced the Cmax of EVL by 76.7%. Mechanism studies revealed that CYP3A4 was markedly activated by curcumin metabolites, which apparently overrode the inhibition effects of curcumin on P-gp. In conclusion, oral intake of curcumin significantly decreased the bioavailability of EVL, a probe substrate of P-gp/CYP 3A4, mainly through marked activation on CYP 3A4.

  16. Loss of CARD9-mediated innate activation attenuates severe influenza pneumonia without compromising host viral immunity.

    PubMed

    Uematsu, Takayuki; Iizasa, Ei'ichi; Kobayashi, Noritada; Yoshida, Hiroki; Hara, Hiromitsu

    2015-01-01

    Influenza virus (IFV) infection is a common cause of severe viral pneumonia associated with acute respiratory distress syndrome (ARDS), which is difficult to control with general immunosuppressive therapy including corticosteroids due to the unfavorable effect on viral replication. Studies have suggested that the excessive activation of the innate immunity by IFV is responsible for severe pathologies. In this study, we focused on CARD9, a signaling adaptor known to regulate innate immune activation through multiple innate sensor proteins, and investigated its role in anti-IFV defense and lung pathogenesis in a mouse model recapitulating severe influenza pneumonia with ARDS. We found that influenza pneumonia was dramatically attenuated in Card9-deficient mice, which showed improved mortality with reduced inflammatory cytokines and chemokines in the infected lungs. However, viral clearance, type-I interferon production, and the development of anti-viral B and T cell immunity were not compromised by CARD9 deficiency. Syk or CARD9-deficient DCs but not macrophages showed impaired cytokine but not type-I interferon production in response to IFV in vitro, indicating a possible role for the Syk-CARD9 pathway in DCs in excessive inflammation of IFV-infected lungs. Therefore, inhibition of this pathway is an ideal therapeutic target for severe influenza pneumonia without affecting viral clearance. PMID:26627732

  17. Loss of CARD9-mediated innate activation attenuates severe influenza pneumonia without compromising host viral immunity

    PubMed Central

    Uematsu, Takayuki; Iizasa, Ei’ichi; Kobayashi, Noritada; Yoshida, Hiroki; Hara, Hiromitsu

    2015-01-01

    Influenza virus (IFV) infection is a common cause of severe viral pneumonia associated with acute respiratory distress syndrome (ARDS), which is difficult to control with general immunosuppressive therapy including corticosteroids due to the unfavorable effect on viral replication. Studies have suggested that the excessive activation of the innate immunity by IFV is responsible for severe pathologies. In this study, we focused on CARD9, a signaling adaptor known to regulate innate immune activation through multiple innate sensor proteins, and investigated its role in anti-IFV defense and lung pathogenesis in a mouse model recapitulating severe influenza pneumonia with ARDS. We found that influenza pneumonia was dramatically attenuated in Card9-deficient mice, which showed improved mortality with reduced inflammatory cytokines and chemokines in the infected lungs. However, viral clearance, type-I interferon production, and the development of anti-viral B and T cell immunity were not compromised by CARD9 deficiency. Syk or CARD9-deficient DCs but not macrophages showed impaired cytokine but not type-I interferon production in response to IFV in vitro, indicating a possible role for the Syk-CARD9 pathway in DCs in excessive inflammation of IFV-infected lungs. Therefore, inhibition of this pathway is an ideal therapeutic target for severe influenza pneumonia without affecting viral clearance. PMID:26627732

  18. Attenuated baroreflex control of sympathetic nerve activity after cardiovascular deconditioning in rats

    NASA Technical Reports Server (NTRS)

    Moffitt, J. A.; Foley, C. M.; Schadt, J. C.; Laughlin, M. H.; Hasser, E. M.

    1998-01-01

    The effect of cardiovascular deconditioning on baroreflex control of the sympathetic nervous system was evaluated after 14 days of hindlimb unloading (HU) or the control condition. Rats were chronically instrumented with catheters and sympathetic nerve recording electrodes for measurement of mean arterial pressure (MAP) and heart rate (HR) and recording of lumbar (LSNA) or renal (RSNA) sympathetic nerve activity. Experiments were conducted 24 h after surgery, with the animals in a normal posture. Baroreflex function was assessed using a logistic function that related HR and LSNA or RSNA to MAP during infusion of phenylephrine and nitroprusside. Baroreflex influence on HR was not affected by HU. Maximum baroreflex-elicited LSNA was significantly reduced in HU rats (204 +/- 11.9 vs. 342 +/- 30.6% baseline LSNA), as was maximum reflex gain (-4.0 +/- 0.6 vs. -7.8 +/- 1.3 %LSNA/mmHg). Maximum baroreflex-elicited RSNA (259 +/- 10.8 vs. 453 +/- 28.0% baseline RSNA), minimum baroreflex-elicited RSNA (-2 +/- 2.8 vs. 13 +/- 4.5% baseline RSNA), and maximum gain (-5.8 +/- 0.5 vs. -13.6 +/- 3.1 %RSNA/mmHg) were significantly decreased in HU rats. Results demonstrate that baroreflex modulation of sympathetic nervous system activity is attenuated after cardiovascular deconditioning in rodents. Data suggest that alterations in the arterial baroreflex may contribute to orthostatic intolerance after a period of bedrest or spaceflight in humans.

  19. Dishevelled attenuates the repelling activity of Wnt signaling during neurite outgrowth in Caenorhabditis elegans

    PubMed Central

    Zheng, Chaogu; Diaz-Cuadros, Margarete; Chalfie, Martin

    2015-01-01

    Wnt proteins regulate axonal outgrowth along the anterior–posterior axis, but the intracellular mechanisms that modulate the strength of Wnt signaling in axon guidance are largely unknown. Using the Caenorhabditis elegans mechanosensory PLM neurons, we found that posteriorly enriched LIN-44/Wnt acts as a repellent to promote anteriorly directed neurite outgrowth through the LIN-17/Frizzled receptor, instead of controlling neuronal polarity as previously thought. Dishevelled (Dsh) proteins DSH-1 and MIG-5 redundantly mediate the repulsive activity of the Wnt signals to induce anterior outgrowth, whereas DSH-1 also provides feedback inhibition to attenuate the signaling to allow posterior outgrowth against the Wnt gradient. This inhibitory function of DSH-1, which requires its dishevelled, Egl-10, and pleckstrin (DEP) domain, acts by promoting LIN-17 phosphorylation and is antagonized by planar cell polarity signaling components Van Gogh (VANG-1) and Prickle (PRKL-1). Our results suggest that Dsh proteins both respond to Wnt signals to shape neuronal projections and moderate its activity to fine-tune neuronal morphology. PMID:26460008

  20. Dishevelled attenuates the repelling activity of Wnt signaling during neurite outgrowth in Caenorhabditis elegans.

    PubMed

    Zheng, Chaogu; Diaz-Cuadros, Margarete; Chalfie, Martin

    2015-10-27

    Wnt proteins regulate axonal outgrowth along the anterior-posterior axis, but the intracellular mechanisms that modulate the strength of Wnt signaling in axon guidance are largely unknown. Using the Caenorhabditis elegans mechanosensory PLM neurons, we found that posteriorly enriched LIN-44/Wnt acts as a repellent to promote anteriorly directed neurite outgrowth through the LIN-17/Frizzled receptor, instead of controlling neuronal polarity as previously thought. Dishevelled (Dsh) proteins DSH-1 and MIG-5 redundantly mediate the repulsive activity of the Wnt signals to induce anterior outgrowth, whereas DSH-1 also provides feedback inhibition to attenuate the signaling to allow posterior outgrowth against the Wnt gradient. This inhibitory function of DSH-1, which requires its dishevelled, Egl-10, and pleckstrin (DEP) domain, acts by promoting LIN-17 phosphorylation and is antagonized by planar cell polarity signaling components Van Gogh (VANG-1) and Prickle (PRKL-1). Our results suggest that Dsh proteins both respond to Wnt signals to shape neuronal projections and moderate its activity to fine-tune neuronal morphology.

  1. Molecular hydrogen attenuates hypoxia/reoxygenation injury of intrahepatic cholangiocytes by activating Nrf2 expression.

    PubMed

    Yu, Jianhua; Zhang, Weiguang; Zhang, Rongguo; Jiang, Guixing; Tang, Haijun; Ruan, Xinxian; Ren, Peitu; Lu, Baochun

    2015-11-01

    Hypoxia/reoxygenation (H/R) injury of cholangiocytes causes serious biliary complications during hepatobiliary surgeries. Molecular hydrogen (H2) has been shown to be effective in protecting various cells and organs against oxidative stress injury. Human liver cholangiocytes were used to determine the potential protective effects of hydrogen against cholangiocyte H/R injury and explore the underlying mechanisms. We found that H2 ameliorated H/R-induced cholangiocytes apoptosis. Our study revealed that H2 activated NF-E2-related factor 2 (Nrf2) and downstream cytoprotective protein expression. However, the protective function of H2 was abolished when Nrf2 was silenced. Apoptosis in cholangiocytes isolated from a rat model of liver ischemia/reperfusion injury indicated that H2 significantly attenuates ischemia/reperfusion cholangiocyte injury in vivo. In conclusion, our study shows that H2 protects intrahepatic cholangiocytes from hypoxia/reoxygenation-induced apoptosis in vitro or in vivo, and this phenomenon may depend on activating Nrf2 expression.

  2. Stretch Marks

    MedlinePlus

    ... changes that can go with bodybuilding. People who use steroid-containing skin creams or ointments (such as hydrocortisone) for more than a few weeks may also get stretch marks. So might people who have to ... surgeon. These doctors may use one of many types of treatments — from actual ...

  3. Three Distinct Patterns of Histone H3Y41 Phosphorylation Mark Active Genes

    PubMed Central

    Dawson, Mark A.; Foster, Samuel D.; Bannister, Andrew J.; Robson, Samuel C.; Hannah, Rebecca; Wang, Xiaonan; Xhemalce, Blerta; Wood, Andrew D.; Green, Anthony R.; Göttgens, Berthold; Kouzarides, Tony

    2012-01-01

    Summary The JAK2 tyrosine kinase is a critical mediator of cytokine-induced signaling. It plays a role in the nucleus, where it regulates transcription by phosphorylating histone H3 at tyrosine 41 (H3Y41ph). We used chromatin immunoprecipitation coupled to massively parallel DNA sequencing (ChIP-seq) to define the genome-wide pattern of H3Y41ph in human erythroid leukemia cells. Our results indicate that H3Y41ph is located at three distinct sites: (1) at a subset of active promoters, where it overlaps with H3K4me3, (2) at distal cis-regulatory elements, where it coincides with the binding of STAT5, and (3) throughout the transcribed regions of active, tissue-specific hematopoietic genes. Together, these data extend our understanding of this conserved and essential signaling pathway and provide insight into the mechanisms by which extracellular stimuli may lead to the coordinated regulation of transcription. PMID:22999934

  4. Resveratrol attenuates inflammatory hyperalgesia by inhibiting glial activation in mice spinal cords.

    PubMed

    Wang, Lin-Lin; Shi, Dong-Ling; Gu, Hui-Yao; Zheng, Ming-Zhi; Hu, Jue; Song, Xing-Hui; Shen, Yue-Liang; Chen, Ying-Ying

    2016-05-01

    The present study aimed to investigate the effect of resveratrol on inflammatory pain. Mice were injected intraperitoneally with lipopolysaccharide (LPS) for 5 consecutive days to induce subacute systemic inflammation. Acetic acid‑induced writhing tests and tail‑flick tests were performed following the final LPS injection. Glial fibrillary acidic protein (GFAP; an astrocyte‑specific activation marker), ionized calcium binding adapter molecule 1 (Iba‑1; a microglia‑specific activation marker) and sirtuin 1 (SIRT1) protein expression levels were detected using immunohistochemistry analysis or western blotting. Following administration of LPS for 5 days, the number of writhes increased and the tail‑flick latency decreased. Resveratrol (10 or 20 mg/kg) partly inhibited LPS‑induced hyperalgesia and prevented the increase in tumor necrosis factor‑α and interleukin 6 levels induced by LPS. LPS injection reduced the SIRT1 protein expression and increased the number of GFAP‑positive and Iba‑1‑positive cells in the spinal cord. Resveratrol increased the SIRT1 protein expression levels and decreased the number of GFAP‑positive and Iba‑1‑positive cells in LPS‑treated mice. The protective effect of resveratrol was partly blocked by a selective SIRT1 inhibitor, EX‑257. Results from the present study suggest that subacute treatment with LPS induced the activation of glial cells and hyperalgesia. Resveratrol was demonstrated to inhibit the activation of glial cells and attenuate inflammatory hyperalgesia in a SIRT1‑dependent manner.

  5. Attenuation of Cocaine-Induced Locomotor Activity in Male and Female Mice by Active Immunization

    PubMed Central

    Kosten, Therese A.; Shen, Xiaoyun Y.; Kinsey, Berma M.; Kosten, Thomas R.; Orson, Frank M.

    2014-01-01

    Background and objectives Immunotherapy for drug addiction is being investigated in several laboratories but most studies are conducted in animals of one sex. Yet, women show heightened immune responses and are more likely to develop autoimmune diseases than men. The purpose of this study was to compare the effects of an active anti-cocaine vaccine, succinyl-norcocaine conjugated to keyhole limpet hemocyanin, for its ability to elicit antibodies and alter cocaine-induced ambulatory activity in male versus female mice. Methods Male and female BALB/c mice were vaccinated (n=44) or served as non-vaccinated controls (n=34). Three weeks after initial vaccination, a booster was given. Ambulatory activity induced by cocaine (20 mg/kg) was assessed at 7-wk and plasma obtained at 8-wk to assess antibody levels. Results High antibody titers were produced in mice of both sexes. The vaccine reduced ambulatory activity cocaine-induced but this effect was greater in female compared to male mice. Discussion and conclusions The efficacy of this anti-cocaine vaccine is demonstrated in mice of both sexes but its functional consequences are greater in females than males. Scientific significance Results point to the importance of testing animals of both sexes in studies of immunotherapies for addiction. PMID:25251469

  6. Palladium and platinum nanoparticles attenuate aging-like skin atrophy via antioxidant activity in mice.

    PubMed

    Shibuya, Shuichi; Ozawa, Yusuke; Watanabe, Kenji; Izuo, Naotaka; Toda, Toshihiko; Yokote, Koutaro; Shimizu, Takahiko

    2014-01-01

    Cu-Zn superoxide dismutase (Sod1) loss causes a redox imbalance as it leads to excess superoxide generation, which results in the appearance of various aging-related phenotypes, including skin atrophy. Noble metal nanoparticles, such as palladium (Pd) and platinum (Pt) nanoparticles, are considered to function as antioxidants due to their strong catalytic activity. In Japan, a mixture of Pd and Pt nanoparticles called PAPLAL has been used to treat chronic diseases over the past 60 years. In the present study, we investigated the protective effects of PAPLAL against aging-related skin pathologies in mice. Transdermal PAPLAL treatment reversed skin thinning associated with increased lipid peroxidation in Sod1-/- mice. Furthermore, PAPLAL normalized the gene expression levels of Col1a1, Mmp2, Has2, Tnf-α, Il-6, and p53 in the skin of the Sod1-/- mice. Pt nanoparticles exhibited marked SOD and catalase activity, while Pd nanoparticles only displayed weak SOD and catalase activity in vitro. Although the SOD and catalase activity of the Pt nanoparticles significantly declined after they had been oxidized in air, a mixture of Pd and Pt nanoparticles continued to exhibit SOD and catalase activity after oxidation. Importantly, a mixture of Pd and Pt nanoparticles with a molar ratio of 3 or 4 to 1 continued to exhibit SOD and catalase activity after oxidation, indicating that Pd nanoparticles prevent the oxidative deterioration of Pt nanoparticles. These findings indicate that PAPLAL stably suppresses intrinsic superoxide generation both in vivo and in vitro via SOD and catalase activity. PAPLAL is a potentially powerful tool for the treatment of aging-related skin diseases caused by oxidative damage. PMID:25333617

  7. Palladium and platinum nanoparticles attenuate aging-like skin atrophy via antioxidant activity in mice.

    PubMed

    Shibuya, Shuichi; Ozawa, Yusuke; Watanabe, Kenji; Izuo, Naotaka; Toda, Toshihiko; Yokote, Koutaro; Shimizu, Takahiko

    2014-01-01

    Cu-Zn superoxide dismutase (Sod1) loss causes a redox imbalance as it leads to excess superoxide generation, which results in the appearance of various aging-related phenotypes, including skin atrophy. Noble metal nanoparticles, such as palladium (Pd) and platinum (Pt) nanoparticles, are considered to function as antioxidants due to their strong catalytic activity. In Japan, a mixture of Pd and Pt nanoparticles called PAPLAL has been used to treat chronic diseases over the past 60 years. In the present study, we investigated the protective effects of PAPLAL against aging-related skin pathologies in mice. Transdermal PAPLAL treatment reversed skin thinning associated with increased lipid peroxidation in Sod1-/- mice. Furthermore, PAPLAL normalized the gene expression levels of Col1a1, Mmp2, Has2, Tnf-α, Il-6, and p53 in the skin of the Sod1-/- mice. Pt nanoparticles exhibited marked SOD and catalase activity, while Pd nanoparticles only displayed weak SOD and catalase activity in vitro. Although the SOD and catalase activity of the Pt nanoparticles significantly declined after they had been oxidized in air, a mixture of Pd and Pt nanoparticles continued to exhibit SOD and catalase activity after oxidation. Importantly, a mixture of Pd and Pt nanoparticles with a molar ratio of 3 or 4 to 1 continued to exhibit SOD and catalase activity after oxidation, indicating that Pd nanoparticles prevent the oxidative deterioration of Pt nanoparticles. These findings indicate that PAPLAL stably suppresses intrinsic superoxide generation both in vivo and in vitro via SOD and catalase activity. PAPLAL is a potentially powerful tool for the treatment of aging-related skin diseases caused by oxidative damage.

  8. Histidine-rich glycoprotein binds DNA and RNA and attenuates their capacity to activate the intrinsic coagulation pathway.

    PubMed

    Vu, Trang T; Leslie, Beverly A; Stafford, Alan R; Zhou, Ji; Fredenburgh, James C; Weitz, Jeffrey I

    2016-01-01

    When triggered by factor (F) XII and nucleic acids, we showed that thrombosis in HRG-deficient mice is accelerated compared with that in wild-type mice. In this study, we set out to identify the mechanisms by which nucleic acids promote contact activation, and to determine whether HRG attenuates their effects. DNA or RNA addition to human plasma enhances thrombin generation via the intrinsic pathway and shortens the clotting time. Their effect on the clotting time is seven- to 14-fold greater in HRG-deficient plasma than in control plasma. Investigations into the mechanisms of activation reveal that nucleic acids a) promote FXII activation in the presence of prekallikrein- and high molecular weight kininogen (HK), and b) enhance thrombin-mediated FXI activation by 10- to 12-fold. Surface plasmon resonance studies show that DNA and RNA bind FXII, FXIIa, HK, FXI, FXIa and thrombin with high affinity. HRG attenuates DNA- and RNA-mediated FXII activation, and FXI activation by FXIIa or by thrombin, suggesting that HRG down regulates the capacity of DNA and RNA to activate the intrinsic pathway. Therefore, HRG attenuates the procoagulant activity of nucleic acids at multiple levels.

  9. Marked Antigiardial Activity of Yucca baccata Extracts: A Potential Natural Alternative for Treating Protozoan Infections

    PubMed Central

    Quihui-Cota, Luis; León-Trujillo, Rocio; Astiazarán-García, Humberto; Esparza-Romero, Julián; Robles, María del Refugio; Robles-Zepeda, Ramón E.; Canett, Rafael; Sánchez-Escalante, Jesús

    2014-01-01

    Human Giardiosis is a public health problem in Mexico, where the national prevalence was estimated to be up to 68%. Misuse of antiprotozoal drugs may result in low effectiveness and undesirable side effects. Research on natural products is a good strategy for discovering more effective antiparasitic compounds. This study evaluated the antigiardial activity of extracts of Yucca baccata, which is native to northwestern Mexico. Forty-two gerbils (females) were weighed and orally inoculated with 5 × 106 Giardia trophozoites. Two gerbils were selected at random to confirm infection. Forty living gerbils were randomly allocated into 5 treatment groups (8 per group). Gerbils were randomly assigned to be treated with 24.4 mg/mL, 12.2 mg/mL, and 6.1 mg/mL of extracts, metronidazole (2 mg/mL) or PBS, which were intragastrically administered once per day for 3 days. Nine gerbils died during the study course. On day 10 postinfection, gerbils were euthanized and trophozoites were quantified. Yucca extracts reduced, albeit not significantly, the trophozoite counts in the duodenum segment. Only the high-extract concentration significantly reduced the trophozoite counts in the proximal segment and it was similar to that of metronidazole. Extracts of Y. baccata may represent an effective and natural therapeutic alternative for human giardiosis. PMID:25250335

  10. Activation of serotonin receptors promotes microglial injury-induced motility but attenuates phagocytic activity.

    PubMed

    Krabbe, Grietje; Matyash, Vitali; Pannasch, Ulrike; Mamer, Lauren; Boddeke, Hendrikus W G M; Kettenmann, Helmut

    2012-03-01

    Microglia, the brain immune cell, express several neurotransmitter receptors which modulate microglial functions. In this project we studied the impact of serotonin receptor activation on distinct microglial properties as serotonin deficiency not only has been linked to a number of psychiatric disease like depression and anxiety but may also permeate from the periphery through blood-brain barrier openings seen in neurodegenerative disease. First, we tested the impact of serotonin on the microglial response to an insult caused by a laser lesion in the cortex of acute slices from Cx3Cr1-GFP-/+ mice. In the presence of serotonin the microglial processes moved more rapidly towards the laser lesion which is considered to be a chemotactic response to ATP. Similarly, the chemotactic response of cultured microglia to ATP was also enhanced by serotonin. Quantification of phagocytic activity by determining the uptake of microspheres showed that the amoeboid microglia in slices from early postnatal animals or microglia in culture respond to serotonin application with a decreased phagocytic activity whereas we could not detect any significant change in ramified microglia in situ. The presence of microglial serotonin receptors was confirmed by patch-clamp experiments in culture and amoeboid microglia and by qPCR analysis of RNA isolated from primary cultured and acutely isolated adult microglia. These data suggest that microglia express functional serotonin receptors linked to distinct microglial properties. PMID:22198120

  11. Cinnamon and Its Metabolite Sodium Benzoate Attenuate the Activation of p21rac and Protect Memory and Learning in an Animal Model of Alzheimer's Disease.

    PubMed

    Modi, Khushbu K; Roy, Avik; Brahmachari, Saurabh; Rangasamy, Suresh B; Pahan, Kalipada

    2015-01-01

    This study underlines the importance of cinnamon, a commonly used natural spice and flavoring material, and its metabolite sodium benzoate (NaB) in attenuating oxidative stress and protecting memory and learning in an animal model of Alzheimer's disease (AD). NaB, but not sodium formate, was found to inhibit LPS-induced production of reactive oxygen species (ROS) in mouse microglial cells. Similarly, NaB also inhibited fibrillar amyloid beta (Aβ)- and 1-methyl-4-phenylpyridinium(+)-induced microglial production of ROS. Although NaB reduced the level of cholesterol in vivo in mice, reversal of the inhibitory effect of NaB on ROS production by mevalonate, and geranylgeranyl pyrophosphate, but not cholesterol, suggests that depletion of intermediates, but not end products, of the mevalonate pathway is involved in the antioxidant effect of NaB. Furthermore, we demonstrate that an inhibitor of p21rac geranylgeranyl protein transferase suppressed the production of ROS and that NaB suppressed the activation of p21rac in microglia. As expected, marked activation of p21rac was observed in the hippocampus of subjects with AD and 5XFAD transgenic (Tg) mouse model of AD. However, oral feeding of cinnamon (Cinnamonum verum) powder and NaB suppressed the activation of p21rac and attenuated oxidative stress in the hippocampus of Tg mice as evident by decreased dihydroethidium (DHE) and nitrotyrosine staining, reduced homocysteine level and increased level of reduced glutathione. This was accompanied by suppression of neuronal apoptosis, inhibition of glial activation, and reduction of Aβ burden in the hippocampus and protection of memory and learning in transgenic mice. Therefore, cinnamon powder may be a promising natural supplement in halting or delaying the progression of AD.

  12. Time-resolved phase-change recording mark formation with zinc oxide near-field optical active layer

    NASA Astrophysics Data System (ADS)

    Kao, Tsung Sheng; Chen, Mu-Ku; Chen, Jia-Wern; Chen, Yi-Hao; Wu, Pei Ru; Tsai, Din Ping

    2015-09-01

    In this paper, an optical active thin film of zinc oxide (ZnOx) nano-composites exploited for the enhancement of optical signals in an ultra-high density recording scheme has been demonstrated. Via the electron microscope investigation, the results display randomly distributed crystalline nanograins in the ZnOx thin films. Optical disks with the ZnOx nanostructured thin films show that the carrier-to-noise ratio (CNR) above 25 dB can be obtained at the mark trains of 100 nm, while the optimal writing power is reduced as a function of the increasing thickness of the ZnOx films. Furthermore, by conducting a series of the optical pump-probe experiments, the optical responses of recording marks on as-deposited phase-change Ge2Sb2Te5 (as-GST) recording layers present that the highly contrast bright recording bits can be acquired with the existence of the ZnOx nanostructured thin films, providing prospective potentials in future data storage and optoelectronic devices.

  13. Chronic active Epstein-Barr virus infection with marked pericardial effusion successfully treated with allogeneic peripheral blood stem cell transplantation.

    PubMed

    Matsui, Shinichiro; Takeda, Yusuke; Isshiki, Yusuke; Yamazaki, Atsuko; Nakao, Sanshiro; Takaishi, Koji; Nagao, Yuhei; Hasegawa, Nagisa; Togasaki, Emi; Shimizu, Ryoh; Kawajiri, Chika; Sakai, Shio; Mimura, Naoya; Takeuchi, Masahiro; Ohwada, Chikako; Sakaida, Emiko; Iseki, Tohru; Imadome, Ken-Ichi; Nakaseko, Chiaki

    2016-05-01

    A 23-year-old woman presented with a persistent fever and shortness of breath. Computed tomography showed marked pericardial effusion, hepatosplenomegaly, and cervical and mediastinal lymph node swelling. Epstein-Barr virus (EBV) antibody titers were abnormally elevated, and the copy number of EBV-DNA was increased in peripheral blood. Based on these observations, she was diagnosed with chronic active EBV infection (CAEBV). The EBV-infected cells in her peripheral blood were CD4(+)T lymphocytes. Fever and pericardial effusion improved following treatment with a combination of prednisolone, etoposide, and cyclosporine; however, peripheral blood EBV-DNA levels remained high. The patient underwent allogeneic peripheral blood stem cell transplantation from an EBV-seronegative, HLA-matched sibling donor, with fludarabine and melphalan conditioning. The post-transplantation course was uneventful, except for mild skin acute graft-versus-host disease (grade 2). EBV-DNA became undetectable in peripheral blood 98 days post transplantation. She has since been in good health without disease recurrence. CAEBV is a potentially fatal disease caused by persistent EBV infection of T lymphocytes or natural killer cells, thus requiring prompt treatment and allogeneic transplantation. Pericardial effusion is rarely observed in CAEBV and can impede its diagnosis. Therefore, we should be aware that patients may present with marked pericardial effusion as an initial manifestation of CAEBV. PMID:27263789

  14. Interleukin 2 secretion by lectin-activated human blood lymphocytes is markedly augmented by vascular endothelial cells

    SciTech Connect

    Guinan, E.C.; Pober, J.S.

    1986-03-01

    Since the initial interaction (and possible activation) of a blood borne T lymphocyte involves contact with the endothelial lining of the vasculature at the site of an immune response, the authors have examined the effect of cultured human endothelial cells (HEC) upon polyclonal T cell activation. Addition of 10/sup 4/ HEC to 10/sup 4/-10/sup 5/ peripheral blood lymphocytes (PBL) stimulated with phytohemagglutinin (PHA, 0.3-10 ..mu..g/ml) leads to marked augmentation of interleukin 2 (IL-2) production. The relative increase in IL-2 (mean of 3 expts. +/- SEM) is present at 24 h (5.8 fold +/- 1.5) and become more marked at 48 h (12.6 fold +/- 3.5) and 72 h (18.5 fold +/- 3.7). This relative enhancement is greater for HEC added to 10/sup 4/ than 10/sup 5/ PBL and is also greater when 10/sup 4/ rather than 2 x 10/sup 3/ HEC are added to a given number of PBL. This increased IL-2 concentration has two biological consequences. First, at suboptimal PHA doses or at low PBL number, PBL proliferation as measured by /sup 3/H-thymidine incorporation is increased up to two fold. Second, the phenotype of the proliferating cells appears altered, including a decrease in mean density of IL-2 receptor. The authors hypothesize that such modulation of the concentration of locally produced IL-2 may play a key role in the nature of an immune response, influencing both its magnitude and the functional profile of the activated and amplified effector cells.

  15. IL-10-dependent Tr1 cells attenuate astrocyte activation and ameliorate chronic central nervous system inflammation

    PubMed Central

    Mayo, Lior; Cunha, Andre Pires Da; Madi, Asaf; Beynon, Vanessa; Yang, Zhiping; Alvarez, Jorge I.; Prat, Alexandre; Sobel, Raymond A.; Kobzik, Lester; Lassmann, Hans; Quintana, Francisco J.

    2016-01-01

    See Winger and Zamvil (doi:10.1093/brain/aww121) for a scientific commentary on this article. The innate immune system plays a central role in the chronic central nervous system inflammation that drives neurological disability in progressive forms of multiple sclerosis, for which there are no effective treatments. The mucosal immune system is a unique tolerogenic organ that provides a physiological approach for the induction of regulatory T cells. Here we report that nasal administration of CD3-specific antibody ameliorates disease in a progressive animal model of multiple sclerosis. This effect is IL-10-dependent and is mediated by the induction of regulatory T cells that share a similar transcriptional profile to Tr1 regulatory cells and that suppress the astrocyte inflammatory transcriptional program. Treatment results in an attenuated inflammatory milieu in the central nervous system, decreased microglia activation, reduced recruitment of peripheral monocytes, stabilization of the blood–brain barrier and less neurodegeneration. These findings suggest a new therapeutic approach for the treatment of progressive forms of multiple sclerosis and potentially other types of chronic central nervous system inflammation. PMID:27246324

  16. Activation of CXCL10/CXCR3 signaling attenuates morphine analgesia: involvement of Gi protein.

    PubMed

    Ye, Dawei; Bu, Huilian; Guo, Genhua; Shu, Bin; Wang, Wei; Guan, Xuehai; Yang, Hui; Tian, Xuebi; Xiang, Hongbing; Gao, Feng

    2014-08-01

    Morphine is a potent agonist of μ-opioid receptor and is widely used to relieve severe pain, including cancer pain. Some chemokines, for example, CX3CL1 and CCL2, participate in the regulation of opioid santinociception. In our previous study, we found overexpression of chemokine CXCL10/CXCR3 in spinal cord participated in the development of cancer-induced bone pain, so we supposed that CXCL10 may have influence in morphine analgesia in cancer pain relief. In this study, we found that a single dose of morphine could transiently increase the expression of CXCL10 in spinal cord. Blocking the function of CXCL10 enhanced morphine antinociception in cancer-induced bone pain rats. However, overexpression of CXCL10 induced acute algesia and decreased the analgesic effect of morphine in normal mice. The algesic effect of CXCL10 was blocked by inhibition of CXCR3 and Gi protein. These results suggested that CXCL10 in spinal cord serves as a novel negative regulator of morphine analgesia and provided evidence that activation of CXCL10/CXCR3 in spinal cord may attenuate antinociceptive potency of morphine in cancer pain relief.

  17. miR-378 attenuates muscle regeneration by delaying satellite cell activation and differentiation in mice.

    PubMed

    Zeng, Ping; Han, Wanhong; Li, Changyin; Li, Hu; Zhu, Dahai; Zhang, Yong; Liu, Xiaohong

    2016-09-01

    Skeletal muscle mass and homeostasis during postnatal muscle development and regeneration largely depend on adult muscle stem cells (satellite cells). We recently showed that global overexpression of miR-378 significantly reduced skeletal muscle mass in mice. In the current study, we used miR-378 transgenic (Tg) mice to assess the in vivo functional effects of miR-378 on skeletal muscle growth and regeneration. Cross-sectional analysis of skeletal muscle tissues showed that the number and size of myofibers were significantly lower in miR-378 Tg mice than in wild-type mice. Attenuated cardiotoxin-induced muscle regeneration in miR-378 Tg mice was found to be associated with delayed satellite cell activation and differentiation. Mechanistically, miR-378 was found to directly target Igf1r in muscle cells both in vitro and in vivo These miR-378 Tg mice may provide a model for investigating the physiological and pathological roles of skeletal muscle in muscle-associated diseases in humans, particularly in sarcopenia. PMID:27563005

  18. Spatial distribution of intrinsic and scattering seismic attenuation in active volcanic islands - I: model and the case of Tenerife Island

    NASA Astrophysics Data System (ADS)

    Prudencio, Janire; Del Pezzo, Edoardo; García-Yeguas, Araceli; Ibáñez, Jesús M.

    2013-12-01

    The complex volcanic system of Tenerife Island is known to have a highly heterogeneous character, as recently confirmed by velocity tomography. We present new information derived from intrinsic quality factor inverse maps (Qi-1), scattering quality factor inverse maps (Qs-1) and total quality factor inverse maps (Qt-1) obtained for the same region. The data set used in this work is the result of the analysis of an active seismic experiment carried out, using offshore shots (air guns) recorded at over 85 onshore seismic stations. The estimates of the attenuation parameters are based on the assumption that the seismogram energy envelopes are determined by seismic energy diffusion processes occurring inside the island. Diffusion model parameters, proportional to Qi-1 and to Qs-1, are estimated from the inversion of the energy envelopes for any source-receiver couple. They are then weighted with a new graphical approach based on a Gaussian space probability function, which allowed us to create `2-D probabilistic maps' representing the space distribution of the attenuation parameters. The 2-D images obtained reveal the existence of a zone in the centre of the island characterized by the lowest attenuation effects. This effect is interpreted as highly rigid and cooled rocks. This low-attenuation region is bordered by zones of high attenuation, associated with the recent historical volcanic activity. We calculate the transport mean free path obtaining a value of around 4 km for the frequency range 6-12 Hz. This result is two orders of magnitude smaller than values calculated for the crust of the Earth. An absorption length between 10 and 14 km is associated with the average intrinsic attenuation parameter. These values, while small in the context of tectonic regions, are greater than those obtained in volcanic regions such as Vesuvius or Merapi. Such differences may be explained by the magnitude of the region of study, over three times larger than the aforementioned study

  19. Fate Mapping for Activation-Induced Cytidine Deaminase (AID) Marks Non-Lymphoid Cells During Mouse Development

    PubMed Central

    Rommel, Philipp C.; Bosque, David; Gitlin, Alexander D.; Croft, Gist F.; Heintz, Nathaniel; Casellas, Rafael; Nussenzweig, Michel C.; Kriaucionis, Skirmantas; Robbiani, Davide F.

    2013-01-01

    The Aicda gene encodes Activation-Induced cytidine Deaminase (AID), an enzyme essential for remodeling antibody genes in mature B lymphocytes. AID is also responsible for DNA damage at oncogenes, leading to their mutation and cancer-associated chromosome translocation in lymphoma. We used fate mapping and AIDGFP reporter mice to determine if AID expression in the mouse extends beyond lymphocytes. We discovered that AIDcre tags a small fraction of non-lymphoid cells starting at 10.5 days post conception (dpc), and that AIDGFP+ cells are detectable at dpc 11.5 and 12.5. Embryonic cells are tagged by AIDcre in the submandibular region, where conditional deletion of the tumor suppressor PTEN causes squamous papillomas. AIDcre also tags non-lymphoid cells in the embryonic central nervous system. Finally, in the adult mouse brain, AIDcre marks a small fraction of diverse neurons and distinct neuronal populations, including pyramidal cells in cortical layer IV. PMID:23861962

  20. Attenuated rabies virus activates, while pathogenic rabies virus evades, the host innate immune responses in the central nervous system.

    PubMed

    Wang, Zhi W; Sarmento, Luciana; Wang, Yuhuan; Li, Xia-qing; Dhingra, Vikas; Tseggai, Tesfai; Jiang, Baoming; Fu, Zhen F

    2005-10-01

    Rabies virus (RV) induces encephalomyelitis in humans and animals. However, the pathogenic mechanism of rabies is not fully understood. To investigate the host responses to RV infection, we examined and compared the pathology, particularly the inflammatory responses, and the gene expression profiles in the brains of mice infected with wild-type (wt) virus silver-haired bat RV (SHBRV) or laboratory-adapted virus B2C, using a mouse genomic array (Affymetrix). Extensive inflammatory responses were observed in animals infected with the attenuated RV, but little or no inflammatory responses were found in mice infected with wt RV. Furthermore, attenuated RV induced the expression of the genes involved in the innate immune and antiviral responses, especially those related to the alpha/beta interferon (IFN-alpha/beta) signaling pathways and inflammatory chemokines. For the IFN-alpha/beta signaling pathways, many of the interferon regulatory genes, such as the signal transduction activation transducers and interferon regulatory factors, as well as the effector genes, for example, 2'-5'-oligoadenylate synthetase and myxovirus proteins, are highly induced in mice infected with attenuated RV. However, many of these genes were not up-regulated in mice infected with wt SHBRV. The data obtained by microarray analysis were confirmed by real-time PCR. Together, these data suggest that attenuated RV activates, while pathogenic RV evades, the host innate immune and antiviral responses.

  1. Dioscin alleviates alcoholic liver fibrosis by attenuating hepatic stellate cell activation via the TLR4/MyD88/NF-κB signaling pathway

    PubMed Central

    Liu, Min; Xu, Youwei; Han, Xu; Yin, Lianhong; Xu, Lina; Qi, Yan; Zhao, Yanyan; Liu, Kexin; Peng, Jinyong

    2015-01-01

    The present work aimed to investigate the activities and underlying mechanisms of dioscin against alcoholic liver fibrosis (ALF). In vivo liver fibrosis in mice was induced by an alcoholic liquid diet, and in vitro studies were performed on activated HSC-T6 and LX2 cells treated with lipopolysaccharide. Our results showed that dioscin significantly attenuated hepatic stellate cells (HSCs) activation, improved collagen accumulation, and attenuated inflammation through down-regulating the levels of myeloid differentiation factor 88 (MyD88), nuclear factor κB (NF-κB), interleukin (IL)-1, IL-6 and tumour necrosis factor-α by decreasing Toll-like receptor (TLR)4 expression both in vivo and in vitro. TLR4 overexpression was also decreased by dioscin, leading to the markedly down-regulated levels of MyD88, NF-κB, transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (α-SMA) and type I collagen (COL1A1) in cultured HSCs. Suppression of cellular MyD88 by ST2825 or abrogation of NF-κB by pyrrolidine dithiocarbamate eliminated the inhibitory effects of dioscin on the levels of TGF-β1, α-SMA and COL1A1. In a word, dioscin exhibited potent effects against ALF via altering TLR4/MyD88/NF-κB signaling pathway, which provided novel insights into the mechanisms of this compound as an antifibrogenic candidate for the treatment of ALF in the future. PMID:26655640

  2. Salvianolic acid B attenuates apoptosis and inflammation via SIRT1 activation in experimental stroke rats.

    PubMed

    Lv, Hongdi; Wang, Ling; Shen, Jinchang; Hao, Shaojun; Ming, Aimin; Wang, Xidong; Su, Feng; Zhang, Zhengchen

    2015-06-01

    Silent information regulator 1 (SIRT1), a histone deacetylase, has been suggested to be effective in ischemic brain diseases. Salvianolic acid B (SalB) is a polyphenolic and one of the active components of Salvia miltiorrhiza Bunge. Previous studies suggested that SalB is protective against ischemic stroke. However, the role of SIRT1 in the protective effect of SalB against cerebral ischemia has not been explored. In this study, the rat brain was subjected to middle cerebral artery occlusion (MCAO). Before this surgery, rats were intraperitoneally administrated SalB with or without EX527, a specific SIRT1 inhibitor. The infarct volume, neurological score and brain water content were assessed. In addition, levels of TNF-α and IL-1β in the brain tissues were detected by commercial ELISA kits. And the expression levels of SIRT, Ac-FOXO1, Bcl-2 and Bax were detected by Western blot. The results suggested that SalB exerted a cerebral-protective effect, as shown by reduced infarct volume, lowered brain edema and increased neurological scores. SalB also exerted anti-inflammatory effects as indicated by the decreased TNF-α and IL-1β levels in the brain tissue. Moreover, SalB upregulated the expression of SIRT1 and Bcl-2 and downregulated the expression of Ac-FOXO1 and Bax. These effects of SalB were abolished by EX527 treatment. In summary, our results demonstrate that SalB treatment attenuates brain injury induced by ischemic stoke via reducing apoptosis and inflammation through the activation of SIRT1 signaling. PMID:25981395

  3. Internal sample attenuator counting (ISAC). A new technique for separating and measuring bound and free activity in radioimmunoassays

    SciTech Connect

    Thorell, J.I.

    1981-12-01

    A new method for the separation counting of bound and free activity in radioimmunoassays is described. Particles containing a radiation-abosrbing (attenuating) material are added to the assay. They shield the radiation from either the antibody-bound or the free radioligand. This obviates such manipulations conventionally involved in the separation and counting steps of radioimmunoassays as centrifugation decanting. Bismuth oxide is used as the attenuator. Particles with different properties are described. In one type, bismuth oxide is combined with active charcoal in an agarose matrix and serves as an absorbant for the free radioligand. In another type bismuth oxide is trapped within a polyacrylamide matrix to which antibodies are coupled. This particle can be used with a first- or a second-antibody bound activity. Application of the technique is illustrated with radioimmunoassays for thyroxin, triiodothyronine, human choriogonadotropin, and lutropin (luteinizing hormone).

  4. Polygonum cuspidatum inhibits pancreatic lipase activity and adipogenesis via attenuation of lipid accumulation

    PubMed Central

    2013-01-01

    major adipogenic transcription factors, were markedly reduced by POCU1b. Moreover, ADRP, perilipin, C/EBP-α, and PPAR-γ mRNA levels were also reduced by POCU1b. Levels of phosphorylated AMP-activated protein kinase (pAMPK) were elevated after POCU1b treatment (5, 10, and 25) in a dose-dependent manner. Conclusions Taken together, these results suggest that the anti-obesity effects of POCU1b involve the inhibition of pancreatic lipase activity and adipogenesis via the down-regulation of lipid accumulation. PMID:24160551

  5. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy.

    PubMed

    Raghavendra, Vasudeva; Tanga, Flobert; DeLeo, Joyce A

    2003-08-01

    Microglia, the intrinsic macrophages of the central nervous system, have previously been shown to be activated in the spinal cord in several rat mononeuropathy models. Activation of microglia and subsequent release of proinflammatory cytokines are known to play a role in inducing a behavioral hypersensitive state (hyperalgesia and allodynia) in these animals. The present study was undertaken to determine whether minocycline, an inhibitor of microglial activation, could attenuate both the development and existing mechanical allodynia and hyperalgesia in an L5 spinal nerve transection model of neuropathic pain. In a preventive paradigm (to study the effect on the development of hypersensitive behaviors), minocycline (10, 20, or 40 mg/kg intraperitoneally) was administered daily, beginning 1 h before nerve transection. This regimen produced a decrease in mechanical hyperalgesia and allodynia, with a maximum inhibitory effect observed at the dose of 20 and 40 mg/kg. The attenuation of the development of hyperalgesia and allodynia by minocycline was associated with an inhibitory action on microglial activation and suppression of proinflammatory cytokines at the L5 lumbar spinal cord of the nerveinjured animals. The effect of minocycline on existing allodynia was examined after its intraperitoneal administration initiated on day 5 post-L5 nerve transection. Although the postinjury administration of minocycline significantly inhibited microglial activation in neuropathic rats, it failed to attenuate existing hyperalgesia and allodynia. These data demonstrate that inhibition of microglial activation attenuated the development of behavioral hypersensitivity in a rat model of neuropathic pain but had no effect on the treatment of existing mechanical allodynia and hyperalgesia.

  6. Rheum palmatum L. Attenuates High Fat Diet-Induced Hepatosteatosis by Activating AMP-Activated Protein Kinase.

    PubMed

    Yang, Mingxing; Li, Xiumin; Zeng, Xin; Ou, Zhimin; Xue, Mei; Gao, Dehong; Liu, Suhuan; Li, Xuejun; Yang, Shuyu

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a common metabolic disorder characterized by the accumulation of excess fat in the liver. Rheum palmatumL. (RP) decoctions have been reported to ameliorate NAFLD. The aim of the present study was to investigate the effects and underlying mechanisms of RP in fatty liver disease induced by a high-fat diet (HFD) in rats. Low and high doses of aqueous RP extraction were orally administered to HFD-fed rats for six weeks. Body weight, tissue weight, glucose tolerance, insulin tolerance, hepatic morphology, and liver triglyceride (TG) content were assessed. The effects of RP on the expressions of lipogenic and lipolysis genes were measured by quantitative real-time PCR. The phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) was determined by Western blotting. Treatment with low-dose RP significantly reduced liver weight, liver TG content, and improved glucose tolerance in HFD-fed rats. Consistently, RP attenuated excess fat accumulation and downregulated the expression of lipogenic genes in the liver. Further, an increased phosphorylation of AMPK and ACC was observed. These findings suggest that low-dose RP alleviates hepatosteatosis, at least in part, by stimulating AMPK activity.

  7. Respiratory Viral Infection in Neonatal Piglets Causes Marked Microglia Activation in the Hippocampus and Deficits in Spatial Learning

    PubMed Central

    Elmore, Monica R. P.; Burton, Michael D.; Conrad, Matthew S.; Rytych, Jennifer L.; Van Alstine, William G.

    2014-01-01

    Environmental insults during sensitive periods can affect hippocampal development and function, but little is known about peripheral infection, especially in humans and other animals whose brain is gyrencephalic and experiences major perinatal growth. Using a piglet model, the present study showed that inoculation on postnatal day 7 with the porcine reproductive and respiratory syndrome virus (PRRSV) caused microglial activation within the hippocampus with 82% and 43% of isolated microglia being MHC II+ 13 and 20 d after inoculation, respectively. In control piglets, <5% of microglia isolated from the hippocampus were MHC II+. PRRSV piglets were febrile (p < 0.0001), anorectic (p < 0.0001), and weighed less at the end of the study (p = 0.002) compared with control piglets. Increased inflammatory gene expression (e.g., IL-1β, IL-6, TNF-α, and IFN-γ) was seen across multiple brain regions, including the hippocampus, whereas reductions in CD200, NGF, and MBP were evident. In a test of spatial learning, PRRSV piglets took longer to acquire the task, had a longer latency to choice, and had a higher total distance moved. Overall, these data demonstrate that viral respiratory infection is associated with a marked increase in activated microglia in the hippocampus, neuroinflammation, and impaired performance in a spatial cognitive task. As respiratory infections are common in human neonates and infants, approaches to regulate microglial cell activity are likely to be important. PMID:24501353

  8. Polar Markings

    NASA Technical Reports Server (NTRS)

    2006-01-01

    [figure removed for brevity, see original site] Context image for PIA02155 Polar Markings

    These bright and dark markings occurred near the end of summer in the south polar region. The dark material is likely dust that has been freed of frost cover.

    Image information: VIS instrument. Latitude -76.3N, Longitude 84.9E. 17 meter/pixel resolution.

    Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time.

    NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara Remote Sensing. The THEMIS investigation is led by Dr. Philip Christensen at Arizona State University. Lockheed Martin Astronautics, Denver, is the prime contractor for the Odyssey project, and developed and built the orbiter. Mission operations are conducted jointly from Lockheed Martin and from JPL, a division of the California Institute of Technology in Pasadena.

  9. Unaltered Angiogenesis-Regulating Activities of Platelets in Mild Type 2 Diabetes Mellitus despite a Marked Platelet Hyperreactivity

    PubMed Central

    Miao, Xinyan; Zhang, Wei; Huang, Zhangsen

    2016-01-01

    Type 2 diabetes mellitus (T2DM) is associated with platelet dysfunction and impaired angiogenesis. Aim of the study is to investigate if platelet dysfunction might hamper platelet angiogenic activities in T2DM patients. Sixteen T2DM patients and gender/age-matched non-diabetic controls were studied. Flow cytometry and endothelial colony forming cell (ECFC) tube formation on matrigel were used to assess platelet reactivity and angiogenic activity, respectively. Thrombin receptor PAR1-activating peptide (PAR1-AP) induced higher platelet P-selectin expression, and evoked more rapid and intense platelet annexin V binding in T2DM patients, seen as a more rapid increase of annexin V+ platelets (24.3±6.4% vs 12.6±3.8% in control at 2 min) and a higher elevation (30.9±5.1% vs 24.3±3.0% at 8 min). However, PAR1-AP and PAR4-AP induced similar releases of angiogenic regulators from platelets, and both stimuli evoked platelet release of platelet angiogenic regulators to similar extents in T2DM and control subjects. Thus, PAR1-stimulated platelet releasate (PAR1-PR) and PAR4-PR similarly enhanced capillary-like network/tube formation of ECFCs, and the enhancements did not differ between T2DM and control subjects. Direct supplementation of platelets to ECFCs at the ratio of 1:200 enhanced ECFC tube formation even more markedly, leading to approximately 100% increases of the total branch points of ECFC tube formation, for which the enhancements were also similar between patients and controls. In conclusion, platelets from T2DM subjects are hyperreactive. Platelet activation induced by high doses of PAR1-AP, however, results in similar releases of angiogenic regulators in mild T2DM and control subjects. Platelets from T2DM and control subjects also demonstrate similar enhancements on ECFC angiogenic activities. PMID:27612088

  10. Unaltered Angiogenesis-Regulating Activities of Platelets in Mild Type 2 Diabetes Mellitus despite a Marked Platelet Hyperreactivity.

    PubMed

    Miao, Xinyan; Zhang, Wei; Huang, Zhangsen; Li, Nailin

    2016-01-01

    Type 2 diabetes mellitus (T2DM) is associated with platelet dysfunction and impaired angiogenesis. Aim of the study is to investigate if platelet dysfunction might hamper platelet angiogenic activities in T2DM patients. Sixteen T2DM patients and gender/age-matched non-diabetic controls were studied. Flow cytometry and endothelial colony forming cell (ECFC) tube formation on matrigel were used to assess platelet reactivity and angiogenic activity, respectively. Thrombin receptor PAR1-activating peptide (PAR1-AP) induced higher platelet P-selectin expression, and evoked more rapid and intense platelet annexin V binding in T2DM patients, seen as a more rapid increase of annexin V+ platelets (24.3±6.4% vs 12.6±3.8% in control at 2 min) and a higher elevation (30.9±5.1% vs 24.3±3.0% at 8 min). However, PAR1-AP and PAR4-AP induced similar releases of angiogenic regulators from platelets, and both stimuli evoked platelet release of platelet angiogenic regulators to similar extents in T2DM and control subjects. Thus, PAR1-stimulated platelet releasate (PAR1-PR) and PAR4-PR similarly enhanced capillary-like network/tube formation of ECFCs, and the enhancements did not differ between T2DM and control subjects. Direct supplementation of platelets to ECFCs at the ratio of 1:200 enhanced ECFC tube formation even more markedly, leading to approximately 100% increases of the total branch points of ECFC tube formation, for which the enhancements were also similar between patients and controls. In conclusion, platelets from T2DM subjects are hyperreactive. Platelet activation induced by high doses of PAR1-AP, however, results in similar releases of angiogenic regulators in mild T2DM and control subjects. Platelets from T2DM and control subjects also demonstrate similar enhancements on ECFC angiogenic activities. PMID:27612088

  11. Apolipoprotein A-I Attenuates Palmitate-Mediated NF-κB Activation by Reducing Toll-Like Receptor-4 Recruitment into Lipid Rafts

    PubMed Central

    Tateya, Sanshiro; Schwartz, Jay; Tang, Chongren; Mitra, Poulami; Oram, John F.; Chait, Alan; Kim, Francis

    2012-01-01

    While high-density lipoprotein (HDL) is known to protect against a wide range of inflammatory stimuli, its anti-inflammatory mechanisms are not well understood. Furthermore, HDL's protective effects against saturated dietary fats have not been previously described. In this study, we used endothelial cells to demonstrate that while palmitic acid activates NF-κB signaling, apolipoprotein A–I, (apoA-I), the major protein component of HDL, attenuates palmitate-induced NF-κB activation. Further, vascular NF-κB signaling (IL-6, MCP-1, TNF-α) and macrophage markers (CD68, CD11c) induced by 24 weeks of a diabetogenic diet containing cholesterol (DDC) is reduced in human apoA-I overexpressing transgenic C57BL/6 mice compared to age-matched WT controls. Moreover, WT mice on DDC compared to a chow diet display increased gene expression of lipid raft markers such as Caveolin-1 and Flotillin-1, and inflammatory Toll-like receptors (TLRs) (TLR2, TLR4) in the vasculature. However apoA-I transgenic mice on DDC show markedly reduced expression of these genes. Finally, we show that in endothelial cells TLR4 is recruited into lipid rafts in response to palmitate, and that apoA-I prevents palmitate-induced TLR4 trafficking into lipid rafts, thereby blocking NF-κB activation. Thus, apoA-I overexpression might be a useful therapeutic tool against vascular inflammation. PMID:22479476

  12. Linalool attenuates lung inflammation induced by Pasteurella multocida via activating Nrf-2 signaling pathway.

    PubMed

    Wu, Qianchao; Yu, Lijun; Qiu, Jiaming; Shen, Bingyu; Wang, Di; Soromou, Lanan Wassy; Feng, Haihua

    2014-08-01

    Pasteurellosis caused by Pasteurella multocida manifest often as respiratory infection in farmed small ruminants. Although the incidence of pasteurellosis due to P. multocida mainly takes the form of pneumonia, there is limited information on host factors that play a role in disease pathogenesis in the milieu of host-pathogen interactions. Nuclear factor-erythroid 2 related factor 2 (Nrf-2), a critical regulator for various inflammatory and immune responses by controlling oxidative stress, may play an important role in the processes of inflammation induced by P. multocida. In this study, linalool, a natural compound of the essential oils in several aromatic plant species, elevated nuclear Nrf-2 protein translocation in the A549 lung cell line and in vivo. The P. multocida-induced pro-inflammatory cytokines expression was abrogated by Nrf-2 siRNA. Postponed treatment with linalool decreased lung neutrophil accumulation and enhanced clearance of P. multocida. Furthermore, linalool significantly increased the expression of antioxidant enzymes regulated by Nrf-2 and diminished lung tissue levels of several pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α) and interleukin (IL)-6. In addition, animals treated with linalool had a marked improvement in survival. These findings have uncovered that linalool acts as a novel Nrf-2 activator for a novel therapeutic strategy in pathogen-mediated lung inflammation.

  13. The Arabidopsis DNA Polymerase δ Has a Role in the Deposition of Transcriptionally Active Epigenetic Marks, Development and Flowering

    PubMed Central

    Iglesias, Francisco M.; Bruera, Natalia A.; Dergan-Dylon, Sebastián; Marino-Buslje, Cristina; Lorenzi, Hernán; Mateos, Julieta L.; Turck, Franziska; Coupland, George; Cerdán, Pablo D.

    2015-01-01

    DNA replication is a key process in living organisms. DNA polymerase α (Polα) initiates strand synthesis, which is performed by Polε and Polδ in leading and lagging strands, respectively. Whereas loss of DNA polymerase activity is incompatible with life, viable mutants of Polα and Polε were isolated, allowing the identification of their functions beyond DNA replication. In contrast, no viable mutants in the Polδ polymerase-domain were reported in multicellular organisms. Here we identify such a mutant which is also thermosensitive. Mutant plants were unable to complete development at 28°C, looked normal at 18°C, but displayed increased expression of DNA replication-stress marker genes, homologous recombination and lysine 4 histone 3 trimethylation at the SEPALLATA3 (SEP3) locus at 24°C, which correlated with ectopic expression of SEP3. Surprisingly, high expression of SEP3 in vascular tissue promoted FLOWERING LOCUS T (FT) expression, forming a positive feedback loop with SEP3 and leading to early flowering and curly leaves phenotypes. These results strongly suggest that the DNA polymerase δ is required for the proper establishment of transcriptionally active epigenetic marks and that its failure might affect development by affecting the epigenetic control of master genes. PMID:25693187

  14. Low LBNP tolerance in men is associated with attenuated activation of the renin-angiotensin system

    NASA Technical Reports Server (NTRS)

    Greenleaf, J. E.; Petersen, T. W.; Gabrielsen, A.; Pump, B.; Bie, P.; Christensen, N. J.; Warberg, J.; Videbaek, R.; Simonson, S. R.; Norsk, P.

    2000-01-01

    Plasma vasoactive hormone concentrations [epinephrine (p(Epi)), norepinephrine (p(NE)), ANG II (p(ANG II)), vasopressin (p(VP)), endothelin-1 (p(ET-1))] and plasma renin activity (p(RA)) were measured periodically and compared during lower body negative pressure (LBNP) to test the hypothesis that responsiveness of the renin-angiotensin system, the latter being one of the most powerful vasoconstrictors in the body, is of major importance for LBNP tolerance. Healthy men on a controlled diet (2,822 cal/day, 2 mmol. kg(-1). day(-1) Na(+)) were exposed to 30 min of LBNP from -15 to -50 mmHg. LBNP was uneventful for seven men [25 +/- 2 yr, high-tolerance (HiTol) group], but eight men (26 +/- 3 yr) reached presyncope after 11 +/- 1 min [P < 0.001, low-tolerance (LoTol) group]. Mean arterial pressure (MAP) did not change measurably, but central venous pressure and left atrial diameter decreased similarly in both groups (5-6 mmHg, by approximately 30%, P < 0.05). Control (0 mmHg LBNP) hormone concentrations were similar between groups, however, p(RA) differed between them (LoTol 0.6 +/- 0.1, HiTol 1.2 +/- 0.1 ng ANG I. ml(-1). h(-1), P < 0.05). LBNP increased (P < 0. 05) p(RA) and p(ANG II), respectively, more in the HiTol group (9.9 +/- 2.2 ng ANG I. ml(-1). h(-1) and 58 +/- 12 pg/ml) than in LoTol subjects (4.3 +/- 0.9 ng ANG I. ml(-1). h(-1) and 28 +/- 6 pg/ml). In contrast, the increase in p(VP) was higher (P < 0.05) in the LoTol than in the HiTol group. The increases (P < 0.05) for p(NE) were nonsignificant between groups, and p(ET-1) remained unchanged. Thus there may be a causal relationship between attenuated activation of p(RA) and p(ANG II) and presyncope, with p(VP) being a possible cofactor. Measurement of resting p(RA) may be of predictive value for those with lower hypotensive tolerance.

  15. Estimation of canopy attenuation for active/passive microwave soil moisture retrieval algorithms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This paper discusses the importance of the proper characterization of scattering and attenuation in trees needed for accurate retrieval of soil moisture in the presence of trees. Emphasis is placed on determining an accurate estimation of the propagation properties of a vegetation canopy using the c...

  16. Mice expressing markedly reduced striatal dopamine transporters exhibit increased locomotor activity, dopamine uptake turnover rate, and cocaine responsiveness.

    PubMed

    Rao, Anjali; Sorkin, Alexander; Zahniser, Nancy R

    2013-10-01

    Variations in the expression levels of the dopamine transporter (DAT) can influence responsiveness to psychostimulant drugs like cocaine. To better understand this relationship, we studied a new DAT-low expresser (DAT-LE) mouse model and performed behavioral and biochemical studies with it. Immunoblotting and [(3) H]WIN 35,428 binding analyses revealed that these mice express ∼35% of wildtype (WT) mouse striatal DAT levels. Compared to WT mice, DAT-LE mice were hyperactive in a novel open-field environment. Despite their higher basal locomotor activity, cocaine (10 or 20 mg/kg, i.p.) induced greater locomotor activation in DAT-LE mice than in WT mice. The maximal velocity (Vmax ) of DAT-mediated [(3) H]DA uptake into striatal synaptosomes was reduced by 46% in DAT-LE mice, as compared to WT. Overall, considering the reduced number of DAT binding sites (Bmax ) along with the reduced Vmax in DAT-LE mice, a 2-fold increase in DA uptake turnover rate (Vmax /Bmax ) was found, relative to WT mice. This suggests that neuroadaptive changes have occurred in the DAT-LE mice that would help to compensate for their low DAT numbers. Interestingly, these changes do not include a reduction in tyrosine hydroxylase levels, as was previously reported in DAT knockout homozygous and heterozygous animals. Further, these changes are not sufficient to prevent elevated novelty- and cocaine-induced locomotor activity. Hence, these mice represent a unique model for studying changes of in vivo DAT function and regulation that result from markedly reduced levels of DAT expression. PMID:23564231

  17. Mice expressing markedly reduced striatal dopamine transporters exhibit increased locomotor activity, dopamine uptake turnover rate, and cocaine responsiveness.

    PubMed

    Rao, Anjali; Sorkin, Alexander; Zahniser, Nancy R

    2013-10-01

    Variations in the expression levels of the dopamine transporter (DAT) can influence responsiveness to psychostimulant drugs like cocaine. To better understand this relationship, we studied a new DAT-low expresser (DAT-LE) mouse model and performed behavioral and biochemical studies with it. Immunoblotting and [(3) H]WIN 35,428 binding analyses revealed that these mice express ∼35% of wildtype (WT) mouse striatal DAT levels. Compared to WT mice, DAT-LE mice were hyperactive in a novel open-field environment. Despite their higher basal locomotor activity, cocaine (10 or 20 mg/kg, i.p.) induced greater locomotor activation in DAT-LE mice than in WT mice. The maximal velocity (Vmax ) of DAT-mediated [(3) H]DA uptake into striatal synaptosomes was reduced by 46% in DAT-LE mice, as compared to WT. Overall, considering the reduced number of DAT binding sites (Bmax ) along with the reduced Vmax in DAT-LE mice, a 2-fold increase in DA uptake turnover rate (Vmax /Bmax ) was found, relative to WT mice. This suggests that neuroadaptive changes have occurred in the DAT-LE mice that would help to compensate for their low DAT numbers. Interestingly, these changes do not include a reduction in tyrosine hydroxylase levels, as was previously reported in DAT knockout homozygous and heterozygous animals. Further, these changes are not sufficient to prevent elevated novelty- and cocaine-induced locomotor activity. Hence, these mice represent a unique model for studying changes of in vivo DAT function and regulation that result from markedly reduced levels of DAT expression.

  18. Asian women have attenuated sympathetic activation but enhanced renal–adrenal responses during pregnancy compared to Caucasian women

    PubMed Central

    Okada, Yoshiyuki; Best, Stuart A; Jarvis, Sara S; Shibata, Shigeki; Parker, Rosemary S; Casey, Brian M; Levine, Benjamin D; Fu, Qi

    2015-01-01

    Abstract Asians have a lower prevalence of hypertensive disorders of pregnancy than Caucasians. Since sympathetic overactivity and dysregulation of the renal–adrenal system (e.g. low aldosterone levels) have been found in preeclamptic women, we hypothesized that Asians have lower muscle sympathetic nerve activity (MSNA) and greater aldosterone concentrations during normal pregnancy than Caucasians. In a prospective study, blood pressure (BP), heart rate (HR), and MSNA were measured during supine and upright tilt (30 deg and 60 deg for 5 min each) in 9 Asians (32 ± 1 years (mean ± SEM)) and 12 Caucasians (29 ± 1 years) during pre-, early (≤8 weeks of gestation) and late (32–36 weeks) pregnancy, and post-partum (6–10 weeks after delivery). Supine MSNA increased with pregnancy in both groups (P < 0.001); it was significantly lower in Asians than Caucasians (14 ± 3 vs. 23 ± 3 bursts min−1 and 16 ± 5 vs. 30 ± 3 bursts min−1 in early and late pregnancy, respectively; P = 0.023). BP decreased during early pregnancy (P < 0.001), but was restored during late pregnancy. HR increased during pregnancy (P < 0.001) with no racial difference (P = 0.758). MSNA increased during tilting and it was markedly lower in Asians than Caucasians in late pregnancy (31 ± 6 vs. 49 ± 3 bursts min−1 at 60 deg tilt; P = 0.003). Upright BP was lower in Asians, even in pre-pregnancy (P = 0.006), and this racial difference persisted during pregnancy. Direct renin and aldosterone increased during pregnancy (both P < 0.001); these hormones were greater in Asians (P = 0.086 and P = 0.014). Thus, Asians have less sympathetic activation but more upregulated renal–adrenal responses than Caucasians during pregnancy. These results may explain, at least in part, why Asian women are at low risk of hypertensive disorders in pregnancy. Key points Asian women have a lower prevalence of hypertensive disorders of pregnancy than Caucasian

  19. Adiponectin attenuates lung fibroblasts activation and pulmonary fibrosis induced by paraquat.

    PubMed

    Yao, Rong; Cao, Yu; He, Ya-rong; Lau, Wayne Bond; Zeng, Zhi; Liang, Zong-an

    2015-01-01

    Pulmonary fibrosis is one of the most common complications of paraquat (PQ) poisoning, which demands for more effective therapies. Accumulating evidence suggests adiponectin (APN) may be a promising therapy against fibrotic diseases. In the current study, we determine whether the exogenous globular APN isoform protects against pulmonary fibrosis in PQ-treated mice and human lung fibroblasts, and dissect the responsible underlying mechanisms. BALB/C mice were divided into control group, PQ group, PQ + low-dose APN group, and PQ + high-dose APN group. Mice were sacrificed 3, 7, 14, and 21 days after PQ treatment. We compared pulmonary histopathological changes among different groups on the basis of fibrosis scores, TGF-β1, CTGF and α-SMA pulmonary content via Western blot and real-time quantitative fluorescence-PCR (RT-PCR). Blood levels of MMP-9 and TIMP-1 were determined by ELISA. Human lung fibroblasts WI-38 were divided into control group, PQ group, APN group, and APN receptor (AdipoR) 1 small-interfering RNA (siRNA) group. Fibroblasts were collected 24, 48, and 72 hours after PQ exposure for assay. Cell viability and apoptosis were determined via Kit-8 (CCK-8) and fluorescein Annexin V-FITC/PI double labeling. The protein and mRNA expression level of collagen type III, AdipoR1, and AdipoR2 were measured by Western blot and RT-PCR. APN treatment significantly decreased the lung fibrosis scores, protein and mRNA expression of pulmonary TGF-β1, CTGF and α-SMA content, and blood MMP-9 and TIMP-1 in a dose-dependent manner (p<0.05). Pretreatment with APN significantly attenuated the reduced cell viability and up-regulated collagen type III expression induced by PQ in lung fibroblasts, (p<0.05). APN pretreatment up-regulated AdipoR1, but not AdipoR2, expression in WI-38 fibroblasts. AdipoR1 siRNA abrogated APN-mediated protective effects in PQ-exposed fibroblasts. Taken together, our data suggests APN protects against PQ-induced pulmonary fibrosis in a dose

  20. Adiponectin attenuates lung fibroblasts activation and pulmonary fibrosis induced by paraquat.

    PubMed

    Yao, Rong; Cao, Yu; He, Ya-rong; Lau, Wayne Bond; Zeng, Zhi; Liang, Zong-an

    2015-01-01

    Pulmonary fibrosis is one of the most common complications of paraquat (PQ) poisoning, which demands for more effective therapies. Accumulating evidence suggests adiponectin (APN) may be a promising therapy against fibrotic diseases. In the current study, we determine whether the exogenous globular APN isoform protects against pulmonary fibrosis in PQ-treated mice and human lung fibroblasts, and dissect the responsible underlying mechanisms. BALB/C mice were divided into control group, PQ group, PQ + low-dose APN group, and PQ + high-dose APN group. Mice were sacrificed 3, 7, 14, and 21 days after PQ treatment. We compared pulmonary histopathological changes among different groups on the basis of fibrosis scores, TGF-β1, CTGF and α-SMA pulmonary content via Western blot and real-time quantitative fluorescence-PCR (RT-PCR). Blood levels of MMP-9 and TIMP-1 were determined by ELISA. Human lung fibroblasts WI-38 were divided into control group, PQ group, APN group, and APN receptor (AdipoR) 1 small-interfering RNA (siRNA) group. Fibroblasts were collected 24, 48, and 72 hours after PQ exposure for assay. Cell viability and apoptosis were determined via Kit-8 (CCK-8) and fluorescein Annexin V-FITC/PI double labeling. The protein and mRNA expression level of collagen type III, AdipoR1, and AdipoR2 were measured by Western blot and RT-PCR. APN treatment significantly decreased the lung fibrosis scores, protein and mRNA expression of pulmonary TGF-β1, CTGF and α-SMA content, and blood MMP-9 and TIMP-1 in a dose-dependent manner (p<0.05). Pretreatment with APN significantly attenuated the reduced cell viability and up-regulated collagen type III expression induced by PQ in lung fibroblasts, (p<0.05). APN pretreatment up-regulated AdipoR1, but not AdipoR2, expression in WI-38 fibroblasts. AdipoR1 siRNA abrogated APN-mediated protective effects in PQ-exposed fibroblasts. Taken together, our data suggests APN protects against PQ-induced pulmonary fibrosis in a dose

  1. Adiponectin Attenuates Lung Fibroblasts Activation and Pulmonary Fibrosis Induced by Paraquat

    PubMed Central

    He, Ya-rong; Lau, Wayne Bond; Zeng, Zhi; Liang, Zong-an

    2015-01-01

    Pulmonary fibrosis is one of the most common complications of paraquat (PQ) poisoning, which demands for more effective therapies. Accumulating evidence suggests adiponectin (APN) may be a promising therapy against fibrotic diseases. In the current study, we determine whether the exogenous globular APN isoform protects against pulmonary fibrosis in PQ-treated mice and human lung fibroblasts, and dissect the responsible underlying mechanisms. BALB/C mice were divided into control group, PQ group, PQ + low-dose APN group, and PQ + high-dose APN group. Mice were sacrificed 3, 7, 14, and 21 days after PQ treatment. We compared pulmonary histopathological changes among different groups on the basis of fibrosis scores, TGF-β1, CTGF and α-SMA pulmonary content via Western blot and real-time quantitative fluorescence-PCR (RT-PCR). Blood levels of MMP-9 and TIMP-1 were determined by ELISA. Human lung fibroblasts WI-38 were divided into control group, PQ group, APN group, and APN receptor (AdipoR) 1 small-interfering RNA (siRNA) group. Fibroblasts were collected 24, 48, and 72 hours after PQ exposure for assay. Cell viability and apoptosis were determined via Kit-8 (CCK-8) and fluorescein Annexin V-FITC/PI double labeling. The protein and mRNA expression level of collagen type III, AdipoR1, and AdipoR2 were measured by Western blot and RT-PCR. APN treatment significantly decreased the lung fibrosis scores, protein and mRNA expression of pulmonary TGF-β1, CTGF and α-SMA content, and blood MMP-9 and TIMP-1 in a dose-dependent manner (p<0.05). Pretreatment with APN significantly attenuated the reduced cell viability and up-regulated collagen type III expression induced by PQ in lung fibroblasts, (p<0.05). APN pretreatment up-regulated AdipoR1, but not AdipoR2, expression in WI-38 fibroblasts. AdipoR1 siRNA abrogated APN-mediated protective effects in PQ-exposed fibroblasts. Taken together, our data suggests APN protects against PQ-induced pulmonary fibrosis in a dose

  2. Mek inhibition results in marked antitumor activity against metastatic melanoma patient-derived melanospheres and in melanosphere-generated xenografts.

    PubMed

    Sette, Giovanni; Fecchi, Katia; Salvati, Valentina; Lotti, Fiorenza; Pilozzi, Emanuela; Duranti, Enrico; Biffoni, Mauro; Pagliuca, Alfredo; Martinetti, Daniela; Memeo, Lorenzo; Milella, Michele; De Maria, Ruggero; Eramo, Adriana

    2013-11-16

    One of the key oncogenic pathways involved in melanoma aggressiveness, development and progression is the RAS/BRAF/MEK pathway, whose alterations are found in most patients. These molecular anomalies are promising targets for more effective anti-cancer therapies. Some Mek inhibitors showed promising antitumor activity, although schedules and doses associated with low systemic toxicity need to be defined. In addition, it is now accepted that cancers can arise from and be maintained by the cancer stem cells (CSC) or tumor-initiating cells (TIC), commonly expanded in vitro as tumorspheres from several solid tumors, including melanoma (melanospheres). Here, we investigated the potential targeting of MEK pathway by exploiting highly reliable in vitro and in vivo pre-clinical models of melanomas based on melanospheres, as melanoma initiating cells (MIC) surrogates. MEK inhibition, through PD0325901, provided a successful strategy to affect survival of mutated-BRAF melanospheres and growth of wild type-BRAF melanospheres. A marked citotoxicity was observed in differentated melanoma cells regardless BRAF mutational status. PD0325901 treatment, dramatically inhibited growth of melanosphere-generated xenografts and determined impaired tumor vascularization of both mutated- and wild type-BRAF tumors, in the absence of mice toxicity. These results suggest that MEK inhibition might represent a valid treatment option for patients with both mutated- or wild type-BRAF melanomas, affecting tumor growth through multiple targets.

  3. [Construction of the genetically attenuated bacteria Bordetella pertussis devoid of dermonecrotic toxin activity and producing modified nontoxic pertussis toxin form].

    PubMed

    Siniashina, L N; Siniashina, L S; Semin, E G; Amelina, I P; Karataev, G I

    2010-01-01

    The recombinant modified (attenuated) bacteria A. pertussis were constructed. These bacteria contained knockout mutation of the dnt gene and produced nontoxic pertussis toxin derivative. The immunological properties of the mutant bacteria B. pertussis strain KS were studied. The recombinant bacteria B. pertussis strain KS were found to be devoid of dermonecrotic toxin activity, conserved the structure of the mutant dnt gene in condition of cultivation on selective growth media, and long-term survival in laboratory animal organism. Intranasal immunization of mice with living bacteria B. pertussis, attenuated strain KS provided protection of animals from virulent strains of the pertussis. The efficiency of the protection was comparable with protection efficiency provided by standard corpuscular pertussis vaccine OSO-3.

  4. Characterisation of microbial activity in the framework of natural attenuation without groundwater monitoring wells?: a new Direct-Push probe.

    PubMed

    Schurig, Christian; Melo, Vinicio Alejandro; Miltner, Anja; Kaestner, Matthias

    2014-01-01

    At many contaminated field sites in Europe, monitored natural attenuation is a feasible site remediation option. Natural attenuation includes several processes but only the microbial degradation leads to real contaminant removal and very few methods are accepted by the authorities providing real evidence of microbial contaminant degradation activity. One of those methods is the recently developed in situ microcosm approach (BACTRAP®). These in situ microcosms consist of perforated stainless steel cages or PTFE tubes filled with an activated carbon matrix that is amended with 13C-labelled contaminants; the microcosms are then exposed within groundwater monitoring wells. Based on this approach, natural attenuation was accepted by authorities as a site remediation option for the BTEX-polluted site Zeitz in Germany. Currently, the in situ microcosms are restricted to the use inside groundwater monitoring wells at the level of the aquifer. The (classical) system therefore is only applicable on field sites with a network of monitoring wells, and only microbial activity inside the monitoring wells at the level of the aquifer can be assessed. In order to overcome these limitations, a new Direct-Push BACTRAP probe was developed on the basis of the Geoprobe® equipment. With respect to the mechanical boundary conditions of the DP technique, these new probes were constructed in a rugged and segmented manner and are adaptable to various sampling concepts. With this new probe, the approach can be extended to field sites without existing monitoring wells, and microbial activity was demonstrated to be measureable even under very dry conditions inside the vadose zone above the aquifer. In a field test, classical and Direct-Push BACTRAPs were applied in the BTEX-contaminated aquifer at the ModelPROBE reference site Zeitz (Germany). Both types of BACTRAPs were incubated in the centre and at the fringe of the BTEX plume. Analysis of phospholipid fatty acid (PLFA) patterns showed

  5. Octyl Gallate Markedly Promotes Anti-Amyloidogenic Processing of APP through Estrogen Receptor-Mediated ADAM10 Activation

    PubMed Central

    Zhang, She-Qing; Sawmiller, Darrell; Li, Song; Rezai-Zadeh, Kavon; Hou, Huayan; Zhou, Shufeng; Shytle, Douglas; Giunta, Brian; Fernandez, Frank; Mori, Takashi; Tan, Jun

    2013-01-01

    Our previous studies showed that the green tea-derived polyphenolic compound (−)-epigallocatechin-3 gallate (EGCG) reduces amyloid-β (Aβ) production in both neuronal and mouse Alzheimer’s disease (AD) models in concert with activation of estrogen receptor-α/phosphatidylinositide 3-kinase/protein kinase B (ERα/PI3K/Akt) signaling and anti-amyloidogenic amyloid precursor protein (APP) α-secretase (a disintegrin and metallopeptidase domain-10, ADAM10) processing. Since the gallate moiety in EGCG may correspond to the 7α position of estrogen, thereby facilitating ER binding, we extensively screened the effect of other gallate containing phenolic compounds on APP anti-amyloidogenic processing. Octyl gallate (OG; 10 µM), drastically decreased Aβ generation, in concert with increased APP α-proteolysis, in murine neuron-like cells transfected with human wild-type APP or “Swedish” mutant APP. OG markedly increased production of the neuroprotective amino-terminal APP cleavage product, soluble APP-α (sAPPα). In accord with our previous study, these cleavage events were associated with increased ADAM10 maturation and reduced by blockade of ERα/PI3k/Akt signaling. To validate these findings in vivo, we treated Aβ-overproducing Tg2576 mice with OG daily for one week by intracerebroventricular injection and found decreased Aβ levels associated with increased sAPPα. These data indicate that OG increases anti-amyloidogenic APP α-secretase processing by activation of ERα/PI3k/Akt signaling and ADAM10, suggesting that this compound may be an effective treatment for AD. PMID:23977176

  6. Some Attenuated Variants of Vesicular Stomatitis Virus Show Enhanced Oncolytic Activity against Human Glioblastoma Cells relative to Normal Brain Cells▿

    PubMed Central

    Wollmann, Guido; Rogulin, Vitaliy; Simon, Ian; Rose, John K.; van den Pol, Anthony N.

    2010-01-01

    Vesicular stomatitis virus (VSV) has been shown in laboratory studies to be effective against a variety of tumors, including malignant brain tumors. However, attenuation of VSV may be necessary to balance the potential toxicity toward normal cells, particularly when targeting brain tumors. Here we compared 10 recombinant VSV variants resulting from different attenuation strategies. Attenuations included gene shifting (VSV-p1-GFP/RFP), M protein mutation (VSV-M51), G protein cytoplasmic tail truncations (VSV-CT1/CT9), G protein deletions (VSV-dG-GFP/RFP), and combinations thereof (VSV-CT9-M51). Using in vitro viability and replication assays, the VSV variants were grouped into three categories, based on their antitumor activity and non-tumor-cell attenuation. In the first group, wild-type-based VSV-G/GFP, tumor-adapted VSV-rp30, and VSV-CT9 showed a strong antitumor profile but also retained some toxicity toward noncancer control cells. The second group, VSV-CT1, VSV-dG-GFP, and VSV-dG-RFP, had significantly diminished toxicity toward normal cells but showed little oncolytic action. The third group displayed a desired combination of diminished general toxicity and effective antitumor action; this group included VSV-M51, VSV-CT9-M51, VSV-p1-GFP, and VSV-p1-RFP. A member of the last group, VSV-p1-GFP, was then compared in vivo against wild-type-based VSV-G/GFP. Intranasal inoculation of young, postnatal day 16 mice with VSV-p1-GFP showed no adverse neurological effects, whereas VSV-G/GFP was associated with high lethality (80%). Using an intracranial tumor xenograft model, we further demonstrated that attenuated VSV-p1-GFP targets and kills human U87 glioblastoma cells after systemic application. We concluded that some, but not all, attenuated VSV mutants display a favorable oncolytic profile and merit further investigation. PMID:19906910

  7. Halofuginone attenuates osteoarthritis by inhibition of TGF-β activity and H-type vessel formation in subchondral bone

    PubMed Central

    Cui, Zhuang; Crane, Janet; Xie, Hui; Jin, Xin; Zhen, Gehua; Li, Changjun; Xie, Liang; Wang, Long; Bian, Qin; Qiu, Tao; Wan, Mei; Xie, Min; Ding, Sheng; Yu, Bin; Cao, Xu

    2016-01-01

    Objectives Examine whether osteoarthritis (OA) progression can be delayed by halofuginone in anterior cruciate ligament transection (ACLT) rodent models. Methods 3-month-old male C57BL/6J (wild type; WT) mice and Lewis rats were randomised to sham-operated, ACLT-operated, treated with vehicle, or ACLT-operated, treated with halofuginone. Articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI)-modified Mankin criteria. Immunostaining, flow cytometry, RT-PCR and western blot analyses were conducted to detect relative protein and RNA expression. Bone micro CT (μCT) and CT-based microangiography were quantitated to detect alterations of microarchitecture and vasculature in tibial subchondral bone. Results Halofuginone attenuated articular cartilage degeneration and subchondral bone deterioration, resulting in substantially lower OARSI scores. Specifically, we found that proteoglycan loss and calcification of articular cartilage were significantly decreased in halofuginone-treated ACLT rodents compared with vehicle-treated ACLT controls. Halofuginone reduced collagen X (Col X), matrix metalloproteinase-13 and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS 5) and increased lubricin, collagen II and aggrecan. In parallel, halofuginone-attenuated uncoupled subchondral bone remodelling as defined by reduced subchondral bone tissue volume, lower trabecular pattern factor (Tb.pf) and increased thickness of subchondral bone plate compared with vehicle-treated ACLT controls. We found that halofuginone exerted protective effects in part by suppressing Th17-induced osteoclastic bone resorption, inhibiting Smad2/3-dependent TGF-β signalling to restore coupled bone remodelling and attenuating excessive angiogenesis in subchondral bone. Conclusions Halofuginone attenuates OA progression by inhibition of subchondral bone TGF-β activity and aberrant angiogenesis as a potential preventive therapy for OA

  8. The glial cell modulators, ibudilast and its amino analog, AV1013, attenuate methamphetamine locomotor activity and its sensitization in mice.

    PubMed

    Snider, Sarah E; Vunck, Sarah A; van den Oord, Edwin J C G; Adkins, Daniel E; McClay, Joseph L; Beardsley, Patrick M

    2012-03-15

    Over 800,000 Americans abuse the psychomotor stimulant, methamphetamine, yet its abuse is without an approved medication. Methamphetamine induces hypermotor activity, and sensitization to this effect is suggested to represent aspects of the addiction process. Methamphetamine's regulation of 3'-5'-cyclic adenosine monophosphate (cAMP) levels may be partially responsible for its behavioral effects, and compounds that inhibit phosphodiesterase (PDE), the enzyme that degrades cAMP, can alter methamphetamine-induced behaviors. Methamphetamine also activates glial cells and causes a subsequent increase in pro-inflammatory cytokine levels. Modulation of glial cell activation is associated with changes in behavioral responses, and substances that oppose inflammatory activity can attenuate drug-induced behaviors. Ibudilast (aka AV411; 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine), inhibits both PDE and glial pro-inflammatory activity. Ibudilast's amino analog, AV1013, modulates similar glial targets but negligibly inhibits PDE. The present study determined whether ibudilast and AV1013 would attenuate methamphetamine-induced locomotor activity and its sensitization in C57BL/6J mice. Mice were treated b.i.d. with ibudilast (1.8-13 mg/kg), AV1013 (10-56 mg/kg) or their vehicles intraperitoneally for 7 days, beginning 48 h before 5 days of daily 1-h locomotor activity tests. Each test was initiated by either a methamphetamine (3 mg/kg) or a saline injection. Ibudilast significantly (P<0.05) reduced the acute, chronic, and sensitization effects of methamphetamine's locomotor activity without significantly affecting activity by itself. AV1013 had similar anti-methamphetamine effects, suggesting that glial cell activity, by itself, can modulate methamphetamine's effects and perhaps serve as a medication target for its abuse.

  9. Rosmarinic Acid Attenuates Sodium Taurocholate-Induced Acute Pancreatitis in Rats by Inhibiting Nuclear Factor-κB Activation.

    PubMed

    Fan, Yu-Ting; Yin, Guo-Jian; Xiao, Wen-Qin; Qiu, Lei; Yu, Ge; Hu, Yan-Ling; Xing, Miao; Wu, De-Qing; Cang, Xiao-Feng; Wan, Rong; Wang, Xing-Peng; Hu, Guo-Yong

    2015-01-01

    Rosmarinic Acid (RA), a caffeic acid ester, has been shown to exert anti-inflammation, anti-oxidant and antiallergic effects. Our study aimed to investigate the effect of RA in sodium taurocholate ( NaTC )-induced acute pancreatitis, both in vivo and in vitro. In vivo, RA (50 mg/kg) was administered intraperitoneally 2 h before sodium taurocholate injection. Rats were sacrificed 12 h, 24 h or 48 h after sodium taurocholate injection. Pretreatment with RA significantly ameliorated pancreas histopathological changes, decreased amylase and lipase activities in serum, lowered myeloperoxidase activity in the pancreas, reduced systematic and pancreatic interleukin-1 β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) levels, and inhibited NF-κB translocation in pancreas. In vitro, pretreating the fresh rat pancreatic acinar cells with 80 μ mol/L RA 2 h before 3750 nmol/L sodium taurocholate or 10 ng/L TNF-α administration significantly attenuated the reduction of isolated pancreatic acinar cell viability and inhibited the nuclear activation and translocation of NF-κB. Based on our findings, RA appears to attenuate damage in sodium taurocholate-induced acute pancreatitis and reduce the release of inflammatory cytokines by inhibiting the activation of NF-κB. These findings might provide a basis for investigating the therapeutic role of RA in managing acute pancreatits. PMID:26364660

  10. Thymoquinone attenuates liver fibrosis via PI3K and TLR4 signaling pathways in activated hepatic stellate cells.

    PubMed

    Bai, Ting; Lian, Li-Hua; Wu, Yan-Ling; Wan, Ying; Nan, Ji-Xing

    2013-02-01

    Thymoquinone (TQ) is the major active compound derived from the medicinal Nigella sativa. In the present study, we investigated the anti-fibrotic mechanism of TQ in lipopolysaccharide (LPS)-activated rat hepatic stellate cells line, T-HSC/Cl-6. T-HSC/Cl-6 cells were treated with TQ (3.125, 6.25 and 12.5μM) prior to LPS (1μg/ml). Our data demonstrated that TQ effectively decreased activated T-HSC/Cl-6 cell viability. TQ significantly attenuated the expression of CD14 and Toll-like receptor 4 (TLR4). TQ also significantly inhibited phosphatidylinositol 3-kinase (PI3K) and serine/threonine kinase-protein kinase B (Akt) phosphorylation. The expression of α-SMA and collagen-I were significantly decreased by TQ. Furthermore, TQ decreased X linked inhibitor of apoptosis (XIAP) and cellular FLIP (c-FLIPL) expression, which are related with the regulation of apoptosis. Furthermore, TQ significantly increased the survival against LPS challenge in d-galactosamine (d-GlaN)-sensitized mice, and decreased the levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which were in line with in vitro results. Our data demonstrated that TQ attenuates liver fibrosis partially via blocking TLR4 expression and PI3K phosphorylation on the activated HSCs. Therefore, TQ may be a potential candidate for the therapy of hepatic fibrosis.

  11. Induction of xanthine oxidase activity, endoplasmic reticulum stress and caspase activation by sodium metabisulfite in rat liver and their attenuation by Ghrelin.

    PubMed

    Ercan, Sevim; Kencebay, Ceren; Basaranlar, Goksun; Derin, Narin; Aslan, Mutay

    2015-02-01

    Sodium metabisulfite is used as a preservative in many food preparations but can oxidize to sulfite radicals initiating molecular oxidation. Ghrelin is a peptide hormone primarily produced in the stomach and has anti-inflammatory and anti-oxidant effects on gastrointestinal and cardiovascular systems. This study was performed to elucidate the effect of ghrelin on sulfite-induced endoplasmic reticulum (ER) stress and caspase activation in rat peripheral organs. Xanthine oxidase (XO), xanthine dehydrogenase (XDH) enzyme activities, ER stress markers [phosphorylated PKR-like ER kinase (pPERK); C/EBP-homologous protein (CHOP)], caspase-3, -8, -9 activities, nuclear factor kappa-B (NF-κB) levels were determined in liver, heart and kidney of rats treated with sodium metabisulfite and/or ghrelin for 5 weeks. Sodium metabisulfite treatment significantly elevated XO activity, induced expression of GRP78, CHOP and increased caspase-3, -8 and -9 activities in liver but had no significant effect in heart and kidney. Ghrelin treatment decreased XO activity to baseline levels and attenuated ER stress and caspase activation in liver tissue of sodium metabisulfite treated rats. In conclusion, metabolism of sodium metabisulfite in liver tissue increased XO activity, induced ER stress and caused caspase activation which was attenuated by ghrelin treatment. Ghrelin's hepatoprotective effect could be through modulation of XO activity. PMID:25486021

  12. Induction of xanthine oxidase activity, endoplasmic reticulum stress and caspase activation by sodium metabisulfite in rat liver and their attenuation by Ghrelin.

    PubMed

    Ercan, Sevim; Kencebay, Ceren; Basaranlar, Goksun; Derin, Narin; Aslan, Mutay

    2015-02-01

    Sodium metabisulfite is used as a preservative in many food preparations but can oxidize to sulfite radicals initiating molecular oxidation. Ghrelin is a peptide hormone primarily produced in the stomach and has anti-inflammatory and anti-oxidant effects on gastrointestinal and cardiovascular systems. This study was performed to elucidate the effect of ghrelin on sulfite-induced endoplasmic reticulum (ER) stress and caspase activation in rat peripheral organs. Xanthine oxidase (XO), xanthine dehydrogenase (XDH) enzyme activities, ER stress markers [phosphorylated PKR-like ER kinase (pPERK); C/EBP-homologous protein (CHOP)], caspase-3, -8, -9 activities, nuclear factor kappa-B (NF-κB) levels were determined in liver, heart and kidney of rats treated with sodium metabisulfite and/or ghrelin for 5 weeks. Sodium metabisulfite treatment significantly elevated XO activity, induced expression of GRP78, CHOP and increased caspase-3, -8 and -9 activities in liver but had no significant effect in heart and kidney. Ghrelin treatment decreased XO activity to baseline levels and attenuated ER stress and caspase activation in liver tissue of sodium metabisulfite treated rats. In conclusion, metabolism of sodium metabisulfite in liver tissue increased XO activity, induced ER stress and caused caspase activation which was attenuated by ghrelin treatment. Ghrelin's hepatoprotective effect could be through modulation of XO activity.

  13. Myricitrin Attenuates High Glucose-Induced Apoptosis through Activating Akt-Nrf2 Signaling in H9c2 Cardiomyocytes.

    PubMed

    Zhang, Bin; Chen, Yaping; Shen, Qiang; Liu, Guiyan; Ye, Jingxue; Sun, Guibo; Sun, Xiaobo

    2016-01-01

    Hyperglycemia, as well as diabetes mellitus, has been shown to trigger cardiac cell apoptosis. We have previously demonstrated that myricitrin prevents endothelial cell apoptosis. However, whether myricitrin can attenuate H9c2 cell apoptosis remains unknown. In this study, we established an experiment model in H9c2 cells exposed to high glucose. We tested the hypothesis that myricitrin may inhibit high glucose (HG)-induced cardiac cell apoptosis as determined by TUNEL staining. Furthermore, myricitrin promoted antioxidative enzyme production, suppressed high glucose-induced reactive oxygen species (ROS) production and decreased mitochondrial membrane potential (MMP) in H9c2 cells. This agent significantly inhibited apoptotic protein expression, activated Akt and facilitated the transcription of NF-E2-related factor 2 (Nrf2)-mediated protein (heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO-1) expression as determined by Western blotting. Significantly, an Akt inhibitor (LY294002) or HO-1 inhibitor (ZnPP) not only inhibited myricitrin-induced HO-1/NQO-1 upregulation but also alleviated its anti-apoptotic effects. In summary, these observations demonstrate that myricitrin activates Nrf2-mediated anti-oxidant signaling and attenuates H9c2 cell apoptosis induced by high glucose via activation of Akt signaling. PMID:27399653

  14. Targeting Attenuated Interferon-α to Myeloma Cells with a CD38 Antibody Induces Potent Tumor Regression with Reduced Off-Target Activity.

    PubMed

    Pogue, Sarah L; Taura, Tetsuya; Bi, Mingying; Yun, Yong; Sho, Angela; Mikesell, Glen; Behrens, Collette; Sokolovsky, Maya; Hallak, Hussein; Rosenstock, Moti; Sanchez, Eric; Chen, Haiming; Berenson, James; Doyle, Anthony; Nock, Steffen; Wilson, David S

    2016-01-01

    Interferon-α (IFNα) has been prescribed to effectively treat multiple myeloma (MM) and other malignancies for decades. Its use has waned in recent years, however, due to significant toxicity and a narrow therapeutic index (TI). We sought to improve IFNα's TI by, first, attaching it to an anti-CD38 antibody, thereby directly targeting it to MM cells, and, second, by introducing an attenuating mutation into the IFNα portion of the fusion protein rendering it relatively inactive on normal, CD38 negative cells. This anti-CD38-IFNα(attenuated) immunocytokine, or CD38-Attenukine™, exhibits 10,000-fold increased specificity for CD38 positive cells in vitro compared to native IFNα and, significantly, is ~6,000-fold less toxic to normal bone marrow cells in vitro than native IFNα. Moreover, the attenuating mutation significantly decreases IFNα biomarker activity in cynomolgus macaques indicating that this approach may yield a better safety profile in humans than native IFNα or a non-attenuated IFNα immunocytokine. In human xenograft MM tumor models, anti-CD38-IFNα(attenuated) exerts potent anti-tumor activity in mice, inducing complete tumor regression in most cases. Furthermore, anti-CD38-IFNα(attenuated) is more efficacious than standard MM treatments (lenalidomide, bortezomib, dexamethasone) and exhibits strong synergy with lenalidomide and with bortezomib in xenograft models. Our findings suggest that tumor-targeted attenuated cytokines such as IFNα can promote robust tumor killing while minimizing systemic toxicity. PMID:27611189

  15. Targeting Attenuated Interferon-α to Myeloma Cells with a CD38 Antibody Induces Potent Tumor Regression with Reduced Off-Target Activity

    PubMed Central

    Pogue, Sarah L.; Taura, Tetsuya; Bi, Mingying; Yun, Yong; Sho, Angela; Mikesell, Glen; Behrens, Collette; Sokolovsky, Maya; Hallak, Hussein; Rosenstock, Moti; Sanchez, Eric; Chen, Haiming; Berenson, James; Doyle, Anthony; Nock, Steffen; Wilson, David S.

    2016-01-01

    Interferon-α (IFNα) has been prescribed to effectively treat multiple myeloma (MM) and other malignancies for decades. Its use has waned in recent years, however, due to significant toxicity and a narrow therapeutic index (TI). We sought to improve IFNα’s TI by, first, attaching it to an anti-CD38 antibody, thereby directly targeting it to MM cells, and, second, by introducing an attenuating mutation into the IFNα portion of the fusion protein rendering it relatively inactive on normal, CD38 negative cells. This anti-CD38-IFNα(attenuated) immunocytokine, or CD38-Attenukine™, exhibits 10,000-fold increased specificity for CD38 positive cells in vitro compared to native IFNα and, significantly, is ~6,000-fold less toxic to normal bone marrow cells in vitro than native IFNα. Moreover, the attenuating mutation significantly decreases IFNα biomarker activity in cynomolgus macaques indicating that this approach may yield a better safety profile in humans than native IFNα or a non-attenuated IFNα immunocytokine. In human xenograft MM tumor models, anti-CD38-IFNα(attenuated) exerts potent anti-tumor activity in mice, inducing complete tumor regression in most cases. Furthermore, anti-CD38-IFNα(attenuated) is more efficacious than standard MM treatments (lenalidomide, bortezomib, dexamethasone) and exhibits strong synergy with lenalidomide and with bortezomib in xenograft models. Our findings suggest that tumor-targeted attenuated cytokines such as IFNα can promote robust tumor killing while minimizing systemic toxicity. PMID:27611189

  16. Activation of PPARγ is required for hydroxysafflor yellow A of Carthamus tinctorius to attenuate hepatic fibrosis induced by oxidative stress.

    PubMed

    Wang, C Y; Liu, Q; Huang, Q X; Liu, J T; He, Y H; Lu, J J; Bai, X Y

    2013-05-15

    Oxidative stress caused hepatic fibrosis by activating hepatic stellate cells (HSCs), which were implemented by depressing PPARγ activation. Hydroxysafflor yellow A (HSYA) as a nature active ingredient with antioxidant capacity was able to effectively attenuate oxidative stress mediated injury. So it will be very interesting to study effect of HSYA on HSCs activation and liver fibrosis, and reveal the role of PPARγ·CCl4 and H2O2 were used to mimic oxidative stress mediated hepatic injury in vitro and in vivo respectively. The anti-fibrosis effects of HSYA were evaluated and its mechanisms were disclosed by applying western blot, histopathological analysis, flow cytometry, RT-PCR and ELISA. Our results showed that HSCs activation and proliferation could be induced by oxidative stress, and the expressive levels of TGF-β1 and TIMP-1, the serum levels of ALT, AST, HA, LN, III-C and IV-C were also enhanced by oxidative stress, which is correlated with liver fibrosis (p<0.05 or p<0.01). HSYA was able to effectively inhibit oxidative stress mediated hepatic injury by increasing the activities of antioxidant enzymes, up regulating the expression of PPARγ and MMP-2, and down regulating the expression of TGF-β1 and TIMP-1, and reducing α-SMA level. The protective effect of HSYA can be significantly attenuated by GW9662 via blocking PPARγ (p<0.05 or p<0.01). Taken together, these results demonstrate that HSYA is able to significantly protect the liver from oxidative stress, which requires for HSYA to stimulate PPARγ activity, reduce cell proliferation and suppress ECM synthesis.

  17. Sirtuin 7 promotes cellular survival following genomic stress by attenuation of DNA damage, SAPK activation and p53 response

    SciTech Connect

    Kiran, Shashi; Oddi, Vineesha; Ramakrishna, Gayatri

    2015-02-01

    Maintaining the genomic integrity is a constant challenge in proliferating cells. Amongst various proteins involved in this process, Sirtuins play a key role in DNA damage repair mechanisms in yeast as well as mammals. In the present work we report the role of one of the least explored Sirtuin viz., SIRT7, under conditions of genomic stress when treated with doxorubicin. Knockdown of SIRT7 sensitized osteosarcoma (U2OS) cells to DNA damage induced cell death by doxorubicin. SIRT7 overexpression in NIH3T3 delayed cell cycle progression by causing delay in G1 to S transition. SIRT7 overexpressing cells when treated with low dose of doxorubicin (0.25 µM) showed delayed onset of senescence, lesser accumulation of DNA damage marker γH2AX and lowered levels of growth arrest markers viz., p53 and p21 when compared to doxorubicin treated control GFP expressing cells. Resistance to DNA damage following SIRT7 overexpression was also evident by EdU incorporation studies where cellular growth arrest was significantly delayed. When treated with higher dose of doxorubicin (>1 µM), SIRT7 conferred resistance to apoptosis by attenuating stress activated kinases (SAPK viz., p38 and JNK) and p53 response thereby shifting the cellular fate towards senescence. Interestingly, relocalization of SIRT7 from nucleolus to nucleoplasm together with its co-localization with SAPK was an important feature associated with DNA damage. SIRT7 mediated resistance to doxorubicin induced apoptosis and senescence was lost when p53 level was restored by nutlin treatment. Overall, we propose SIRT7 attenuates DNA damage, SAPK activation and p53 response thereby promoting cellular survival under conditions of genomic stress. - Highlights: • Knockdown of SIRT7 sensitized cells to DNA damage induced apoptosis. • SIRT7 delayed onset of premature senescence by attenuating DNA damage response. • Overexpression of SIRT7 delayed cell cycle progression by delaying G1/S transition. • Upon DNA damage SIRT

  18. Intravenous multipotent adult progenitor cell therapy attenuates activated microglial/macrophage response and improves spatial learning after traumatic brain injury.

    PubMed

    Bedi, Supinder S; Hetz, Robert; Thomas, Chelsea; Smith, Philippa; Olsen, Alex B; Williams, Stephen; Xue, Hasen; Aroom, Kevin; Uray, Karen; Hamilton, Jason; Mays, Robert W; Cox, Charles S

    2013-12-01

    We previously demonstrated that the intravenous delivery of multipotent adult progenitor cells (MAPCs) after traumatic brain injury (TBI) in rodents provides neuroprotection by preserving the blood-brain barrier and systemically attenuating inflammation in the acute time frame following cell treatment; however, the long-term behavioral and anti-inflammatory effects of MAPC administration after TBI have yet to be explored. We hypothesized that the intravenous injection of MAPCs after TBI attenuates the inflammatory response (as measured by microglial morphology) and improves performance at motor tasks and spatial learning (Morris water maze [MWM]). MAPCs were administered intravenously 2 and 24 hours after a cortical contusion injury (CCI). We tested four groups at 120 days after TBI: sham (uninjured), injured but not treated (CCI), and injured and treated with one of two concentrations of MAPCs, either 2 million cells per kilogram (CCI-2) or 10 million cells per kilogram (CCI-10). CCI-10 rats showed significant improvement in left hind limb deficit on the balance beam. On the fifth day of MWM trials, CCI-10 animals showed a significant decrease in both latency to platform and distance traveled compared with CCI. Probe trials revealed a significant decrease in proximity measure in CCI-10 compared with CCI, suggesting improved memory retrieval. Neuroinflammation was quantified by enumerating activated microglia in the ipsilateral hippocampus. We observed a significant decrease in the number of activated microglia in the dentate gyrus in CCI-10 compared with CCI. Our results demonstrate that intravenous MAPC treatment after TBI in a rodent model offers long-term improvements in spatial learning as well as attenuation of neuroinflammation.

  19. NOTE: Localization of sentinel nodes in breast cancer: novel method and device to help pen marking of active nodes during gamma camera imaging

    NASA Astrophysics Data System (ADS)

    Laasanen, Mikko S.; Heikkinen, Jari O.; Saarakkala, Simo; Paajanen, Hannu

    2005-04-01

    Gamma camera imaging with Tc-99m marking is a widely used method to locate sentinel lymph nodes (SNs) in breast cancer patients. Prior to SN biopsy, the anterior and lateral location of the SN is marked on the patient's skin using an ink pen. The pen marks guide the surgeon during an operation. However, in many cases the marking is difficult due to limited space under the detectors of a gamma camera. The aim of this study was to improve the pen marking method. Eleven female patients were imaged 3 4 h after injection of Tc-99m labelled Nanocol©. Injection was performed to parenchyma surrounding the breast tumour. To facilitate pen marking, two polycarbonate (PC) plates with 40 × 32 holes (spacing = 10 mm) were engineered for anterior and lateral side imaging and then installed on the bed of a dual-head gamma camera. Two drops of Tc-99m were placed into the top corners of both the PC plates, in order to trace the corresponding x y coordinates first from the acquired images and then from the plates. After imaging, the x y coordinates of the SN(s) were determined from the anterior and lateral side images. Subsequently, the location of each SN was marked with an ink pen on the skin through the small holes in the PC plates. According to the surgeon's evaluation, the distance between the marks and the true location of the SNs was 4.5 ± 6.9 mm. Measurements with a custom made phantom revealed that the accuracy of the novel method was significantly (P = 0.06) higher as compared with the traditional method (2.7 ± 3.0 mm versus 9.2 ± 3.0 mm). In addition, we were not able to mark the weakest activity (0.02 MBq) with the traditional method. Taken together, the marking process was considerably easier with the novel method, it had better accuracy and sensitivity than the traditional method and the device is simple enough to be adapted for most gamma cameras.

  20. Inhibition of p300 histone acetyltransferase activity in palate mesenchyme cells attenuates Wnt signaling via aberrant E-cadherin expression.

    PubMed

    Warner, Dennis R; Smith, Scott C; Smolenkova, Irina A; Pisano, M Michele; Greene, Robert M

    2016-03-01

    p300 is a multifunctional transcriptional coactivator that interacts with numerous transcription factors and exhibits protein/histone acetyltransferase activity. Loss of p300 function in humans and in mice leads to craniofacial defects. In this study, we demonstrated that inhibition of p300 histone acetyltransferase activity with the compound, C646, altered the expression of several genes, including Cdh1 (E-cadherin) in mouse maxillary mesenchyme cells, which are the cells that give rise to the secondary palate. The increased expression of plasma membrane-bound E-cadherin was associated with reduced cytosolic β-catenin, that led to attenuated signaling through the canonical Wnt pathway. Furthermore, C646 reduced both cell proliferation and the migratory ability of these cells. These results suggest that p300 histone acetyltransferase activity is critical for Wnt-dependent palate mesenchymal cell proliferation and migration, both processes that play a significant role in morphogenesis of the palate.

  1. Inorganic nitrite attenuates NADPH oxidase-derived superoxide generation in activated macrophages via a nitric oxide-dependent mechanism.

    PubMed

    Yang, Ting; Peleli, Maria; Zollbrecht, Christa; Giulietti, Alessia; Terrando, Niccolo; Lundberg, Jon O; Weitzberg, Eddie; Carlström, Mattias

    2015-06-01

    Oxidative stress contributes to the pathogenesis of many disorders, including diabetes and cardiovascular disease. Immune cells are major sources of superoxide (O2(∙-)) as part of the innate host defense system, but exaggerated and sustained O2(∙-) generation may lead to progressive inflammation and organ injuries. Previous studies have proven organ-protective effects of inorganic nitrite, a precursor of nitric oxide (NO), in conditions manifested by oxidative stress and inflammation. However, the mechanisms are still not clear. This study aimed at investigating the potential role of nitrite in modulating NADPH oxidase (NOX) activity in immune cells. Mice peritoneal macrophages or human monocytes were activated by lipopolysaccharide (LPS), with or without coincubation with nitrite. O2(∙-) and peroxynitrite (ONOO(-)) formation were detected by lucigenin-based chemiluminescence and fluorescence techniques, respectively. The intracellular NO production was measured by DAF-FM DA fluorescence. NOX isoforms and inducible NO synthase (iNOS) expression were detected by qPCR. LPS increased both O2(∙-) and ONOO(-) production in macrophages, which was significantly reduced by nitrite (10µmol/L). Mechanistically, the effects of nitrite are (1) linked to increased NO generation, (2) similar to that observed with the NO donor DETA-NONOate, and (3) can be abolished by the NO scavenger carboxy-PTIO or by the xanthine oxidase (XO) inhibitor febuxostat. Nox2 expression was increased in activated macrophages, but was not influenced by nitrite. However, nitrite attenuated LPS-induced upregulation of iNOS expression. Similar to that observed in mice macrophages, nitrite also reduced O2(∙-) generation in LPS-activated human monocytes. In conclusion, XO-mediated reduction of nitrite attenuates NOX activity in activated macrophages, which may modulate the inflammatory response. PMID:25724690

  2. Biomass conversion inhibitors furfural and 5-hydroxymethylfurfural induce formation of messenger RNP granules and attenuate translation activity in Saccharomyces cerevisiae.

    PubMed

    Iwaki, Aya; Kawai, Takao; Yamamoto, Yosuke; Izawa, Shingo

    2013-03-01

    Various forms of stress can cause an attenuation of bulk translation activity and the accumulation of nontranslating mRNAs into cytoplasmic messenger RNP (mRNP) granules termed processing bodies (P-bodies) and stress granules (SGs) in eukaryotic cells. Furfural and 5-hydroxymethylfurfural (HMF), derived from lignocellulosic biomass, inhibit yeast growth and fermentation as stressors. Since there is no report regarding their effects on the formation of cytoplasmic mRNP granules, here we investigated whether furfural and HMF cause the assembly of yeast P-bodies and SGs accompanied by translational repression. We found that furfural and HMF cause the attenuation of bulk translation activity and the assembly of cytoplasmic mRNP granules in Saccharomyces cerevisiae. Notably, a combination of furfural and HMF induced the remarkable repression of translation initiation and SG formation. These findings provide new information about the physiological effects of furfural and HMF on yeast cells, and also suggest the potential usefulness of cytoplasmic mRNP granules as a warning sign or index of the deterioration of cellular physiological status in the fermentation of lignocellulosic hydrolysates.

  3. Curcumin Attenuated Bupivacaine-Induced Neurotoxicity in SH-SY5Y Cells Via Activation of the Akt Signaling Pathway.

    PubMed

    Fan, You-Ling; Li, Heng-Chang; Zhao, Wei; Peng, Hui-Hua; Huang, Fang; Jiang, Wei-Hang; Xu, Shi-Yuan

    2016-09-01

    Bupivacaine is widely used for regional anesthesia, spinal anesthesia, and pain management. However, bupivacaine could cause neuronal injury. Curcumin, a low molecular weight polyphenol, has a variety of bioactivities and may exert neuroprotective effects against damage induced by some stimuli. In the present study, we tested whether curcumin could attenuate bupivacaine-induced neurotoxicity in SH-SY5Y cells. Cell injury was evaluated by examining cell viability, mitochondrial damage and apoptosis. We also investigated the levels of activation of the Akt signaling pathway and the effect of Akt inhibition by triciribine on cell injury following bupivacaine and curcumin treatment. Our findings showed that the bupivacaine treatment could induce neurotoxicity. Pretreatment of the SH-SY5Y cells with curcumin significantly attenuated bupivacaine-induced neurotoxicity. Interestingly, the curcumin treatment increased the levels of Akt phosphorylation. More significantly, the pharmacological inhibition of Akt abolished the cytoprotective effect of curcumin against bupivacaine-induced cell injury. Our data suggest that pretreating SH-SY5Y cells with curcumin provides a protective effect on bupivacaine-induced neuronal injury via activation of the Akt signaling pathway.

  4. Bioturbation delays attenuation of DDT by clean sediment cap but promotes sequestration by thin-layered activated carbon.

    PubMed

    Lin, Diana; Cho, Yeo-Myoung; Werner, David; Luthy, Richard G

    2014-01-21

    The effects of bioturbation on the performance of attenuation by sediment deposition and activated carbon to reduce risks from DDT-contaminated sediment were assessed for DDT sediment-water flux, biouptake, and passive sampler (PE) uptake in microcosm experiments with a freshwater worm, Lumbriculus variegatus. A thin-layer of clean sediment (0.5 cm) did not reduce the DDT flux when bioturbation was present, while a thin (0.3 cm) AC cap was still capable of reducing the DDT flux by 94%. Bioturbation promoted AC sequestration by reducing the 28-day DDT biouptake (66%) and DDT uptake into PE (>99%) compared to controls. Bioturbation further promoted AC-sediment contact by mixing AC particles into underlying sediment layers, reducing PE uptake (55%) in sediment compared to the AC cap without bioturbation. To account for the observed effects from bioturbation, a mass transfer model together with a biodynamic model were developed to simulate DDT flux and biouptake, respectively, and models confirmed experimental results. Both experimental measurements and modeling predictions imply that thin-layer activated carbon placement on sediment is effective in reducing the risks from contaminated sediments in the presence of bioturbation, while natural attenuation process by clean sediment deposition may be delayed by bioturbation.

  5. Direct optical activation of skeletal muscle fibres efficiently controls muscle contraction and attenuates denervation atrophy.

    PubMed

    Magown, Philippe; Shettar, Basavaraj; Zhang, Ying; Rafuse, Victor F

    2015-10-13

    Neural prostheses can restore meaningful function to paralysed muscles by electrically stimulating innervating motor axons, but fail when muscles are completely denervated, as seen in amyotrophic lateral sclerosis, or after a peripheral nerve or spinal cord injury. Here we show that channelrhodopsin-2 is expressed within the sarcolemma and T-tubules of skeletal muscle fibres in transgenic mice. This expression pattern allows for optical control of muscle contraction with comparable forces to nerve stimulation. Force can be controlled by varying light pulse intensity, duration or frequency. Light-stimulated muscle fibres depolarize proportionally to light intensity and duration. Denervated triceps surae muscles transcutaneously stimulated optically on a daily basis for 10 days show a significant attenuation in atrophy resulting in significantly greater contractile forces compared with chronically denervated muscles. Together, this study shows that channelrhodopsin-2/H134R can be used to restore function to permanently denervated muscles and reduce pathophysiological changes associated with denervation pathologies.

  6. Direct optical activation of skeletal muscle fibres efficiently controls muscle contraction and attenuates denervation atrophy

    PubMed Central

    Magown, Philippe; Shettar, Basavaraj; Zhang, Ying; Rafuse, Victor F.

    2015-01-01

    Neural prostheses can restore meaningful function to paralysed muscles by electrically stimulating innervating motor axons, but fail when muscles are completely denervated, as seen in amyotrophic lateral sclerosis, or after a peripheral nerve or spinal cord injury. Here we show that channelrhodopsin-2 is expressed within the sarcolemma and T-tubules of skeletal muscle fibres in transgenic mice. This expression pattern allows for optical control of muscle contraction with comparable forces to nerve stimulation. Force can be controlled by varying light pulse intensity, duration or frequency. Light-stimulated muscle fibres depolarize proportionally to light intensity and duration. Denervated triceps surae muscles transcutaneously stimulated optically on a daily basis for 10 days show a significant attenuation in atrophy resulting in significantly greater contractile forces compared with chronically denervated muscles. Together, this study shows that channelrhodopsin-2/H134R can be used to restore function to permanently denervated muscles and reduce pathophysiological changes associated with denervation pathologies. PMID:26460719

  7. Restoration of Akt activity by the bisperoxovanadium compound bpV(pic) attenuates hippocampal apoptosis in experimental neonatal pneumococcal meningitis.

    PubMed

    Sury, Matthias D; Vorlet-Fawer, Lorianne; Agarinis, Claudia; Yousefi, Shida; Grandgirard, Denis; Leib, Stephen L; Christen, Stephan

    2011-01-01

    Pneumococcal meningitis causes apoptosis of developing neurons in the dentate gyrus of the hippocampus. The death of these cells is accompanied with long-term learning and memory deficits in meningitis survivors. Here, we studied the role of the PI3K/Akt (protein kinase B) survival pathway in hippocampal apoptosis in a well-characterized infant rat model of pneumococcal meningitis. Meningitis was accompanied by a significant decrease of the PI3K product phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) and of phosphorylated (i.e., activated) Akt in the hippocampus. At the cellular level, phosphorylated Akt was decreased in both the granular layer and the subgranular zone of the dentate gyrus, the region where the developing neurons undergo apoptosis. Protein levels and activity of PTEN, the major antagonist of PI3K, were unaltered by infection, suggesting that the observed decrease in PIP(3) and Akt phosphorylation is a result of decreased PI3K signaling. Treatment with the PTEN inhibitor bpV(pic) restored Akt activity and significantly attenuated hippocampal apoptosis. Co-treatment with the specific PI3K inhibitor LY294002 reversed the restoration of Akt activity and attenuation of hippocampal apoptosis, while it had no significant effect on these parameters on its own. These results indicate that the inhibitory effect of bpV(pic) on apoptosis was mediated by PI3K-dependent activation of Akt, strongly suggesting that bpV(pic) acted on PTEN. Treatment with bpV(pic) also partially inhibited the concentration of bacteria and cytokines in the CSF, but this effect was not reversed by LY294002, indicating that the effect of bpV(pic) on apoptosis was independent of its effect on CSF bacterial burden and cytokine levels. These results indicate that the PI3K/Akt pathway plays an important role in the death and survival of developing hippocampal neurons during the acute phase of pneumococcal meningitis.

  8. Fluorofenidone attenuates TGF-β1-induced lung fibroblast activation via restoring the expression of caveolin-1.

    PubMed

    Liu, Jingjing; Song, Cheng; Xiao, Qiming; Hu, Gaoyun; Tao, Lijian; Meng, Jie

    2015-02-01

    Caveolin-1 plays an important role in the pathogenesis of idiopathic pulmonary fibrosis. We previously showed that fluorofenidone (FD), a novel pyridine agent, can attenuate bleomycin-induced experimental pulmonary fibrosis and restore the production of caveolin-1. In this study, we explore mainly whether caveolin-1 plays a critical role in the anti-pulmonary fibrosis effects of FD in vitro. The normal human lung fibroblasts (NHLFs) were cultured with transforming growth factor-β1 (TGF-β1) and then were treated with FD. Subsequently, NHLFs transfected with cav-1-siRNA were treated with TGF-β1 and/or FD. The expressions of α-smooth muscle actin (α-SMA), fibronectin, collagen I, caveolin-1, phosphorylated extracellular signal-regulated kinase (p-ERK), phosphorylated c-Jun N-terminal kinase (p-JNK), and phosphorylated P38 were measured by Western blot and/or real-time polymerase chain reaction. Fluorofenidone attenuated TGF-β1-induced expressions of α-SMA, fibronectin, and collagen I; inhibited phosphorylation of ERK, JNK, and P38; and restored caveolin-1 protein expression but cannot increase caveolin-1 mRNA level in vitro. After caveolin-1 was silenced, FD could not downregulate TGF-β1-induced expressions of α-SMA, fibronectin, and collagen I or phosphorylation of ERK, JNK, and P38. These studies demonstrate that FD, a potential antifibrotic agent, may attenuate TGF-β1-induced activation of NHLFs by restoring the expression of caveolin-1.

  9. Macrophages as effector cells of protective immunity in murine schistosomiasis: macrophage activation in mice vaccinated with radiation-attenuated cercariae.

    PubMed Central

    James, S L; Natovitz, P C; Farrar, W L; Leonard, E J

    1984-01-01

    Cell-mediated immune responses contributing to macrophage activation were compared in mice that demonstrated partial resistance to challenge Schistosoma mansoni infection as a result of vaccination with radiation-attenuated cercariae or of ongoing low-grade primary infection. Vaccinated mice developed significant delayed hypersensitivity reactions to soluble schistosome antigens in vivo. Splenocytes from vaccinated animals responded to in vitro culture with various specific antigens (soluble adult worm extract, living or disrupted schistosomula) by proliferation and production of macrophage-activating lymphokines as did lymphocytes from S. mansoni-infected animals. Macrophage-activating factors produced by spleen cells from vaccinated mice upon specific antigen stimulation eluted as a single peak on Sephadex G-100 with a molecular weight of approximately 50,000 and contained gamma interferon activity. Moreover, peritoneal macrophages with larvicidal and tumoricidal activity were recovered from vaccinated mice after intraperitoneal challenge with soluble schistosome antigens, a procedure also observed to elicit activated macrophages in S. mansoni-infected animals. These observations demonstrate that vaccination with irradiated cercariae stimulates many of the same cellular responses observed after primary S. mansoni infection, and suggest that lymphokine-activated macrophages may participate in the effector mechanism of vaccine-induced and concomitant immunity to challenge schistosome infection. This is the first demonstration of a potential immune effector mechanism in the irradiated vaccine model. PMID:6609885

  10. Lack of Hypocretin Attenuates Behavioral Changes Produced by Glutamatergic Activation of the Perifornical-Lateral Hypothalamic Area

    PubMed Central

    Kostin, Andrey; Siegel, Jerome M.; Alam, Md. Noor

    2014-01-01

    Study Objectives: The hypocretins (HCRTs) are two hypothalamic peptides predominantly localized to neurons in the perifornical, dorsomedial, and lateral hypothalamic area (PF-LHA). Evidence suggests that HCRT signaling is critical for the promotion and stabilization of active-arousal and its loss or malfunction leads to symptoms of narcolepsy. In the PF-LHA, HCRT neurons are intermingled with glutamate-expressing neurons and also co-express glutamate. Evidence suggests that HCRT-glutamate interactions within the PF-LHA may play a critical role in maintaining behavioral arousal. However, the relative contributions of the glutamate and HCRT in sleep-wake regulation are not known. Design: We determined whether a lack of HCRT signaling in the prepro-orexin-knockout (HCRT-KO) mouse attenuates/compromises the wake-promoting ability of glutamatergic activation of the PF-LHA region. We used reverse microdialysis to deliver N-methyl-D-aspartate (NMDA) into the HCRT zone of the PF-LHA in HCRT-KO and wild-type (WT) mice to evaluate the contributions of glutamatergic vs. HCRT signaling in sleep-wake regulation. Measurements and Results: As compared to respective controls, local perfusion of NMDA into the PF-LHA, dose-dependently increased active-waking with concomitant reductions in nonREM and REM sleep in spontaneously sleeping WT as well as HCRT-KO mice. However, compared to WT, the NMDA-induced behavioral changes in HCRT-KO mice were significantly attenuated, as evidenced by the higher dose of NMDA needed and lower magnitude of changes induced in sleep-wake parameters. Although not observed in WT mice, the number of cataplectic events increased significantly during NMDA-induced behavioral arousal in HCRT-KO mice. Conclusions: The findings of this study are consistent with a hypothesis that synergistic interactions between hypocretin and glutamatergic mechanisms within the perifornical, dorsomedial, and lateral hypothalamic area are critical for maintaining behavioral

  11. Immobilized nickel hexacyanoferrate on activated carbons for efficient attenuation of radio toxic Cs(I) from aqueous solutions

    NASA Astrophysics Data System (ADS)

    Lalhmunsiama; Lalhriatpuia, C.; Tiwari, Diwakar; Lee, Seung-Mok

    2014-12-01

    The aim of this study is to immobilize nickel hexacyanoferrate onto the large surface of activated carbons (ACs) precursor to rice hulls and areca nut waste materials. These nickel hexacyanoferrate immobilized materials are then assessed in the effective attenuation of radio logically important cesium ions from aqueous solutions. The solid samples are characterized by the XRD analytical method and surface morphology is obtained from the SEM images. The batch reactor experiments show that an increase in sorptive pH (2.0-10.0) apparently not affecting the high percent uptake of Cs(I). Equilibrium modeling studies suggest that the data are reasonably and relatively fitted well to the Langmuir adsorption isotherm. Kinetic studies show that sorption process is fairly rapid and the kinetic data are fitted well to the pseudo-second order rate model. Increasing the background electrolyte concentration from 0.001 to 0.1 mol/L NaCl causes insignificant decrease in Cs(I) removal which infers the higher selectivity of these materials for Cs(I) from aqueous solutions. Further, the column reactor operations enable to obtain the breakthrough data which are then fitted to the Thomas non-linear equation as to obtain the loading capacity of column for Cs(I). The results show that the modified materials show potential applicability in the attenuation of radio toxic cesium from aqueous solution.

  12. Propensity of activated sludge to amplify or attenuate tetracycline resistance genes and tetracycline resistant bacteria: a mathematical modeling approach.

    PubMed

    Kim, Sungpyo; Park, Hongkeun; Chandran, Kartik

    2010-02-01

    The overall goal of this study was to quantify the propensity of the activated sludge (AS) process at three wastewater treatment plants (WWTP) to amplify or attenuate tetracycline resistant bacteria (TRB) and tetracycline resistance genes (TRG). Accordingly, the abundance and fraction of TRB and seven TRG in different unit operations of these WWTP were analytically measured and modeled using a mass balance approach widely used for AS design. Based on the model, the AS process of the different WWTP neither amplified nor attenuated the TRB and TRG fractions. Of the TRG tested, the ribosomal protection genes, tet(O) and tet(W) were the most abundant, along the treatment train of the WWTP, on all sampling dates and sampling locations. Significant amounts of TRB and TRG were discharged in the effluent streams. Notably, in selected samples, the fraction of TRB increased in response to ultraviolet disinfection of treated wastewater compared to chlorination. This study therefore implicates wastewater treatment processes as significant point sources of tetracycline resistance determinants to the environment, and provides a mathematical basis to compute the production capacity of these determinants in the AS process.

  13. UCR1C is a novel activator of phosphodiesterase 4 (PDE4) long isoforms and attenuates cardiomyocyte hypertrophy

    PubMed Central

    Wang, Li; Burmeister, Brian T.; Johnson, Keven R.; Baillie, George S.; Karginov, Andrei V.; Skidgel, Randal A.; O’Bryan, John P.; Carnegie, Graeme K.

    2015-01-01

    Hypertrophy increases the risk of heart failure and arrhythmia. Prevention or reversal of the maladaptive hypertrophic phenotype has thus been proposed to treat heart failure. Chronic β-adrenergic receptor (β-AR) stimulation induces cardiomyocyte hypertrophy by elevating 3′, 5′-cyclic adenosine monophosphate (cAMP) levels and activating downstream effectors such protein kinase A (PKA). Conversely, hydrolysis of cAMP by phosphodiesterases (PDEs) spatiotemporally restricts cAMP signaling. Here, we demonstrate that PDE4, but not PDE3, is critical in regulating cardiomyocyte hypertrophy, and may represent a potential target for preventing maladaptive hypertrophy. We identify a sequence within the upstream conserved region 1 of PDE4D, termed UCR1C, as a novel activator of PDE4 long isoforms. UCR1C activates PDE4 in complex with A-Kinase anchoring protein (AKAP)-Lbc resulting in decreased PKA signaling facilitated by AKAP-Lbc. Expression of UCR1C in cardiomyocytes inhibits hypertrophy in response to chronic β-AR stimulation. This effect is partially due to inhibition of nuclear PKA activity, which decreases phosphorylation of the transcription factor cAMP response element-binding protein (CREB). In conclusion, PDE4 activation by UCR1C attenuates cardiomyocyte hypertrophy by specifically inhibiting nuclear PKA activity. PMID:25683917

  14. Attenuation of empennage buffet response through active control of damping using piezoelectric material

    NASA Technical Reports Server (NTRS)

    Heeg, Jennifer; Miller, Jonathan M.; Doggett, Robert V., Jr.

    1993-01-01

    Dynamic response and damping data obtained from buffet studies conducted in a low-speed wind tunnel by using a simple, rigid model attached to spring supports are presented. The two parallel leaf spring supports provided a means for the model to respond in a vertical translation mode, thus simulating response in an elastic first bending mode. Wake-induced buffeting flow was created by placing an airfoil upstream of the model of that the wake of the airfoil impinged on the model. Model response was sensed by a strain gage mounted on one of the springs. The output signal from the strain gage was fed back through a control law implemented on a desktop computer. The processed signals were used to 'actuate' a piezoelectric bending actuator bonded to the other spring in such a way as to add damping as the model responded. The results of this 'proof-of-concept' study show that the piezoelectric actuator was effective in attenuating the wake-induced buffet response over the range of parameters investigated.

  15. Activation of toll like receptor 4 attenuates GABA synthesis and postsynaptic GABA receptor activities in the spinal dorsal horn via releasing interleukin-1 beta.

    PubMed

    Yan, Xisheng; Jiang, Enshe; Weng, Han-Rong

    2015-01-09

    Toll like receptor 4 (TLR4) is an innate immune pattern recognition receptor, expressed predominantly on microglia in the CNS. Activation of spinal TLR4 plays a critical role in the genesis of pathological pain induced by nerve injury, bone cancer, and tissue inflammation. Currently, it remains unknown how synaptic activities in the spinal dorsal horn are regulated by TLR4 receptors. Through recording GABAergic currents in neurons and glial glutamate transporter currents in astrocytes in rodent spinal slices, we determined whether and how TLR4 modulates GABAergic synaptic activities in the superficial spinal dorsal horn. We found that activation of TLR4 by lipopolysaccharide (LPS) reduces GABAergic synaptic activities through both presynaptic and postsynaptic mechanisms. Specifically, LPS causes the release of IL-1β from microglia. IL-1β in turn suppresses GABA receptor activities at the postsynaptic site through activating protein kinase C (PKC) in neurons. GABA synthesis at the presynaptic site is reduced upon activation of TLR4. Glial glutamate transporter activities are suppressed by IL-1β and PKC activation induced by LPS. The suppression of glial glutamate transporter activities leads to a deficiency of glutamine supply, which results in an attenuation of the glutamate-glutamine cycle-dependent GABA synthesis. These findings shed light on understanding synaptic plasticity induced by activation of TLR4 under neuroinflammation and identify GABA receptors, glial glutamate transporters, IL-1β and PKC as therapeutic targets to abrogate abnormal neuronal activities following activation of TLR4 in pathological pain conditions.

  16. Curcumin Attenuates Hydrogen Peroxide-Induced Premature Senescence via the Activation of SIRT1 in Human Umbilical Vein Endothelial Cells.

    PubMed

    Sun, Yueliu; Hu, Xiaorong; Hu, Gangying; Xu, Changwu; Jiang, Hong

    2015-01-01

    Endothelial senescence has been proposed to be involved in endothelial dysfunction and atherogenesis. Curcumin, a natural phenol, possesses antioxidant and anti-inflammatory properties. However, the effect of curcumin on endothelial senescence is unclear. This study explores the effect of curcumin on hydrogen peroxide (H2O2)-induced endothelial premature senescence and the mechanisms involved. Human umbilical vein endothelial cells (HUVECs) were cultured, and premature senescence was induced with 100 µM H2O2. Results showed that pretreatment with curcumin significantly attenuated the H2O2-induced HUVECs' premature senescence, which was evidenced by a decreased percentage of senescence-associated β-galactosidase positive cells, improved cell division and decreased expression of senescence-associated protein p21 (all p<0.05). Pretreatment with curcumin decreased oxidative stress and apoptosis in H2O2-treated HUVECs. Treatment of HUVECs with H2O2 also down-regulated the phosphorylation of endothelial nitric oxide synthase (eNOS), decreased the level of nitric oxide in the culture medium, and inhibited the protein expression and enzymatic activity of silent information regulator 1 (SIRT1), while pretreatment with curcumin partly reversed these effects (all p<0.05). Treatment with curcumin alone enhanced the enzymatic activity of SIRT1, but didn't affect cellular senescence, cell growth or apoptosis compared to the Control. The inhibition of SIRT1 using SIRT1 short interfering RNA (siRNA) could decrease the expression and phosphorylation of eNOS and abrogate the protective effect of curcumin on H2O2-induced premature senescence. These findings suggest that curcumin could attenuate oxidative stress-induced HUVECs' premature senescence via the activation of SIRT1.

  17. Set7 facilitates hepatitis C virus replication via enzymatic activity-dependent attenuation of the IFN-related pathway.

    PubMed

    Han, Tao; Wan, Yushun; Wang, Jun; Zhao, Peng; Yuan, Yue; Wang, Li; She, Yinglong; Broering, Ruth; Lu, Mengji; Ye, Linbai; Zhu, Ying

    2015-03-15

    Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, usually resulting in persistent infection involving hepatic steatosis, cirrhosis, and hepatocellular carcinoma via escape of the host's immune response. Set7 is a lysine-specific methyltransferase that is involved in gene regulation and virus replication. However, the mechanism underlying the immune evasion between HCV and Set7 is not well understood. In this study, we observed that the expression of Set7 in Huh7.5.1 cells was upregulated by HCV infection, and high levels of Set7 expression were also found in the sera, PBMCs, and liver tissue of HCV patients relative to healthy individuals. Further investigation showed that Set7 enhanced HCV replication in an enzymatic activity-dependent manner. Moreover, our data showed that Set7 decreased the expression of virus-induced IFN and IFN-related effectors, such as dsRNA-activated protein kinase and 2',5'-oligoadenylate synthetase. Further investigation suggested that Set7 suppressed the endogenous IFN expression by reducing the nuclear translocation of IFN regulatory factor 3/7 and the p65 subunit of NF-κB and reduced IFN-induced dsRNA-activated protein kinase and 2',5'-oligoadenylate synthetase via attenuation of the phosphorylation of STAT1 and STAT2. Additionally, IFN receptors, including IFNAR1 and IFNAR2, which are located upstream of the JAK/STAT pathway, were reduced by Set7. Taken together, our results reveal that Set7 facilitates HCV replication through the attenuation of IFN signaling pathways and IFN-related effectors.

  18. Pyrroloquinoline quinone (PQQ) inhibits lipopolysaccharide induced inflammation in part via downregulated NF-κB and p38/JNK activation in microglial and attenuates microglia activation in lipopolysaccharide treatment mice.

    PubMed

    Yang, Chongfei; Yu, Lifeng; Kong, Lingbo; Ma, Rui; Zhang, Juliang; Zhu, Qingsheng; Zhu, Jinyu; Hao, Dingjun

    2014-01-01

    Therapeutic strategies designed to inhibit the activation of microglia may lead to significant advancement in the treatment of most neurodegenerative diseases. Pyrroloquinoline quinone (PQQ) is a naturally occurring redox cofactor that acts as an essential nutrient, antioxidant, and has been reported to exert potent immunosuppressive effects. In the present study, the anti-inflammatory effects of PQQ was investigated in LPS treated primary microglia cells. Our observations showed that pretreatment with PQQ significantly inhibited the production of NO and PGE2 and suppressed the expression of pro-inflammatory mediators such as iNOS, COX-2, TNF-a, IL-1b, IL-6, MCP-1 and MIP-1a in LPS treated primary microglia cells. The nuclear translocation of NF-κB and the phosphorylation level of p65, p38 and JNK MAP kinase pathways were also inhibited by PQQ in LPS stimulated primary microglia cells. Further a systemic LPS treatment acute inflammation murine brain model was used to study the suppressive effects of PQQ against neuroinflammation in vivo. Mice treated with PQQ demonstrated marked attenuation of neuroinflammation based on Western blotting and immunohistochemistry analysis of Iba1-against antibody in the brain tissue. Indicated that PQQ protected primary cortical neurons against microglia-mediated neurotoxicity. These results collectively suggested that PQQ might be a promising therapeutic agent for alleviating the progress of neurodegenerative diseases associated with microglia activation.

  19. Pyrroloquinoline Quinone (PQQ) Inhibits Lipopolysaccharide Induced Inflammation in Part via Downregulated NF-κB and p38/JNK Activation in Microglial and Attenuates Microglia Activation in Lipopolysaccharide Treatment Mice

    PubMed Central

    Ma, Rui; Zhang, Juliang; Zhu, Qingsheng; Zhu, Jinyu; Hao, Dingjun

    2014-01-01

    Therapeutic strategies designed to inhibit the activation of microglia may lead to significant advancement in the treatment of most neurodegenerative diseases. Pyrroloquinoline quinone (PQQ) is a naturally occurring redox cofactor that acts as an essential nutrient, antioxidant, and has been reported to exert potent immunosuppressive effects. In the present study, the anti-inflammatory effects of PQQ was investigated in LPS treated primary microglia cells. Our observations showed that pretreatment with PQQ significantly inhibited the production of NO and PGE2 and suppressed the expression of pro-inflammatory mediators such as iNOS, COX-2, TNF-a, IL-1b, IL-6, MCP-1 and MIP-1a in LPS treated primary microglia cells. The nuclear translocation of NF-κB and the phosphorylation level of p65, p38 and JNK MAP kinase pathways were also inhibited by PQQ in LPS stimulated primary microglia cells. Further a systemic LPS treatment acute inflammation murine brain model was used to study the suppressive effects of PQQ against neuroinflammation in vivo. Mice treated with PQQ demonstrated marked attenuation of neuroinflammation based on Western blotting and immunohistochemistry analysis of Iba1-against antibody in the brain tissue. Indicated that PQQ protected primary cortical neurons against microglia-mediated neurotoxicity. These results collectively suggested that PQQ might be a promising therapeutic agent for alleviating the progress of neurodegenerative diseases associated with microglia activation. PMID:25314304

  20. Demethyleneberberine attenuates non-alcoholic fatty liver disease with activation of AMPK and inhibition of oxidative stress.

    PubMed

    Qiang, Xiaoyan; Xu, Lulu; Zhang, Miao; Zhang, Pengcheng; Wang, Yinhang; Wang, Yongchen; Zhao, Zheng; Chen, Huan; Liu, Xie; Zhang, Yubin

    2016-04-15

    Non-alcoholic fatty liver disease (NAFLD) has reached an epidemic level globally, which is recognized to form non-alcoholic steatohepatitis (NASH) by the "two-hit" model, including oxidative stress and inflammation. AMP-activated protein kinase (AMPK) has long been regarded as a key regulator of energy metabolism, which is recognized as a critical target for NAFLD treatment. Here we introduce a natural product, demethyleneberberine (DMB), which potentially ameliorated NAFLD by activating AMPK pathways. Our study showed that the intraperitoneal injection of DMB (20 or 40 mg/kg body weight) decreased hepatic lipid accumulation in methionine and choline deficient (MCD) high-fat diet feeding mice and db/db mice. The further investigation demonstrated that DMB activated AMPK by increasing its phosphorylation in vitro and in vivo. Accompanied with AMPK activation, the expression of lipogenic genes were significantly reduced while genes responsible for the fatty acid β-oxidation were restored in DMB-treated NAFLD mice. In addition, the remarkable oxidative damage and inflammation induced by NAFLD were both attenuated by DMB treatment, which is reflected by decreased lipid oxidative product, malonaldehyde (MDA) and inflammatory factors, tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β). Based on all above, DMB could serve as a novel AMPK activator for treating NAFLD and preventing the pathologic progression from NAFLD to NASH by inhibiting the oxidative stress and inflammation.

  1. Chloroform extract of aged black garlic attenuates TNF-α-induced ROS generation, VCAM-1 expression, NF-κB activation and adhesiveness for monocytes in human umbilical vein endothelial cells.

    PubMed

    Lee, Eun Na; Choi, Young Whan; Kim, Hye Kyung; Park, Jin Kyeong; Kim, Hyo Jin; Kim, Myoung June; Lee, Hee Woo; Kim, Ki-Hyung; Bae, Sun Sik; Kim, Bong Seon; Yoon, Sik

    2011-01-01

    Aged black garlic is a type of fermented garlic (Allium sativum) which has been used in Oriental countries for a long time because of various biological properties of garlic derivatives. The current study explored the potential of the chloroform extract of aged black garlic (CEABG) in attenuating the activities of adhesion molecules in tumor necrosis factor-α (TNF-α)-stimulated human umbilical vein endothelial cells (HUVECs). The study was performed on HUVECs that were pretreated with 30 μg/mL of CEABG before TNF-α treatment. Treatment of HUVECs with CEABG significantly inhibited TNF-α-induced reactive oxygen species (ROS) formation. HUVECs treated with CEABG showed markedly suppressed TNF-α-induced mRNA expression of VCAM-1, but little alteration in ICAM-1 and E-selectin mRNA expression. CEABG treatment also significantly decreased the TNF-α-induced cell surface and total protein expression of VCAM-1 without affecting ICAM-1 and E-selectin expression. In addition, treatment of HUVECs with CEABG markedly reduced THP-1 monocyte adhesion to TNF-α-stimulated HUVECs. Furthermore, CEABG significantly inhibited NF-κB transcription factor activation in TNF-α-stimulated HUVECs. The data provide new evidence of the antiinflammatory properties of CEABG that may have a potential therapeutic use for the prevention and treatment of vascular diseases such as atherosclerosis through mechanisms involving the inhibition of VCAM-1 expression and NF-κB activation in vascular endothelial cells.

  2. EGCG inhibits the growth and tumorigenicity of nasopharyngeal tumor-initiating cells through attenuation of STAT3 activation.

    PubMed

    Lin, Chien-Hung; Chao, Li-Keng; Hung, Peir-Haur; Chen, Yann-Jang

    2014-01-01

    A subset of cancer cells, termed cancer stem cells (CSCs) or tumor-initiating cells (TICs) could initiate tumors and are responsible for tumor recurrence and chemotherapeutic resistance. In this study, we enriched TICs in nasopharyngeal carcinoma (NPC) by the spheres formation and characterized the stem-like signatures such as self-renewal, proliferation, chemoresistance and tumorigenicity. By this method, we investigated that epigallocathechin gallate (EGCG), the major polyphenol in green tea could target TICs and potently inhibit sphere formation, eliminate the stem-like properties and enhance chemosensitivity in NPC through attenuation of STAT3 activation, which could be important in regulating the stemness expression in NPC. Our results demonstrated that STAT3 pathway plays an important role in mediating tumor-initiating capacities in NPC and suggest that inactivation of STAT3 with EGCG may represent a potential preventive and therapeutic approach for NPC. PMID:24966947

  3. Honokiol activates the LKB1–AMPK signaling pathway and attenuates the lipid accumulation in hepatocytes

    SciTech Connect

    Seo, Min Suk; Kim, Jung Hwan; Kim, Hye Jung; Chang, Ki Churl; Park, Sang Won

    2015-04-15

    Honokiol is a bioactive neolignan compound isolated from the species of Magnolia. This study was designed to elucidate the cellular mechanism by which honokiol alleviates the development of non-alcoholic steatosis. HepG2 cells were treated with honokiol for 1 h, and then exposed to 1 mM free fatty acid (FFA) for 24 h to simulate non-alcoholic steatosis in vitro. C57BL/6 mice were fed with a high-fat diet for 28 days, and honokiol (10 mg/kg/day) was daily treated. Honokiol concentration-dependently attenuated intracellular fat overloading and triglyceride (TG) accumulation in FFA-exposed HepG2 cells. These effects were blocked by pretreatment with an AMP-activated protein kinase (AMPK) inhibitor. Honokiol significantly inhibited sterol regulatory element-binding protein-1c (SREBP-1c) maturation and the induction of lipogenic proteins, stearoyl-CoA desaturase-1 (SCD-1) and fatty acid synthase (FAS) in FFA-exposed HepG2 cells, but these effects were blocked by pretreatment of an AMPK inhibitor. Honokiol induced AMPK phosphorylation and subsequent acetyl-CoA carboxylase (ACC) phosphorylation, which were inhibited by genetic deletion of liver kinase B1 (LKB1). Honokiol stimulated LKB1 phosphorylation, and genetic deletion of LKB1 blocked the effect of honokiol on SREBP-1c maturation and the induction of SCD-1 and FAS proteins in FFA-exposed HepG2 cells. Honokiol attenuated the increases in hepatic TG and lipogenic protein levels and fat accumulation in the mice fed with high-fat diet, while significantly induced LKB1 and AMPK phosphorylation. Taken together, our findings suggest that honokiol has an anti-lipogenic effect in hepatocytes, and this effect may be mediated by the LKB1–AMPK signaling pathway, which induces ACC phosphorylation and inhibits SREBP-1c maturation in hepatocytes. - Highlights: • Honokiol attenuates lipid accumulation induced by free fatty acid in hepatocyte. • Honokiol inhibits the increase in lipogenic enzyme levels induced by free fatty

  4. Vitamin K3 attenuates lipopolysaccharide-induced acute lung injury through inhibition of nuclear factor-κB activation

    PubMed Central

    Tanaka, S; Nishiumi, S; Nishida, M; Mizushina, Y; Kobayashi, K; Masuda, A; Fujita, T; Morita, Y; Mizuno, S; Kutsumi, H; Azuma, T; Yoshida, M

    2010-01-01

    Vitamin K is a family of fat-soluble compounds including phylloquinone (vitamin K1), menaquinone (vitamin K2) and menadione (vitamin K3). Recently, it was reported that vitamin K, especially vitamins K1 and K2, exerts a variety of biological effects, and these compounds are expected to be candidates for therapeutic agents against various diseases. In this study, we investigated the anti-inflammatory effects of vitamin K3 in in vitro cultured cell experiments and in vivo animal experiments. In human embryonic kidney (HEK)293 cells, vitamin K3 inhibited the tumour necrosis factor (TNF)-α-evoked translocation of nuclear factor (NF)-κB into the nucleus, although vitamins K1 and K2 did not. Vitamin K3 also suppressed the lipopolysaccharide (LPS)-induced nuclear translocation of NF-κB and production of TNF-α in mouse macrophage RAW264·7 cells. Moreover, the addition of vitamin K3 before and after LPS administration attenuated the severity of lung injury in an animal model of acute lung injury/acute respiratory distress syndrome (ARDS), which occurs in the setting of acute severe illness complicated by systemic inflammation. In the ARDS model, vitamin K3 also suppressed the LPS-induced increase in the serum TNF-α level and inhibited the LPS-evoked nuclear translocation of NF-κB in lung tissue. Despite marked efforts, little therapeutic progress has been made, and the mortality rate of ARDS remains high. Vitamin K3 may be an effective therapeutic strategy against acute lung injury including ARDS. PMID:20030669

  5. Influence of Vertical Attenuation of Photosynthetically Active Radiation on the Growth of Submerged Aquatic Vegetation in Tropical Reservoir.

    NASA Astrophysics Data System (ADS)

    da Silva Rotta, L. H.; Mishra, D. R.; Alcântara, E. H.; Imai, N. N.

    2015-12-01

    Reservoir construction cause many changes in lotic ecosystems and can favor the aquatic macrophyte growth. Nova Avanhandava Reservoir (São Paulo, Brazil), is fully inhabited by submerged aquatic vegetation (SAV) which may cause serious problems to hydropower and irrigation systems. The goal of this study was to assess the radiation availability in the water column in Nova Avanhandava and analyze its influence on SAV development and growth. The measurements were carried out between 28th and 30th June, 2013, at 19 sampling stations. Water samples for analytical determination of the suspended solids and chlorophyll-a concentration were collected. Hyperspectral downwelling irradiance (Ed) data, at several depths, were measured using the TriOS/RAMSES optical sensor. Depths and SAV heights were collected through hydroacoustic measurements by transects using the scientific digital sonar BioSonics DT-X (Echosounder). The Ed data were normalized, than calculated the Kd PAR - downwelling diffuse attenuation coefficient of photosynthetically active radiation, and the euphotic zone depth (ZEZ). Results showed that SAV height values were lower at upstream (around P01) with highest TSS (Total Suspended Solids) and Kd, compared to areas downstream (around P19) (Figure). The maximum depth of SAV development, average SAV height, maximum SAV height, variability, and depth of occurrence of SAV were primarily influenced by Kd. A linear inverse relationship between the average SAV height and the Kd PAR (R2 = 0.56, p<0.001), and between maximum SAV height and Kd PAR (R²=0.5, p<0.001) demonstrated that the SAV heigth can be estimated by Kd PAR with significant accuracy. Therefore, studies on subaquatic radiation availability measured by the vertical attenuation of Ed PAR in the water column and the optically active components can be effiectivly linked to SAV growth and occurrence and aid in understanding SAV in tropical reservoirs, contributing to its management.

  6. Activation of central PPAR-γ attenuates angiotensin II-induced hypertension.

    PubMed

    Yu, Yang; Xue, Bao-Jian; Wei, Shun-Guang; Zhang, Zhi-Hua; Beltz, Terry G; Guo, Fang; Johnson, Alan Kim; Felder, Robert B

    2015-08-01

    Inflammation and renin-angiotensin system activity in the brain contribute to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. We recently reported that activation of brain peroxisome proliferator-activated receptor (PPAR)-γ in heart failure rats reduced inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorated the peripheral manifestations of heart failure. We hypothesized that the activation of brain PPAR-γ might have beneficial effects in angiotensin II-induced hypertension. Sprague-Dawley rats received a 2-week subcutaneous infusion of angiotensin II (120 ng/kg per minute) combined with a continuous intracerebroventricular infusion of vehicle, the PPAR-γ agonist pioglitazone (3 nmol/h) or the PPAR-γ antagonist GW9662 (7 nmol/h). Angiotensin II+vehicle rats had increased mean blood pressure, increased sympathetic drive as indicated by the mean blood pressure response to ganglionic blockade, and increased water consumption. PPAR-γ mRNA in subfornical organ and hypothalamic paraventricular nucleus was unchanged, but PPAR-γ DNA-binding activity was reduced. mRNA for interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2, and angiotensin II type 1 receptor was augmented in both nuclei, and hypothalamic paraventricular nucleus neuronal activity was increased. The plasma vasopressin response to a 6-hour water restriction also increased. These responses to angiotensin II were exacerbated by GW9662 and ameliorated by pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA-binding activity in subfornical organ and hypothalamic paraventricular nucleus. Pioglitazone and GW9662 had no effects on control rats. The results suggest that activating brain PPAR-γ to reduce central inflammation and brain renin-angiotensin system activity may be a useful adjunct in the treatment of angiotensin II-dependent hypertension.

  7. Activation of Central PPAR-γ Attenuates Angiotensin II-Induced Hypertension

    PubMed Central

    Yu, Yang; Xue, Bao-Jian; Wei, Shun-Guang; Zhang, Zhi-Hua; Beltz, Terry G; Guo, Fang; Johnson, Alan Kim; Felder, Robert B

    2015-01-01

    Inflammation and renin-angiotensin system activity in the brain contribute to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. We recently reported that activation of brain peroxisome proliferator-activated receptor (PPAR)-γ in heart failure rats reduced inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorated the peripheral manifestations of heart failure. We hypothesized that activation of brain PPAR-γ might have beneficial effects in angiotensin II-induced hypertension. Sprague-Dawley rats received a 2-week subcutaneous infusion of angiotensin II (120 ng/kg/min) combined with a continuous intracerebroventricular infusion of vehicle, the PPAR-γ agonist pioglitazone (3 nmol/h) or the PPAR-γ antagonist GW9662 (7 nmol/h). Angiotensin II+vehicle rats had increased mean blood pressure, increased sympathetic drive as indicated by the mean blood pressure response to ganglionic blockade, and increased water consumption. PPAR-γ mRNA in subfornical organ and hypothalamic paraventricular nucleus was unchanged, but PPAR-γ DNA binding activity was reduced. mRNA for interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2 and angiotensin II type-1 receptor was augmented in both nuclei, and hypothalamic paraventricular nucleus neuronal activity was increased. The plasma vasopressin response to a 6-hour water restriction also increased. These responses to angiotensin II were exacerbated by GW9662 and ameliorated by pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA binding activity in subfornical organ and hypothalamic paraventricular nucleus. Pioglitazone and GW9662 had no effects on control rats. The results suggest that activating brain PPAR-γ to reduce central inflammation and brain renin-angiotensin system activity may be a useful adjunct in the treatment of angiotensin II-dependent hypertension. PMID:26101342

  8. A novel natural Nrf2 activator with PPARγ-agonist (monascin) attenuates the toxicity of methylglyoxal and hyperglycemia

    SciTech Connect

    Hsu, Wei-Hsuan; Lee, Bao-Hong; Chang, Yu-Ying; Hsu, Ya-Wen; Pan, Tzu-Ming

    2013-11-01

    Methylglyoxal (MG) is a toxic-glucose metabolite and a major precursor of advanced glycation endproducts (AGEs). MG has been reported to result in inflammation by activating receptor for AGEs (RAGE). We recently found that Monascus-fermented metabolite monascin acts as a novel natural peroxisome proliferator-activated receptor-γ (PPARγ) agonist that improves insulin sensitivity. We investigated the metabolic, biochemical, and molecular abnormalities characteristic of type 2 diabetes in MG-treated Wistar rats treated with oral administration of monascin or rosiglitazone. Monascin (a novel PPARγ agonist) activated nuclear factor-erythroid 2-related factor 2 (Nrf2) and down-regulated hyperinsulinmia in oral glucose tolerance test (OGTT). Monascin was able to elevate glyoxalase-1 expression via activation of hepatic Nrf2, hence, resulting in MG metabolism to D-lactic acid and protected from AGEs production in MG-treated rats. Rosiglitazone did not activate Nrf2 nor glyoxalase expression to lower serum and hepatic AGEs levels. Monascin acts as a novel natural Nrf2 activator with PPARγ-agonist activity were confirmed by Nrf2 and PPARγ reporter assays in Hep G2 cells. These findings suggest that monascin acts as an anti-diabetic and anti-oxidative stress agent to a greater degree than rosiglitazone and thus may have therapeutic potential for the prevention of diabetes. - Highlights: • Monascin acts as a PPARgamma agonist. • Monascin activates Nrf2 and AMPK. • Monascin promotes MG metabolism into D-lactic acid. • Monascin attenuates inflammation and diabetes in vivo.

  9. RING E3-Catalyzed E2 Self-Ubiquitination Attenuates the Activity of Ube2E Ubiquitin-Conjugating Enzymes.

    PubMed

    Banka, Prerana Agarwal; Behera, Adaitya Prasad; Sarkar, Sayani; Datta, Ajit B

    2015-07-01

    Ubiquitination of a target protein is accomplished through sequential actions of the E1, E2s, and the E3s. E2s dictate the modification topology while E3 ligases confer substrate specificity and recruit the cognate E2. Human genome codes for ~35 different E2 proteins; all of which contain the characteristic ubiquitin-conjugating UBC core domain sufficient for catalysis. Many of these E2 enzymes also have N- or C-terminal extensions; roles of which are not very well understood. We show that the N-terminal extension of Ube2E1 undergoes intramolecular auto-ubiquitination. This self-ubiquitination activity is enhanced in the presence of interacting RING E3 ligases and results in a progressive attenuation of the E2 activity toward substrate/E3 modification. We also find that the N-terminal ubiquitination sites are conserved in all the three Ube2Es and replacing them with arginine renders all three full-length Ube2Es equally active as their core UBC domains. Based on these results, we propose that E3-catalyzed self-ubiquitination acts as a key regulatory mechanism that controls the activity of Ube2E class of ubiquitin E2s.

  10. Neotuberostemonine attenuates bleomycin-induced pulmonary fibrosis by suppressing the recruitment and activation of macrophages.

    PubMed

    Xiang, Juan; Cheng, Si; Feng, Tianlong; Wu, Yan; Xie, Weina; Zhang, Mian; Xu, Xianghong; Zhang, Chaofeng

    2016-07-01

    Neotuberostemonine (NTS) is one of the main antitussive alkaloids in the root of Stemona tuberosa Lour. This study aimed to investigate the effects of NTS on bleomycin (BLM)-induced pulmonary fibrosis in mice and the underlying mechanism. After BLM administration, NTS were orally administered to mice at 20 and 40mg/kg per day from days 8 to 21, with nintedanib as a positive control. The effect of NTS on BLM-induced mice was assessed via histopathological examination by HE and Masson's trichrome staining, TGF-β1 level and macrophage recruitment by immunohistochemical staining, expression of profibrotic media and M1/M2 polarization by western blot. RAW 264.7 cells were used to evaluate whether NTS (1, 10, 100μM) directly affected macrophages. The results revealed that NTS treatment significantly ameliorated lung histopathological changes and decreased inflammatory cell counts in the bronchoalveolar lavage fluid. The over-expression of collagen, α-SMA and TGF-β1 was reduced by NTS. Furthermore, NTS markedly lowered the expression of MMP-2 and TIMP-1 while raised the expression of MMP-9. A further analysis showed that NTS was able to decrease the recruitment of macrophages and to inhibit the M2 polarization in mice lung tissues. The experiment in vitro showed that NTS significantly reduced the arginase-1 (marker for M2) expression in a dose-dependent manner but down-regulated the iNOS (marker for M1) expression only at 100μM. In conclusion, our study demonstrated for the first time that NTS has a significant protective effect on BLM-induced pulmonary fibrosis through suppressing the recruitment and M2 polarization of macrophages. PMID:27144994

  11. Neotuberostemonine attenuates bleomycin-induced pulmonary fibrosis by suppressing the recruitment and activation of macrophages.

    PubMed

    Xiang, Juan; Cheng, Si; Feng, Tianlong; Wu, Yan; Xie, Weina; Zhang, Mian; Xu, Xianghong; Zhang, Chaofeng

    2016-07-01

    Neotuberostemonine (NTS) is one of the main antitussive alkaloids in the root of Stemona tuberosa Lour. This study aimed to investigate the effects of NTS on bleomycin (BLM)-induced pulmonary fibrosis in mice and the underlying mechanism. After BLM administration, NTS were orally administered to mice at 20 and 40mg/kg per day from days 8 to 21, with nintedanib as a positive control. The effect of NTS on BLM-induced mice was assessed via histopathological examination by HE and Masson's trichrome staining, TGF-β1 level and macrophage recruitment by immunohistochemical staining, expression of profibrotic media and M1/M2 polarization by western blot. RAW 264.7 cells were used to evaluate whether NTS (1, 10, 100μM) directly affected macrophages. The results revealed that NTS treatment significantly ameliorated lung histopathological changes and decreased inflammatory cell counts in the bronchoalveolar lavage fluid. The over-expression of collagen, α-SMA and TGF-β1 was reduced by NTS. Furthermore, NTS markedly lowered the expression of MMP-2 and TIMP-1 while raised the expression of MMP-9. A further analysis showed that NTS was able to decrease the recruitment of macrophages and to inhibit the M2 polarization in mice lung tissues. The experiment in vitro showed that NTS significantly reduced the arginase-1 (marker for M2) expression in a dose-dependent manner but down-regulated the iNOS (marker for M1) expression only at 100μM. In conclusion, our study demonstrated for the first time that NTS has a significant protective effect on BLM-induced pulmonary fibrosis through suppressing the recruitment and M2 polarization of macrophages.

  12. Low-power laser irradiation (LPLI) attenuates microglial cytotoxicity through the activation of Src pathway

    NASA Astrophysics Data System (ADS)

    Song, Sheng; Zhou, Feifan; Chen, Wei R.

    2014-02-01

    It has been known for a long time that microglial activation plays an important role in the pathology of neurodegenerative diseases. Once activated, they have macrophage-like capabilities, which can be detrimental by producing proinflammatory and neurotoxic factors including cytokines, reactive oxygen species (ROS) and nitric oxide that directly or indirectly cause neurodegeneration. Therefore, the regulation of microglial-induced neuroinflammation is considered a useful strategy in searching for neuroprotective treatments. In this study, our results showed that low power laser irradiation (LPLI) (20 J/cm2) could suppress microglial-induced neuroinflammation in LPS-activated microglia. We found that LPLI-mediated neuroprotection was achieved by activating tyrosine kinases Src, which led to MyD88 tyrosine phosphorylation, thus impairing MyD88-dependent proinflammatory signaling cascade. Our research may provide a feasible therapeutic approach to control the progression of neurodegenerative diseases.

  13. Kaiso depletion attenuates transforming growth factor-β signaling and metastatic activity of triple-negative breast cancer cells

    PubMed Central

    Bassey-Archibong, B I; Kwiecien, J M; Milosavljevic, S B; Hallett, R M; Rayner, L G A; Erb, M J; Crawford-Brown, C J; Stephenson, K B; Bédard, P-A; Hassell, J A; Daniel, J M

    2016-01-01

    Triple-negative breast cancers (TNBCs) represent a subset of breast tumors that are highly aggressive and metastatic, and are responsible for a disproportionate number of breast cancer-related deaths. Several studies have postulated a role for the epithelial-to-mesenchymal transition (EMT) program in the increased aggressiveness and metastatic propensity of TNBCs. Although EMT is essential for early vertebrate development and wound healing, it is frequently co-opted by cancer cells during tumorigenesis. One prominent signaling pathway involved in EMT is the transforming growth factor-β (TGFβ) pathway. In this study, we report that the novel POZ-ZF transcription factor Kaiso is highly expressed in TNBCs and correlates with a shorter metastasis-free survival. Notably, Kaiso expression is induced by the TGFβ pathway and silencing Kaiso expression in the highly invasive breast cancer cell lines, MDA-MB-231 (hereafter MDA-231) and Hs578T, attenuated the expression of several EMT-associated proteins (Vimentin, Slug and ZEB1), abrogated TGFβ signaling and TGFβ-dependent EMT. Moreover, Kaiso depletion attenuated the metastasis of TNBC cells (MDA-231 and Hs578T) in a mouse model. Although high Kaiso and high TGFβR1 expression is associated with poor overall survival in breast cancer patients, overexpression of a kinase-active TGFβR1 in the Kaiso-depleted cells was insufficient to restore the metastatic potential of these cells, suggesting that Kaiso is a key downstream component of TGFβ-mediated pro-metastatic responses. Collectively, these findings suggest a critical role for Kaiso in TGFβ signaling and the metastasis of TNBCs. PMID:26999717

  14. Mitochondrial Aldehyde Dehydrogenase Activation by Alda‐1 Inhibits Atherosclerosis and Attenuates Hepatic Steatosis in Apolipoprotein E‐Knockout Mice

    PubMed Central

    Stachowicz, Aneta; Olszanecki, Rafał; Suski, Maciej; Wiśniewska, Anna; Totoń‐Żurańska, Justyna; Madej, Józef; Jawień, Jacek; Białas, Magdalena; Okoń, Krzysztof; Gajda, Mariusz; Głombik, Katarzyna; Basta‐Kaim, Agnieszka; Korbut, Ryszard

    2014-01-01

    Background Mitochondrial dysfunction has been shown to play an important role in the development of atherosclerosis and nonalcoholic fatty liver disease (NAFLD). Mitochondrial aldehyde dehydrogenase (ALDH2), an enzyme responsible for the detoxification of reactive aldehydes, is considered to exert protective function in mitochondria. We investigated the influence of Alda‐1, an activator of ALDH2, on atherogenesis and on the liver steatosis in apolipoprotein E knockout (apoE−/−) mice. Methods and Results Alda‐1 caused decrease of atherosclerotic lesions approximately 25% as estimated by “en face” and “cross‐section” methods without influence on plasma lipid profile, atherosclerosis‐related markers of inflammation, and macrophage and smooth muscle content in the plaques. Plaque nitrotyrosine was not changed upon Alda‐1 treatment, and there were no changes in aortic mRNA levels of factors involved in antioxidative defense, regulation of apoptosis, mitogenesis, and autophagy. Hematoxylin/eosin staining showed decrease of steatotic changes in liver of Alda‐1‐treated apoE−/− mice. Alda‐1 attenuated formation of 4‐hydroxy‐2‐nonenal (4‐HNE) protein adducts and decreased triglyceride content in liver tissue. Two‐dimensional electrophoresis coupled with mass spectrometry identified 20 differentially expressed mitochondrial proteins upon Alda‐1 treatment in liver of apoE−/− mice, mostly proteins related to metabolism and oxidative stress. The most up‐regulated were the proteins that participated in beta oxidation of fatty acids. Conclusions Collectively, Alda‐1 inhibited atherosclerosis and attenuated NAFLD in apoE−/− mice. The pattern of changes suggests a beneficial effect of Alda‐1 in NAFLD; however, the exact liver functional consequences of the revealed alterations as well as the mechanism(s) of antiatherosclerotic Alda‐1 action require further investigation. PMID:25392542

  15. Cannabidiol attenuates catalepsy induced by distinct pharmacological mechanisms via 5-HT1A receptor activation in mice.

    PubMed

    Gomes, Felipe V; Del Bel, Elaine A; Guimarães, Francisco S

    2013-10-01

    Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa plant that produces antipsychotic effects in rodents and humans. It also reverses L-dopa-induced psychotic symptoms and improves motor function in Parkinson's patients. This latter effect raised the possibility that CBD could have beneficial effects on motor related striatal disorders. To investigate this possibility we evaluated if CBD would prevent catalepsy induced by drugs with distinct pharmacological mechanisms. The catalepsy test is largely used to investigate impairments of motor function caused by interference on striatal function. Male Swiss mice received acute pretreatment with CBD (5, 15, 30 or 60mg/kg, ip) 30min prior to the D2 receptor antagonist haloperidol (0.6mg/kg), the non-selective nitric oxide synthase (NOS) inhibitor L-nitro-N-arginine (L-NOARG, 80mg/kg) or the CB1 receptor agonist WIN55,212-2 (5mg/kg). The mice were tested 1, 2 or 4h after haloperidol, L-NOARG or WIN55,212-2 injection. These drugs significantly increased catalepsy time and this effect was attenuated dose-dependently by CBD. CBD, by itself, did not induce catalepsy. In a second set of experiments the mechanism of CBD effects was investigated. Thirty minutes before CBD (30mg/kg) the animals received the 5-HT1A receptor antagonist WAY100635 (0.1mg/kg). The anticataleptic effect of CBD was prevented by WAY100635. These findings indicate that CBD can attenuate catalepsy caused by different mechanisms (D2 blockade, NOS inhibition and CB1 agonism) via 5-HT1A receptor activation, suggesting that it could be useful in the treatment of striatal disorders.

  16. Kaiso depletion attenuates transforming growth factor-β signaling and metastatic activity of triple-negative breast cancer cells.

    PubMed

    Bassey-Archibong, B I; Kwiecien, J M; Milosavljevic, S B; Hallett, R M; Rayner, L G A; Erb, M J; Crawford-Brown, C J; Stephenson, K B; Bédard, P-A; Hassell, J A; Daniel, J M

    2016-01-01

    Triple-negative breast cancers (TNBCs) represent a subset of breast tumors that are highly aggressive and metastatic, and are responsible for a disproportionate number of breast cancer-related deaths. Several studies have postulated a role for the epithelial-to-mesenchymal transition (EMT) program in the increased aggressiveness and metastatic propensity of TNBCs. Although EMT is essential for early vertebrate development and wound healing, it is frequently co-opted by cancer cells during tumorigenesis. One prominent signaling pathway involved in EMT is the transforming growth factor-β (TGFβ) pathway. In this study, we report that the novel POZ-ZF transcription factor Kaiso is highly expressed in TNBCs and correlates with a shorter metastasis-free survival. Notably, Kaiso expression is induced by the TGFβ pathway and silencing Kaiso expression in the highly invasive breast cancer cell lines, MDA-MB-231 (hereafter MDA-231) and Hs578T, attenuated the expression of several EMT-associated proteins (Vimentin, Slug and ZEB1), abrogated TGFβ signaling and TGFβ-dependent EMT. Moreover, Kaiso depletion attenuated the metastasis of TNBC cells (MDA-231 and Hs578T) in a mouse model. Although high Kaiso and high TGFβR1 expression is associated with poor overall survival in breast cancer patients, overexpression of a kinase-active TGFβR1 in the Kaiso-depleted cells was insufficient to restore the metastatic potential of these cells, suggesting that Kaiso is a key downstream component of TGFβ-mediated pro-metastatic responses. Collectively, these findings suggest a critical role for Kaiso in TGFβ signaling and the metastasis of TNBCs.

  17. Foreign Body Giant Cell Formation Is Preceded by Lamellipodia Formation and Can Be Attenuated by Inhibition of Rac1 Activation

    PubMed Central

    Jay, Steven M.; Skokos, Eleni; Laiwalla, Farah; Krady, Marie-Marthe; Kyriakides, Themis R.

    2007-01-01

    Macrophages that are recruited to the site of implanted biomaterials undergo fusion to form surface-damaging foreign body giant cells. Exposure of peripheral blood monocytes to interleukin-4 can recapitulate the fusion process in vitro. In this study, we used interleukin-4 to induce multinucleation of murine bone marrow-derived macrophages and observed changes in cell shape, including elongation and lamellipodia formation, before fusion. Because cytoskeletal rearrangements are regulated by small GTPases, we examined the effects of inhibitors of Rho kinase (Y-32885) and Rac activation (NSC23766) on fusion. Y-32885 did not prevent cytoskeletal changes or fusion but limited the extent of multinucleation. NSC23766, on the other hand, inhibited lamellipodia formation and fusion in a dose-dependent manner. In addition, we found that in control cells, these changes were preceded by Rac1 activation. However, NSC23766 did not block the uptake of polystyrene microspheres. Likewise, short interfering RNA knockdown of Rac1 limited fusion without limiting phagocytosis. Thus, phagocytosis and fusion can be partially decoupled based on their susceptibility to NSC23766. Furthermore, poly(ethylene-co-vinyl acetate) scaffolds containing NSC23766 attenuated foreign body giant cell formation in vivo. These observations suggest that targeting Rac1 activation could protect biomaterials without compromising the ability of macrophages to perform beneficial phagocytic functions at implantation sites. PMID:17556592

  18. Foreign body giant cell formation is preceded by lamellipodia formation and can be attenuated by inhibition of Rac1 activation.

    PubMed

    Jay, Steven M; Skokos, Eleni; Laiwalla, Farah; Krady, Marie-Marthe; Kyriakides, Themis R

    2007-08-01

    Macrophages that are recruited to the site of implanted biomaterials undergo fusion to form surface-damaging foreign body giant cells. Exposure of peripheral blood monocytes to interleukin-4 can recapitulate the fusion process in vitro. In this study, we used interleukin-4 to induce multinucleation of murine bone marrow-derived macrophages and observed changes in cell shape, including elongation and lamellipodia formation, before fusion. Because cytoskeletal rearrangements are regulated by small GTPases, we examined the effects of inhibitors of Rho kinase (Y-32885) and Rac activation (NSC23766) on fusion. Y-32885 did not prevent cytoskeletal changes or fusion but limited the extent of multinucleation. NSC23766, on the other hand, inhibited lamellipodia formation and fusion in a dose-dependent manner. In addition, we found that in control cells, these changes were preceded by Rac1 activation. However, NSC23766 did not block the uptake of polystyrene microspheres. Likewise, short interfering RNA knockdown of Rac1 limited fusion without limiting phagocytosis. Thus, phagocytosis and fusion can be partially decoupled based on their susceptibility to NSC23766. Furthermore, poly(ethylene-co-vinyl acetate) scaffolds containing NSC23766 attenuated foreign body giant cell formation in vivo. These observations suggest that targeting Rac1 activation could protect biomaterials without compromising the ability of macrophages to perform beneficial phagocytic functions at implantation sites.

  19. Cocaine dependent individuals with attenuated striatal activation during reinforcement learning are more susceptible to relapse.

    PubMed

    Stewart, Jennifer L; Connolly, Colm G; May, April C; Tapert, Susan F; Wittmann, Marc; Paulus, Martin P

    2014-08-30

    Cocaine-dependent individuals show altered brain activation during decision making. It is unclear, however, whether these activation differences are related to relapse vulnerability. This study tested the hypothesis that brain-activation patterns during reinforcement learning are linked to relapse 1 year later in individuals entering treatment for cocaine dependence. Subjects performed a Paper-Scissors-Rock task during functional magnetic resonance imaging (fMRI). A year later, we examined whether subjects had remained abstinent (n=15) or relapsed (n=15). Although the groups did not differ on demographic characteristics, behavioral performance, or lifetime substance use, abstinent patients reported greater motivation to win than relapsed patients. The fMRI results indicated that compared with abstinent individuals, relapsed users exhibited lower activation in (1) bilateral inferior frontal gyrus and striatum during decision making more generally; and (2) bilateral middle frontal gyrus and anterior insula during reward contingency learning in particular. Moreover, whereas abstinent patients exhibited greater left middle frontal and striatal activation to wins than losses, relapsed users did not demonstrate modulation in these regions as a function of outcome valence. Thus, individuals at high risk for relapse relative to those who are able to abstain allocate fewer neural resources to action-outcome contingency formation and decision making, as well as having less motivation to win on a laboratory-based task.

  20. Activation of farnesoid X receptor downregulates visfatin and attenuates diabetic nephropathy.

    PubMed

    Zhou, Baoshang; Feng, Bing; Qin, Zhexue; Zhao, Youguang; Chen, Yu; Shi, Zhengmin; Gong, Yi; Zhang, Jing; Yuan, Fahuan; Mu, Jiao

    2016-01-01

    Visfatin, a recently discovered adipocytokine, has been shown to have an important role in the pathogenesis of diabetic nephropathy (DN). The farnesoid X receptor (FXR), a ligand-activated nuclear receptor, plays a protective role in DN. The regulation between FXR and visfatin and their interaction in DN has not been well established. In this study, we reported that FXR agonist GW4064 reduced high glucose induced human mesangial cells (HMCs) inflammation, fibrosis and proliferation by downregulating visfatin expression, which can be blunted by exogenous visfatin treatment. Moreover, luciferase reporter assay showed FXR regulated visfatin transcription activity probably by binding to the -1607 bp and -1192 bp region of the visfatin promoter. In vivo study also showed that GW4064 ameliorated the progression of DN in db/db mice with a decreased visfatin expression. These findings suggest that FXR activation delayed the progression of diabetic nephropathy and this effect is through downregulating visfatin.

  1. Non-exercise physical activity attenuates motor symptoms in Parkinson disease independent from nigrostriatal degeneration

    PubMed Central

    Snider, Jon; Müller, Martijn L.T.M; Kotagal, Vikas; Koeppe, Robert A; Scott, Peter J.H.; Frey, Kirk A; Albin, Roger L.; Bohnen, Nicolaas I.

    2015-01-01

    Objective To investigate the relationship between time spent in non-exercise and exercise physical activity and severity of motor functions in Parkinson disease (PD). Background Increasing motor impairments of PD incline many patients to a sedentary lifestyle. We investigated the relationship between duration of both non-exercise and exercise physical activity over a 4-week period using the Community Health Activities Model Program for Seniors (CHAMPS) questionnaire and severity of clinical motor symptoms in PD. We accounted for the magnitude of nigrostriatal degeneration. Methods Cross-sectional study. PD subjects, n=48 (40M); 69.4±7.4 (56–84) years old; 8.4±4.2 (2.5–20) years motor disease duration, mean UPDRS motor score 27.5 ± 10.3 (7–53) and mean MMSE score 28.4 ± 1.9 (22–30) underwent [11C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation and completed the CHAMPS questionnaire and clinical assessment. Results Bivariate correlations showed an inverse relationship between motor UPDRS severity scores and duration of non-exercise physical activity (R= −0.37, P=0.0099) but not with duration of exercise physical activity (R= −0.05, P= 0.76) over 4 weeks. Multiple regression analysis using UPDRS motor score as outcome variable demonstrated a significant regressor effect for duration of non-exercise physical activity (F=6.15, P=0.017) while accounting for effects of nigrostriatal degeneration (F=4.93, P=0.032), levodopa-equivalent dose (LED; F=1.07, P=0.31), age (F=4.37, P=0.043) and duration of disease (F=1.46, P=0.23; total model (F=5.76, P=0.0004). Conclusions Non-exercise physical activity is a correlate of motor symptom severity in PD independent of the magnitude of nigrostriatal degeneration. Non-exercise physical activity may have positive effects on functional performance in PD. PMID:26330028

  2. Phytochemicals attenuating aberrant activation of ß-catenin in cancer cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Phytochemicals are a rich source of chemoprevention agents but their effects on modulating the Wnt/ß-catenin signaling pathway have remained largely uninvestigated. Aberrantly activated Wnt signaling can result in the abnormal stabilization of ß-catenin, a key causative step in a broad spectrum of c...

  3. Levo-Tetrahydropalmatine Attenuates Bone Cancer Pain by Inhibiting Microglial Cells Activation

    PubMed Central

    Zhang, Mao-yin; Liu, Yue-peng; Zhang, Lian-yi; Yue, Dong-mei; Qi, Dun-yi; Liu, Gong-jian; Liu, Su

    2015-01-01

    Objective. The present study is to investigate the analgesic roles of L-THP in rats with bone cancer pain caused by tumor cell implantation (TCI). Methods. Thermal hyperalgesia and mechanical allodynia were measured at different time points before and after operation. L-THP (20, 40, and 60 mg/kg) were administrated intragastrically at early phase of postoperation (before pain appearance) and later phase of postoperation (after pain appearance), respectively. The concentrations of TNF-α, IL-1β, and IL-18 in spinal cord were measured by enzyme-linked immunosorbent assay. Western blot was used to test the activation of astrocytes and microglial cells in spinal cord after TCI treatment. Results. TCI treatment induced significant thermal hyperalgesia and mechanical allodynia. Administration of L-THP at high doses significantly prevented and/or reversed bone cancer-related pain behaviors. Besides, TCI-induced activation of microglial cells and the increased levels of TNF-α and IL-18 were inhibited by L-THP administration. However, L-THP failed to affect TCI-induced astrocytes activation and IL-1β increase. Conclusion. This study suggests the possible clinical utility of L-THP in the treatment of bone cancer pain. The analgesic effects of L-THP on bone cancer pain maybe underlying the inhibition of microglial cells activation and proinflammatory cytokines increase. PMID:26819501

  4. Enhanced Phosphatase Activity Attenuates α-Synucleinopathy in a Mouse Model

    PubMed Central

    Lee, Kang-Woo; Chen, Walter; Junn, Eunsung; Im, Joo-Young; Grosso, Hilary; Sonsalla, Patricia K.; Feng, Xuyan; Ray, Neelanjana; Fernandez, Jose R.; Chao, Yang; Masliah, Eliezer; Voronkov, Michael; Braithwaite, Steven P.; Stock, Jeffry B.; Mouradian, M. Maral

    2016-01-01

    α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson’s disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that protein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129, and that this activity is greatly enhanced by carboxyl methylation of the catalytic C subunit of PP2A. α-Syn transgenic mice raised on a diet supplemented with eicosinoyl-5-hydroxytryptamide (EHT), an agent that enhances PP2A methylation, dramatically reduced both α-Syn phosphorylation at Serine 129 and α-Syn aggregation in the brain. These biochemical changes were associated with enhanced neuronal activity, increased dendritic arborizations, reduced astroglial and microglial activation, as well as improved motor performance. These findings support the notion that serine 129 phosphorylation of α-Syn is of pathogenetic significance, and that promoting PP2A activity is a viable disease modifying therapeutic strategy for α-synucleinopathies such as PD. PMID:21562258

  5. Does a physically active lifestyle attenuate decline in all cognitive functions in old age?

    PubMed

    Ballesteros, Soledad; Mayas, Julia; Reales, Jose Manuel

    2013-07-01

    In this study, the performance of a group of 20 physically active older adults was compared with that of a group of 20 sedentary healthy older adults while performing a series of cognitive tasks. These tasks were designed to assess processes that deteriorate most with age, namely executive control (assessed with the Wisconsin Card Sorting Task) and processing speed (simple and choice reaction time tasks). A repetition priming task that does not decline with age, involving attended and unattended picture outlines at encoding, was also included as a control task. The results show that a physically active lifestyle has a positive influence on executive control, processing speed, and controlled processing. As expected, a physically active lifestyle did not enhance repetition priming for attended stimuli, nor did it produce priming for unattended stimuli at encoding. Both groups exhibited robust priming for attended stimuli and no priming for unattended ones. Executive control functions are of vital importance for independent living in old age. These results have practical implications for enhancing the cognitive processes that decline most in old age. Promoting a physically active lifestyle throughout adulthood could significantly reduce the decline of effortful executive control functions in old age.

  6. Bay11-7082 attenuates murine lupus nephritis via inhibiting NLRP3 inflammasome and NF-κB activation.

    PubMed

    Zhao, Jijun; Zhang, Hui; Huang, Yuefang; Wang, Hongyue; Wang, Shuang; Zhao, Chunmei; Liang, Yingjie; Yang, Niansheng

    2013-09-01

    Nuclear factor-kappa B (NF-κB) and NLRP3 inflammasome are involved in inflammation and autoimmunity. In vitro data have shown that Bay11-7082 selectively inhibits NLRP3 inflammasome activity independent of NF-κB activity. In this study, we evaluated the therapeutic effects of Bay11-7082 on murine lupus nephritis (LN) in vivo. Twelve-week-old MRL/lpr mice were treated with either Bay11-7082 (5mg/kg) or vehicle (DMSO/PBS buffer) by intraperitoneal injection thrice per week for 8 weeks. NLRP3 inflammasome formation and NF-κB activation were measured. Histopathology, immune complex deposits, proteinuria, renal function and production of anti-dsDNA antibody as well as inflammatory markers were evaluated. Bay11-7082 treatment inhibited renal NLRP3 inflammasome formation and NF-κB activation in vivo. Bay11-7082 decreased proteinuria, blood urea nitrogen, resulting in dramatically attenuated renal damage. Bay11-7082-treated mice had decreased serum anti-dsDNA level and less renal immune complex deposition. The IL-1β, TNF-α and chemokine (C-C Motif) ligand 2 (CCL2) levels and infiltration of macrophages as well as the mortality were significantly reduced by Bay11-7082 treatment. This study suggests that dual inhibition of NLRP3 inflammasome and NF-κB activation using Bay11-7082 or its analogues may be a promising therapeutic strategy for preventing the progression of LN.

  7. Bay11-7082 attenuates murine lupus nephritis via inhibiting NLRP3 inflammasome and NF-κB activation.

    PubMed

    Zhao, Jijun; Zhang, Hui; Huang, Yuefang; Wang, Hongyue; Wang, Shuang; Zhao, Chunmei; Liang, Yingjie; Yang, Niansheng

    2013-09-01

    Nuclear factor-kappa B (NF-κB) and NLRP3 inflammasome are involved in inflammation and autoimmunity. In vitro data have shown that Bay11-7082 selectively inhibits NLRP3 inflammasome activity independent of NF-κB activity. In this study, we evaluated the therapeutic effects of Bay11-7082 on murine lupus nephritis (LN) in vivo. Twelve-week-old MRL/lpr mice were treated with either Bay11-7082 (5mg/kg) or vehicle (DMSO/PBS buffer) by intraperitoneal injection thrice per week for 8 weeks. NLRP3 inflammasome formation and NF-κB activation were measured. Histopathology, immune complex deposits, proteinuria, renal function and production of anti-dsDNA antibody as well as inflammatory markers were evaluated. Bay11-7082 treatment inhibited renal NLRP3 inflammasome formation and NF-κB activation in vivo. Bay11-7082 decreased proteinuria, blood urea nitrogen, resulting in dramatically attenuated renal damage. Bay11-7082-treated mice had decreased serum anti-dsDNA level and less renal immune complex deposition. The IL-1β, TNF-α and chemokine (C-C Motif) ligand 2 (CCL2) levels and infiltration of macrophages as well as the mortality were significantly reduced by Bay11-7082 treatment. This study suggests that dual inhibition of NLRP3 inflammasome and NF-κB activation using Bay11-7082 or its analogues may be a promising therapeutic strategy for preventing the progression of LN. PMID:23770281

  8. Valproate Attenuates Nitroglycerin-Induced Trigeminovascular Activation by Preserving Mitochondrial Function in a Rat Model of Migraine.

    PubMed

    Li, Ruxian; Liu, Yushuang; Chen, Nan; Zhang, Yitong; Song, Ge; Zhang, Zhongling

    2016-01-01

    BACKGROUND Migraine is a chronic disease that interferes with life quality and work productivity. Valproate shows protective effects against migraine, yet the underlying mechanisms are unclear. This study aimed to evaluate the potential effect of valproate on migraine using a rat model of nitroglycerin-induced trigeminovascular activation, as well as to explore the underlying mechanism. MATERIAL AND METHODS Intraperitoneal injection of nitroglycerin was conducted to induce trigeminovascular activation in rats. To explore the protective effect of valproate, a low dose (100 mg/kg) or a high dose (200 mg/kg) of valproate was intraperitoneally injected into rats, and then the levels of 5-hydroxytryptamine and nitric oxide in the peripheral blood were examined. The mtDNA copy number and the protein levels of peroxisome proliferator-activated receptor-γ coactivator 1α, mitochondrial transcription factor A, and peroxisome proliferator-activated receptor-γ in the spinal trigeminal nucleus were detected to evaluate the biogenesis of mitochondria. The mitochondrial energy metabolism was determined by the mitochondrial membrane potential and the levels of adenosine triphosphate, cytochrome C oxidase, and reactive oxygen species. RESULTS Valproate attenuated nitroglycerin-induced trigeminovascular activation in rats, with reduced scratching behavior and restored 5-hydroxytryptamine and nitric oxide levels. Moreover, the mitochondrial energy metabolism and the biogenesis of mitochondria were preserved by valproate in nitroglycerin-treated rats. CONCLUSIONS The protective effect of valproate against migraine may be achieved through the modulation of mitochondrial biogenesis and function. Our study provides evidence for the potential use of valproate in the treatment of migraine. PMID:27618395

  9. Valproate Attenuates Nitroglycerin-Induced Trigeminovascular Activation by Preserving Mitochondrial Function in a Rat Model of Migraine

    PubMed Central

    Li, Ruxian; Liu, Yushuang; Chen, Nan; Zhang, Yitong; Song, Ge; Zhang, Zhongling

    2016-01-01

    Background Migraine is a chronic disease that interferes with life quality and work productivity. Valproate shows protective effects against migraine, yet the underlying mechanisms are unclear. This study aimed to evaluate the potential effect of valproate on migraine using a rat model of nitroglycerin-induced trigeminovascular activation, as well as to explore the underlying mechanism. Material/Methods Intraperitoneal injection of nitroglycerin was conducted to induce trigeminovascular activation in rats. To explore the protective effect of valproate, a low dose (100 mg/kg) or a high dose (200 mg/kg) of valproate was intraperitoneally injected into rats, and then the levels of 5-hydroxytryptamine and nitric oxide in the peripheral blood were examined. The mtDNA copy number and the protein levels of peroxisome proliferator-activated receptor-γ coactivator 1α, mitochondrial transcription factor A, and peroxisome proliferator-activated receptor-γ in the spinal trigeminal nucleus were detected to evaluate the biogenesis of mitochondria. The mitochondrial energy metabolism was determined by the mitochondrial membrane potential and the levels of adenosine triphosphate, cytochrome C oxidase, and reactive oxygen species. Results Valproate attenuated nitroglycerin-induced trigeminovascular activation in rats, with reduced scratching behavior and restored 5-hydroxytryptamine and nitric oxide levels. Moreover, the mitochondrial energy metabolism and the biogenesis of mitochondria were preserved by valproate in nitroglycerin-treated rats. Conclusions The protective effect of valproate against migraine may be achieved through the modulation of mitochondrial biogenesis and function. Our study provides evidence for the potential use of valproate in the treatment of migraine. PMID:27618395

  10. D-Methionine attenuated cisplatin-induced vestibulotoxicity through altering ATPase activities and oxidative stress in guinea pigs

    SciTech Connect

    Cheng, P.-W.; Liu, S.-H.; Young, Y.-H.; Lin-Shiau, Shoei-Yn . E-mail: syl@ha.mc.ntu.edu.tw

    2006-09-01

    Cisplatin has been used as a chemotherapeutic agent to treat many kinds of malignancies. Its damage to the vestibulo-ocular reflex (VOR) system has been reported. However, the underlying biochemical change in the inner ear or central vestibular nervous system is not fully understood. In this study, we attempted to examine whether cisplatin-induced vestibulotoxicity and D-methionine protection were correlated with the changes of ATPase activities and oxidative stress of ampullary tissue of vestibules as well as cerebellar cortex (the inhibitory center of VOR system) of guinea pigs. By means of a caloric test coupled with electronystagmographic recordings, we found that cisplatin exposure caused a dose-dependent (1, 3, or 5 mg/kg) vestibular dysfunction as revealed by a decrease of slow phase velocity (SPV). In addition, cisplatin significantly inhibited the Na{sup +}, K{sup +}-ATPase and Ca{sup 2+}-ATPase activities in the ampullary tissue with a good dose-response relationship but not those of cerebellar cortex. Regression analysis indicated that a decrease of SPV was well correlated with the reduction of Na{sup +}, K{sup +}-ATPase and Ca{sup 2+}-ATPase activities of the ampullary tissue. D-Methionine (300 mg/kg) reduced both abnormalities of SPV and ATPase activities in a correlated manner. Moreover, cisplatin exposure led to a significant dose-dependent increase of lipid peroxidation and nitric oxide concentrations of the vestibules, which could be significantly suppressed by D-methionine. However, cisplatin did not alter the levels of lipid peroxidation and nitric oxide of the cerebellum. In conclusion, cisplatin inhibited ATPase activities and increased oxidative stress in guinea pig vestibular labyrinths. D-Methionine attenuated cisplatin-induced vestibulotoxicity associated with ionic disturbance through its antioxidative property.

  11. Acute tianeptine treatment selectively modulates neuronal activation in the central nucleus of the amygdala and attenuates fear extinction.

    PubMed

    Godsil, B P; Bontempi, B; Mailliet, F; Delagrange, P; Spedding, M; Jay, T M

    2015-11-01

    Antidepressant drugs are commonly prescribed treatments for anxiety disorders, and there is growing interest in understanding how these drugs impact fear extinction because extinction learning is pivotal to successful exposure-based therapy (EBT). A key objective within this domain is understanding how antidepressants alter the activation of specific elements of the limbic-based network that governs such fear processing. Chronic treatment with the antidepressant tianeptine has been shown to reduce the acquisition of extinction learning in rats, yet the drug's acute influence on activation in prefrontal and amygdalar regions, and on extinction learning are not well understood. To assess its influence on cellular activation, rats were injected with tianeptine and Fos immunoreactivity was measured in these regions. Acute tianeptine treatment selectively altered Fos expression within subdivisions of the central nucleus of the amygdala (CEA) in a bidirectional manner that varied in relation to ongoing activation within the capsular subdivision and its prefrontal and intra-amygdalar inputs. This pattern of results suggests that the drug can conditionally modulate the activation of CEA subdivisions, which contain microcircuits strongly implicated in fear processing. The effect of acute tianeptine was also examined with respect to the acquisition, consolidation and expression of fear extinction in rats. Acute tianeptine attenuated extinction learning as well as the recall of extinction memory, which underscores that acute dosing with the drug could alter learning during EBT. Together these findings provide a new perspective for understanding the mechanism supporting tianeptine's clinical efficacy, as well as its potential influence on CEA-based learning mechanisms. PMID:25560759

  12. Acute tianeptine treatment selectively modulates neuronal activation in the central nucleus of the amygdala and attenuates fear extinction.

    PubMed

    Godsil, B P; Bontempi, B; Mailliet, F; Delagrange, P; Spedding, M; Jay, T M

    2015-11-01

    Antidepressant drugs are commonly prescribed treatments for anxiety disorders, and there is growing interest in understanding how these drugs impact fear extinction because extinction learning is pivotal to successful exposure-based therapy (EBT). A key objective within this domain is understanding how antidepressants alter the activation of specific elements of the limbic-based network that governs such fear processing. Chronic treatment with the antidepressant tianeptine has been shown to reduce the acquisition of extinction learning in rats, yet the drug's acute influence on activation in prefrontal and amygdalar regions, and on extinction learning are not well understood. To assess its influence on cellular activation, rats were injected with tianeptine and Fos immunoreactivity was measured in these regions. Acute tianeptine treatment selectively altered Fos expression within subdivisions of the central nucleus of the amygdala (CEA) in a bidirectional manner that varied in relation to ongoing activation within the capsular subdivision and its prefrontal and intra-amygdalar inputs. This pattern of results suggests that the drug can conditionally modulate the activation of CEA subdivisions, which contain microcircuits strongly implicated in fear processing. The effect of acute tianeptine was also examined with respect to the acquisition, consolidation and expression of fear extinction in rats. Acute tianeptine attenuated extinction learning as well as the recall of extinction memory, which underscores that acute dosing with the drug could alter learning during EBT. Together these findings provide a new perspective for understanding the mechanism supporting tianeptine's clinical efficacy, as well as its potential influence on CEA-based learning mechanisms.

  13. Sinomenine induces the generation of intestinal Treg cells and attenuates arthritis via activation of aryl hydrocarbon receptor.

    PubMed

    Tong, Bei; Yuan, Xusheng; Dou, Yannong; Wu, Xin; Wang, Yuhui; Xia, Yufeng; Dai, Yue

    2016-10-01

    Sinomenine (SIN), an anti-arthritis drug, has previously been proven to exert immunomodulatory activity in rats by inducing intestinal regulatory T-cells (Treg cells). Here, we assessed the effect of SIN on the generation and function of Treg cells in autoimmune arthritis, and the underlying mechanisms in view of aryl hydrocarbon receptor (AhR). The proportions of Treg cells and IL-17-producing T-cells (Th17 cells) differentiated from naive T-cells were analyzed by flow cytometric analysis. The AhR agonistic effect of SIN was tested by analyzing the activation of downstream signaling pathways and target genes. The dependence of intestinal Treg cell induction and arthritis alleviation by SIN on AhR activation was confirmed in a mouse collagen-induced arthritis (CIA) model. SIN promoted the differentiation and function of intestinal Treg cells in vitro. It induced the expression and activity of AhR target gene, promoted AhR/Hsp90 dissociation and AhR nuclear translocation, induced XRE reporter activity, and facilitated AhR/XRE binding in vitro, displaying the potential to be an agonist of AhR. In CIA mice, SIN induced the generation of intestinal Treg cells, and facilitated the immunosuppressive function of these Treg cells as shown by an adoptive transfer test. In addition, the induction of intestinal Treg cells and the anti-arthritic effect of SIN in CIA mice could be largely diminished by the AhR antagonist resveratrol. SIN attenuates arthritis by promoting the generation and function of Treg cells in an AhR-dependent manner. PMID:27617398

  14. Diosgenin attenuates hepatic stellate cell activation through transforming growth factor-β/Smad signaling pathway

    PubMed Central

    Xie, Wei-Lin; Jiang, Rong; Shen, Xiao-Lu; Chen, Zhi-Yu; Deng, Xiao-Ming

    2015-01-01

    Activation of hepatic stellate cells (HSC) plays a pivotal role in the development of hepatic fibrosis. Transforming growth factor-β1 (TGF-β1) is considered to be the main stimuli factor responsible for the activation of HSC. Diosgenin is a steroidal saponin found in several plants including Solanum and Dioscorea species, and it inhibited high glucose-induced renal tubular fibrosis. However, the effects of diosgenin against hepatic fibrosis remain elusive. Therefore, in this study, we investigated the effects of diosgenin on TGF-β1-induced HSCs and elucidate the possible mechanism of its anti-fibrotic effect. Our results demonstrated that diosgenin inhibited TGF-β1-induced HSC proliferation, reduced the expression of collagen I and α-smooth muscle actin (α-SMA), as well as the expression of TGF-β receptor I (TGF-β RI) and II. Moreover, diosgenin suppressed TGF-β1-induced phosphorylation of Smad3 in HSCs. In conclusion, our data demonstrate that diosgenin inhibited HSC-T6 cell proliferation and activation, at least in part, via the TGF-β1/Smad signaling pathway. These results provide that diosgenin may have potential to treat liver fibrosis. PMID:26884947

  15. Continuous Melatonin Attenuates the Regressing Activities of Short Photoperiod in Male Golden Hamsters

    PubMed Central

    Choi, Donchan

    2013-01-01

    Golden hamsters reproduce in a limited time of a year. Their sexual activities are active in summer but inactive in winter during which day length does not exceed night time and environmental conditions are severe to them. The reproductive activities are determined by the length of light in a day (photoperiod). Melatonin is synthesized and secreted only at night time from the pineal gland. Duration of elevated melatonin is longer in winter than summer, resulting in gonadal regression. The present study aimed at the influences of continuous melatonin treatments impinging on the gonadal function in male golden hamsters. Animals received empty or melatonin-filled capsules for 10 weeks. They were divided into long photoperiod (LP) and short photoperiod (SP). All the animals maintained in LP (either empty or melatonin-filled capsules) showed large testes, implying that melatonin had no effects on testicular functions. Animals housed in SP displayed completely regressed testes. But animals kept in SP and implanted with melatonin capsules exhibited blockage of full regression by SP. These results suggest that constant release of melatonin prohibits the regressing influence of SP. PMID:25949127

  16. Diosgenin attenuates hepatic stellate cell activation through transforming growth factor-β/Smad signaling pathway.

    PubMed

    Xie, Wei-Lin; Jiang, Rong; Shen, Xiao-Lu; Chen, Zhi-Yu; Deng, Xiao-Ming

    2015-01-01

    Activation of hepatic stellate cells (HSC) plays a pivotal role in the development of hepatic fibrosis. Transforming growth factor-β1 (TGF-β1) is considered to be the main stimuli factor responsible for the activation of HSC. Diosgenin is a steroidal saponin found in several plants including Solanum and Dioscorea species, and it inhibited high glucose-induced renal tubular fibrosis. However, the effects of diosgenin against hepatic fibrosis remain elusive. Therefore, in this study, we investigated the effects of diosgenin on TGF-β1-induced HSCs and elucidate the possible mechanism of its anti-fibrotic effect. Our results demonstrated that diosgenin inhibited TGF-β1-induced HSC proliferation, reduced the expression of collagen I and α-smooth muscle actin (α-SMA), as well as the expression of TGF-β receptor I (TGF-β RI) and II. Moreover, diosgenin suppressed TGF-β1-induced phosphorylation of Smad3 in HSCs. In conclusion, our data demonstrate that diosgenin inhibited HSC-T6 cell proliferation and activation, at least in part, via the TGF-β1/Smad signaling pathway. These results provide that diosgenin may have potential to treat liver fibrosis. PMID:26884947

  17. CTCF and CohesinSA-1 Mark Active Promoters and Boundaries of Repressive Chromatin Domains in Primary Human Erythroid Cells

    PubMed Central

    Steiner, Laurie A.; Schulz, Vincent; Makismova, Yelena; Lezon-Geyda, Kimberly; Gallagher, Patrick G.

    2016-01-01

    Background CTCF and cohesinSA-1 are regulatory proteins involved in a number of critical cellular processes including transcription, maintenance of chromatin domain architecture, and insulator function. To assess changes in the CTCF and cohesinSA-1 interactomes during erythropoiesis, chromatin immunoprecipitation coupled with high throughput sequencing and mRNA transcriptome analyses via RNA-seq were performed in primary human hematopoietic stem and progenitor cells (HSPC) and primary human erythroid cells from single donors. Results Sites of CTCF and cohesinSA-1 co-occupancy were enriched in gene promoters in HSPC and erythroid cells compared to single CTCF or cohesin sites. Cell type-specific CTCF sites in erythroid cells were linked to highly expressed genes, with the opposite pattern observed in HSPCs. Chromatin domains were identified by ChIP-seq with antibodies against trimethylated lysine 27 histone H3, a modification associated with repressive chromatin. Repressive chromatin domains increased in both number and size during hematopoiesis, with many more repressive domains in erythroid cells than HSPCs. CTCF and cohesinSA-1 marked the boundaries of these repressive chromatin domains in a cell-type specific manner. Conclusion These genome wide data, changes in sites of protein occupancy, chromatin architecture, and related gene expression, support the hypothesis that CTCF and cohesinSA-1 have multiple roles in the regulation of gene expression during erythropoiesis including transcriptional regulation at gene promoters and maintenance of chromatin architecture. These data from primary human erythroid cells provide a resource for studies of normal and perturbed erythropoiesis. PMID:27219007

  18. Curcumin attenuates hyperglycaemia-mediated AMPK activation and oxidative stress in cerebrum of streptozotocin-induced diabetic rat.

    PubMed

    Lakshmanan, Arun Prasath; Watanabe, Kenichi; Thandavarayan, Rajarajan A; Sari, Flori R; Meilei, Harima; Soetikno, Vivian; Arumugam, Somasundaram; Giridharan, Vijayasree V; Suzuki, Kenji; Kodama, Makoto

    2011-07-01

    Oxidative stress has been strongly implicated in the pathogenesis of diabetic encephalopathy (DE). Numerous studies have demonstrated a close relationship between oxidative stress and AMPK activation in various disorders, including diabetes-related brain disorders. Since curcumin has powerful antioxidant properties, this study investigated its effects on hyperglycaemia-mediated oxidative stress and AMPK activation in rats with DE. Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ-55 mg/kg BW). The diabetic rats were then orally administered curcumin (100 mg/kg BW) or vehicle for 8 weeks. The cerebra of the diabetic rats displayed upregulated protein expression of AdipoR1, p-AMPKα1, Tak1, GLUT4, NADPH oxidase sub-units, caspase-12 and 3-NT and increased lipid peroxidation in comparison with the controls and all of these effects were significantly attenuated with curcumin treatment, except for the increase in AdipoR1 expressions. These results provide a new insight into the beneficial effects of curcumin on hyperglycaemia-mediated DE, which are produced through the down-regulation of AMPK-mediated gluconeogenesis associated with its anti-oxidant property.

  19. Catechins and Sialic Acid Attenuate Helicobacter pylori-Triggered Epithelial Caspase-1 Activity and Eradicate Helicobacter pylori Infection

    PubMed Central

    Yang, Jyh-Chin; Yang, Hung-Chih; Shun, Chia-Tung; Wang, Teh-Hong; Chien, Chiang-Ting; Kao, John Y.

    2013-01-01

    The inflammasome/caspase-1 signaling pathway in immune cells plays a critical role in bacterial pathogenesis; however, the regulation of this pathway in the gastric epithelium during Helicobacter pylori infection is yet to be elucidated. Here, we investigated the effect of catechins (CAs), sialic acid (SA), or combination of CA and SA (CASA) on H. pylori-induced caspase-1-mediated epithelial damage, as well as H. pylori colonization in vitro (AGS cells) and in vivo (BALB/c mice). Our results indicate that the activity of caspase-1 and the expression of its downstream substrate IL-1β were upregulated in H. pylori-infected AGS cells. In addition, we observed increased oxidative stress, NADPH oxidase gp91phox, CD68, caspase-1/IL-1β, and apoptosis, but decreased autophagy, in the gastric mucosa of H. pylori-infected mice. We have further demonstrated that treatment with CASA led to synergistic anti-H. pylori activity and was more effective than treatment with CA or SA alone. In particular, treatment with CASA for 10 days eradicated H. pylori infection in up to 95% of H. pylori-infected mice. Taken together, we suggest that the pathogenesis of H. pylori involves a gastric epithelial inflammasome/caspase-1 signaling pathway, and our results show that CASA was able to attenuate this pathway and effectively eradicate H. pylori infection. PMID:23653660

  20. Whole body heat stress attenuates baroreflex control of muscle sympathetic nerve activity during postexercise muscle ischemia

    PubMed Central

    Cui, Jian; Shibasaki, Manabu; Davis, Scott L.; Low, David A.; Keller, David M.; Crandall, Craig G.

    2009-01-01

    Both whole body heat stress and stimulation of muscle metabolic receptors activate muscle sympathetic nerve activity (MSNA) through nonbaroreflex pathways. In addition to stimulating muscle metaboreceptors, exercise has the potential to increase internal temperature. Although we and others report that passive whole body heating does not alter the gain of the arterial baroreflex, it is unknown whether increased body temperature, often accompanying exercise, affects baroreflex function when muscle metaboreceptors are stimulated. This project tested the hypothesis that whole body heating alters the gain of baroreflex control of muscle sympathetic nerve activity (MSNA) and heart rate during muscle metaboreceptor stimulation engaged via postexercise muscle ischemia (PEMI). MSNA, blood pressure (BP, Finometer), and heart rate were recorded from 11 healthy volunteers. The volunteers performed isometric handgrip exercise until fatigue, followed by 2.5 min of PEMI. During PEMI, BP was acutely reduced and then raised pharmacologically using the modified Oxford technique. This protocol was repeated two to three times when volunteers were normothermic, and again during heat stress (increase core temperature ∼ 0.7°C) conditions. The slope of the relationship between MSNA and BP during PEMI was less negative (i.e., decreased baroreflex gain) during whole body heating when compared with the normothermic condition (−4.34 ± 0.40 to −3.57 ± 0.31 units·beat−1·mmHg−1, respectively; P = 0.015). The gain of baroreflex control of heart rate during PEMI was also decreased during whole body heating (P < 0.001). These findings indicate that whole body heat stress reduces baroreflex control of MSNA and heart rate during muscle metaboreceptor stimulation. PMID:19213933

  1. Novel matrine derivative MD-1 attenuates hepatic fibrosis by inhibiting EGFR activation of hepatic stellate cells.

    PubMed

    Feng, Yi; Ying, Hai-Yan; Qu, Ying; Cai, Xiao-Bo; Xu, Ming-Yi; Lu, Lun-Gen

    2016-09-01

    Matrine (MT), the effective component of Sophora flavescens Ait, has been shown to have anti-inflammation, immune-suppressive, anti-tumor, and anti-hepatic fibrosis activities. However, the pharmacological effects of MT still need to be strengthened due to its relatively low efficacy and short half-life. In the present study, we report a more effective thio derivative of MT, MD-1, and its inhibitory effects on the activation of hepatic stellate cells (HSCs) in both cell culture and animal models. Cytological experiments showed that MD-1 can inhibit the proliferation of HSC-T6 cells with a half-maximal inhibitory concentration (IC50) of 62 μmol/L. In addition, MD-1 more strongly inhibits the migration of HSC-T6 cells compared to MT and can more effectively induce G0/G1 arrest and apoptosis. Investigating the biological mechanisms underlying anti-hepatic fibrosis in the presence of MD-1, we found that MD-1 can bind the epidermal growth factor receptor (EGFR) on the surface of HSC-T6 cells, which can further inhibit the phosphorylation of EGFR and its downstream protein kinase B (Akt), resulting in decreased expression of cyclin D1 and eventual inhibition of the activation of HSC-T6 cells. Furthermore, in rats with dimethylnitrosamine (DMN)-induced hepatic fibrosis, MD-1 slowed the development and progression of hepatic fibrosis, protecting hepatic parenchymal cells and improving hepatic functions. Therefore, MD-1 is a potential drug for anti-hepatic fibrosis.

  2. Activation of guanylate cyclase-C attenuates stretch responses and sensitization of mouse colorectal afferents

    PubMed Central

    Feng, Bin; Kiyatkin, Michael E.; La, Jun-Ho; Ge, Pei; Solinga, Robert; Silos-Santiago, Inmaculada; Gebhart, G.F.

    2013-01-01

    Irritable bowel syndrome (IBS) is characterized by altered bowel habits, persistent pain and discomfort, and typically colorectal hypersensitivity. Linaclotide, a peripherally-restricted 14-amino acid peptide approved for the treatment of IBS with constipation, relieves constipation and reduces IBS-associated pain in these patients presumably by activation of guanylate cyclase-C (GC-C), which stimulates production and release of cyclic guanosine monophosphate (cGMP) from intestinal epithelial cells. We investigated whether activation of GC-C by the endogenous agonist uroguanylin or the primary downstream effector of that activation, cGMP, directly modulates responses and sensitization of mechanosensitive colorectal primary afferents. The distal 2 cm of mouse colorectum with attached pelvic nerve was harvested, pinned flat mucosal side up for in vitro single-fiber recordings and the encoding properties of mechanosensitive afferents (serosal, mucosal, muscular and muscular-mucosal) to probing and circumferential stretch studied. Both cGMP (10–300μM) and uroguanylin (1–1000nM) applied directly to colorectal receptive endings significantly reduced responses of muscular and muscular-mucosal afferents to stretch; serosal and mucosal afferents were not affected. Sensitized responses (i.e., increased responses to stretch) of muscular and muscular-mucosal afferents were reversed by cGMP, returning responses to stretch to control. Blocking the transport of cGMP from colorectal epithelia by probenecid, a mechanism validated by studies in cultured intestinal T84 cells, abolished the inhibitory effect of uroguanylin on muscular-mucosal afferents. These results suggest that GC-C agonists like linaclotide alleviate colorectal pain and hypersensitivity by dampening stretch-sensitive afferent mechanosensitivity and normalizing afferent sensitization. PMID:23739979

  3. Baicalin attenuates acute myocardial infarction of rats via mediating the mitogen-activated protein kinase pathway.

    PubMed

    Liu, Xiaobing; Gu, Jianmin; Fan, Yuqi; Shi, Huihua; Jiang, Mier

    2013-01-01

    Baicalin is a bioactive ingredient from the herb and has possessed various pharmacological actions. The present study was performed to evaluate the cardioprotective potential of baicalin against myocardial infarction and explore the potential mechanism. Baicalin was intraperitoneally injected into the rats by the doses of 50, 100 and 200 mg/kg, respectively, once a day for 7 d and, 30 min after the last administration, the left coronary artery was ligated. Infarct size was measured to analyze the myocardial damage. Myocardial specific enzymes, including creatine kinase (CK), the MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase (LDH) and cardiac troponin T (cTnT) were determined with the colorimetric method. Evidence for myocardial apoptosis was detected by caspase-3 activity measurement and Western blot analysis. We also examined the protein levels of three major subgroups of mitogen-activated protein kinases (MAPKs), namely, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 by immuoblotting. Our results indicated that baicalin significantly reduced the infarct size and myocardial enzymes (CK, CK-MB, LDH and cTnT). Administration of baicalin also suppressed the activity and protein expression of caspase-3. Moreover, the protein level of phosphorylated ERK (p-ERK) was found to be evidently augmented while the phosphorylated JNK (p-JNK) and phosphorylated p38 (p-p38) were strikingly diminished in infarcted rats with baicalin treatment. These findings suggest that the baicalin's cardioprotection associates with mediation of MAPK cascades in acute myocardial infarction of rats.

  4. Galantamine attenuates amyloid-β deposition and astrocyte activation in APP/PS1 transgenic mice.

    PubMed

    Wu, Zhaoxuan; Zhao, Lingling; Chen, Xinxin; Cheng, Xiaoying; Zhang, Yan

    2015-12-01

    While galantamine may not provide a cure for Alzheimer's disease (AD), it decelerates the progression and provides symptomatic relief for this disorder. The aim of this study was to investigate the effect of chronic galantamine treatment on cognitive performance, Aβ deposition and astrocyte activation in the transgenic APP/PS1 mouse model of AD. Galantamine (5mg/kg, i.p.) or 0.9% saline was administrated twice daily for eight weeks in 10-month-old APP/PS1 mice. In addition a separate group of 10-month old male C57BL/6 wild type mice was included as a reference control. Compared with saline treated APP/PS1 mice, galantamine treated mice exhibited significantly improved escape latencies on Days 6 and 7 of testing (p<0.05) and significantly decreased numbers of platform crossings (p<0.01) as assessed in the Morris water maze. Galantamine reduced the total area of amyloid load within the hippocampus of transgenic APP/PS1 mice, inhibited astrocyte activation as assessed by immunohistochemistry and decreased intracellular TNF-α and IL-6 expression as determined by immunofluorescence. Galantamine failed to alter hippocampal levels of TNF-α and IL-6 as assayed by ELISA. Galantamine may be involved in modifying AD pathophysiological mechanisms by alleviating Aβ deposition and neuroinflammation. The results from this study provide new evidence for use of galantamine in the treatment of AD. PMID:26521029

  5. NuSAP modulates the dynamics of kinetochore microtubules by attenuating MCAK depolymerisation activity

    PubMed Central

    Li, Chenyu; Zhang, Yajun; Yang, Qiaoyun; Ye, Fan; Sun, Stella Ying; Chen, Ee Sin; Liou, Yih-Cherng

    2016-01-01

    Nucleolar and spindle-associated protein (NuSAP) is a microtubule-associated protein that functions as a microtubule stabiliser. Depletion of NuSAP leads to severe mitotic defects, however the mechanism by which NuSAP regulates mitosis remains elusive. In this study, we identify the microtubule depolymeriser, mitotic centromere-associated kinesin (MCAK), as a novel binding partner of NuSAP. We show that NuSAP regulates the dynamics and depolymerisation activity of MCAK. Phosphorylation of MCAK by Aurora B kinase, a component of the chromosomal passenger complex, significantly enhances the interaction of NuSAP with MCAK and modulates the effects of NuSAP on the depolymerisation activity of MCAK. Our results reveal an underlying mechanism by which NuSAP controls kinetochore microtubule dynamics spatially and temporally by modulating the depolymerisation function of MCAK in an Aurora B kinase-dependent manner. Hence, this study provides new insights into the function of NuSAP in spindle formation during mitosis. PMID:26733216

  6. H2S Inhibits Hyperglycemia-Induced Intrarenal Renin-Angiotensin System Activation via Attenuation of Reactive Oxygen Species Generation

    PubMed Central

    Ni, Jun; Li, Chen; Shao, Decui; Liu, Jia; Shen, Yang; Wang, Zhen; Zhou, Li; Zhang, Wei; Huang, Yu; Yu, Chen; Wang, Rui; Lu, Limin

    2013-01-01

    Decrease in endogenous hydrogen sulfide (H2S) was reported to participate in the pathogenesis of diabetic nephropathy (DN). This study is aimed at exploring the relationship between the abnormalities in H2S metabolism, hyperglycemia-induced oxidative stress and the activation of intrarenal renin-angiotensin system (RAS). Cultured renal mesangial cells (MCs) and streptozotocin (STZ) induced diabetic rats were used for the studies. The expressions of angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin II (Ang II) type I receptor (AT1), transforming growth factor-β1 (TGF-β1) and collagen IV were measured by real time PCR and Western blot. Reactive oxygen species (ROS) production was assessed by fluorescent probe assays. Cell proliferation was analyzed by 5'-bromo-2'-deoxyuridine incorporation assay. Ang II concentration was measured by an enzyme immunoassay. AGT, ACE and AT1 receptor mRNA levels and Ang II concentration were increased in high glucose (HG) -treated MCs, the cell proliferation rate and the production of TGF-β1 and of collagen IV productions were also increased. The NADPH oxidase inhibitor diphenylenechloride iodonium (DPI) was able to reverse the HG-induced RAS activation and the changes in cell proliferation and collagen synthesis. Supplementation of H2S attenuated HG-induced elevations in ROS and RAS activation. Blockade on H2S biosynthesis from cystathione-γ-lyase (CSE) by DL-propargylglycine (PPG) resulted in effects similar to that of HG treatment. In STZ-induced diabetic rats, the changes in RAS were also reversed by H2S supplementation without affecting blood glucose concentration. These data suggested that the decrease in H2S under hyperglycemic condition leads to an imbalance between oxidative and reductive species. The increased oxidative species results in intrarenal RAS activation, which, in turn, contributes to the pathogenesis of renal dysfunction. PMID:24058553

  7. Perindopril Attenuates Lipopolysaccharide-Induced Amyloidogenesis and Memory Impairment by Suppression of Oxidative Stress and RAGE Activation.

    PubMed

    Goel, Ruby; Bhat, Shahnawaz Ali; Hanif, Kashif; Nath, Chandishwar; Shukla, Rakesh

    2016-02-17

    Clinical and preclinical studies account hypertension as a risk factor for dementia. We reported earlier that angiotensin-converting enzyme (ACE) inhibition attenuated the increased vulnerability to neurodegeneration in hypertension and prevented lipopolysaccharide (LPS)-induced memory impairment in normotensive wistar rats (NWRs) and spontaneously hypertensive rats (SHRs). Recently, a receptor for advanced glycation end products (RAGE) has been reported to induce amyloid beta (Aβ1-42) deposition and memory impairment in hypertensive animals. However, the involvement of ACE in RAGE activation and amyloidogenesis in the hypertensive state is still unexplored. Therefore, in this study, we investigated the role of ACE on RAGE activation and amyloidogenesis in memory-impaired NWRs and SHRs. Memory impairment was induced by repeated (on days 1, 4, 7, and 10) intracerebroventricular (ICV) injections of LPS in SHRs (25 μg) and NWRs (50 μg). Our data showed that SHRs exhibited increased oxidative stress (increased gp91-phox/NOX-2 expression and ROS generation), RAGE, and β-secretase (BACE) expression without Aβ1-42 deposition. LPS (25 μg, ICV) further amplified oxidative stress, RAGE, and BACE activation, culminating in Aβ1-42 deposition and memory impairment in SHRs. Similar changes were observed at the higher dose of LPS (50 μg, ICV) in NWRs. Further, LPS-induced oxidative stress was associated with endothelial dysfunction and reduction in cerebral blood flow (CBF), more prominently in SHRs than in NWRs. Finally, we showed that perindopril (0.1 mg/kg, 15 days) prevented memory impairment by reducing oxidative stress, RAGE activation, amyloidogenesis, and improved CBF in both SHRs and NWRs. These findings suggest that perindopril might be used as a therapeutic strategy for the early stage of dementia. PMID:26689453

  8. Coenzyme Q10 Attenuates High Glucose-Induced Endothelial Progenitor Cell Dysfunction through AMP-Activated Protein Kinase Pathways.

    PubMed

    Tsai, Hsiao-Ya; Lin, Chih-Pei; Huang, Po-Hsun; Li, Szu-Yuan; Chen, Jia-Shiong; Lin, Feng-Yen; Chen, Jaw-Wen; Lin, Shing-Jong

    2016-01-01

    Coenzyme Q10 (CoQ10), an antiapoptosis enzyme, is stored in the mitochondria of cells. We investigated whether CoQ10 can attenuate high glucose-induced endothelial progenitor cell (EPC) apoptosis and clarified its mechanism. EPCs were incubated with normal glucose (5 mM) or high glucose (25 mM) environment for 3 days, followed by treatment with CoQ10 (10 μM) for 24 hr. Cell proliferation, nitric oxide (NO) production, and JC-1 assay were examined. The specific signal pathways of AMP-activated protein kinase (AMPK), eNOS/Akt, and heme oxygenase-1 (HO-1) were also assessed. High glucose reduced EPC functional activities, including proliferation and migration. Additionally, Akt/eNOS activity and NO production were downregulated in high glucose-stimulated EPCs. Administration of CoQ10 ameliorated high glucose-induced EPC apoptosis, including downregulation of caspase 3, upregulation of Bcl-2, and increase in mitochondrial membrane potential. Furthermore, treatment with CoQ10 reduced reactive oxygen species, enhanced eNOS/Akt activity, and increased HO-1 expression in high glucose-treated EPCs. These effects were negated by administration of AMPK inhibitor. Transplantation of CoQ10-treated EPCs under high glucose conditions into ischemic hindlimbs improved blood flow recovery. CoQ10 reduced high glucose-induced EPC apoptosis and dysfunction through upregulation of eNOS, HO-1 through the AMPK pathway. Our findings provide a potential treatment strategy targeting dysfunctional EPC in diabetic patients.

  9. [Estimation of Diffuse Attenuation Coefficient of Photosynthetically Active Radiation in Xin'anjiang Reservoir Based on Landsat 8 Data].

    PubMed

    Zhang, Yi-bo; Zhang, Yun-lin; Zha, Yong; Shi, Kun; Zhou, Yong-qiang; Liu, Ming-liang

    2015-12-01

    Photosynthetically active radiation (PAR) is defined as the wavelength band of 400 to 700 nm, representing most of the visible solar radiation that could be used for photosynthesis. PAR is attenuated by the absorption and scattering of nonpigment suspended matter, chromophoric dissolved organic matter and phytoplankton, and it plays an important role in determining the density and distribution of aquatic organisms. This study developed an empirical model and presented the spatial-temporal distribution of PAR diffuse attenuation coefficient [Kd (PAR)] for the slightly turbid Xin'anjiang Reservoir based on the in situ ground data and the matching Landsat 8 data. The results showed that the three-hand combinational model of Kd ( PAR) using Band 2, Band 3 and Band 8 could give a reasonable and acceptable estimation accuracy with a determination coefficient of 0. 87. Independent dataset was used to validate the model with a mean relative error of 9.16% and a root mean square error of 0.06 m⁻¹. Therefore, the three-band combination using Landsat 8 data could be used to accurately estimate Kd (PAR) in the slightly turbid Xin'anjiang Reservoir. Kd (PAR) exhibited significant seasonal and spatial differences. Kd (PAR) was higher in autumn (September-November) and summer (June-August) with the average Kd (PAR) of (0.82 ± 0.60) m⁻¹ and (0.77 ± 0.41) m⁻¹, but lower in winter (December-February) and spring (March-May) with the average Kd (PAR) of (0.56 ± 0.50) m⁻¹ and (0.40 ± 0.45 ) m⁻¹, respectively. Spatially, Kd (PAR) ranged from 0.002 to 13.86 m⁻¹ with an average of (0.64 ± 0.49) m⁻¹. The temporal heterogeneity of Kd (PAR) was mainly caused by the seasonal rainfall and seasonal growth of phytoplankton. The spatial heterogeneity was mainly caused by suspended matter concentration derived from watershed inputs and human dredging activity. PMID:27011976

  10. Structural basis for the requirement of additional factors for MLL1 SET domain activity and recognition of epigenetic marks.

    PubMed

    Southall, Stacey M; Wong, Poon-Sheng; Odho, Zain; Roe, S Mark; Wilson, Jon R

    2009-01-30

    The mixed-lineage leukemia protein MLL1 is a transcriptional regulator with an essential role in early development and hematopoiesis. The biological function of MLL1 is mediated by the histone H3K4 methyltransferase activity of the carboxyl-terminal SET domain. We have determined the crystal structure of the MLL1 SET domain in complex with cofactor product AdoHcy and a histone H3 peptide. This structure indicates that, in order to form a well-ordered active site, a highly variable but essential component of the SET domain must be repositioned. To test this idea, we compared the effect of the addition of MLL complex members on methyltransferase activity and show that both RbBP5 and Ash2L but not Wdr5 stimulate activity. Additionally, we have determined the effect of posttranslational modifications on histone H3 residues downstream and upstream from the target lysine and provide a structural explanation for why H3T3 phosphorylation and H3K9 acetylation regulate activity. PMID:19187761

  11. Ulinastatin attenuates brain edema after traumatic brain injury in rats.

    PubMed

    Cui, Tao; Zhu, Gangyi

    2015-03-01

    Traumatic brain injury (TBI) remains the leading cause of injury-related death and disability. Brain edema, one of the most major complications of TBI, contributes to elevated intracranial pressure, and poor prognosis following TBI. The objective of this study was to evaluate whether Ulinastatin (UTI), a serine protease inhibitor, attenuates brain edema following TBI. Our results showed that treatment with UTI at a dose of 50,000 U/kg attenuated the brain edema, as assayed by water content 24 h after TBI induction. This attenuation was associated with a significant decrease of the expression level of aquaporin-4. In addition, we showed that UTI treatment also markedly inhibited the expression of pro-inflammatory cytokines including IL-1β and TNF-α as well as activity of NF-κB. Collectively, our findings suggested that UTI may be a promising strategy to treat brain edema following TBI.

  12. Astrocyte reactivity to Fas activation is attenuated in TIMP-1 deficient mice, an in vitro study

    PubMed Central

    Ogier, Crystel; Creidy, Rita; Boucraut, José; Soloway, Paul D; Khrestchatisky, Michel; Rivera, Santiago

    2005-01-01

    Background Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a multifunctional secreted protein with pleiotropic actions, including the inhibition of matrix metalloproteinases (MMPs), cell death/survival and growth promoting activities. After inflammatory challenge, the levels of TIMP-1 are highly and selectively upregulated in astrocytes among glial cells, but little is know about its role in these neural cells. We investigated the influence of TIMP-1 null mutation in the reactivity of cultured astrocytes to pro-inflammatory stimuli with TNF-α and anti-Fas antibody. Results When compared to WT, mutant astrocytes displayed an overall increased constitutive gelatinase expression and were less responsive to Fas-mediated upregulation of MMP-9, of monocyte chemoattractant protein-1 (MCP-1) and of intercellular cell adhesion molecule-1 (ICAM-1), all markers of astrocyte inflammatory response. In contrast, TNF-α treatment induced all these factors similarly regardless of the astrocyte genotype. The incorporation of 3H-thymidin, a marker of cell proliferation, increased in wild-type (WT) astrocytes after treatment with anti-Fas antibody or recombinant TIMP-1 but not in mutant astrocytes. Finally, lymphocyte chemotaxis was differentially regulated by TNF-α in WT and TIMP-1 deficient astrocytes. Conclusion We provide evidence that the alteration of the MMP/TIMP balance in astrocytes influences their reactivity to pro-inflammatory stimuli and that Fas activation modulates the expression of members of the MMP/TIMP axis. We hypothesise that the Fas/FasL transduction pathway and the MMP/TIMP system interact in astrocytes to modulate their inflammatory response to environmental stimuli. PMID:16316466

  13. Apigenin Attenuates Oxidative Injury in ARPE-19 Cells thorough Activation of Nrf2 Pathway

    PubMed Central

    Li, Min; Chen, Weiwei; Yu, Haitao; Yang, Yan; Hang, Li

    2016-01-01

    The current study was aimed at evaluating the therapeutic implication of apigenin and to elucidate the underlying mechanism. The tert-butyl hydroperoxide (t-BHP) at 200 μM was used to induce oxidative stress-associated injury in ARPE-19 cells. Apigenin at concentrations less than 800 μM did not cause cytotoxic effects on ARPE-19 cells. Cell viability assay showed that apigenin at 200 μM significantly promoted cell survival in t-BHP-treated ARPE-19 cells. Additionally, apigenin at 100 μM significantly protected ARPE-19 cells from t-BHP-induced apoptosis. Molecular examinations demonstrated that apigenin at 400 μM significantly upregulated the mRNA and protein expression of Nrf2 and stimulated its nuclear translocation in ARPE-19 cells treated with or without t-BHP. Apigenin 400 μM also significantly elevated the expression of HO-1, NQO1, and GCLM at both mRNA and protein levels in the presence or absence of t-BHP. Furthermore, apigenin at 400 μM significantly increased the activities of SOD, CAT, GSH-PX, and T-AOC and reduced the levels of ROS and MDA in t-BHP-treated ARPE-19 cells. However, these effects of apigenin were all abolished by being transfected with Nrf2 siRNA. Collectively, our current data indicated that apigenin exerted potent antioxidant properties in ARPE-19 cells challenged with t-BHP, which were dependent on activation of Nrf2 signaling.

  14. Apigenin Attenuates Oxidative Injury in ARPE-19 Cells thorough Activation of Nrf2 Pathway

    PubMed Central

    Li, Min; Chen, Weiwei; Yu, Haitao; Yang, Yan; Hang, Li

    2016-01-01

    The current study was aimed at evaluating the therapeutic implication of apigenin and to elucidate the underlying mechanism. The tert-butyl hydroperoxide (t-BHP) at 200 μM was used to induce oxidative stress-associated injury in ARPE-19 cells. Apigenin at concentrations less than 800 μM did not cause cytotoxic effects on ARPE-19 cells. Cell viability assay showed that apigenin at 200 μM significantly promoted cell survival in t-BHP-treated ARPE-19 cells. Additionally, apigenin at 100 μM significantly protected ARPE-19 cells from t-BHP-induced apoptosis. Molecular examinations demonstrated that apigenin at 400 μM significantly upregulated the mRNA and protein expression of Nrf2 and stimulated its nuclear translocation in ARPE-19 cells treated with or without t-BHP. Apigenin 400 μM also significantly elevated the expression of HO-1, NQO1, and GCLM at both mRNA and protein levels in the presence or absence of t-BHP. Furthermore, apigenin at 400 μM significantly increased the activities of SOD, CAT, GSH-PX, and T-AOC and reduced the levels of ROS and MDA in t-BHP-treated ARPE-19 cells. However, these effects of apigenin were all abolished by being transfected with Nrf2 siRNA. Collectively, our current data indicated that apigenin exerted potent antioxidant properties in ARPE-19 cells challenged with t-BHP, which were dependent on activation of Nrf2 signaling. PMID:27656262

  15. Flavonoid derivative 7,8-DHF attenuates TBI pathology via TrkB activation.

    PubMed

    Agrawal, Rahul; Noble, Emily; Tyagi, Ethika; Zhuang, Yumei; Ying, Zhe; Gomez-Pinilla, Fernando

    2015-05-01

    Traumatic brain injury (TBI) is followed by a state of metabolic dysfunction, affecting the ability of neurons to use energy and support brain plasticity; there is no effective therapy to counteract the TBI pathology. Brain-derived neurotrophic factor (BDNF) has an exceptional capacity to support metabolism and plasticity, which highly contrasts with its poor pharmacological profile. We evaluated the action of a flavonoid derivative 7,8-dihydroxyflavone (7,8-DHF), a BDNF receptor (TrkB) agonist with the pharmacological profile congruent for potential human therapies. Treatment with 7,8-DHF (5mg/kg, ip, daily for 7 days) was effective to ameliorate the effects of TBI on plasticity markers (CREB phosphorylation, GAP-43 and syntaxin-3 levels) and memory function in Barnes maze test. Treatment with 7,8-DHF restored the decrease in protein and phenotypic expression of TrkB phosphorylation after TBI. In turn, intrahippocampal injections of K252a, a TrkB antagonist, counteracted the 7,8-DHF induced TrkB signaling activation and memory improvement in TBI, suggesting the pivotal role of TrkB signaling in cognitive performance after brain injury. A potential action of 7,8-DHF on cell energy homeostasis was corroborated by the normalization in levels of PGC-1α, TFAM, COII, AMPK and SIRT1 in animals subjected to TBI. Results suggest a potential mechanism by which 7,8-DHF counteracts TBI pathology via activation of the TrkB receptor and engaging the interplay between cell energy management and synaptic plasticity. Since metabolic dysfunction is an important risk factor for the development of neurological and psychiatric disorders, these results set a precedent for the therapeutic use of 7,8-DHF in a larger context.

  16. Flavonoid derivative 7,8-DHF attenuates TBI pathology via TrkB activation

    PubMed Central

    Agrawal, Rahul; Noble, Emily; Tyagi, Ethika; Zhuang, Yumei; Ying, Zhe; Gomez-Pinilla, Fernando

    2015-01-01

    Traumatic brain injury (TBI) is followed by a state of metabolic dysfunction, affecting the ability of neurons to use energy and support brain plasticity; there is no effective therapy to counteract the TBI pathology. Brain-derived neurotrophic factor (BDNF) has an exceptional capacity to support metabolism and plasticity, which highly contrasts with its poor pharmacological profile. We evaluated the action of a flavonoid derivative 7,8-dihydroxyflavone (7,8-DHF), a BDNF receptor (TrkB) agonist with the pharmacological profile congruent for potential human therapies. Treatment with 7,8-DHF (5 mg/kg, ip, daily for 7 days) was effective to ameliorate the effects of TBI on plasticity markers (CREB phosphorylation, GAP-43 and syntaxin-3 levels) and memory function in Barnes maze test. Treatment with 7,8-DHF restored the decrease in protein and phenotypic expression of TrkB phosphorylation after TBI. In turn, intrahippocampal injections of K252a, a TrkB antagonist, counteracted the 7,8-DHF induced TrkB signaling activation and memory improvement in TBI, suggesting the pivotal role of TrkB signaling in cognitive performance after brain injury. A potential action of 7,8-DHF on cell energy homeostasis was corroborated by the normalization in levels of PGC-1α, TFAM, COII, AMPK and SIRT1 in animals subjected to TBI. Results suggest a potential mechanism by which 7,8-DHF counteracts TBI pathology via activation of the TrkB receptor and engaging the interplay between cell energy management and synaptic plasticity. Since metabolic dysfunction is an important risk factor for the development of neurological and psychiatric disorders, these results set a precedent for the therapeutic use of 7,8-DHF in a larger context. PMID:25661191

  17. Senescence-associated β-galactosidase activity marks the visceral endoderm of mouse embryos but is not indicative of senescence.

    PubMed

    Huang, Tingting; Rivera-Pérez, Jaime A

    2014-04-01

    Senescence-associated β-galactosidase (SA-β-gal) activity is widely used as a marker of cellular senescence and as an indicator of organismal aging. Here, we report that SA-β-gal activity is present in the visceral endoderm layer of early postimplantation mouse embryos in predictable patterns that vary as the embryo progresses in development. However, determination of the mitotic index and analysis of the expression of Cdkn1a (p21), a marker of senescent cells, do not indicate cellular senescence. Instead, analysis of embryos in culture revealed the presence of SA-β-gal activity in apical vacuoles of visceral endoderm cells likely a reflection of acidic β-galactosidase function in these organelles. SA-β-gal serves as a practical marker of the dynamics of the visceral endoderm that can be applied to developmental as well as functional studies of early mammalian embryos.

  18. Copper Ion Attenuated the Antiproliferative Activity of Di-2-pyridylhydrazone Dithiocarbamate Derivative; However, There Was a Lack of Correlation between ROS Generation and Antiproliferative Activity.

    PubMed

    Wang, Tingting; Fu, Yun; Huang, Tengfei; Liu, Youxun; Wu, Meihao; Yuan, Yanbin; Li, Shaoshan; Li, Changzheng

    2016-08-20

    The use of chelators for cancer treatment has been an alternative option. Dithiocarbamates have recently attracted considerable attention owning to their diverse biological activities; thus, the preparation of new dithiocarbamate derivatives with improved antitumor activity and selectivity as well as probing the underlying molecular mechanism are required. In this study, di-2-pyridylhydrazone dithiocarbamate S-propionic acid (DpdtpA) and its copper complex were prepared and characterized, and its antiproliferative activity was evaluated. The proliferation inhibition assay showed that DpdtpA exhibited excellent antiproliferative effect in hepatocellular carcinoma (IC50 = 1.3 ± 0.3 μM for HepG2, and 2.5 ± 0.6 μM for Bel-7402). However, in the presence of copper ion, the antiproliferative activity of DpdtpA was dramatically attenuated (20-30 fold) owing to the formation of copper chelate. A preliminarily mechanistic study revealed that reactive oxygen species (ROS) generation mediated the antiproliferative activity of DpdtpA, and accordingly induced apoptosis, DNA cleavage, and autophagy. Surprisingly, the cytotoxicity of DpdtpA copper complex (DpdtpA-Cu) was also involved in ROS generation; however, a paradoxical relation between cellular ROS level and cytotoxicity was observed. Further investigation indicated that DpdtpA could induce cell cycle arrest at the S phase; however, DpdtpA-Cu lacked this effect, which explained the difference in their antiproliferative activity.

  19. Copper Ion Attenuated the Antiproliferative Activity of Di-2-pyridylhydrazone Dithiocarbamate Derivative; However, There Was a Lack of Correlation between ROS Generation and Antiproliferative Activity.

    PubMed

    Wang, Tingting; Fu, Yun; Huang, Tengfei; Liu, Youxun; Wu, Meihao; Yuan, Yanbin; Li, Shaoshan; Li, Changzheng

    2016-01-01

    The use of chelators for cancer treatment has been an alternative option. Dithiocarbamates have recently attracted considerable attention owning to their diverse biological activities; thus, the preparation of new dithiocarbamate derivatives with improved antitumor activity and selectivity as well as probing the underlying molecular mechanism are required. In this study, di-2-pyridylhydrazone dithiocarbamate S-propionic acid (DpdtpA) and its copper complex were prepared and characterized, and its antiproliferative activity was evaluated. The proliferation inhibition assay showed that DpdtpA exhibited excellent antiproliferative effect in hepatocellular carcinoma (IC50 = 1.3 ± 0.3 μM for HepG2, and 2.5 ± 0.6 μM for Bel-7402). However, in the presence of copper ion, the antiproliferative activity of DpdtpA was dramatically attenuated (20-30 fold) owing to the formation of copper chelate. A preliminarily mechanistic study revealed that reactive oxygen species (ROS) generation mediated the antiproliferative activity of DpdtpA, and accordingly induced apoptosis, DNA cleavage, and autophagy. Surprisingly, the cytotoxicity of DpdtpA copper complex (DpdtpA-Cu) was also involved in ROS generation; however, a paradoxical relation between cellular ROS level and cytotoxicity was observed. Further investigation indicated that DpdtpA could induce cell cycle arrest at the S phase; however, DpdtpA-Cu lacked this effect, which explained the difference in their antiproliferative activity. PMID:27556432

  20. Recognizing Proofreaders' Marks and Using Them in Editing. Audiovisual Package. Instructor's Guide [and] Student Activity Packet. Office Occupations.

    ERIC Educational Resources Information Center

    Johnson, Diane E.

    Designed for use with 38 full-color slides and a cassette tape presentation, this instructional package consists of an instructor's guide and a student activity packet. The instructor's guide includes general instructions for presenting the instructional unit as well as specific instructions for introducing, implementing, and evaluating student…

  1. Streptococcus pyogenes CAMP factor attenuates phagocytic activity of RAW 264.7 cells.

    PubMed

    Kurosawa, Mie; Oda, Masataka; Domon, Hisanori; Saitoh, Issei; Hayasaki, Haruaki; Terao, Yutaka

    2016-02-01

    Streptococcus pyogenes produces molecules that inhibit the function of human immune system, thus allowing the pathogen to grow and spread in tissues. It is known that S. pyogenes CAMP factor increases erythrocytosis induced by Staphylococcus aureus β-hemolysin. However, the effects of CAMP factor for immune cells are unclear. In this study, we investigated the effects of CAMP factor to macrophages. Western blotting analysis demonstrated that all examined strains expressed CAMP factor protein. In the presence of calcium or magnesium ion, CAMP factor was significantly released in the supernatant. In addition, both culture supernatant from S. pyogenes strain SSI-9 and recombinant CAMP factor dose-dependently induced vacuolation in RAW 264.7 cells, but the culture supernatant from Δcfa isogenic mutant strain did not. CAMP factor formed oligomers in RAW 264.7 cells in a time-dependent manner. CAMP factor suppressed cell proliferation via G2 phase cell cycle arrest without inducing cell death. Furthermore, CAMP factor reduced the uptake of S. pyogenes and phagocytic activity indicator by RAW 264.7 cells. These results suggest that CAMP factor works as a macrophage dysfunction factor. Therefore, we conclude that CAMP factor allows S. pyogenes to escape the host immune system, and contribute to the spread of streptococcal infection.

  2. Loss of UCP2 attenuates mitochondrial dysfunction without altering ROS production and uncoupling activity.

    PubMed

    Kukat, Alexandra; Dogan, Sukru Anil; Edgar, Daniel; Mourier, Arnaud; Jacoby, Christoph; Maiti, Priyanka; Mauer, Jan; Becker, Christina; Senft, Katharina; Wibom, Rolf; Kudin, Alexei P; Hultenby, Kjell; Flögel, Ulrich; Rosenkranz, Stephan; Ricquier, Daniel; Kunz, Wolfram S; Trifunovic, Aleksandra

    2014-06-01

    Although mitochondrial dysfunction is often accompanied by excessive reactive oxygen species (ROS) production, we previously showed that an increase in random somatic mtDNA mutations does not result in increased oxidative stress. Normal levels of ROS and oxidative stress could also be a result of an active compensatory mechanism such as a mild increase in proton leak. Uncoupling protein 2 (UCP2) was proposed to play such a role in many physiological situations. However, we show that upregulation of UCP2 in mtDNA mutator mice is not associated with altered proton leak kinetics or ROS production, challenging the current view on the role of UCP2 in energy metabolism. Instead, our results argue that high UCP2 levels allow better utilization of fatty acid oxidation resulting in a beneficial effect on mitochondrial function in heart, postponing systemic lactic acidosis and resulting in longer lifespan in these mice. This study proposes a novel mechanism for an adaptive response to mitochondrial cardiomyopathy that links changes in metabolism to amelioration of respiratory chain deficiency and longer lifespan. PMID:24945157

  3. Monomerization of cytosolic mature smac attenuates interaction with IAPs and potentiation of caspase activation.

    PubMed

    Burke, Stephen P; Smith, Jeffrey B

    2010-10-01

    The four residues at the amino-terminus of mature Smac/DIABLO are an IAP binding motif (IBM). Upon exit from mitochondria, mature Smac interacts with inhibitor of apoptosis proteins (IAPs), abrogating caspase inhibition. We used the ubiquitin fusion model to express mature Smac in the cytosol. Transiently expressed mature Smac56-239 (called Smac56) and Smac60-239 (called Smac60), which lacks the IBM, interacted with X-linked inhibitor of apoptosis protein (XIAP). However, stable expression produced wild type Smac56 that failed to homodimerize, interact with XIAP, and potentiate caspase activation. Cytosolic Smac60 retained these functions. Cytosolic Smac56 apparently becomes posttranslationally modified at the dimer interface region, which obliterated the epitope for a monoclonal antibody. Cytosolic Smacδ, which has the IBM but lacks amino acids 62-105, homodimerized and weakly interacted with XIAP, but failed to potentiate apoptosis. These findings suggest that the IBM of Smac is a recognition point for a posttranslational modification(s) that blocks homodimerization and IAP interaction, and that amino acids 62-105 are required for the proapoptotic function of Smac.

  4. Saffron (its active constituent, crocin) supplementation attenuates lipid peroxidation and protects against tissue injury.

    PubMed

    Altinoz, E; Ozmen, T; Oner, Z; Elbe, H; Erdemli, M E; Bag, H G

    2016-01-01

    The aim of the current study was to investigate the outcomes in a rat model of an acute swimming exercise induced oxidative stress in brain, kidney, liver, skeletal and cardiac muscles using supplementation with crocin. Rats were divided into the eight groups; Normal Control (NC: Untreated and did not swim), Crocin Control (CC: Received crocin and did not swim), Exercise-1 (E-1: Untreated and swam), Exercise-24 (E-24: Untreated and swam), Exercise-48 (E-48: Untreated and swam), Exercise+Crocin-1 (EC-1: Received crocin and swam), Exercise+Crocin-24 (EC-24: Received crocin and swam), Exercise+Crocin-48 (EC-48: Received crocin and swam). The malondialdehyde (MDA) and xanthine oxidase (XO) enzymes levels increased after swimming in untreated and crocin treated groups, but there was a lower increase in crocin treated groups. The highest MDA levels in all tissues were observed in E-1 compared to all other groups. There were significant differences between control and exercise groups in MDA levels of tissues (p < 0.001). In contrast, there were significant differences between control and exercise groups in glutathione (GSH) levels of tissues.In addition, the crocin supplementation significantly increased GSH levels and decreased MDA and XO enzyme levels when compared to untreated exercise groups. Crocin can protect the tissues against exercise induced oxidative stress by enhancing antioxidant activity (Tab. 3, Fig. 1, Ref. 37). PMID:27546539

  5. Loss of UCP2 attenuates mitochondrial dysfunction without altering ROS production and uncoupling activity.

    PubMed

    Kukat, Alexandra; Dogan, Sukru Anil; Edgar, Daniel; Mourier, Arnaud; Jacoby, Christoph; Maiti, Priyanka; Mauer, Jan; Becker, Christina; Senft, Katharina; Wibom, Rolf; Kudin, Alexei P; Hultenby, Kjell; Flögel, Ulrich; Rosenkranz, Stephan; Ricquier, Daniel; Kunz, Wolfram S; Trifunovic, Aleksandra

    2014-06-01

    Although mitochondrial dysfunction is often accompanied by excessive reactive oxygen species (ROS) production, we previously showed that an increase in random somatic mtDNA mutations does not result in increased oxidative stress. Normal levels of ROS and oxidative stress could also be a result of an active compensatory mechanism such as a mild increase in proton leak. Uncoupling protein 2 (UCP2) was proposed to play such a role in many physiological situations. However, we show that upregulation of UCP2 in mtDNA mutator mice is not associated with altered proton leak kinetics or ROS production, challenging the current view on the role of UCP2 in energy metabolism. Instead, our results argue that high UCP2 levels allow better utilization of fatty acid oxidation resulting in a beneficial effect on mitochondrial function in heart, postponing systemic lactic acidosis and resulting in longer lifespan in these mice. This study proposes a novel mechanism for an adaptive response to mitochondrial cardiomyopathy that links changes in metabolism to amelioration of respiratory chain deficiency and longer lifespan.

  6. Loss of UCP2 Attenuates Mitochondrial Dysfunction without Altering ROS Production and Uncoupling Activity

    PubMed Central

    Kukat, Alexandra; Dogan, Sukru Anil; Edgar, Daniel; Mourier, Arnaud; Jacoby, Christoph; Maiti, Priyanka; Mauer, Jan; Becker, Christina; Senft, Katharina; Wibom, Rolf; Kudin, Alexei P.; Hultenby, Kjell; Flögel, Ulrich; Rosenkranz, Stephan; Ricquier, Daniel; Kunz, Wolfram S.; Trifunovic, Aleksandra

    2014-01-01

    Although mitochondrial dysfunction is often accompanied by excessive reactive oxygen species (ROS) production, we previously showed that an increase in random somatic mtDNA mutations does not result in increased oxidative stress. Normal levels of ROS and oxidative stress could also be a result of an active compensatory mechanism such as a mild increase in proton leak. Uncoupling protein 2 (UCP2) was proposed to play such a role in many physiological situations. However, we show that upregulation of UCP2 in mtDNA mutator mice is not associated with altered proton leak kinetics or ROS production, challenging the current view on the role of UCP2 in energy metabolism. Instead, our results argue that high UCP2 levels allow better utilization of fatty acid oxidation resulting in a beneficial effect on mitochondrial function in heart, postponing systemic lactic acidosis and resulting in longer lifespan in these mice. This study proposes a novel mechanism for an adaptive response to mitochondrial cardiomyopathy that links changes in metabolism to amelioration of respiratory chain deficiency and longer lifespan. PMID:24945157

  7. The role of attenuated astrocyte activation in infantile neuronal ceroid lipofuscinosis.

    PubMed

    Macauley, Shannon L; Pekny, Milos; Sands, Mark S

    2011-10-26

    Infantile neuronal ceroid lipofuscinosis (INCL) is an inherited neurodegenerative disorder affecting the CNS during infancy. INCL is caused by mutations in the CLN1 gene that lead to a deficiency in the lysosomal hydrolase, palmitoyl protein thioesterase 1 (PPT1). A murine model of INCL, the PPT1-deficient (PPT1(-/-)) mouse, is an accurate phenocopy of the human disease. The first pathological change observed in the PPT1(-/-) brain is regional areas of glial fibrillary acidic protein (GFAP) upregulation, which predicts future areas of neurodegeneration. We hypothesized that preventing GFAP and vimentin upregulation in reactive astrocytes will alter the CNS disease. To test this hypothesis, we generated mice simultaneously carrying null mutations in the GFAP, Vimentin, and PPT1 genes (GFAP(-/-)Vimentin(-/-)PPT1(-/-)). Although the clinical and pathological features of the GFAP(-/-)Vimentin(-/-)PPT1(-/-) mice are similar to INCL, the disease appears earlier and progresses more rapidly. One mechanism underlying this accelerated phenotype is a profound neuroinflammatory response within the CNS. Thus, our data identify a protective role for intermediate filament upregulation during astrocyte activation in INCL, a model of chronic neurodegeneration.

  8. Houttuynia cordata attenuates lipid accumulation via activation of AMP-activated protein kinase signaling pathway in HepG2 cells.

    PubMed

    Kang, Hyun; Koppula, Sushruta

    2014-01-01

    Houttuynia cordata (H. cordata) from the family Saururaceae is a perennial herb native to Southeast Asia. It possesses a range of medicinal properties to treat several disease symptoms including allergic inflammation and anaphylaxis. In the present investigation, we provided the molecular mechanisms underlying the role of H. cordata extract (HCE) in the prevention of high glucose-induced lipid accumulation in human HepG2 hepatocytes. HepG2 cells were pre-treated with various concentrations of HCE (0, 10, 20, 40, and 80 μg/mL) and treated with serum-free medium with normal glucose (5 mM) for 1 h, followed by exposure to high glucose (25 mM D-glucose) for 24 h. HCE significantly and dose-dependently attenuated lipid accumulation in human HepG2 hepatocytes when exposed to high glucose (25 mM D-glucose) (p < 0.05, p < 0.01 and p < 0.001 at 20, 40, and 80 μg/mL concentrations, respectively). Further, HCE attenuated the expression of fatty acid synthase (FAS), sterol regulatory element-binding protein-1 and glycerol 3-phosphate acyltransferases (GPATs). The adenosine monophosphate-activated protein kinase (AMPK) was also activated by HCE treatment when exposed to high glucose (25 mM D-glucose) in human HepG2 hepatocytes. This study suggests the hypolipidemic effects of HCE by the inhibition of lipid biosynthesis mediated through AMPK signaling, which may play an active role and can be developed as an anti-obesity agent. PMID:24871657

  9. Helenalin attenuates alcohol-induced hepatic fibrosis by enhancing ethanol metabolism, inhibiting oxidative stress and suppressing HSC activation.

    PubMed

    Lin, Xing; Zhang, Shijun; Huang, Renbin; Wei, Ling; Tan, Shimei; Liang, Shuang; Tian, Yuanchun; Wu, Xiaoyan; Lu, Zhongpeng; Huang, Quanfang

    2014-06-01

    A compound was isolated from Centipeda minima using bioassay-guided screening. The structure of this compound was elucidated based on its spectral data, and it was identified as helenalin. The hepatoprotective effect of helenalin was evaluated using a liver fibrosis model induced by intragastric administration with alcohol within 24 weeks in rats. The results revealed that helenalin significantly prevented alcohol-induced hepatic injury and fibrogenesis, as evidenced by the decrease in serum aminotransferase, the attenuation of histopathological changes, and the inhibition of the hepatic fibrosis indicators, such as hyaluronic acid, type III precollagen, laminin, hydroxyproline and collagen α type I. Mechanistically, studies showed that helenalin expedited ethanol metabolism by enhancing the alcohol and aldehyde dehydrogenase activities. Furthermore, helenalin alleviated lipid peroxidation, recruited the antioxidative defense system, inhibited CYP2E1 activity, and reduced the inflammatory mediators, including TGF-β1, TNF-α, IL-6 and IL-1β and myeloperoxidase, via down-regulation of NF-κB. Helenalin significantly decreased collagen deposition by reducing the profibrotic cytokines like transforming growth factor-β, platelet-derived growth factor-β and connective tissue growth factor, and promoted extracellular matrix degradation by modulating the levels of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-9. In addition, helenalin inhibited HSC activation as evidenced by the down-regulation of α-SMA and TGF-β levels. In conclusion, helenalin had a significant protective effect on chronic ethanol-induced hepatic fibrosis and may be a major bioactive ingredient of C. minima.

  10. Acute hypernatremia promotes anxiolysis and attenuates stress-induced activation of the hypothalamic-pituitary-adrenal axis in male mice

    PubMed Central

    Smith, Justin A.; Wang, Lei; Hiller, Helmut; Taylor, Christopher T.; de Kloet, Annette D.; Krause, Eric G.

    2014-01-01

    Previous investigation by our laboratory found that acute hypernatremia potentiates an oxytocinergic tone that inhibits parvocellular neurosecretory neurons in the paraventricular nucleus of the hypothalamus (PVN), attenuates restraint-induced surges in corticosterone (CORT), and reduces anxiety-like behavior in male rats. To investigate the neural mechanisms mediating these effects and extend our findings to a more versatile species, we repeated our studies using laboratory mice. In response to 2.0 M NaCl injections, mice had increased plasma sodium concentrations which were associated with a blunted rise in CORT subsequent to restraint challenge relative to 0.15 M NaCl injected controls. Immunofluorescent identification of the immediate early gene product Fos found that 2.0 M NaCl treatment increased the number of activated neurons producing oxytocin in the PVN. To evaluate the effect of acute hypernatremia on PVN neurons producing corticotropin-releasing hormone (CRH), we used the Cre-lox system to generate mice that produced the red fluorescent protein, tdTomato, in cells that had Cre-recombinase activity driven by CRH gene expression. Analysis of brain tissue from these CRH-reporter mice revealed 2.0 M NaCl treatment caused a dramatic reduction in Fos-positive nuclei specifically in CRH-producing PVN neurons. This altered pattern of activity was predictive of alleviated anxiety-like behavior as mice administered 2.0 M NaCl spent more time exploring the open arms of an elevated-plus maze than 0.15 M NaCl treated controls. Taken together, these results further implicate an oxytocin-dependent inhibition of CRH neurons in the PVN and demonstrate the impact that slight elevations in plasma sodium have on hypothalamic-pituitary-adrenocortical axis output and anxiety-like behavior. PMID:24704193

  11. Valproic acid attenuates microgliosis in injured spinal cord and purinergic P2X4 receptor expression in activated microglia.

    PubMed

    Lu, Wen-Hsin; Wang, Chih-Yen; Chen, Po-See; Wang, Jing-Wen; Chuang, De-Maw; Yang, Chung-Shi; Tzeng, Shun-Fen

    2013-05-01

    Peripheral injection with a high dose of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, into animals with mild or moderate spinal cord injury (SCI) for 1 week can reduce spinal cord tissue loss and promote hindlimb locomotor recovery. A purinergic adenosine triphosphate (ATP) receptor subtype, P2X4 receptor (P2X4 R), has been considered as a potential target to diminish SCI-associated inflammatory responses. In this study, using a minipump-based infusion system, we found that intraspinal infusion with VPA for 3 days into injured spinal cord significantly improved hindlimb locomotion of rats with severe SCI induced by a 10-g NYU impactor dropping from the height of 50 mm onto the spinal T9/10 segment. The neuronal fibers in the injured spinal cord tissues were significantly preserved in VPA-treated rats compared with those observed in vehicle-treated animals. Moreover, the accumulation of microglia/macrophages and astrocytes in the injured spinal cord was attenuated in the animal group receiving VPA infusion. VPA also significantly reduced P2X4 R expression post-SCI. Furthermore, in vitro study indicated that VPA, but not the other HDAC inhibitors, sodium butyrate and trichostatin A (TSA), caused downregulation of P2X4 R in microglia activated with lipopolysaccharide (LPS). Moreover, p38 mitogen-activated protein kinase (MAPK)-triggered signaling was involved in the effect of VPA on the inhibition of P2X4 R gene expression. In addition to the findings from others, our results also provide important evidence to show the inhibitory effect of VPA on P2X4 R expression in activated microglia, which may contribute to reduction of SCI-induced gliosis and subsequently preservation of spinal cord tissues. © 2013 Wiley Periodicals, Inc.

  12. Low LBNP Tolerance in Men is Associated With Attenuated Activation of The Renin-Angiotensin System

    NASA Technical Reports Server (NTRS)

    Greenleaf, J. E.; Petersen, T. W.; Gabrielsen, A.; Pump, B.; Bie, P.; Christensen, N.-J.; Warberg, J.; Videbaeck, R.; Simonson, S. R.; Norsk, P.

    1999-01-01

    Vasoactive hormone concentrations [epinephrine (pE), norepinephrine (pNE), angiotensin II (pATII), vasopressin (pVP), endothelin 1 (pET1)] and plasma renin activity (pRA) were measured during lower body negative pressure (LBNP) to test the hypothesis that responsiveness of the renin-angiotensin system is related to LBNP tolerance. Healthy men (2,822 cal/day(exp -1), 2 mmol*kg(exp -1)*day(exp -1)) Na(+)) were exposed to 30 minutes of progressive LBNP to -50 mmHg. LBNP was uneventful for seven men (25 +/- 2 years, HiTol group), but eight men (26 +/- 3 years) reached pre-syncope after 11 +/- 1 minutes (P < 0.001, LoTol group). Mean arterial pressure was unchanged. Central venous pressure and left atrial diameter decreased in both groups (5-6 mmHg by approx. 30%, P < 0.05). Control [hormone] were similar but, pRA differed between groups (LoTol 0.6 +/- 0.1, HiTol 1.2 +/- 0.1 ng Ang1/(ml(exp -1)*h(exp -1)), P < 0.05). LBNP increased (P < 0.05) pRA and pATII more in HiTol (9.9 +/- 2.2 ng Ang1/(ml(exp -1)*h(exp -1)) and 58 +/- 12 pg/ml(exp -1)) than LoTol (4.3 +/- 0.9 ng Ang1/(ml*h) and 28 +/- 6 pg/ml(exp -1)). In contrast, pVP was higher (P < 0.05) in LoTol than in HiTol. The response of the renin-angiotensin system seems linked to the occurrence of pre-syncope, and measurement of resting pRA may be predictive.

  13. Reduced Levels of Hspa9 Attenuates Stat5 Activation in Mouse B-cells

    PubMed Central

    Krysiak, Kilannin; Tibbitts, Justin F.; Shao, Jin; Liu, Tuoen; Ndonwi, Matthew; Walter, Matthew J.

    2014-01-01

    HSPA9 is located on chromosome 5q31.2 in humans, a region that is commonly deleted in patients with myeloid malignancies [del(5q)], including myelodysplastic syndromes (MDS). HSPA9 expression is reduced by 50% in patients with del(5q)-associated MDS, consistent with haploinsufficient levels. Zebrafish mutants and knockdown studies in human and mouse cells have implicated a role for HSPA9 in hematopoiesis. To comprehensively evaluate the effects of Hspa9 haploinsufficiency on hematopoiesis, we generated an Hspa9 knockout mouse model. While homozygous knockout of Hspa9 is embryonic lethal, mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop MDS. However, Hspa9+/− mice have a cell- intrinsic reduction in bone marrow CFU-PreB colony formation without alterations in the number of B-cell progenitors in vivo, consistent with a functional defect in Hspa9+/− B-cell progenitors. We further reduced Hspa9 expression (<50%) using RNAi and observe reduced B-cell progenitors in vivo, indicating that appropriate levels (≥50%) of Hspa9 are required for normal B- lymphopoiesis in vivo. Knockdown of Hspa9 in an IL-7 dependent mouse B-cell line reduced Stat5 phosphorylation following IL-7 receptor stimulation, supporting a role for Hspa9 in Stat5 signaling in B-cells. Collectively, these data implicate a role for Hspa9 in B-lymphopoiesis and Stat5 activation downstream of IL-7 signaling. PMID:25550197

  14. Low LBNP Tolerance in Men is Associated With Attenuated Activation of Renin-Angiotensin System

    NASA Technical Reports Server (NTRS)

    Greenleaf, John E.; Petersen, T. W.; Gabrielsen, A.; Pump, B.; Bie, P.; Christensen, N.-J.; Warberg, J.; Videbaeck, R.; Simonson, S. R.; Norsk, P.; Dalton, Bonnie P. (Technical Monitor)

    1999-01-01

    Vasoactive hormone concentrations (epinephrine (pE), norepinephrine (pNE), angiotensin II (pATII), vasopressin (pVP), endothelin 1 (pET1)] and plasma renin activity (pRA) were measured during lower body negative pressure (LBNP) to test the hypothesis that responsiveness of the reninangiotensin system is related to LBNP tolerance. Healthy men (2,822 cal per day, 2 mmol per kilogram per day Na (+)) were exposed to 30 min of progressive LBNP to -50mmHg. LBNP was uneventful for 7 men (2512 yr, HiTol group), but 8 men (26 plus or minus 3 yr) reached pre-syncope after 11 plus or minus 1 min (P less than 0.001, LoTol group). Mean arterial pressure was unchanged. Central venous pressure and left atrial diameter decreased in both groups (5-6 mmHg by 30%, P less than 0.05). Control [hormone] were similar but, pRA differed between groups (LoTol 0.6 plus or minus 0.1, HiTol 1.2 plus or minus 0.1 ng Ang1 per milliliter per hour, per hour, P less than 0.05). LBNP increased (P less than 0.05) pRA and pATII more in HiTol (9.9 plus or minus 2.2 ng Ang1 per milliliter per hour and 58 plus or minus 12 pg per milliliter) than LoTol (4.3 plus or minus 0.9 ng Angl per milliliter per hour and 28 plus or minus 6 pg per milliliter). In contrast, pVP was higher (P less than 0.05) in LoTol than in HiTol. The response of the renin-angiotensin system seems linked to the occurrence of pre-syncope, and measurement of resting pRA may be predictive.

  15. Berberine hydrochloride attenuates lipopolysaccharide-induced endometritis in mice by suppressing activation of NF-κB signal pathway.

    PubMed

    Fu, Kaiqiang; Lv, Xiaopei; Li, Weishi; Wang, Yu; Li, Huatao; Tian, Wenru; Cao, Rongfeng

    2015-01-01

    Endometritis is a common disease in animal production and influences breeding all over the world. Berberine is one of the main alkaloids isolated from Rhizoma coptidis. Previous reports showed that berberine has anti-inflammatory potential. However, there have been a limited number of published reports on the anti-inflammatory effect of berberine hydrochloride on LPS-induced endometritis. The purpose of the present study was to investigate the effects of berberine hydrochloride on LPS-induced mouse endometritis. Berberine hydrochloride was administered intraperitoneally at 1h before and 12h after LPS induction. Then, a biopsy was performed, and uterine myeloperoxidase (MPO) and nitric oxide (NO) concentrations were determined. Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels in the uterus homogenate were measured by ELISA. The extent of IκB-α and P65 phosphorylation was detected by Western blot. The results showed that berberine hydrochloride significantly attenuated neutrophil infiltration, suppressed myeloperoxidase activity and decreased NO, TNF-αand IL-1βproduction. Furthermore, berberine hydrochloride inhibited the phosphorylation of the NF-κB p65 subunit and the degradation of its inhibitor, IκBα. These findings suggest that berberine hydrochloride exerts potent anti-inflammatory effects on LPS-induced mouse endometritis and might be a potential therapeutic agent for endometritis. PMID:25479718

  16. Physical activity attenuates the negative effect of low birth weight on leptin levels in European adolescents; the HELENA study.

    PubMed

    Labayen, I; Ortega, F B; Moreno, L A; Gonzalez-Gross, M; Jimenez-Pavon, D; Martínez-Gómez, D; Breidenassel, C; Marcos, A; Molnar, D; Manios, Y; Plada, M; Kafatos, A; De Henauw, S; Mauro, B; Zaccaria, M; Widhalm, K; Gottrand, F; Castillo, M J; Sjöström, M; Ruiz, J R

    2013-04-01

    We examined whether physical activity (PA) influences the association between birth weight and serum leptin in adolescents. The study comprised a total of 538 adolescents (315 girls), aged 12.5-17.49 years, born at term (≥ 37 weeks of gestation). We measured serum leptin levels and time engaged in moderate-vigorous PA (MVPA) by accelerometry. There was an interaction effect between birth weight and meeting the PA recommendations (60 min/day MVPA) on leptin levels in girls (P = 0.023) but not in boys (P = 0.809). Birth weight was negatively associated with leptin levels in girls not meeting the PA recommendations (i.e. more than 60 min/day of MVPA) (β = -0.096, P = 0.009), whereas no significant association was observed in those meeting the PA recommendations (β = -0.061, P = 0.433). In conclusion, meeting the PA recommendations may attenuate the negative effect of low birth weight on serum leptin levels in European female adolescents.

  17. Lack of Platelet-Activating Factor Receptor Attenuates Experimental Food Allergy but Not Its Metabolic Alterations regarding Adipokine Levels

    PubMed Central

    Batista, Nathália Vieira; Fonseca, Roberta Cristelli; Perez, Denise; Pereira, Rafaela Vaz Sousa; de Lima Alves, Juliana; Pinho, Vanessa; Faria, Ana Maria Caetano; Cara, Denise Carmona

    2016-01-01

    Platelet-activating factor (PAF) is known to be an important mediator of anaphylaxis. However, there is a lack of information in the literature about the role of PAF in food allergy. The aim of this work was to elucidate the participation of PAF during food allergy development and the consequent adipose tissue inflammation along with its alterations. Our data demonstrated that, both before oral challenge and after 7 days receiving ovalbumin (OVA) diet, OVA-sensitized mice lacking the PAF receptor (PAFR) showed a decreased level of anti-OVA IgE associated with attenuated allergic markers in comparison to wild type (WT) mice. Moreover, there was less body weight and adipose tissue loss in PAFR-deficient mice. However, some features of inflamed adipose tissue presented by sensitized PAFR-deficient and WT mice after oral challenge were similar, such as a higher rate of rolling leukocytes in this tissue and lower circulating levels of adipokines (resistin and adiponectin) in comparison to nonsensitized mice. Therefore, PAF signaling through PAFR is important for the allergic response to OVA but not for the adipokine alterations caused by this inflammatory process. Our work clarifies some effects of PAF during food allergy along with its role on the metabolic consequences of this inflammatory process. PMID:27314042

  18. Attenuated viral hepatitis in Trem1−/− mice is associated with reduced inflammatory activity of neutrophils

    PubMed Central

    Kozik, Jan-Hendrik; Trautmann, Tanja; Carambia, Antonella; Preti, Max; Lütgehetmann, Marc; Krech, Till; Wiegard, Christiane; Heeren, Joerg; Herkel, Johannes

    2016-01-01

    TREM1 (Triggering Receptor Expressed on Myeloid Cells 1) is a pro-inflammatory receptor expressed by phagocytes, which can also be released as a soluble molecule (sTREM1). The roles of TREM1 and sTREM1 in liver infection and inflammation are not clear. Here we show that patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection manifest elevated serum levels of sTREM1. In mice, experimental viral hepatitis induced by infection with Lymphocytic Choriomeningitis Virus (LCMV)-WE was likewise associated with increased sTREM1 in serum and urine, and with increased TREM1 and its associated adapter molecule DAP12 in the liver. Trem1−/− mice showed accelerated clearance of LCMV-WE and manifested attenuated liver inflammation and injury. TREM1 expression in the liver of wild-type mice was mostly confined to infiltrating neutrophils, which responded to LCMV by secretion of CCL2 and TNF-α, and release of sTREM1. Accordingly, the production of CCL2 and TNF-α was decreased in the livers of LCMV-infected Trem1−/− mice, as compared to LCMV-infected wildtype mice. These findings indicate that TREM1 plays a role in viral hepatitis, in which it seems to aggravate the immunopathology associated with viral clearance, mainly by increasing the inflammatory activity of neutrophils. PMID:27328755

  19. The Histone Variant H3.3 Is Enriched at Drosophila Amplicon Origins but Does Not Mark Them for Activation

    PubMed Central

    Paranjape, Neha P.; Calvi, Brian R.

    2016-01-01

    Eukaryotic DNA replication begins from multiple origins. The origin recognition complex (ORC) binds origin DNA and scaffolds assembly of a prereplicative complex (pre-RC), which is subsequently activated to initiate DNA replication. In multicellular eukaryotes, origins do not share a strict DNA consensus sequence, and their activity changes in concert with chromatin status during development, but mechanisms are ill-defined. Previous genome-wide analyses in Drosophila and other organisms have revealed a correlation between ORC binding sites and the histone variant H3.3. This correlation suggests that H3.3 may designate origin sites, but this idea has remained untested. To address this question, we examined the enrichment and function of H3.3 at the origins responsible for developmental gene amplification in the somatic follicle cells of the Drosophila ovary. We found that H3.3 is abundant at these amplicon origins. H3.3 levels remained high when replication initiation was blocked, indicating that H3.3 is abundant at the origins before activation of the pre-RC. H3.3 was also enriched at the origins during early oogenesis, raising the possibility that H3.3 bookmarks sites for later amplification. However, flies null mutant for both of the H3.3 genes in Drosophila did not have overt defects in developmental gene amplification or genomic replication, suggesting that H3.3 is not essential for the assembly or activation of the pre-RC at origins. Instead, our results imply that the correlation between H3.3 and ORC sites reflects other chromatin attributes that are important for origin function. PMID:27172191

  20. Estimation of (41)Ar activity concentration and release rate from the TRIGA Mark-II research reactor.

    PubMed

    Hoq, M Ajijul; Soner, M A Malek; Rahman, A; Salam, M A; Islam, S M A

    2016-03-01

    The BAEC TRIGA research reactor (BTRR) is the only nuclear reactor in Bangladesh. Bangladesh Atomic Energy Regulatory Authority (BAERA) regulations require that nuclear reactor licensees undertake all reasonable precautions to protect the environment and the health and safety of persons, including identifying, controlling and monitoring the release of nuclear substances to the environment. The primary activation product of interest in terms of airborne release from the reactor is (41)Ar. (41)Ar is a noble gas readily released from the reactor stacks and most has not decayed by the time it moves offsite with normal wind speed. Initially (41)Ar is produced from irradiation of dissolved air in the primary water which eventually transfers into the air in the reactor bay. In this study, the airborne radioisotope (41)Ar generation concentration, ground level concentration and release rate from the BTRR bay region are evaluated theoretically during the normal reactor operation condition by several governing equations. This theoretical calculation eventually minimizes the doubt about radiological safety to determine the radiation level for (41)Ar activity whether it is below the permissible limit or not. Results show that the estimated activity for (41)Ar is well below the maximum permissible concentration limit set by the regulatory body, which is an assurance for the reactor operating personnel and general public. Thus the analysis performed within this paper is so much effective in the sense of ensuring radiological safety for working personnel and the environment.

  1. Estimation of (41)Ar activity concentration and release rate from the TRIGA Mark-II research reactor.

    PubMed

    Hoq, M Ajijul; Soner, M A Malek; Rahman, A; Salam, M A; Islam, S M A

    2016-03-01

    The BAEC TRIGA research reactor (BTRR) is the only nuclear reactor in Bangladesh. Bangladesh Atomic Energy Regulatory Authority (BAERA) regulations require that nuclear reactor licensees undertake all reasonable precautions to protect the environment and the health and safety of persons, including identifying, controlling and monitoring the release of nuclear substances to the environment. The primary activation product of interest in terms of airborne release from the reactor is (41)Ar. (41)Ar is a noble gas readily released from the reactor stacks and most has not decayed by the time it moves offsite with normal wind speed. Initially (41)Ar is produced from irradiation of dissolved air in the primary water which eventually transfers into the air in the reactor bay. In this study, the airborne radioisotope (41)Ar generation concentration, ground level concentration and release rate from the BTRR bay region are evaluated theoretically during the normal reactor operation condition by several governing equations. This theoretical calculation eventually minimizes the doubt about radiological safety to determine the radiation level for (41)Ar activity whether it is below the permissible limit or not. Results show that the estimated activity for (41)Ar is well below the maximum permissible concentration limit set by the regulatory body, which is an assurance for the reactor operating personnel and general public. Thus the analysis performed within this paper is so much effective in the sense of ensuring radiological safety for working personnel and the environment. PMID:26736180

  2. Optimised k0-instrumental neutron activation method using the TRIGA MARK I IPR-R1 reactor at CDTN/CNEN, Belo Horizonte, Brazil

    NASA Astrophysics Data System (ADS)

    Menezes, M. Â. B. C.; Jaćimović, R.

    2006-08-01

    The Nuclear Technology Development Centre/Brazilian Commission for Nuclear Energy, CDTN/CNEN, is the only Brazilian Institution to apply the k0-standardisation method of instrumental neutron activation technique determining elements using its own nuclear reactor, TRIGA MARK I IPR-R1. After changes in the reactor core configuration, the reactor neutron flux distribution in typical irradiation channels had to be updated, as well as the parameters f and α, needed to apply the k0-method of neutron activation analysis. The neutron flux distribution in the rotary rack was evaluated through the specific count rate of 198Au and the parameters f and α, were determined in five selected channels applying the "Cd-ratio for multi-monitor" method, using a set of Al-(0.1%)Au and Zr (99.8%) monitors. Several reference materials were analysed, indicating the effectiveness of the improved method.

  3. CD28/B7 Deficiency Attenuates Systolic Overload-Induced Congestive Heart Failure, Myocardial and Pulmonary Inflammation, and Activated T Cell Accumulation in the Heart and Lungs.

    PubMed

    Wang, Huan; Kwak, Dongmin; Fassett, John; Hou, Lei; Xu, Xin; Burbach, Brandon J; Thenappan, Thenappan; Xu, Yawei; Ge, Jun-Bo; Shimizu, Yoji; Bache, Robert J; Chen, Yingjie

    2016-09-01

    The inflammatory response regulates congestive heart failure (CHF) development. T cell activation plays an important role in tissue inflammation. We postulate that CD28 or B7 deficiency inhibits T cell activation and attenuates CHF development by reducing systemic, cardiac, and pulmonary inflammation. We demonstrated that chronic pressure overload-induced end-stage CHF in mice is characterized by profound accumulation of activated effector T cells (CD3(+)CD44(high) cells) in the lungs and a mild but significant increase of these cells in the heart. In knockout mice lacking either CD28 or B7, there was a dramatic reduction in the accumulation of activated effector T cells in both hearts and lungs of mice under control conditions and after transverse aortic constriction. CD28 or B7 knockout significantly attenuated transverse aortic constriction-induced CHF development, as indicated by less increase of heart and lung weight and less reduction of left ventricle contractility. CD28 or B7 knockout also significantly reduced transverse aortic constriction-induced CD45(+) leukocyte, T cell, and macrophage infiltration in hearts and lungs, lowered proinflammatory cytokine expression (such as tumor necrosis factor-α and interleukin-1β) in lungs. Furthermore, CD28/B7 blockade by CTLA4-Ig treatment (250 μg/mouse every 3 days) attenuated transverse aortic constriction-induced T cell activation, left ventricle hypertrophy, and left ventricle dysfunction. Our data indicate that CD28/B7 deficiency inhibits activated effector T cell accumulation, reduces myocardial and pulmonary inflammation, and attenuates the development of CHF. Our findings suggest that strategies targeting T cell activation may be useful in treating CHF. PMID:27432861

  4. CD28/B7 Deficiency Attenuates Systolic Overload-Induced Congestive Heart Failure, Myocardial and Pulmonary Inflammation, and Activated T Cell Accumulation in the Heart and Lungs.

    PubMed

    Wang, Huan; Kwak, Dongmin; Fassett, John; Hou, Lei; Xu, Xin; Burbach, Brandon J; Thenappan, Thenappan; Xu, Yawei; Ge, Jun-Bo; Shimizu, Yoji; Bache, Robert J; Chen, Yingjie

    2016-09-01

    The inflammatory response regulates congestive heart failure (CHF) development. T cell activation plays an important role in tissue inflammation. We postulate that CD28 or B7 deficiency inhibits T cell activation and attenuates CHF development by reducing systemic, cardiac, and pulmonary inflammation. We demonstrated that chronic pressure overload-induced end-stage CHF in mice is characterized by profound accumulation of activated effector T cells (CD3(+)CD44(high) cells) in the lungs and a mild but significant increase of these cells in the heart. In knockout mice lacking either CD28 or B7, there was a dramatic reduction in the accumulation of activated effector T cells in both hearts and lungs of mice under control conditions and after transverse aortic constriction. CD28 or B7 knockout significantly attenuated transverse aortic constriction-induced CHF development, as indicated by less increase of heart and lung weight and less reduction of left ventricle contractility. CD28 or B7 knockout also significantly reduced transverse aortic constriction-induced CD45(+) leukocyte, T cell, and macrophage infiltration in hearts and lungs, lowered proinflammatory cytokine expression (such as tumor necrosis factor-α and interleukin-1β) in lungs. Furthermore, CD28/B7 blockade by CTLA4-Ig treatment (250 μg/mouse every 3 days) attenuated transverse aortic constriction-induced T cell activation, left ventricle hypertrophy, and left ventricle dysfunction. Our data indicate that CD28/B7 deficiency inhibits activated effector T cell accumulation, reduces myocardial and pulmonary inflammation, and attenuates the development of CHF. Our findings suggest that strategies targeting T cell activation may be useful in treating CHF.

  5. Surfactant Protein A Prevents IFN-γ/IFN-γ Receptor Interaction and Attenuates Classical Activation of Human Alveolar Macrophages.

    PubMed

    Minutti, Carlos M; García-Fojeda, Belén; Sáenz, Alejandra; de Las Casas-Engel, Mateo; Guillamat-Prats, Raquel; de Lorenzo, Alba; Serrano-Mollar, Anna; Corbí, Ángel L; Casals, Cristina

    2016-07-15

    Lung surfactant protein A (SP-A) plays an important function in modulating inflammation in the lung. However, the exact role of SP-A and the mechanism by which SP-A affects IFN-γ-induced activation of alveolar macrophages (aMϕs) remains unknown. To address these questions, we studied the effect of human SP-A on rat and human aMϕs stimulated with IFN-γ, LPS, and combinations thereof and measured the induction of proinflammatory mediators as well as SP-A's ability to bind to IFN-γ or IFN-γR1. We found that SP-A inhibited (IFN-γ + LPS)-induced TNF-α, iNOS, and CXCL10 production by rat aMϕs. When rat macrophages were stimulated with LPS and IFN-γ separately, SP-A inhibited both LPS-induced signaling and IFN-γ-elicited STAT1 phosphorylation. SP-A also decreased TNF-α and CXCL10 secretion by ex vivo-cultured human aMϕs and M-CSF-derived macrophages stimulated by either LPS or IFN-γ or both. Hence, SP-A inhibited upregulation of IFN-γ-inducible genes (CXCL10, RARRES3, and ETV7) as well as STAT1 phosphorylation in human M-CSF-derived macrophages. In addition, we found that SP-A bound to human IFN-γ (KD = 11 ± 0.5 nM) in a Ca(2+)-dependent manner and prevented IFN-γ interaction with IFN-γR1 on human aMϕs. We conclude that SP-A inhibition of (IFN-γ + LPS) stimulation is due to SP-A attenuation of both inflammatory agents and that the binding of SP-A to IFN-γ abrogates IFN-γ effects on human macrophages, suppressing their classical activation and subsequent inflammatory response.

  6. Insights into activation and RNA binding of trp RNA-binding attenuation protein (TRAP) through all-atom simulations.

    PubMed

    Murtola, Teemu; Vattulainen, Ilpo; Falck, Emma

    2008-06-01

    Tryptophan biosynthesis in Bacillus stearothermophilus is regulated by a trp RNA binding attenuation protein (TRAP). It is a ring-shaped 11-mer of identical 74 residue subunits. Tryptophan binding pockets are located between adjacent subunits, and tryptophan binding activates TRAP to bind RNA. Here, we report results from all-atom molecular dynamics simulations of the system, complementing existing extensive experimental studies. We focus on two questions. First, we look at the activation mechanism, of which relatively little is known experimentally. We find that the absence of tryptophan allows larger motions close to the tryptophan binding site, and we see indication of a conformational change in the BC loop. However, complete deactivation seems to occur on much longer time scales than the 40 ns studied here. Second, we study the TRAP-RNA interactions. We look at the relative flexibilities of the different bases in the complex and analyze the hydrogen bonds between the protein and RNA. We also study the role of Lys37, Lys56, and Arg58, which have been experimentally identified as essential for RNA binding. Hydrophobic stacking of Lys37 with the nearby RNA base is confirmed, but we do not see direct hydrogen bonding between RNA and the other two residues, in contrast to the crystal structure. Rather, these residues seem to stabilize the RNA-binding surface, and their positive charge may also play a role in RNA binding. Simulations also indicate that TRAP is able to attract RNA nonspecifically, and the interactions are quantified in more detail using binding energy calculations. The formation of the final binding complex is a very slow process: within the simulation time scale of 40 ns, only two guanine bases become bound (and no others), indicating that the binding initiates at these positions. In general, our results are in good agreement with experimental studies, and provide atomic-scale insights into the processes. PMID:18186477

  7. Evaluation of Vibration and Shock Attenuation Performance of a Suspension Seat with a Semi-Active Magnetorheological Fluid Damper

    NASA Astrophysics Data System (ADS)

    MCMANUS, S. J.; ST. CLAIR, K. A.; BOILEAU, P. É.; BOUTIN, J.; RAKHEJA, S.

    2002-05-01

    The potential benefits of a semi-active magnetorheological (MR) damper in reducing the incidence and severity of end-stop impacts of a low natural frequency suspension seat are investigated. The MR damper considered is a commercially developed product, referred to as “Motion Master semi-active damping system” and manufactured by Lord Corporation. The end-stop impact and vibration attenuation performance of a seat equipped with such a damper are evaluated and compared with those of the same seat incorporating a conventional damper. The evaluation is performed on a servo-hydraulic vibration exciter by subjecting the seat-damper combinations to a transient excitation with dominant frequency close to that of the seat and continuous random excitation class EM1 applicable to earth-moving machinery, and a more severe excitation realized by amplifying the EM1 excitation by 150%. Tests are performed for medium and firm settings of the MR damper and for seat height positions corresponding to mid-ride and ±2·54 and ±5·08 cm relative to mid-ride. The results indicate that significantly higher levels of transient excitation are necessary to induce end-stop impacts for the seat equipped with the MR damper, particularly when set for firm damping, the difference with the conventional damper being more pronounced for seat positions closer to the end-stops. Under the EM1 excitation, the results indicate that under conditions which would otherwise favour the occurrence of end-stop impacts for a seat equipped with a conventional damper, the use of the MR damper can result in considerably less severe impacts and correspondingly lower vibration exposure levels, particularly when positioned closer to its compression or rebound limit stop.

  8. Peroxisome proliferator-activated receptor α activation attenuates the inflammatory response to protect the liver from acute failure by promoting the autophagy pathway.

    PubMed

    Jiao, M; Ren, F; Zhou, L; Zhang, X; Zhang, L; Wen, T; Wei, L; Wang, X; Shi, H; Bai, L; Zhang, X; Zheng, S; Zhang, J; Chen, Y; Han, Y; Zhao, C; Duan, Z

    2014-08-28

    Peroxisome proliferator-activated receptor α (PPARα) has been reported to induce a potent anti-inflammatory response. Autophagy is a recently recognized rudimentary cellular response to inflammation and injury. The aim of the present study was to test the hypothesis that PPARα activation mediates autophagy to inhibit liver inflammation and protect against acute liver failure (ALF). PPARα expression during ALF and the impact of PPARα activation by Wy-14 643 on the hepatic immune response were studied in a D-galactosamine/lipopolysaccharide-induced mouse model. Autophagy was inhibited by 3-methyladenine or small interfering RNA (siRNA) against Atg7. In both the mouse model and human ALF subjects, PPARα was significantly downregulated in the injured liver. PPARα activation by pretreatment with Wy-14 643 protected against liver injury in mice. The protective effect of PPARα activation relied on the suppression of inflammatory mechanisms through the induction of autophagy. This hypothesis is supported by the following evidence: first, PPARα activation suppressed proinflammatory responses and inhibited phosphorylated NF-κBp65, phosphorylated JNK and phosphorylated ERK pathways in vivo. Second, protection by PPARα activation was due to the induction of autophagy because inhibition of autophagy by 3-methyladenine or Atg7 siRNA reversed liver protection and inflammation. Third, PPARα activation directly induced autophagy in primary macrophages in vitro, which protected cells from a lipopolysaccharide-induced proinflammatory response. Here, for the first time, we have demonstrated that PPARα-mediated induction of autophagy ameliorated liver injury in cases of ALF by attenuating inflammatory responses, indicating a potential therapeutic application for ALF treatment.

  9. Exposure of brown Norway rats to diesel exhaust particles prior to ovalbumin (OVA) sensitization elicits IgE adjuvant activity but attenuates OVA-induced airway inflammation.

    PubMed

    Dong, Caroline C; Yin, Xuejun J; Ma, Jane Y C; Millecchia, Lyndell; Barger, Mark W; Roberts, Jenny R; Zhang, Xing-Dong; Antonini, James M; Ma, Joseph K H

    2005-11-01

    Exposure to diesel exhaust particles (DEP) during the sensitization process has been shown to increase antigen-specific IgE production and aggravate allergic airway inflammation in human and animal models. In this study, we evaluated the effect of short-term DEP exposure on ovalbumin (OVA)-mediated responses using a post-sensitization model. Brown Norway rats were first exposed to filtered air or DEP (20.6 +/- 2.7 mg/m3) for 4 h/day for five consecutive days. One day after the final air or DEP exposure (day 1), rats were sensitized with aerosolized OVA (40.5 +/- 6.3 mg/m3), and then again on days 8 and 15, challenged with OVA on day 29, and sacrificed on days 9 or 30, 24 h after the second OVA exposure or the final OVA challenge, respectively. Control animals received aerosolized saline instead of OVA. DEP were shown to elicit an adjuvant effect on the production of antigen-specific IgE and IgG on day 30. At both time points, no significant airway inflammatory responses and lung injury were found for DEP exposure alone. However, the OVA-induced inflammatory cell infiltration, acellular lactate dehydrogenase activity and albumin content in bronchoalveolar lavage (BAL) fluid, and numbers of T cells and their CD4+ and CD8+ subsets in lung-draining lymph nodes were markedly reduced by DEP on day 30 compared with the air-plus-OVA exposure group. The OVA-induced nitric oxide (NO) in the BAL fluid and production of NO, interleukin (IL)-10, and IL-12 by alveolar macrophages (AM) were also significantly lowered by DEP on day 30 as well as day 9. DEP or OVA alone decreased intracellular glutathione (GSH) in AM and lymphocytes on days 9 and 30. The combined DEP and OVA exposure resulted in further depletion of GSH in both cell types. These results show that short-term DEP exposure prior to sensitization had a delayed effect on enhancement of the sensitization in terms of allergen-specific IgE and IgG production, but caused an attenuation of the allergen-induced airway

  10. Osteoprotegerin (OPG) activates integrin, focal adhesion kinase (FAK), and Akt signaling in ovarian cancer cells to attenuate TRAIL-induced apoptosis

    PubMed Central

    2013-01-01

    Background Resistance to apoptosis is a major problem in ovarian cancer (OC) and correlates with poor prognosis. Osteoprotegerin (OPG) is a soluble secreted factor that acts as a decoy receptor for receptor activator of NF-κB ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). OPG has been reported to attenuate TRAIL-induced apoptosis in a variety of cancer cells, including OC cells. OPG-mediated protection against TRAIL has been attributed to its decoy receptor function. However, OPG activates integrin/focal adhesion kinase (FAK) signaling in endothelial cells. In OC cells, activation of integrin/FAK signaling inhibits TRAIL-induced apoptosis. Based on these observations, we hypothesized that OPG could attenuate TRAIL-induced apoptosis in OC cells through integrin/FAK signaling. Methods In vitro experiments including immunoblots, colony formation assays, and apoptosis measurements were used to assess the effect of OPG on TRAIL-induced apoptosis. Results Exogenous OPG protected from TRAIL-induced apoptosis in a TRAIL binding-independent manner and OPG protection was αvβ3 and αvβ5 integrin/FAK signaling-dependent. Moreover, OPG-mediated activation of integrin/FAK signaling resulted in the activation of Akt. Inhibition of both integrin/FAK and Akt signaling significantly inhibited OPG-mediated attenuation of TRAIL-induced apoptosis. Although OPG also stimulated ERK1/2 phosphorylation, inhibition of ERK1/2 signaling did not significantly altered OPG protection. Conclusions Our studies provide evidence, for the first time, that OPG can attenuate TRAIL-induced apoptosis in a TRAIL binding-independent manner through the activation of integrin/FAK/Akt signaling in OC cells. PMID:24267510

  11. F14512, a polyamine-vectorized inhibitor of topoisomerase II, exhibits a marked anti-tumor activity in ovarian cancer.

    PubMed

    Thibault, Benoît; Clement, Emily; Zorza, Grégoire; Meignan, Samuel; Delord, Jean-Pierre; Couderc, Bettina; Bailly, Christian; Narducci, Fabrice; Vandenberghe, Isabelle; Kruczynski, Anna; Guilbaud, Nicolas; Ferré, Pierre; Annereau, Jean-Philippe

    2016-01-01

    Epithelial ovarian cancer is the fourth cause of death among cancer-bearing women and frequently associated with carboplatin resistance, underlining the need for more efficient and targeted therapies. F14512 is an epipodophylotoxin-core linked to a spermine chain which enters cells via the polyamine transport system (PTS). Here, we investigate this novel concept of vectorization in ovarian cancer. We compared the effects of etoposide and F14512 on a panel of five carboplatin-sensitive or resistant ovarian cancer models. We assessed the incorporation of F17073, a spermine-linked fluorescent probe, in these cells and in 18 clinical samples. We then showed that F14512 exhibits a high anti-proliferative and pro-apoptotic activity, particularly in cells with high levels of F17073 incorporation. Consistently, F14512 significantly inhibited tumor growth compared to etoposide, in a cisplatin-resistant A2780R subcutaneous model, at a dose of 1.25 mg/kg. In addition, ex vivo analysis indicated that 15 out of 18 patients presented a higher F17073 incorporation into tumor cells compared to normal cells. Overall, our data suggest that F14512, a targeted drug with a potent anti-tumor efficacy, constitutes a potential new therapy for highly PTS-positive and platinum-resistant ovarian cancer-bearing patients.

  12. Marking nut anaphylaxis.

    PubMed

    Fok, Jie Shen; Kral, Anita Christine; Hayball, John; Smith, William B

    2016-07-01

    Marking nut Semecarpus anacardium, so-called because it contains a pigment that has been used in the past to mark fabrics, is a known cause of contact hypersensitivity. It may be ingested as an ingredient of some traditional Hindi foods. We describe the first reported case of anaphylaxis to marking nut. PMID:27489793

  13. Marking nut anaphylaxis.

    PubMed

    Fok, Jie Shen; Kral, Anita Christine; Hayball, John; Smith, William B

    2016-07-01

    Marking nut Semecarpus anacardium, so-called because it contains a pigment that has been used in the past to mark fabrics, is a known cause of contact hypersensitivity. It may be ingested as an ingredient of some traditional Hindi foods. We describe the first reported case of anaphylaxis to marking nut.

  14. Marking nut anaphylaxis

    PubMed Central

    Kral, Anita Christine; Hayball, John; Smith, William B

    2016-01-01

    Marking nut Semecarpus anacardium, so-called because it contains a pigment that has been used in the past to mark fabrics, is a known cause of contact hypersensitivity. It may be ingested as an ingredient of some traditional Hindi foods. We describe the first reported case of anaphylaxis to marking nut. PMID:27489793

  15. Mastering Marking Madness

    ERIC Educational Resources Information Center

    Moore, Brooke

    2009-01-01

    Teachers are smart people, so why does marking reduce them to stressed and soulless messes? Because in their hearts they know that students do not learn from it, and that drives them nuts. Researchers like Lorna Earl and Dylan Wiliam have looked closely at marking systems and have proven what teachers already know deep down: marking student work…

  16. Markedly inhibited 7-dehydrocholesterol-delta 7-reductase activity in liver microsomes from Smith-Lemli-Opitz homozygotes.

    PubMed Central

    Shefer, S; Salen, G; Batta, A K; Honda, A; Tint, G S; Irons, M; Elias, E R; Chen, T C; Holick, M F

    1995-01-01

    We investigated the enzyme defect in late cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome, a recessively inherited developmental disorder characterized by facial dysmorphism, mental retardation, and multiple organ congenital anomalies. Reduced plasma and tissue cholesterol with increased 7-dehydrocholesterol concentrations are biochemical features diagnostic of the inherited enzyme defect. Using isotope incorporation assays, we measured the transformation of the precursors, [3 alpha- 3H]lathosterol and [1,2-3H]7-dehydrocholesterol into cholesterol by liver microsomes from seven controls and four Smith-Lemli-Opitz homozygous subjects. The introduction of the double bond in lathosterol at C-5[6] to form 7-dehydrocholesterol that is catalyzed by lathosterol-5-dehydrogenase was equally rapid in controls and homozygotes liver microsomes (120 +/- 8 vs 100 +/- 7 pmol/mg protein per min, P = NS). In distinction, the reduction of the double bond at C-7 [8] in 7-dehydrocholesterol to yield cholesterol catalyzed by 7-dehydrocholesterol-delta 7-reductase was nine times greater in controls than homozygotes microsomes (365 +/- 23 vs 40 +/- 4 pmol/mg protein per min, P < 0.0001). These results demonstrate that the pathway of lathosterol to cholesterol in human liver includes 7-dehydrocholesterol as a key intermediate. In Smith-Lemli-Opitz homozygotes, the transformation of 7-dehydrocholesterol to cholesterol by hepatic microsomes was blocked although 7-dehydrocholesterol was produced abundantly from lathosterol. Thus, lathosterol 5-dehydrogenase is equally active which indicates that homozygotes liver microsomes are viable. Accordingly, microsomal 7-dehydrocholesterol-delta 7-reductase is inherited abnormally in Smith-Lemli-Opitz homozygotes. PMID:7560069

  17. The human insulin gene displays transcriptionally active epigenetic marks in islet-derived mesenchymal precursor cells in the absence of insulin expression.

    PubMed

    Mutskov, Vesco; Raaka, Bruce M; Felsenfeld, Gary; Gershengorn, Marvin C

    2007-12-01

    Human islet-derived precursor cells (hIPCs), mesenchymal cells derived in vitro from adult pancreas, proliferate freely and do not express insulin but can be differentiated to epithelial cells that express insulin. hIPCs have been studied with the goal of obtaining large quantities of insulin-producing cells suitable for transplantation into patients suffering from type 1 diabetes. It appeared that undifferentiated hIPCs are "committed" to a pancreatic endocrine phenotype through multiple cell divisions, suggesting that epigenetic modifications at the insulin locus could be responsible. We determined patterns of histone modifications over the insulin gene in human islets and hIPCs and compared them with HeLa and human bone marrow-derived mesenchymal stem cells (hBM-MSCs), neither of which expresses insulin. The insulin gene in islets displays high levels of histone modifications (H4 hyperacetylation and dimethylation of H3 lysine 4) typical of active genes. These are not present in HeLa and hBM-MSCs, which instead have elevated levels of H3 lysine 9 dimethylation, a mark of inactive genes. hIPCs, in contrast, show significant levels of active chromatin modifications, as much as half those seen in islets, and show no measurable H3 K9 methylation. Cells expanded from a minor population of mesenchymal stromal cells found in islets exhibit the same histone modifications as established hIPCs. We conclude that hIPCs, which do not express the insulin gene, nonetheless uniquely exhibit epigenetic marks that could poise them for activation of insulin expression. This epigenetic signature may be a general mechanism whereby tissue-derived precursor cells are committed to a distinct specification. Disclosure of potential conflicts of interest is found at the end of this article.

  18. The cinnamon-oil ingredient trans-cinnamaldehyde fails to target Campylobacter jejuni strain KC 40 in the broiler chicken cecum despite marked in vitro activity.

    PubMed

    Hermans, David; Martel, An; van Deun, Kim; van Immerseel, Filip; Heyndrickx, Marc; Haesebrouck, Freddy; Pasmans, Frank

    2011-10-01

    Campylobacter jejuni is the most common bacterial cause of diarrheal disease in humans worldwide, with poultry products being a major source. Therefore, strategies to decrease Campylobacter colonization during primary production might aid in reducing the number of human campylobacteriosis cases. Several plant-derived compounds have been reported to possess anti-Campylobacter properties in vitro, so they could be promising candidates to reduce Campylobacter colonization in broiler chickens. To test this hypothesis, selected plant-derived antimicrobials (caffeic, gallic, protocatechuic, and vanillic acids, epigallocatechin gallate, trans-cinnamaldehyde, and thymol) were screened for anti-Campylobacter activity by determining MICs and setting up time-kill curves for C. jejuni strain KC 40. These experiments revealed marked antibacterial activity, especially for the cinnamon oil ingredient trans-cinnamaldehyde (CIN). This compound was tested in a broiler chick seeder model; it was added to the feed in coated form at an effective concentration of 0.3 % from day-of-hatch for the entire 22-day duration of the experiment. At 14 days of age, one-third of the birds were inoculated with C. jejuni strain KC 40 and served as seeders. CIN was not able to reduce cecal Campylobacter colonization in this model, which was confirmed in a cecal loop experiment. Despite CIN concentrations much higher than the MIC, C. jejuni numbers were not reduced compared with those in nontreated ceca at 2 and 24 h after injection. In conclusion, this study shows a marked discrepancy between in vitro and in vivo activity of CIN against C. jejuni strain KC 40. PMID:22004822

  19. Plasminogen Activator Inhibitor-1 Antagonist TM5484 Attenuates Demyelination and Axonal Degeneration in a Mice Model of Multiple Sclerosis.

    PubMed

    Pelisch, Nicolas; Dan, Takashi; Ichimura, Atsuhiko; Sekiguchi, Hiroki; Vaughan, Douglas E; van Ypersele de Strihou, Charles; Miyata, Toshio

    2015-01-01

    Multiple sclerosis (MS) is characterized by inflammatory demyelination and deposition of fibrinogen in the central nervous system (CNS). Elevated levels of a critical inhibitor of the mammalian fibrinolitic system, plasminogen activator inhibitor 1 (PAI-1) have been demonstrated in human and animal models of MS. In experimental studies that resemble neuroinflammatory disease, PAI-1 deficient mice display preserved neurological structure and function compared to wild type mice, suggesting a link between the fibrinolytic pathway and MS. We previously identified a series of PAI-1 inhibitors on the basis of the 3-dimensional structure of PAI-1 and on virtual screening. These compounds have been reported to provide a number of in vitro and in vivo benefits but none was tested in CNS disease models because of their limited capacity to penetrate the blood-brain barrier (BBB). The existing candidates were therefore optimized to obtain CNS-penetrant compounds. We performed an in vitro screening using a model of BBB and were able to identify a novel, low molecular PAI-1 inhibitor, TM5484, with the highest penetration ratio among all other candidates. Next, we tested the effects on inflammation and demyelination in an experimental allergic encephalomyelitis mice model. Results were compared to either fingolimod or 6α-methylprednisolone. Oral administration of TM5484 from the onset of signs, ameliorates paralysis, attenuated demyelination, and axonal degeneration in the spinal cord of mice. Furthermore, it modulated the expression of brain-derived neurotrophic factor, which plays a protective role in neurons against various pathological insults, and choline acetyltransferase, a marker of neuronal density. Taken together, these results demonstrate the potential benefits of a novel PAI-1 inhibitor, TM5484, in the treatment of MS.

  20. Ebselen attenuates oxidative DNA damage and enhances its repair activity in the thalamus after focal cortical infarction in hypertensive rats.

    PubMed

    He, Meixia; Xing, Shihui; Yang, Bo; Zhao, Liqun; Hua, Haiying; Liang, Zhijian; Zhou, Wenliang; Zeng, Jinsheng; Pei, Zhong

    2007-11-21

    Oxidative DNA damage has been proposed to be a major contributor to focal cerebral ischemic injury. However, little is known about the role of oxidative DNA damage in remote damage secondary to the primary infarction. In the present study, we investigated oxidative damage within the ventroposterior nucleus (VPN) after distal middle cerebral artery occlusion (MCAO) in hypertensive rats. We also examined the possible protective effect of ebselen, one glutathione peroxidase mimic, on delayed degeneration in the VPN after distal MCAO. Neuronal damage in the ipsilateral VPN was examined by Nissl staining. Oxidative DNA damage and base repair enzyme activity were assessed by analyzing immunoreactivity of 8-hydroxy-2'-deoxyguanosine (8-ohdG) and 8-oxoguanine DNA glycosylase (OGG1), respectively. The number of intact neurons in the ipsilateral VPN decreased by 52% compared to the contralateral side in ischemia group 2 weeks after distal cerebral cortical infarction. The immunoreactivity of 8-ohdG significantly increased while OGG1 immunoreactivity significantly decreased in the ipsilateral VPN 2 weeks after distal cortical infarction (all p<0.01). Compared with vehicle treatment, ebselen significantly attenuated the neuron loss, ameliorated ischemia-induced increase in 8-ohdG level as well as decrease in OGG1 level within the ipsilateral VPN (all p<0.01). OGG1 was further demonstrated to mainly express in neurons. These findings strongly suggest that oxidative DNA damage may be involved in the delayed neuronal death in the VPN region following distal MCAO. Furthermore, ebselen protects against the delayed damage in the VPN when given at 24 h following distal MCAO.

  1. Genetic mutation of recombination activating gene 1 in Dahl salt-sensitive rats attenuates hypertension and renal damage.

    PubMed

    Mattson, David L; Lund, Hayley; Guo, Chuanling; Rudemiller, Nathan; Geurts, Aron M; Jacob, Howard

    2013-03-15

    Hypertension and renal damage in Dahl SS rats are associated with increased infiltrating immune cells in the kidney. To examine the role of infiltrating immune cells in this disease process, a zinc finger nuclease targeting bases 672-706 of recombination-activating gene 1 (Rag1) was injected into the pronucleus of Dahl SS (SS/JrHsdMcwi) strain embryos and implanted in pseudopregnant females. This strategy yielded a rat strain with a 13-base frame-shift mutation in the target region of Rag1 and a deletion of immunoreactive Rag1 protein in the thymus. Flow cytometry demonstrated that the Rag1-null mutant rats have a significant reduction in T and B lymphocytes in the circulation and spleen. Studies were performed on SS and Rag1-null rats fed a 4.0% NaCl diet for 3 wk. The infiltration of T cells into the kidney following high-salt intake was significantly blunted in the Rag1-null rats (1.7 ± 0.6 × 10(5) cells/kidney) compared with the Dahl SS (5.6 ± 0.9 × 10(5) cells/kidney). Accompanying the reduction in infiltration of immune cells in the kidney, mean arterial blood pressure and urinary albumin excretion rate were significantly lower in Rag1-null mutants (158 ± 3 mmHg and 60 ± 16 mg/day, respectively) than in SS rats (180 ± 11 mmHg and 251 ± 37 mg/day). Finally, a histological analysis revealed that the glomerular and tubular damage in the kidneys of the SS rats fed a high-salt diet was also attenuated in the Rag1 mutants. These studies demonstrate the importance of renal infiltration of immune cells in the pathogenesis of hypertension and renal damage in Dahl SS rats.

  2. A standard, single dose of inhaled terbutaline attenuates hyperpnea-induced bronchoconstriction and mast cell activation in athletes

    PubMed Central

    Simpson, A. J.; Bood, J. R.; Anderson, S. D.; Romer, L. M.; Dahlén, B.; Dahlén, S.-E.

    2016-01-01

    Release of bronchoactive mediators from mast cells during exercise hyperpnea is a key factor in the pathophysiology of exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effect of a standard, single dose of an inhaled β2-adrenoceptor agonist on mast cell activation in response to dry air hyperpnea in athletes with EIB. Twenty-seven athletes with EIB completed a randomized, double-blind, placebo-controlled, crossover study. Terbutaline (0.5 mg) or placebo was inhaled 15 min prior to 8 min of eucapnic voluntary hyperpnea (EVH) with dry air. Pre- and postbronchial challenge, urine samples were analyzed by enzyme immunoassay for 11β-prostaglandin F2α (11β-PGF2α). The maximum fall in forced expiratory volume in 1 s of 14 (12–20)% (median and interquartile range) following placebo was attenuated to 7 (5–9)% with the administration of terbutaline (P < 0.001). EVH caused a significant increase in 11β-PGF2α from 41 (27–57) ng/mmol creatinine at baseline to 58 (43–72) ng/mmol creatinine at its peak post-EVH following placebo (P = 0.002). The rise in 11β-PGF2α was inhibited with administration of terbutaline: 39 (28–44) ng/mmol creatinine at baseline vs. 40 (33–58) ng/mmol creatinine at its peak post-EVH (P = 0.118). These data provide novel in vivo evidence of mast cell stabilization following inhalation of a standard dose of terbutaline prior to bronchial provocation with EVH in athletes with EIB. PMID:26846550

  3. BET Inhibition Attenuates Helicobacter pylori-Induced Inflammatory Response by Suppressing Inflammatory Gene Transcription and Enhancer Activation.

    PubMed

    Chen, Jinjing; Wang, Zhen; Hu, Xiangming; Chen, Ruichuan; Romero-Gallo, Judith; Peek, Richard M; Chen, Lin-Feng

    2016-05-15

    Helicobacter pylori infection causes chronic gastritis and peptic ulceration. H. pylori-initiated chronic gastritis is characterized by enhanced expression of many NF-κB-regulated inflammatory cytokines. Brd4 has emerged as an important NF-κB regulator and regulates the expression of many NF-κB-dependent inflammatory genes. In this study, we demonstrated that Brd4 was not only actively involved in H. pylori-induced inflammatory gene mRNA transcription but also H. pylori-induced inflammatory gene enhancer RNA (eRNA) synthesis. Suppression of H. pylori-induced eRNA synthesis impaired H. pylori-induced mRNA synthesis. Furthermore, H. pylori stimulated NF-κB-dependent recruitment of Brd4 to the promoters and enhancers of inflammatory genes to facilitate the RNA polymerase II-mediated eRNA and mRNA synthesis. Inhibition of Brd4 by JQ1 attenuated H. pylori-induced eRNA and mRNA synthesis for a subset of NF-κB-dependent inflammatory genes. JQ1 also inhibited H. pylori-induced interaction between Brd4 and RelA and the recruitment of Brd4 and RNA polymerase II to the promoters and enhancers of inflammatory genes. Finally, we demonstrated that JQ1 suppressed inflammatory gene expression, inflammation, and cell proliferation in H. pylori-infected mice. These studies highlight the importance of Brd4 in H. pylori-induced inflammatory gene expression and suggest that Brd4 could be a potential therapeutic target for the treatment of H. pylori-triggered inflammatory diseases and cancer. PMID:27084101

  4. Plasminogen Activator Inhibitor-1 Antagonist TM5484 Attenuates Demyelination and Axonal Degeneration in a Mice Model of Multiple Sclerosis.

    PubMed

    Pelisch, Nicolas; Dan, Takashi; Ichimura, Atsuhiko; Sekiguchi, Hiroki; Vaughan, Douglas E; van Ypersele de Strihou, Charles; Miyata, Toshio

    2015-01-01

    Multiple sclerosis (MS) is characterized by inflammatory demyelination and deposition of fibrinogen in the central nervous system (CNS). Elevated levels of a critical inhibitor of the mammalian fibrinolitic system, plasminogen activator inhibitor 1 (PAI-1) have been demonstrated in human and animal models of MS. In experimental studies that resemble neuroinflammatory disease, PAI-1 deficient mice display preserved neurological structure and function compared to wild type mice, suggesting a link between the fibrinolytic pathway and MS. We previously identified a series of PAI-1 inhibitors on the basis of the 3-dimensional structure of PAI-1 and on virtual screening. These compounds have been reported to provide a number of in vitro and in vivo benefits but none was tested in CNS disease models because of their limited capacity to penetrate the blood-brain barrier (BBB). The existing candidates were therefore optimized to obtain CNS-penetrant compounds. We performed an in vitro screening using a model of BBB and were able to identify a novel, low molecular PAI-1 inhibitor, TM5484, with the highest penetration ratio among all other candidates. Next, we tested the effects on inflammation and demyelination in an experimental allergic encephalomyelitis mice model. Results were compared to either fingolimod or 6α-methylprednisolone. Oral administration of TM5484 from the onset of signs, ameliorates paralysis, attenuated demyelination, and axonal degeneration in the spinal cord of mice. Furthermore, it modulated the expression of brain-derived neurotrophic factor, which plays a protective role in neurons against various pathological insults, and choline acetyltransferase, a marker of neuronal density. Taken together, these results demonstrate the potential benefits of a novel PAI-1 inhibitor, TM5484, in the treatment of MS. PMID:25915660

  5. Curcumin Attenuates Beta-Amyloid-Induced Neuroinflammation via Activation of Peroxisome Proliferator-Activated Receptor-Gamma Function in a Rat Model of Alzheimer's Disease.

    PubMed

    Liu, Zun-Jing; Li, Zhong-Hao; Liu, Lei; Tang, Wen-Xiong; Wang, Yu; Dong, Ming-Rui; Xiao, Cheng

    2016-01-01

    Neuroinflammation is known to have a pivotal role in the pathogenesis of Alzheimer's disease (AD), and curcumin has been reported to have therapeutical effects on AD because of its anti-inflammatory effects. Curcumin is not only a potent PPARγ agonist, but also has neuroprotective effects on cerebral ischemic injury. However, whether PPARγ activated by curcumin is responsible for the anti-neuroinflammation and neuroprotection on AD remains unclear, and needs to be further investigated. Here, using both APP/PS1 transgenic mice and beta-amyloid-induced neuroinflammation in mixed neuronal/glial cultures, we showed that curcumin significantly alleviated spatial memory deficits in APP/PS1 mice and promoted cholinergic neuronal function in vivo and in vitro. Curcumin also reduced the activation of microglia and astrocytes, as well as cytokine production and inhibited nuclear factor kappa B (NF-κB) signaling pathway, suggesting the beneficial effects of curcumin on AD are attributable to the suppression of neuroinflammation. Attenuation of these beneficial effects occurred when co-administrated with PPARγ antagonist GW9662 or silence of PPARγ gene expression, indicating that PPARγ might be involved in anti-inflammatory effects. Circular dichroism and co-immunoprecipitation analysis showed that curcumin directly bound to PPARγ and increased the transcriptional activity and protein levels of PPARγ. Taking together, these data suggested that PPARγ might be a potential target of curcumin, acting to alleviate neuroinflammation and improve neuronal function in AD. PMID:27594837

  6. Curcumin Attenuates Beta-Amyloid-Induced Neuroinflammation via Activation of Peroxisome Proliferator-Activated Receptor-Gamma Function in a Rat Model of Alzheimer's Disease

    PubMed Central

    Liu, Zun-Jing; Li, Zhong-Hao; Liu, Lei; Tang, Wen-Xiong; Wang, Yu; Dong, Ming-Rui; Xiao, Cheng

    2016-01-01

    Neuroinflammation is known to have a pivotal role in the pathogenesis of Alzheimer's disease (AD), and curcumin has been reported to have therapeutical effects on AD because of its anti-inflammatory effects. Curcumin is not only a potent PPARγ agonist, but also has neuroprotective effects on cerebral ischemic injury. However, whether PPARγ activated by curcumin is responsible for the anti-neuroinflammation and neuroprotection on AD remains unclear, and needs to be further investigated. Here, using both APP/PS1 transgenic mice and beta-amyloid-induced neuroinflammation in mixed neuronal/glial cultures, we showed that curcumin significantly alleviated spatial memory deficits in APP/PS1 mice and promoted cholinergic neuronal function in vivo and in vitro. Curcumin also reduced the activation of microglia and astrocytes, as well as cytokine production and inhibited nuclear factor kappa B (NF-κB) signaling pathway, suggesting the beneficial effects of curcumin on AD are attributable to the suppression of neuroinflammation. Attenuation of these beneficial effects occurred when co-administrated with PPARγ antagonist GW9662 or silence of PPARγ gene expression, indicating that PPARγ might be involved in anti-inflammatory effects. Circular dichroism and co-immunoprecipitation analysis showed that curcumin directly bound to PPARγ and increased the transcriptional activity and protein levels of PPARγ. Taking together, these data suggested that PPARγ might be a potential target of curcumin, acting to alleviate neuroinflammation and improve neuronal function in AD.

  7. Curcumin Attenuates Beta-Amyloid-Induced Neuroinflammation via Activation of Peroxisome Proliferator-Activated Receptor-Gamma Function in a Rat Model of Alzheimer's Disease

    PubMed Central

    Liu, Zun-Jing; Li, Zhong-Hao; Liu, Lei; Tang, Wen-Xiong; Wang, Yu; Dong, Ming-Rui; Xiao, Cheng

    2016-01-01

    Neuroinflammation is known to have a pivotal role in the pathogenesis of Alzheimer's disease (AD), and curcumin has been reported to have therapeutical effects on AD because of its anti-inflammatory effects. Curcumin is not only a potent PPARγ agonist, but also has neuroprotective effects on cerebral ischemic injury. However, whether PPARγ activated by curcumin is responsible for the anti-neuroinflammation and neuroprotection on AD remains unclear, and needs to be further investigated. Here, using both APP/PS1 transgenic mice and beta-amyloid-induced neuroinflammation in mixed neuronal/glial cultures, we showed that curcumin significantly alleviated spatial memory deficits in APP/PS1 mice and promoted cholinergic neuronal function in vivo and in vitro. Curcumin also reduced the activation of microglia and astrocytes, as well as cytokine production and inhibited nuclear factor kappa B (NF-κB) signaling pathway, suggesting the beneficial effects of curcumin on AD are attributable to the suppression of neuroinflammation. Attenuation of these beneficial effects occurred when co-administrated with PPARγ antagonist GW9662 or silence of PPARγ gene expression, indicating that PPARγ might be involved in anti-inflammatory effects. Circular dichroism and co-immunoprecipitation analysis showed that curcumin directly bound to PPARγ and increased the transcriptional activity and protein levels of PPARγ. Taking together, these data suggested that PPARγ might be a potential target of curcumin, acting to alleviate neuroinflammation and improve neuronal function in AD. PMID:27594837

  8. A TIR Domain Protein from E. faecalis Attenuates MyD88-Mediated Signaling and NF-κB Activation

    PubMed Central

    Zou, Jun; Baghdayan, Arto S.; Payne, Sarah J.; Shankar, Nathan

    2014-01-01

    Toll-like receptor signaling, mediated by functional Toll/interleukin-1 receptor (TIR) domains, plays a critical role in activating the innate immune response responsible for controlling and clearing infection. Bacterial protein mimics of components of this signaling pathway have been identified and function through inhibition of interactions between Toll-like receptors (TLRs) and their adaptor proteins, mediated by TIR domains. A previously uncharacterized gene, which we have named tcpF (for TIR domain-containing protein in E. faecalis) was identified in the genome of Enterococcus faecalis V583, and predicted to encode a protein resembling mammalian and bacterial TIR proteins. We overexpressed and purified TcpF from E. coli and found that the recombinant protein could bind to phosphatidylinositol phosphates in vitro, suggesting a mechanism by which TcpF may be anchored to the plasma membrane in close proximity to TIR domains of TLRs and adaptor proteins. Purified TcpF was also found to interact specifically with the TIR adaptor protein MyD88, and this interaction was dependent on the BB loop domain in the Box 2 region of TcpF. Despite no evidence of TcpF being a secreted protein, recombinant TcpF was effectively able to enter RAW264.7 cells in vitro although the mechanism by which this occurs remains to be determined. Overexpression of TcpF in mammalian cells suppressed the NF-κB activation induced by bacterial lipoteichoic acid. A mutant lacking the tcpF gene was attenuated for survival in macrophages, with increased ability to activate NF-κB compared to the wild type strain. Complementation in trans restored growth, and inhibition of NF-κB, to that of wild type levels. No appreciable difference in bacterial persistence, dissemination or pathogenesis was observed between the wild type and mutant in a mouse peritonitis model however, which suggested either a subtle role for TcpF or functional overlap with other redundant factor(s) in this virulence model. PMID

  9. Activation of Constitutive Androstane Receptor (CAR) in Mice Results in Maintained Biliary Excretion of Bile Acids Despite a Marked Decrease of Bile Acids in Liver.

    PubMed

    Lickteig, Andrew J; Csanaky, Iván L; Pratt-Hyatt, Matthew; Klaassen, Curtis D

    2016-06-01

    Activation of Constitutive Androstane Receptor (CAR) protects against bile acid (BA)-induced liver injury. This study was performed to determine the effect of CAR activation on bile flow, BA profile, as well as expression of BA synthesis and transport genes. Synthetic CAR ligand 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) was administered to mice for 4 days. BAs were quantified by UPLC-MS/MS (ultraperformance liquid chromatography-tandem mass spectrometry). CAR activation decreases total BAs in livers of male (49%) and female mice (26%), largely attributable to decreases of the 12α-hydroxylated BA taurocholic acid (T-CA) (males (M) 65%, females (F) 45%). Bile flow in both sexes was increased by CAR activation, and the increases were BA-independent. CAR activation did not alter biliary excretion of total BAs, but overall BA composition changed. Excretion of muricholic (6-hydroxylated) BAs was increased in males (101%), and the 12α-OH proportion of biliary BAs was decreased in both males (37%) and females (28%). The decrease of T-CA in livers of males and females correlates with the decreased mRNA of the sterol 12α-hydroxylase Cyp8b1 in males (71%) and females (54%). As a response to restore BAs to physiologic concentrations in liver, mRNA of Cyp7a1 is upregulated following TCPOBOP (males 185%, females 132%). In ilea, mRNA of the negative feedback regulator Fgf15 was unaltered by CAR activation, indicating biliary BA excretion was sufficient to maintain concentrations of total BAs in the small intestine. In summary, the effects of CAR activation on BAs in male and female mice are quite similar, with a marked decrease in the major BA T-CA in the liver.

  10. MicroRNA-128 inhibition attenuates myocardial ischemia/reperfusion injury-induced cardiomyocyte apoptosis by the targeted activation of peroxisome proliferator-activated receptor gamma

    PubMed Central

    ZENG, XIAO CONG; LI, LANG; WEN, HONG; BI, QI

    2016-01-01

    The aim of the present study was to investigate the effects of microRNA (miR)-128 inhibition on the targeted activation of peroxisome proliferator-activated receptor gamma (PPARG) and on cardiomyocyte apoptosis induced by myocardial ischemia/reperfusion (I/R) injury. In vitro, the expression of PPARG was detected by reverse transcription-quantitative polymerase chain reaction and western blotting in neonatal rat ventricular myocytes (NRVMs) and HEK293 cells transfected with the mimics or inhibitors of miR-128 or control RNA. Luciferase reporter assays were used to identify whether PPARG is a direct target of miR-128. In vivo, miR-128 was knocked down via ear vein injection of antagomir-128 in a rabbit myocardial I/R injury model. Western blotting investigated the activation of Akt [phosphorylated (p)-Akt] and the expression of total-Akt, PPARG and myeloid leukemia cell differentiation protein-1 (Mcl-1) in the myocardium. Cardiomyocyte apoptosis was examined with transmission electron microscropy and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. PPARG mRNA and protein were downregulated in NRVMs transfected with miR-128 mimics, but upregulated by antagomir-128 compared with control. This indicates that PPARG is a direct miR-128 target. Activation of Akt (p-Akt), Mcl-1 and PPARG expression in the myocardium were increased by miR-128 inhibition. Furthermore, miR-128 antagomirs significantly reduced apoptosis in hearts subjected to I/R injury, which was blocked by the PPARG inhibitor GW9662. In conclusion, miR-128 inhibition attenuated I/R injury-induced cardiomyocyte apoptosis by the targeted activation of PPARG signaling. PMID:27150726

  11. Baicalin attenuates focal cerebral ischemic reperfusion injury through inhibition of nuclear factor {kappa}B p65 activation

    SciTech Connect

    Xue, Xia; Qu, Xian-Jun; Yang, Ying; Sheng, Xie-Huang; Cheng, Fang; Jiang, E-Nang; Wang, Jian-hua; Bu, Wen; Liu, Zhao-Ping

    2010-12-17

    Research highlights: {yields} Permanent NF-{kappa}B p65 activation contributes to the infarction after ischemia-reperfusion injury in rats. {yields} Baicalin can markedly inhibit the nuclear NF-{kappa}B p65 expression and m RNA levels after ischemia-reperfusion injury in rats. {yields} Baicalin decreased the cerebral infarction area via inhibiting the activation of nuclear NF-{kappa}B p65. -- Abstract: Baicalin is a flavonoid compound purified from plant Scutellaria baicalensis Georgi. We aimed to evaluate the neuroprotective effects of baicalin against cerebral ischemic reperfusion injury. Male Wistar rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion for 24 h. Baicalin at doses of 50, 100 and 200 mg/kg was intravenously injected after ischemia onset. Twenty-four hours after reperfusion, the neurological deficit was scored and infarct volume was measured. Hematoxylin and eosin (HE) staining was performed to analyze the histopathological changes of cortex and hippocampus neurons. We examined the levels of NF-{kappa}B p65 in ischemic cortexes by Western blot analysis and RT-PCR assay. The results showed that the neurological deficit scores were significantly decreased from 2.0 {+-} 0.7 to 1.2 {+-} 0.4 and the volume of infarction was reduced by 25% after baicalin injection. Histopathological examination showed that the increase of neurons with pycnotic shape and condensed nuclear in cortex and hippocampus were not observed in baicalin treated animals. Further examination showed that NF-{kappa}B p65 in cortex was increased after ischemia reperfusion injury, indicating the molecular mechanism of ischemia reperfusion injury. The level of NF-{kappa}B p65 was decreased by 73% after baicalin treatment. These results suggest that baicalin might be useful as a potential neuroprotective agent in stroke therapy. The neuroprotective effects of baicalin may relate to inhibition of NF-{kappa}B p65.

  12. Asian women have attenuated sympathetic activation but enhanced renal-adrenal responses during pregnancy compared to Caucasian women.

    PubMed

    Okada, Yoshiyuki; Best, Stuart A; Jarvis, Sara S; Shibata, Shigeki; Parker, Rosemary S; Casey, Brian M; Levine, Benjamin D; Fu, Qi

    2015-03-01

    Asians have a lower prevalence of hypertensive disorders of pregnancy than Caucasians. Since sympathetic overactivity and dysregulation of the renal-adrenal system (e.g. low aldosterone levels) have been found in preeclamptic women, we hypothesized that Asians have lower muscle sympathetic nerve activity (MSNA) and greater aldosterone concentrations during normal pregnancy than Caucasians. In a prospective study, blood pressure (BP), heart rate (HR), and MSNA were measured during supine and upright tilt (30 deg and 60 deg for 5 min each) in 9 Asians (32 ± 1 years (mean ± SEM)) and 12 Caucasians (29 ± 1 years) during pre-, early (≤8 weeks of gestation) and late (32-36 weeks) pregnancy, and post-partum (6-10 weeks after delivery). Supine MSNA increased with pregnancy in both groups (P < 0.001); it was significantly lower in Asians than Caucasians (14 ± 3 vs. 23 ± 3 bursts min(-1) and 16 ± 5 vs. 30 ± 3 bursts min(-1) in early and late pregnancy, respectively; P = 0.023). BP decreased during early pregnancy (P < 0.001), but was restored during late pregnancy. HR increased during pregnancy (P < 0.001) with no racial difference (P = 0.758). MSNA increased during tilting and it was markedly lower in Asians than Caucasians in late pregnancy (31 ± 6 vs. 49 ± 3 bursts min(-1) at 60 deg tilt; P = 0.003). Upright BP was lower in Asians, even in pre-pregnancy (P = 0.006), and this racial difference persisted during pregnancy. Direct renin and aldosterone increased during pregnancy (both P < 0.001); these hormones were greater in Asians (P = 0.086 and P = 0.014). Thus, Asians have less sympathetic activation but more upregulated renal-adrenal responses than Caucasians during pregnancy. These results may explain, at least in part, why Asian women are at low risk of hypertensive disorders in pregnancy. PMID:25545472

  13. Lycopene Attenuates Colistin-Induced Nephrotoxicity in Mice via Activation of the Nrf2/HO-1 Pathway

    PubMed Central

    Dai, Chongshan; Tang, Shusheng; Deng, Sijun; Zhang, Shen; Zhou, Yan; Velkov, Tony

    2014-01-01

    Nephrotoxicity is the major dose-limiting factor for the clinical use of colistin against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to investigate the protective effect of lycopene on colistin-induced nephrotoxicity in a mouse model. Fifty mice were randomly divided into 5 groups: the control group (saline solution), the lycopene group (20 mg/kg of body weight/day administered orally), the colistin group (15 mg/kg/day administered intravenously), the colistin (15 mg/kg/day) plus lycopene (5 mg/kg/day) group, and the colistin (15 mg/kg/day) plus lycopene (20 mg/kg/day) group; all mice were treated for 7 days. At 12 h after the last dose, blood was collected for measurements of blood urea nitrogen (BUN) and serum creatinine levels. The kidney tissue samples were obtained for examination of biomarkers of oxidative stress and apoptosis, histopathological assessment, and quantitative reverse transcription-PCR (qRT-PCR) analysis. Colistin treatment significantly increased concentrations of BUN and serum creatinine, tubular apoptosis/necrosis, lipid peroxidation, and heme oxygenase 1 (HO-1) activity, while the treatment decreased the levels of endogenous antioxidant biomarkers glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Notably, the changes in the levels of all biomarkers were attenuated in the kidneys of mice treated with colistin by lycopene (5 or 20 mg/kg). Lycopene treatment, especially in the colistin plus lycopene (20 mg/kg) group, significantly downregulated the expression of NF-κB mRNA (P < 0.01) but upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1 mRNA (both P < 0.01) in the kidney compared with the results seen with the colistin group. Our data demonstrated that coadministration of 20 mg/kg/day lycopene can protect against colistin-induced nephrotoxicity in mice. This effect may be attributed to the antioxidative property of lycopene and its ability to activate the Nrf2/HO

  14. Attenuation of negative pain affect produced by unilateral spinal nerve injury in the rat following anterior cingulate cortex activation.

    PubMed

    LaBuda, C J; Fuchs, P N

    2005-01-01

    The affective and the sensory dimensions of pain processing can be differentiated in humans through the use of questionnaires and verbal communication. It is difficult to dissociate these two components of pain processing in rodents, and an understanding of the underlying mechanisms for each component is unclear. The quantification of a novel behavioral response to a repeated noxious cutaneous stimulus together with a measurement of tactile allodynia in nerve-injured rats might be used to differentially explore the sensory and affective components of pain processing in the rat. The present study utilized electrical stimulation of the anterior cingulate cortex, a structure implicated in affective pain processing but not sensory processing, in nerve-injured rats (L5 spinal nerve ligation) and found that the aversive quality of noxious cutaneous hindpaw stimulation was attenuated. There were no effects on sensory processing, because anterior cingulate cortex stimulation did not produce an anti-allodynic effect in L5 spinal nerve ligation animals. Furthermore, anterior cingulate cortex stimulation in animals with bilateral ventrolateral periaqueductal gray area lesions did not affect tactile sensitivity in L5 spinal nerve ligation rats, indicating that an endogenous pain suppression system was not likely activated by anterior cingulate cortex stimulation. However, bilateral ventrolateral periaqueductal gray area lesions in L5 spinal nerve ligation rats blocked the effect produced by anterior cingulate cortex stimulation in the place escape/avoidance paradigm. Specifically, these animals avoided noxious stimulation of the allodynic paw significantly more than anterior cingulate cortex-stimulated, sham or incomplete ventrolateral periaqueductal gray area-lesioned, L5 spinal nerve ligation animals. These findings provide the first quantified report that the activation of the anterior cingulate cortex reduced the aversive quality of repeated noxious tactile stimulation in

  15. Lycopene attenuates colistin-induced nephrotoxicity in mice via activation of the Nrf2/HO-1 pathway.

    PubMed

    Dai, Chongshan; Tang, Shusheng; Deng, Sijun; Zhang, Shen; Zhou, Yan; Velkov, Tony; Li, Jian; Xiao, Xilong

    2015-01-01

    Nephrotoxicity is the major dose-limiting factor for the clinical use of colistin against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to investigate the protective effect of lycopene on colistin-induced nephrotoxicity in a mouse model. Fifty mice were randomly divided into 5 groups: the control group (saline solution), the lycopene group (20 mg/kg of body weight/day administered orally), the colistin group (15 mg/kg/day administered intravenously), the colistin (15 mg/kg/day) plus lycopene (5 mg/kg/day) group, and the colistin (15 mg/kg/day) plus lycopene (20 mg/kg/day) group; all mice were treated for 7 days. At 12 h after the last dose, blood was collected for measurements of blood urea nitrogen (BUN) and serum creatinine levels. The kidney tissue samples were obtained for examination of biomarkers of oxidative stress and apoptosis, histopathological assessment, and quantitative reverse transcription-PCR (qRT-PCR) analysis. Colistin treatment significantly increased concentrations of BUN and serum creatinine, tubular apoptosis/necrosis, lipid peroxidation, and heme oxygenase 1 (HO-1) activity, while the treatment decreased the levels of endogenous antioxidant biomarkers glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Notably, the changes in the levels of all biomarkers were attenuated in the kidneys of mice treated with colistin by lycopene (5 or 20 mg/kg). Lycopene treatment, especially in the colistin plus lycopene (20 mg/kg) group, significantly downregulated the expression of NF-κB mRNA (P < 0.01) but upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1 mRNA (both P < 0.01) in the kidney compared with the results seen with the colistin group. Our data demonstrated that coadministration of 20 mg/kg/day lycopene can protect against colistin-induced nephrotoxicity in mice. This effect may be attributed to the antioxidative property of lycopene and its ability to activate the Nrf2/HO

  16. Decreased hepatic phosphorylated p38 mitogen-activated protein kinase contributes to attenuation of thioacetamide-induced hepatic necrosis in diet-induced obese mice.

    PubMed

    Shirai, Makoto; Arakawa, Shingo; Teranishi, Munehiro; Kai, Kiyonori

    2016-04-01

    We previously reported that thioacetamide (TA)-induced hepatocellular necrosis was attenuated in mice fed a high-fat diet (HFD mice) compared with mice fed a normal rodent diet (ND mice). In this study, we investigated whether p38 mitogen-activated protein kinase (p38 MAPK) was involved in this attenuation. Western blot analysis revealed that hepatic phosphorylated p38 MAPK protein decreased at 8 and 24 hours (hr) after TA dosing in the HFD mice, while it decreased only at 24 hr in the ND mice in comparison to the time- and diet-matched, vehicle-treated mice. p38 MAPK regulates various biological functions including inflammation, therefore, hepatic metabolomics analysis focusing on pro-inflammatory lipid mediators was performed. At 24 hr after TA dosing, only one pro-inflammatory mediator, 12-hydroxyeicosatetraenoic acid (HETE), was higher in the HFD mice. On the other hand, in addition to 12-HETE, 15-HETE and 12-hydroxyeicosapentaenoic acid (HEPE) were higher and omega-3/omega-6 polyunsaturated fatty acids ratios were lower in the ND mice at 24 hr. These results of metabolomics indicated that less pro-inflammatory state was seen in HFD mice than in ND mice at 24 hr. Finally, to confirm whether the observed decrease in phosphorylated p38 MAPK could attenuate TA-induced hepatocellular necrosis, we showed that SB203580 hydrochloride, an inhibitor of p38 MAPK, partially attenuated TA-induced hepatic necrosis in ND mice. Collectively, these results suggest that a prompt decrease in phosphorylation of p38 MAPK after TA administration is one of the factors that attenuate TA-induced hepatic necrosis in HFD mice. PMID:26961609

  17. Nek2A destruction marks APC/C activation at the prophase-to-prometaphase transition by spindle-checkpoint-restricted Cdc20.

    PubMed

    Boekhout, Michiel; Wolthuis, Rob

    2015-04-15

    Nek2 isoform A (Nek2A) is a presumed substrate of the anaphase-promoting complex/cyclosome containing Cdc20 (APC/C(Cdc20)). Nek2A, like cyclin A, is degraded in mitosis while the spindle checkpoint is active. Cyclin A prevents spindle checkpoint proteins from binding to Cdc20 and is recruited to the APC/C in prometaphase. We found that Nek2A and cyclin A avoid being stabilized by the spindle checkpoint in different ways. First, enhancing mitotic checkpoint complex (MCC) formation by nocodazole treatment inhibited the degradation of geminin and cyclin A, whereas Nek2A disappeared at a normal rate. Second, depleting Cdc20 effectively stabilized cyclin A but not Nek2A. Nevertheless, Nek2A destruction crucially depended on Cdc20 binding to the APC/C. Third, in contrast to cyclin A, Nek2A was recruited to the APC/C before the start of mitosis. Interestingly, the spindle checkpoint very effectively stabilized an APC/C-binding mutant of Nek2A, which required the Nek2A KEN box. Apparently, in cells, the spindle checkpoint primarily prevents Cdc20 from binding destruction motifs. Nek2A disappearance marks the prophase-to-prometaphase transition, when Cdc20, regardless of the spindle checkpoint, activates the APC/C. However, Mad2 depletion accelerated Nek2A destruction, showing that spindle checkpoint release further increases APC/C(Cdc20) catalytic activity. PMID:25673878

  18. Marked inhibition of Na+, K(+)- ATPase activity and the respiratory chain by phytanic acid in cerebellum from young rats: possible underlying mechanisms of cerebellar ataxia in Refsum disease.

    PubMed

    Busanello, Estela Natacha Brandt; Zanatta, Ângela; Tonin, Anelise Miotti; Viegas, Carolina Maso; Vargas, Carmen Regla; Leipnitz, Guilhian; Ribeiro, César Augusto João; Wajner, Moacir

    2013-02-01

    Refsum disease is an autosomal recessive disorder of peroxisomal metabolism biochemically characterized by highly elevated concentrations of phytanic acid (Phyt) in a variety of tissues including the cerebellum. Reduction of plasma Phyt levels by dietary restriction intake ameliorates ataxia, a common clinical manifestation of this disorder, suggesting a neurotoxic role for this branched-chain fatty acid. Therefore, considering that the underlying mechanisms of cerebellum damage in Refsum disease are poorly known, in the present study we tested the effects of Phyt on important parameters of bioenergetics, such as the activities of the respiratory chain complexes I to IV, creatine kinase and Na(+), K(+)- ATPase in cerebellum preparations from young rats. The activities of complexes I, II, I-III and II-III and Na(+), K(+)- ATPase were markedly inhibited (65-85%) in a dose-dependent manner by Phyt. In contrast, creatine kinase and complex IV activities were not altered by this fatty acid. Therefore, it is presumed that impairment of the electron flow through the respiratory chain and inhibition of Na(+), K(+)- ATPase that is crucial for synaptic function may be involved in the pathophysiology of the cerebellar abnormalities manifested as ataxia in Refsum disease and in other peroxisomal disorders in which brain Phyt accumulates.

  19. Mutations in the NS1 protein of swine influenza virus impair anti-interferon activity and confer attenuation in pigs.

    PubMed

    Solórzano, Alicia; Webby, Richard J; Lager, Kelly M; Janke, Bruce H; García-Sastre, Adolfo; Richt, Jürgen A

    2005-06-01

    It has been shown previously that the nonstructural protein NS1 of influenza virus is an alpha/beta interferon (IFN-alpha/beta) antagonist, both in vitro and in experimental animal model systems. However, evidence of this function in a natural host has not yet been obtained. Here we investigated the role of the NS1 protein in the virulence of a swine influenza virus (SIV) isolate in pigs by using reverse genetics. The virulent wild-type A/Swine/Texas/4199-2/98 (TX/98) virus and various mutants encoding carboxy-truncated NS1 proteins were rescued. Growth properties of TX/98 viruses with mutated NS1, induction of IFN in tissue culture, and virulence-attenuation in pigs were analyzed and compared to those of the recombinant wild-type TX/98 virus. Our results indicate that deletions in the NS1 protein decrease the ability of the TX/98 virus to prevent IFN-alpha/beta synthesis in pig cells. Moreover, all NS1 mutant viruses were attenuated in pigs, and this correlated with the amount of IFN-alpha/beta induced in vitro. These data suggest that the NS1 protein of SIV is a virulence factor. Due to their attenuation, NS1-mutated swine influenza viruses might have a great potential as live attenuated vaccine candidates against SIV infections of pigs.

  20. GCF Mark IV development

    NASA Technical Reports Server (NTRS)

    Mortensen, L. O.

    1982-01-01

    The Mark IV ground communication facility (GCF) as it is implemented to support the network consolidation program is reviewed. Changes in the GCF are made in the area of increased capacity. Common carrier circuits are the medium for data transfer. The message multiplexing in the Mark IV era differs from the Mark III era, in that all multiplexing is done in a GCF computer under GCF software control, which is similar to the multiplexing currently done in the high speed data subsystem.

  1. Lateralized Delay Period Activity Marks the Focus of Spatial Attention in Working Memory: Evidence from Somatosensory Event-Related Brain Potentials

    PubMed Central

    Eimer, Martin

    2015-01-01

    The short-term retention of sensory information in working memory (WM) is known to be associated with a sustained enhancement of neural activity. What remains controversial is whether this neural trace indicates the sustained storage of information or the allocation of attention. To evaluate the storage and attention accounts, we examined sustained tactile contralateral delay activity (tCDA component) of the event-related potential. The tCDA manifests over somatosensory cortex contralateral to task-relevant tactile information during stimulus retention. Two tactile sample sets (S1, S2) were presented sequentially, separated by 1.5 s. Each set comprised two stimuli, one per hand. Human participants memorized the location of one task-relevant stimulus per sample set and judged whether one of these locations was stimulated again at memory test. The two relevant pulses were unpredictably located on the same hand (stay trials) or on different hands (shift trials). Initially, tCDA components emerged contralateral to the relevant S1 pulse. Sequential loading of WM enhanced the tCDA after S2 was presented on stay trials. On shift trials, the tCDA's polarity reversed after S2 presentation, resulting in delay activity that was now contralateral to the task-relevant S2 pulse. The disappearance of a lateralized neural trace for the relevant S1 pulse did not impair memory accuracy for this stimulus on shift trials. These results contradict the storage account and suggest that delay period activity indicates the sustained engagement of an attention-based rehearsal mechanism. In conclusion, somatosensory delay period activity marks the current focus of attention in tactile WM. PMID:25926447

  2. Lateralized delay period activity marks the focus of spatial attention in working memory: evidence from somatosensory event-related brain potentials.

    PubMed

    Katus, Tobias; Eimer, Martin

    2015-04-29

    The short-term retention of sensory information in working memory (WM) is known to be associated with a sustained enhancement of neural activity. What remains controversial is whether this neural trace indicates the sustained storage of information or the allocation of attention. To evaluate the storage and attention accounts, we examined sustained tactile contralateral delay activity (tCDA component) of the event-related potential. The tCDA manifests over somatosensory cortex contralateral to task-relevant tactile information during stimulus retention. Two tactile sample sets (S1, S2) were presented sequentially, separated by 1.5 s. Each set comprised two stimuli, one per hand. Human participants memorized the location of one task-relevant stimulus per sample set and judged whether one of these locations was stimulated again at memory test. The two relevant pulses were unpredictably located on the same hand (stay trials) or on different hands (shift trials). Initially, tCDA components emerged contralateral to the relevant S1 pulse. Sequential loading of WM enhanced the tCDA after S2 was presented on stay trials. On shift trials, the tCDA's polarity reversed after S2 presentation, resulting in delay activity that was now contralateral to the task-relevant S2 pulse. The disappearance of a lateralized neural trace for the relevant S1 pulse did not impair memory accuracy for this stimulus on shift trials. These results contradict the storage account and suggest that delay period activity indicates the sustained engagement of an attention-based rehearsal mechanism. In conclusion, somatosensory delay period activity marks the current focus of attention in tactile WM.

  3. Platelet-activating factor antagonist TCV-309 attenuates the induction of the cytokine network in experimental endotoxemia in chimpanzees.

    PubMed

    Kuipers, B; van der Poll, T; Levi, M; van Deventer, S J; ten Cate, H; Imai, Y; Hack, C E; ten Cate, J W

    1994-03-01

    Platelet-activating factor (PAF) has been postulated to play a role in the pathogenesis of sepsis. Additionally, in vitro studies have revealed tight interactions between PAF and the cytokine network, and PAF is considered to be an important stimulator of neutrophil functions. To assess the intermediate role of PAF in the induction of cytokines and neutrophil degranulation in endotoxemia in vivo, 12 healthy adult chimpanzees were i.v. injected with a bolus dose of Escherichia coli endotoxin (4 ng/kg); four animals received endotoxin alone, whereas the other chimpanzees were infused with the specific and potent PAF antagonist TCV-309 (bolus of 100 micrograms/kg, followed by either 100 micrograms/kg/h (n = 4) or 500 micrograms/kg/h (n = 4) for 5 h). At both doses TCV-309 significantly inhibited the endotoxin-induced rise in cytokine levels. Peak TNF concentrations after injection of endotoxin alone were 366 +/- 96 pg/ml, vs 105 +/- 47 and 115 +/- 56 pg/ml after administration of endotoxin together with the lower or higher dose of TCV-309, respectively (p < 0.05). TCV-309 also reduced the appearance of soluble TNFRs. Maximal levels of the type I soluble TNFR were diminished from 2.53 +/- 0.27 ng/ml (endotoxin alone) to 1.69 +/- 0.36 ng/ml (high dose TCV-309; p < 0.05); peak values of the type II soluble TNFR were diminished from 8.62 +/- 1.19 ng/ml to 5.76 +/- 0.92 ng/ml (p < 0.05). Furthermore, TCV-309 attenuated the endotoxin-induced release of IL-6 (160 +/- 82 pg/ml after endotoxin alone, vs 63 +/- 30 pg/ml in the low dose TCV-309 group (p < 0.05) and 65 +/- 29 pg/ml in the high dose group (p = 0.07) as well as that of IL-8 (279 +/- 168, vs 71 +/- 15 and 46 +/- 17 pg/ml, respectively; both p < 0.05). TCV-309 tended to reduce the endotoxin-provoked rise in serum IL-1R antagonist levels. In contrast, TCV-309 did not affect the neutrophilic leukocytosis elicited by endotoxin, nor did it inhibit endotoxin-induced neutrophil degranulation, as monitored by the plasma

  4. IgM-Enriched Immunoglobulin Attenuates Systemic Endotoxin Activity in Early Severe Sepsis: A Before-After Cohort Study

    PubMed Central

    Kirbach, Christin; Warszawska, Joanna; Meybohm, Patrick; Zacharowski, Kai; Koch, Alexander

    2016-01-01

    Introduction Sepsis remains associated with a high mortality rate. Endotoxin has been shown to influence viscoelastic coagulation parameters, thus suggesting a link between endotoxin levels and the altered coagulation phenotype in septic patients. This study evaluated the effects of systemic polyspecific IgM-enriched immunoglobulin (IgM-IVIg) (Pentaglobin® [Biotest, Dreieich, Germany]) on endotoxin activity (EA), inflammatory markers, viscoelastic and conventional coagulation parameters. Methods Patients with severe sepsis were identified by daily screening in a tertiary, academic, surgical ICU. After the inclusion of 15 patients, the application of IgM-IVIg (5 mg/kg/d over three days) was integrated into the unit’s standard operation procedure (SOP) to treat patients with severe sepsis, thereby generating “control” and “IgM-IVIg” groups. EA assays, thrombelastometry (ROTEM®) and impedance aggregometry (Multiplate®) were performed on whole blood. Furthermore, routine laboratory parameters were determined according to unit’s standards. Results Data from 26 patients were included. On day 1, EA was significantly decreased in the IgM-IVIg group following 6 and 12 hours of treatment (0.51 ±0.06 vs. 0.26 ±0.07, p<0.05 and 0.51 ±0.06 vs. 0.25 ±0.04, p<0.05) and differed significantly compared with the control group following 6 hours of treatment (0.26 ±0.07 vs. 0.43 ±0.07, p<0.05). The platelet count was significantly higher in the IgM-IVIg group following four days of IgM-IVIg treatment (200/nl ±43 vs. 87/nl ±20, p<0.05). The fibrinogen concentration was significantly lower in the control group on day 2 (311 mg/dl ±37 vs. 475 mg/dl ±47 (p = 0.015)) and day 4 (307 mg/dl ±35 vs. 420 mg/dl ±16 (p = 0.017)). No differences in thrombelastometric or aggregometric measurements, or inflammatory markers (interleukin-6 (IL-6), leukocyte, lipopolysaccharide binding protein (LBP)) were observed. Conclusion Treatment with IgM-enriched immunoglobulin

  5. Attenuated Leishmania induce pro-inflammatory mediators and influence leishmanicidal activity by p38 MAPK dependent phagosome maturation in Leishmania donovani co-infected macrophages.

    PubMed

    Banerjee, Somenath; Bose, Dipayan; Chatterjee, Nabanita; Das, Subhadip; Chakraborty, Sreeparna; Das, Tanya; Saha, Krishna Das

    2016-01-01

    Promastigote form of Leishmania, an intracellular pathogen, delays phagosome maturation and resides inside macrophages. But till date limited study has been done to manipulate the phagosomal machinery of macrophages to restrict Leishmania growth. Attenuated Leishmania strain exposed RAW 264.7 cells showed a respiratory burst and enhanced production of pro-inflammatory mediators. The augmentation of pro-inflammatory activity is mostly attributed to p38 MAPK and p44/42 MAPK. In our study, these activated macrophages are found to induce phagosome maturation when infected with pathogenic Leishmania donovani. Increased co-localization of carboxyfluorescein succinimidyl ester labeled pathogenic L. donovani with Lysosome was found. Moreover, increased co-localization was observed between pathogenic L. donovani and late phagosomal markers viz. Rab7, Lysosomal Associated Membrane Protein 1, Cathepsin D, Rab9, and V-ATPase which indicate phagosome maturation. It was also observed that inhibition of V-type ATPase caused significant hindrance in attenuated Leishmania induced phagosome maturation. Finally, it was confirmed that p38 MAPK is the key player in acidification and maturation of phagosome in attenuated Leishmania strain pre-exposed macrophages. To our knowledge, this study for the first time reported an approach to induce phagosome maturation in L. donovani infected macrophages which could potentiate short-term prophylactic response in future. PMID:26928472

  6. Attenuated Leishmania induce pro-inflammatory mediators and influence leishmanicidal activity by p38 MAPK dependent phagosome maturation in Leishmania donovani co-infected macrophages

    PubMed Central

    Banerjee, Somenath; Bose, Dipayan; Chatterjee, Nabanita; Das, Subhadip; Chakraborty, Sreeparna; Das, Tanya; Saha, Krishna Das

    2016-01-01

    Promastigote form of Leishmania, an intracellular pathogen, delays phagosome maturation and resides inside macrophages. But till date limited study has been done to manipulate the phagosomal machinery of macrophages to restrict Leishmania growth. Attenuated Leishmania strain exposed RAW 264.7 cells showed a respiratory burst and enhanced production of pro-inflammatory mediators. The augmentation of pro-inflammatory activity is mostly attributed to p38 MAPK and p44/42 MAPK. In our study, these activated macrophages are found to induce phagosome maturation when infected with pathogenic Leishmania donovani. Increased co-localization of carboxyfluorescein succinimidyl ester labeled pathogenic L. donovani with Lysosome was found. Moreover, increased co-localization was observed between pathogenic L. donovani and late phagosomal markers viz. Rab7, Lysosomal Associated Membrane Protein 1, Cathepsin D, Rab9, and V-ATPase which indicate phagosome maturation. It was also observed that inhibition of V-type ATPase caused significant hindrance in attenuated Leishmania induced phagosome maturation. Finally, it was confirmed that p38 MAPK is the key player in acidification and maturation of phagosome in attenuated Leishmania strain pre-exposed macrophages. To our knowledge, this study for the first time reported an approach to induce phagosome maturation in L. donovani infected macrophages which could potentiate short-term prophylactic response in future. PMID:26928472

  7. Curcumin attenuates glutamate neurotoxicity in the hippocampus by suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in a manner dependent on AMPK

    SciTech Connect

    Li, Ying; Li, Jia; Li, Shanshan; Li, Yi; Wang, Xiangxiang; Liu, Baolin; Fu, Qiang; Ma, Shiping

    2015-07-01

    Curcumin is a natural polyphenolic compound in Curcuma longa with beneficial effects on neuronal protection. This study aims to investigate the action of curcumin in the hippocampus subjected to glutamate neurotoxicity. Glutamate stimulation induced reactive oxygen species (ROS), endoplasmic reticulum stress (ER stress) and TXNIP/NLRP3 inflammasome activation, leading to damage in the hippocampus. Curcumin treatment in the hippocampus or SH-SY5Y cells inhibited IRE1α and PERK phosphorylation with suppression of intracellular ROS production. Curcumin increased AMPK activity and knockdown of AMPKα with specific siRNA abrogated its inhibitory effects on IRE1α and PERK phosphorylation, indicating that AMPK activity was essential for the suppression of ER stress. As a result, curcumin reduced TXNIP expression and inhibited NLRP3 inflammasome activation by downregulation of NLRP3 and cleaved caspase-1 induction, and thus reduced IL-1β secretion. Specific fluorescent probe and flow cytometry analysis showed that curcumin prevented mitochondrial malfunction and protected cell survival from glutamate neurotoxicity. Moreover, oral administration of curcumin reduced brain infarct volume and attenuated neuronal damage in rats subjected to middle cerebral artery occlusion. Immunohistochemistry showed that curcumin inhibited p-IRE1α, p-PERK and NLRP3 expression in hippocampus CA1 region. Together, these results showed that curcumin attenuated glutamate neurotoxicity by inhibiting ER stress-associated TXNIP/NLRP3 inflammasome activation via the regulation of AMPK, and thereby protected the hippocampus from ischemic insult. - Highlights: • Curcumin attenuates glutamate neurotoxicity in the hippocampus. • Curcumin suppresses ER stress in glutamate-induced hippocampus slices. • Curcumin inhibits TXNIP/NLRP3 inflammasome activation. • Regulation of AMPK by curcumin contributes to suppressing ER stress.

  8. Monitored natural attenuation.

    PubMed

    Jørgensen, Kirsten S; Salminen, Jani M; Björklöf, Katarina

    2010-01-01

    Monitored natural attenuation (MNA) is an in situ remediation technology that relies on naturally occurring and demonstrable processes in soil and groundwater which reduce the mass and concentration of the contaminants. Natural attenuation (NA) involves both aerobic and anaerobic degradation of the contaminants due to the fact that oxygen is used up near the core of the contaminant plume. The aerobic and anaerobic microbial processes can be assessed by microbial activity measurements and molecular biology methods in combination with chemical analyses. The sampling and knowledge on the site conditions are of major importance for the linkage of the results obtained to the conditions in situ. Rates obtained from activity measurements can, with certain limitations, be used in modeling of the fate of contaminants whereas most molecular methods mainly give qualitative information on the microbial community and gene abundances. However, molecular biology methods are fast and describe the in situ communities and avoid the biases inherent to activity assays requiring laboratory incubations.

  9. Marking as Judgment

    ERIC Educational Resources Information Center

    Brooks, Val

    2012-01-01

    An aspect of assessment which has received little attention compared with perennial concerns, such as standards or reliability, is the role of judgment in marking. This paper explores marking as an act of judgment, paying particular attention to the nature of judgment and the processes involved. It brings together studies which have explored…

  10. Interleukin-22 ameliorates liver fibrogenesis by attenuating hepatic stellate cell activation and downregulating the levels of inflammatory cytokines

    PubMed Central

    Lu, Dong-Hong; Guo, Xiao-Yun; Qin, Shan-Yu; Luo, Wei; Huang, Xiao-Li; Chen, Mei; Wang, Jia-Xu; Ma, Shi-Jia; Yang, Xian-Wen; Jiang, Hai-Xing

    2015-01-01

    AIM: To investigate the effect of interleukin (IL)-22 on hepatic fibrosis in mice and the possible mechanism involved. METHODS: Liver fibrosis was induced in male BALB/c mice by CCl4. Recombinant IL-22 (rmIL-22) was administered intraperitoneally in CCl4-treated mice. Fibrosis was assessed by histology and Masson staining. The activation of hepatic stellate cells (HSCs) was investigated by analysis of α-smooth muscle actin expression. The frequencies of T helper (Th) 22 cells, Th17 cells and Th1 cells, the expression of inflammatory cytokines [IL-22, IL-17A, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-6, IL-1β] and transcription factors [aryl hydrocarbon receptor (AHR), RAR-related orphan receptor (RORγt), T-bet] mRNA in the liver were investigated. In addition, the plasma levels of IL-22, IL-17A, IFN-γ, TNF-α, IL-6 and IL-1β were evaluated. RESULTS: Significant elevations in circulating Th22 cells, Th17 cells, Th1 cells, IL-22, IL-17A, and IFN-γ were observed in the hepatic fibrosis group compared with the control group (P < 0.01). Treatment with rmIL-22 in mice with hepatic fibrosis ameliorated the severity of hepatic fibrosis, which was confirmed by lower hepatic fibrosis pathological scores (P < 0.01). RmIL-22 decreased the frequencies of Th22 cells (6.71% ± 0.97% vs 8.09% ± 0.74%, P < 0.01), Th17 cells (4.34% ± 0.37% vs 5.71% ± 0.24%, P < 0.01), Th1 cells (3.09% ± 0.49% vs 4.91% ± 0.73%, P < 0.01), and the levels of IL-22 (56.23 ± 3.08 vs 70.29 ± 3.01, P < 0.01), IL-17A (30.74 ± 2.77 vs 45.68 ± 2.71, P < 0.01), and IFN-γ (74.78 ± 2.61 vs 124.89 ± 2.82, P < 0.01). Down-regulation of IL-22, IL-17A, IFN-γ, TNF-α, IL-6, IL-1β, AHR RORγt, and T-bet gene expression in the liver was observed in the rmIL-22 group (P < 0.01). CONCLUSION: The frequencies of Th22, Th17 and Th1 cells are elevated in hepatic fibrosis. RmIL-22 can attenuate HSC activation and down-regulate the levels of inflammatory cytokines, thereby ameliorating

  11. Use of Activated Carbon in Packaging to Attenuate Formaldehyde-Induced and Formic Acid-Induced Degradation and Reduce Gelatin Cross-Linking in Solid Dosage Forms.

    PubMed

    Colgan, Stephen T; Zelesky, Todd C; Chen, Raymond; Likar, Michael D; MacDonald, Bruce C; Hawkins, Joel M; Carroll, Sophia C; Johnson, Gail M; Space, J Sean; Jensen, James F; DeMatteo, Vincent A

    2016-07-01

    Formaldehyde and formic acid are reactive impurities found in commonly used excipients and can be responsible for limiting drug product shelf-life. Described here is the use of activated carbon in drug product packaging to attenuate formaldehyde-induced and formic acid-induced drug degradation in tablets and cross-linking in hard gelatin capsules. Several pharmaceutical products with known or potential vulnerabilities to formaldehyde-induced or formic acid-induced degradation or gelatin cross-linking were subjected to accelerated stability challenges in the presence and absence of activated carbon. The effects of time and storage conditions were determined. For all of the products studied, activated carbon attenuated drug degradation or gelatin cross-linking. This novel use of activated carbon in pharmaceutical packaging may be useful for enhancing the chemical stability of drug products or the dissolution stability of gelatin-containing dosage forms and may allow for the 1) extension of a drug product's shelf-life when the limiting attribute is a degradation product induced by a reactive impurity, 2) marketing of a drug product in hotter and more humid climatic zones than currently supported without the use of activated carbon, and 3) enhanced dissolution stability of products that are vulnerable to gelatin cross-linking.

  12. Curcumin attenuates glutamate neurotoxicity in the hippocampus by suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in a manner dependent on AMPK.

    PubMed

    Li, Ying; Li, Jia; Li, Shanshan; Li, Yi; Wang, Xiangxiang; Liu, Baolin; Fu, Qiang; Ma, Shiping

    2015-07-01

    Curcumin is a natural polyphenolic compound in Curcuma longa with beneficial effects on neuronal protection. This study aims to investigate the action of curcumin in the hippocampus subjected to glutamate neurotoxicity. Glutamate stimulation induced reactive oxygen species (ROS), endoplasmic reticulum stress (ER stress) and TXNIP/NLRP3 inflammasome activation, leading to damage in the hippocampus. Curcumin treatment in the hippocampus or SH-SY5Y cells inhibited IRE1α and PERK phosphorylation with suppression of intracellular ROS production. Curcumin increased AMPK activity and knockdown of AMPKα with specific siRNA abrogated its inhibitory effects on IRE1α and PERK phosphorylation, indicating that AMPK activity was essential for the suppression of ER stress. As a result, curcumin reduced TXNIP expression and inhibited NLRP3 inflammasome activation by downregulation of NLRP3 and cleaved caspase-1 induction, and thus reduced IL-1β secretion. Specific fluorescent probe and flow cytometry analysis showed that curcumin prevented mitochondrial malfunction and protected cell survival from glutamate neurotoxicity. Moreover, oral administration of curcumin reduced brain infarct volume and attenuated neuronal damage in rats subjected to middle cerebral artery occlusion. Immunohistochemistry showed that curcumin inhibited p-IRE1α, p-PERK and NLRP3 expression in hippocampus CA1 region. Together, these results showed that curcumin attenuated glutamate neurotoxicity by inhibiting ER stress-associated TXNIP/NLRP3 inflammasome activation via the regulation of AMPK, and thereby protected the hippocampus from ischemic insult. PMID:25791922

  13. [Radiometers performance attenuation and data correction in long-term observation of total radiation and photosynthetically active radiation in typical forest ecosystems in China].

    PubMed

    Zhu, Zhi-Lin; Sun, Xiao-Min; Yu, Gui-Rui; Wen, Xue-Fa; Zhang, Yi-Ping; Han, Shi-Jie; Yan, Jun-Hua; Wang, Hui-Min

    2011-11-01

    Based on the total radiation and photosynthetically active radiation (PAR) observations with net radiometer (CNR1) and quantum sensor (Li-190SB) in 4 ChinaFLUX forest sites (Changbaishan, Qianyanzhou, Dinghushan, and Xishuangbanna) in 2003-2008, this paper analyzed the uncertainties and the radiometers performance changes in long-term and continuous field observation. The results showed that the 98% accuracy of the total radiation measured with CNR1 (Q(cNR1)) could satisfy the technical criterion for the sites except Xishuangbanna where the Q(CNR1) was averagely about 7% lower than Q(CM11), the radiation measured with high accuracy pyranometer CM11. For most sites, though the temperature had definite effects on the performance of CNR1, the effects were still within the allowable range of the accuracy of the instrument. Besides temperature, the seasonal fog often occurred in tropical rain forests in Xishuangbanna also had effects on the performance of CNR1. Based on the long-term variations of PAR, especially its ratio to total radiation in the 4 sites, it was found that quantum sensor (Li-190SB) had obvious performance attenuation, with the mean annual attenuation rate being about 4%. To correct the observation error caused by Li-190SB, an attempt was made to give a post-correction of the PAR observations, which could basically eliminate the quantum sensor's performance attenuation due to long-term field measurement.

  14. Icariin attenuates titanium-particle inhibition of bone formation by activating the Wnt/β-catenin signaling pathway in vivo and in vitro

    PubMed Central

    Wang, Junhua; Tao, Yunxia; Ping, Zichuan; Zhang, Wen; Hu, Xuanyang; Wang, Yijun; Wang, Liangliang; Shi, Jiawei; Wu, Xiexing; Yang, Huilin; Xu, Yaozeng; Geng, Dechun

    2016-01-01

    Wear-debris-induced periprosthetic osteolysis (PIO) is a common clinical condition following total joint arthroplasty, which can cause implant instability and failure. The host response to wear debris promotes bone resorption and impairs bone formation. We previously demonstrated that icariin suppressed wear-debris-induced osteoclastogenesis and attenuated particle-induced osteolysis in vivo. Whether icariin promotes bone formation in a wear-debris-induced osteolytic site remains unclear. Here, we demonstrated that icariin significantly attenuated titanium-particle inhibition of osteogenic differentiation of mesenchymal stem cells (MSCs). Additionally, icariin increased bone mass and decreased bone loss in titanium-particle-induced osteolytic sites. Mechanistically, icariin inhibited decreased β-catenin stability induced by titanium particles in vivo and in vitro. To confirm icariin mediated its bone-protective effects via the Wnt/β-catenin signaling pathway, we demonstrated that ICG-001, a selective Wnt/β-catenin inhibitor, attenuated the effects of icariin on MSC mineralization in vitro and bone formation in vivo. Therefore, icariin could induce osteogenic differentiation of MSCs and promote new bone formation at a titanium-particle-induced osteolytic site via activation of the Wnt/β-catenin signaling pathway. These results further support the protective effects of icariin on particle-induced bone loss and provide novel mechanistic insights into the recognized bone-anabolic effects of icariin and an evidence-based rationale for its use in PIO treatment. PMID:27029606

  15. Lanthanum Chloride Attenuates Osteoclast Formation and Function Via the Downregulation of Rankl-Induced Nf-κb and Nfatc1 Activities.

    PubMed

    Jiang, Chuan; Shang, Jiangyinzi; Li, Zhe; Qin, An; Ouyang, Zhengxiao; Qu, Xinhua; Li, Haowei; Tian, Bo; Wang, Wengang; Wu, Chuanlong; Wang, Jinwu; Dai, Min

    2016-01-01

    The biological activities of lanthanum chloride (LaCl3 ) and the molecular mechanisms of action underlying its anti-inflammatory, anti-hyperphosphatemic, and osteoblast-enhancing effects have been studied previously, but less is known about the effects of LaCl3 on osteoclasts. The present study used in vivo and in vitro approaches to explore the effects of LaCl3 on osteoclasts and osteolysis. The results indicated that LaCl3 concentrations that were non-cytotoxic to mouse bone marrow-derived monocytes attenuated receptor activator of nuclear factor-κB ligand (RANKL)-stimulated osteoclastogenesis, bone resorption, mRNA expression of osteoclastogenic genes in these cells, including cathepsin K, calcitonin receptor, and tartrate-resistant acid phosphatase (TRAP). Further, LaCl3 inhibited RANKL-mediated activation of the nuclear factor-κB (NF-κB) signaling pathway, and downregulated mRNA and protein levels of nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1), and c-fos. In vivo, LaCl3 attenuated titanium (Ti) particle-induced bone loss in a murine calvarial osteolysis model. Histological analyses revealed that LaCl3 ameliorated bone destruction and decreased the number of TRAP-positive osteoclasts in this model. These results demonstrated that LaCl3 inhibited osteoclast formation, function, and osteoclast-specific gene expression in vitro, and attenuated Ti particle-induced mouse calvarial osteolysis in vivo, where the inhibition of NF-κB signaling and downregulation of NFATc1 and c-fos played an important role.

  16. Oxygen Plasma Modification of Poss-Coated Kapton(Registered TradeMark) HN Films

    NASA Technical Reports Server (NTRS)

    Wohl, C. J.; Belcher, M. A.; Ghose, S.; Connell, J. W.

    2008-01-01

    The surface energy of a material depends on both surface composition and topographic features. In an effort to modify the surface topography of Kapton(Registered TradeMark) HN film, organic solutions of a polyhedral oligomeric silsesquioxane, octakis(dimethylsilyloxy)silsesquioxane (POSS), were spray-coated onto the Kapton(Registered TradeMark) HN surface. Prior to POSS application, the Kapton(Registered TradeMark) HN film was activated by exposure to radio frequency (RF)-generated oxygen plasma. After POSS deposition and solvent evaporation, the films were exposed to various durations of RF-generated oxygen plasma to create a topographically rich surface. The modified films were characterized using optical microscopy, attenuated total reflection infrared (ATR-IR) spectroscopy, and high-resolution scanning electron microscopy (HRSEM). The physical properties of the modified films will be presented.

  17. Aesthetic laser marking assessment

    NASA Astrophysics Data System (ADS)

    Ng, T. W.; Yeo, S. C.

    2000-04-01

    In this paper, the CIE color difference formula was applied to evaluate four types of material surfaces; anodized aluminium, stainless steel, poly-butylene tetra-phthalate (PBT), and phenol formaldehyde, marked using a Nd:YAG laser, and viewed under three common modes of illumination; tungsten, fluorescent and daylight. The color difference values were based on the spectral reflectance readings obtained from a spectrophotometer. Each material exhibited different color difference trends in relation to marking speed for the different modes of illumination. Nevertheless, general comparisons could be made in terms of operational marking speeds and the maximal color difference values for each material.

  18. Sequential activation of alpha-actin genes during avian cardiogenesis: vascular smooth muscle alpha-actin gene transcripts mark the onset of cardiomyocyte differentiation

    PubMed Central

    1988-01-01

    The expression of cytoplasmic beta-actin and cardiac, skeletal, and smooth muscle alpha-actins during early avian cardiogenesis was analyzed by in situ hybridization with mRNA-specific single-stranded DNA probes. The cytoplasmic beta-actin gene was ubiquitously expressed in the early chicken embryo. In contrast, the alpha-actin genes were sequentially activated in avian cardiac tissue during the early stages of heart tube formation. The accumulation of large quantities of smooth muscle alpha-actin transcripts in epimyocardial cells preceded the expression of the sarcomeric alpha-actin genes. The accumulation of skeletal alpha-actin mRNAs in the developing heart lagged behind that of cardiac alpha-actin by several embryonic stages. At Hamburger- Hamilton stage 12, the smooth muscle alpha-actin gene was selectively down-regulated in the heart such that only the conus, which subsequently participates in the formation of the vascular trunks, continued to express this gene. This modulation in smooth muscle alpha- actin gene expression correlated with the beginning of coexpression of sarcomeric alpha-actin transcripts in the epimyocardium and the onset of circulation in the embryo. The specific expression of the vascular smooth muscle alpha-actin gene marks the onset of differentiation of cardiac cells and represents the first demonstration of coexpression of both smooth muscle and striated alpha-actin genes within myogenic cells. PMID:3204121

  19. Heartwood extract of Rhus verniciflua Stokes and its active constituent fisetin attenuate vasoconstriction through calcium-dependent mechanism in rat aorta.

    PubMed

    Park, Jung-Min; Lee, Jun-Hyeong; Na, Chun-Soo; Lee, Dongho; Lee, Jin-Yong; Satoh, Masahiko; Lee, Moo-Yeol

    2016-01-01

    Rhus verniciflua Stokes (RVS) exert cardiovascular protective activity by promoting blood circulation, but its active ingredients and underlying mechanism have yet to be identified. This study investigated the vascular effects of RVS, focusing on vasoconstriction and smooth muscle Ca(2+) signaling. RVS heartwood extract attenuated contraction of aortic rings induced by the vasoconstrictors serotonin and phenylephrine, and inhibited the Ca(2+) signaling evoked by serotonin in vascular smooth muscle cells. Subsequent activity-guided fractionation identified fisetin as an active constituent exerting a Ca(2+) inhibitory effect. Fisetin could inhibit major Ca(2+) mobilization pathways including extracellular Ca(2+) influx mediated by the L-type voltage-gated Ca(2+) channel, Ca(2+) release from the intracellular store and store-operated Ca(2+) entry. In accordance with Ca(2+) inhibitory effect, fisetin attenuated vasoconstriction by serotonin and phenylephrine. These results suggest that the anticontractile effect, which is presumably mediated by inhibition of Ca(2+) signaling, may contribute to the improvement of blood circulation by RVS.

  20. Ames Fellows Award - Mark

    NASA Video Gallery

    Dr. Hans Mark is a leading expert in the fields of aerospace design and national defense policy. From 1969 to 1977, he served as Director of the NASA Ames Research Center. During his tenure, Ames b...

  1. Hyperglycemia Induces a Dynamic Cooperativity of Histone Methylase and Demethylase Enzymes Associated With Gene-Activating Epigenetic Marks That Coexist on the Lysine Tail

    PubMed Central

    Brasacchio, Daniella; Okabe, Jun; Tikellis, Christos; Balcerczyk, Aneta; George, Prince; Baker, Emma K.; Calkin, Anna C.; Brownlee, Michael; Cooper, Mark E.; El-Osta, Assam

    2009-01-01

    OBJECTIVE Results from the Diabetes Control Complications Trial (DCCT) and the subsequent Epidemiology of Diabetes Interventions and Complications (EDIC) Study and more recently from the U.K. Prospective Diabetes Study (UKPDS) have revealed that the deleterious end-organ effects that occurred in both conventional and more aggressively treated subjects continued to operate >5 years after the patients had returned to usual glycemic control and is interpreted as a legacy of past glycemia known as “hyperglycemic memory.” We have hypothesized that transient hyperglycemia mediates persistent gene-activating events attributed to changes in epigenetic information. RESEARCH DESIGN AND METHODS Models of transient hyperglycemia were used to link NFκB-p65 gene expression with H3K4 and H3K9 modifications mediated by the histone methyltransferases (Set7 and SuV39h1) and the lysine-specific demethylase (LSD1) by the immunopurification of soluble NFκB-p65 chromatin. RESULTS The sustained upregulation of the NFκB-p65 gene as a result of ambient or prior hyperglycemia was associated with increased H3K4m1 but not H3K4m2 or H3K4m3. Furthermore, glucose was shown to have other epigenetic effects, including the suppression of H3K9m2 and H3K9m3 methylation on the p65 promoter. Finally, there was increased recruitment of the recently identified histone demethylase LSD1 to the p65 promoter as a result of prior hyperglycemia. CONCLUSIONS These studies indicate that the active transcriptional state of the NFκB-p65 gene is linked with persisting epigenetic marks such as enhanced H3K4 and reduced H3K9 methylation, which appear to occur as a result of effects of the methyl-writing and methyl-erasing histone enzymes. PMID:19208907

  2. Pretreatment of rats with increased bioavailable berberine attenuates cerebral ischemia-reperfusion injury via down regulation of adenosine-5'monophosphate kinase activity.

    PubMed

    Chen, Weijia; Wei, Shengnan; Yu, Yang; Xue, Huan; Yao, Fan; Zhang, Ming; Xiao, Jun; Hatch, Grant M; Chen, Li

    2016-05-15

    Berberine (BBR) exhibits multiple beneficial biological effects. However, poor bioavailability of BBR has limited its clinical application. We previously demonstrated that solid dispersion of BBR with sodium caprate (HGSD) remarkably improves its bioavailability. We examined whether this increased bioavailability of BBR could protect the brain from ischemia-reperfusion (IR) induced injury. Rats treated with HGSD, SC and saline for 7 days then subjected to cerebral ischemia reperfusion by middle cerebral artery occlusion for 2h followed 12h reperfusion. Neurological deficit scores, infarct size, SOD, MDA and NO levels were examined. P-AMPK, Bax, cleaved-Caspase-3 in brain was determined. To further probe for the mechanism of beneficial effect of HGSD, PC12 cells were incubated with serum from control or HGSD pretreated animals, incubated with 300μM H2O2 to induce apoptosis. Caspase-3 activity and cell apoptosis was evaluated. HGSD pretreatment significantly attenuated neurological deficit scores, reduced infarct size, increased SOD and decreased MDA and NO after cerebral IR injury compared to controls. Meanwhile, HGSD pretreatment significantly reduced expression of p-AMPK, Bax, cleaved-Caspase-3 after cerebral IR injury. Sodium caprate (100mg/kg/d) pretreatment alone did not exhibit any of these beneficial effects. PC12 cell apoptosis was attenuated when cells were cultured with HGSD serum compared to control. The presence of AMPK activator (AICAR) attenuated whereas AMPK inhibitor (Compound C) augmented the protective effect of HGSD serum on PC12 cell apoptosis.The results indicate that HGSD-pretreatment of rats protects the brain from ischemia-reperfusion injury and the mechanism is due to its anti-apoptotic effect mediated by decreased activation of AMPK. PMID:26957053

  3. Wnt pathway activation and ABCB1 expression account for attenuation of Proteasome inhibitor-mediated apoptosis in multidrug-resistant cancer cells

    PubMed Central

    Chong, Kowit Yu; Hsu, Chih-Jung; Hung, Tsai-Hsien; Hu, Han-Shu; Huang, Tsung-Teng; Wang, Tzu-Hao; Wang, Chihuei; Chen, Chuan-Mu; Choo, Kong Bung; Tseng, Ching-Ping

    2015-01-01

    Multiple drug resistance (MDR) is a major obstacle to attenuating the effectiveness of chemotherapy to many human malignancies. Proteasome inhibition induces apoptosis in a variety of cancer cells and is recognized as a novel anticancer therapy approach. Despite its success, some multiple myeloma patients are resistant or become refractory to ongoing treatment by bortezomib suggesting that chemoresistant cancer cells may have developed a novel mechanism directed against the proteasome inhibitor. The present study aimed to investigate potential mechanism(s) of attenuation in a MDR cell line, MES-SA/Dx5. We found that compared to the parental human uterus sarcoma cell line MES-SA cells, MES-SA/Dx5 cells highly expressed the ABCB1 was more resistant to MG132 and bortezomib, escaping the proteasome inhibitor-induced apoptosis pathway. The resistance was reversed by co-treatment of MG132 and the ABCB1 inhibitor verapamil. The data indicated that ABCB1 might play a role in the efflux of MG132 from the MES-SA/Dx5 cells to reduce MG132-induced apoptosis. Furthermore, the canonical Wnt pathway was found activated only in the MES-SA/Dx5 cells through active β-catenin and related transactivation activities. Western blot analysis demonstrated that Wnt-targeting genes, including c-Myc and cyclin D1, were upregulated and were relevant in inhibiting the expression of p21 in MES-SA/Dx5 cells. On the other hand, MES-SA cells expressed high levels of p21 and downregulated cyclin D1 and caused cell cycle arrest. Together, our study demonstrated the existence and participation of ABCB1 and the Wnt pathway in an MDR cell line that attenuated proteasome inhibitor-induced apoptosis. PMID:25590413

  4. Mark IVA microprocessor support

    NASA Technical Reports Server (NTRS)

    Burford, A. L.

    1982-01-01

    The requirements and plans for the maintenance support of microprocessor-based controllers in the Deep Space Network Mark IVA System are discussed. Additional new interfaces and 16-bit processors have introduced problems not present in the Mark III System. The need for continuous training of maintenance personnel to maintain a level of expertise consistent with the sophistication of the required tools is also emphasized.

  5. [Analysis of bite marks].

    PubMed

    Spiessens, Marc; Van der Velden, Bram; Willems, Guy

    2005-01-01

    Precise photographs, supplemented by impressions are used to research and compare bite marks. Different materials for impressions are available to the forensic odontologist. Subsequently, the acquired information of the bite mark will be compared with the dentition of a suspect through photographs, intra- and extra oral examination and impressions. The overlay, which can be created using a variety of methods, allows the comparison between the bite mark and the dentition of the suspect. Among the most commonly used are hand-tracing of study models, wax bites or photocopies, or the radio-opaque wax bite method. Thanks to modern technology and the use of computers, analyses of bite marks have gradually become more accurate. Current research carried out at the Katholieke Universiteit Leuven will demonstrate whether the computer program ForensicIQ is able to offer an even more precise comparison between a given bite mark and the dentition of a suspect. By no means should bite mark analysis alone be allowed to lead to a guilty verdict, but it will offer the opportunity to exclude a suspect from a crime when the data do not correspond. PMID:16370436

  6. TSG-6 secreted by human umbilical cord-MSCs attenuates severe burn-induced excessive inflammation via inhibiting activations of P38 and JNK signaling

    PubMed Central

    Liu, Lingying; Song, Huifeng; Duan, Hongjie; Chai, Jiake; Yang, Jing; Li, Xiao; Yu, Yonghui; Zhang, Xulong; Hu, Xiaohong; Xiao, Mengjing; Feng, Rui; Yin, Huinan; Hu, Quan; Yang, Longlong; Du, Jundong; Li, Tianran

    2016-01-01

    The hMSCs have become a promising approach for inflammation treatment in acute phase. Our previous study has demonstrated that human umbilical cord-MSCs could alleviate the inflammatory reaction of severely burned wound. In this study, we further investigated the potential role and mechanism of the MSCs on severe burn-induced excessive inflammation. Wistar rats were randomly divided into following groups: Sham, Burn, Burn+MSCs, Burn+MAPKs inhibitors, and Burn, Burn+MSCs, Burn+Vehicle, Burn+siTSG-6, Burn+rhTSG-6 in the both experiments. It was found that MSCs could only down-regulate P38 and JNK signaling, but had no effect on ERK in peritoneal macrophages of severe burn rats. Furthermore, suppression of P38 and JNK activations significantly reduced the excessive inflammation induced by severe burn. TSG-6 was secreted by MSCs using different inflammatory mediators. TSG-6 from MSCs and recombinant human (rh)TSG-6 all significantly reduced activations of P38 and JNK signaling induced by severe burn and then attenuated excessive inflammations. On the contrary, knockdown TSG-6 in the cells significantly increased phosphorylation of P38 and JNK signaling and reduced therapeutic effect of the MSCs on excessive inflammation. Taken together, this study suggested TSG-6 from MSCs attenuated severe burn-induced excessive inflammation via inhibiting activation of P38 and JNK signaling. PMID:27444207

  7. Baicalin Attenuates Hypoxia-Induced Pulmonary Arterial Hypertension to Improve Hypoxic Cor Pulmonale by Reducing the Activity of the p38 MAPK Signaling Pathway and MMP-9.

    PubMed

    Yan, Shuangquan; Wang, Yiran; Liu, Panpan; Chen, Ali; Chen, Mayun; Yao, Dan; Xu, Xiaomei; Wang, Liangxing; Huang, Xiaoying

    2016-01-01

    Baicalin has a protective effect on hypoxia-induced pulmonary hypertension in rats, but the mechanism of this effect remains unclear. Thus, investigating the potential mechanism of this effect was the aim of the present study. Model rats that display hypoxic pulmonary hypertension and cor pulmonale under control conditions were successfully generated. We measured a series of indicators to observe the levels of pulmonary arterial hypertension, pulmonary arteriole remodeling, and right ventricular remodeling. We assessed the activation of p38 mitogen-activated protein kinase (MAPK) in the pulmonary arteriole walls and pulmonary tissue homogenates using immunohistochemistry and western blot analyses, respectively. The matrix metalloproteinase- (MMP-) 9 protein and mRNA levels in the pulmonary arteriole walls were measured using immunohistochemistry and in situ hybridization. Our results demonstrated that baicalin not only reduced p38 MAPK activation in both the pulmonary arteriole walls and tissue homogenates but also downregulated the protein and mRNA expression levels of MMP-9 in the pulmonary arteriole walls. This downregulation was accompanied by the attenuation of pulmonary hypertension, arteriole remodeling, and right ventricular remodeling. These results suggest that baicalin may attenuate pulmonary hypertension and cor pulmonale, which are induced by chronic hypoxia, by downregulating the p38 MAPK/MMP-9 pathway. PMID:27688788

  8. Baicalin Attenuates Hypoxia-Induced Pulmonary Arterial Hypertension to Improve Hypoxic Cor Pulmonale by Reducing the Activity of the p38 MAPK Signaling Pathway and MMP-9

    PubMed Central

    Wang, Yiran; Chen, Ali; Chen, Mayun; Yao, Dan; Xu, Xiaomei; Wang, Liangxing

    2016-01-01

    Baicalin has a protective effect on hypoxia-induced pulmonary hypertension in rats, but the mechanism of this effect remains unclear. Thus, investigating the potential mechanism of this effect was the aim of the present study. Model rats that display hypoxic pulmonary hypertension and cor pulmonale under control conditions were successfully generated. We measured a series of indicators to observe the levels of pulmonary arterial hypertension, pulmonary arteriole remodeling, and right ventricular remodeling. We assessed the activation of p38 mitogen-activated protein kinase (MAPK) in the pulmonary arteriole walls and pulmonary tissue homogenates using immunohistochemistry and western blot analyses, respectively. The matrix metalloproteinase- (MMP-) 9 protein and mRNA levels in the pulmonary arteriole walls were measured using immunohistochemistry and in situ hybridization. Our results demonstrated that baicalin not only reduced p38 MAPK activation in both the pulmonary arteriole walls and tissue homogenates but also downregulated the protein and mRNA expression levels of MMP-9 in the pulmonary arteriole walls. This downregulation was accompanied by the attenuation of pulmonary hypertension, arteriole remodeling, and right ventricular remodeling. These results suggest that baicalin may attenuate pulmonary hypertension and cor pulmonale, which are induced by chronic hypoxia, by downregulating the p38 MAPK/MMP-9 pathway. PMID:27688788

  9. Baicalin Attenuates Hypoxia-Induced Pulmonary Arterial Hypertension to Improve Hypoxic Cor Pulmonale by Reducing the Activity of the p38 MAPK Signaling Pathway and MMP-9

    PubMed Central

    Wang, Yiran; Chen, Ali; Chen, Mayun; Yao, Dan; Xu, Xiaomei; Wang, Liangxing

    2016-01-01

    Baicalin has a protective effect on hypoxia-induced pulmonary hypertension in rats, but the mechanism of this effect remains unclear. Thus, investigating the potential mechanism of this effect was the aim of the present study. Model rats that display hypoxic pulmonary hypertension and cor pulmonale under control conditions were successfully generated. We measured a series of indicators to observe the levels of pulmonary arterial hypertension, pulmonary arteriole remodeling, and right ventricular remodeling. We assessed the activation of p38 mitogen-activated protein kinase (MAPK) in the pulmonary arteriole walls and pulmonary tissue homogenates using immunohistochemistry and western blot analyses, respectively. The matrix metalloproteinase- (MMP-) 9 protein and mRNA levels in the pulmonary arteriole walls were measured using immunohistochemistry and in situ hybridization. Our results demonstrated that baicalin not only reduced p38 MAPK activation in both the pulmonary arteriole walls and tissue homogenates but also downregulated the protein and mRNA expression levels of MMP-9 in the pulmonary arteriole walls. This downregulation was accompanied by the attenuation of pulmonary hypertension, arteriole remodeling, and right ventricular remodeling. These results suggest that baicalin may attenuate pulmonary hypertension and cor pulmonale, which are induced by chronic hypoxia, by downregulating the p38 MAPK/MMP-9 pathway.

  10. Phloroglucinol attenuates motor functional deficits in an animal model of Parkinson's disease by enhancing Nrf2 activity.

    PubMed

    Ryu, Junghwa; Zhang, Rui; Hong, Bo-Hyun; Yang, Eun-Jung; Kang, Kyoung Ah; Choi, Moonseok; Kim, Ki Cheon; Noh, Su-Jin; Kim, Hee Soo; Lee, Nam-Ho; Hyun, Jin Won; Kim, Hye-Sun

    2013-01-01

    In this study, we investigated whether phloroglucinol (1,3,5-trihydroxybenzene) has therapeutic effects in cellular and animal model of Parkinson's disease (PD). PD is the second most common, chronic and progressive neurodegenerative disease, and is clinically characterized with motor dysfunctions such as bradykinesia, rigidity, postural instability, gait impairment, and resting tremor. In the brains of PD patients, dopaminergic neuronal loss is observed in the Substantia nigra. Although the exact mechanisms underlying PD are largely unknown, mitochondrial dysfunction and oxidative stress are thought to be critical factors that induce the onset of the disease. Here, phloroglucinol administration was shown to attenuate motor functional deficits evaluated with rota-rod and apomorphine-induced rotation tests in 6-hydroxydopamine (6-OHDA)-induced PD animal models. Moreover, phloroglucinol ameliorated the loss of synapses as assessed with protein levels and immunoreactivity against synaptophysin in the midbrain region of the 6-OHDA-lesioned rats. In addition, in SH-SY5Y cultures, the cytotoxicity of 6-OHDA was reduced by pre-treatment with phloroglucinol. The increase in the reactive oxygen species, lipid peroxidation, protein carbonyl formation and 8-hydroxyguanine caused by treatment with 6-OHDA was attenuated by phloroglucinol in SH-SY5Y cells. Furthermore, phloroglucinol treatment rescued the reduced levels of nuclear Nrf2, antioxidant enzymes, i.e., catalase and glutathione peroxidase, in 6-OHDA-treated cells. Taken together, phloroglucinol has a therapeutic potential for treatment of PD.

  11. Vascular and Central Activation of Peroxisome Proliferator-Activated Receptor-β Attenuates Angiotensin II-Induced Hypertension: Role of RGS-5.

    PubMed

    Romero, Miguel; Jiménez, Rosario; Toral, Marta; León-Gómez, Elvira; Gómez-Gúzman, Manuel; Sánchez, Manuel; Zarzuelo, María José; Rodríguez-Gómez, Isabel; Rath, Geraldine; Tamargo, Juan; Pérez-Vizcaíno, Francisco; Dessy, Chantal; Duarte, Juan

    2016-07-01

    Activation of peroxisome proliferator-activated receptor-β/δ (PPARβ) lowers blood pressure in genetic and mineralocorticoid-induced hypertension. Regulator of G-protein-coupled receptor signaling 5 (RGS5) protein, which interferes in angiotensin II (AngII) signaling, is a target gene to PPARβ The aim of the present study was to examine whether PPARβ activation in resistance arteries and brain tissues prevents the elevated blood pressure in AngII-induced hypertension and evaluate the role of RGS5 in this effect. C57BL/6J male mice were divided into five groups (control mice, PPARβ agonist [4-[[[2-[3-Fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy]acetic acid (GW0742)-treated mice AngII-infused mice, GW0742-treated AngII-infused mice, and AngII-infused mice treated with GW0742 plus PPARβ antagonist 3-[[[2-Methoxy-4-(phenylamino)phenyl]amino]sulfonyl]-2-thiophenecarboxylic acid methyl ester (GSK0660)) and were followed for 3 weeks. GW0742 prevented the increase in both arterial blood pressure and plasma noradrenaline levels and the higher reduction of blood pressure after ganglionic blockade, whereas it reduced the mesenteric arterial remodeling and the hyper-responsiveness to vasoconstrictors (AngII and endothelin-1) in AngII-infused mice. These effects were accompanied by an inhibition of NADPH oxidase expression and activity in the brain. Gene expression profiling revealed a marked loss of brainstem and vascular RGS5 in AngII-infused mice, which was restored by GW0742. GW0742-induced effects were abolished by GSK0660. Small interfering RNA targeting RGS5 caused augmented contractile response to AngII in resistance mesenteric arteries and blunted the inhibitory effect of GW0742 on this response. In conclusion, GW0742 exerted antihypertensive effects, restoring sympathetic tone and vascular structure and function in AngII-infused mice by PPARβ activation in brain and vessels inhibiting AngII signaling as a result of RGS5

  12. Overexpression of activin-A and -B in malignant mesothelioma – Attenuated Smad3 signaling responses and ERK activation promote cell migration and invasive growth

    SciTech Connect

    Tamminen, Jenni A.; Yin, Miao; Rönty, Mikko; Sutinen, Eva; Pasternack, Arja; Ritvos, Olli; Myllärniemi, Marjukka; Koli, Katri

    2015-03-01

    Activin-A and activin-B, members of the TGF-β superfamily, are regulators of reproductive functions, inflammation and wound healing. These dimeric molecules regulate various cellular activities such as proliferation, migration and suvival. Malignant mesothelioma is an asbestos exposure related tumor affecting mainly pleura and it usually has a dismal prognosis. Here, we demonstrate that both activin-A and -B are abundantly expressed in mesothelioma tumor tissue as well as in cultured primary and established mesothelioma cells. Migratory and invasive mesothelioma cells were also found to have attenuated activation of the Smad2/3 pathway in response to activins. Migration and invasive growth of the cells in three-dimentional matrix was prevented by inhibition of activin activity using a soluble activin receptor 2B (sActR2B-Fc). This was associated with decreased ERK activity. Furthermore, migration and invasive growth was significantly inhibited by blocking ERK phosphorylation. Mesothelioma tumors are locally invasive and our results clearly suggest that acivins have a tumor-promoting function in mesothelioma through increasing expression and switching from canonical Smad3 pathway to non-canonical ERK pathway signaling. Blocking activin activity offers a new therapeutic approach for inhibition of mesothelioma invasive growth. - Highlights: • Activin-A and activin-B are highly expressed in mesothelioma. • Mesothelioma cell migration and invasive growth can be blocked with sActR2B. • Activin induced Smad3 activity is attenuated in invasive mesothelioma cells. • Activins induce ERK activity in mesothelioma cells.

  13. Meetings with Mark Vishik

    NASA Astrophysics Data System (ADS)

    Kalikinskaya, E. I.

    2014-12-01

    Mark Iosifovich Vishik was my husband Vladimir Chepyzhov's advisor during his years as a student in the Faculty of Mechanics and Mathematics at Moscow State University, and afterwards they worked together for almost 30 years. This is why I knew him personally while not being a mathematician myself: we sometimes talked on the phone, and met during common trips and a few holidays. In his last years, after the death of his devoted wife who was also his best friend, my husband and I decided to visit Mark regularly in order to comfort him in his loneliness, and many other of his friends did the same. I can say without exaggeration that Mark loved to talk with me about everyday matters, to reminisce about his wife Asya Moiseevna, their friends and relatives, to tell stories of his youth and the wonderful encounters that had so enriched his life. We had the idea to write down our conversations and publish them as a book. Unfortunately, few such conversations lay ahead. The last one took place in January 2010. We did not write a book, but we did write an article [1], which was published in English in the form of an interview with Mark. The present article is based on our conversations with Mark. Here I will try to recount his memories about people who played an important role in his life.

  14. α-Asarone attenuates microglia-mediated neuroinflammation by inhibiting NF kappa B activation and mitigates MPTP-induced behavioral deficits in a mouse model of Parkinson's disease.

    PubMed

    Kim, Byung-Wook; Koppula, Sushruta; Kumar, Hemant; Park, Ju-Young; Kim, Il-Woung; More, Sandeep V; Kim, In-Su; Han, Sang-Don; Kim, Si-Kwan; Yoon, Sung-Hwa; Choi, Dong-Kug

    2015-10-01

    The selective loss of dopaminergic neurons in Parkinson's disease (PD) is associated with microglial activation. Therefore, the importance of early therapeutic intervention to inhibit microglial activation would be an effective strategy to alleviate the progression of PD. α-Asarone, an active compound found in Araceae and Annonaceae plant species has been used to improve various disease conditions including central nervous system disorders. In the present study the in vitro and in vivo therapeutic effects of α-asarone isolated from the rhizome of Acorus gramineus Solander was evaluated on microglia-mediated neuroinflammation and neuroprotection. Lipopolysaccharide (LPS)-stimulated BV-2 microglial cells were used to evaluate in vitro effects. 1-methyl-4 phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mouse model of PD was developed to study the neuroprotective effects of α-asarone in vivo. The results indicated that α-asarone significantly attenuated the LPS-stimulated increase in neuroinflammatory responses and suppressed pro-inflammatory cytokine production in BV-2 cells. Mechanistic study revealed that α-asarone inhibited the LPS-stimulated activation via regulation of nuclear factor kappa-B by blocking degradation of inhibitor kappa B-alpha signaling in BV-2 microglial cells. In in vivo studies, MPTP intoxication to mice resulted in brain microglial activation and significant behavioral deficits. Prophylactic treatment with α-asarone suppressed microglial activation and attenuated PD-like behavioral impairments as assessed by the Y-maze and pole tests. Taken together, these data demonstrate that α-asarone is a promising neuroprotective agent that should be further evaluated and developed for future prevention and treatment of microglia-mediated neuroinflammatory conditions including PD.

  15. Attenuation of the macrophage inflammatory activity by TiO₂ nanotubes via inhibition of MAPK and NF-κB pathways.

    PubMed

    Neacsu, Patricia; Mazare, Anca; Schmuki, Patrik; Cimpean, Anisoara

    2015-01-01

    Biomaterial implantation in a living tissue triggers the activation of macrophages in inflammatory events, promoting the transcription of pro-inflammatory mediator genes. The initiation of macrophage inflammatory processes is mainly regulated by signaling proteins of mitogen-activated protein kinase (MAPK) and by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. We have previously shown that titania nanotubes modified Ti surfaces (Ti/TiO2) mitigate the immune response, compared with flat Ti surfaces; however, little is known regarding the underlying mechanism. Therefore, the aim of this study is to investigate the mechanism(s) by which this nanotopography attenuates the inflammatory activity of macrophages. Thus, we analyzed the effects of TiO2 nanotubes on the activation of MAPK and NF-κB signaling pathways in standard and lipopolysaccharide-evoked conditions. Results showed that the Ti/TiO2 significantly reduce the expression levels of the phosphorylated forms of p38, ERK1/2, c-Jun NH2-terminal kinase (JNK), IKKβ, and IkB-α. Furthermore, a significant reduction in the p65 nuclear accumulation on the nanotubular surface was remarked. Following, by using specific MAPK inhibitors, we observed that lipopolysaccharide-induced production of monocyte chemotactic protein-1 and nitric oxide was significantly inhibited on the Ti/TiO2 surface via p38 and ERK1/2, but not via JNK. However, the selective inhibitor for JNK signaling pathway (SP600125) was effective in reducing tumor necrosis factor alpha release as well as monocyte chemotactic protein-1 and nitric oxide production. Altogether, these data suggest that titania nanotubes can attenuate the macrophage inflammatory response via suppression of MAPK and NF-κB pathways providing a potential mechanism for their anti-inflammatory activity.

  16. A benzenediamine derivative fc-99 attenuates lupus-like syndrome in MRL/lpr mice related to suppression of pDC activation.

    PubMed

    Ji, Jianjian; Fan, Hongye; Li, Fanlin; Li, Xiaojing; Dong, Guanjun; Gong, Wei; Song, Yuxian; Liu, Fei; Hua, Chunyan; Tan, Renxiang; Dou, Huan; Hou, Yayi

    2015-12-01

    Systemic lupus erythematosus (SLE) is an autoimmune disease with prominent chronic inflammatory aspects. Plasmacytoid dendritic cells (pDCs), which are the principal interferon-α (IFN-α)-producing cells, have known to be critically involved in SLE pathogenesis. Our previous research demonstrated that a benzenediamine derivative FC-99 possessed anti-inflammatory activities. However, the effects of FC-99 on SLE have not been investigated to date. In this study, we found that FC-99 attenuated lupus-like pathological symptoms and lupus nephritis as well as the expression of pro-inflammatory cytokines in kidneys of MRL/lpr mice. FC-99 also decreased both the total IgM, total IgG and anti-dsDNA IgG levels in sera and the activation of B cells in the PBMCs and spleens of MRL/lpr mice. Moreover, FC-99 inhibited the abnormal activation and number of pDCs from PBMCs and spleens and levels of IFN-α in MRL/lpr mice. Notably, FC-99 significantly suppressed the expression of IFN-inducible genes in peripheral blood mononuclear cells (PBMCs) and spleens from MRL/lpr mice. As expected, in vitro experiments demonstrated that FC-99 decreased both the activation and IFN-α production of pDCs and inhibited IRAK4 phosphorylation in pDCs upon TLR7 and TLR9 stimulation. We further confirm that the inhibition of FC-99 on B cell activation depended on level of pDCs-secreting IFN-α. These data indicate that FC-99 attenuated lupus-like syndrome in MRL/lpr mice related to suppression of pDC activation, especially pDCs-secreting IFN-α. This study suggests that FC-99 may be a potential therapeutic candidate for the treatment of SLE.

  17. Attenuation of the macrophage inflammatory activity by TiO2 nanotubes via inhibition of MAPK and NF-κB pathways

    PubMed Central

    Neacsu, Patricia; Mazare, Anca; Schmuki, Patrik; Cimpean, Anisoara

    2015-01-01

    Biomaterial implantation in a living tissue triggers the activation of macrophages in inflammatory events, promoting the transcription of pro-inflammatory mediator genes. The initiation of macrophage inflammatory processes is mainly regulated by signaling proteins of mitogen-activated protein kinase (MAPK) and by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. We have previously shown that titania nanotubes modified Ti surfaces (Ti/TiO2) mitigate the immune response, compared with flat Ti surfaces; however, little is known regarding the underlying mechanism. Therefore, the aim of this study is to investigate the mechanism(s) by which this nanotopography attenuates the inflammatory activity of macrophages. Thus, we analyzed the effects of TiO2 nanotubes on the activation of MAPK and NF-κB signaling pathways in standard and lipopolysaccharide-evoked conditions. Results showed that the Ti/TiO2 significantly reduce the expression levels of the phosphorylated forms of p38, ERK1/2, c-Jun NH2-terminal kinase (JNK), IKKβ, and IkB-α. Furthermore, a significant reduction in the p65 nuclear accumulation on the nanotubular surface was remarked. Following, by using specific MAPK inhibitors, we observed that lipopolysaccharide-induced production of monocyte chemotactic protein-1 and nitric oxide was significantly inhibited on the Ti/TiO2 surface via p38 and ERK1/2, but not via JNK. However, the selective inhibitor for JNK signaling pathway (SP600125) was effective in reducing tumor necrosis factor alpha release as well as monocyte chemotactic protein-1 and nitric oxide production. Altogether, these data suggest that titania nanotubes can attenuate the macrophage inflammatory response via suppression of MAPK and NF-κB pathways providing a potential mechanism for their anti-inflammatory activity. PMID:26491301

  18. An early granulocyte colony-stimulating factor treatment attenuates neuropathic pain through activation of mu opioid receptors on the injured nerve

    PubMed Central

    Liao, Ming-Feng; Yeh, Shin-Rung; Lo, Ai-Lun; Chao, Po-Kuan; Lee, Yun-Lin; Hung, Yu-Hui; Lu, Kwok-Tung; Ro, Long-Sun

    2016-01-01

    Several studies have shown that the mu opioid receptor (MOR) located in the peripheral nerves can be activated after nerve injury and that it attenuates peripheral nociceptive signals to the spinal dorsal horn. Various cytokines and phosphorylated-p38 (p-p38) activation in the dorsal horn also play an important role in neuropathic pain development. Granulocyte-colony stimulating factor (GCSF) is a growth factor that can stimulate granulocyte formation and has been shown to exert an analgesic effect on neuropathic pain through recruiting opioid-containing leukocytes to the injured nerve. However, the underlying mechanisms are not well understood. Herein, the results of behavior tests in addition to MOR levels in the injured sciatic nerve and the levels of p-p38 and various cytokines in the spinal dorsal horn were studied in vehicle-treated or GCSF-treated chronic constriction injured (CCI) rats at different time points (i.e., 1, 3, and 7 days, respectively) after nerve injury. The results showed that a single early systemic GCSF treatment after nerve injury can up-regulate MORs in the injured nerve, which can decrease peripheral nociceptive signals. Thereafter, those changes suppress the pro-inflammatory cytokine IL-6 but enhance the anti-inflammatory cytokine IL-4, followed by decreases in p-p38 in the dorsal horn, and thus further attenuate neuropathic pain. PMID:27180600

  19. Persimmon peel extract attenuates PDGF-BB-induced human aortic smooth muscle cell migration and invasion through inhibition of c-Src activity.

    PubMed

    Son, Joe Eun; Hwang, Mun Kyung; Lee, Eunjung; Seo, Sang Gwon; Kim, Jong-Eun; Jung, Sung Keun; Kim, Jong Rhan; Ahn, Gwang-Hwan; Lee, Ki Won; Lee, Hyong Joo

    2013-12-15

    The unregulated migration and invasion of human aortic smooth muscle cells (HASMCs) into the intima is a crucial step in the development of atherosclerosis. Recently, the oriental persimmon extract (Diospyros kaki Thunb. cv. Fuyu) has been investigated for its anti-atherogenic properties, but the molecular mechanisms involved remain unclear. We investigated the inhibitory effects of persimmon peel and flesh extract on the platelet-derived growth factor (PDGF) BB-induced MMP-1 expression using Western blot, and abnormal migration and invasion of HASMCs using a modified Boyden chamber assay and a wound healing assay. We also evaluated the inhibitory effects of persimmon peel extract on aortic vessel thickening using a rat aortic sprouting assay. Persimmon peel (PPE), but not flesh extract (PFE), inhibited PDGF-BB-induced MMP-1 expression, cell migration and invasion in HASMCs, while suppressing the rat aortic sprouting. Western blot and in vitro kinase assay data demonstrated that PPE inhibited Src kinase activity and subsequently attenuated PDGF-BB-induced phosphorylation of MAPK and Akt signalling pathways. Taken together, our results indicate that persimmon peel might possess a potential anti-atherogenic effect through attenuation of ASMCs migration and invasion and aortic sprouting by direct inhibition of the c-Src kinase activity.

  20. Aircraft vortex marking program

    NASA Technical Reports Server (NTRS)

    Pompa, M. F.

    1979-01-01

    A simple, reliable device for identifying atmospheric vortices, principally as generated by in-flight aircraft and with emphasis on the use of nonpolluting aerosols for marking by injection into such vortex (-ices) is presented. The refractive index and droplet size were determined from an analysis of aerosol optical and transport properties as the most significant parameters in effecting vortex optimum light scattering (for visual sighting) and visual persistency of at least 300 sec. The analysis also showed that a steam-ejected tetraethylene glycol aerosol with droplet size near 1 micron and refractive index of approximately 1.45 could be a promising candidate for vortex marking. A marking aerosol was successfully generated with the steam-tetraethylene glycol mixture from breadboard system hardware. A compact 25 lb/f thrust (nominal) H2O2 rocket chamber was the key component of the system which produced the required steam by catalytic decomposition of the supplied H2O2.

  1. The PCB mark

    SciTech Connect

    1994-12-01

    Polychlorinated biphenyls (PCBs) are a class of organic chemicals that had become widely used in industrial applications due to their practical physical and chemical properties. Historical uses of PCBs include dielectric fluids (used in utility transformers, capacitors, etc.), hydraulic fluids, and other applications requiring stable, fire-retardant materials. Due to findings that PCBs may cause adverse health effects and due to their persistence and accumulation in the environment. The Toxic Substances Control Act (TSCA), enacted on October 11, 1976, banned the manufacture of PCBs after 1978 [Section 6(e)]. The first PCB regulations, promulgated at 40 CFR Part 761, were finalized on February 17, 1978. These PCB regulations include requirements specifying disposal methods and marking (labeling) procedures, and controlling PCB use. To assist the Department of Energy (DOE) in its efforts to comply with the TSCA statute and implementing regulations, the Office of Environmental Guidance has prepared the document ``Guidance on the Management of Polychlorinated Biphenyls (PCBs).`` That document explains the requirements specified in the statute and regulations for managing PCBs including PCB use, storage, transport, and disposal. The requirements outlined at 40 CFR 761.40 through 761.45 specify marking requirements for most PCB items (i.e., any PCB Article, PCB Container, PCB Article Container, or PCB Equipment that contains PCBs). Most PCB items require PCB marks, which are defined as a descriptive name, instructions, cautions, or other information applied to PCB Items or other objects subject to these regulations. The marking regulations include requirements for PCB marks on PCB Items, storage areas, and temporary storage areas. This Information Brief supplements the PCB guidance document by responding to common questions concerning marking requirements for PCBs. It is one of a series of Information Briefs pertinent to PCB management issues.

  2. Antagonism of rat orexin receptors by almorexant attenuates central chemoreception in wakefulness in the active period of the diurnal cycle.

    PubMed

    Li, Aihua; Nattie, Eugene

    2010-08-01

    Central chemoreception, the highly sensitive ventilatory response to small changes in CO(2)/pH, involves many sites. Hypothalamic orexin neurons are CO(2) sensitive in vitro, prepro-orexin knockout mice have a reduced CO(2) response prominently in wakefulness, and focal antagonism of the orexin receptor 1 (OX(1)R) in two central chemoreceptor sites, the retrotrapezoid nucleus (RTN) or the medullary raphé, results in a reduction of the CO(2) response predominately in wakefulness (-30% and -16%, respectively). Here we hypothesize that acute and selective inhibition of both orexin receptors (OX(1)R and OX(2)R) at all central locations by an orally administered dual orexin receptor antagonist, almorexant, will substantially attenuate the CO(2) response in a vigilance-state- and diurnal-cycle-dependent manner. We found that almorexant attenuated the CO(2) response by 26% only in wakefulness during the dark period of the diurnal cycle to a level observed during NREM sleep in the light period in controls suggesting that the sleep-wake difference in the CO(2) response can be in large part attributed to orexin. Almorexant also decreased wakefulness and increased NREM and REM sleep during the dark period, as previously reported, and unexpectedly decreased the number of sighs and post-sigh apnoeas during wakefulness in both the light and the dark period and during both wakefulness and NREM sleep in the dark period. The results support our hypothesis that the orexin system participates importantly in central chemoreception in a vigilance-state- and diurnal-cycle-dependent manner and indicate a role for orexin in the important process of sighing.

  3. Activation of CB1 and CB2 receptors attenuates the induction and maintenance of inflammatory pain in the rat.

    PubMed

    Elmes, Steven J R; Winyard, Lisa A; Medhurst, Stephen J; Clayton, Nick M; Wilson, Alex W; Kendall, David A; Chapman, Victoria

    2005-12-01

    The aim of the present study was to investigate the effects of cannabinoid agonists on established inflammatory hyperalgesia. We have compared the effects of pre-administration versus post-administration of a potent non-selective cannabinoid agonist HU210 and a selective CB2 receptor agonist JWH-133 on hindpaw weight bearing and paw oedema in the carrageenan model of inflammatory hyperalgesia. For comparative purposes we also determined the effects of the mu-opioid receptor agonist morphine and the COX2 inhibitor rofecoxib in this model. At 3 h following intraplantar injection of carrageenan (2%, 100 microl) there was a significant (P < 0.001) reduction in weight bearing on the ipsilateral hindpaw, compared to vehicle treated rats and a concomitant increase in ipsilateral hindpaw volume (P < 0.001), compared to vehicle treated rats. Systemic administration of HU210 (10 microg/kg) and JWH-133 (10 mg/kg) at 3 h following injection of carrageenan, significantly attenuated decreases in ipsilateral hindpaw weight bearing (P < 0.05 for both) and paw volume (P < 0.001 for both). Pre-administration of HU210 and JWH-133 had similar effects on weight bearing in this model. Pre-administered HU210 also significantly decreased carrageenan-induced changes in paw volume (P < 0.001), this was not the case for JWH-133. Effects of post-administered HU210 and JWH-133 on ipsilateral hindpaw weight bearing and paw volume were comparable to the effect of systemic post-administration of morphine and rofecoxib (3 mg/kg for both). In summary, both HU210 and JWH-133 attenuated established inflammatory hypersensitivity and swelling, suggesting that cannabinoid-based drugs have clinical potential for the treatment of established inflammatory pain responses.

  4. 25 CFR 141.16 - Price marking.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 25 Indians 1 2013-04-01 2013-04-01 false Price marking. 141.16 Section 141.16 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR FINANCIAL ACTIVITIES BUSINESS PRACTICES ON THE NAVAJO, HOPI AND ZUNI RESERVATIONS General Business Practices § 141.16 Price marking. The price of each...

  5. 25 CFR 141.16 - Price marking.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 25 Indians 1 2011-04-01 2011-04-01 false Price marking. 141.16 Section 141.16 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR FINANCIAL ACTIVITIES BUSINESS PRACTICES ON THE NAVAJO, HOPI AND ZUNI RESERVATIONS General Business Practices § 141.16 Price marking. The price of each...

  6. 25 CFR 141.16 - Price marking.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 25 Indians 1 2012-04-01 2011-04-01 true Price marking. 141.16 Section 141.16 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR FINANCIAL ACTIVITIES BUSINESS PRACTICES ON THE NAVAJO, HOPI AND ZUNI RESERVATIONS General Business Practices § 141.16 Price marking. The price of each...

  7. 25 CFR 141.16 - Price marking.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 25 Indians 1 2014-04-01 2014-04-01 false Price marking. 141.16 Section 141.16 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR FINANCIAL ACTIVITIES BUSINESS PRACTICES ON THE NAVAJO, HOPI AND ZUNI RESERVATIONS General Business Practices § 141.16 Price marking. The price of each...

  8. 46 CFR 161.012-15 - Markings.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...: SPECIFICATIONS AND APPROVAL ELECTRICAL EQUIPMENT Personal Flotation Device Lights § 161.012-15 Markings. (a) Each light manufactured under Coast Guard approval must be permanently and legibly marked with: (1) The... number asssigned to light; and (3) Instructions on how to activate the light. (b) The power source...

  9. 46 CFR 161.012-15 - Markings.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...: SPECIFICATIONS AND APPROVAL ELECTRICAL EQUIPMENT Personal Flotation Device Lights § 161.012-15 Markings. (a) Each light manufactured under Coast Guard approval must be permanently and legibly marked with: (1) The... number asssigned to light; and (3) Instructions on how to activate the light. (b) The power source...

  10. 25 CFR 141.16 - Price marking.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false Price marking. 141.16 Section 141.16 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR FINANCIAL ACTIVITIES BUSINESS PRACTICES ON THE NAVAJO, HOPI AND ZUNI RESERVATIONS General Business Practices § 141.16 Price marking. The price of each...

  11. Marked ghost imaging

    NASA Astrophysics Data System (ADS)

    Chen, Wen; Chen, Xudong

    2014-06-01

    In recent years, ghost imaging has been widely applied in various areas, such as optical security. Here, we report how an object and multiple hidden marks can be simultaneously recovered by using only one rebuilt reference intensity sequence in ghost imaging. The reconstructed object can be clearly observed during the decoding, and multiple marks can be effectively hidden. This unique characteristic is established for ghost imaging system due to random selections of pixels from each reference intensity pattern, which also guarantees high security. This finding may open up a different research perspective for ghost-imaging-based security system.

  12. Structure-Function Basis of Attenuated Inverse Agonism of Angiotensin II Type 1 Receptor Blockers for Active-State Angiotensin II Type 1 Receptor

    PubMed Central

    Unal, Hamiyet; Karnik, Sadashiva S.; Node, Koichi

    2015-01-01

    Ligand-independent signaling by the angiotensin II type 1 receptor (AT1R) can be activated in clinical settings by mechanical stretch and autoantibodies as well as receptor mutations. Transition of the AT1R to the activated state is known to lower inverse agonistic efficacy of clinically used AT1R blockers (ARBs). The structure-function basis for reduced efficacy of inverse agonists is a fundamental aspect that has been understudied not only in relation to the AT1R but also regarding other homologous receptors. Here, we demonstrate that the active-state transition in the AT1R indeed attenuates an inverse agonistic effect of four biphenyl-tetrazole ARBs through changes in specific ligand-receptor interactions. In the ground state, tight interactions of four ARBs with a set of residues (Ser109TM3, Phe182ECL2, Gln257TM6, Tyr292TM7, and Asn295TM7) results in potent inverse agonism. In the activated state, the ARB-AT1R interactions shift to a different set of residues (Val108TM3, Ser109TM3, Ala163TM4, Phe182ECL2, Lys199TM5, Tyr292TM7, and Asn295TM7), resulting in attenuated inverse agonism. Interestingly, V108I, A163T, N295A, and F182A mutations in the activated state of the AT1R shift the functional response to the ARB binding toward agonism, but in the ground state the same mutations cause inverse agonism. Our data show that the second extracellular loop is an important regulator of the functional states of the AT1R. Our findings suggest that the quest for discovering novel ARBs, and improving current ARBs, fundamentally depends on the knowledge of the unique sets of residues that mediate inverse agonistic potency in the two states of the AT1R. PMID:26121982

  13. The Attenuated Brucella abortus Strain 19 Invades, Persists in, and Activates Human Dendritic Cells, and Induces the Secretion of IL-12p70 but Not IL-23

    PubMed Central

    Weinhold, Mario; Eisenblätter, Martin; Jasny, Edith; Fehlings, Michael; Finke, Antje; Gayum, Hermine; Rüschendorf, Ursula; Renner Viveros, Pablo; Moos, Verena; Allers, Kristina; Schneider, Thomas; Schaible, Ulrich E.; Schumann, Ralf R.; Mielke, Martin E.; Ignatius, Ralf

    2013-01-01

    Background Bacterial vectors have been proposed as novel vaccine strategies to induce strong cellular immunity. Attenuated strains of Brucella abortus comprise promising vector candidates since they have the potential to induce strong CD4+ and CD8+ T-cell mediated immune responses in the absence of excessive inflammation as observed with other Gram-negative bacteria. However, some Brucella strains interfere with the maturation of dendritic cells (DCs), which is essential for antigen-specific T-cell priming. In the present study, we investigated the interaction of human monocyte-derived DCs with the smooth attenuated B. abortus strain (S) 19, which has previously been employed successfully to vaccinate cattle. Methodology/Principal findings We first looked into the potential of S19 to hamper the cytokine-induced maturation of DCs; however, infected cells expressed CD25, CD40, CD80, and CD86 to a comparable extent as uninfected, cytokine-matured DCs. Furthermore, S19 activated DCs in the absence of exogeneous stimuli, enhanced the expression of HLA-ABC and HLA-DR, and was able to persist intracellularly without causing cytotoxicity. Thus, DCs provide a cellular niche for persisting brucellae in vivo as a permanent source of antigen. S19-infected DCs produced IL-12/23p40, IL-12p70, and IL-10, but not IL-23. While heat-killed bacteria also activated DCs, soluble mediators were not involved in S19-induced activation of human DCs. HEK 293 transfectants revealed cellular activation by S19 primarily through engagement of Toll-like receptor (TLR)2. Conclusions/Significance Thus, as an immunological prerequisite for vaccine efficacy, B. abortus S19 potently infects and potently activates (most likely via TLR2) human DCs to produce Th1-promoting cytokines. PMID:23805193

  14. Digitally Marking RSA Moduli

    SciTech Connect

    Johnston, A.M.

    2000-10-09

    The moduli used in RSA (see [5]) can be generated by many different sources. The generator of that modulus (assuming a single entity generates the modulus) knows its factorization. They would have the ability to forge signatures or break any system based on this moduli. If a moduli and the RSA parameters associated with it were generated by a reputable source, the system would have higher value than if the parameters were generated by an unknown entity. So for tracking, security, confidence and financial reasons it would be beneficial to know who the generator of the RSA modulus was. This is where digital marking comes in. An RSA modulus ia digitally marked, or digitally trade marked, if the generator and other identifying features of the modulus (such as its intended user, the version number, etc.) can be identified and possibly verified by the modulus itself. The basic concept of digitally marking an RSA modulus would be to fix the upper bits of the modulus to this tag. Thus anyone who sees the public modulus can tell who generated the modulus and who the generator believes the intended user/owner of the modulus is.

  15. Interview with Mark Ashwill

    ERIC Educational Resources Information Center

    Landsberger, Joe

    2006-01-01

    This article presents an interview with Mark Ashwill, Director of the Institute of International Education-Vietnam in Ha Noi, Vietnam, a branch of the Institute of International Education (IIE). In this interview, Ashwill talks about his work as Director of the Institute of International Education-Vietnam, the role that communications technology…

  16. Mark 22 Reactivity

    SciTech Connect

    Buckner, M.R.

    2001-07-02

    Calculations for reactivity held in control rods have underpredicted the observed Mark 22 reactivity. Reactivity predictions by charge designers have accounted for this by including large biases which change with exposure and reactor region. The purpose of this study was to thoroughly investigate the methods and data used in the reactivity calculations. The goal was to identify errors and improvements and make necessary corrections.

  17. Teaching with Mark Dion

    ERIC Educational Resources Information Center

    Fusaro, Joe

    2011-01-01

    Mark Dion creates sculptures, installations, and interactive environments that sometimes seem contrary to what one expects from visual artists. Remarkable curiosity cabinets and carefully arranged artifacts from specific places and time periods make up a large part of his work. His work does not neatly fit into traditional lessons about elements…

  18. DC attenuation meter

    DOEpatents

    Hargrove, Douglas L.

    2004-09-14

    A portable, hand-held meter used to measure direct current (DC) attenuation in low impedance electrical signal cables and signal attenuators. A DC voltage is applied to the signal input of the cable and feedback to the control circuit through the signal cable and attenuators. The control circuit adjusts the applied voltage to the cable until the feedback voltage equals the reference voltage. The "units" of applied voltage required at the cable input is the system attenuation value of the cable and attenuators, which makes this meter unique. The meter may be used to calibrate data signal cables, attenuators, and cable-attenuator assemblies.

  19. Hydroxysafflor yellow A of Carthamus tinctorius attenuates lung injury of aged rats exposed to gasoline engine exhaust by down-regulating platelet activation.

    PubMed

    Wang, Chaoyun; Wang, Chunhua; Ma, Chunlei; Huang, Qingxian; Sun, Hongliu; Zhang, Xiaomin; Bai, Xianyong

    2014-02-15

    Long-term inhalation of gasoline engine exhaust (GEE) increases the risk of respiratory disease. Studies have suggested involvement of platelets in the development of some lung diseases. Hydroxysafflor yellow A (HSYA), a flavonoid compound, prevents hemostasis. Therefore, we investigated its effects on GEE-induced lung injury, and role of platelets in injury. Sixty-week-old male Sprague-Dawley rats were exposed to GEE for 4h/day for 6 weeks, and then grouped as follows: control, GEE, GEE+HSYA, GEE+HSYA+GW9662, and GEE+GW9662. Arterial oxygen tension (PaO2), carbon dioxide tension (PaCO2), pH, and the PaO2/fraction of inspired oxygen ratio (PaO2/FiO2) in the blood were detected using a blood gas analyzer. Wet/dry lung weight ratio, total protein in bronchoalveolar lavage fluid (BALF), and cytokine concentrations in serum and BALF were determined. Furthermore, cyclic adenosine monophosphate (cAMP) level and expression levels of target proteins were analyzed. Platelets were counted and their state was evaluated. HSYA attenuated GEE-mediated decreases in PaO2, PaO2/FiO2, platelet cAMP level, protein kinase A (PKA) activity, and peroxisome proliferator-activated receptor γ (PPARγ) expression. HSYA also attenuated GEE-mediated increases in lung permeability, cytokine levels in serum and BALF, plasma platelet count, and ADP-mediated platelet aggregation. Moreover, it suppressed GEE-induced increases in the expression of adhesion molecules and proinflammatory cytokines in platelets and lung tissue. Therefore, HSYA is therapeutically effective for GEE-mediated lung injury and acts by enhancing PKA activity and inhibiting platelet activation.

  20. Bipolar spinal cord stimulation attenuates mechanical hypersensitivity at an intensity that activates a small portion of A-fiber afferents in spinal nerve-injured rats.

    PubMed

    Yang, F; Carteret, A F; Wacnik, P W; Chung, C-Y; Xing, L; Dong, X; Meyer, R A; Raja, S N; Guan, Y

    2011-12-29

    Spinal cord stimulation (SCS) is used clinically to treat neuropathic pain states, but the precise mechanism by which it attenuates neuropathic pain remains to be established. The profile of afferent fiber activation during SCS and how it may correlate with the efficacy of SCS-induced analgesia are unclear. After subjecting rats to an L5 spinal nerve ligation (SNL), we implanted a miniature quadripolar electrode similar to that used clinically. Our goal was to determine the population and number of afferent fibers retrogradely activated by SCS in SNL rats by recording the antidromic compound action potential (AP) at the sciatic nerve after examining the ability of bipolar epidural SCS to alleviate mechanical hypersensitivity in this model. Notably, we compared the profiles of afferent fiber activation to SCS between SNL rats that exhibited good SCS-induced analgesia (responders) and those that did not (nonresponders). Additionally, we examined how different contact configurations affect the motor threshold (MoT) and compound AP threshold. Results showed that three consecutive days of SCS treatment (50 Hz, 0.2 ms, 30 min, 80-90% of MoT), but not sham stimulation, gradually alleviated mechanical hypersensitivity in SNL rats. The MoT obtained in the animal behavioral study was significantly less than the Aα/β-threshold of the compound AP determined during electrophysiological recording, suggesting that SCS could attenuate mechanical hypersensitivity with a stimulus intensity that recruits only a small fraction of the A-fiber population in SNL rats. Although both the MoT and compound AP threshold were similar between responders and nonresponders, the size of the compound AP waveform at higher stimulation intensities was larger in the responders, indicating a more efficient activation of the dorsal column structure in responders. PMID:22001681

  1. Blockade of PARP activity attenuates poly(ADP-ribosyl)ation but offers only partial neuroprotection against NMDA-induced cell death in the rat retina.

    PubMed

    Goebel, Dennis J; Winkler, Barry S

    2006-09-01

    Recent reports have linked neuronal cell death by necrosis to poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation. It is believed that under stress, the activity of this enzyme is up-regulated, resulting in extensive poly(ADP-ribosyl)ation of nuclear proteins, using NAD(+) as its substrate, which, in turn, leads to the depletion of NAD(+). In efforts to restore the level of NAD(+), depletion of ATP occurs, resulting in the shutdown of ATP-dependent ionic pumps. This results in cell swelling and eventual loss of membrane selectivity, hallmarks of necrosis. Reports from in vitro and in vivo studies in the brain have shown that NMDA receptor activation stimulates PARP activity and that blockade of the enzyme provides substantial neuroprotection. The present study was undertaken to determine whether PARP activity is regulated by NMDA in the rat retina, and whether blockade of PARP activity provides protection against toxic effects of NMDA. Rat retinas exposed to intravitreal injections containing NMDA, with or without the PARP inhibitor N-(6-oxo-5, 6-dihydrophenanthridin-2-yl)-(N,-dimethylamino) acetamide hydrochloride (PJ-34), were assessed for changes in PARP-1 activity as evidenced by poly(ADP-ribosyl)ation (PAR), loss of membrane integrity, morphological indicators of apoptosis and necrosis, and ganglion cell loss. Results showed that: NMDA increased PAR formation in a concentration-dependent manner and caused a decline in retinal ATP levels; PJ-34 blockade attenuated the NMDA-induced formation of PAR and decline in ATP; NMDA induced the loss of membrane selectivity to ethidium bromide (EtBr) in inner retinal neurons, but loss of membrane selectivity was not prevented by blocking PARP activity; cells stained with EtBr, or reacted for TUNEL-labeling, displayed features characteristic of both apoptosis and necrosis. In the presence of PJ-34, greater numbers of cells exhibited apoptotic features; PJ-34 provided partial neuroprotection against NMDA-induced ganglion

  2. A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-kappaB and hypoxia-inducible factor-1alpha.

    PubMed

    Lee, Kyung Sun; Kim, So Ri; Park, Hee Sun; Park, Seoung Ju; Min, Kyung Hoon; Lee, Ka Young; Choe, Yeong Hun; Hong, Sang Hyun; Han, Hyo Jin; Lee, Young Rae; Kim, Jong Suk; Atlas, Daphne; Lee, Yong Chul

    2007-12-31

    Reactive oxygen species (ROS) play an important role in the pathogenesis of airway inflammation and hyperresponsiveness. Recent studies have demonstrated that antioxidants are able to reduce airway inflammation and hyperreactivity in animal models of allergic airway disease. A newly developed antioxidant, small molecular weight thiol compound, N-acetylcysteine amide (AD4) has been shown to increase cellular levels of glutathione and to attenuate oxidative stress related disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. However, the effects of AD4 on allergic airway disease such as asthma are unknown. We used ovalbumin (OVA)-inhaled mice to evaluate the role of AD4 in allergic airway disease. In this study with OVA-inhaled mice, the increased ROS generation, the increased levels of Th2 cytokines and VEGF, the increased vascular permeability, the increased mucus production, and the increased airway resistance in the lungs were significantly reduced by the administration of AD4. We also found that the administration of AD4 decreased the increases of the NF-kappaB and hypoxia-inducible factor-1alpha (HIF-1alpha) levels in nuclear protein extracts of lung tissues after OVA inhalation. These results suggest that AD4 attenuates airway inflammation and hyperresponsiveness by regulating activation of NF-kappaB and HIF-1alpha as well as reducing ROS generation in allergic airway disease. PMID:18160846

  3. A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-kappaB and hypoxia-inducible factor-1alpha.

    PubMed

    Lee, Kyung Sun; Kim, So Ri; Park, Hee Sun; Park, Seoung Ju; Min, Kyung Hoon; Lee, Ka Young; Choe, Yeong Hun; Hong, Sang Hyun; Han, Hyo Jin; Lee, Young Rae; Kim, Jong Suk; Atlas, Daphne; Lee, Yong Chul

    2007-12-31

    Reactive oxygen species (ROS) play an important role in the pathogenesis of airway inflammation and hyperresponsiveness. Recent studies have demonstrated that antioxidants are able to reduce airway inflammation and hyperreactivity in animal models of allergic airway disease. A newly developed antioxidant, small molecular weight thiol compound, N-acetylcysteine amide (AD4) has been shown to increase cellular levels of glutathione and to attenuate oxidative stress related disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. However, the effects of AD4 on allergic airway disease such as asthma are unknown. We used ovalbumin (OVA)-inhaled mice to evaluate the role of AD4 in allergic airway disease. In this study with OVA-inhaled mice, the increased ROS generation, the increased levels of Th2 cytokines and VEGF, the increased vascular permeability, the increased mucus production, and the increased airway resistance in the lungs were significantly reduced by the administration of AD4. We also found that the administration of AD4 decreased the increases of the NF-kappaB and hypoxia-inducible factor-1alpha (HIF-1alpha) levels in nuclear protein extracts of lung tissues after OVA inhalation. These results suggest that AD4 attenuates airway inflammation and hyperresponsiveness by regulating activation of NF-kappaB and HIF-1alpha as well as reducing ROS generation in allergic airway disease.

  4. Monitoring of river water for free cyanide pollution from mining activity in Papua New Guinea and attenuation of cyanide by biochar.

    PubMed

    Sawaraba, Ian; Rao, B K Rajashekhar

    2015-01-01

    Cyanide (CN) pollution was reported in the downstream areas of Watut and Markham Rivers due to effluent discharges from gold mining and processing activities of Hidden Valley mines in Morobe province of Papua New Guinea. We monitored free cyanide levels in Watut and Markham River waters randomly three times in years for 2 years (2012 and 2013). Besides, a short-term static laboratory study was conducted to evaluate the potential of river sediment to attenuate externally added cyanide, with and without the presence of biochar material. Results indicated that the free cyanide content ranged between 0.17 and 1.32 μg L(-1) in the river waters. The free cyanide content were found to be significantly (p < 0.05) greater in June (0.87 μg L(-1)) and May (0.77 μg L(-1)) months of 2012 and 2013, respectively, than the rest of the months. However, free cyanide levels in all four monitoring sites across three sampling intervals were lower than 0.20 mg L(-1) which is the maximum contaminant level (MCL) permitted according to US Environmental Protection Agency. Under laboratory conditions, the biochar-impregnated sediment showed ∼3 times more attenuation capacity for cyanide than non-amended sediment, thus indicating possibility of using biochar to cleanse cyanide from spills or other sources of pollution.

  5. Ifenprodil attenuates the acquisition and expression of methamphetamine-induced behavioral sensitization and activation of Ras-ERK1/2 cascade in the caudate putamen.

    PubMed

    Li, Lu; Qiao, Chuchu; Chen, Gang; Qian, Hongyan; Hou, Ying; Li, Tao; Liu, Xinshe

    2016-10-29

    Chronic discontinuous use of many psychomotor stimulants leads to behavioral sensitization and, owing to it shares common mechanisms with relapse, most researchers use its animal model to explore the neurobiological mechanisms of addiction. Recent studies have proved that N-methyl-d-aspartate receptors (NMDARs) are implicated in psychomotor stimulant-induced behavioral sensitization. However, the function of GluN2B-containing NMDARs and their potential downstream cascade(s) in the acquisition and expression of behavioral sensitization to methamphetamine (METH) have not been explored. In this study, 2.5, 5, and 10mg/kg ifenprodil, the specific inhibitor of GluN2B, was used to explore the function of these receptors in distinct phases of behavioral sensitization to METH in mice. Then, using western blot, Ras, pERK1/2/ERK1/2, and ΔFosB levels in the prefrontal cortex (PFc), nucleus accumbens (NAc), and caudate putamen (CPu) were detected. Behavioral results showed that low-dose ifenprodil attenuated the acquisition and expression of behavioral sensitization to METH significantly. Western blot analysis revealed that pre-injection of low-dose ifenprodil in the acquisition markedly attenuated METH-induced ascent of Ras, pERK1/2/ERK1/2, and ΔFosB protein levels in the CPu. However, pre-treatment in the expression only affected the alterations of Ras and pERK1/2/ERK1/2 levels in the CPu. Moreover, chronic METH administration increased pERK1/2/ERK1/2 level in the NAc. In conclusion, GluN2B-containing NMDARs contribute to both the acquisition and expression of behavioral sensitization to METH in mice. Furthermore, the acquisition phase might be mediated by the Ras-ERK1/2-ΔFosB cascade in the CPu while the expression phase may be regulated by the Ras-ERK1/2 cascade in the CPu. PMID:27544406

  6. Pretreatment with a 55-kDa tumor necrosis factor receptor-immunoglobulin fusion protein attenuates activation of coagulation, but not of fibrinolysis, during lethal bacteremia in baboons.

    PubMed

    van der Poll, T; Jansen, P M; Van Zee, K J; Hack, C E; Oldenburg, H A; Loetscher, H; Lesslauer, W; Lowry, S F; Moldawer, L L

    1997-07-01

    Baboons (Papio anubis) receiving a lethal intravenous infusion with live Escherichia coli were pretreated with either a 55-kDa tumor necrosis factor (TNF) receptor-IgG fusion protein (TNFR55:IgG) (n = 4, 4.6 mg/kg) or placebo (n = 4). Neutralization of TNF activity in TNFR55:IgG-treated animals was associated with a complete prevention of mortality and a strong attenuation of coagulation activation as reflected by the plasma concentrations of thrombin-antithrombin III complexes (P < .05). Activation of fibrinolysis was not influenced by TNFR55:IgG (plasma tissue-type plasminogen activator and plasmin-alpha2-antiplasmin complexes), whereas TNFR55:IgG did inhibit the release of plasminogen activator inhibitor type I (P < .05). Furthermore, TNFR55:IgG inhibited neutrophil degranulation (plasma levels of elastase-alpha1-antitrypsin complexes, P < .05) and modestly reduced release of secretory phospholipase A2. These data suggest that endogenous TNF contributes to activation of coagulation, but not to stimulation of fibrinolysis, during severe bacteremia.

  7. Quetiapine Attenuates Glial Activation and Proinflammatory Cytokines in APP/PS1 Transgenic Mice via Inhibition of Nuclear Factor-κB Pathway

    PubMed Central

    Zhu, Shenghua; Shi, Ruoyang; Li, Victor; Wang, Junhui; Zhang, Ruiguo; Tempier, Adrien; He, Jue; Kong, Jiming; Wang, Jun-Feng

    2015-01-01

    Background: In Alzheimer’s disease, growing evidence has shown that uncontrolled glial activation and neuroinflammation may contribute independently to neurodegeneration. Antiinflammatory strategies might provide benefits for this devastating disease. The aims of the present study are to address the issue of whether glial activation and proinflammatory cytokine increases could be modulated by quetiapine in vivo and in vitro and to explore the underlying mechanism. Methods: Four-month–old amyloid precursor protein (APP) and presenilin 1 (PS1) transgenic and nontransgenic mice were treated with quetiapine (5mg/kg/d) in drinking water for 8 months. Animal behaviors, total Aβ levels, and glial activation were evaluated by behavioral tests, enzyme-linked immunosorbent assay, immunohistochemistry, and Western blot accordingly. Inflammatory cytokines and the nuclear factor kappa B pathway were analyzed in vivo and in vitro. Results: Quetiapine improves behavioral performance, marginally affects total Aβ40 and Aβ42 levels, attenuates glial activation, and reduces proinflammatory cytokines in APP/PS1 mice. Quetiapine suppresses Aβ1-42-induced activation of primary microglia by decresing proinflammatory cytokines. Quetiapine inhibits the activation of nuclear factor kappa B p65 pathway in both transgenic mice and primary microglia stimulated by Aβ1–42. Conclusions: The antiinflammatory effects of quetiapine in Alzheimer’s disease may be involved in the nuclear factor kappa B pathway. Quetiapine may be an efficacious and promising treatment for Alzheimer’s disease targeting on neuroinflammation. PMID:25618401

  8. Activation of sonic hedgehog signaling attenuates oxidized low-density lipoprotein-stimulated brain microvascular endothelial cells dysfunction in vitro.

    PubMed

    Jiang, Xiu-Long; Chen, Ting; Zhang, Xu

    2015-01-01

    The study was performed to investigate the role of sonic hedgehog (SHH) in the oxidized low-density lipoprotein (oxLDL)-induced blood-brain barrier (BBB) disruption. The primary mouse brain microvascular endothelial cells (MBMECs) were exposed to oxLDL. The results indicated that treatment of MBMECs with oxLDL decreased the cell viability, and oxidative stress was involved in oxLDL-induce MBMECs dysfunction with increasing intracellular ROS and MDA formation as well as decreasing NO release and eNOS mRNA expression. In addition, SHH signaling components, such as SHH, Smo and Gli1, mRNA and protein levels were significantly decreased after incubation with increasing concentrations of oxLDL. Treatment with oxLDL alone or SHH loss-of-function significantly increased the permeability of MBMECs, and overexpression of SHH attenuated oxLDL-induced elevation of permeability in MBMECs. Furthermore, SHH gain-of-function could reverse oxLDL-induced apoptosis through inhibition caspase3 and caspase8 levels in MBMECs. Taken together, these results demonstrated that the suppression of SHH in MBMECs might contribute to the oxLDL-induced disruption of endothelial barrier. However, the overexpression of SHH could reverse oxLDL-induced endothelial cells dysfunction in vitro.

  9. Tocotrienol Attenuates Stress-Induced Gastric Lesions via Activation of Prostaglandin and Upregulation of COX-1 mRNA

    PubMed Central

    Kamisah, Yusof; Chua, Kien Hui; Qodriyah, Hj Mohd Saad

    2013-01-01

    The present study aims to distinguish the effect of tocotrienol on an important gastric protective factor, prostaglandin E2 (PGE2), in stress-induced gastric injury. Twenty-eight Wistar rats were divided into four groups of seven rats each. Two control groups were fed commercial rat diet, and two treatment groups were fed the same diet but with additional dose of omeprazole (20 mg/kg) or tocotrienol (60 mg/kg). After 28 days, rats from one control group and both treated groups were subjected to water-immersion restraint stress for 3.5 hours once. The rats were then sacrificed, their stomach isolated and gastric juice collected, lesions examined, and gastric PGE2 content and cyclooxygenase (COX) mRNA expression were determined. Both the regimes significantly attenuated the total lesion area in the stomach compared to the control. Gastric acidity, which was increased in stress, was significantly reduced in rats supplemented with omeprazole and tocotrienol. The PGE2 content was also significantly higher in the rats given tocotrienol supplementation compared to the control followed by an increase in COX-1 mRNA expression. We conclude that tocotrienol supplementation protected rat gastric mucosa against stress-induced lesions possibly by reducing gastric acidity and preserving gastric PGE2 by increasing COX-1 mRNA. PMID:23970937

  10. C1P Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Preventing NF-κB Activation in Neutrophils.

    PubMed

    Baudiß, Kristin; de Paula Vieira, Rodolfo; Cicko, Sanja; Ayata, Korcan; Hossfeld, Madelon; Ehrat, Nicolas; Gómez-Muñoz, Antonio; Eltzschig, Holger K; Idzko, Marco

    2016-03-01

    Recently, ceramide-1-phosphate (C1P) has been shown to modulate acute inflammatory events. Acute lung injury (Arnalich et al. 2000. Infect. Immun. 68: 1942-1945) is characterized by rapid alveolar injury, lung inflammation, induced cytokine production, neutrophil accumulation, and vascular leakage leading to lung edema. The aim of this study was to investigate the role of C1P during LPS-induced acute lung injury in mice. To evaluate the effect of C1P, we used a prophylactic and therapeutic LPS-induced ALI model in C57BL/6 male mice. Our studies revealed that intrapulmonary application of C1P before (prophylactic) or 24 h after (therapeutic) LPS instillation decreased neutrophil trafficking to the lung, proinflammatory cytokine levels in bronchoalveolar lavage, and alveolar capillary leakage. Mechanistically, C1P inhibited the LPS-triggered NF-κB levels in lung tissue in vivo. In addition, ex vivo experiments revealed that C1P also attenuates LPS-induced NF-κB phosphorylation and IL-8 production in human neutrophils. These results indicate C1P playing a role in dampening LPS-induced acute lung inflammation and suggest that C1P could be a valuable candidate for treatment of ALI. PMID:26800872

  11. Activation of sonic hedgehog signaling attenuates oxidized low-density lipoprotein-stimulated brain microvascular endothelial cells dysfunction in vitro.

    PubMed

    Jiang, Xiu-Long; Chen, Ting; Zhang, Xu

    2015-01-01

    The study was performed to investigate the role of sonic hedgehog (SHH) in the oxidized low-density lipoprotein (oxLDL)-induced blood-brain barrier (BBB) disruption. The primary mouse brain microvascular endothelial cells (MBMECs) were exposed to oxLDL. The results indicated that treatment of MBMECs with oxLDL decreased the cell viability, and oxidative stress was involved in oxLDL-induce MBMECs dysfunction with increasing intracellular ROS and MDA formation as well as decreasing NO release and eNOS mRNA expression. In addition, SHH signaling components, such as SHH, Smo and Gli1, mRNA and protein levels were significantly decreased after incubation with increasing concentrations of oxLDL. Treatment with oxLDL alone or SHH loss-of-function significantly increased the permeability of MBMECs, and overexpression of SHH attenuated oxLDL-induced elevation of permeability in MBMECs. Furthermore, SHH gain-of-function could reverse oxLDL-induced apoptosis through inhibition caspase3 and caspase8 levels in MBMECs. Taken together, these results demonstrated that the suppression of SHH in MBMECs might contribute to the oxLDL-induced disruption of endothelial barrier. However, the overexpression of SHH could reverse oxLDL-induced endothelial cells dysfunction in vitro. PMID:26722472

  12. Ligustrazine attenuates oxidative stress-induced activation of hepatic stellate cells by interrupting platelet-derived growth factor-β receptor-mediated ERK and p38 pathways

    SciTech Connect

    Zhang, Feng; Ni, Chunyan; Kong, Desong; Zhang, Xiaoping; Zhu, Xiaojing; Chen, Li; Lu, Yin; Zheng, Shizhong

    2012-11-15

    Hepatic fibrosis represents a frequent event following chronic insult to trigger wound healing reactions with accumulation of extracellular matrix (ECM) in the liver. Activation of hepatic stellate cells (HSCs) is the pivotal event during liver fibrogenesis. Compelling evidence indicates that oxidative stress is concomitant with liver fibrosis irrespective of the underlying etiology. Natural antioxidant ligustrazine exhibits potent antifibrotic activities, but the mechanisms are poorly understood. Our studies were to investigate the ligustrazine effects on HSC activation stimulated by hydrogen peroxide (H{sub 2}O{sub 2}), an in vitro model mimicking the oxidative stress in liver fibrogenesis, and to elucidate the possible mechanisms. Our results demonstrated that H{sub 2}O{sub 2} at 5 μM significantly stimulated HSC proliferation and expression of marker genes of HSC activation; whereas ligustrazine dose-dependently suppressed proliferation and induced apoptosis in H{sub 2}O{sub 2}-activated HSCs, and attenuated expression of fibrotic marker genes. Mechanistic investigations revealed that ligustrazine reduced platelet-derived growth factor-β receptor (PDGF-βR) expression and blocked the phosphorylation of extracellular regulated protein kinase (ERK) and p38 kinase, two downstream effectors of PDGF-βR. Further molecular evidence suggested that ligustrazine interruption of ERK and p38 pathways was dependent on the blockade of PDGF-βR and might be involved in ligustrazine reduction of fibrotic marker gene expression under H{sub 2}O{sub 2} stimulation. Furthermore, ligustrazine modulated some proteins critical for HSC activation and ECM homeostasis in H{sub 2}O{sub 2}-stimulated HSCs. These data collectively indicated that ligustrazine could attenuate HSC activation caused by oxidative stress, providing novel insights into ligustrazine as a therapeutic option for hepatic fibrosis. Highlights: ► Ligustrazine inhibits oxidative stress-induced HSC activation.

  13. Mas-Related Gene (Mrg) C Activation Attenuates Bone Cancer Pain via Modulating Gi and NR2B

    PubMed Central

    Lu, Cui’e; Lei, Yishan; Ma, Zhengliang; Gu, Xiaoping

    2016-01-01

    Objective This study is to investigate the role of Mas-related gene (Mrg) C in the pathogenesis and treatment of bone cancer pain (BCP). Methods BCP mouse model was established by osteosarcoma cell inoculation. Pain-related behaviors were assessed with the spontaneous lifting behavior test and mechanical allodynia test. Expression levels of MrgC, Gi, and NR2B in the spinal cord were detected with Western blot analysis and immunohistochemistry. Results Pain-related behavior tests showed significantly increased spontaneous flinches (NSF) and decreased paw withdrawal mechanical threshold (PWMT) in mouse models of BCP. Western blot analysis showed that, compared with the control group and before modeling, all the expression levels of MrgC, Gi, and NR2B in the spinal cord of BCP mice were dramatically elevated, which were especially increased at day 7 after operation and thereafter, in a time-dependent manner. Moreover, the treatment of MrgC agonist BAM8-22 significantly up-regulated Gi and down-regulated NR2B expression levels, in the spinal cord of BCP mice, in a time-dependent manner. On the other hand, anti-MrgC significantly down-regulated Gi expression, while dramatically up-regulated NR2B expression, in the BCP mice. Similar results were obtained from the immunohistochemical detection. Importantly, BAM8-22 significantly attenuated the nociceptive behaviors in the BCP mice. Conclusion Our results indicated the MrgC-mediated Gi and NR2B expression alterations in the BCP mice, which might contribute to the pain hypersensitivity. These findings may provide a novel strategy for the treatment of BCP in clinic. PMID:27152740

  14. Attenuation of actinomyosinII contractile activity in growth cones accelerates filopodia-guided and microtubule-based neurite elongation.

    PubMed

    Rösner, Harald; Möller, Wolfgang; Wassermann, Torsten; Mihatsch, Julia; Blum, Martin

    2007-10-24

    The myosinII-specific inhibitor blebbistatin was used to attenuate actinomyosinII contractility in E7-chicken retina explant, medulla and spinal cord neuronal cell cultures. Addition of 20-100 microM blebbistatin, a concentration range that reversibly disrupts actin stress fibers, led to a reduction of growth cone lamellipodial areas and to an elongation of filopodia within 5 to 10 min. These morphological changes were completely reversed after removing the inhibitor. In the continued presence of blebbistatin for several hours, a dose-dependent acceleration (up to 6-fold) of neurite outgrowth was observed. The rapidly elongating neuritic processes displayed narrowed growth cones with one to three long filopodia at the leading edge. At the same time, thin neuritic branches emerged in a "push"-like fashion guided by filopodial extensions. Immunocytochemical characterization of these thin sprouts revealed that they contained actin filaments, myosinIIA, phosphorylated neurofilament/tau epitopes, MAP2, NCAM-PSA, and microtubules, demonstrating that these processes presented neurites and not filopodia. The crucial involvement of microtubules in blebbistatin-induced accelerated neurite extension was confirmed by its inhibition in the presence of nocodazole or taxol. The promotion by blebbistatin of neurite outgrowth occurred on polylysine, laminin, as well as on fibronectin as substrate. The presence of the Rho/ROCK-inhibitor Y-27632 also caused a dose-dependent promotion of neurite growth which was, however, 3-fold less pronounced as compared to blebbistatin. In contrast to blebbistatin, Y-27632 led to the enlargement of growth cone lamellipodial extensions. Our data demonstrate that neurite outgrowth and branching are inversely correlated with the degree of actinomyosinII contractility which determines the speed of retrograde flow and turnover of actin filaments and, by this, microtubule extension.

  15. Relative fission product yield determination in the USGS TRIGA Mark I reactor

    NASA Astrophysics Data System (ADS)

    Koehl, Michael A.

    Fission product yield data sets are one of the most important and fundamental compilations of basic information in the nuclear industry. This data has a wide range of applications which include nuclear fuel burnup and nonproliferation safeguards. Relative fission yields constitute a major fraction of the reported yield data and reduce the number of required absolute measurements. Radiochemical separations of fission products reduce interferences, facilitate the measurement of low level radionuclides, and are instrumental in the analysis of low-yielding symmetrical fission products. It is especially useful in the measurement of the valley nuclides and those on the extreme wings of the mass yield curve, including lanthanides, where absolute yields have high errors. This overall project was conducted in three stages: characterization of the neutron flux in irradiation positions within the U.S. Geological Survey TRIGA Mark I Reactor (GSTR), determining the mass attenuation coefficients of precipitates used in radiochemical separations, and measuring the relative fission products in the GSTR. Using the Westcott convention, the Westcott flux, modified spectral index, neutron temperature, and gold-based cadmium ratios were determined for various sampling positions in the USGS TRIGA Mark I reactor. The differential neutron energy spectrum measurement was obtained using the computer iterative code SAND-II-SNL. The mass attenuation coefficients for molecular precipitates were determined through experiment and compared to results using the EGS5 Monte Carlo computer code. Difficulties associated with sufficient production of fission product isotopes in research reactors limits the ability to complete a direct, experimental assessment of mass attenuation coefficients for these isotopes. Experimental attenuation coefficients of radioisotopes produced through neutron activation agree well with the EGS5 calculated results. This suggests mass attenuation coefficients of molecular

  16. NDRG2 promotes myoblast proliferation and caspase 3/7 activities during differentiation, and attenuates hydrogen peroxide - But not palmitate-induced toxicity.

    PubMed

    Anderson, Kimberley J; Russell, Aaron P; Foletta, Victoria C

    2015-01-01

    The function of the stress-responsive N-myc downstream-regulated gene 2 (NDRG2) in the control of myoblast growth, and the amino acids contributing to its function, are not well characterized. Here, we investigated the effect of increased NDRG2 levels on the proliferation, differentiation and apoptosis in skeletal muscle cells under basal and stress conditions. NDRG2 overexpression increased C2C12 myoblast proliferation and the expression of positive cell cycle regulators, cdk2, cyclin B and cyclin D, and phosphorylation of Rb, while the serine/threonine-deficient NDRG2, 3A-NDRG2, had less effect. The onset of differentiation was enhanced by NDRG2 as determined through the myogenic regulatory factor expression profiles and myocyte fusion index. However, the overall level of differentiation in myotubes was not different. While NDRG2 up-regulated caspase 3/7 activities during differentiation, no increase in apoptosis was measured by TUNEL assay or through cleavage of caspase 3 and PARP proteins. During H2O2 treatment to induce oxidative stress, NDRG2 helped protect against the loss of proliferation and ER stress as measured by GRP78 expression with 3A-NDRG2 displaying less protection. NDRG2 also attenuated apoptosis by reducing cleavage of PARP and caspase 3 and expression of pro-apoptotic Bax while enhancing the pro-survival Bcl-2 and Bcl-xL levels. In contrast, Mcl-1 was not altered, and NDRG2 did not protect against palmitate-induced lipotoxicity. Our findings show that NDRG2 overexpression increases myoblast proliferation and caspase 3/7 activities without increasing overall differentiation. Furthermore, NDRG2 attenuates H2O2-induced oxidative stress and specific serine and threonine amino acid residues appear to contribute to its function in muscle cells. PMID:26380811

  17. Lactobacillus rhamnosus GR-1 Ameliorates Escherichia coli-Induced Inflammation and Cell Damage via Attenuation of ASC-Independent NLRP3 Inflammasome Activation.

    PubMed

    Wu, Qiong; Liu, Ming-Chao; Yang, Jun; Wang, Jiu-Feng; Zhu, Yao-Hong

    2016-02-01

    Escherichia coli is a major environmental pathogen causing bovine mastitis, which leads to mammary tissue damage and cell death. We explored the effects of the probiotic Lactobacillus rhamnosus GR-1 on ameliorating E. coli-induced inflammation and cell damage in primary bovine mammary epithelial cells (BMECs). Increased Toll-like receptor 4 (TLR4), NOD1, and NOD2 mRNA expression was observed following E. coli challenge, but this increase was attenuated by L. rhamnosus GR-1 pretreatment. Immunofluorescence and Western blot analyses revealed that L. rhamnosus GR-1 pretreatment decreased the E. coli-induced increases in the expression of the NOD-like receptor family member pyrin domain-containing protein 3 (NLRP3) and the serine protease caspase 1. However, expression of the adaptor protein apoptosis-associated speck-like protein (ASC, encoded by the Pycard gene) was decreased during E. coli infection, even with L. rhamnosus GR-1 pretreatment. Pretreatment with L. rhamnosus GR-1 counteracted the E. coli-induced increases in interleukin-1β (IL-1β), -6, -8, and -18 and tumor necrosis factor alpha mRNA expression but upregulated IL-10 mRNA expression. Our data indicate that L. rhamnosus GR-1 reduces the adhesion of E. coli to BMECs, subsequently ameliorating E. coli-induced disruption of cellular morphology and ultrastructure and limiting detrimental inflammatory responses, partly via promoting TLR2 and NOD1 synergism and attenuating ASC-independent NLRP3 inflammasome activation. Although the residual pathogenic activity of L. rhamnosus, the dosage regimen, and the means of probiotic supplementation in cattle remain undefined, our data enhance our understanding of the mechanism of action of this candidate probiotic, allowing for development of specific probiotic-based therapies and strategies for preventing pathogenic infection of the bovine mammary gland. PMID:26655757

  18. Intrathecal Infusion of Hydrogen-Rich Normal Saline Attenuates Neuropathic Pain via Inhibition of Activation of Spinal Astrocytes and Microglia in Rats

    PubMed Central

    Sun, Xuejun; Xiang, Zhenghua; Yang, Liqun; Huang, Shengdong; Lu, Zhijie; Sun, Yuming; Yu, Wei-Feng

    2014-01-01

    Background Reactive oxygen and nitrogen species are key molecules that mediate neuropathic pain. Although hydrogen is an established antioxidant, its effect on chronic pain has not been characterized. This study was to investigate the efficacy and mechanisms of hydrogen-rich normal saline induced analgesia. Methodology/Principal findings In a rat model of neuropathic pain induced by L5 spinal nerve ligation (L5 SNL), intrathecal injection of hydrogen-rich normal saline relieved L5 SNL-induced mechanical allodynia and thermal hyperalgesia. Importantly, repeated administration of hydrogen-rich normal saline did not lead to tolerance. Preemptive treatment with hydrogen-rich normal saline prevented development of neuropathic pain behavior. Immunofluorochrome analysis revealed that hydrogen-rich normal saline treatment significantly attenuated L5 SNL-induced increase of 8-hydroxyguanosine immunoreactive cells in the ipsilateral spinal dorsal horn. Western blot analysis of SDS/PAGE-fractionated tyrosine-nitrated proteins showed that L5 SNL led to increased expression of tyrosine-nitrated Mn-containing superoxide dismutase (MnSOD) in the spinal cord, and hydrogen-rich normal saline administration reversed the tyrosine-nitrated MnSOD overexpression. We also showed that the analgesic effect of hydrogen-rich normal saline was associated with decreased activation of astrocytes and microglia, attenuated expression of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the spinal cord. Conclusion/Significance Intrathecal injection of hydrogen-rich normal saline produced analgesic effect in neuropathic rat. Hydrogen-rich normal saline-induced analgesia in neuropathic rats is mediated by reducing the activation of spinal astrocytes and microglia, which is induced by overproduction of hydroxyl and peroxynitrite. PMID:24857932

  19. Lactobacillus rhamnosus GR-1 Ameliorates Escherichia coli-Induced Inflammation and Cell Damage via Attenuation of ASC-Independent NLRP3 Inflammasome Activation

    PubMed Central

    Wu, Qiong; Liu, Ming-Chao; Yang, Jun; Wang, Jiu-Feng

    2015-01-01

    Escherichia coli is a major environmental pathogen causing bovine mastitis, which leads to mammary tissue damage and cell death. We explored the effects of the probiotic Lactobacillus rhamnosus GR-1 on ameliorating E. coli-induced inflammation and cell damage in primary bovine mammary epithelial cells (BMECs). Increased Toll-like receptor 4 (TLR4), NOD1, and NOD2 mRNA expression was observed following E. coli challenge, but this increase was attenuated by L. rhamnosus GR-1 pretreatment. Immunofluorescence and Western blot analyses revealed that L. rhamnosus GR-1 pretreatment decreased the E. coli-induced increases in the expression of the NOD-like receptor family member pyrin domain-containing protein 3 (NLRP3) and the serine protease caspase 1. However, expression of the adaptor protein apoptosis-associated speck-like protein (ASC, encoded by the Pycard gene) was decreased during E. coli infection, even with L. rhamnosus GR-1 pretreatment. Pretreatment with L. rhamnosus GR-1 counteracted the E. coli-induced increases in interleukin-1β (IL-1β), -6, -8, and -18 and tumor necrosis factor alpha mRNA expression but upregulated IL-10 mRNA expression. Our data indicate that L. rhamnosus GR-1 reduces the adhesion of E. coli to BMECs, subsequently ameliorating E. coli-induced disruption of cellular morphology and ultrastructure and limiting detrimental inflammatory responses, partly via promoting TLR2 and NOD1 synergism and attenuating ASC-independent NLRP3 inflammasome activation. Although the residual pathogenic activity of L. rhamnosus, the dosage regimen, and the means of probiotic supplementation in cattle remain undefined, our data enhance our understanding of the mechanism of action of this candidate probiotic, allowing for development of specific probiotic-based therapies and strategies for preventing pathogenic infection of the bovine mammary gland. PMID:26655757

  20. Kainate receptor-mediated apoptosis in primary cultures of cerebellar granule cells is attenuated by mitogen-activated protein and cyclin-dependent kinase inhibitors

    PubMed Central

    Giardina, Sarah F; Beart, Philip M

    2002-01-01

    Previous studies have suggested that neuronal apoptosis is the result of an abortive attempt to re-enter the cell cycle, and more recently the cyclin-dependent (CDKs) and the mitogen-activated protein (MAP) kinases, two superfamilies of kinases that influence and control cell cycle progression, have been implicated in neuronal apoptosis. Here, to examine whether CDK/MAPK related pathways are involved in excitotoxicity, we studied the actions of various kinase inhibitors on apoptosis induced by the ionotropic glutamate (Glu) receptor agonist, kainate (KA), in primary cultures of murine cerebellar granule cells (CGCs). KA-mediated neurotoxicity was concentration-dependent, as determined by a cell viability assay monitoring the reduction of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and largely apoptotic in nature, as shown by morphological examination and labelling of DNA fragmentation in situ using terminal deoxynucleotidyl transferase (TdT)-mediated dUTP digoxigenin nick-end labelling (TUNEL). KA-mediated neurotoxicity and apoptosis was completely attenuated by the mixed CDK and MAP kinase inhibitor, olomoucine, in a concentration-dependent manner (50 – 600 μM), and partially by roscovitine (1 – 100 μM), a more selective CDK inihibitor. The p38 MAP kinase inhibitor, SB203580 (1 – 100 μM), partially attenuated KA receptor-mediated apoptosis, as did the MAP kinase kinase inhibitors PD98509 (1 – 100 μM) and U0126 (1 – 100 μM). These findings provide new evidence for a complex network of interacting pathways involving CDK/MAPK that control apoptosis downstream of KA receptor activation in excitotoxic neuronal cell death. PMID:11934814

  1. Cynanchum wilfordii Radix attenuates liver fat accumulation and damage by suppressing hepatic cyclooxygenase-2 and mitogen-activated protein kinase in mice fed with a high-fat and high-fructose diet.

    PubMed

    Jang, Seon-A; Lee, SungRyul; Sohn, Eun-Hwa; Yang, Jaehyuk; Park, Dae Won; Jeong, Yong Joon; Kim, Inhye; Kwon, Jung Eun; Song, Hae Seong; Cho, Young Mi; Meng, Xue; Koo, Hyun Jung; Kang, Se Chan

    2016-09-01

    Excessive consumption of fat and fructose augments the pathological progression of nonalcoholic fatty liver disease through hepatic fibrosis, inflammation, and hepatic de novo lipogenesis. We hypothesized that supplementation with Cynanchum wilfordii extract (CWE) decreases fat accumulation in the liver by suppressing cyclooxygenase-2 (COX-2), the nuclear translocation of nuclear factor κB (NF-κB), and p38 mitogen-activated protein kinase (MAPK). The beneficial effect of CWE was evaluated in a murine model of nonalcoholic fatty liver disease. Mice were fed either a normal diet or an atherogenic diet with fructose (ATHFR) in the presence or absence of CWE (50, 100, or 200 mg/kg; n=6/group). Treatment with ATHFR induced a hepatosplenomegaly-like condition (increased liver and spleen weight); this pathological change was attenuated in the presence of CWE. The ATHFR group exhibited impaired liver function, as evidenced by increased blood levels of glutamic oxaloacetic transaminase and glutamic pyruvic transaminase, fat accumulation in the liver, and lipid profiles. Supplementation of CWE (100 and 200 mg/kg, P<.05) ameliorated these impaired liver functions. Atherogenic diet with fructose increased the protein levels of COX-2 and p38 MAPK, as well as the nuclear translocation of NF-κB. These signaling pathways, which are associated with the inflammatory response, were markedly suppressed after CWE treatment (100 and 200 mg/kg). In summary, CWE supplementation reduced high-fat and high-fructose diet-induced fat accumulation and damage in the liver by suppressing COX-2, NF-κB, and p38 MAPK. PMID:27632911

  2. Case Marking Strategies in Kope.

    ERIC Educational Resources Information Center

    Clifton, John

    Case marking strategies in Kope, a Papuan language of Papua New Guinea, are analyzed in light of previous claims that most Papuan languages have one strategy for marking core relations and another for marking peripheral relations. A brief grammatical overview illustrates how core and peripheral relations are marked in Kope, including nominal case…

  3. Activation of AMPK attenuates LPS-induced acute lung injury by upregulation of PGC1α and SOD1

    PubMed Central

    Wang, Guizuo; Song, Yang; Feng, Wei; Liu, Lu; Zhu, Yanting; Xie, Xinming; Pan, Yilin; Ke, Rui; Li, Shaojun; Li, Fangwei; Yang, Lan; Li, Manxiang

    2016-01-01

    Evidence suggests that an imbalance between oxidation and antioxidation is involved in the pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Activation of AMP-activated protein kinase (AMPK) has been shown to inhibit the occurrence of ALI/ARDS. However, it is unknown whether activation of AMPK benefits ALI/ARDS by restoration of the oxidant and antioxidant balance, and which mechanisms are responsible for this process. The present study aimed to address these issues. Lipopolysaccharide (LPS) induced pronounced pathological changes of ALI in mice; these were accompanied by elevated production of malondialdehyde (MDA) and decreased activity of superoxide dismutase (SOD) compared with control mice. Prior treatment of mice with the AMPK agonist metformin significantly suppressed the LPS-induced development of ALI, reduced the elevation of MDA and increased the activity of SOD. Further analysis indicated that activation of AMPK also stimulated the protein expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and superoxide dismutase 1 (SOD1). This study suggests that activation of AMPK by metformin inhibits oxidative stress by upregulation of PGC1α and SOD1, thereby suppressing the development of ALI/ARDS, and has potential value in the clinical treatment of such conditions. PMID:27602077

  4. Inhibition of factor XII in septic baboons attenuates the activation of complement and fibrinolytic systems and reduces the release of interleukin-6 and neutrophil elastase.

    PubMed

    Jansen, P M; Pixley, R A; Brouwer, M; de Jong, I W; Chang, A C; Hack, C E; Taylor, F B; Colman, R W

    1996-03-15

    In previous studies, we have shown that administration of monoclonal antibody (MoAb) C6B7 against human factor XII to baboons challenged with a lethal dose of Escherichia coli abrogates activation of the contact system and modulates secondary hypotension. To evaluate the contribution of activated contact proteases to the appearance of other inflammatory mediators in this experimental model of sepsis, we studied the effect of administration of MoAb C6B7 on activation of complement and fibrinolytic cascades, stimulation of neutrophil degranulation, and release of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Activation of the complement system, as reflected by circulating C3b/c and C4b/c levels, was significantly reduced in five animals that had received MoAb C6B7 before a lethal dose of E coli as compared with five control animals that had been given a lethal challenge only. Inhibition of contact activation also modulated the fibrinolytic response, since the release of tissue-type plasminogen activator (t-PA) and the appearance of plasmin-alpha2-antiplasmin (PAP) complexes into the circulation was significantly attenuated upon pretreatment with anti-factor XII MoAb. In contrast, plasma levels of plasminogen activator inhibitor (PAI) were modestly enhanced in the treatment group. Degranulation of neutrophils, as assessed by circulating elastase-alpha1-protease inhibitor complexes, and release of IL-6 but not of TNF-alpha was decreased in anti-factor XII-treated animals. Observed differences in the inflammatory response between treatment and control groups were not likely due to different challenges, since the number of E coli that had been infused, as well as circulating levels of endotoxin after the challenge, were similar for both groups. These data suggest that activation of the contact system modulates directly or indirectly various mediator systems involved in the inflammatory response during severe sepsis in

  5. Diallylsulfide attenuates excessive collagen production and apoptosis in a rat model of bleomycin induced pulmonary fibrosis through the involvement of protease activated receptor-2

    SciTech Connect

    Kalayarasan, Srinivasan Sriram, Narayanan; Soumyakrishnan, Syamala; Sudhandiran, Ganapasam

    2013-09-01

    Pulmonary fibrosis (PF) can be a devastating lung disease. It is primarily caused by inflammation leading to severe damage of the alveolar epithelial cells. The pathophysiology of PF is not yet been clearly defined, but studying lung parenchymal injury by involving reactive oxygen species (ROS) through the activation of protease activated receptor-2 (PAR-2) may provide promising results. PAR-2 is a G-protein coupled receptor is known to play an important role in the development of PF. In this study, we investigated the inhibitory role of diallylsulfide (DAS) against ROS mediated activation of PAR-2 and collagen production accompanied by epithelial cell apoptosis. Bleomycin induced ROS levels may prompt to induce the expression of PAR-2 as well as extracellular matrix proteins (ECM), such as MMP 2 and 9, collagen specific proteins HSP-47, α-SMA, and cytokines IL-6, and IL-8RA. Importantly DAS treatment effectively decreased the expression of all these proteins. The inhibitory effect of DAS on profibrotic molecules is mediated by blocking the ROS level. To identify apoptotic signaling as a mediator of PF induction, we performed apoptotic protein expression, DNA fragmentation analysis and ultrastructural details of the lung tissue were performed. DAS treatment restored all these changes to near normalcy. In conclusion, treatment of PF bearing rats with DAS results in amelioration of the ROS production, PAR-2 activation, ECM production, collagen synthesis and alveolar epithelial cell apoptosis during bleomycin induction. We attained the first evidence that treatment of DAS decreases the ROS levels and may provide a potential therapeutic effect attenuating bleomycin induced PF. - Highlights: • DAS inhibits PAR-2 activity; bleomycin stimulates PAR-2 activity. • Increase in PAR-2 activity is correlated with pulmonary fibrosis • DAS reduces pro-inflammatory activity linked to facilitating pulmonary fibrosis. • DAS inhibits apoptosis of alveolar epithelial cells.

  6. Date syrup-derived polyphenols attenuate angiogenic responses and exhibits anti-inflammatory activity mediated by vascular endothelial growth factor and cyclooxygenase-2 expression in endothelial cells.

    PubMed

    Taleb, Hajer; Morris, R Keith; Withycombe, Cathryn E; Maddocks, Sarah E; Kanekanian, Ara D

    2016-07-01

    Bioactive components such as polyphenols, present in many plants, are purported to have anti-inflammatory and antiangiogenic properties. Date syrup, produced from date fruit of the date palm tree, has traditionally been used to treat a wide range of diseases with etiologies involving angiogenesis and inflammation. It was hypothesized that polyphenols in date syrup reduce angiogenic responses such as cell migration, tube formation, and matrix metalloproteinase activity in an inflammatory model by exhibiting anti-inflammatory activity mediated by vascular endothelial growth factor (VEGF) and the prostaglandin enzyme cyclooxygenase-2 (COX-2) in endothelial cells. Date syrup polyphenols at 60 and 600μg/mL reduced inflammation and suppressed several stages of angiogenesis, including endothelial cell migration, invasion, matrix metalloproteinase activity, and tube formation, without evidence of cytotoxicity. VEGF and COX-2 expression induced by tumor necrosis factor-alpha at both gene expression and protein level was significantly reduced by date syrup polyphenols in comparison to untreated cells. In conclusion, polyphenols in date syrup attenuated angiogenic responses and exhibited anti-inflammatory activity mediated by VEGF and COX-2 expression in endothelial cells. PMID:27333954

  7. Medial frontal ∼4-Hz activity in humans and rodents is attenuated in PD patients and in rodents with cortical dopamine depletion

    PubMed Central

    Parker, Krystal L.; Chen, Kuan-Hua; Kingyon, Johnathan R.; Cavanagh, James F.

    2015-01-01

    The temporal control of action is a highly conserved and critical mammalian behavior. Here, we investigate the neuronal basis of this process using an interval timing task. In rats and humans, instructional timing cues triggered spectral power across delta and theta bands (2–6 Hz) from the medial frontal cortex (MFC). Humans and rodents with dysfunctional dopamine have impaired interval timing, and we found that both humans with Parkinson's disease (PD) and rodents with local MFC dopamine depletion had attenuated delta and theta activity. In rodents, spectral activity in this range could functionally couple single MFC neurons involved in temporal processing. Without MFC dopamine, these neurons had less functional coupling with delta/theta activity and less temporal processing. Finally, in humans this 2- to 6-Hz activity was correlated with executive function in matched controls but not in PD patients. Collectively, these findings suggest that cue-evoked low-frequency rhythms could be a clinically important biomarker of PD that is translatable to rodent models, facilitating mechanistic inquiry and the development of neurophysiological biomarkers for human disease. PMID:26133799

  8. Pitavastatin attenuates monocyte activation in response to orthopedic implant-derived wear particles by suppressing the NF-κB signaling pathway.

    PubMed

    Zhang, Zehua; Dai, Fei; Cheng, Peng; Luo, Fei; Hou, Tianyong; Zhou, Qiang; Xie, Zhao; Deng, Moyuan; Xu, Jian-Zhong

    2015-11-01

    Aseptic loosening secondary to particle‑induced periprosthetic osteolysis is considered to be the primary cause of long‑term implant failure in orthopedic surgery. Implant‑derived wear particles activate and recruit macrophages and osteoclasts, which cause a persistent inflammatory response with bone destruction that is followed by a loosening of the implant. Thus, strategies for inhibiting macrophage and osteoclast function may provide a therapeutic benefit for preventing aseptic loosening. The aim of the present study was to determine the effects of pitavastatin on the activation and cytokine response of polymethyl methacrylate (PMMA) particle‑induced monocytes. Peripheral blood monocytes were obtained and treated with PMMA and pitavastatin. ELISA demonstrated that pitavastatin inhibited mRNA and protein expression of interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α. Western blot analysis and immunofluorescence staining demonstrated that pitavastatin downregulated inhibitor of κB phosphorylation and degradation, and nuclear factor κ‑light‑chain‑enhancer of activated B cells (NF‑κB) p65 translocation. Together, these results indicate that pitavastatin may attenuate monocyte activation in response to orthopedic implant wear particles by suppression of the NF‑κB signaling pathway.

  9. Saponins from Aralia taibaiensis attenuate D-galactose-induced aging in rats by activating FOXO3a and Nrf2 pathways.

    PubMed

    Li, Ying-Na; Guo, Yu; Xi, Miao-Miao; Yang, Pei; Zhou, Xue-Ying; Yin, Shuang; Hai, Chun-Xu; Li, Jin-Gang; Qin, Xu-Jun

    2014-01-01

    Reactive oxygen species (ROS) are closely related to the aging process. In our previous studies, we found that the saponins from Aralia taibaiensis have potent antioxidant activity, suggesting the potential protective activity on the aging. However, the protective effect of the saponins and the possible underlying molecular mechanism remain unknown. In the present study, we employed a D-galactose-induced aging rat model to investigate the protective effect of the saponins. We found that D-galactose treatment induced obvious aging-related changes such as the decreased thymus and spleen coefficients, the increased advanced glycation end products (AGEs) level, senescence-associated β-galactosidase (SAβ-gal) activity, and malondialdehyde (MDA) level. Further results showed that Forkhead box O3a (FOXO3a), nuclear factor-erythroid 2-related factor 2 (Nrf2), and their targeted antioxidants such as superoxide dismutase 2 (SOD2), catalase (CAT), glutathione reductase (GR), glutathione (GSH), glutamate-cysteine ligase (GCL), and heme oxygenase 1 (HO-1) were all inhibited in the aging rats induced by D-galactose treatment. Saponins supplementation showed effective protection on these changes. These results demonstrate that saponins from Aralia taibaiensis attenuate the D-galactose-induced rat aging. By activating FOXO3a and Nrf2 pathways, saponins increase their downstream multiple antioxidants expression and function, at least in part contributing to the protection on the D-galactose-induced aging in rats. PMID:24669284

  10. Inhibition of spinal UCHL1 attenuates pain facilitation in a cancer-induced bone pain model by inhibiting ubiquitin and glial activation.

    PubMed

    Cheng, Wei; Chen, Yuan-Li; Wu, Liang; Miao, Bei; Yin, Qin; Wang, Jin-Feng; Fu, Zhi-Jian

    2016-01-01

    The present study examined alterations of spinal ubiquitin C-terminal hydrolase L1 (UCHL1), ubiquitin expression and glial activation in the cancer-induced bone pain rats. Furthermore, whether inhibition of spinal UCHL1 could alleviate cancer-induced bone pain was observed. The CIBP model was established by intrathecal Walker 256 mammary gland carcinoma cells in SD rats. The rats of CIBP developed significant pain facilitation in the Von Frey test. Double immunofluorescence analyses revealed that in the spines of CIBP rats, ubiquitin co-localized with NeuN, Iba-1 or GFAP; UCHL1 and NeuN were co-expressed and UCHL1 also co-localized with ubiquitin. The CIBP model induced up-regulation of ubiquitin and UCHL1 in the spines, as well as glial activation. Inhibition of spinal UCHL1 attenuated pain facilitation by down-regulation of ubiquitin expression and glial activation. in the CIBP rats. Our data suggests that UCHL1/ubiquitin distributed and increased in the spines of CIBP rats, that glial activation also increased in the CIBP model and that inhibition of spinal UCHL1 may be an effective method to alleviate cancer-induced bone pain. PMID:27508024

  11. Inhibition of spinal UCHL1 attenuates pain facilitation in a cancer-induced bone pain model by inhibiting ubiquitin and glial activation

    PubMed Central

    Cheng, Wei; Chen, Yuan-Li; Wu, Liang; Miao, Bei; Yin, Qin; Wang, Jin-Feng; Fu, Zhi-Jian

    2016-01-01

    The present study examined alterations of spinal ubiquitin C-terminal hydrolase L1 (UCHL1), ubiquitin expression and glial activation in the cancer-induced bone pain rats. Furthermore, whether inhibition of spinal UCHL1 could alleviate cancer-induced bone pain was observed. The CIBP model was established by intrathecal Walker 256 mammary gland carcinoma cells in SD rats. The rats of CIBP developed significant pain facilitation in the Von Frey test. Double immunofluorescence analyses revealed that in the spines of CIBP rats, ubiquitin co-localized with NeuN, Iba-1 or GFAP; UCHL1 and NeuN were co-expressed and UCHL1 also co-localized with ubiquitin. The CIBP model induced up-regulation of ubiquitin and UCHL1 in the spines, as well as glial activation. Inhibition of spinal UCHL1 attenuated pain facilitation by down-regulation of ubiquitin expression and glial activation. in the CIBP rats. Our data suggests that UCHL1/ubiquitin distributed and increased in the spines of CIBP rats, that glial activation also increased in the CIBP model and that inhibition of spinal UCHL1 may be an effective method to alleviate cancer-induced bone pain. PMID:27508024

  12. Sepiapterin attenuates 1-methyl-4-phenylpyridinium-induced apoptosis in neuroblastoma cells transfected with neuronal NOS: role of tetrahydrobiopterin, nitric oxide, and proteasome activation.

    PubMed

    Shang, Tiesong; Kotamraju, Srigiridhar; Zhao, Hongtao; Kalivendi, Shasi V; Hillard, Cecilia J; Kalyanaraman, B

    2005-10-15

    In this study, we investigated the molecular mechanism of toxicity of 1-methyl-4-phenylpyridinium (MPP+), an ultimate toxic metabolite of a mitochondrial neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, that causes parkinsonism in experimental animals and humans. Using wild-type and human neuronal nitric oxide synthase (nNOS) stably transfected neuroblastoma cells (SH-SY5Y), we showed that nNOS overexpression in SH-SY5Y cells greatly enhanced proteasome activity and mitigated MPP+-induced apoptosis. During MPP+-induced oxidative stress, intracellular BH4 levels decreased, resulting in nNOS "uncoupling" (i.e., switching from nitric oxide to superoxide generation). Increasing the intracellular BH4 levels by sepiapterin supplementation restored the nNOS activity, inhibited superoxide formation, increased proteasome activity, decreased protein ubiquitination, and attenuated apoptosis in MPP+-treated cells. Implications of BH4 depletion in dopaminergic cells and sepiapterin supplementation to augment the striatal nNOS activity in the pathogenesis mechanism and treatment of Parkinson disease are discussed. PMID:16198233

  13. A novel natural Nrf2 activator with PPARγ-agonist (monascin) attenuates the toxicity of methylglyoxal and hyperglycemia.

    PubMed

    Hsu, Wei-Hsuan; Lee, Bao-Hong; Chang, Yu-Ying; Hsu, Ya-Wen; Pan, Tzu-Ming

    2013-11-01

    Methylglyoxal (MG) is a toxic-glucose metabolite and a major precursor of advanced glycation endproducts (AGEs). MG has been reported to result in inflammation by activating receptor for AGEs (RAGE). We recently found that Monascus-fermented metabolite monascin acts as a novel natural peroxisome proliferator-activated receptor-γ (PPARγ) agonist that improves insulin sensitivity. We investigated the metabolic, biochemical, and molecular abnormalities characteristic of type 2 diabetes in MG-treated Wistar rats treated with oral administration of monascin or rosiglitazone. Monascin (a novel PPARγ agonist) activated nuclear factor-erythroid 2-related factor 2 (Nrf2) and down-regulated hyperinsulinmia in oral glucose tolerance test (OGTT). Monascin was able to elevate glyoxalase-1 expression via activation of hepatic Nrf2, hence, resulting in MG metabolism to d-lactic acid and protected from AGEs production in MG-treated rats. Rosiglitazone did not activate Nrf2 nor glyoxalase expression to lower serum and hepatic AGEs levels. Monascin acts as a novel natural Nrf2 activator with PPARγ-agonist activity were confirmed by Nrf2 and PPARγ reporter assays in Hep G2 cells. These findings suggest that monascin acts as an anti-diabetic and anti-oxidative stress agent to a greater degree than rosiglitazone and thus may have therapeutic potential for the prevention of diabetes. PMID:23954466

  14. Superoxide Dismutase Mimetic, MnTE-2-PyP, Attenuates Chronic Hypoxia-Induced Pulmonary Hypertension, Pulmonary Vascular Remodeling, and Activation of the NALP3 Inflammasome

    PubMed Central

    Villegas, Leah R.; Kluck, Dylan; Field, Carlie; Oberley-Deegan, Rebecca E.; Woods, Crystal; Yeager, Michael E.; El Kasmi, Karim C.; Savani, Rashmin C.; Bowler, Russell P.

    2013-01-01

    Abstract Aims: Pulmonary hypertension (PH) is characterized by an oxidant/antioxidant imbalance that promotes abnormal vascular responses. Reactive oxygen species, such as superoxide (O2•−), contribute to the pathogenesis of PH and vascular responses, including vascular remodeling and inflammation. This study sought to investigate the protective role of a pharmacological catalytic antioxidant, a superoxide dismutase (SOD) mimetic (MnTE-2-PyP), in hypoxia-induced PH, vascular remodeling, and NALP3 (NACHT, LRR, and PYD domain-containing protein 3)–mediated inflammation. Results: Mice (C57/BL6) were exposed to hypobaric hypoxic conditions, while subcutaneous injections of MnTE-2-PyP (5 mg/kg) or phosphate-buffered saline (PBS) were given 3× weekly for up to 35 days. SOD mimetic-treated groups demonstrated protection against increased right ventricular systolic pressure, indirect measurements of pulmonary artery pressure, and RV hypertrophy. Vascular remodeling was assessed by Ki67 staining to detect vascular cell proliferation, α-smooth muscle actin staining to analyze small vessel muscularization, and hyaluronan (HA) measurements to assess extracellular matrix modulation. Activation of the NALP3 inflammasome pathway was measured by NALP3 expression, caspase-1 activation, and interleukin 1-beta (IL-1β) and IL-18 production. Hypoxic exposure increased PH, vascular remodeling, and NALP3 inflammasome activation in PBS-treated mice, while mice treated with MnTE-2-PyP showed an attenuation in each of these endpoints. Innovation: This study is the first to demonstrate activation of the NALP3 inflammasome with cleavage of caspase-1 and release of active IL-1 β and IL-18 in chronic hypoxic PH, as well as its attenuation by the SOD mimetic, MnTE-2-PyP. Conclusion: The ability of the SOD mimetic to scavenge extracellular O2•− supports our previous observations in EC-SOD-overexpressing mice that implicate extracellular oxidant/antioxidant imbalance in hypoxic PH

  15. Pressure surge attenuator

    DOEpatents

    Christie, Alan M.; Snyder, Kurt I.

    1985-01-01

    A pressure surge attenuation system for pipes having a fluted region opposite crushable metal foam. As adapted for nuclear reactor vessels and heads, crushable metal foam is disposed to attenuate pressure surges.

  16. Inhibition of glycogen synthase kinase 3β activity with lithium prevents and attenuates paclitaxel-induced neuropathic pain.

    PubMed

    Gao, M; Yan, X; Weng, H-R

    2013-12-19

    Paclitaxel (taxol) is a first-line chemotherapy-drug used to treat many types of cancers. Neuropathic pain and sensory dysfunction are the major toxicities, which are dose-limiting and significantly reduce the quality of life in patients. Two known critical spinal mechanisms underlying taxol-induced neuropathic pain are an increased production of pro-inflammatory cytokines including interleukin-1β (IL-1β) and suppressed glial glutamate transporter activities. In this study, we uncovered that increased activation of glycogen synthase kinase 3beta (GSK3β) in the spinal dorsal horn was concurrently associated with increased protein expressions of GFAP, IL-1β and a decreased protein expression of glial glutamate transporter 1 (GLT-1), as well as the development and maintenance of taxol-induced neuropathic pain. The enhanced GSK3β activities were supported by the concurrently decreased AKT and mTOR activities. The changes of all these biomarkers were basically prevented when animals received pre-emptive lithium (a GSK3β inhibitor) treatment, which also prevented the development of taxol-induced neuropathic pain. Further, chronic lithium treatment, which began on day 11 after the first taxol injection, reversed the existing mechanical and thermal allodynia induced by taxol. The taxol-induced increased GSK3β activities and decreased AKT and mTOR activities in the spinal dorsal horn were also reversed by lithium. Meanwhile, protein expressions of GLT-1, GFAP and IL-1β in the spinal dorsal horn were improved. Hence, suppression of spinal GSK3β activities is a key mechanism used by lithium to reduce taxol-induced neuropathic pain, and targeting spinal GSK3β is an effective approach to ameliorate GLT-1 expression and suppress the activation of astrocytes and IL-1β over-production in the spinal dorsal horn.

  17. Minocycline attenuates microglia activation and blocks the long-term epileptogenic effects of early-life seizures.

    PubMed

    Abraham, Jayne; Fox, Patrick D; Condello, Carlo; Bartolini, Alyssa; Koh, Sookyong

    2012-05-01

    Innate immunity mediated by microglia appears to play a crucial role in initiating and propagating seizure-induced inflammatory responses. To address the role of activated microglia in the pathogenesis of childhood epilepsy, we first examined the time course of microglia activation following kainic acid-induced status epilepticus (KA-SE) in Cx3cr1(GFP/+) transgenic mice whose microglia are fluorescently labeled. We then determined whether this seizure-induced microglia activation primes the central immune response to overreact and to increase the susceptibility to a second seizure later in life. We used an inhibitor of microglia activation, minocycline, to block the seizure-induced inflammation to determine whether innate immunity plays a causal role in mediating the long-term epileptogenic effects of early-life seizure. First status epilepticus was induced at postnatal day (P) 25 and a second status at P39. KA-SE at P25 caused nearly a two-fold increase in microglia activation within 24h. Significant seizure-induced activation persisted for 7 days and returned to baseline by 14 days. P39 animals with prior exposure to KA-SE not only responded with greater microglial activation in response to "second hit" of KA, but shorter latency to express seizures. Inhibition of seizure-induced inflammation by 7 day minocycline post-treatment abrogated both the exaggerated microglia activation and the increased susceptibility to the second seizure later in life. The priming effect of early-life seizures is accompanied by modified and rapidly reactivated microglia. Our results suggest that anti-inflammatory therapy after SE may be useful to block the epileptogenic process and mitigate the long-term damaging effects of early-life seizures. PMID:22366182

  18. Fulvene-5 inhibition of Nadph oxidases attenuates activation of epithelial sodium channels in A6 distal nephron cells.

    PubMed

    Trac, David; Liu, Bingchen; Pao, Alan C; Thomas, Sheela V; Park, Michael; Downs, Charles A; Ma, He-Ping; Helms, My N

    2013-10-01

    Nadph oxidase 4 is an important cellular source of reactive oxygen species (ROS) generation in the kidney. Novel antioxidant drugs, such as Nox4 inhibitor compounds, are being developed. There is, however, very little experimental evidence for the biological role and regulation of Nadph oxidase isoforms in the kidney. Herein, we show that Fulvene-5 is an effective inhibitor of Nox-generated ROS and report the role of Nox isoforms in activating epithelial sodium channels (ENaC) in A6 distal nephron cells via oxidant signaling and cell stretch activation. Using single-channel patch-clamp analysis, we report that Fulvene-5 blocked the increase in ENaC activity that is typically observed with H2O2 treatment of A6 cells: average ENaC NPo values decreased from a baseline level of 1.04 ± 0.18 (means ± SE) to 0.25 ± 0.08 following Fulvene-5 treatment. H2O2 treatment failed to increase ENaC activity in the presence of Fulvene-5. Moreover, Fulvene-5 treatment of A6 cells blocked the osmotic cell stretch response of A6 cells, indicating that stretch activation of Nox-derived ROS plays an important role in ENaC regulation. Together, these findings indicate that Fulvene-5, and perhaps other classes of antioxidant inhibitors, may represent a novel class of compounds useful for the treatment of pathological disorders stemming from inappropriate ion channel activity, such as hypertension. PMID:23863470

  19. Thermal cooking changes the profile of phenolic compounds, but does not attenuate the anti-inflammatory activities of black rice

    PubMed Central

    Bhawamai, Sassy; Lin, Shyh-Hsiang; Hou, Yuan-Yu; Chen, Yue-Hwa

    2016-01-01

    Background Evidence on biological activities of cooked black rice is limited. This study examined the effects of washing and cooking on the bioactive ingredients and biological activities of black rice. Methods Cooked rice was prepared by washing 0–3 times followed by cooking in a rice cooker. The acidic methanol extracts of raw and cooked rice were used for the analyses. Results Raw black rice, both washed and unwashed, had higher contents of polyphenols, anthocyanins, and cyanidin-3-glucoside (C3G), but lower protocatechuic acid (PA), than did cooked samples. Similarly, raw rice extracts were higher in ferric-reducing antioxidant power (FRAP) activities than extracts of cooked samples. Nonetheless, extracts of raw and cooked rice showed similar inhibitory potencies on nitric oxide, tumor necrosis factor-α, and interleukin-6 productions in lipopolysaccharide-activated macrophages, whereas equivalent amounts of C3G and PA did not possess such inhibitory effects. Conclusions Thermal cooking decreased total anthocyanin and C3G contents and the FRAP antioxidative capacity, but did not affect anti-inflammatory activities of black rice. Neither C3G nor PA contributed to the anti-inflammatory activity of black rice. PMID:27652685

  20. Interferon-β treatment in multiple sclerosis attenuates inflammatory gene expression through inducible activity of the phosphatase SHP-1

    PubMed Central

    Christophi, George P.; Panos, Michael; Hudson, Chad A.; Tsikkou, Chriso; Mihai, Cornelia; Mejico, Luis J.; Jubelt, Burk; Massa, Paul T.

    2009-01-01

    Interferon-β is a current treatment for multiple sclerosis (MS). Interferon-β is thought to exert its therapeutic effects on MS by down-modulating the immune response by multiple potential pathways. Here, we document that treatment of MS patients with interferon β-1a (Rebif) results in a significant increase in the levels and function of the protein tyrosine phosphatase SHP-1 in PBMCs. SHP-1 is a crucial negative regulator of cytokine signaling, inflammatory gene expression, and CNS demyelination as evidenced in mice deficient in SHP-1. In order to examine the functional significance of SHP-1 induction in MS PBMCs, we analyzed the activity of proinflammatory signaling molecules STAT1, STAT6, and NF-κB, which are known SHP-1 targets. Interferon-β treatment in vivo resulted in decreased NF-κB and STAT6 activation and increased STAT1 activation. Further analysis in vitro showed that cultured PBMCs of MS patients and normal subjects had a significant SHP-1 induction following interferon-β treatment that correlated with decreased NF-κB and STAT6 activation. Most importantly, experimental depletion of SHP-1 in cultured PBMCs abolished the anti-inflammatory effects of interferon-β treatment, indicating that SHP-1 is a predominant mediator of interferon-β activity. In conclusion, interferon-β treatment upregulates SHP-1 expression resulting in decreased transcription factor activation and inflammatory gene expression important in MS pathogenesis. PMID:19559654

  1. Cocaine attenuates blood flow but not neuronal responses to stimulation while preserving neurovascular coupling for resting brain activity.

    PubMed

    Chen, W; Liu, P; Volkow, N D; Pan, Y; Du, C

    2016-10-01

    Cocaine affects neuronal activity and constricts cerebral blood vessels, making it difficult to determine whether cocaine-induced changes in cerebral blood flow (CBF) reflect neuronal activation or its vasoactive effects. Here we assessed the effects of acute cocaine on both resting-state and stimulation responses to investigate cocaine's effects on neurovascular coupling and to differentiate its effects on neuronal activity from its vasoactive actions. We concurrently measured cortical field potentials via thinned-skull electroencephalography recordings and CBF with laser Doppler flowmetry in the rat's somatosensory cortex for both resting state and forepaw stimulation before and following cocaine administration (1 mg kg(-1), intravenously). Results show both resting-state field potentials and CBF were depressed after cocaine administration (19.8±4.7% and 52.1±13.4%, respectively) and these changes were strongly correlated with each other (r=0.81, P<0.001), indicating that cocaine did not affect neurovascular coupling at rest and that the reduction in resting CBF reflected reduction in synchronized spontaneous neuronal activity rather than vasoconstriction. In contrast, the forepaw stimulation-evoked neuronal activity was not changed by cocaine (P=0.244), whereas the CBF to the stimulation was reduced 49.9±2.6% (P=0.028) gradually recovering ∼20 min after cocaine injection, indicating that neurovascular coupling during stimulation was temporarily disrupted by cocaine. Neurovascular uncoupling by cocaine during stimulation but not during rest indicates that distinct processes might underlie neurovascular regulation for both stimulation and spontaneous activity. The greater reductions by cocaine to the stimulation-induced CBF increases than to the background CBF should be considered when interpreting functional MRI studies comparing activation responses between controls and cocaine abusers. Neurovascular uncoupling could contribute to cocaine

  2. Chronic activation of central AMPK attenuates glucose-stimulated insulin secretion and exacerbates hepatic insulin resistance in diabetic rats.

    PubMed

    Park, Sunmin; Kim, Da Sol; Kang, Suna; Shin, Bae Keun

    2014-09-01

    We investigated the effects of chronic AMP-activated kinase (AMPK) activation in the hypothalamus on energy and glucose metabolism in 90% pancreatectomized diabetic rats. Diabetic rats fed a high fat diet were divided into 3 groups and intracerebroventricular (ICV) administered with one of the following: 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR, AMPK activator; 80 μg/day), AICAR+compound C (AMPK inhibitor; 6.2 μg/day), or an artificial cerebrospinal fluid (control) by means of osmotic pumps for 4 weeks. In the hypothalamus, central AICAR activated the phosphorylation of AMPK whereas adding compound C suppressed the activation. AICAR increased body weight and epididymal and retroperitoneal fat mass by increasing energy intake for the first 2 weeks and decreasing energy expenditure, whereas compound C reversed the AICAR effect on energy metabolism. Indirect calorimetry revealed that ICV-AICAR decreased carbohydrate oxidation, but not fat oxidation, compared to the control. During euglycemic hyperinsulinemic clamp, central AICAR increased hepatic glucose output at hyperinsulinemic states. ICV-AICAR increased expressions of hepatic genes involved in fatty acid synthesis and decreased expression of hepatic genes related to thermogenesis whereas compound C nullified the AICAR effect. Insulin secretion in the first and second phases decreased in AICAR-treated rats at hyperglycemic clamp, but compound C nullified the decrease. However, central AICAR did not alter β-cell mass via its proliferation or apoptosis. In conclusion, chronic hypothalamic AMPK activation impaired energy metabolism and glucose homeostasis by increasing food intake, increasing hepatic glucose output and decreasing insulin secretion in diabetic rats. The impairment of energy and glucose homeostasis by AMPK activation was nullified by an AMPK inhibitor.

  3. Cocaine attenuates blood flow but not neuronal responses to stimulation while preserving neurovascular coupling for resting brain activity

    PubMed Central

    Chen, Wei; Liu, Peng; Volkow, Nora D.; Pan, Yingtian; Du, Congwu

    2016-01-01

    Cocaine affects neuronal activity and constricts cerebral blood vessels, making it difficult to determine whether cocaine-induced chang