From COX-2 inhibitor nimesulide to potent anti-cancer agent: synthesis, in vitro, in vivo and pharmacokinetic evaluation

PubMed Central

Chennamaneni, Snigdha; Yi, Xin; Liu, lili; Pink, John J.; Dowlati, Afshin; Xu, Yan; Zhou, Aimin; Su, Bin

2014-01-01

Cyclooxygenase-2 (COX-2) inhibitor nimesulide inhibits the proliferation of various types of cancer cells mainly via COX-2 independent mechanisms, which makes it a good lead compound for anti-cancer drug development. In the presented study, a series of new nimesulide analogs were synthesized based on the structure–function analysis generated previously. Some of them displayed very potent anti-cancer activity with IC50s around 100nM to 200nM to inhibit SKBR-3 breast cancer cell growth. CSUOH0901 (NSC751382) from the compound library also inhibits the growth of the 60 cancer cell lines used at National Cancer Institute Developmental therapeutics Program (NCIDTP) with IC50s around 100nM to 500nM. Intraperitoneal injection with a dosage of 5mg/kg/d of CSUOH0901 to nude mice suppresses HT29 colorectal xenograft growth. Pharmacokinetic studies demonstrate the good bioavailability of the compound. PMID:22119125

Nimesulide, a COX-2 inhibitor, does not reduce lesion size or number in a nude mouse model of endometriosis.

PubMed

Hull, M L; Prentice, A; Wang, D Y; Butt, R P; Phillips, S C; Smith, S K; Charnock-Jones, D S

2005-02-01

Women with endometriosis have elevated levels of cyclooxygenase-2 (COX-2) in peritoneal macrophages and endometriotic tissue. Inhibition of COX-2 has been shown to reduce inflammation, angiogenesis and cellular proliferation. It may also downregulate aromatase activity in ectopic endometrial lesions. Ectopic endometrial establishment and growth are therefore likely to be suppressed in the presence of COX-2 inhibitors. We hypothesized that COX-2 inhibition would reduce the size and number of ectopic human endometrial lesions in a nude mouse model of endometriosis. The selective COX-2 inhibitor, nimesulide, was administered to estrogen-supplemented nude mice implanted with human endometrial tissue. Ten days after implantation, the number and size of ectopic endometrial lesions were evaluated and compared with lesions from a control group. Immunohistochemical assessment of vascular development and macrophage and myofibroblast infiltration in control and treated lesions was performed. There was no difference in the number or size of ectopic endometrial lesions in control and nimesulide-treated nude mice. Nimesulide did not induce a visually identifiable difference in blood vessel development or macrophage or myofibroblast infiltration in nude mouse explants. The hypothesized biological properties of COX-2 inhibition did not influence lesion number or size in the nude mouse model of endometriosis.

Optimization of nanostructured lipid carriers for topical delivery of nimesulide using Box-Behnken design approach.

PubMed

Moghddam, Seyedeh Marziyeh Mahdavi; Ahad, Abdul; Aqil, Mohd; Imam, Syed Sarim; Sultana, Yasmin

2017-05-01

The aim of the present study was to develop and optimize topically applied nimesulide-loaded nanostructured lipid carriers. Box-Behnken experimental design was applied for optimization of nanostructured lipid carriers. The independent variables were ratio of stearic acid: oleic acid (X 1 ), poloxamer 188 concentration (X 2 ) and lecithin concentration (X 3 ) while particle size (Y 1 ) and entrapment efficiency (Y 2 ) were the chosen responses. Further, skin penetration study, in vitro release, confocal laser scanning microscopy and stability study were also performed. The optimized nanostructured lipid carriers of nimesulide provide reasonable particle size, flux, and entrapment efficiency. Optimized formulation (F9) with mean particle size of 214.4 ± 11 nm showed 89.4 ± 3.40% entrapment efficiency and achieved mean flux 2.66 ± 0.09 μg/cm 2 /h. In vitro release study showed prolonged drug release from the optimized formulation following Higuchi release kinetics with R 2 value of 0.984. Confocal laser scanning microscopy revealed an enhanced penetration of Rhodamine B-loaded nanostructured lipid carriers to the deeper layers of the skin. The stability study confirmed that the optimized formulation was considerably stable at refrigerator temperature as compared to room temperature. Our results concluded that nanostructured lipid carriers are an efficient carrier for topical delivery of nimesulide.

COX-2 plays a role in angiogenic DBA(+) uNK cell subsets activation and pregnancy protection in LPS-exposed mice.

PubMed

Zavan, Bruno; De Almeida, Eliana Martins; Salles, Évila da Silva Lopes; do Amarante-Paffaro, Andréa Mollica; Paffaro, Valdemar Antonio

2016-08-01

Although uterine Natural Killer (uNK) cells have cytoplasmic granules rich in perforin and granzymes, these cells do not degranulate in normal pregnancy. DBA lectin(+) uNK cells produce angiogenic factors which stimulate remodeling of uterine arterioles to increase blood flow within the growing feto-placental unit. We sought to investigate the importance of COX-2 on mouse pregnancy inoculated with Gram-negative bacteria Lipopolysaccharide (LPS) by treating with a selective COX-2 inhibitor (nimesulide). We have combined histochemical, immunohistochemical, stereological, morphometric, behavioral, and litter analyses to investigate mouse pregnancy inoculated with LPS with or without pre-treatment with nimesulide 30 min before LPS injections, focusing on DBA(+) uNK cell response and viability of the pregnancy. LPS caused sickness behavior, an immature DBA(+) uNK influx, decreased mature DBA(+) uNK cell numbers, and triggered a new DBA(low) uNK appearance. These effects of LPS, except the sickness behavior, were prevented by nimesulide. COX-2 inhibition also prevented the down-regulation of uNK perforin and spiral arteriole α-actin expression stimulated by LPS. While the litter size from Nimesulide + LPS-treated mothers was significantly smaller compared to those from LPS-treated group, nimesulide alone showed no effect on the offspring. Collectively, our data indicate that COX-2 changes angiogenic DBA(+) uNK cells in order to protect mouse pregnancy after LPS injection. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ameliorative potential of rutin in combination with nimesulide in STZ model of diabetic neuropathy: targeting Nrf2/HO-1/NF-kB and COX signalling pathway.

PubMed

Mittal, Ruchika; Kumar, Anil; Singh, Dhirendra Pratap; Bishnoi, Mahendra; Nag, Tapas Chandra

2018-06-01

Emerging role of Nrf-2/HO-1 in pathogenesis of diabetic neuropathy has been suggested. Diabetic neuropathy is one of the most common complications of diabetes and more than 50% patients of diabetes develop diabetic neuropathy. Rutin has been well documented to show protective effect in various complications, e.g., diabetic neuropathy. However, its mechanistic insight is still not completely understood. The present study has been designed to explore the protective effect of rutin and its interaction with COX-2 inhibitor, nimesulide in diabetic neuropathy. DN (diabetic neuropathy) rats were maintained with or without rutin (100 and 200 mg/kg), nimesulide (5 and 10 mg/kg), and their combinations for 8 weeks. Body weight, serum glucose, pain assessment (mechanical allodynia, cold allodynia, mechanical hyperalgesia, and thermal hyperalgesia), and motor nerve conduction velocity (MNCV) were measured in all groups. Oxidative damage was assessed through biochemical estimation and mitochondrial ROS production, followed by inflammatory and apoptotic markers (TNF-α, caspase-3, Nrf-2, HO-1, and NF-kBp65) for their activity, protein, and gene expression. The structural changes were also reported through transmission electron microscope. Streptozotocin injection (55 mg/kg) induced diabetes reduced body weight, reduced the threshold for pain in various pain assessment parameters. Oxidative damage (increased MDA, decreased SOD, catalase, and GSH levels) increased mitochondrial ROS production followed by increased expression of inflammatory markers and decreased expression of Nrf-2/HO-1 in sciatic nerve. Treatment with rutin (100 and 200 mg/kg) and nimesulide (5 and 10 mg/kg) significantly attenuates these alterations as compared to DN control rats. Furthermore, combination of rutin (200 mg/kg) and nimesulide (10 mg/kg) significantly potentiated their protective effect which was significant as compared to their effect alone in streptozotocin-treated rats. The present study suggests the involvement of Nrf-2/HO-1 pathway in the protective effect of rutin against streptozotocin-induced diabetic neuropathy.

A novel Arometic compound acts synergistically with a naturally occurring monoterpene to elicit strong behavioral responses in Asian citrus psyllid

USDA-ARS?s Scientific Manuscript database

Inscent, Inc. has developed methodologies for rapidly screening potential ligands of chemosensory proteins (CSPs) isolated from the antennae of target insects. These novel ligands, referred to as Arometics, mimic naturally-occurring odorants and may function as super-stimuli because of their strong ...

CYCLOOXYGENASE COMPETITIVE INHIBITORS ALTER TYROSYL RADICAL DYNAMICS IN PROSTAGLANDIN H SYNTHASE-2†

PubMed Central

Wu, Gang; Tsai, Ah-Lim; Kulmacz, Richard J.

2009-01-01

Reaction of prostaglandin H synthase (PGHS) isoforms 1 or 2 with peroxide forms a radical at Tyr385 that is required for cyclooxygenase catalysis, and another radical at Tyr504, whose function is unknown. Both tyrosyl radicals are transient and rapidly dissipated by reductants, suggesting that cyclooxygenase catalysis might be vulnerable to suppression by intracellular antioxidants. Our initial hypothesis was that the two radicals are in equilibrium and that their proportions and stability are altered upon binding of fatty acid substrate. As a test, we examined the effects of three competitive inhibitors (nimesulide, flurbiprofen and diclofenac) on the proportions and stability of the two radicals in PGHS-2 pretreated with peroxide. Adding nimesulide after ethyl peroxide led to some narrowing of the tyrosyl radical signal detected by EPR spectroscopy, consistent with a small increase in the proportion of the Tyr504 radical. Neither flurbiprofen nor diclofenac changed the EPR linewidth when added after peroxide. In contrast, the effects of cyclooxygenase inhibitors on the stability of the preformed tyrosyl radicals were dramatic. The half-life of total tyrosyl radical was 4.1 min in the control, >10 hr with added nimesulide, 48 min with flurbiprofen, and 0.8 min with diclofenac. Stabilization of the tyrosyl radicals was evident even at substoichiometric levels of nimesulide. Thus, the inhibitors had potent, structure-dependent, effects on the stability of both tyrosyl radicals. This dramatic modulation of tyrosyl radical stability by cyclooxygenase site ligands suggests a mechanism for regulating the reactivity of PGHS tyrosyl radicals with cellular antioxidants. PMID:19894761

Crystallization of a non-steroidal anti-inflammatory drug from ethanol-water solution in presence of polymers: physicochemical characterization and release behaviour from suppositories.

PubMed

Mallick, Subrata; Dey, Pintu K; Sannigrahi, Santanu; Mitra, Avishek

2004-01-01

Altered crystallization condition has been designed and adopted to a model non-steroidal anti-inflammatory drug, while crystallizing from ethanol-water solution in absence and presence of polymers such as Eudragit RS and ethylcellulose. To minimize the gastro-intestinal side effects nimesulide was considered as a model drug candidate for the development of suppository formulation. Physicochemical characteristics of the crystals were evaluated by Scanning Electron Microscopy (SEM). X-ray diffraction (XRD) and Fourier Transformed Infrared Spectroscopy (FT-IR). Smoothness and sharpness of the crystal have been decreased with increased concentration of a polymer. A little change in crystal habit and geometry has also been observed. Crystals are discrete in nature and more than 90% were in the range of 20-90 micron. The X-ray diffractions of nimesulide crystallized in absence of polymer and physical mixture of drug-polymer revealed fewer high intensity reflections when compared with the drug crystallized in presence of Eudragit RS, which testified a slight decreased ordering of crystal lattice in the latter. In presence of ethylcellulose, slightly increased ordering of crystal lattice was observed. No strong interactions were noticed as revealed by FT-IR spectroscopy. Drug dissolution rate from suppository formulations containing nimesulide crystallized in presence of polymer was found to delay as compared with the suppository prepared by nimesulide crystallized in absence of polymer.

Inhibition of Cyclooxygenase-2 (COX-2) Initiates Autophagy and Potentiates MPTP-Induced Autophagic Cell Death of Human Neuroblastoma Cells, SH-SY5Y: an Inside in the Pathology of Parkinson's Disease.

PubMed

Niranjan, Rituraj; Mishra, Kaushal Prasad; Thakur, Ashwani Kumar

2018-03-01

Cyclooxygenase-2 or COX-2 has been known to be crucial for Parkinson's disease (PD) pathogenesis; however, its exact role is still not known. We first time report that inhibition of COX-2 promotes 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP)-induced neuronal cell death via induction of autophagic mechanisms. We found that treatment with MPTP induced cell death of neuroblastoma cells SH-SY5Y in a dose dependent manner. Treatment of MPTP has also upregulated the expressions of autophagic proteins such as LC3, beclin, ATG-5, and p62. Interestingly, nimesulide, a preferential COX-2 inhibitor, further potentiated the MPTP-induced cell death of human neuroblastoma cells. Treatment of nimesulide with MPTP further potentiated expressions of p62, ATG-5, beclin-1, LC3 autophagic proteins. Furthermore, nimesulide with MPTP increased apoptotic protein cleaved caspase-3 and also induced expression of p53 gene. Interestingly, it was observed that Akt inhibitor significantly increased MPTP-induced cell death of neuroblastoma cells. However, (-) deprenyl, a monoamine oxidase B (MAO B) inhibitor, attenuated MPTP-induced autophagic response and protected cell death. The prior treatment with prostaglandin E2 protected against nimesulide induced-death of neuronal cells. This study confirms that neuroinflammation is associated to the autophagy and may be one of the main pathological mechanisms in Parkinson's disease and other inflammation-associated disorders.

Human recombinant lactoferrin acts synergistically with antimicrobials commonly used in neonatal practice against coagulase-negative staphylococci and Candida albicans causing neonatal sepsis.

PubMed

Venkatesh, Mohan Pammi; Rong, Liang

2008-09-01

Neonatal sepsis causes significant mortality and morbidity. Coagulase-negative staphylococci (CoNS) and Candida frequently cause neonatal sepsis at >72 h of age. Lactoferrin, which is present in human milk, is a component of innate immunity and has broad-spectrum antimicrobial activity. The synergistic effects of lactoferrin with antibiotics against neonatal isolates have not been systematically evaluated. Here, eight clinical strains (seven neonatal) of CoNS and three strains (two neonatal) of Candida albicans were studied. MIC50 and MIC90 values of human recombinant lactoferrin (talactoferrin; TLF), vancomycin (VAN) and nafcillin (NAF) against CoNS, and of TLF, amphotericin B (AMB) and fluconazole (FLC) against C. albicans, were evaluated according to established guidelines. Antimicrobial combinations of TLF with NAF or VAN against CoNS, and TLF with AMB or FLC against C. albicans, were evaluated by a checkerboard method with serial twofold dilutions. Synergy was evaluated by the median effects principle, and combination indices and dose reduction indices were reported at 50, 75 and 90% inhibitory effect at several drug-dose ratios. It was found that TLF acted synergistically with NAF and VAN against CoNS, and with AMB and FLC against C. albicans, at multiple dose effects and drug-dose ratios with few exceptions. In synergistic combinations, drug reduction indices indicated a significant reduction in doses of antibiotics, which may be clinically relevant. Thus TLF acts synergistically with anti-staphylococcal and anti-Candida agents commonly used in neonatal practice and is a promising agent that needs to be evaluated in clinical studies.

Neuroprotective mechanism of losartan and its interaction with nimesulide against chronic fatigue stress.

PubMed

Kumar, Anil; Singh, Barinder; Mishra, Jitendriya; Sah, Sangeeta Pilkhwal; Pottabathini, Raghavender

2015-12-01

Potential role of angiotensin-II and cyclooxygenase have been suggested in the pathophysiology of chronic fatigue stress. The present study has been designed to evaluate the neuroprotective effect of losartan and its interaction with nimesulide against chronic fatigue stress and related complications in mice. In the present study, male Laca mice (20-30 g) were subjected to running wheel activity test session (RWATS) for 6 min daily for 21 days. Losartan, nimesulide and their combinations were administered daily for 21 days, 45 min before being subjected to RWATS. Various behavioral and biochemical and neuroinflammatory mediators were assessed subsequently. 21 days RWATS treatment significantly decreased number of wheel rotations/6 min indicating fatigue stress like behaviors as compared to naive group. 21 days treatment with losartan (10 and 20 mg/kg, ip), nimesulide (5 and 10 mg/kg, po) and their combinations significantly improved behavior [increased number of wheel rotations, reversal of post-exercise fatigue, locomotor activity, antianxiety-like behavior (number of entries, latency to enter and time spent in mirror chamber), and memory performance (transfer latency in plus-maze performance task)], biochemical parameters (reduced serum corticosterone, brain lipid peroxidation, nitrite concentration, acetylcholinesterase activity, restored reduced glutathione levels and catalase activity) as compared to RWATS control. Besides, TNF-α, CRP levels were significantly attenuated by these drugs and their combinations as compared to control. The present study highlights the role of cyclooxygenase modulation in the neuroprotective effect of losartan against chronic fatigue stress-induced behavioral, biochemical and cellular alterations in mice.

A potent dauer pheromone component in Caenorhabditis elegans that acts synergistically with other components.

PubMed

Butcher, Rebecca A; Ragains, Justin R; Kim, Edward; Clardy, Jon

2008-09-23

In the model organism Caenorhabditis elegans, the dauer pheromone is the primary cue for entry into the developmentally arrested, dauer larval stage. The dauer is specialized for survival under harsh environmental conditions and is considered "nonaging" because larvae that exit dauer have a normal life span. C. elegans constitutively secretes the dauer pheromone into its environment, enabling it to sense its population density. Several components of the dauer pheromone have been identified as derivatives of the dideoxy sugar ascarylose, but additional unidentified components of the dauer pheromone contribute to its activity. Here, we show that an ascaroside with a 3-hydroxypropionate side chain is a highly potent component of the dauer pheromone that acts synergistically with previously identified components. Furthermore, we show that the active dauer pheromone components that are produced by C. elegans vary depending on cultivation conditions. Identifying the active components of the dauer pheromone, the conditions under which they are produced, and their mechanisms of action will greatly extend our understanding of how chemosensory cues from the environment can influence such fundamental processes as development, metabolism, and aging in nematodes and in higher organisms.

Formulation design and optimization of mouth dissolve tablets of nimesulide using vacuum drying technique.

PubMed

Gohel, Mukesh; Patel, Madhabhai; Amin, Avani; Agrawal, Ruchi; Dave, Rikita; Bariya, Nehal

2004-04-26

The purpose of this research was to develop mouth dissolve tablets of nimesulide. Granules containing nimesulide, camphor, crospovidone, and lactose were prepared by wet granulation technique. Camphor was sublimed from the dried granules by exposure to vacuum. The porous granules were then compressed. Alternatively, tablets were first prepared and later exposed to vacuum. The tablets were evaluated for percentage friability, wetting time, and disintegration time. In the investigation, a 32 full factorial design was used to investigate the joint influence of 2 formulation variables: amount of camphor and crospovidone. The results of multiple linear regression analysis revealed that for obtaining a rapidly disintegrating dosage form, tablets should be prepared using an optimum concentration of camphor and a higher percentage of crospovidone. A contour plot is also presented to graphically represent the effect of the independent variables on the disintegration time and percentage friability. A checkpoint batch was also prepared to prove the validity of the evolved mathematical model. Sublimation of camphor from tablets resulted in superior tablets as compared with the tablets prepared from granules that were exposed to vacuum. The systematic formulation approach helped in understanding the effect of formulation processing variables.

Prefoldin and Pins synergistically regulate asymmetric division and suppress dedifferentiation

PubMed Central

Zhang, Yingjie; Rai, Madhulika; Wang, Cheng; Gonzalez, Cayetano; Wang, Hongyan

2016-01-01

Prefoldin is a molecular chaperone complex that regulates tubulin function in mitosis. Here, we show that Prefoldin depletion results in disruption of neuroblast polarity, leading to neuroblast overgrowth in Drosophila larval brains. Interestingly, co-depletion of Prefoldin and Partner of Inscuteable (Pins) leads to the formation of gigantic brains with severe neuroblast overgrowth, despite that Pins depletion alone results in smaller brains with partially disrupted neuroblast polarity. We show that Prefoldin acts synergistically with Pins to regulate asymmetric division of both neuroblasts and Intermediate Neural Progenitors (INPs). Surprisingly, co-depletion of Prefoldin and Pins also induces dedifferentiation of INPs back into neuroblasts, while depletion either Prefoldin or Pins alone is insufficient to do so. Furthermore, knocking down either α-tubulin or β-tubulin in pins- mutant background results in INP dedifferentiation back into neuroblasts, leading to the formation of ectopic neuroblasts. Overexpression of α-tubulin suppresses neuroblast overgrowth observed in prefoldin pins double mutant brains. Our data elucidate an unexpected function of Prefoldin and Pins in synergistically suppressing dedifferentiation of INPs back into neural stem cells. PMID:27025979

Use of Nonsteroidal Anti-Inflammatory Drugs for Symptomatic Treatment of Episodic Headache.

PubMed

Affaitati, Giannapia; Martelletti, Paolo; Lopopolo, Mariangela; Tana, Claudio; Massimini, Francesca; Cipollone, Francesco; Lapenna, Domenico; Giamberardino, Maria Adele; Costantini, Raffaele

2017-03-01

Primary headaches have high epidemiologic impact but their symptomatic treatment often remains problematic. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used, but their modality of employment and efficacy/differential efficacy are highly variable. This study investigated current NSAID use for episodic headache at an Italian headache center (January 2000 to February 2013). A retrospective evaluation was performed on 6,443 patient records: migraine (n = 2,330), tension-type headache (TTH; n = 807), and migraine plus TTH (n = 3,306). Among migraine patients, 80% had used NSAIDs in the past year. Preferences were: nimesulide (57%), ketoprofen (25%), and ibuprofen (24%); complete efficacy was significantly higher than incomplete/absent efficacy (P < 0.0001). NSAIDs were replaced with triptans in 53% of patients at first visit; after 1 year there was a spontaneous significant return to NSAIDs (56%; P < 0.0005). Among TTH patients, 90% were NSAID users; preferences were: nimesulide (48%), ketoprofen (47%), and diclofenac (19%), with significantly higher complete vs. incomplete/absent efficacy (nimesulide and ketoprofen, P < 0.02). Replacement with analgesics was performed in 24% of patients; after 1 year, there was a 29% return to NSAIDs. Among migraine plus TTH patients, 89% were NSAID users. Preferences were: nimesulide (44%), ibuprofen (42%), and ketoprofen (38%), with significantly higher complete vs. incomplete/absent efficacy (0.001 < P < 0.0001). Replacement with analgesics was performed in 31% of patients; after 1 year, there was a 37% return to NSAIDs. Nonsteroidal anti-inflammatory drug use in headache was higher than could be hypothesized based on guidelines, with NSAID preferences not entirely coinciding with international recommendations. This outcome suggests the need for greater awareness of all treatment options in headache by both patients and physicians. © 2016 World Institute of Pain.

A dual drug regimen synergistically blocks human parainfluenza virus infection

NASA Astrophysics Data System (ADS)

Bailly, Benjamin; Dirr, Larissa; El-Deeb, Ibrahim M.; Altmeyer, Ralf; Guillon, Patrice; von Itzstein, Mark

2016-04-01

Human parainfluenza type-3 virus (hPIV-3) is one of the principal aetiological agents of acute respiratory illness in infants worldwide and also shows high disease severity in the elderly and immunocompromised, but neither therapies nor vaccines are available to treat or prevent infection, respectively. Using a multidisciplinary approach we report herein that the approved drug suramin acts as a non-competitive in vitro inhibitor of the hPIV-3 haemagglutinin-neuraminidase (HN). Furthermore, the drug inhibits viral replication in mammalian epithelial cells with an IC50 of 30 μM, when applied post-adsorption. Significantly, we show in cell-based drug-combination studies using virus infection blockade assays, that suramin acts synergistically with the anti-influenza virus drug zanamivir. Our data suggests that lower concentrations of both drugs can be used to yield high levels of inhibition. Finally, using NMR spectroscopy and in silico docking simulations we confirmed that suramin binds HN simultaneously with zanamivir. This binding event occurs most likely in the vicinity of the protein primary binding site, resulting in an enhancement of the inhibitory potential of the N-acetylneuraminic acid-based inhibitor. This study offers a potentially exciting avenue for the treatment of parainfluenza infection by a combinatorial repurposing approach of well-established approved drugs.

Autoimmune hepatitis unmasked by nimesulide.

PubMed

Magalhães, Rita; Fonseca, Margarida; Brandão, Ilídio; Caridade, Sofia

2016-01-20

A 49-year-old woman presented at the emergency department, with acute hepatic failure, 2 weeks after taking nimesulide. Presenting with a MELD score of 25.0, the patient was transferred to a specialised liver transplant unit, with the probable diagnosis of toxic hepatitis. After a clinical improvement with supportive care and acetylcysteine, a liver biopsy was executed. The histology revealed micronodular cirrhosis associated with acute hepatitis, with features suggestive of autoimmune hepatitis. The patient was then started on azathioprine 50 mg/day and prednisolone 30 mg/day, and tapering of prednisolone was carried out in the following months. Twenty eight months after treatment, another liver biopsy was performed, showing almost full remission of the disease, with only mild fibrosis and no significant inflammatory infiltrate. 2016 BMJ Publishing Group Ltd.

Autoimmune hepatitis unmasked by nimesulide

PubMed Central

Fonseca, Margarida; Brandão, Ilídio; Caridade, Sofia

2016-01-01

A 49-year-old woman presented at the emergency department, with acute hepatic failure, 2 weeks after taking nimesulide. Presenting with a MELD score of 25.0, the patient was transferred to a specialised liver transplant unit, with the probable diagnosis of toxic hepatitis. After a clinical improvement with supportive care and acetylcysteine, a liver biopsy was executed. The histology revealed micronodular cirrhosis associated with acute hepatitis, with features suggestive of autoimmune hepatitis. The patient was then started on azathioprine 50 mg/day and prednisolone 30 mg/day, and tapering of prednisolone was carried out in the following months. Twenty eight months after treatment, another liver biopsy was performed, showing almost full remission of the disease, with only mild fibrosis and no significant inflammatory infiltrate. PMID:26791119

JAK2-V617F-induced MAPK activity is regulated by PI3K and acts synergistically with PI3K on the proliferation of JAK2-V617F-positive cells

PubMed Central

Wolf, Alexandra; Eulenfeld, René; Gäbler, Karoline; Rolvering, Catherine; Haan, Serge; Behrmann, Iris; Denecke, Bernd; Haan, Claude; Schaper, Fred

2013-01-01

The identification of a constitutively active JAK2 mutant, namely JAK2-V617F, was a milestone in the understanding of Philadelphia chromosome-negative myeloproliferative neoplasms. The JAK2-V617F mutation confers cytokine hypersensitivity, constitutive activation of the JAK-STAT pathway, and cytokine-independent growth. In this study we investigated the mechanism of JAK2-V617F-dependent signaling with a special focus on the activation of the MAPK pathway. We observed JAK2-V617F-dependent deregulated activation of the multi-site docking protein Gab1 as indicated by constitutive, PI3K-dependent membrane localization and tyrosine phosphorylation of Gab1. Furthermore, we demonstrate that PI3K signaling regulates MAPK activation in JAK2-V617F-positve cells. This cross-regulation of the MAPK pathway by PI3K affects JAK2-V617F-specific target gene induction, erythroid colony formation, and regulates proliferation of JAK2-V617F-positive patient cells in a synergistically manner. PMID:24069558

Contaminations of herbal products determined by NMR fingerprint.

PubMed

Nicoletti, Marcello; Petitto, Valentina

2010-09-01

The utilisation of NMR fingerprinting is proposed as a rapid, available and reliable method to determine the contamination of herbal products. The presence of nimesulide has been reported recently as the contaminant of P.C. 28 Plus, a product based on herbal drugs marketed by the Italian company Cosval. The presence of the substance, as well as its relevant concentration (5%), was first reported by HPLC/MS analysis by other authors. The use of an NMR fingerprint confirmed the previous contamination with nimesulide in P.C. 28 Plus. The same contaminant was also found in P.C. 28 Pink. Furthermore, an analysis of Alergix Plus, another product of the same factory, evidenced the presence of bromhexin.

Nimesulide, a cyclooxygenase-2 selective inhibitor, suppresses obesity-related non-alcoholic fatty liver disease and hepatic insulin resistance through the regulation of peroxisome proliferator-activated receptor γ

PubMed Central

Tsujimoto, Shunsuke; Kishina, Manabu; Koda, Masahiko; Yamamoto, Yasutaka; Tanaka, Kohei; Harada, Yusuke; Yoshida, Akio; Hisatome, Ichiro

2016-01-01

Cyclooxygenase (COX)-2 selective inhibitors suppress non-alcoholic fatty liver disease (NAFLD); however, the precise mechanism of action remains unknown. The aim of this study was to examine how the COX-2 selective inhibitor nimesulide suppresses NAFLD in a murine model of high-fat diet (HFD)-induced obesity. Mice were fed either a normal chow diet (NC), an HFD, or HFD plus nimesulide (HFD-nime) for 12 weeks. Body weight, hepatic COX-2 mRNA expression and triglyceride accumulation were significantly increased in the HFD group. Triglyceride accumulation was suppressed in the HFD-nime group. The mRNA expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ) and the natural PPARγ agonist 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) were significantly increased in the HFD group and significantly suppressed in the HFD-nime group. Glucose metabolism was impaired in the HFD group compared with the NC group, and it was significantly improved in the HFD-nime group. In addition, the plasma insulin levels in the HFD group were increased compared with those in the NC group, and were decreased in the HFD-nime group. These results indicate that HFD-induced NAFLD is mediated by the increased hepatic expression of COX-2. We suggest that the production of 15d-PGJ2, which is mediated by COX-2, induces NAFLD and hepatic insulin resistance by activating PPARγ. Furthermore, the mRNA expression of tissue inhibitor of metalloproteinases-1 (TIMP-1), procollagen-1 and monocyte chemoattractant protein-1 (MCP-1), as well as the number of F4/80-positive hepatic (Kupffer) cells, were significantly increased in the HFD group compared with the NC group, and they were reduced by nimesulide. In conclusion, COX-2 may emerge as a molecular target for preventing the development of NAFLD and insulin resistance in diet-related obesity. PMID:27431935

A Study on Factors Affecting Low Back Pain and Safety and Efficacy of NSAIDs in Acute Low Back Pain in a Tertiary Care Hospital of Western Nepal

PubMed Central

Bhattarai, Srijana; Chhetri, Himal Paudel; Alam, Kadir; Thapa, Pabin

2013-01-01

Introduction: Low back pain is characterized by a range of symptoms which include pain, muscle tension or stiffness, and is localized between the shoulder blades and the folds of the buttocks, with or without spreading to the legs. Non-Steroidal Anti Inflammatory Drugs (NSAIDs) are the drugs of choice which provide an analgesic effect for acute low back pain. Aim: To study the factors affecting low back pain, efficacy and safety of different non-steroidal anti-inflammatory drugs (aceclofenac, diclofenac, naproxen and nimesulide) in low back pain. Methodology: Data collection form and numeric pain rating scale were used as study tools for studying patients’ demographies and severities of pain respectively. Patients prescribed with aceclofenac 100 mg , diclofenac 100 mg, naproxen 500 mg and nimesulide 100 mg for acute low back pain at Orthopaedics Outpatients Department of Manipal Teaching Hospital, Nepal, were enrolled in this study. The decrease in pain scores was recorded on 5th and 10th days of follow-up and pain scores were calculated. Descriptive statistics and Kruskal Wallis non parametric test were used for analysis. Results: Among 150 patients, 67.3% were females (n=101). Low back pain was more prevalent (24.7%) in age-group of 59-68 years and a positive correlation was seen. Similarly, low back pain was found to be high among people involved in agriculture, heavy weight lifters and non smokers. The decrease in average pain scores was more in the patients treated with aceclofenac (4.83 ± 0.537), followed by that in those who were treated with naproxen (4.13 ± 0.067) and diclofenac (3.84 ± 0.086). The decrease in pain scores was found to be lowest among patients who were treated with nimesulide (2.11 ± 0.148). Nimesulide presented more number of side-effects than the comparative drugs. Conclusion: Different factors affect low back pain, such as age, gender, personal habit, posture, occupation, weight lifting. Aceclofenac showed greater decrease in pain scores with lesser number of side-effects. PMID:24551630

Berberine and Evodiamine Act Synergistically Against Human Breast Cancer MCF-7 Cells by Inducing Cell Cycle Arrest and Apoptosis.

PubMed

Du, Jia; Sun, Yang; Lu, Yi-Yu; Lau, Eric; Zhao, Ming; Zhou, Qian-Mei; Su, Shi-Bing

2017-11-01

The synergistic combinations of natural products have long been the basis of Traditional Chinese herbal Medicine formulas. In this study, we investigated the synergistic effects of a combination of berberine and evodiamine against human breast cancer MCF-7 cells in vitro and in vivo, and explored its mechanism. Cell survival was measured using the MTT assay. Apoptosis-related proteins were observed using western blot analysis. Apoptosis was detected with flow cytometric analysis and by Hoechst 33258 staining. Tumor xenografts were used in vivo. Compared to berberine or evodiamine treatments alone, the combination treatment of berberine (25 μM) and evodiamine (15 μM) synergistically inhibited the proliferation of MCF-7 cells in a time-dependent manner and resulted in the G 0 /G 1 phase accumulation of cells that exhibited increased expression levels of the CDK inhibitors p21 and p27 with a concomitant reduction in the expression levels of cell-cycle checkpoint proteins cyclin D1, cyclin E, CDK4, and CDK6. Furthermore, the combination treatment induced apoptosis that was accompanied by increased expression levels of p53 and Bax, reduced expression levels of Bcl-2, activation of caspase-7, and caspase-9, and the cleavage of PARP. The combination of berberine and evodiamine synergistically inhibited tumor growth in vivo in MCF-7 human breast cancer xenografts. Combination of berberine and evodiamine acts synergistically to suppress the proliferation of MCF-7 cells by inducing cell cycle arrest and apoptosis, illustrating the potential synergistic and combinatorial application of bioactive natural products. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Development and validation of a discriminative dissolution test for nimesulide suspensions.

PubMed

da Fonseca, Laís Bastos; Labastie, Márcio; de Sousa, Valéria Pereira; Volpato, Nadia Maria

2009-01-01

The dissolution test for oral dosage forms has recently widened to a variety of special dosage forms such as suspensions. For class II drugs, such as nimesulide (NMS), this study is very important because formulation problems may compromise drug bioavailability. In the present work, tests with four brands of commercially available NMS (RA, TS, TB, and TC) have been performed in order to study their dissolution at different conditions. The suspensions have been characterized relatively to particle size, pH, and density besides NMS assay and the amount of drug in solution in the suspension vehicles. The dissolution study was conducted using the following media: simulated intestinal fluid, pH 6.8, containing polysorbate 80 (P80) or sodium lauryl sulfate (SLS); phosphate buffer, pH 7.4, with P80 and aqueous solution of SLS. Concerning the quantitative analysis, the UV-VIS spectrophotometry could have been used in substitution to high-performance liquid chromatography since the methodology had been adequately validated. The influence of the drug particle size distribution was significant on the dissolution profiles of NMS formulations, confirming to be a factor that should be strictly controlled in the development of oral suspensions.

Canonical Wnt signaling acts synergistically on BMP9-induced osteo/odontoblastic differentiation of stem cells of dental apical papilla (SCAPs)

PubMed Central

Zhang, Hongmei; Wang, Jinhua; Deng, Fang; Huang, Enyi; Yan, Zhengjian; Wang, Zhongliang; Deng, Youlin; Zhang, Qian; Zhang, Zhonglin; Ye, Jixing; Qiao, Min; Li, Ruifang; Wang, Jing; Wei, Qiang; Zhou, Guolin; Luu, Hue H.; Haydon, Rex C.; He, Tong-Chuan; Deng, Feng

2014-01-01

Dental pulp/dentin regeneration using dental stem cells combined with odontogenic factors may offer great promise to treat and/or prevent premature tooth loss. Here, we investigate if BMP9 and Wnt/β-catenin act synergistically on odontogenic differentiation. Using the immortalized SCAPs (iSCAPs) isolated from mouse apical papilla tissue, we demonstrate that Wnt3A effectively induces early osteogenic marker alkaline phosphatase (ALP) in iSCAPs, which is reduced by β-catenin knockdown. While Wnt3A and BMP9 enhance each other’s ability to induce ALP activity in iSCAPs, silencing β- catenin significantly diminishes BMP9-induced osteo/odontogenic differentiation. Furthermore, silencing β-catenin reduces BMP9-induced expression of osteocalcin and osteopontin and in vitro matrix mineralization of iSCAPs. In vivo stem cell implantation assay reveals that while BMP9-transduced iSCAPs induce robust ectopic bone formation, iSCAPs stimulated with both BMP9 and Wnt3A exhibit more mature and highly mineralized trabecular bone formation. However, knockdown of β-catenin in iSCAPs significantly diminishes BMP9 or BMP9/Wnt3A-induced ectopic bone formation in vivo. Thus, our results strongly suggest that β-catenin may play an important role in BMP9-induced osteo/ondontogenic signaling and that BMP9 and Wnt3A may act synergistically to induce osteo/odontoblastic differentiation of iSCAPs. It’s conceivable that BMP9 and/or Wnt3A may be explored as efficacious biofactors for odontogenic regeneration and tooth engineering. PMID:25468367

Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice.

PubMed

Praticò, D; Tillmann, C; Zhang, Z B; Li, H; FitzGerald, G A

2001-03-13

The cyclooxygenase (COX) product, prostacyclin (PGI(2)), inhibits platelet activation and vascular smooth-muscle cell migration and proliferation. Biochemically selective inhibition of COX-2 reduces PGI(2) biosynthesis substantially in humans. Because deletion of the PGI(2) receptor accelerates atherogenesis in the fat-fed low density lipoprotein receptor knockout mouse, we wished to determine whether selective inhibition of COX-2 would accelerate atherogenesis in this model. To address this hypothesis, we used dosing with nimesulide, which inhibited COX-2 ex vivo, depressed urinary 2,3 dinor 6-keto PGF(1alpha) by approximately 60% but had no effect on thromboxane formation by platelets, which only express COX-1. By contrast, the isoform nonspecific inhibitor, indomethacin, suppressed platelet function and thromboxane formation ex vivo and in vivo, coincident with effects on PGI(2) biosynthesis indistinguishable from nimesulide. Indomethacin reduced the extent of atherosclerosis by 55 +/- 4%, whereas nimesulide failed to increase the rate of atherogenesis. Despite their divergent effects on atherogenesis, both drugs depressed two indices of systemic inflammation, soluble intracellular adhesion molecule-1, and monocyte chemoattractant protein-1 to a similar but incomplete degree. Neither drug altered serum lipids and the marked increase in vascular expression of COX-2 during atherogenesis. Accelerated progression of atherosclerosis is unlikely during chronic intake of specific COX-2 inhibitors. Furthermore, evidence that COX-1-derived prostanoids contribute to atherogenesis suggests that controlled evaluation of the effects of nonsteroidal anti-inflammatory drugs and/or aspirin on plaque progression in humans is timely.

Adsorption of diclofenac and nimesulide on activated carbon: Statistical physics modeling and effect of adsorbate size

NASA Astrophysics Data System (ADS)

Sellaoui, Lotfi; Mechi, Nesrine; Lima, Éder Cláudio; Dotto, Guilherme Luiz; Ben Lamine, Abdelmottaleb

2017-10-01

Based on statistical physics elements, the equilibrium adsorption of diclofenac (DFC) and nimesulide (NM) on activated carbon was analyzed by a multilayer model with saturation. The paper aimed to describe experimentally and theoretically the adsorption process and study the effect of adsorbate size using the model parameters. From numerical simulation, the number of molecules per site showed that the adsorbate molecules (DFC and NM) were mostly anchored in both sides of the pore walls. The receptor sites density increase suggested that additional sites appeared during the process, to participate in DFC and NM adsorption. The description of the adsorption energy behavior indicated that the process was physisorption. Finally, by a model parameters correlation, the size effect of the adsorbate was deduced indicating that the molecule dimension has a negligible effect on the DFC and NM adsorption.

[The role of chronic gastritis in past medical history with NSAID administration in patients with osteoarthrosis].

PubMed

Zak, M Iu

2014-11-01

122 patients with osteoarthrosis, who have in the past medical history verified chronic gastritis (50 males and 72 females) at the age from 42 to 64 have been examined. Control group was comprised of 40 patients with osteoarthrosis without gastroduodenal zone pathology in the past medical history. For arthralgia relief patients were prescribed meloxicam (average dose--12.5 - 1.39 mg daily) or nimesulide (average dose--150 ± 14.91 mg daily). As a result of this research it was determined that administration of selective NSAID (meloxicam and nimesulide) in patients with chronic gastritis in the past medical history raised the risk of NSAID gastropathy/dyspepsia 2.9 times (P < 0.03) than in patients without associated gastroduodenal zone pathology. Atrophy of gastric mucosa is associated with higher risks (P > 0.05) of erosive gastropathy. Patients with chronic gastritis in the past medical history when taking NSAID with the purpose of gastropathy prevention are recommended to undergo gastroprotective therapy.

Inhibition of p38 MAPK enhances ABT-737-induced cell death in melanoma cell lines: novel regulation of PUMA.

PubMed

Keuling, Angela M; Andrew, Susan E; Tron, Victor A

2010-06-01

The mitogen-activated protein kinase (MAPK) pathway is constitutively activated in the majority of melanomas, promoting cell survival, proliferation and migration. In addition, anti-apoptotic Bcl-2 family proteins Mcl-1, Bcl-xL and Bcl-2 are frequently overexpressed, contributing to melanoma's well-documented chemoresistance. Recently, it was reported that the combination of MAPK pathway inhibition by specific MEK inhibitors and Bcl-2 family inhibition by BH3-mimetic ABT-737 synergistically induces apoptotic cell death in melanoma cell lines. Here we provide the first evidence that inhibition of another key MAPK, p38, synergistically induces apoptosis in melanoma cells in combination with ABT-737. We also provide novel mechanistic data demonstrating that inhibition of p38 increases expression of pro-apoptotic Bcl-2 protein PUMA. Furthermore, we demonstrate that PUMA can be cleaved by a caspase-dependent mechanism during apoptosis and identify what appears to be the PUMA cleavage product. Thus, our findings suggest that the combination of ABT-737 and inhibition of p38 is a promising, new treatment strategy that acts through a novel PUMA-dependent mechanism.

Repositioning of antibiotic levofloxacin as a mitochondrial biogenesis inhibitor to target breast cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Min; Li, Ruishu, E-mail: liruishu2016@yahoo.com; Zhang, Juan

Targeting mitochondrial biogenesis has become a potential therapeutic strategy in cancer due to their unique metabolic dependencies. In this study, we show that levofloxacin, a FDA-approved antibiotic, is an attractive candidate for breast cancer treatment. This is achieved by the inhibition of proliferation and induction of apoptosis in a panel of breast cancer cell lines while sparing normal breast cells. It also acts synergistically with conventional chemo drug in two independent in vivo breast xenograft mouse models. Importantly, levofloxacin inhibits mitochondrial biogenesis as shown by the decreased level of mitochondrial respiration, membrane potential and ATP. In addition, the anti-proliferative and pro-apoptoticmore » effects of levofloxacin are reversed by acetyl-L-Carnitine (ALCAR, a mitochondrial fuel), confirming that levofloxacin's action in breast cancer cells is through inhibition of mitochondrial biogenesis. A consequence of mitochondrial biogenesis inhibition by levofloxacin in breast cancer cells is the deactivation of PI3K/Akt/mTOR and MAPK/ERK pathways. We further demonstrate that breast cancer cells have increased mitochondrial biogenesis than normal breast cells, and this explains their different sensitivity to levofloxacin. Our work suggest that levofloxacin is a useful addition to breast cancer treatment. Our work also establish the essential role of mitochondrial biogenesis on the activation of PI3K/Akt/mTOR and MAPK/ERK pathways in breast cancer cells. - Highlights: • Levofloxacin targets a panel of breast cancer cell lines in vitro and in vivo. • Levofloxacin acts synergistically with 5-Fluorouracil in breast cancer. • Levofloxacin targets breast cancer cells via inhibiting mitochondrial biogenesis. • Breast cancer cells have increased mitochondrial biogenesis than normal cells. • Mitochondrial biogenesis inhibition lead to deactivation of PI3K/Akt/mTOR pathway.« less

The SMC-5/6 Complex and the HIM-6 (BLM) Helicase Synergistically Promote Meiotic Recombination Intermediate Processing and Chromosome Maturation during Caenorhabditis elegans Meiosis.

PubMed

Hong, Ye; Sonneville, Remi; Agostinho, Ana; Meier, Bettina; Wang, Bin; Blow, J Julian; Gartner, Anton

2016-03-01

Meiotic recombination is essential for the repair of programmed double strand breaks (DSBs) to generate crossovers (COs) during meiosis. The efficient processing of meiotic recombination intermediates not only needs various resolvases but also requires proper meiotic chromosome structure. The Smc5/6 complex belongs to the structural maintenance of chromosome (SMC) family and is closely related to cohesin and condensin. Although the Smc5/6 complex has been implicated in the processing of recombination intermediates during meiosis, it is not known how Smc5/6 controls meiotic DSB repair. Here, using Caenorhabditis elegans we show that the SMC-5/6 complex acts synergistically with HIM-6, an ortholog of the human Bloom syndrome helicase (BLM) during meiotic recombination. The concerted action of the SMC-5/6 complex and HIM-6 is important for processing recombination intermediates, CO regulation and bivalent maturation. Careful examination of meiotic chromosomal morphology reveals an accumulation of inter-chromosomal bridges in smc-5; him-6 double mutants, leading to compromised chromosome segregation during meiotic cell divisions. Interestingly, we found that the lethality of smc-5; him-6 can be rescued by loss of the conserved BRCA1 ortholog BRC-1. Furthermore, the combined deletion of smc-5 and him-6 leads to an irregular distribution of condensin and to chromosome decondensation defects reminiscent of condensin depletion. Lethality conferred by condensin depletion can also be rescued by BRC-1 depletion. Our results suggest that SMC-5/6 and HIM-6 can synergistically regulate recombination intermediate metabolism and suppress ectopic recombination by controlling chromosome architecture during meiosis.

Cyclo-oxygenase isozymes in mucosal ulcergenic and functional responses following barrier disruption in rat stomachs.

PubMed

Hirata, T; Ukawa, H; Yamakuni, H; Kato, S; Takeuchi, K

1997-10-01

1. We examined the effects of selective and nonselective cyclo-oxygenase (COX) inhibitors on various functional changes in the rat stomach induced by topical application of taurocholate (TC) and investigated the preferential role of COX isozymes in these responses. 2. Rat stomachs mounted in ex vivo chambers were perfused with 50 mM HCl and transmucosal potential difference (p.d.), mucosal blood flow (GMBF), luminal acid loss and luminal levels of prostaglandin E2 (PGE2) were measured before, during and after exposure to 20 mM TC. 3. Mucosal application of TC in control rats caused a reduction in p.d., followed by an increase of luminal acid loss and GMBF, and produced only minimal damage in the mucosa 2 h later. Pretreatment with indomethacin (10 mg kg[-1], s.c.), a nonselective COX-1 and COX-2 inhibitor, attenuated the gastric hyperaemic response caused by TC without affecting p.d. and acid loss, resulting in haemorrhagic lesions in the mucosa. In contrast, selective COX-2 inhibitors, such as NS-398 and nimesulide (10 mg kg[-1], s.c.), had no effect on any of the responses induced by TC and did not cause gross damage in the mucosa. 4. Luminal PGE2 levels were markedly increased during and after exposure to TC and this response was significantly inhibited by indomethacin but not by either NS-398 or nimesulide. The expression of COX-1-mRNA was consistently detected in the gastric mucosa before and after TC treatment, while a faint expression of COX-2-mRNA was detected only 2 h after TC treatment. 5. Both NS-398 and nimesulide significantly suppressed carrageenan-induced rat paw oedema, similar to indomethacin. 6. These results confirmed a mediator role for prostaglandins in the gastric hyperaemic response following TC-induced barrier disruption, and suggest that COX-1 but not COX-2 is a key enzyme in maintaining 'housekeeping' functions in the gastric mucosa under both normal and adverse conditions.

Nimesulide, a cyclooxygenase-2 selective inhibitor, suppresses obesity-related non-alcoholic fatty liver disease and hepatic insulin resistance through the regulation of peroxisome proliferator-activated receptor γ.

PubMed

Tsujimoto, Shunsuke; Kishina, Manabu; Koda, Masahiko; Yamamoto, Yasutaka; Tanaka, Kohei; Harada, Yusuke; Yoshida, Akio; Hisatome, Ichiro

2016-09-01

Cyclooxygenase (COX)-2 selective inhibitors suppress non-alcoholic fatty liver disease (NAFLD); however, the precise mechanism of action remains unknown. The aim of this study was to examine how the COX-2 selective inhibitor nimesulide suppresses NAFLD in a murine model of high-fat diet (HFD)‑induced obesity. Mice were fed either a normal chow diet (NC), an HFD, or HFD plus nimesulide (HFD-nime) for 12 weeks. Body weight, hepatic COX-2 mRNA expression and triglyceride accumulation were significantly increased in the HFD group. Triglyceride accumulation was suppressed in the HFD-nime group. The mRNA expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ) and the natural PPARγ agonist 15-deoxy-Δ12,14-prostaglandin J2 (15d‑PGJ2) were significantly increased in the HFD group and significantly suppressed in the HFD-nime group. Glucose metabolism was impaired in the HFD group compared with the NC group, and it was significantly improved in the HFD-nime group. In addition, the plasma insulin levels in the HFD group were increased compared with those in the NC group, and were decreased in the HFD-nime group. These results indicate that HFD-induced NAFLD is mediated by the increased hepatic expression of COX-2. We suggest that the production of 15d-PGJ2, which is mediated by COX-2, induces NAFLD and hepatic insulin resistance by activating PPARγ. Furthermore, the mRNA expression of tissue inhibitor of metalloproteinases-1 (TIMP‑1), procollagen-1 and monocyte chemoattractant protein-1 (MCP-1), as well as the number of F4/80-positive hepatic (Kupffer) cells, were significantly increased in the HFD group compared with the NC group, and they were reduced by nimesulide. In conclusion, COX-2 may emerge as a molecular target for preventing the development of NAFLD and insulin resistance in diet-related obesity.

The SMC-5/6 Complex and the HIM-6 (BLM) Helicase Synergistically Promote Meiotic Recombination Intermediate Processing and Chromosome Maturation during Caenorhabditis elegans Meiosis

PubMed Central

Hong, Ye; Sonneville, Remi; Agostinho, Ana; Meier, Bettina; Wang, Bin; Blow, J. Julian; Gartner, Anton

2016-01-01

Meiotic recombination is essential for the repair of programmed double strand breaks (DSBs) to generate crossovers (COs) during meiosis. The efficient processing of meiotic recombination intermediates not only needs various resolvases but also requires proper meiotic chromosome structure. The Smc5/6 complex belongs to the structural maintenance of chromosome (SMC) family and is closely related to cohesin and condensin. Although the Smc5/6 complex has been implicated in the processing of recombination intermediates during meiosis, it is not known how Smc5/6 controls meiotic DSB repair. Here, using Caenorhabditis elegans we show that the SMC-5/6 complex acts synergistically with HIM-6, an ortholog of the human Bloom syndrome helicase (BLM) during meiotic recombination. The concerted action of the SMC-5/6 complex and HIM-6 is important for processing recombination intermediates, CO regulation and bivalent maturation. Careful examination of meiotic chromosomal morphology reveals an accumulation of inter-chromosomal bridges in smc-5; him-6 double mutants, leading to compromised chromosome segregation during meiotic cell divisions. Interestingly, we found that the lethality of smc-5; him-6 can be rescued by loss of the conserved BRCA1 ortholog BRC-1. Furthermore, the combined deletion of smc-5 and him-6 leads to an irregular distribution of condensin and to chromosome decondensation defects reminiscent of condensin depletion. Lethality conferred by condensin depletion can also be rescued by BRC-1 depletion. Our results suggest that SMC-5/6 and HIM-6 can synergistically regulate recombination intermediate metabolism and suppress ectopic recombination by controlling chromosome architecture during meiosis. PMID:27010650

Putative Inv is essential for basolateral invasion of Caco-2 cells and acts synergistically with OmpA to affect in vitro and in vivo virulence of Cronobacter sakazakii ATCC 29544.

PubMed

Chandrapala, Dilini; Kim, Kyumson; Choi, Younho; Senevirathne, Amal; Kang, Dong-Hyun; Ryu, Sangryeol; Kim, Kwang-Pyo

2014-05-01

Cronobacter sakazakii is an opportunistic pathogen that causes neonatal meningitis and necrotizing enterocolitis. Its interaction with intestinal epithelium is important in the pathogenesis of enteric infections. In this study, we investigated the involvement of the inv gene in the virulence of C. sakazakii ATCC 29544 in vitro and in vivo. Sequence analysis of C. sakazakii ATCC 29544 inv revealed that it is different from other C. sakazakii isolates. In various cell culture models, an Δinv deletion mutant showed significantly lowered invasion efficiency, which was restored upon genetic complementation. Studying invasion potentials using tight-junction-disrupted Caco-2 cells suggested that the inv gene product mediates basolateral invasion of C. sakazakii ATCC 29544. In addition, comparison of invasion potentials of double mutant (ΔompA Δinv) and single mutants (ΔompA and Δinv) provided evidence for an additive effect of the two putative outer membrane proteins. Finally, the importance of inv and the additive effect of putative Inv and OmpA were also proven in an in vivo rat pup model. This report is the first to demonstrate two proteins working synergistically in vitro, as well as in vivo in C. sakazakii pathogenesis.

Putative Inv Is Essential for Basolateral Invasion of Caco-2 Cells and Acts Synergistically with OmpA To Affect In Vitro and In Vivo Virulence of Cronobacter sakazakii ATCC 29544

PubMed Central

Chandrapala, Dilini; Kim, Kyumson; Choi, Younho; Senevirathne, Amal; Kang, Dong-Hyun; Ryu, Sangryeol

2014-01-01

Cronobacter sakazakii is an opportunistic pathogen that causes neonatal meningitis and necrotizing enterocolitis. Its interaction with intestinal epithelium is important in the pathogenesis of enteric infections. In this study, we investigated the involvement of the inv gene in the virulence of C. sakazakii ATCC 29544 in vitro and in vivo. Sequence analysis of C. sakazakii ATCC 29544 inv revealed that it is different from other C. sakazakii isolates. In various cell culture models, an Δinv deletion mutant showed significantly lowered invasion efficiency, which was restored upon genetic complementation. Studying invasion potentials using tight-junction-disrupted Caco-2 cells suggested that the inv gene product mediates basolateral invasion of C. sakazakii ATCC 29544. In addition, comparison of invasion potentials of double mutant (ΔompA Δinv) and single mutants (ΔompA and Δinv) provided evidence for an additive effect of the two putative outer membrane proteins. Finally, the importance of inv and the additive effect of putative Inv and OmpA were also proven in an in vivo rat pup model. This report is the first to demonstrate two proteins working synergistically in vitro, as well as in vivo in C. sakazakii pathogenesis. PMID:24549330

Increased expression of cyclooxygenase-2 protein during rat hepatocarcinogenesis caused by a choline-deficient, L-amino acid-defined diet and chemopreventive efficacy of a specific inhibitor, nimesulide.

PubMed

Denda, Ayumi; Kitayama, Wakashi; Murata, Akiko; Kishida, Hideki; Sasaki, Yasutaka; Kusuoka, Osamu; Tsujiuchi, Toshifumi; Tsutsumi, Masahiro; Nakae, Dai; Takagi, Hidetoshi; Konishi, Yoichi

2002-02-01

Expression of cyclooxygenase (COX)-2 protein during rat hepatocarcinogenesis associated with fatty change, fibrosis, cirrhosis and oxidative DNA damage, caused by a choline-deficient, L-amino acid-defined (CDAA) diet were investigated in F344 male rats, along with the chemopreventive efficacy of the specific COX-2 inhibitor, nimesulide (NIM). Nimesulide, which was administered in the diet at concentrations of 200, 400, 600 and 800 p.p.m. for 12 weeks, decreased the number and size of preneoplastic enzyme-altered liver foci, levels of oxidative DNA damage, and the grade and incidence of fibrosis in a dose-dependent manner. A preliminary long-term study of 65 weeks also revealed that 800 p.p.m. NIM decreased the multiplicity of neoplastic nodules and hepatocellular carcinomas and prevented the development of cirrhosis. Western blot analysis revealed that COX-2 protein was barely expressed in control livers and increased approximately 2.9-fold in the livers of rats fed on a CDAA diet for 12 weeks and approximately 4.5-5.4-fold in tumors, with a diameter larger than 5 mm, at 80 weeks. Immunohistochemically, COX-2 protein was positive in sinusoidal and stromal cells in fibrotic septa, which were identified by immunoelectron microscopy as Kupffer cells, macrophages, either activated Ito cells or fibroblasts, after exposure to the CDAA diet for 12 weeks, whereas it was only occasionally weakly positive in sinusoidal, probably Kupffer, cells in control livers. In neoplastic nodules in rats fed on a CDAA diet for 30 and 80 weeks, sinusoidal cells and cells with relatively large round nuclei and scanty cytoplasm were strongly positive for COX-2 protein, with the neoplastic hepatocytes in the minority of the nodules, but not the cancer cells, being moderately positive. These results clearly indicate that rat hepatocarcinogenesis, along with fatty change, fibrosis and cirrhosis, is associated with increased expression of COX-2 protein, and point to the chemopreventive efficacy of a selective COX-2 inhibitor against, at least, the early stages of hepatocarcinogenesis.

Lallemantia reylenne seeds as superdisintegrant: Formulation and evaluation of nimesulide orodispersible tablets

PubMed Central

Malik, Karan; Arora, Gurpreet; Singh, Inderbir; Arora, Sandeep

2011-01-01

Aim: Orodispersible tablets also known as fast dissolving tablets disintegrate instantaneously within the mouth and thus can be consumed without water. The present study was aimed to formulate orodispersible tablets of nimesulide by using Lallemantia reylenne seeds as natural superdisintegrant. Materials and Methods: Powdered lallemantia seeds were characterized for powder flow properties (bulk density, tapped density, carr's consolidation index, hausner ratio, angle of repose), swelling index, viscosity, pH, and loss on drying. The prepared tablets were evaluated for different tablet parametric tests, wetting time, water absorption ratio, effective pore radius, porosity, packing fraction, in vitro and in vivo disintegration time, in vitro dissolution and stability studies. Results and Discussion: Increase in Lallementia reylenne concentration had an appreciable effect on tablet hardness and friability which clearly indicated binding potential of the seeds. Water absorption ratio increased with increase in Lallemantia reylenne concentration from batch A1 to A4. Water uptake coupled natural polymer swelling could be the most probable mechanism for concentration dependent reduction in disintegration time by the Lallemantia reylenne seeds. Porosity of the formulated tablets was found to increase from batch A1-A4. The in vitro disintegration results were in line with in vivo disintegration results. Conclusion: It could be concluded that Lallemantia reylenne seeds could be used as natural superdisintegrant in the formulation of orodispersible tablets. PMID:23071942

Tooth wear: attrition, erosion, and abrasion.

PubMed

Litonjua, Luis A; Andreana, Sebastiano; Bush, Peter J; Cohen, Robert E

2003-06-01

Attrition, erosion, and abrasion result in alterations to the tooth and manifest as tooth wear. Each classification acts through a distinct process that is associated with unique clinical characteristics. Accurate prevalence data for each classification are not available since indices do not necessarily measure one specific etiology, or the study populations may be too diverse in age and characteristics. The treatment of teeth in each classification will depend on identifying the factors associated with each etiology. Some cases may require specific restorative procedures, while others will not require treatment. A review of the literature points to the interaction of the three entities in the initiation and progression of lesions that may act synchronously or sequentially, synergistically or additively, or in conjunction with other entities to mask the true nature of tooth wear, which appears to be multifactorial.

Dynamic Model for Life History of Scyphozoa

PubMed Central

Xie, Congbo; Fan, Meng; Wang, Xin; Chen, Ming

2015-01-01

A two-state life history model governed by ODEs is formulated to elucidate the population dynamics of jellyfish and to illuminate the triggering mechanism of its blooms. The polyp-medusa model admits trichotomous global dynamic scenarios: extinction, polyps survival only, and both survival. The population dynamics sensitively depend on several biotic and abiotic limiting factors such as substrate, temperature, and predation. The combination of temperature increase, substrate expansion, and predator diminishment acts synergistically to create a habitat that is more favorable for jellyfishes. Reducing artificial marine constructions, aiding predator populations, and directly controlling the jellyfish population would help to manage the jellyfish blooms. The theoretical analyses and numerical experiments yield several insights into the nature underlying the model and shed some new light on the general control strategy for jellyfish. PMID:26114642

Inductions of granulosa cell luteinization and cumulus expansion are dependent on the fibronectin-integrin pathway during ovulation process in mice.

PubMed

Kitasaka, Hiroya; Kawai, Tomoko; Hoque, S A Masudul; Umehara, Takashi; Fujita, Youko; Shimada, Masayuki

2018-01-01

It has been known that EGF-like factor secreted from LH-stimulated granuloma cells acts on granulosa cells and cumulus cells to induce ovulation process. Granulosa cells are changed the morphology with differentiating cell functions to produce progesterone. Cumulus cells are detached to make a space between the cells to accumulate hyaluronan rich matrix. LH also changes extracellular matrix (ECM) components including fibronectin in the follicular walls and granulosa cell layers. EGF like factor and fibronectin synergistically play important roles in numerous cell functions, especially cancer cell migration, estimating that fibronectin would impact on granulosa cells and cumulus cells. To clear this hypothesis, the localizations of fibronectin and its receptor integrin were observed by immunofluorescence technique. The functions were monitored by the detection of downstream signaling pathway, focal adhesion kinase (FAK). The pharmacological approach in both in vivo and in vitro were used for analyzing the physiological roles of FAK during ovulation process. The immunofluorescence staining revealed that fibronectin and integrin were observed in granulosa cells, cumulus cells and the space between cumulus cells and oocyte at 4 and 8 h after hCG injection. Concomitantly with the changes of fibronectin-integrin localization, FAK was phosphorylated in periovulatory follicles. The injection of FAK inhibitor suppressed not only ovulation but also luteinization of granulosa cells and cumulus expansion. In cultured-granulosa cells, fibronectin-integrin synergistically activated FAK with amphiregulin (AREG). Such cooperative stimulations induced a morphological change in granulosa cells, which resulted in the maximum level of progesterone production via the induction of Hsd3b. When cumulus-oocyte complexes (COCs) were cultured with AREG in the presence of serum, the maximum level of cumulus expansion was observed. The AREG-induced cumulus expansion was also suppressed by FAK inhibitor. Thus, it is concluded that fibronectin and AREG synergistically activate FAK not only in granulosa cells and cumulus cells to induce successful ovulation process.

The Ubiquitin Receptor DA1 Interacts with the E3 Ubiquitin Ligase DA2 to Regulate Seed and Organ Size in Arabidopsis[C][W

PubMed Central

Xia, Tian; Li, Na; Dumenil, Jack; Li, Jie; Kamenski, Andrei; Bevan, Michael W.; Gao, Fan; Li, Yunhai

2013-01-01

Seed size in higher plants is determined by the coordinated growth of the embryo, endosperm, and maternal tissue. Several factors that act maternally to regulate seed size have been identified, such as AUXIN RESPONSE FACTOR2, APETALA2, KLUH, and DA1, but the genetic and molecular mechanisms of these factors in seed size control are almost totally unknown. We previously demonstrated that the ubiquitin receptor DA1 acts synergistically with the E3 ubiquitin ligase ENHANCER1 OF DA1 (EOD1)/BIG BROTHER to regulate the final size of seeds in Arabidopsis thaliana. Here, we describe another RING-type protein with E3 ubiquitin ligase activity, encoded by DA2, which regulates seed size by restricting cell proliferation in the maternal integuments of developing seeds. The da2-1 mutant forms large seeds, while overexpression of DA2 decreases seed size of wild-type plants. Overexpression of rice (Oryza sativa) GRAIN WIDTH AND WEIGHT2, a homolog of DA2, restricts seed growth in Arabidopsis. Genetic analyses show that DA2 functions synergistically with DA1 to regulate seed size, but does so independently of EOD1. Further results reveal that DA2 interacts physically with DA1 in vitro and in vivo. Therefore, our findings define the genetic and molecular mechanisms of three ubiquitin-related proteins DA1, DA2, and EOD1 in seed size control and indicate that they are promising targets for crop improvement. PMID:24045020

Dynamic Model for Life History of Scyphozoa.

PubMed

Xie, Congbo; Fan, Meng; Wang, Xin; Chen, Ming

2015-01-01

A two-state life history model governed by ODEs is formulated to elucidate the population dynamics of jellyfish and to illuminate the triggering mechanism of its blooms. The polyp-medusa model admits trichotomous global dynamic scenarios: extinction, polyps survival only, and both survival. The population dynamics sensitively depend on several biotic and abiotic limiting factors such as substrate, temperature, and predation. The combination of temperature increase, substrate expansion, and predator diminishment acts synergistically to create a habitat that is more favorable for jellyfishes. Reducing artificial marine constructions, aiding predator populations, and directly controlling the jellyfish population would help to manage the jellyfish blooms. The theoretical analyses and numerical experiments yield several insights into the nature underlying the model and shed some new light on the general control strategy for jellyfish.

Reactive astrocyte COX2-PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury.

PubMed

Shiow, Lawrence R; Favrais, Geraldine; Schirmer, Lucas; Schang, Anne-Laure; Cipriani, Sara; Andres, Christian; Wright, Jaclyn N; Nobuta, Hiroko; Fleiss, Bobbi; Gressens, Pierre; Rowitch, David H

2017-12-01

Inflammation is a major risk factor for neonatal white matter injury (NWMI), which is associated with later development of cerebral palsy. Although recent studies have demonstrated maturation arrest of oligodendrocyte progenitor cells (OPCs) in NWMI, the identity of inflammatory mediators with direct effects on OPCs has been unclear. Here, we investigated downstream effects of pro-inflammatory IL-1β to induce cyclooxygenase-2 (COX2) and prostaglandin E2 (PGE2) production in white matter. First, we assessed COX2 expression in human fetal brain and term neonatal brain affected by hypoxic-ischemic encephalopathy (HIE). In the developing human brain, COX2 was expressed in radial glia, microglia, and endothelial cells. In human term neonatal HIE cases with subcortical WMI, COX2 was strongly induced in reactive astrocytes with "A2" reactivity. Next, we show that OPCs express the EP1 receptor for PGE2, and PGE2 acts directly on OPCs to block maturation in vitro. Pharmacologic blockade with EP1-specific inhibitors (ONO-8711, SC-51089), or genetic deficiency of EP1 attenuated effects of PGE2. In an IL-1β-induced model of NWMI, astrocytes also exhibit "A2" reactivity and induce COX2. Furthermore, in vivo inhibition of COX2 with Nimesulide rescues hypomyelination and behavioral impairment. These findings suggest that neonatal white matter astrocytes can develop "A2" reactivity that contributes to OPC maturation arrest in NWMI through induction of COX2-PGE2 signaling, a pathway that can be targeted for neonatal neuroprotection. © 2017 Wiley Periodicals, Inc.

Effects of dexamethasone and nimesulide on bisphosphonate-related osteonecrosis of the jaw: An experimental study.

PubMed

Oliveira, Camila Carvalho de; Barros Silva, Paulo Goberlânio de; Ferreira, Antonio Ernando Carlos; Gonçalves, Romélia Pinheiro; Sousa, Fabrício Bitu de; Mota, Mário Rogério Lima; Alves, Ana Paula Negreiros Nunes

2017-11-01

To evaluate the effects of dexamethasone (DEX) and nimesulide (NIM) on Bisphosphonate-related Osteonecrosis of the Jaw (BRONJ) in rats. BRONJ was induced by zoledronic acid (ZA) infusion (0.2mg/kg) in Wistar rats (n=8), followed by extraction of the left lower first molar (BRONJ groups). Control groups (n=40) received saline (IV). For eight weeks, DEX (0.04, 0.4, 4mg/kg) or saline (SAL) were administered by gavage 24h before each infusion of ZA or saline (IV), or NIM (10.3mg/kg) was administered 24h and 12h before each infusion of ZA or saline (IV). The haematological analyses were conducted weekly. After euthanasia (day 70), the jaws were submitted to radiographic and microscopic analysis. Kidney, liver, spleen and stomach were analysed histopathologically. The BRONJ groups showed a higher radiolucent area compared with the control groups (p<0.05). Histomorphometric analysis revealed healing and new bone formation in the control groups, while the BRONJ groups exhibited devitalized bone with bacterial colonies and inflammatory infiltrate. The BRONJ-DEX 0.4 and 4mg/kg groups had a greater number of bacterial colonies (p<0.05) and an increased polymorphonuclear cell count compared to the saline-BRONJ group, while the BRONJ-NIM group had a lower polymorphonuclear count (p<0.05). The BRONJ groups had leucocytosis, which was reduced by DEX administration. Treatments with DEX with or without ZA caused white pulp atrophy. Thus, DEX or NIM therapy was not effective in preventing radiographic and histopathologic events associated with BRONJ. Treatment with DEX attenuated leucocytosis post-infusion with ZA. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of a cyclooxygenase-2 preferential inhibitor in young healthy dogs exposed to air pollution: a pilot study.

PubMed

Calderón-Garcidueñas, Lilian; Mora-Tiscareño, Antonieta; Gómez-Garza, Gilberto; Carrasco-Portugal, Miriam Del C; Pérez-Guillé, Beatriz; Flores-Murrieta, Francisco J; Pérez-Guillé, Gabriela; Osnaya, Norma; Juárez-Olguín, Hugo; Monroy, Maria E; Monroy, Silvia; González-Maciel, Angelica; Reynoso-Robles, Rafael; Villarreal-Calderon, Rafael; Patel, Sarjubhai A; Kumarathasan, Prem; Vincent, Renaud; Henríquez-Roldán, Carlos; Torres-Jardón, Ricardo; Maronpot, Robert R

2009-08-01

Residency in cities with high air pollution is associated with neuroinflammation and neurodegeneration in healthy children, young adults, and dogs. Nonsteroidal anti-inflammatory drugs may offer neuroprotection. The authors measured the plasma concentrations of 3-nitrotyrosine and the cerebro-spinal-fluid concentrations of prostaglandin E2 metabolite and the oligomeric form of amyloid derived diffusible ligand; measured the mRNA expression of cyclooxygenase-2, interleukin 1beta, CD14, and Aquaporin-4 in target brain areas; and evaluated brain MRI, cognition, and neuropathology in 8 dogs treated with a preferential cyclooxygenase-2 inhibitor (Nimesulide) versus 7 untreated litter-matched Mexico City dogs. Nimesulide significantly decreased nitrotyrosine in plasma (p < .0001), frontal gray IL1beta (p = .03), and heart IL1beta (p = .02). No effect was seen in mRNA COX2, amyloid, and PGE2 in CSF or the MRI white matter lesions. All exposed dogs exhibited olfactory bulb and frontal accumulation of Abeta(42) in neurons and blood vessels and frontal vascular subcortical pathology. White matter hyperintense MRI frontal lesions were seen in 4/6 non-treated and 6/8 treated dogs. Nonsteroidal anti-inflammatory drugs may offer limited neuroprotection in the setting of severe air pollution exposures. The search for potentially beneficial drugs useful to ameliorate the brain effects of pollution represents an enormous clinical challenge.

Chlorophyll a Fluorescence in Evaluation of the Effect of Heavy Metal Soil Contamination on Perennial Grasses

PubMed Central

Żurek, Grzegorz; Rybka, Krystyna; Pogrzeba, Marta; Krzyżak, Jacek; Prokopiuk, Kamil

2014-01-01

Chlorophyll a fluorescence gives information about the plant physiological status due to its coupling to the photosynthetic electron transfer chain and to the further biochemical processes. Environmental stresses, which acts synergistically, disturbs the photosynthesis. The OJIP test, elaborated by Strasser and co-workers, enables comparison of the physiological status of plants grown on polluted vs. control areas. The paper shows that the Chl a measurements are very useful tool in evaluating of heavy metal ions influence on perennial grasses, tested as potential phytoremediators. Among 5 cultivars tested, the highest concentration of Cd and Zn ions, not associated with the yield reduction, was detected in the biomass of tall fescue cv. Rahela. Chl a fluorescence interpreted as double normalized curves pointed out Rahela as the outstanding cultivar under the HM ions stress. PMID:24633293

Eutectic, monotectic and immiscibility systems of nimesulide with water-soluble carriers: phase equilibria, solid-state characterisation and in-vivo/pharmacodynamic evaluation.

PubMed

Abdelkader, Hamdy; Abdallah, Ossama Y; Salem, Hesham; Alani, Adam W G; Alany, Raid G

2014-10-01

The solid-state interactions of fused mixtures nimesulide (ND) with polyethylene glycol (PEG) 4000, urea or mannitol were studied through constructing thaw-melt phase equilibrium diagrams. The solid-state characteristics were investigated using differential scanning calorimetry (DSC) and X-ray diffraction (XRD). Various types of interactions were identified such as the formation of a eutectic system of ND-PEG 4000, monotectic system of ND-urea and complete solid immiscibility of ND with mannitol. The effects of carrier concentrations on the equilibrium solubility and in-vitro dissolution characteristics were studied. Linear increases (R(2)  > 0.99) in the aqueous solubility of ND in various concentrations of PEG 4000 and urea were obtained, whereas mannitol did not exhibit any effect on the solubility of ND. Similar trends were obtained with the dissolution efficiency of the fused mixtures of ND with PEG 4000 and urea compared with the corresponding physical mixtures and untreated drug. The analgesic effects of untreated ND and the selected formulations were investigated by evaluating the drug's ability to inhibit the acetic acid-induced writhing response. The analgesic effect of ND in a eutectic mixture with PEG 4000 and a monotectic mixture with urea was potentiated by 3.2 and 2.7-fold respectively compared with the untreated drug. © 2014 Royal Pharmaceutical Society.

Repurposing ebselen for treatment of multidrug-resistant staphylococcal infections.

PubMed

Thangamani, Shankar; Younis, Waleed; Seleem, Mohamed N

2015-06-26

Novel antimicrobials and new approaches to developing them are urgently needed. Repurposing already-approved drugs with well-characterized toxicology and pharmacology is a novel way to reduce the time, cost, and risk associated with antibiotic innovation. Ebselen, an organoselenium compound, is known to be clinically safe and has a well-known pharmacology profile. It has shown potent bactericidal activity against multidrug-resistant clinical isolates of staphylococcus aureus, including methicillin- and vancomycin-resistant S. aureus (MRSA and VRSA). We demonstrated that ebselen acts through inhibition of protein synthesis and subsequently inhibited toxin production in MRSA. Additionally, ebselen was remarkably active and significantly reduced established staphylococcal biofilms. The therapeutic efficacy of ebselen was evaluated in a mouse model of staphylococcal skin infections. Ebselen 1% and 2% significantly reduced the bacterial load and the levels of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and monocyte chemo attractant protein-1 (MCP-1) in MRSA USA300 skin lesions. Furthermore, it acts synergistically with traditional antimicrobials. This study provides evidence that ebselen has great potential for topical treatment of MRSA skin infections and lays the foundation for further analysis and development of ebselen as a potential treatment for multidrug-resistant staphylococcal infections.

Targeting gastrin-releasing peptide as a new approach to treat aggressive refractory neuroblastomas.

PubMed

Paul, Pritha; Gillory, Lauren A; Kang, JungHee; Qiao, Jingbo; Chung, Dai H

2011-03-01

The overall survival for neuroblastoma remains dismal, in part due to the emergence of resistance to chemotherapeutic drugs. We have demonstrated that gastrin-releasing peptide (GRP), a gut peptide secreted by neuroblastoma, acts as an autocrine growth factor. We hypothesized that knockdown of GRP will induce apoptosis in neuroblastoma cells and potentiate the cytotoxic effects of chemotherapeutic agents. The human neuroblastoma cell lines (JF, SK-N-SH) were transfected with small interfering (si) RNA targeted at GRP. Apoptosis was assessed by DNA fragmentation assay. Immunoblotting was used to confirm molecular markers of apoptosis, and flow cytometry was performed to determine cell cycle arrest after GRP knockdown. siGRP resulted in an increase in apoptosis in the absence of chemotherapeutic interventions. A combination of GRP silencing and chemotherapeutic drugs resulted in enhanced apoptosis when compared to either of the treatments alone. GRP silencing led to increased expression of proapoptotic proteins, p53 and p21. Silencing of GRP induces apoptosis in neuroblastoma cells; it acts synergistically with chemotherapeutic effects of etoposide and vincristine. GRP knockdown-mediated apoptosis appears to be associated with upregulation of p53 in neuroblastoma cells. Targeting GRP may be postulated as a potential novel agent for combinational treatment to treat aggressive neuroblastomas. Copyright © 2011 Mosby, Inc. All rights reserved.

Ethylene Responses in Rice Roots and Coleoptiles Are Differentially Regulated by a Carotenoid Isomerase-Mediated Abscisic Acid Pathway[OPEN

PubMed Central

Yin, Cui-Cui; Ma, Biao; Collinge, Derek Phillip; Pogson, Barry James; He, Si-Jie; Xiong, Qing; Duan, Kai-Xuan; Chen, Hui; Yang, Chao; Lu, Xiang; Wang, Yi-Qin; Zhang, Wan-Ke; Chu, Cheng-Cai; Sun, Xiao-Hong; Fang, Shuang; Chu, Jin-Fang; Lu, Tie-Gang; Chen, Shou-Yi; Zhang, Jin-Song

2015-01-01

Ethylene and abscisic acid (ABA) act synergistically or antagonistically to regulate plant growth and development. ABA is derived from the carotenoid biosynthesis pathway. Here, we analyzed the interplay among ethylene, carotenoid biogenesis, and ABA in rice (Oryza sativa) using the rice ethylene response mutant mhz5, which displays a reduced ethylene response in roots but an enhanced ethylene response in coleoptiles. We found that MHZ5 encodes a carotenoid isomerase and that the mutation in mhz5 blocks carotenoid biosynthesis, reduces ABA accumulation, and promotes ethylene production in etiolated seedlings. ABA can largely rescue the ethylene response of the mhz5 mutant. Ethylene induces MHZ5 expression, the production of neoxanthin, an ABA biosynthesis precursor, and ABA accumulation in roots. MHZ5 overexpression results in enhanced ethylene sensitivity in roots and reduced ethylene sensitivity in coleoptiles. Mutation or overexpression of MHZ5 also alters the expression of ethylene-responsive genes. Genetic studies revealed that the MHZ5-mediated ABA pathway acts downstream of ethylene signaling to inhibit root growth. The MHZ5-mediated ABA pathway likely acts upstream but negatively regulates ethylene signaling to control coleoptile growth. Our study reveals novel interactions among ethylene, carotenogenesis, and ABA and provides insight into improvements in agronomic traits and adaptive growth through the manipulation of these pathways in rice. PMID:25841037

Systems Pharmacology Dissection of Multi-Scale Mechanisms of Action for Herbal Medicines in Stroke Treatment and Prevention

PubMed Central

Zhang, Jingxiao; Li, Yan; Chen, Xuetong; Pan, Yanqiu; Zhang, Shuwei; Wang, Yonghua

2014-01-01

Annually, tens of millions of first-ever strokes occur in the world; however, currently there is lack of effective and widely applicable pharmacological treatments for stroke patients. Herbal medicines, characterized as multi-constituent, multi-target and multi-effect, have been acknowledged with conspicuous effects in treating stroke, and attract extensive interest of researchers although the mechanism of action is yet unclear. In this work, we introduce an innovative systems-pharmacology method that combines pharmacokinetic prescreening, target fishing and network analysis to decipher the mechanisms of action of 10 herbal medicines like Salvia miltiorrhizae, Ginkgo biloba and Ephedrae herba which are efficient in stroke treatment and prevention. Our systematic analysis results display that, in these anti-stroke herbal medicines, 168 out of 1285 constituents with the favorable pharmacokinetic profiles might be implicated in stroke therapy, and the systematic use of these compounds probably acts through multiple mechanisms to synergistically benefit patients with stroke, which can roughly be classified as preventing ischemic inflammatory response, scavenging free radicals and inhibiting neuronal apoptosis against ischemic cerebral damage, as well as exhibiting lipid-lowering, anti-diabetic, anti-thrombotic and antiplatelet effects to decrease recurrent strokes. Relying on systems biology-based analysis, we speculate that herbal medicines, being characterized as the classical combination therapies, might be not only engaged in multiple mechanisms of action to synergistically improve the stroke outcomes, but also might be participated in reducing the risk factors for recurrent strokes. PMID:25093322

Internal amino acid state modulates yeast taste neurons to support protein homeostasis in Drosophila

PubMed Central

Itskov, Pavel M; Baltazar, Célia; Moreira, José-Maria

2018-01-01

To optimize fitness, animals must dynamically match food choices to their current needs. For drosophilids, yeast fulfills most dietary protein and micronutrient requirements. While several yeast metabolites activate known gustatory receptor neurons (GRNs) in Drosophila melanogaster, the chemosensory channels mediating yeast feeding remain unknown. Here we identify a class of proboscis GRNs required for yeast intake. Within this class, taste peg GRNs are specifically required to sustain yeast feeding. Sensillar GRNs, however, mediate feeding initiation. Furthermore, the response of yeast GRNs, but not sweet GRNs, is enhanced following deprivation from amino acids, providing a potential basis for protein-specific appetite. Although nutritional and reproductive states synergistically increase yeast appetite, reproductive state acts independently of nutritional state, modulating processing downstream of GRNs. Together, these results suggest that different internal states act at distinct levels of a dedicated gustatory circuit to elicit nutrient-specific appetites towards a complex, ecologically relevant protein source. PMID:29393045

OMP Peptides Activate the DegS Stress-Sensor Protease by a Relief of Inhibition Mechanism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sohn, Jungsan; Grant, Robert A.; Sauer, Robert T.

2010-03-19

In the E. coli periplasm, C-terminal peptides of misfolded outer-membrane porins (OMPs) bind to the PDZ domains of the trimeric DegS protease, triggering cleavage of a transmembrane regulator and transcriptional activation of stress genes. We show that an active-site DegS mutation partially bypasses the requirement for peptide activation and acts synergistically with mutations that disrupt contacts between the protease and PDZ domains. Biochemical results support an allosteric model, in which these mutations, active-site modification, and peptide/substrate binding act in concert to stabilize proteolytically active DegS. Cocrystal structures of DegS in complex with different OMP peptides reveal activation of the proteasemore » domain with varied conformations of the PDZ domain and without specific contacts from the bound OMP peptide. Taken together, these results indicate that the binding of OMP peptides activates proteolysis principally by relieving inhibitory contacts between the PDZ domain and the protease domain of DegS.« less

Functional cooperativity between two TPA responsive elements in undifferentiated F9 embryonic stem cells.

PubMed Central

Okuda, A; Imagawa, M; Sakai, M; Muramatsu, M

1990-01-01

We have recently identified an enhancer, termed GPEI, in the 5'-flanking region of the rat glutathione transferase P gene, that is composed of two imperfect TPA (phorbol 12-O-tetradecanoate 13-acetate) responsive elements (TREs). Unlike other TRE-containing enhancers, GPEI exhibits a strong transcriptional enhancing activity in F9 embryonic stem cells. Mutational analyses have revealed that the high activity of GPEI is mediated by two imperfect TREs. Each TRE-like sequence has no activity by itself but acts synergistically to form a strong enhancer which is active even in the very low level of AP-1 activity in F9 cells. Furthermore, we show that synthetic DNAs containing two perfect TREs in certain arrangements have strong transcriptional enhancing activities in F9 cells and the activity is greatly influenced by the relative orientation and the distance of two TREs. Images Fig. 1. Fig. 2. Fig. 3. PMID:2323334

Microwave-assisted activated carbon from cocoa shell as adsorbent for removal of sodium diclofenac and nimesulide from aqueous effluents.

PubMed

Saucier, Caroline; Adebayo, Matthew A; Lima, Eder C; Cataluña, Renato; Thue, Pascal S; Prola, Lizie D T; Puchana-Rosero, M J; Machado, Fernando M; Pavan, Flavio A; Dotto, G L

2015-05-30

Microwave-induced chemical activation process was used to prepare an activated carbon from cocoa shell for efficient removal of two anti-inflammatories, sodium diclofenac (DFC) and nimesulide (NM), from aqueous solutions. A paste was obtained from a mixture of cocoa shell and inorganic components; with a ratio of inorganic: organic of 1 (CSC-1.0). The mixture was pyrolyzed in a microwave oven in less than 10 min. The CSC-1.0 was acidified with a 6 mol L(-1) HCl under reflux to produce MWCS-1.0. The CSC-1.0 and MWCS-1.0 were characterized using FTIR, SEM, N2 adsorption/desorption curves, X-ray diffraction, and point of zero charge (pHpzc). Experimental variables such as initial pH of the adsorbate solutions and contact time were optimized for adsorptive characteristics of MWCS-1.0. The optimum pH for removal of anti-inflammatories ranged between 7.0 and 8.0. The kinetic of adsorption was investigated using general order, pseudo first-order and pseu do-second order kinetic models. The maximum amounts of DCF and NM adsorbed onto MWCS-1.0 at 25 °C are 63.47 and 74.81 mg g(-1), respectively. The adsorbent was tested on two simulated hospital effluents. MWCS-1.0 is capable of efficient removal of DCF and NM from a medium that contains high sugar and salt concentrations. Copyright © 2015 Elsevier B.V. All rights reserved.

Characterisation of nimesulide-betacyclodextrins systems prepared by supercritical fluid impregnation.

PubMed

Moneghini, M; Kikic, I; Perissutti, B; Franceschinis, E; Cortesi, A

2004-11-01

The purpose of this study was to apply the supercritical CO(2) impregnation process for preparing solvent-free nimesulide (NMS)-betacyclodextrins (BCD) association systems with enhanced drug dissolution rate. Several drug-to-carrier molar ratios were tested (1:1; 1:2.5; 1:3.5) at different conditions of temperatures (40, 100, and 130 degrees C) and pressures (140, 190 or 220 bar). The physical and morphological characterisation of the systems using powder X-ray diffraction, thermal analysis, diffuse reflectance Fourier transform-infrared spectroscopy and scanning electron microscopy was carried out to understand the influence of this technological process on the physical status of single components and binary systems and to detect possible interactions between drug and carrier. These analyses provided no evidence of a complete inclusion of NMS in the carrier but the existence of interactions between drug and carrier together with a partial dehydration of the BCD and the formation of drug crystallites with lower melting point and heat of fusion than the native NMS. These phenomena were more intense when severe conditions of pressure and temperature (220 bar and 130 degrees C) were used during impregnation trials and when the amount of BCD augmented in the systems. These activated solid state of the impregnated systems promoted an enhancement of drug dissolution rate that, in keeping with the results of the physical characterisation, was function of the process conditions and BCD content.

Synergistic interactions of lipids and myelin basic protein

NASA Astrophysics Data System (ADS)

Hu, Yufang; Doudevski, Ivo; Wood, Denise; Moscarello, Mario; Husted, Cynthia; Genain, Claude; Zasadzinski, Joseph A.; Israelachvili, Jacob

2004-09-01

This report describes force measurements and atomic force microscope imaging of lipid-protein interactions that determine the structure of a model membrane system that closely mimics the myelin sheath. Our results suggest that noncovalent, mainly electrostatic and hydrophobic, interactions are responsible for the multilamellar structure and stability of myelin. We find that myelin basic protein acts as a lipid coupler between two apposed bilayers and as a lipid "hole-filler," effectively preventing defect holes from developing. From our protein-mediated-adhesion and force-distance measurements, we develop a simple quantitative model that gives a reasonably accurate picture of the molecular mechanism and adhesion of bilayer-bridging proteins by means of noncovalent interactions. The results and model indicate that optimum myelin adhesion and stability depend on the difference between, rather than the product of, the opposite charges on the lipid bilayers and myelin basic protein, as well as on the repulsive forces associated with membrane fluidity, and that small changes in any of these parameters away from the synergistically optimum values can lead to large changes in the adhesion or even its total elimination. Our results also show that the often-asked question of which membrane species, the lipids or the proteins, are the "important ones" may be misplaced. Both components work synergistically to provide the adhesion and overall structure. A better appreciation of the mechanism of this synergy may allow for a better understanding of stacked and especially myelin membrane structures and may lead to better treatments for demyelinating diseases such as multiple sclerosis. lipid-protein interactions | myelin membrane structure | membrane adhesion | membrane regeneration/healing | demyelinating diseases

A manganese photosensitive tricarbonyl molecule [Mn(CO)3(tpa-κ3N)]Br enhances antibiotic efficacy in a multi-drug-resistant Escherichia coli.

PubMed

Rana, Namrata; Jesse, Helen E; Tinajero-Trejo, Mariana; Butler, Jonathan A; Tarlit, John D; von Und Zur Muhlen, Milena L; Nagel, Christoph; Schatzschneider, Ulrich; Poole, Robert K

2017-10-01

Carbon monoxide-releasing molecules (CORMs) are a promising class of new antimicrobials, with multiple modes of action that are distinct from those of standard antibiotics. The relentless increase in antimicrobial resistance, exacerbated by a lack of new antibiotics, necessitates a better understanding of how such novel agents act and might be used synergistically with established antibiotics. This work aimed to understand the mechanism(s) underlying synergy between a manganese-based photoactivated carbon monoxide-releasing molecule (PhotoCORM), [Mn(CO)3(tpa-κ 3 N)]Br [tpa=tris(2-pyridylmethyl)amine], and various classes of antibiotics in their activities towards Escherichia coli EC958, a multi-drug-resistant uropathogen. The title compound acts synergistically with polymyxins [polymyxin B and colistin (polymyxin E)] by damaging the bacterial cytoplasmic membrane. [Mn(CO)3(tpa-κ 3 N)]Br also potentiates the action of doxycycline, resulting in reduced expression of tetA, which encodes a tetracycline efflux pump. We show that, like tetracyclines, the breakdown products of [Mn(CO)3(tpa-κ 3 N)]Br activation chelate iron and trigger an iron starvation response, which we propose to be a further basis for the synergies observed. Conversely, media supplemented with excess iron abrogated the inhibition of growth by doxycycline and the title compound. In conclusion, multiple factors contribute to the ability of this PhotoCORM to increase the efficacy of antibiotics in the polymyxin and tetracycline families. We propose that light-activated carbon monoxide release is not the sole basis of the antimicrobial activities of [Mn(CO)3(tpa-κ 3 N)]Br.

Ocimum Sanctum seeds, a natural superdisintegrant: formulation and evaluation of fast melt tablets of nimesulide.

PubMed

Malik, Karan; Arora, Gurpreet; Singh, Inderbir

2012-01-01

Fast melt tablets, also known as fast dissolving tablets, disintegrate instantaneously within the mouth and thus can be consumed without water. The present study was aimed to formulate fast melt tablets of nimesulide by using Ocimum Sanctum seeds as a natural tablet superdisintegrant. Powdered Ocimum seeds were characterized for powder flow properties (bulk density, tapped density, Carr's consolidation index, Hausner ratio, angle of repose), swelling index, viscosity, pH, loss on drying and microbial load. The prepared tablets were evaluated for different tablet parametric tests, wetting time, water absorption ratio, effective pore radius, porosity, packing fraction, in vitro and in vivo disintegration time, in-vitro dissolution and stability studies. The swelling index was evaluated to be 1600. An appreciable effect of the natural material was seen on tablet hardness and friability. The water absorption ratio increased from 56.15 +/- 0.85 to 80.76 +/- 0.70 (A1-A4). Water uptake coupled natural polymer swelling could be the most probable mechanism for concentration dependent reduction in disintegration time by the Ocimum Sanctum seeds. Porosity of the formulated tablets was found to increase from batch A1-A4. The in vitro disintegration results were in line with in vivo disintegration results. The f2 values (in comparison with Nimulid MD) of 95.90 and 93.65 were obtained with A3 and A4 batches respectively. It could be concluded that Ocimum Sanctum seeds could be used as a natural superdisintegrant in the formulation of fast melt tablets.

Airway remodeling in murine asthma correlates with a defect in PGE2 synthesis by lung fibroblasts

PubMed Central

Stumm, Camila Leindecker; Wettlaufer, Scott H.; Jancar, Sonia

2011-01-01

Asthma is a chronic lung disease characterized by local inflammation that can result in structural alterations termed airway remodeling. One component of airway remodeling involves fibroblast accumulation and activation, resulting in deposition of collagen I around small bronchi. Prostaglandin E2 (PGE2) is the main eicosanoid lipid mediator produced by lung fibroblasts, and it exerts diverse anti-fibrotic actions. Dysregulation of the PGE2 synthesis/response axis has been identified in human pulmonary fibrotic diseases and implicated in the pathogenesis of animal models of lung parenchymal fibrosis. Here we investigated the relationship between the fibroblast PGE2 axis and airway fibrosis in an animal model of chronic allergic asthma. Airway fibrosis increased progressively as the number of airway challenges with antigen increased from 3 to 7 to 12. Compared with cells from control lungs, fibroblasts grown from the lungs of asthmatic animals, regardless of challenge number, exhibited no defect in the ability of PGE2 or its analogs to inhibit cellular proliferation and collagen I expression. This correlated with intact expression of the EP2 receptor, which is pivotal for PGE2 responsiveness. However, cytokine-induced upregulation of PGE2 biosynthesis as well as expression of cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 declined with increasing numbers of antigen challenges. In addition, treatment with the COX-2-selective inhibitor nimesulide potentiated the degree of airway fibrosis following repeated allergen challenge. Because endogenous COX-2-derived PGE2 acts as a brake on airway fibrosis, the inability of fibroblasts to upregulate PGE2 generation in the inflammatory milieu presented by repeated allergen exposure could contribute to the airway remodeling and fibrosis observed in chronic asthma. PMID:21873451

Tetrahydrobiopterin, l-Arginine and Vitamin C Act Synergistically to Decrease Oxidant Stress and Increase Nitric Oxide That Increases Blood Flow Recovery after Hindlimb Ischemia in the Rat

PubMed Central

Yan, Jinglian; Tie, Guodong; Messina, Louis M

2012-01-01

Nitric oxide (NO) derived from endothelial nitric oxide synthase (eNOS) is a potent vasodilator and signaling molecule that plays essential roles in neovascularization. During limb ischemia, decreased NO bioavailability occurs secondary to increased oxidant stress, decreased l-arginine and tetrahydrobiopterin. This study tested the hypothesis that dietary cosupplementation with tetrahydrobiopterin (BH4), l-arginine and vitamin C acts synergistically to decrease oxidant stress, increase NO and thereby increase blood flow recovery after hindlimb ischemia. Rats were fed normal chow, chow supplemented with BH4 or l-arginine (alone or in combination) or chow supplemented with BH4 + l-arginine + vitamin C for 1 wk before induction of hindlimb ischemia. In the is-chemic hindlimb, cosupplementation with BH4 + l-arginine resulted in greater eNOS and phospho-eNOS (P-eNOS) expression, Ca2+-dependent NOS activity and NO concentration in the ischemic calf region (gastrocnemius), as well as greater NO concentration in the region of collateral arteries (gracilis). Rats receiving cosupplementation of BH4 + l-arginine led to greater recovery of foot perfusion and greater collateral enlargement than did rats receiving either agent separately. The addition of vitamin C to the BH4 + l-arginine regimen further increased these dependent variables. In addition, rats given all three supplements showed significantly less Ca2+-independent activity, less nitrotyrosine accumulation, greater glutathione (GSH)–to–glutathione disulfide (GSSG) ratio and less gastrocnemius muscle necrosis, on both macroscopic and microscopic levels. In conclusion, co-supplementation with BH4 + l-arginine + vitamin C significantly increased blood flow recovery after hindlimb ischemia by reducing oxidant stress, increasing NO bioavailability, enlarging collateral arteries and reducing muscle necrosis. Oral cosupplementation of BH4, l-arginine and vitamin C holds promise as a biological therapy to induce collateral artery enlargement. PMID:23212846

Drosophila Nanos acts as a molecular clamp that modulates the RNA-binding and repression activities of Pumilio

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weidmann, Chase A.; Qiu, Chen; Arvola, René M.

Collaboration among the multitude of RNA-binding proteins (RBPs) is ubiquitous, yet our understanding of these key regulatory complexes has been limited to single RBPs. We investigated combinatorial translational regulation by Drosophila Pumilio (Pum) and Nanos (Nos), which control development, fertility, and neuronal functions. Our results show how the specificity of one RBP (Pum) is modulated by cooperative RNA recognition with a second RBP (Nos) to synergistically repress mRNAs. Crystal structures of Nos-Pum-RNA complexes reveal that Nos embraces Pum and RNA, contributes sequence-specific contacts, and increases Pum RNA-binding affinity. Nos shifts the recognition sequence and promotes repression complex formation on mRNAsmore » that are not stably bound by Pum alone, explaining the preponderance of sub-optimal Pum sites regulated in vivo. Our results illuminate the molecular mechanism of a regulatory switch controlling crucial gene expression programs, and provide a framework for understanding how the partnering of RBPs evokes changes in binding specificity that underlie regulatory network dynamics.« less

Drosophila Nanos acts as a molecular clamp that modulates the RNA-binding and repression activities of Pumilio.

PubMed

Weidmann, Chase A; Qiu, Chen; Arvola, René M; Lou, Tzu-Fang; Killingsworth, Jordan; Campbell, Zachary T; Tanaka Hall, Traci M; Goldstrohm, Aaron C

2016-08-02

Collaboration among the multitude of RNA-binding proteins (RBPs) is ubiquitous, yet our understanding of these key regulatory complexes has been limited to single RBPs. We investigated combinatorial translational regulation by Drosophila Pumilio (Pum) and Nanos (Nos), which control development, fertility, and neuronal functions. Our results show how the specificity of one RBP (Pum) is modulated by cooperative RNA recognition with a second RBP (Nos) to synergistically repress mRNAs. Crystal structures of Nos-Pum-RNA complexes reveal that Nos embraces Pum and RNA, contributes sequence-specific contacts, and increases Pum RNA-binding affinity. Nos shifts the recognition sequence and promotes repression complex formation on mRNAs that are not stably bound by Pum alone, explaining the preponderance of sub-optimal Pum sites regulated in vivo. Our results illuminate the molecular mechanism of a regulatory switch controlling crucial gene expression programs, and provide a framework for understanding how the partnering of RBPs evokes changes in binding specificity that underlie regulatory network dynamics.

Inhibition of Wnt/beta-catenin signaling downregulates expression of aldehyde dehydrogenase isoform 3A1 (ALDH3A1) to reduce resistance against temozolomide in glioblastoma in vitro.

PubMed

Suwala, Abigail Kora; Koch, Katharina; Rios, Dayana Herrera; Aretz, Philippe; Uhlmann, Constanze; Ogorek, Isabella; Felsberg, Jörg; Reifenberger, Guido; Köhrer, Karl; Deenen, René; Steiger, Hans-Jakob; Kahlert, Ulf D; Maciaczyk, Jaroslaw

2018-04-27

Glioblastoma is the most aggressive type of glioma. The Wingless (Wnt) signaling pathway has been shown to promote stem cell properties and resistance to radio- and chemotherapy in glioblastoma. Here, we demonstrate that pharmacological Wnt pathway inhibition using the porcupine inhibitor LGK974 acts synergistically with temozolomide (TMZ), the chemotherapeutic drug currently used as standard treatment for glioblastoma, to suppress in vitro growth of glioma cells. Synergistic growth inhibition was independent of the O 6 -alkylguanine DNA alkyltransferase ( MGMT ) promoter methylation status. Transcriptomic analysis revealed that expression of aldehyde dehydrogenase 3A1 ( ALDH3A1 ) was significantly down-regulated when cells were treated with LGK974 and TMZ. Suppressing ALDH3A1 expression increased the efficacy of TMZ and reduced clonogenic potential accompanied by decreased expression of stem cell markers CD133, Nestin and Sox2. Taken together, our study suggests that previous observations concerning Wnt signaling blockade to reduce chemoresistance in glioblastoma is at least in part mediated by inhibition of ALDH3A1.

[Folates and fetal programming: role of epigenetics and epigenomics].

PubMed

Guéant, Jean-Louis; Daval, Jean-Luc; Vert, Paul; Nicolas, Jean-Pierre

2012-12-01

Folates are needed for synthesis of methionine, the precursor of S-adenosyl methionine (SAM). They play therefore a key role in nutrition and epigenomics by fluxing monocarbons towards synthesis or methylation of DNA and RNA, and methylation of gene transregulators, respectively. The deficiency produces intrauterine growth retardation and birth dejects. Folate deficiency deregulates epigenomic mechanisms related to fetal programming through decreased cellular availability of SAM. Epigenetic mechanisms of folate deficiency are illustrated by inheritance of coat colour of agouti mice model and altered expression of Igf2/H19 imprinting genes. Dietary exposure to fumonisin FB1 acts synergistically with folate deficiency on alterations of heterochromatin assembly. Deficiency in folate and vitamin B12 produces impaired fatty acid oxidation in liver and heart through imbalanced methylation and acetylation of PGC1-alpha and decreased expression of SIRT1, and long-lasting cognitive disabilities through impaired hippocampal cell proliferation, differentiation and plasticity and atrophy of hippocampal CA1. Deciphering these mechanisms will help understand the discordances between experimental models and population studies on folate supplementation.

Alterations of antioxidant status in asymptomatic hypercholesterolemic individuals after resveratrol intake.

PubMed

Apostolidou, C; Adamopoulos, K; Iliadis, S; Kourtidou-Papadeli, C

2015-08-01

High cholesterol is one of the risk factors for atherogenesis, leading to oxidative stress and cardiovascular disease (CVD). The focus of this study was to evaluate the role and the pathways of action of a natural antioxidant, resveratrol, in asymptomatic hypercholesterolemic (AHC) individuals. Forty healthy AHCs and normocholesterolemics (NCs) participated in the study. They received random-order resveratrol and placebo capsules for four weeks. Total antioxidant capacity (TAC), vitamin E and total cholesterol (TC) were measured at baseline and at the end of each intervention. Resveratrol provided a direct antioxidant effect in healthy NC individuals, but in AHC individuals, with a higher demand for antioxidant activity due to higher cholesterol levels, it acted by facilitating an increase in vitamin E. Our findings suggest that resveratrol acts synergistically with other antioxidants against oxidative stress and highlights the importance of hypercholesterolemic individuals consuming natural antioxidants instead of medications to reduce the risk of CVD, while the situation is still reversible.

Modulation of the multidrug efflux pump EmrD-3 from Vibrio cholerae by Allium sativum extract and the bioactive agent allyl sulfide plus synergistic enhancement of antimicrobial susceptibility by A. sativum extract.

PubMed

Bruns, Merissa M; Kakarla, Prathusha; Floyd, Jared T; Mukherjee, Mun Mun; Ponce, Robert C; Garcia, John A; Ranaweera, Indrika; Sanford, Leslie M; Hernandez, Alberto J; Willmon, T Mark; Tolson, Grace L; Varela, Manuel F

2017-10-01

The causative agent of cholera, Vibrio cholerae, is a public health concern. Multidrug-resistant V. cholerae variants may reduce chemotherapeutic efficacies of severe cholera. We previously reported that the multidrug efflux pump EmrD-3 from V. cholerae confers resistance to multiple structurally distinct antimicrobials. Medicinal plant compounds are potential candidates for EmrD-3 efflux pump modulation. The antibacterial activities of garlic Allium sativum, although poorly understood, predicts that a main bioactive component, allyl sulfide, modulates EmrD-3 efflux. Thus, we tested whether A. sativum extract acts in synergy with antimicrobials and that a main bioactive component allyl sulfide inhibits EmrD-3 efflux. We found that A. sativum extract and allyl sulfide inhibited ethidium bromide efflux in cells harboring EmrD-3 and that A. sativum lowered the MICs of multiple antibacterials. We conclude that A. sativum and allyl sulfide inhibit EmrD-3 and that A. sativum extract synergistically enhances antibacterial agents.

Complementary activities of TPX2 and chTOG constitute an efficient importin-regulated microtubule nucleation module

PubMed Central

Roostalu, Johanna; Cade, Nicholas I.; Surrey, Thomas

2016-01-01

Spindle assembly and function require precise control of microtubule nucleation and dynamics. The chromatin-driven spindle assembly pathway exerts such control locally in the vicinity of chromosomes. One of the key targets of this pathway is TPX2. The molecular mechanism of how TPX2 stimulates microtubule nucleation is not understood. Using microscopy-based dynamic in vitro reconstitution assays with purified proteins, we find that human TPX2 directly stabilises growing microtubule ends and stimulates microtubule nucleation by stabilising early microtubule nucleation intermediates. Human microtubule polymerase chTOG (XMAP215/Msps/Stu2p/Dis1/Alp14 homolog) only weakly promotes nucleation, but acts synergistically with TPX2. Hence, a combination of distinct and complementary activities is sufficient for efficient microtubule formation in vitro. Importins control the efficiency of the microtubule nucleation by selectively blocking TPX2’s interaction with microtubule nucleation intermediates. This in vitro reconstitution reveals the molecular mechanism of regulated microtubule formation by a minimal nucleation module essential for chromatin-dependent microtubule nucleation in cells. PMID:26414402

Locomotion defects, together with Pins, regulates heterotrimeric G-protein signaling during Drosophila neuroblast asymmetric divisions

PubMed Central

Yu, Fengwei; Wang, Hongyan; Qian, Hongliang; Kaushik, Rachna; Bownes, Mary; Yang, Xiaohang; Chia, William

2005-01-01

Heterotrimeric G proteins mediate asymmetric division of Drosophila neuroblasts. Free Gβγ appears to be crucial for the generation of an asymmetric mitotic spindle and consequently daughter cells of distinct size. However, how Gβγ is released from the inactive heterotrimer remains unclear. Here we show that Locomotion defects (Loco) interacts and colocalizes with Gαi and, through its GoLoco motif, acts as a guanine nucleotide dissociation inhibitor (GDI) for Gαi. Simultaneous removal of the two GoLoco motif proteins, Loco and Pins, results in defects that are essentially indistinguishable from those observed in Gβ13F or Gγ1 mutants, suggesting that Loco and Pins act synergistically to release free Gβγ in neuroblasts. Furthermore, the RGS domain of Loco can also accelerate the GTPase activity of Gαi to regulate the equilibrium between the GDP- and the GTP-bound forms of Gαi. Thus, Loco can potentially regulate heterotrimeric G-protein signaling via two distinct modes of action during Drosophila neuroblast asymmetric divisions. PMID:15937221

Albumin, in the Presence of Calcium, Elicits a Massive Increase in Extracellular Bordetella Adenylate Cyclase Toxin

PubMed Central

Gonyar, Laura A.; Gray, Mary C.; Christianson, Gregory J.; Mehrad, Borna

2017-01-01

ABSTRACT Pertussis (whooping cough), caused by Bordetella pertussis, is resurging in the United States and worldwide. Adenylate cyclase toxin (ACT) is a critical factor in establishing infection with B. pertussis and acts by specifically inhibiting the response of myeloid leukocytes to the pathogen. We report here that serum components, as discovered during growth in fetal bovine serum (FBS), elicit a robust increase in the amount of ACT, and ≥90% of this ACT is localized to the supernatant, unlike growth without FBS, in which ≥90% is associated with the bacterium. We have found that albumin, in the presence of physiological concentrations of calcium, acts specifically to enhance the amount of ACT and its localization to the supernatant. Respiratory secretions, which contain albumin, promote an increase in amount and localization of active ACT that is comparable to that elicited by serum and albumin. The response to albumin is not mediated through regulation of ACT at the transcriptional level or activation of the Bvg two-component system. As further illustration of the specificity of this phenomenon, serum collected from mice that lack albumin does not stimulate an increase in ACT. These data, demonstrating that albumin and calcium act synergistically in the host environment to increase production and release of ACT, strongly suggest that this phenomenon reflects a novel host-pathogen interaction that is central to infection with B. pertussis and other Bordetella species. PMID:28396321

Consequences of Lethal-Whole-Body Gamma Radiation and Possible Ameliorative Role of Melatonin

PubMed Central

Mihandoost, Ehsan; Shirazi, Alireza; Mahdavi, Seied Rabie; Aliasgharzadeh, Akbar

2014-01-01

Gamma radiation induces the generation of free radicals, leading to serious cellular damages in biological systems. Radioprotectors act as prophylactic agents that are administered to shield normal cells and tissues from the deleterious effects of radiation. Melatonin synergistically acts as an immune-stimulator and antioxidant. We investigated the possible radioprotective role of melatonin (100 mg/kg i.p.) against lethal-whole-body radiation- (10 Gy) induced sickness, body weight loss, and mortality in rats. Results of the present study suggest that exposure to lethal-whole-body radiation incurred mortality, body weight loss, and apoptosis and it also depleted the immunity and the antioxidant status of the rats. Our results show that melatonin pretreatment provides protection against radiation induced mortality, oxidative stress, and immune-suppression. The melatonin pretreated irradiated rats showed less change in body weight as compared to radiation only group. On the other hand, melatonin appeared to have another radioprotective role, suggesting that melatonin may reduce apoptosis through a caspase-3-mediated pathway by blocking caspase-3 activity. PMID:25431791

Physical and functional interactions between Drosophila TRAF2 and Pelle kinase contribute to Dorsal activation.

PubMed

Shen, B; Liu, H; Skolnik, E Y; Manley, J L

2001-07-17

Signaling through the Toll receptor is required for dorsal/ventral polarity in Drosophila embryos, and also plays an evolutionarily conserved role in the immune response. Upon ligand binding, Toll appears to multimerize and activate the associated kinase, Pelle. However, the immediate downstream targets of Pelle have not been identified. Here we show that Drosophila tumor necrosis factor receptor-associated factor 2 (dTRAF2), a homologue of human TRAF6, physically and functionally interacts with Pelle, and is phosphorylated by Pelle in vitro. Importantly, dTRAF2 and Pelle cooperate to activate Dorsal synergistically in cotransfected Schneider cells. Deletion of the C-terminal TRAF domain of dTRAF2 enhances Dorsal activation, perhaps reflecting the much stronger interaction of the mutant protein with phosphorylated, active Pelle. Taken together, our results indicate that Pelle and dTRAF2 physically and functionally interact, and that the TRAF domain acts as a regulator of this interaction. dTRAF2 thus appears to be a downstream target of Pelle. We discuss these results in the context of Toll signaling in flies and mammals.

Drosophila Nanos acts as a molecular clamp that modulates the RNA-binding and repression activities of Pumilio

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weidmann, Chase A.; Qiu, Chen; Arvola, René M.

Collaboration among the multitude of RNA-binding proteins (RBPs) is ubiquitous, yet our understanding of these key regulatory complexes has been limited to single RBPs. We investigated combinatorial translational regulation byDrosophilaPumilio (Pum) and Nanos (Nos), which control development, fertility, and neuronal functions. Our results show how the specificity of one RBP (Pum) is modulated by cooperative RNA recognition with a second RBP (Nos) to synergistically repress mRNAs. Crystal structures of Nos-Pum-RNA complexes reveal that Nos embraces Pum and RNA, contributes sequence-specific contacts, and increases Pum RNA-binding affinity. Nos shifts the recognition sequence and promotes repression complex formation on mRNAs that aremore » not stably bound by Pum alone, explaining the preponderance of sub-optimal Pum sites regulatedin vivo. Our results illuminate the molecular mechanism of a regulatory switch controlling crucial gene expression programs, and provide a framework for understanding how the partnering of RBPs evokes changes in binding specificity that underlie regulatory network dynamics.« less

Planarian yorkie/YAP functions to integrate adult stem cell proliferation, organ homeostasis and maintenance of axial patterning.

PubMed

Lin, Alexander Y T; Pearson, Bret J

2014-03-01

During adult homeostasis and regeneration, the freshwater planarian must accomplish a constant balance between cell proliferation and cell death, while also maintaining proper tissue and organ size and patterning. How these ordered processes are precisely modulated remains relatively unknown. Here we show that planarians use the downstream effector of the Hippo signaling cascade, yorkie (yki; YAP in vertebrates) to control a diverse set of pleiotropic processes in organ homeostasis, stem cell regulation, regeneration and axial patterning. We show that yki functions to maintain the homeostasis of the planarian excretory (protonephridial) system and to limit stem cell proliferation, but does not affect the differentiation process or cell death. Finally, we show that Yki acts synergistically with WNT/β-catenin signaling to repress head determination by limiting the expression domains of posterior WNT genes and that of the WNT-inhibitor notum. Together, our data show that yki is a key gene in planarians that integrates stem cell proliferation control, organ homeostasis, and the spatial patterning of tissues.

[Influence of conjugated linoleic acids on metabolic processes in cells and tissues].

PubMed

Siwiec, Ewa; Stachowska, Ewa

2017-01-01

Conjugated linoleic acids (CLA) are constitutional and geometric isomers of this acid. The most commonly consumed geometric isomers are cis-9,trans-11 (c9, t11) CLA and trans-10, cis-12 (t10,c12) CLA. These isomers together with trans-9,trans-11 CLA and trans-10,trans-12 CLA constitute about 90% of all CLA in natural products. Different structure of the isomers affects their functions in the body. Differences in the effects on organs and tissues are sometimes small and sometimes opposed, sometimes the isomers work synergistically. Diverse influence has been shown mainly in neoplastic processes and lipid metabolism. For example, differences in inhibition of proliferation of prostate cancer cells are explained by different pathways: t10,c12 CLA acts on apoptosis and cell cycle control genes, while c9,t11 CLA regulates genes involved in metabolism of arachidonic acid with subsequent impairment of eicosanoids synthesis. Other studies have shown that t10,c12 CLA, but not c9,t11 CLA, can induce fat reduction in adipose tissue and apoptosis of adipocytes in mice.

Anticancer potential and mechanism of action of mango ginger (Curcuma amada Roxb.) supercritical CO₂ extract in human glioblastoma cells.

PubMed

Ramachandran, Cheppail; Lollett, Ivonne V; Escalon, Enrique; Quirin, Karl-Werner; Melnick, Steven J

2015-04-01

Mango ginger (Curcuma amada Roxb.) is among the less-investigated species of Curcuma for anticancer properties. We have investigated the anticancer potential and the mechanism of action of a supercritical CO2 extract of mango ginger (CA) in the U-87MG human glioblastoma cell line. CA demonstrated higher cytotoxicity than temozolomide, etoposide, curcumin, and turmeric force with IC50, IC75, and IC90 values of 4.92 μg/mL, 12.87 μg/mL, and 21.30 μg/mL, respectively. Inhibitory concentration values of CA for normal embryonic mouse hypothalamus cell line (mHypoE-N1) is significantly higher than glioblastoma cell line, indicating the specificity of CA against brain tumor cells. CompuSyn analysis indicates that CA acts synergistically with temozolomide and etoposide for the cytotoxicity with combination index values of <1. CA treatment also induces apoptosis in glioblastoma cells in a dose-dependent manner and downregulates genes associated with apoptosis, cell proliferation, telomerase activity, oncogenesis, and drug resistance in glioblastoma cells. © The Author(s) 2014.

Complementary activities of TPX2 and chTOG constitute an efficient importin-regulated microtubule nucleation module.

PubMed

Roostalu, Johanna; Cade, Nicholas I; Surrey, Thomas

2015-11-01

Spindle assembly and function require precise control of microtubule nucleation and dynamics. The chromatin-driven spindle assembly pathway exerts such control locally in the vicinity of chromosomes. One of the key targets of this pathway is TPX2. The molecular mechanism of how TPX2 stimulates microtubule nucleation is not understood. Using microscopy-based dynamic in vitro reconstitution assays with purified proteins, we find that human TPX2 directly stabilizes growing microtubule ends and stimulates microtubule nucleation by stabilizing early microtubule nucleation intermediates. Human microtubule polymerase chTOG (XMAP215/Msps/Stu2p/Dis1/Alp14 homologue) only weakly promotes nucleation, but acts synergistically with TPX2. Hence, a combination of distinct and complementary activities is sufficient for efficient microtubule formation in vitro. Importins control the efficiency of the microtubule nucleation by selectively blocking the interaction of TPX2 with microtubule nucleation intermediates. This in vitro reconstitution reveals the molecular mechanism of regulated microtubule formation by a minimal nucleation module essential for chromatin-dependent microtubule nucleation in cells.

The anesthetic action of ethanol analyzed by genetics in Caenorhabditis elegans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Mingi; Choi, Myung Kyu; Lee, Junho

2008-02-29

Acute exposure to ethanol causes paralysis at high concentrations in the nematode Caenorhabditis elegans. We set out to elucidate the mechanism of the anesthetic action of ethanol by genetic approaches. We identified nine mutations that conferred reduced sensitivity to ethanol after chemical, irradiation, or transposon insertion mutagenesis. Of these nine, we further characterized five mutations that defined four genes, jud-1-jud-4. Analysis of the phenotypes of the animals heterozygous for two unlinked genes revealed that jud-1 and jud-3 act synergistically in a gene dose-dependent manner. We cloned jud-4 and found that it encodes a protein with limited homology to human Homermore » proteins. jud-4 was expressed in the hypodermis and vulva muscles, suggesting that this gene acts in tissues directly exposed to the external environment. Characterization of the other mutations identified in this study will facilitate the elucidation of the molecular mechanism for the anesthetic action of ethanol.« less

Resveratrol sensitization of DU145 prostate cancer cells to ionizing radiation is associated to ceramide increase.

PubMed

Scarlatti, Francesca; Sala, Giusy; Ricci, Clara; Maioli, Claudio; Milani, Franco; Minella, Marco; Botturi, Marco; Ghidoni, Riccardo

2007-08-08

Radiotherapy is an established therapeutic modality for prostate cancer. Since it is well known that radiotherapy is limited due to its severe toxicity towards normal cells at high dose and minimal effect at low dose, the search for biological compounds that increase the sensitivity of tumors cells to radiation may improve the efficacy of therapy. Resveratrol, a natural antioxidant, was shown to inhibit carcinogenesis in animal models, and to block the process of tumor initiation and progression. The purpose of this study was to examine whether or not resveratrol can sensitize DU145, an androgen-independent human prostate cancer cell line, to ionizing radiation. We report here that DU145 cells are resistant to ionizing radiation-induced cell death, but pretreatment with resveratrol significantly enhances cell death. Resveratrol acts synergistically with ionizing radiation to inhibit cell survival in vitro. Resveratrol also potentiates ionizing radiation-induced ceramide accumulation, by promoting its de novo biosynthesis. This confirms ceramide as an effective mediator of the anticancer potential induced by resveratrol.

Drosophila Nanos acts as a molecular clamp that modulates the RNA-binding and repression activities of Pumilio

DOE PAGES

Weidmann, Chase A.; Qiu, Chen; Arvola, René M.; ...

2016-08-02

Collaboration among the multitude of RNA-binding proteins (RBPs) is ubiquitous, yet our understanding of these key regulatory complexes has been limited to single RBPs. We investigated combinatorial translational regulation by Drosophila Pumilio (Pum) and Nanos (Nos), which control development, fertility, and neuronal functions. Our results show how the specificity of one RBP (Pum) is modulated by cooperative RNA recognition with a second RBP (Nos) to synergistically repress mRNAs. Crystal structures of Nos-Pum-RNA complexes reveal that Nos embraces Pum and RNA, contributes sequence-specific contacts, and increases Pum RNA-binding affinity. Nos shifts the recognition sequence and promotes repression complex formation on mRNAsmore » that are not stably bound by Pum alone, explaining the preponderance of sub-optimal Pum sites regulated in vivo. Our results illuminate the molecular mechanism of a regulatory switch controlling crucial gene expression programs, and provide a framework for understanding how the partnering of RBPs evokes changes in binding specificity that underlie regulatory network dynamics.« less

Anti-Trichomonas vaginalis activity of ursolic acid derivative: a promising alternative.

PubMed

Bitencourt, Fernanda Gobbi; de Brum Vieira, Patrícia; Meirelles, Lucia Collares; Rigo, Graziela Vargas; da Silva, Elenilson Figueiredo; Gnoatto, Simone Cristina Baggio; Tasca, Tiana

2018-05-01

Trichomonas vaginalis is an extracellular parasite that binds to the epithelium of the human urogenital tract and causes the sexually transmitted infection, trichomoniasis. In view of increased resistance to drugs belonging to the 5-nitroimidazole class, new treatment alternatives are urgently needed. In this study, eight semisynthetized triterpene derivatives were evaluated for in vitro anti-T. vaginalis activity. Ursolic acid and its derivative, 3-oxime-urs-12-en-28-oic-ursolic acid (9), presented the best anti-T. vaginalis activity when compared to other derivatives, with minimum inhibitory concentration (MIC) at 25 μM. Moreover, 9 was active against several T. vaginalis fresh clinical isolates. Hemolysis assay demonstrated that 9 presented a low hemolytic effect. Importantly, 25 μM 9 was not cytotoxic against the Vero cell lineage. Finally, we demonstrated that compound 9 acts synergistically with metronidazole against a T. vaginalis metronidazole-resistant isolate. This report reveals the high potential of the triterpenoid derivative 9 as trichomonicidal agent.

Effectiveness of an educational feedback intervention on drug prescribing in dental practice.

PubMed

Rauniar, G P; Das, B P; Manandhar, T R; Bhattacharya, S K

2012-01-01

Irrational use of drugs as well as inappropriate and over drug prescribing leads to unnecessary expenditures and emergence of resistant bacterial strains. Feedback intervention on drug prescribing habits and face to face educational intervention of prescription audit would be effective in rationalizing prescribing practices. To measure the impact of educational feedback intervention on the prescribing behavior of dental surgeons. Prospective audit of twelve hundred outpatients prescriptions in dental OPD at BPKIHS of those dental surgeon who attended the educational intervention session was collected randomly by trained persons on customized data collection sheet before and after educational intervention. A total 1200 prescription were collected, 300 before and 300 after intervention period at the internal of one month, three months and six months. Majority of the prescriptions (39.33%) contained four drugs but after intervention, prescriptions contained mostly one drug, 73% in first month, 78.67% in third month and 65.34% in six month. Mean number of drugs per prescription after intervention were decreased. There was increased number of generic names of drugs after intervention. Amoxicillin, Metronidazole, Chlorhexidine, Povidone iodine gargle, Nimesulide, Ibuprofen, Ibuprofen + paracetamol, and Paracetamol were most commonly prescribed by dental prescribers before and after intervention. Selection of antimicrobial was done on empirical basis which was correct because Amoxicillin concentration reaches effectively in gingival crevicular fluid and Metronidazole covered effectively against anaerobic bacteria were found in orodental infection. The uses of topical anti-infective preparation as irrigants of choice that can kill majority of micro-organisms found is root canal and dental tubules and minimize systemic use of antimicrobials. Nimesulide prescribing needs to be rationalized. Feedback educational intervention of prescription audit is effective to improve their prescribing behaviors and rationalize drug utilization pattern for the benefit of the patients.

Albumin, in the Presence of Calcium, Elicits a Massive Increase in Extracellular Bordetella Adenylate Cyclase Toxin.

PubMed

Gonyar, Laura A; Gray, Mary C; Christianson, Gregory J; Mehrad, Borna; Hewlett, Erik L

2017-06-01

Pertussis (whooping cough), caused by Bordetella pertussis , is resurging in the United States and worldwide. Adenylate cyclase toxin (ACT) is a critical factor in establishing infection with B. pertussis and acts by specifically inhibiting the response of myeloid leukocytes to the pathogen. We report here that serum components, as discovered during growth in fetal bovine serum (FBS), elicit a robust increase in the amount of ACT, and ≥90% of this ACT is localized to the supernatant, unlike growth without FBS, in which ≥90% is associated with the bacterium. We have found that albumin, in the presence of physiological concentrations of calcium, acts specifically to enhance the amount of ACT and its localization to the supernatant. Respiratory secretions, which contain albumin, promote an increase in amount and localization of active ACT that is comparable to that elicited by serum and albumin. The response to albumin is not mediated through regulation of ACT at the transcriptional level or activation of the Bvg two-component system. As further illustration of the specificity of this phenomenon, serum collected from mice that lack albumin does not stimulate an increase in ACT. These data, demonstrating that albumin and calcium act synergistically in the host environment to increase production and release of ACT, strongly suggest that this phenomenon reflects a novel host-pathogen interaction that is central to infection with B. pertussis and other Bordetella species. Copyright © 2017 American Society for Microbiology.

[STUDYING GASTRIC ULCERATION EFFECT OF A NEW DRUG INTENDED FOR TREATMENT OF CHRONIC INFLAMMATORY DISEASES OF KIDNEYS AND URINARY TRACT.

PubMed

Murashko, T O; Smirnov, I V; Ivanov, A A; Postnikov, P S; Nemtsev, A O; Bondarev, A A; Udut, V V; Prisukhin, A N; Kornaukhov, A N; Sergeev, T S

2016-08-01

Gastric ulceration properties (gastrointestinal toxicity) of the sodium salt of 4-(0-β-D-glucopyranosyloxy) benzoic acid, a new nonsteroidal anti-inflammatory drug (NSAID) intended for the treatment of chronic inflammatory diseases of the kidney and urinary tract, have been tested on laboratory animals. Acute NSAID-induced gastropathy was induced in rats by oral administration of indomethacin, nimesulide, diclofenac, acetylsalicylic acid and the new drug. Test animals were killed by instantaneous decapitation 4 h after treatment and their gastrointestinal tracts were studied by pathomorphological methods on micropreparations and histological sections of gastric mucosa. It was established that the new drug, in contrast to reference NSAIDS, did not exhibit gastropathic action on the gastric mucosa.

NSAIDs utilization for musculoskeletal indications in elderly patients with cerebro/cardiovascular disease.

PubMed

Roberto, Giuseppe; Bartolini, Claudia; Rea, Federico; Onder, Graziano; Vitale, Cristiana; Trifirò, Gianluca; Kirchmayer, Ursula; Chinellato, Alessandro; Lucenteforte, Ersilia; Corrao, Giovanni; Mugelli, Alessandro; Lapi, Francesco; Gini, Rosa

2018-05-01

To describe NSAID utilization for musculoskeletal conditions in a large cohort of Italian elderly with cerebro/cardiovascular disease, a population in which NSAIDs should be generally avoided due to the prothrombotic potential. Administrative data from five Italian geographic areas were analyzed. Patients aged ≥ 65 with a cerebro/cardiovascular event recorded between 2008 and 2011 (cohort entry) were selected. Prescription NSAIDs reimbursed for musculoskeletal conditions and dispensed during 1 year follow-up were retrieved to describe (i) prevalence of use, (ii) average amount of defined daily doses of NSAIDs claimed by users per day of follow-up, and (iii) distribution of the received daily dose (RDD) among patients with ≥ 2 dispensings. Among new users, i.e., patients without NSAID dispensings during 2 years before cohort entry, the first dispensed NSAID molecule was observed. Overall, 511,989 patients were selected. Across the five geographic areas, prevalence of use ranged from 48 to 21% and average consumption ranged between 30 and 67 DDD/1000 users/day. Around 10% of patients in the overall cohort had a RDD > 1. Nimesulide (9.6%) and diclofenac (7.5%) had the highest prevalence of use. The most consumed NSAIDs were nimesulide and coxibs with 10.6 and 7.5 DDD/1000 users/day, respectively. Among new users recruited in 2011, 30% had diclofenac or a coxibs as the first prescription. NSAID use was common in the study cohort, particularly in central-southern areas. In contrast with current recommendations, coxibs and diclofenac were among the most prescribed active principles, even in new users. Interventions to promote appropriateness of use are warranted.

Docosahexaenoic acid ester of phloridzin inhibit lipopolysaccharide-induced inflammation in THP-1 differentiated macrophages.

PubMed

Sekhon-Loodu, Satvir; Ziaullah; Rupasinghe, H P Vasantha

2015-03-01

Phloridzin or phlorizin (PZ) is a predominant phenolic compound found in apple and also used in various natural health products. Phloridzin shows poor absorption and cellular uptake due to its hydrophilic nature. The aim was to investigate and compare the effect of docosahexaenoic acid (DHA) ester of PZ (PZ-DHA) and its parent compounds (phloridzin and DHA), phloretin (the aglycone of PZ) and cyclooxygenase inhibitory drugs (diclofenac and nimesulide) on production of pro-inflammatory biomarkers in inflammation-induced macrophages by lipopolysaccharide (LPS)-stimulation. Human THP-1 monocytes were seeded in 24-well plates (5×10(5)/well) and treated with phorbol 12-myristate 13-acetate (PMA, 0.1μg/mL) for 48h to induce macrophage differentiation. After 48h, the differentiated macrophages were washed with Hank's buffer and treated with various concentrations of test compounds for 4h, followed by the LPS-stimulation (18h). Pre-exposure of PZ-DHA ester was more effective in reducing tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) protein levels compared to DHA and nimesulide. However, diclofenac was the most effective in reducing prostaglandin (PGE2) level by depicting a dose-dependent response. However, PZ-DHA ester and DHA were the most effective in inhibiting the activation of nuclear factor-kappa B (NF-κB) among other test compounds. Our results suggest that PZ-DHA ester might possess potential therapeutic activity to treat inflammation related disorders such as type 2 diabetes, asthma, atherosclerosis and inflammatory bowel disease. Copyright © 2015 Elsevier B.V. All rights reserved.

Optimization of the Ion Source-Mass Spectrometry Parameters in Non-Steroidal Anti-Inflammatory and Analgesic Pharmaceuticals Analysis by a Design of Experiments Approach

NASA Astrophysics Data System (ADS)

Paíga, Paula; Silva, Luís M. S.; Delerue-Matos, Cristina

2016-10-01

The flow rates of drying and nebulizing gas, heat block and desolvation line temperatures and interface voltage are potential electrospray ionization parameters as they may enhance sensitivity of the mass spectrometer. The conditions that give higher sensitivity of 13 pharmaceuticals were explored. First, Plackett-Burman design was implemented to screen significant factors, and it was concluded that interface voltage and nebulizing gas flow were the only factors that influence the intensity signal for all pharmaceuticals. This fractionated factorial design was projected to set a full 22 factorial design with center points. The lack-of-fit test proved to be significant. Then, a central composite face-centered design was conducted. Finally, a stepwise multiple linear regression and subsequently an optimization problem solving were carried out. Two main drug clusters were found concerning the signal intensities of all runs of the augmented factorial design. p-Aminophenol, salicylic acid, and nimesulide constitute one cluster as a result of showing much higher sensitivity than the remaining drugs. The other cluster is more homogeneous with some sub-clusters comprising one pharmaceutical and its respective metabolite. It was observed that instrumental signal increased when both significant factors increased with maximum signal occurring when both codified factors are set at level +1. It was also found that, for most of the pharmaceuticals, interface voltage influences the intensity of the instrument more than the nebulizing gas flowrate. The only exceptions refer to nimesulide where the relative importance of the factors is reversed and still salicylic acid where both factors equally influence the instrumental signal.

Simultaneous determination of cetirizine, phenyl propanolamine and nimesulide using third derivative spectrophotometry and high performance liquid chromatography in pharmaceutical preparations.

PubMed

Aly, Fatma Ahmed; El-Enany, Nahed; Elmansi, Heba; Nabil, Amany

2017-10-05

The combination between cetirizine (CET), phenylpropanolamine (PPA) and nimesulide (NMS) under trade name Nemeriv Cp tablet is prescribed for nasal congestion, cold, sneezing, and allergy. Among all published methods for the three drugs; there is no reported method concerning estimation of CTZ, PPA and NMS simultaneously and this motivates us to develop new and simple methods for their assay in pure form and tablet preparations. Two new methodologies were described for the simultaneous quantification of cetirizine (CTZ), PPA and NMS. Spectrophotometric procedures relies on measuring the amplitudes of the third derivative curves at 238 nm for CTZ, 218 nm for PPA and 305 nm for NMS. The calibration graphs were rectilinear over the ranges of 8-90 µg/mL for CTZ, 20-100 µg/mL for PPA and 20-200 µg/mL for NMS respectively. Regarding the HPLC method; monolithic column (100 mm × 4.6 mm i.d) was used for the separation. The used mobile phase composed of 0.1 M phosphate buffer and methanol in the ratio of 40:60, v/v at pH 7.0. The analysis was performed using UV detector at 215 nm. Calibration curves showed the linearity over concentration ranges of 5-40, 10-100 and 10-120 µg/mL for CTZ, PPA and NMS. Application of the proposed methods to the laboratory prepared tablets was carried out successfully. The results were compared with those obtained from previously published methods and they were satisfactory. Graphical abstract Graphical abstract represents the chemical structures, representative chromatogram for the HPLC separation of a PPA, b NMS and c CTZ and third derivative absorption spectra of a PPA, b NMS and c CTZ for the spectrophotometric method.

Optimization of the Ion Source-Mass Spectrometry Parameters in Non-Steroidal Anti-Inflammatory and Analgesic Pharmaceuticals Analysis by a Design of Experiments Approach.

PubMed

Paíga, Paula; Silva, Luís M S; Delerue-Matos, Cristina

2016-10-01

The flow rates of drying and nebulizing gas, heat block and desolvation line temperatures and interface voltage are potential electrospray ionization parameters as they may enhance sensitivity of the mass spectrometer. The conditions that give higher sensitivity of 13 pharmaceuticals were explored. First, Plackett-Burman design was implemented to screen significant factors, and it was concluded that interface voltage and nebulizing gas flow were the only factors that influence the intensity signal for all pharmaceuticals. This fractionated factorial design was projected to set a full 2(2) factorial design with center points. The lack-of-fit test proved to be significant. Then, a central composite face-centered design was conducted. Finally, a stepwise multiple linear regression and subsequently an optimization problem solving were carried out. Two main drug clusters were found concerning the signal intensities of all runs of the augmented factorial design. p-Aminophenol, salicylic acid, and nimesulide constitute one cluster as a result of showing much higher sensitivity than the remaining drugs. The other cluster is more homogeneous with some sub-clusters comprising one pharmaceutical and its respective metabolite. It was observed that instrumental signal increased when both significant factors increased with maximum signal occurring when both codified factors are set at level +1. It was also found that, for most of the pharmaceuticals, interface voltage influences the intensity of the instrument more than the nebulizing gas flowrate. The only exceptions refer to nimesulide where the relative importance of the factors is reversed and still salicylic acid where both factors equally influence the instrumental signal. Graphical Abstract ᅟ.

Docking studies on NSAID/COX-2 isozyme complexes using Contact Statistics analysis

NASA Astrophysics Data System (ADS)

Ermondi, Giuseppe; Caron, Giulia; Lawrence, Raelene; Longo, Dario

2004-11-01

The selective inhibition of COX-2 isozymes should lead to a new generation of NSAIDs with significantly reduced side effects; e.g. celecoxib (Celebrex®) and rofecoxib (Vioxx®). To obtain inhibitors with higher selectivity it has become essential to gain additional insight into the details of the interactions between COX isozymes and NSAIDs. Although X-ray structures of COX-2 complexed with a small number of ligands are available, experimental data are missing for two well-known selective COX-2 inhibitors (rofecoxib and nimesulide) and docking results reported are controversial. We use a combination of a traditional docking procedure with a new computational tool (Contact Statistics analysis) that identifies the best orientation among a number of solutions to shed some light on this topic.

Cu-mediated C–H 18F-fluorination of electron-rich (hetero)arenes

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCammant, Matthew S.; Thompson, Stephen; Brooks, Allen F.

This communication describes a method for the nucleophilic radiofluorination of electron-rich arenes. The reaction involves the initial C(sp 2)–H functionalization of an electron-rich arene with MesI(OH)OTs to form a (mesityl)(aryl)iodonium salt. This salt is then used in situ in a Cu-mediated radiofluorination with [ 18F]KF. This approach leverages the stability and availability of electron-rich arene starting materials to enable mild late-stage radiofluorination of toluene, anisole, aniline, pyrrole, and thiophene derivatives. Finally, the radiofluorination has been automated to access a 41 mCi dose of an 18F-labeled nimesulide derivative in high (2800 ± 700 Ci/mmol) specific activity.

A Caveolin Dominant Negative Mutant Associates with Lipid Bodies and Induces Intracellular Cholesterol Imbalance

PubMed Central

Pol, Albert; Luetterforst, Robert; Lindsay, Margaret; Heino, Sanna; Ikonen, Elina; Parton, Robert G.

2001-01-01

Recent studies have indicated a role for caveolin in regulating cholesterol-dependent signaling events. In the present study we have analyzed the role of caveolins in intracellular cholesterol cycling using a dominant negative caveolin mutant. The mutant caveolin protein, cav-3DGV, specifically associates with the membrane surrounding large lipid droplets. These structures contain neutral lipids, and are accessed by caveolin 1–3 upon overexpression. Fluorescence, electron, and video microscopy observations are consistent with formation of the membrane-enclosed lipid rich structures by maturation of subdomains of the ER. The caveolin mutant causes the intracellular accumulation of free cholesterol (FC) in late endosomes, a decrease in surface cholesterol and a decrease in cholesterol efflux and synthesis. The amphiphile U18666A acts synergistically with cavDGV to increase intracellular accumulation of FC. Incubation of cells with oleic acid induces a significant accumulation of full-length caveolins in the enlarged lipid droplets. We conclude that caveolin can associate with the membrane surrounding lipid droplets and is a key component involved in intracellular cholesterol balance and lipid transport in fibroblasts. PMID:11238460

In Vitro and In Vivo Synergy of the Oxadiazole Class of Antibacterials with β-Lactams.

PubMed

Janardhanan, Jeshina; Meisel, Jayda E; Ding, Derong; Schroeder, Valerie A; Wolter, William R; Mobashery, Shahriar; Chang, Mayland

2016-09-01

The oxadiazole antibacterials target the bacterial cell wall and are bactericidal. We investigated the synergism of ND-421 with the commonly used β-lactams and non-β-lactam antibiotics by the checkerboard method and by time-kill assays. ND-421 synergizes well with β-lactam antibiotics, and it also exhibits a long postantibiotic effect (4.7 h). We also evaluated the in vivo efficacy of ND-421 in a murine neutropenic thigh infection model alone and in combination with oxacillin. ND-421 has in vivo efficacy by itself in a clinically relevant infection model (1.49 log10 bacterial reduction for ND-321 versus 0.36 log10 for linezolid with NRS119) and acts synergistically with β-lactam antibiotics in vitro and in vivo, and the combination of ND-421 with oxacillin is efficacious in a mouse neutropenic thigh methicillin-resistant Staphylococcus aureus (MRSA) infection model (1.60 log10 bacterial reduction). The activity of oxacillin was potentiated in the presence of ND-421, as the strain would have been resistant to oxacillin otherwise. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Detection of the Cyanotoxins L-BMAA Uptake and Accumulation in Primary Neurons and Astrocytes.

PubMed

Tan, Vanessa X; Mazzocco, Claire; Varney, Bianca; Bodet, Dominique; Guillemin, Tristan A; Bessede, Alban; Guillemin, Gilles J

2018-01-01

We show for the first time that a newly developed polyclonal antibody (pAb) can specifically target the cyanotoxin β-methylamino-L-alanine (BMAA) and can be used to enable direct visualization of BMAA entry and accumulation in primary brain cells. We used this pAb to investigate the effect of acute and chronic accumulation, and toxicity of both BMAA and its natural isomer 2,4-diaminobutyric acid (DAB), separately or in combination, on primary cultures of rat neurons. We further present evidence that co-treatment with BMAA and DAB increased neuronal death, as measured by MAP2 fluorescence level, and appeared to reduce BMAA accumulation. DAB is likely to be acting synergistically with BMAA resulting in higher level of cellular toxicity. We also found that glial cells such as microglia and astrocytes are also able to directly uptake BMAA indicating that additional brain cell types are affected by BMAA-induced toxicity. Therefore, BMAA clearly acts at multiple cellular levels to possibly increase the risk of developing neurodegenerative diseases, including neuro- and gliotoxicity and synergetic exacerbation with other cyanotoxins.

Drosophila Nanos acts as a molecular clamp that modulates the RNA-binding and repression activities of Pumilio

PubMed Central

Weidmann, Chase A; Qiu, Chen; Arvola, René M; Lou, Tzu-Fang; Killingsworth, Jordan; Campbell, Zachary T; Tanaka Hall, Traci M; Goldstrohm, Aaron C

2016-01-01

Collaboration among the multitude of RNA-binding proteins (RBPs) is ubiquitous, yet our understanding of these key regulatory complexes has been limited to single RBPs. We investigated combinatorial translational regulation by Drosophila Pumilio (Pum) and Nanos (Nos), which control development, fertility, and neuronal functions. Our results show how the specificity of one RBP (Pum) is modulated by cooperative RNA recognition with a second RBP (Nos) to synergistically repress mRNAs. Crystal structures of Nos-Pum-RNA complexes reveal that Nos embraces Pum and RNA, contributes sequence-specific contacts, and increases Pum RNA-binding affinity. Nos shifts the recognition sequence and promotes repression complex formation on mRNAs that are not stably bound by Pum alone, explaining the preponderance of sub-optimal Pum sites regulated in vivo. Our results illuminate the molecular mechanism of a regulatory switch controlling crucial gene expression programs, and provide a framework for understanding how the partnering of RBPs evokes changes in binding specificity that underlie regulatory network dynamics. DOI: http://dx.doi.org/10.7554/eLife.17096.001 PMID:27482653

Cu-mediated C–H 18F-fluorination of electron-rich (hetero)arenes

DOE PAGES

McCammant, Matthew S.; Thompson, Stephen; Brooks, Allen F.; ...

2017-06-30

This communication describes a method for the nucleophilic radiofluorination of electron-rich arenes. The reaction involves the initial C(sp 2)–H functionalization of an electron-rich arene with MesI(OH)OTs to form a (mesityl)(aryl)iodonium salt. This salt is then used in situ in a Cu-mediated radiofluorination with [ 18F]KF. This approach leverages the stability and availability of electron-rich arene starting materials to enable mild late-stage radiofluorination of toluene, anisole, aniline, pyrrole, and thiophene derivatives. Finally, the radiofluorination has been automated to access a 41 mCi dose of an 18F-labeled nimesulide derivative in high (2800 ± 700 Ci/mmol) specific activity.

Squalene Synthase As a Target for Chagas Disease Therapeutics

PubMed Central

Chan, Hsiu-Chien; Li, Jikun; Zheng, Yingying; Huang, Chun-Hsiang; Ren, Feifei; Chen, Chun-Chi; Zhu, Zhen; Galizzi, Melina; Li, Zhu-Hong; Rodrigues-Poveda, Carlos A.; Gonzalez-Pacanowska, Dolores; Veiga-Santos, Phercyles; de Carvalho, Tecia Maria Ulisses; de Souza, Wanderley; Urbina, Julio A.; Wang, Andrew H.-J.; Docampo, Roberto; Li, Kai; Liu, Yi-Liang; Oldfield, Eric; Guo, Rey-Ting

2014-01-01

Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel anti-infective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS) from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease. PMID:24789335

Synergistic antitumor activity of withaferin A combined with oxaliplatin triggers reactive oxygen species-mediated inactivation of the PI3K/AKT pathway in human pancreatic cancer cells.

PubMed

Li, Xu; Zhu, Feng; Jiang, Jianxin; Sun, Chengyi; Wang, Xin; Shen, Ming; Tian, Rui; Shi, Chengjian; Xu, Meng; Peng, Feng; Guo, Xingjun; Wang, Min; Qin, Renyi

2015-02-01

Application of oxaliplatin for the treatment of pancreatic cancer (PC) is restricted owing to its toxic side effects and drug resistance. We investigated how withaferin A (WA), a bioactive component isolated from the medicinal plant Withania somnifera, acts synergistically with oxaliplatin on human PC in vitro and in vivo. We found that WA enhanced oxaliplatin-induced growth suppression and apoptosis in PC cells dramatically through a mechanism involving mitochondrial dysfunction and inactivation of the PI3K/AKT pathway. Combination treatment resulted in significant accumulation of intracellular reactive oxygen species (ROS). Pretreatment of cells with the ROS scavenger N-acetylcysteine completely blocked the apoptosis induced by combination treatment, and recovered expression of AKT inactivation, which revealed the important role of ROS in apoptosis and AKT regulation. In vivo, combination therapy showed the strongest anti-tumor effects compared with single agents, without obvious additional toxicity. These results support the notion that combination treatment with oxaliplatin and WA could facilitate development of an effective strategy for PC treatment. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Genetic regulation of mammalian gonad development.

PubMed

Eggers, Stefanie; Ohnesorg, Thomas; Sinclair, Andrew

2014-11-01

Sex-specific gonadal development starts with formation of the bipotential gonad, which then differentiates into either a mature testis or an ovary. This process is dependent on activation of either the testis-specific or the ovary-specific pathway while the opposite pathway is continuously repressed. A network of transcription factors tightly regulates initiation and maintenance of these distinct pathways; disruption of these networks can lead to disorders of sex development in humans and male-to-female or female-to-male sex reversal in mice. Sry is the Y-linked master switch that is both required and sufficient to drive the testis-determining pathway. Another key component of the testis pathway is Sox9, which acts immediately downstream of Sry. In contrast to the testis pathway, no single sex-determining factor has been identified in the ovary pathway; however, multiple genes, such as Foxl2, Rspo1, Ctnnb1, and Wnt4, seem to work synergistically and in parallel to ensure proper ovary development. Our understanding of the regulatory networks that underpin testis and ovary development has grown substantially over the past two decades.

Aromatase expression in a human osteoblastic cell line increases in response to prostaglandin E(2) in a dexamethasone-dependent fashion.

PubMed

Watanabe, M; Noda, M; Nakajin, S

2007-09-01

Recent progress supports the importance of local estrogen secretion in human bone tissue to increase and maintain bone-mineral density. In a previous report, we found that forskolin (FSK) synergistically induces aromatase (CYP19: a rate-limiting enzyme for estrogen synthesis) expression in dexamethasone (Dex) dependent manner in a human osteoblastic cell line, SV-HFO [Watanabe M, Ohno S, Nakajin S. Forskolin and dexamethasone synergistically induce aromatase (CYP19) expression in the human osteoblastic cell line SV-HFO. Eur J Endocrinol 2005;152:619-24]. In this report, we investigated whether prostaglandin (PG) E(2) induces estrogen production, in other words, if PGE(2) exerts the same effect as FSK because PGE(2) is the major prostanoid in the bone and is one of the key molecules in the osteoblast. We found PGE(2) up-regulates aromatase activity synergistically, but this up-regulation depends on Dex. CYP19 gene expression was also increased synergistically by Dex and PGE(2). Promoter I.4 was activated synergistically by PGE(2) and Dex. PGE(2) receptor, EP(1), EP(2) and EP(4) were involved in the up-regulation of aromatase activity in response to PGE(2) in a Dex-dependent manner. The cAMP-PKA pathway and Ca(2+) signaling pathway were involved in the up-regulation of aromatase activity in response to PGE(2). Furthermore, glucocorticoid response element on promoter I.4 sequence was an essential minimum requirement for its activity and synergism of PGE(2) and Dex. These findings are the first report on osteoblastic cell line which uses predominantly promoter I.4 to drive aromatase expression. These findings also suggest that endogenous PGE(2) produced in bone mainly may synergistically support local estrogen production in osteoblastic cells in the presence of glucocorticoid.

Interaction or relationship between Helicobacter pylori and non-steroidal anti-inflammatory drugs in upper gastrointestinal diseases.

PubMed

Ji, Kai-Yu; Hu, Fu-Lian

2006-06-28

According to a meta-analysis, H pylori and non-steroidal anti-inflammatory drugs (NSAID) independently and significantly increase the risk of gastroduodenal ulcer and ulcer bleeding. Their coincidence is frequent, demonstration of a possible relationship and consequent attitude is of important implications. But unfortunately, no consensus has been approved in the past years and their interactions are still controversial. H pylori and NSAID are known to share a number of pathogenic mechanisms, but there is no evidence for the significant synergic action between these two risk factors. Their relationship is independent, additive, synergistic or antagonistic without considering the influence of other factors because studies on this subject are different in almost all aspects of their methodology, including the definition of a NSAID user as well as the types, doses, duration and their indications for NSAID use, as well as their end-points, definition of dyspepsia and regimes used for eradication of H pylori. These might contribute to the conflicting results and opinions. H pylori infection in humans does not act synergistically with NSAID on ulcer healing, and there is no need to eradicate it. This notion is supported by the finding that the eradication of H pylori does not affect NSAID-induced gastropathy treated with omeprazole and that H pylori infection induces a strong cyclooxygenase-2 (COX-2) expression resulting in excessive biosynthesis of gastroprotective prostaglandin which in turn counteracts NSAID-induced gastropathy and heals the existing ulcer. Other investigators claimed that H pylori infection acts synergistically with NSAID on ulcer development, and H pylori should be eradicated, particularly at the start of long-term NSAID therapy. Eradication of H pylori prior to NSAID treatment does not appear to accelerate ulcer healing or to prevent recurrent ulcers in NSAID users. However, some recommendations can be drawn from the results of clinical trails.

Interaction of PGHS-2 and glutamatergic mechanisms controlling the ovine fetal hypothalamus-pituitary-adrenal axis

PubMed Central

Knutson, Nathan

2010-01-01

Prostaglandins, generated within the fetal brain, are integral components of the mechanism controlling the fetal hypothalamus-pituitary-adrenal (HPA) axis. Previous studies in this laboratory demonstrated that prostaglandin G/H synthase isozyme 2 (PGHS-2) inhibition reduces the fetal HPA axis response to cerebral hypoperfusion, blocks the preparturient rise in fetal plasma ACTH concentration, and delays parturition. We also discovered that blockade of N-methyl-d-aspartate (NMDA) receptors reduces the fetal ACTH response to cerebral hypoperfusion. The present study was designed to test the hypothesis that PGHS-2 action and the downstream effect of HPA axis stimulation are stimulated by NMDA-mediated glutamatergic neurotransmission. Chronically catheterized late-gestation fetal sheep (n = 8) were injected with NMDA (1 mg iv). All responded with increases in fetal plasma ACTH and cortisol concentrations. Pretreatment with resveratrol (100 mg iv, n = 5), a specific inhibitor of PGHS-1, did not alter the magnitude of the HPA axis response to NMDA. Pretreatment with nimesulide (10 mg iv, n = 6), a specific inhibitor of PGHS-2, significantly reduced the HPA axis response to NMDA. To further explore this interaction, we injected NMDA in six chronically catheterized fetal sheep that were chronically infused with nimesulide (n = 6) at a rate of 1 mg/day into the lateral cerebral ventricle for 5–7 days. In this group, there was no significant ACTH response to NMDA. Finally, we tested whether the HPA axis response to prostaglandin E2 (PGE2) is mediated by NMDA receptors. Seven chronically catheterized late-gestation fetal sheep were injected with 100 ng of PGE2, which significantly increased fetal plasma ACTH and cortisol concentrations. Pretreatment with ketamine (10 mg iv), an NMDA antagonist, did not alter the ACTH or cortisol response to PGE2. We conclude that generation of prostanoids via the action of PGHS-2 in the fetal brain augments the fetal HPA axis response to NMDA-mediated glutamatergic stimulation. PMID:20445154

Interaction or relationship between Helicobacter pylori and non-steroidal anti-inflammatory drugs in upper gastrointestinal diseases

PubMed Central

Ji, Kai-Yu; Hu, Fu-Lian

2006-01-01

According to a meta-analysis, H pylori and non-steroidal anti-inflammatory drugs (NSAID) independently and significantly increase the risk of gastroduodenal ulcer and ulcer bleeding. Their coincidence is frequent, demonstration of a possible relationship and consequent attitude is of important implications. But unfortunately, no consensus has been approved in the past years and their interactions are still controversial. H pylori and NSAID are known to share a number of pathogenic mechanisms, but there is no evidence for the significant synergic action between these two risk factors. Their relationship is independent, additive, synergistic or antagonistic without considering the influence of other factors because studies on this subject are different in almost all aspects of their methodology, including the definition of a NSAID user as well as the types, doses, duration and their indications for NSAID use, as well as their end-points, definition of dyspepsia and regimes used for eradication of H pylori. These might contribute to the conflicting results and opinions. H pylori infection in humans does not act synergistically with NSAID on ulcer healing, and there is no need to eradicate it. This notion is supported by the finding that the eradication of H pylori does not affect NSAID-induced gastropathy treated with omeprazole and that H pylori infection induces a strong cyclooxygenase-2 (COX-2) expression resulting in excessive biosynthesis of gastroprotective prostaglandin which in turn counteracts NSAID-induced gastropathy and heals the existing ulcer. Other investigators claimed that H pylori infection acts synergistically with NSAID on ulcer development, and H pylori should be eradicated, particularly at the start of long-term NSAID therapy. Eradication of H pylori prior to NSAID treatment does not appear to accelerate ulcer healing or to prevent recurrent ulcers in NSAID users. However, some recommendations can be drawn from the results of clinical trails. PMID:16804960

Fibroblast growth factor 2 and cyclic AMP synergistically regulate bone sialoprotein gene expression.

PubMed

Shimizu, Emi; Nakayama, Youhei; Nakajima, Yu; Kato, Naoko; Takai, Hideki; Kim, Dong-Soon; Arai, Masato; Saito, Ryoichiro; Sodek, Jaro; Ogata, Yorimasa

2006-07-01

Bone sialoprotein (BSP) is a noncollagenous protein of the mineralized bone extracellular matrix. We here report that FGF2 and cAMP act synergistically to stimulate BSP gene expression. Treatment of ROS 17/2.8 cells with either 10 ng/ml FGF2 or 1 microM FSK for 6 h resulted in 5.4- and 8.2-fold increases, respectively, in the levels of BSP mRNA. However, in the presence of both FGF2 and forskolin (FGF/FSK), BSP mRNA levels were increased synergistically by 20.4-fold. Using a luciferase reporter construct, encompassing BSP promoter nucleotides -116 to +60, transcription was also increased synergistically by 15.0-fold with FGF/FSK, compared to stimulations of 2.6- and 5.3-fold, respectively, for FGF2 and FSK alone. Transcriptional stimulation by FGF/FSK abrogated in constructs included 2 bp mutations in the inverted CCAAT, CRE, FRE and Pit-1 elements. Whereas the FRE-protein complex was increased by FGF2 and FGF/FSK, the Pit-1-protein complex was decreased by FSK and FGF/FSK. Notably, transcriptional activity induced by FGF/FSK was blocked by protein kinase A, tyrosine kinase and MEK inhibitors. These studies indicate that the combinatorial effects of FGF and FSK act through PKA, tyrosine kinase and MAP-kinase-dependent pathways, which target the inverted CCAAT, CRE, FRE and Pit-1 elements in the BSP gene to synergistically increase BSP expression.

Importance of Real-Time Assays To Distinguish Multidrug Efflux Pump-Inhibiting and Outer Membrane-Destabilizing Activities in Escherichia coli.

PubMed

Misra, Rajeev; Morrison, Keith D; Cho, Hyun Jae; Khuu, Thanh

2015-08-01

The constitutively expressed AcrAB multidrug efflux system of Escherichia coli shows a high degree of homology with the normally silent AcrEF system. Exposure of a strain with acrAB deleted to antibiotic selection pressure frequently leads to the insertion sequence-mediated activation of the homologous AcrEF system. In this study, we used strains constitutively expressing either AcrAB or AcrEF from their normal chromosomal locations to resolve a controversy about whether phenylalanylarginine β-naphthylamide (PAβN) inhibits the activities of AcrAB and AcrEF and/or acts synergistically with antibiotics by destabilizing the outer membrane permeability barrier. Real-time efflux assays allowed a clear distinction between the efflux pump-inhibiting activity of PAβN and the outer membrane-destabilizing action of polymyxin B nonapeptide (PMXBN). When added in equal amounts, PAβN, but not PMXBN, strongly inhibited the efflux activities of both AcrAB and AcrEF pumps. In contrast, when outer membrane destabilization was assessed by the nitrocefin hydrolysis assay, PMXBN exerted a much greater damaging effect than PAβN. Strong action of PAβN in inhibiting efflux activity compared to its weak action in destabilizing the outer membrane permeability barrier suggests that PAβN acts mainly by inhibiting efflux pumps. We concluded that at low concentrations, PAβN acts specifically as an inhibitor of both AcrAB and AcrEF efflux pumps; however, at high concentrations, PAβN in the efflux-proficient background not only inhibits efflux pump activity but also destabilizes the membrane. The effects of PAβN on membrane integrity are compounded in cells unable to extrude PAβN. The increase in multidrug-resistant bacterial pathogens at an alarming rate has accelerated the need for implementation of better antimicrobial stewardship, discovery of new antibiotics, and deeper understanding of the mechanism of drug resistance. The work carried out in this study highlights the importance of employing real-time fluorescence-based assays in differentiating multidrug efflux-inhibitory and outer membrane-destabilizing activities of antibacterial compounds. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases.

PubMed

Hui, Wang; Litherland, Gary J; Elias, Martina S; Kitson, Gareth I; Cawston, Tim E; Rowan, Andrew D; Young, David A

2012-03-01

To investigate the effect of leptin on cartilage destruction. Collagen release was assessed in bovine cartilage explant cultures, while collagenolytic and gelatinolytic activities in culture supernatants were determined by bioassay and gelatin zymography. The expression of matrix metalloproteinases (MMP) was analysed by real-time RT-PCR. Signalling pathway activation was studied by immunoblotting. Leptin levels in cultured osteoarthritic joint infrapatellar fat pad or peri-enthesal deposit supernatants were measured by immunoassay. Leptin, either alone or in synergy with IL-1, significantly induced collagen release from bovine cartilage by upregulating collagenolytic and gelatinolytic activity. In chondrocytes, leptin induced MMP1 and MMP13 expression with a concomitant activation of STAT1, STAT3, STAT5, MAPK (JNK, Erk, p38), Akt and NF-κB signalling pathways. Selective inhibitor blockade of PI3K, p38, Erk and Akt pathways significantly reduced MMP1 and MMP13 expression in chondrocytes, and reduced cartilage collagen release induced by leptin or leptin plus IL-1. JNK inhibition had no effect on leptin-induced MMP13 expression or leptin plus IL-1-induced cartilage collagen release. Conditioned media from cultured white adipose tissue (WAT) from osteoarthritis knee joint fat pads contained leptin, induced cartilage collagen release and increased MMP1 and MMP13 expression in chondrocytes; the latter being partly blocked with an anti-leptin antibody. Leptin acts as a pro-inflammatory adipokine with a catabolic role on cartilage metabolism via the upregulation of proteolytic enzymes and acts synergistically with other pro-inflammatory stimuli. This suggests that the infrapatellar fat pad and other WAT in arthritic joints are local producers of leptin, which may contribute to the inflammatory and degenerative processes in cartilage catabolism, providing a mechanistic link between obesity and osteoarthritis.

Elucidation of Chromatin Remodeling Machinery Involved in Regulation of Estrogen Receptor Alpha Expression in Human Breast Cancer Cells

DTIC Science & Technology

2006-08-01

depsipeptide with 5-aza-dC has been shown to synergistically reactivate silenced tumor suppressor genes in human cancer cells, including MLH1 , TIMP3...depsipeptide with 5- aza-dC has been shown to synergistically reactivate silenced tumor suppressor genes in human cancer cells, including MLH1 , TIMP3

Metformin combined with quercetin synergistically repressed prostate cancer cells via inhibition of VEGF/PI3K/Akt signaling pathway.

PubMed

Sun, Shuben; Gong, Fanger; Liu, Ping; Miao, Qilong

2018-04-17

The aim of present study was to examine whether metformin in association with quercetin has any synergistically anti-tumor effects on prostate cancer. Our findings showed that metformin in combination with quercetin synergistically inhibited the growth, migration and invasion of both PC-3 and LNCaP cells. Co-treatment of these two agents induced more apoptosis than single agent treatment. The co-treatment-induced apoptosis was caspase-dependent and accompanied by the down-regulation of Bcl-2 family members. Our data also indicated that co-treatment of metformin and quercetin strongly inhibited the VEGF/Akt/PI3K pathway. Moreover, these two agents acted synergistically to repress the growth of human prostate cancer cell xenograft in vivo in nude mice. In conclusion, our findings indicate that the combination therapy of metformin and quercetin exerted synergistic antitumor effects in prostate cancers via inhibition of VEGF/Akt/PI3K pathway. Thus, combination treatment of metformin and quercetin would be a promising therapeutic strategy for prostate cancer patients. Copyright © 2017. Published by Elsevier B.V.

Inhibition of Hsp90 acts synergistically with topoisomerase II poisons to increase the apoptotic killing of cells due to an increase in topoisomerase II mediated DNA damage.

PubMed

Barker, Catherine R; McNamara, Anne V; Rackstraw, Stephen A; Nelson, David E; White, Mike R; Watson, Alastair J M; Jenkins, John R

2006-01-01

Topoisomerase II plays a crucial role during chromosome condensation and segregation in mitosis and meiosis and is a highly attractive target for chemotherapeutic agents. We have identified previously topoisomerase II and heat shock protein 90 (Hsp90) as part of a complex. In this paper we demonstrate that drug combinations targeting these two enzymes cause a synergistic increase in apoptosis. The objective of our study was to identify the mode of cell killing and the mechanism behind the increase in topoisomerase II mediated DNA damage. Importantly we demonstrate that Hsp90 inhibition results in an increased topoiosmerase II activity but not degradation of topoisomerase II and it is this, in the presence of a topoisomerase II poison that causes the increase in cell death. Our results suggest a novel mechanism of action where the inhibition of Hsp90 disrupts the Hsp90-topoisomerase II interaction leading to an increase in and activation of unbound topoisomerase II, which, in the presence of a topoisomerase II poison leads to the formation of an increased number of cleavable complexes ultimately resulting in rise in DNA damage and a subsequent increase cell death.

Effect of anabolic steroids on overloaded and overloaded suspended skeletal muscle

NASA Technical Reports Server (NTRS)

Tsika, R. W.; Herrick, R. E.; Baldwin, K. M.

1987-01-01

The effect of treatment with an anabolic steroid (nandrolone decanoate) on the muscle mass, the subcellular protein content, and the myosin patterns of normal overloaded and suspended overloaded plantaris muscle in female rat was investigated, dividing rats into six groups: normal control (NC), overload (OV), OV steroid (OV-S), normal suspended (N-sus), OV suspended (OV-sus), and OV suspended steroid (OV-sus-S). Relative to control values, overload produced a sparing effect on the muscle weight of the OV-sus group as well as increases of muscle weight of the OV group; increased protein content; and an increased expression of slow myosin in both OV and OV-sus groups. Steroid treatment of OV animals did not after the response of any parameter analyzed for the OV group, but in the OV-sus group steroid treatment induced increases in muscle weight and in protein content of the OV-sus-S group. The treatment did not alter the pattern of isomyosin expression observed in the OV or the OV-sus groups. These result suggest that the steroid acts synergistically with functional overload only under conditions in which the effect of overload is minimized by suspension.

[Tapentadol: with two mechanisms of action in one molecule effective against nociceptive and neuropathic pain. Preclinical overview].

PubMed

Tzschentke, T M; Christoph, T; Schröder, W; Englberger, W; De Vry, J; Jahnel, U; Kögel, B Y

2011-02-01

Tapentadol (3-[(1R, 2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl] phenol) is a centrally acting analgesic of a new substance class for the treatment of severe nociceptive and neuropathic pain. Tapentadol combines μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in one molecule. Because of the combined mechanisms of action tapentadol offers a broad therapeutic spectrum for nociceptive as well as neuropathic pain. In different animal models its high efficacy was shown in acute nociceptive, acute and chronic inflammatory as well as in chronic neuropathic pain. Using several preclinical approaches it was shown that the noradrenergic component of tapentadol interacts with the opioid component and that both synergistically contribute to the analgesic effect of the substance. In comparison to known drugs with only one of the two modes of action, tapentadol, despite its high potency, has an improved tolerability profile in the relevant animal models, particularly with regard to gastrointestinal and central side effects. Tapentadol acts directly without metabolic activation and without formation of analgesically relevant metabolites. In different interaction studies a low potential for interactions was shown, thus clinically relevant drug-drug interactions are unlikely. Overall, tapentadol provides a safe pharmacodynamic-pharmacokinetic profile.

Cordyceps sinensis polysaccharide inhibits PDGF-BB-induced inflammation and ROS production in human mesangial cells.

PubMed

Wang, Ying; Wang, Yan; Liu, Dan; Wang, Wang; Zhao, Huan; Wang, Min; Yin, Hongping

2015-07-10

CPS-F, a polysaccharide derived from Cordyceps sinensis, is a potential anti-inflammatory and anti-oxidative agent. We demonstrated that CPS-F not only inhibits platelet-derived growth factor BB (PDGF-BB)-induced intracellular reactive oxygen species (ROS) generation, and up-regulation of tumor necrosis factor-α (TNF-α), TNF-α receptor 1 (TNFR1), and monocyte chemotactic protein-1 (MCP-1), but also acts synergistically in combination with MAPK/ERK inhibitor U0126 and PI3K/Akt inhibitor LY294002. Additionally, up-regulation of pro-inflammatory factors was reversed by use of a combination of CPS-F and NADPH oxidase (NOX) inhibitor diphenyleneiodonium chloride (DPI) or silencing of NOX1. Furthermore, CPS-F prevents the PDGF receptor β (PDGFRβ) promoter activity induced by PDGF-BB in transfected cells and ameliorates increased levels of TNF-α, TNFR1, and MCP-1 when PDGFRβ is silenced, thereby suggesting that CPS-F possesses a bidirectional regulatory function. Our findings suggest CPS-F may exert its therapeutic effect for the treatment of glomerulonephritis related to human mesangial cells (HMCs) through the ERK1/2/Akt pathways. Copyright © 2015 Elsevier Ltd. All rights reserved.

S-Nitrosoglutathione is a component of wound- and salicylic acid-induced systemic responses in Arabidopsis thaliana.

PubMed

Espunya, M Carme; De Michele, Roberto; Gómez-Cadenas, Aurelio; Martínez, M Carmen

2012-05-01

S-Nitrosoglutathione (GSNO) is a bioactive, stable, and mobile reservoir of nitric oxide (NO), and an important player in defence responses to herbivory and pathogen attack in plants. It has been demonstrated previously that GSNO reductase (GSNOR) is the main enzyme responsible for the in vivo control of intracellular levels of GSNO. In this study, the role of S-nitrosothiols, in particular of GSNO, in systemic defence responses in Arabidopsis thaliana was investigated further. It was shown that GSNO levels increased rapidly and uniformly in injured Arabidopsis leaves, whereas in systemic leaves GSNO was first detected in vascular tissues and later spread over the parenchyma, suggesting that GSNO is involved in the transmission of the wound mobile signal through the vascular tissue. Moreover, GSNO accumulation was required to activate the jasmonic acid (JA)-dependent wound responses, whereas the alternative JA-independent wound-signalling pathway did not involve GSNO. Furthermore, extending previous work on the role of GSNOR in pathogenesis, it was shown that GSNO acts synergistically with salicylic acid in systemic acquired resistance activation. In conclusion, GSNOR appears to be a key regulator of systemic defence responses, in both wounding and pathogenesis.

SELF-PRUNING Acts Synergistically with DIAGEOTROPICA to Guide Auxin Responses and Proper Growth Form.

PubMed

Silva, Willian B; Vicente, Mateus H; Robledo, Jessenia M; Reartes, Diego S; Ferrari, Renata C; Bianchetti, Ricardo; Araújo, Wagner L; Freschi, Luciano; Peres, Lázaro E P; Zsögön, Agustin

2018-04-01

The SELF PRUNING ( SP ) gene is a key regulator of growth habit in tomato ( Solanum lycopersicum ). It is an ortholog of TERMINAL FLOWER1 , a phosphatidylethanolamine-binding protein with antiflorigenic activity in Arabidopsis ( Arabidopsis thaliana ). A spontaneous loss-of-function mutation ( sp ) has been bred into several industrial tomato cultivars, as it produces a suite of pleiotropic effects that are favorable for mechanical harvesting, including determinate growth habit, short plant stature, and simultaneous fruit ripening. However, the physiological basis for these phenotypic differences has not been thoroughly explained. Here, we show that the sp mutation alters polar auxin transport as well as auxin responses, such as gravitropic curvature and elongation of excised hypocotyl segments. We also demonstrate that free auxin levels and auxin-regulated gene expression patterns are altered in sp mutants. Furthermore, diageotropica , a mutation in a gene encoding a cyclophilin A protein, appears to confer epistatic effects with sp Our results indicate that SP affects the tomato growth habit at least in part by influencing auxin transport and responsiveness. These findings suggest potential novel targets that could be manipulated for controlling plant growth habit and improving productivity. © 2018 American Society of Plant Biologists. All Rights Reserved.

Synergistic regulation of competence development in Bacillus subtilis by two Rap-Phr systems.

PubMed

Bongiorni, Cristina; Ishikawa, Shu; Stephenson, Sophie; Ogasawara, Naotake; Perego, Marta

2005-07-01

The 11 Rap proteins of Bacillus subtilis comprise a conserved family of tetratricopeptide (TPR)-containing regulatory proteins. Their activity is inhibited by specific Phr pentapeptides produced from the product of phr genes through an export-import maturation process. We found that one of the proteins, namely RapF, is involved in the regulation of competence to DNA transformation. The ComA response regulator and transcription factor for initiation of competence development is the target of RapF. Specific binding of RapF to the carboxy-terminal DNA-binding domain of ComA inhibits the response regulator's ability to bind its target DNA promoters. The PhrF C-terminal pentapeptide, QRGMI, inhibits RapF activity. The activity of RapF and PhrF in regulating competence development is analogous to the previously described activity of RapC and PhrC (L. J. Core and M. Perego, Mol. Microbiol. 49:1509-1522, 2003). In fact, the RapF and PhrF pair of proteins acts synergistically with RapC and PhrC in the overall regulation of the ComA transcription factor. Since the transcription of the RapC- and RapF-encoding genes is positively regulated by their own target ComA, an autoregulatory circuit must exist for the competence transcription factor in order to modulate its activity.

Synergistic Regulation of Competence Development in Bacillus subtilis by Two Rap-Phr Systems† ‡

PubMed Central

Bongiorni, Cristina; Ishikawa, Shu; Stephenson, Sophie; Ogasawara, Naotake; Perego, Marta

2005-01-01

The 11 Rap proteins of Bacillus subtilis comprise a conserved family of tetratricopeptide (TPR)-containing regulatory proteins. Their activity is inhibited by specific Phr pentapeptides produced from the product of phr genes through an export-import maturation process. We found that one of the proteins, namely RapF, is involved in the regulation of competence to DNA transformation. The ComA response regulator and transcription factor for initiation of competence development is the target of RapF. Specific binding of RapF to the carboxy-terminal DNA-binding domain of ComA inhibits the response regulator's ability to bind its target DNA promoters. The PhrF C-terminal pentapeptide, QRGMI, inhibits RapF activity. The activity of RapF and PhrF in regulating competence development is analogous to the previously described activity of RapC and PhrC (L. J. Core and M. Perego, Mol. Microbiol. 49:1509-1522, 2003). In fact, the RapF and PhrF pair of proteins acts synergistically with RapC and PhrC in the overall regulation of the ComA transcription factor. Since the transcription of the RapC- and RapF-encoding genes is positively regulated by their own target ComA, an autoregulatory circuit must exist for the competence transcription factor in order to modulate its activity. PMID:15968044

Inhibition of Hsp90 acts synergistically with topoisomerase II poisons to increase the apoptotic killing of cells due to an increase in topoisomerase II mediated DNA damage

PubMed Central

Barker, Catherine R.; McNamara, Anne V.; Rackstraw, Stephen A.; Nelson, David E.; White, Mike R.; Watson, Alastair J. M.; Jenkins, John R.

2006-01-01

Topoisomerase II plays a crucial role during chromosome condensation and segregation in mitosis and meiosis and is a highly attractive target for chemotherapeutic agents. We have identified previously topoisomerase II and heat shock protein 90 (Hsp90) as part of a complex. In this paper we demonstrate that drug combinations targeting these two enzymes cause a synergistic increase in apoptosis. The objective of our study was to identify the mode of cell killing and the mechanism behind the increase in topoisomerase II mediated DNA damage. Importantly we demonstrate that Hsp90 inhibition results in an increased topoiosmerase II activity but not degradation of topoisomerase II and it is this, in the presence of a topoisomerase II poison that causes the increase in cell death. Our results suggest a novel mechanism of action where the inhibition of Hsp90 disrupts the Hsp90–topoisomerase II interaction leading to an increase in and activation of unbound topoisomerase II, which, in the presence of a topoisomerase II poison leads to the formation of an increased number of cleavable complexes ultimately resulting in rise in DNA damage and a subsequent increase cell death. PMID:16504968

Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion.

PubMed

Veazey, Ronald S; Klasse, Per Johan; Schader, Susan M; Hu, Qinxue; Ketas, Thomas J; Lu, Min; Marx, Preston A; Dufour, Jason; Colonno, Richard J; Shattock, Robin J; Springer, Martin S; Moore, John P

2005-11-03

Human immunodeficiency virus type 1 (HIV-1) continues to spread, principally by heterosexual sex, but no vaccine is available. Hence, alternative prevention methods are needed to supplement educational and behavioural-modification programmes. One such approach is a vaginal microbicide: the application of inhibitory compounds before intercourse. Here, we have evaluated the microbicide concept using the rhesus macaque 'high dose' vaginal transmission model with a CCR5-receptor-using simian-human immunodeficiency virus (SHIV-162P3) and three compounds that inhibit different stages of the virus-cell attachment and entry process. These compounds are BMS-378806, a small molecule that binds the viral gp120 glycoprotein and prevents its attachment to the CD4 and CCR5 receptors, CMPD167, a small molecule that binds to CCR5 to inhibit gp120 association, and C52L, a bacterially expressed peptide inhibitor of gp41-mediated fusion. In vitro, all three compounds inhibit infection of T cells and cervical tissue explants, and C52L acts synergistically with CMPD167 or BMS-378806 to inhibit infection of cell lines. In vivo, significant protection was achieved using each compound alone and in combinations. CMPD167 and BMS-378806 were protective even when applied 6 h before challenge.

Toward Control of Universal Scaling in Critical Dynamics

DTIC Science & Technology

2016-01-27

program that aims to synergistically combine two powerful and very successful theories for non-linear stochastic dynamics of cooperative multi...RESPONSIBLE PERSON 19b. TELEPHONE NUMBER Uwe Tauber Uwe C. T? uber , Michel Pleimling, Daniel J. Stilwell 611102 c. THIS PAGE The public reporting burden...to synergistically combine two powerful and very successful theories for non-linear stochastic dynamics of cooperative multi-component systems, namely

Antioxidant Prophylaxis in the Prevention of Prostatic Epithelial Neoplasia

DTIC Science & Technology

2007-02-01

additional year until the end of March 2008. 105Co-enzyme Q10 105Grape seed extract 31.5Alpha Lipoic acid 10.5Lutein 10.5Lycopene...antioxidants used in the study. Ascorbic acid is a potent antioxidant that interacts synergistically with Lipoic acid to destroy many types of free radicals...co-enzyme Q10. Lycopene and lutein are fat soluble carotenoids that work synergistically and possess very high antioxidant activity. Lipoic acid not

BATTLE: Biomarker-Based Approaches of Targeted Therapy for Lung Cancer Elimination

DTIC Science & Technology

2007-04-01

localization, which • The combination of erlotinib and Ad-dnIGF-1R synergistically inhibits the growth of tumors in xenograft mouse models . able outcomes...of erlotinib and Ad-dnIGF-1R synergistically inhibits the growth of tumors in xenograft mouse models . Specific Aim 2.3: To investigate the...biomarkers and adaptive randomization via hierarchical Bayes modeling . 2) To study the molecular mechanisms of response and resistance to targeted

Synergistically combined gene delivery for enhanced VEGF secretion and anti-apoptosis

PubMed Central

Won, Young-Wook; Lee, Minhyung; Kim, Hyun Ah; Nam, Kihoon; Bull, David A.; Kim, Sung Wan

2013-01-01

With current pharmacological treatments, preventing the remodeling of the left ventricle and the progression to heart failure is a difficult task. Gene therapy is considered to provide a direct treatment to the long-term complications of ischemic heart diseases. Although current gene therapies that use single molecular targets seem potentially possible, they have not achieved a success in the treatment of ischemic diseases. With an efficient polymeric gene carrier, PAM-ABP, we designed a synergistically combined gene delivery strategy to enhance vascular endothelial growth factor (VEGF) secretion and prolong anti-apoptotic effects. A hypoxia-inducible plasmid expressing both hypoxia-inducible heme oxygenase-1 (HO-1) and the Src homology domain-2 containing tyrosine phosphatase-1 microRNA (miSHP 1) and a hypoxia-responsive VEGF plasmid were combined in this study. The positive feedback circuit between HO-1 and VEGF, and the negative regulatory role of SHP-1 in angiogenesis enhance VEGF secretion synergistically. The synergy in VEGF secretion as a consequence of the gene combination and the prolonged HO-1 activity was confirmed in hypoxic cardiomyocytes and cardiomyocyte apoptosis under hypoxia, and was decreased synergistically. These results suggest that the synergistic combination of VEGF, HO-1, and miSHP-1 may be promising for the clinical treatment of ischemic diseases. PMID:24007285

DOT1L inhibitor EPZ-5676 displays synergistic antiproliferative activity in combination with standard of care drugs and hypomethylating agents in MLL-rearranged leukemia cells.

PubMed

Klaus, Christine R; Iwanowicz, Dorothy; Johnston, Danielle; Campbell, Carly A; Smith, Jesse J; Moyer, Mikel P; Copeland, Robert A; Olhava, Edward J; Scott, Margaret Porter; Pollock, Roy M; Daigle, Scott R; Raimondi, Alejandra

2014-09-01

EPZ-5676 [(2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol], a small-molecule inhibitor of the protein methyltransferase DOT1L, is currently under clinical investigation for acute leukemias bearing MLL-rearrangements (MLL-r). In this study, we evaluated EPZ-5676 in combination with standard of care (SOC) agents for acute leukemias as well as other chromatin-modifying drugs in cellular assays with three human acute leukemia cell lines: MOLM-13 (MLL-AF9), MV4-11 (MLL-AF4), and SKM-1 (non-MLL-r). Studies were performed to evaluate the antiproliferative effects of EPZ-5676 combinations in a cotreatment model in which the second agent was added simultaneously with EPZ-5676 at the beginning of the assay, or in a pretreatment model in which cells were incubated for several days in the presence of EPZ-5676 prior to the addition of the second agent. EPZ-5676 was found to act synergistically with the acute myeloid leukemia (AML) SOC agents cytarabine or daunorubicin in MOLM-13 and MV4-11 MLL-r cell lines. EPZ-5676 is selective for MLL-r cell lines as demonstrated by its lack of effect either alone or in combination in the nonrearranged SKM-1 cell line. In MLL-r cells, the combination benefit was observed even when EPZ-5676 was washed out prior to the addition of the chemotherapeutic agents, suggesting that EPZ-5676 sets up a durable, altered chromatin state that enhances the chemotherapeutic effects. Our evaluation of EPZ-5676 in conjunction with other chromatin-modifying drugs also revealed a consistent combination benefit, including synergy with DNA hypomethylating agents. These results indicate that EPZ-5676 is highly efficacious as a single agent and synergistically acts with other chemotherapeutics, including AML SOC drugs and DNA hypomethylating agents in MLL-r cells. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Population Density, Climate Variables and Poverty Synergistically Structure Spatial Risk in Urban Malaria in India

PubMed Central

Santos-Vega, Mauricio; Bouma, Menno J; Kohli, Vijay; Pascual, Mercedes

2016-01-01

Background The world is rapidly becoming urban with the global population living in cities projected to double by 2050. This increase in urbanization poses new challenges for the spread and control of communicable diseases such as malaria. In particular, urban environments create highly heterogeneous socio-economic and environmental conditions that can affect the transmission of vector-borne diseases dependent on human water storage and waste water management. Interestingly India, as opposed to Africa, harbors a mosquito vector, Anopheles stephensi, which thrives in the man-made environments of cities and acts as the vector for both Plasmodium vivax and Plasmodium falciparum, making the malaria problem a truly urban phenomenon. Here we address the role and determinants of within-city spatial heterogeneity in the incidence patterns of vivax malaria, and then draw comparisons with results for falciparum malaria. Methodology/principal findings Statistical analyses and a phenomenological transmission model are applied to an extensive spatio-temporal dataset on cases of Plasmodium vivax in the city of Ahmedabad (Gujarat, India) that spans 12 years monthly at the level of wards. A spatial pattern in malaria incidence is described that is largely stationary in time for this parasite. Malaria risk is then shown to be associated with socioeconomic indicators and environmental parameters, temperature and humidity. In a more dynamical perspective, an Inhomogeneous Markov Chain Model is used to predict vivax malaria risk. Models that account for climate factors, socioeconomic level and population size show the highest predictive skill. A comparison to the transmission dynamics of falciparum malaria reinforces the conclusion that the spatio-temporal patterns of risk are strongly driven by extrinsic factors. Conclusion/significance Climate forcing and socio-economic heterogeneity act synergistically at local scales on the population dynamics of urban malaria in this city. The stationarity of malaria risk patterns provides a basis for more targeted intervention, such as vector control, based on transmission ‘hotspots’. This is especially relevant for P. vivax, a more resilient parasite than P. falciparum, due to its ability to relapse and the operational shortcomings of delivering a “radical cure”. PMID:27906962

Synergistic Activity between Two Antifungal Proteins, the Plant Defensin NaD1 and the Bovine Pancreatic Trypsin Inhibitor

PubMed Central

Dawson, Charlotte S.; McKenna, James A.; Quimbar, Pedro; Hayes, Brigitte M. E.; van der Weerden, Nicole L.

2017-01-01

ABSTRACT Defensins are a large family of small, cationic, cysteine-rich proteins that are part of the defense arsenal that plants use for protection against potentially damaging fungal infections. The plant defensin NaD1 from Nicotiana alata is a potent antifungal protein that inhibits growth and kills a variety of fungal pathogens that affect both plant and animal (human) hosts. Some serine protease inhibitors have also been reported to be antifungal molecules, while others have no inhibitory activity against fungi. Here we describe the synergistic activity of the plant defensin NaD1 with a selection of serine protease inhibitors against the plant pathogens Fusarium graminearum and Colletotrichum graminicola and the animal pathogen Candida albicans. The synergistic activity was not related to the protease inhibitory activity of these molecules but may arise from activation of fungal stress response pathways. The bovine pancreatic trypsin inhibitor (BPTI) displayed the most synergy with NaD1. BPTI also acted synergistically with several other antifungal molecules. The observation that NaD1 acts synergistically with protease inhibitors provides the foundation for the design of transgenic plants with improved resistance to fungal disease. It also supports the possibility of naturally occurring accessory factors that function to enhance the activity of innate immunity peptides in biological systems. IMPORTANCE This work describes the increased activity of a natural antifungal peptide in the presence of another antifungal peptide from a different family. This is termed antifungal synergy. Synergy is important for decreasing the amount of antifungal molecule needed to control the disease. Traditionally, naturally occurring antifungal molecules are assayed in isolation. Identification of synergistic interactions between antifungal peptides means that their activities in a complex biological system are likely to be different from what we observe when examining them individually. This study identified synergy between an antifungal peptide and a group of peptides that do not affect fungal growth in vitro. This provides the foundation for generation of transgenic plants with increased resistance to fungal disease and identification of antifungal accessory factors that enhance the activity of innate immune molecules but do not have an antifungal effect on their own. PMID:29062897

Drug particle size influence on enteric beads produced by a droplet extrusion/precipitation method.

PubMed

Cerdeira, A M; Gouveia, L F; Goucha, P; Almeida, A J

2000-01-01

The influence of drug particle size on the production of enteric beads by a polymer precipitation technique was investigated. Drug particle dimensions are known to play an important role in most microencapsulation techniques. Bead morphology was greatly influenced by drug particle size, and spherical shaped beads could only be obtained after size reduction of nimesulide crystals. This is confirmed by the angle of repose measurements, which show a significant decrease in theta values when beads are formulated with smaller drug particles. Furthermore, results show that drug encapsulation efficiency and in vitro drug release rates are also greatly dependent on both drug particle size and drug/polymer ratio in the initial suspension. Preparations containing 10.2 microm drug particles show a two-fold increase in the release rates when compared to those prepared with 40 microm particles.

Population Density, Climate Variables and Poverty Synergistically Structure Spatial Risk in Urban Malaria in India.

PubMed

Santos-Vega, Mauricio; Bouma, Menno J; Kohli, Vijay; Pascual, Mercedes

2016-12-01

The world is rapidly becoming urban with the global population living in cities projected to double by 2050. This increase in urbanization poses new challenges for the spread and control of communicable diseases such as malaria. In particular, urban environments create highly heterogeneous socio-economic and environmental conditions that can affect the transmission of vector-borne diseases dependent on human water storage and waste water management. Interestingly India, as opposed to Africa, harbors a mosquito vector, Anopheles stephensi, which thrives in the man-made environments of cities and acts as the vector for both Plasmodium vivax and Plasmodium falciparum, making the malaria problem a truly urban phenomenon. Here we address the role and determinants of within-city spatial heterogeneity in the incidence patterns of vivax malaria, and then draw comparisons with results for falciparum malaria. Statistical analyses and a phenomenological transmission model are applied to an extensive spatio-temporal dataset on cases of Plasmodium vivax in the city of Ahmedabad (Gujarat, India) that spans 12 years monthly at the level of wards. A spatial pattern in malaria incidence is described that is largely stationary in time for this parasite. Malaria risk is then shown to be associated with socioeconomic indicators and environmental parameters, temperature and humidity. In a more dynamical perspective, an Inhomogeneous Markov Chain Model is used to predict vivax malaria risk. Models that account for climate factors, socioeconomic level and population size show the highest predictive skill. A comparison to the transmission dynamics of falciparum malaria reinforces the conclusion that the spatio-temporal patterns of risk are strongly driven by extrinsic factors. Climate forcing and socio-economic heterogeneity act synergistically at local scales on the population dynamics of urban malaria in this city. The stationarity of malaria risk patterns provides a basis for more targeted intervention, such as vector control, based on transmission 'hotspots'. This is especially relevant for P. vivax, a more resilient parasite than P. falciparum, due to its ability to relapse and the operational shortcomings of delivering a "radical cure".

Peripheral analgesic sites of action of anti-inflammatory drugs.

PubMed

Ferreira, S H

2002-07-01

Inflammatory signs and symptoms of redness, swelling, heat and pain are due to the effects of inflammatory mediators released during the inflammatory response. Depending on the type of injurious stimuli and the tissue involved, the array of mediators may differ but eicosanoids are involved in the genesis of inflammatory pain. They are responsible for the hypersensitisation of the nociceptors (allodynialhyperalgesia). The basic mechanism of analgesic action of nonsteroidal anti-inflammatory drugs results from the inhibition of prostaglandin synthesis (prostacyclin or PGE2), thus preventing nociceptor threshold lowering. Because there is a temporal hierarchy in the release of inflammatory mediators, there are several targets for the action of peripheral acting analgesics before and after the inhibition of prostaglandin synthesis. Blockade of the release and inhibition of inducible cyclooxygenase explain the analgesic action of glucocorticoids. Nimesulide also has an inhibitory action on the cascade of hypersensitising cytokines. Some analgesics, such as dipyrone, flurbiprofen or diclofenac, act directly upon ongoing inflammatory hypersensitisation. Those analgesics restore the nociceptor by stimulating the arginine/NO/cGMP/K(ATP) channel pathway.

Occurrence of pharmaceutical compounds in wastewater process streams in Dublin, Ireland.

PubMed

Lacey, Clair; Basha, Shaik; Morrissey, Anne; Tobin, John M

2012-01-01

The aim of this work is to establish baseline levels of pharmaceuticals in three wastewater treatment plant (WWTP) streams in the greater Dublin region to assess the removal efficiency of the selected WWTPs and to investigate the existence of any seasonal variability. Twenty compounds including several classes of antibiotics, acidic and basic pharmaceuticals, and prescribed medications were selected for investigation using a combination of membrane filtration, solid phase extraction (SPE) cleanup, and liquid chromatography-electrospray ionization tandem mass spectrometry. Fourteen of the selected compounds were found in the samples. Increased effluent concentrations, compared to influent concentrations, for a number of compounds (carbamazepine, clotrimazole, propranolol, nimesulide, furosemide, mefenamic acid, diclofenac, metoprolol, and gemfibrozil) were observed. The detected concentrations were generally below toxicity levels and based on current knowledge are unlikely to pose any threat to aquatic species. Mefenamic acid concentrations detected in both Leixlip and Swords effluents may potentially exert ecotoxicological effects with maximum risk quotients (i.e., ratio of predicted exposure concentration to predicted no effect concentration) of 4.04 and 1.33, respectively.

Evidence suggesting a stimulatory role for interleukin-10 in erythropoiesis in vitro.

PubMed

Wang, C Q; Udupa, K B; Lipschitz, D A

1996-02-01

Interleukin-10 (IL-10) has been shown to exert anti-inflammatory effects by suppressing macrophage proliferation and inhibiting cytokine production. In this study we show that in the presence of erythropoietin (EPO), the addition of IL-10 results in a significant dose-dependent increase in both Burst Forming Unit-Erythroid (BFU-E) and Colony Forming Unit-Erythroid (CFU-E) colony growth in both serum-containing and serum-free murine cultures in vitro. IL-10 acts at the later stages of erythroid cell proliferation and differentiation as the increase in colony number was greater in CFU-E than in BFU-E, and was similar when IL-10 was added to BFU-E cultures at the time of culture initiation as when its addition to culture was delayed for 7 days. Furthermore, no increase in BFU-E colony number was noted when IL-10, added at the time of culture initiation, was neutralized by the addition to culture of a monoclonal anti-IL-10 antibody up to 7 days later. The increases in BFU-E by IL-10 addition were not the result of prolongation of BFU-E colony lifespan, which was not significantly different in IL-10 treated and control cultures, respectively. Rather IL-10 stimulated the proliferation of erythroid clusters that were now large enough to be recognized as colonies. IL-10-induced stimulation of erythropoiesis appeared to be independent of its inhibitory effects on macrophage function, as stimulation of erythroid colony growth was similar in macrophage-containing and depleted cultures. Studies to determine if the IL-10 effect was direct or indirect yielded equivocal results. A limiting dilution assay suggested a direct effect. However, a log/log dose response curve with IL-10 did not pass through the origin suggesting an indirect effect. These studies indicate that IL-10 acts synergistically with EPO to significantly increase stimulation of erythroid differentiation and proliferation in vitro and may be involved in the regulation of normal erythropoiesis in vivo.

Identification of a novel splice variant isoform of TREM-1 in human neutrophil granules1

PubMed Central

Baruah, Sankar; Keck, Kathy; Vrenios, Michelle; Pope, Marshall; Pearl, Merideth; Doerschug, Kevin; Klesney-Tait, Julia

2015-01-01

Triggering receptor expressed on myeloid cells-1 (TREM-1) is critical for inflammatory signal amplification. Humans have two forms of TREM-1: a membrane receptor (mbTREM-1), associated with the adaptor DAP12, and a soluble receptor detected at times of infection. The membrane receptor isoform acts synergistically with the TLR pathway to promote cytokine secretion and neutrophil migration while the soluble receptor functions as a counter regulatory molecule. In multiple models of sepsis, exogenous administration of soluble forms of TREM-1 attenuates inflammation and markedly improves survival. Despite intense interest in soluble TREM-1 both as a clinical predictor of survival and as a therapeutic tool, the origin of native soluble TREM-1 remains controversial. Utilizing human neutrophils, we identified a 15 kDa TREM-1 isoform in primary (azurophilic) and secondary (specific) granules. Mass spectrometric analysis, ELISA, and immunoblot confirm that the 15 kD protein is a novel splice variant of TREM-1 (TREM-1sv). Neutrophil stimulation with P. aeruginosa, LPS, or PAM(3)Cys4 resulted in degranulation and release of TREM-1sv. The addition of exogenous TREM-1sv inhibited TREM-1 receptor mediated proinflammatory cytokine production. Thus these data reveal that TREM-1 isoforms simultaneously activate and inhibit inflammation via the canonical membrane TREM-1 molecule and this newly discovered granular isoform, TREM-1sv. PMID:26561551

Modeling tandem AAG8-MEK inhibition in melanoma cells

PubMed Central

Sun, Bing; Kawahara, Masahiro; Nagamune, Teruyuki

2014-01-01

Drug resistance presents a challenge to the treatment of cancer patients, especially for melanomas, most of which are caused by the hyperactivation of MAPK signaling pathway. Innate or acquired drug-resistant relapse calls for the investigation of the resistant mechanisms and new anti-cancer drugs to provide implications for the ultimate goal of curative therapy. Aging-associated gene 8 (AAG8, encoded by the SIGMAR1 gene) is a chaperone protein profoundly elaborated in neurology. However, roles of AAG8 in carcinogenesis remain unclear. Herein, we discover AAG8 antagonists as new MEK inhibitors in melanoma cells and propose a novel drug combination strategy for melanoma therapy by presenting the experimental evidences. We report that specific antagonism of AAG8, efficiently suppresses melanoma cell growth and migration through, at least in part, the inactivation of the RAS-CRAF-MEK signaling pathway. We further demonstrate that melanoma cells that are resistant to AAG8 antagonist harbor refractory CRAF-MEK activity. MEK acts as a central mediator for anti-cancer effects and also for the resistance mechanism, leading to our proposal of tandem AAG8-MEK inhibition in melanoma cells. Combination of AAG8 antagonist and very low concentration of a MEK inhibitor synergistically restricts the growth of drug-resistant cells. These data collectively pinpoint AAG8 as a potential target and delineate a promising drug combination strategy for melanoma therapy. PMID:24634165

Vitamin K2 and cotylenin A synergistically induce monocytic differentiation and growth arrest along with the suppression of c-MYC expression and induction of cyclin G2 expression in human leukemia HL-60 cells.

PubMed

Maniwa, Yasuhisa; Kasukabe, Takashi; Kumakura, Shunichi

2015-08-01

Although all-trans retinoic acid (ATRA) is a standard and effective drug used for differentiation therapy in acute promyelocytic leukemia, ATRA-resistant leukemia cells ultimately emerge during this treatment. Therefore, the development of new drugs or effective combination therapy is urgently needed. We demonstrate that the combined treatment of vitamin K2 and cotylenin A synergistically induced monocytic differentiation in HL-60 cells. This combined treatment also synergistically induced NBT-reducing activity and non-specific esterase-positive cells as well as morphological changes to monocyte/macrophage-like cells. Vitamin K2 and cotylenin A cooperatively inhibited the proliferation of HL-60 cells in short-term and long-term cultures. This treatment also induced growth arrest at the G1 phase. Although 5 µg/ml cotylenin A or 5 µM vitamin K2 alone reduced c-MYC gene expression in HL-60 cells to approximately 45% or 80% that of control cells, respectively, the combined treatment almost completely suppressed c-MYC gene expression. We also demonstrated that the combined treatment of vitamin K2 and cotylenin A synergistically induced the expression of cyclin G2, which had a positive effect on the promotion and maintenance of cell cycle arrest. These results suggest that the combination of vitamin K2 and cotylenin A has therapeutic value in the treatment of acute myeloid leukemia.

Roles for both FtsA and the FtsBLQ subcomplex in FtsN-stimulated cell constriction in Escherichia coli

PubMed Central

Liu, Bing; Persons, Logan; Lee, Lynda; de Boer, Piet A. J.

2015-01-01

SUMMARY Escherichia coli FtsN is a bitopic membrane protein that is essential for triggering active cell constriction. A small periplasmic subdomain (EFtsN) is required and sufficient for function, but its mechanism of action is unclear. We isolated extragenic EFtsN*-suppressing mutations that restore division in cells producing otherwise non-functional variants of FtsN. These mapped to the IC domain of FtsA in the cytoplasm and to small subdomains of the FtsB and FtsL proteins in the periplasm. All FtsB and FtsL variants allowed survival without EFtsN, but many then imposed a new requirement for interaction between the cytoplasmic domain of FtsN (NFtsN) with FtsA. Alternatively, variants of FtsA, FtsB or FtsL acted synergistically to allow cell division in the complete absence of FtsN. Strikingly, moreover, substitution of a single residue in FtsB (E56) proved sufficient to rescue ΔftsN cells as well. In FtsN+ cells, EFtsN*-suppressing mutations promoted cell fission at an abnormally small cell size, and caused cell shape and integrity defects under certain conditions. This and additional evidence support a model in which FtsN acts on either side of the membrane to induce a conformational switch in both FtsA and the FtsBLQ subcomplex to derepress septal peptidoglycan synthesis and membrane invagination. PMID:25496160

The Effect of Hydrostatic Pressure on Enrichments of Hydrocarbon Degrading Microbes From the Gulf of Mexico Following the Deepwater Horizon Oil Spill

PubMed Central

Marietou, Angeliki; Chastain, Roger; Beulig, Felix; Scoma, Alberto; Hazen, Terry C.; Bartlett, Douglas H.

2018-01-01

The Deepwater Horizon oil spill was one of the largest and deepest oil spills recorded. The wellhead was located at approximately 1500 m below the sea where low temperature and high pressure are key environmental characteristics. Using cells collected 4 months following the Deepwater Horizon oil spill at the Gulf of Mexico, we set up Macondo crude oil enrichments at wellhead temperature and different pressures to determine the effect of increasing depth/pressure to the in situ microbial community and their ability to degrade oil. We observed oil degradation under all pressure conditions tested [0.1, 15, and 30 megapascals (MPa)], although oil degradation profiles, cell numbers, and hydrocarbon degradation gene abundances indicated greatest activity at atmospheric pressure. Under all incubations the growth of psychrophilic bacteria was promoted. Bacteria closely related to Oleispira antarctica RB-8 dominated the communities at all pressures. At 30 MPa we observed a shift toward Photobacterium, a genus that includes piezophiles. Alphaproteobacterial members of the Sulfitobacter, previously associated with oil-degradation, were also highly abundant at 0.1 MPa. Our results suggest that pressure acts synergistically with low temperature to slow microbial growth and thus oil degradation in deep-sea environments. PMID:29755436

Fumonisin FB1 treatment acts synergistically with methyl donor deficiency during rat pregnancy to produce alterations of H3- and H4-histone methylation patterns in fetuses.

PubMed

Pellanda, Hélène; Forges, Thierry; Bressenot, Aude; Chango, Abalo; Bronowicki, Jean-Pierre; Guéant, Jean-Louis; Namour, Fares

2012-06-01

Prenatal folate and methyl donor malnutrition lead to epigenetic alterations that could enhance susceptibility to disease. Methyl-deficient diet (MDD) and fumonisin FB1 are risk factors for neural tube defects and cancers. Evidence indicates that FB1 impairs folate metabolism. Folate receptors and four heterochromatin markers were investigated in rat fetuses liver derived from dams exposed to MDD and/or FB1 administered at a dose twice higher than the provisional maximum tolerable daily intake (PMTDI = 2 μg/kg/day). Even though folate receptors transcription seemed up-regulated by methyl depletion regardless of FB1 treatment, combined MDD/FB1 exposure might reverse this up-regulation since folate receptors transcripts were lower in the MDD/FB1 versus MDD group. Methyl depletion decreased H4K20me3. Combined MDD/FB1 decreased H4K20me3 even more and increased H3K9me3. The elevated H3K9me3 can be viewed as a defense mechanism inciting the cell to resist heterochromatin disorganization. H3R2me2 and H4K16Ac varied according to this mechanism even though statistical significance was not consistent. Considering that humans are exposed to FB1 levels above the PMTDI, this study is relevant because it suggests that low doses of FB1 interact with MDD thus contributing to disrupt the epigenetic landscape. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Extracellular ATP is a mitogen for 3T3, 3T6, and A431 cells and acts synergistically with other growth factors.

PubMed Central

Huang, N; Wang, D J; Heppel, L A

1989-01-01

Extracellular ATP in concentrations of 5-50 microM displayed very little mitogenic activity by itself but it caused synergistic stimulation of [3H]thymidine incorporation in the presence of phorbol 12-tetradecanoate 13-acetate, epidermal growth factor, platelet-derived growth factor, insulin, adenosine, or 5'-(N-ethyl)carboxamidoadenosine. Cultures of Swiss 3T3, Swiss 3T6, A431, DDT1-MF2, and HFF cells were used. The percent of cell nuclei labeled with [3H]thymidine and cell number were also increased. ADP was equally mitogenic, while UTP and ITP were much less active. The effect of ATP was not due to hydrolysis by ectoenzymes to form adenosine, a known growth factor. Thus, the nonhydrolyzable analogue adenosine 5'-[beta, gamma-imido]triphosphate was mitogenic. In addition, it was found that ATP showed synergism in 3T6 and 3T3 cells when present for only the first hour of an incorporation assay, during which time no significant hydrolysis occurred. Furthermore, prolonged preincubation of cells with ATP reduced the mitogenic response to ATP but not to adenosine; preincubation with adenosine or N6-(R-phenylisopropyl)adenosine had the reverse effect. Finally, the effect of adenosine, but not of ATP, was inhibited by aminophylline. We conclude that extracellular ATP is a mitogen that interacts with P2 purinoceptors on the plasma membrane. PMID:2813367

Synergism between Trichuris suis and the microbial flora of the large intestine causing dysentery in pigs.

PubMed

Rutter, J M; Beer, R J

1975-02-01

The role of the microbial flora of the large intestine in experimental Trichuris suis infection was studied by comparing the clinical syndrome in conventionally reared (CR) pigs, specific pathogen-free pigs, and gnotobiotic pigs. Thedisease in CR pigs was characterized by a severe mucohemorrhagic enteritis; in contrast, a mild catarrhal enteritis was observed in specific pathogen-free and gnotobiotic pigs. Spirochaetes and vibrio-like organisms were observed only in CR pigs and increased during the clinical phase of the disease. The clinical syndrome was not transmitted by oral administration of intestinal or fecal material from infected CR pigs to CR pigs free of T. suis. Smaller numbers of T. suis produced diarrhea in CR pigs and significantly reduced the growth rates of infected animals; clinical signs and the reduction in growth rate was prevented by incorporating an antibacterial substance (dimetridazole) in the food. Although clinical trichuriasis closely resembles swin dysentery, the two syndromes seem to be distinct. The present results suggest that a microbial component acts synergistically with T. suis to produce the severe clinical syndrome in CR pigs, but identification of the microbial component and the mechanism by which clinical signs are produced await further studies of the bacterial flora of the large intestine of pigs.

Combinatorial Control of Light Induced Chromatin Remodeling and Gene Activation in Neurospora

PubMed Central

Sancar, Cigdem; Ha, Nati; Yilmaz, Rüstem; Tesorero, Rafael; Fisher, Tamas; Brunner, Michael; Sancar, Gencer

2015-01-01

Light is an important environmental cue that affects physiology and development of Neurospora crassa. The light-sensing transcription factor (TF) WCC, which consists of the GATA-family TFs WC1 and WC2, is required for light-dependent transcription. SUB1, another GATA-family TF, is not a photoreceptor but has also been implicated in light-inducible gene expression. To assess regulation and organization of the network of light-inducible genes, we analyzed the roles of WCC and SUB1 in light-induced transcription and nucleosome remodeling. We show that SUB1 co-regulates a fraction of light-inducible genes together with the WCC. WCC induces nucleosome eviction at its binding sites. Chromatin remodeling is facilitated by SUB1 but SUB1 cannot activate light-inducible genes in the absence of WCC. We identified FF7, a TF with a putative O-acetyl transferase domain, as an interaction partner of SUB1 and show their cooperation in regulation of a fraction of light-inducible and a much larger number of non light-inducible genes. Our data suggest that WCC acts as a general switch for light-induced chromatin remodeling and gene expression. SUB1 and FF7 synergistically determine the extent of light-induction of target genes in common with WCC but have in addition a role in transcription regulation beyond light-induced gene expression. PMID:25822411

Synergism between resveratrol and other phytochemicals: implications for obesity and osteoporosis.

PubMed

Rayalam, Srujana; Della-Fera, Mary Anne; Baile, Clifton A

2011-08-01

Resveratrol, a phytoalexin, has gained much attention recently due to its effects on sirtuins. While the anti-cancer properties of resveratrol have been extensively investigated, the anti-adipogenic and osteogenic effects of resveratrol are also gaining considerable interest. The finding that resveratrol supplementation mimics caloric restriction prompted researchers to study the effects of resveratrol on lipid metabolism. Mesenchymal stem cells are the precursors for both adipocytes and osteoblasts. In the aging population, differentiation to adipocytes dominates over the differentiation to osteoblasts in bone marrow, contributing to the increased tendency for fractures to occur in the elderly. Thus, an inverse relationship exists between adipocytes and osteoblasts in the bone marrow. Resveratrol acts on several molecular targets in adipocytes and osteoblasts leading to a decrease in adipocyte number and size and an increase in osteogenesis. Furthermore, resveratrol in combination with genistein and quercetin synergistically decreased adipogenesis in murine and human adipocytes. A recent in vivo study showed that phytochemicals including resveratrol in combination with vitamin D prevented weight gain and bone loss in a postmenopausal rat model. Therefore, combinations of resveratrol with other phytochemicals may lead to potential novel potent therapies for both obesity and osteoporosis. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Cationic Polymer That Shows High Antifungal Activity against Diverse Human Pathogens.

PubMed

Rank, Leslie A; Walsh, Naomi M; Liu, Runhui; Lim, Fang Yun; Bok, Jin Woo; Huang, Mingwei; Keller, Nancy P; Gellman, Samuel H; Hull, Christina M

2017-10-01

Invasive fungal diseases are generally difficult to treat and often fatal. The therapeutic agents available to treat fungi are limited, and there is a critical need for new agents to combat these deadly infections. Antifungal compound development has been hindered by the challenge of creating agents that are highly active against fungal pathogens but not toxic to the host. Host defense peptides (HDPs) are produced by eukaryotes as a component of the innate immune response to pathogens and have served as inspiration for the development of many new antibacterial compounds. HDP mimics, however, have largely failed to exhibit potent and selective antifungal activity. Here, we present an HDP-like nylon-3 copolymer that is effective against diverse fungi while displaying only mild to moderate toxicity toward mammalian cells. This polymer is active on its own and in synergy with existing antifungal drugs against multiple species of Candida and Cryptococcus , reaching levels of efficacy comparable to those of the clinical agents amphotericin B and fluconazole in some cases. In addition, the polymer acts synergistically with azoles against different species of Aspergillus , including some azole-resistant strains. These findings indicate that nylon-3 polymers are a promising lead for development of new antifungal therapeutic strategies. Copyright © 2017 American Society for Microbiology.

The role of omega-3 polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids in the treatment of major depression and Alzheimer's disease: Acting separately or synergistically?

PubMed

Song, Cai; Shieh, Chu-Hsin; Wu, Yi-Shyuan; Kalueff, Allan; Gaikwad, Siddharth; Su, Kuan-Pin

2016-04-01

Omega-3 polyunsaturated fatty acids (n-3-PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may improve or prevent some psychiatric and neurodegenerative diseases in both experimental and clinical studies. As important membrane components, these PUFAs benefit brain health by modulating neuroimmune and apoptotic pathways, changing membrane function and/or competing with n-6 PUFAs, the precursors of inflammatory mediators. However, the exact role of each fatty acid in neuroimmune modulation and neurogenesis, the interaction between EPA and DHA, and the best EPA:DHA ratios for improving brain disorders, remain unclear. It is also unknown whether EPA, as a DHA precursor, acts directly or via DHA. Here, we discuss recent evidence of EPA and DHA effects in the treatment of major depression and Alzheimer's disease, as well as their potential synergistic action on anti-inflammatory, antioxidant and neurotrophic processes in the brain. We further analyze the cellular and molecular mechanisms by which EPA, DHA or their combination may benefit these diseases. We also outline the limitations of current studies and suggest new genetic models and novel approaches to overcome these limitations. Finally, we summarize future strategies for translational research in this field. Copyright © 2016 Elsevier B.V. All rights reserved.

Gibberellin Promotes Shoot Branching in the Perennial Woody Plant Jatropha curcas

PubMed Central

Ni, Jun; Gao, Congcong; Chen, Mao-Sheng; Pan, Bang-Zhen; Ye, Kaiqin; Xu, Zeng-Fu

2015-01-01

Strigolactone (SL), auxin and cytokinin (CK) interact to regulate shoot branching. CK has long been considered to be the only key phytohormone to promote lateral bud outgrowth. Here we report that gibberellin also acts as a positive regulator in the control of shoot branching in the woody plant Jatropha curcas. We show that gibberellin and CK synergistically promote lateral bud outgrowth, and that both hormones influence the expression of putative branching regulators, J. curcas BRANCHED1 and BRANCHED2, which are key transcription factors maintaining bud dormancy. Moreover, treatment with paclobutrazol, an inhibitor of de novo gibberellin biosynthesis, significantly reduced the promotion of bud outgrowth by CK, suggesting that gibberellin is required for CK-mediated axillary bud outgrowth. In addition, SL, a plant hormone involved in the repression of shoot branching, acted antagonistically to both gibberellin and CK in the control of lateral bud outgrowth. Consistent with this, the expression of JcMAX2, a J. curcas homolog of Arabidopsis MORE AXILLARY GROWTH 2 encoding an F-box protein in the SL signaling pathway, was repressed by gibberellin and CK treatment. We also provide physiological evidence that gibberellin also induces shoot branching in many other trees, such as papaya, indicating that a more complicated regulatory network occurs in the control of shoot branching in some perennial woody plants. PMID:26076970

Lack of immunotoxicity of saquinavir (Ro 31-8959) used alone or in double or triple combination with AZT and ddC.

PubMed

Viora, M; Di Genova, G; Quaranta, M G; Boirivant, M; Camponeschi, B

1998-09-01

Saquinavir (Ro 31-8959; SQV) has been demonstrated to be a potent inhibitor of human immunodeficiency virus (HIV) proteinases and acts synergistically with dideoxynucleoside analogues. The aim of this study was to investigate the in vitro immunomodulatory effects of SQV on normal human peripheral blood mononuclear cells (PBMC) and on lamina propria mononuclear cells (LPMC). We used the drug either alone or in double and triple combination with AZT and ddC to assess whether SQV enhances the immunomodulatory effects induced by AZT and ddC that we previously observed. We demonstrated that SQV did not induce any modulation of the proliferative response either in PBMC or in LPMC. Similarly, NK cell-mediated cytotoxic activity and cytokine production were not modified by SQV. More importantly, SQV/AZT, SQV/ddC, and SQV/AZT/ddC combinations did not strengthen neither the inhibition of PBMC and LPMC proliferative response or the modulation of cytokine production induced by AZT, ddC, and AZT/ddC. On the other hand, the increased IL-2 production induced by AZT and ddC was not observed adding SQV to the dideoxynucleoside analogues. In conclusion, we demonstrated that SQV used in combination with AZT and ddC did not add any further immunotoxicity.

Nuclear Photosynthetic Gene Expression Is Synergistically Modulated by Rates of Protein Synthesis in Chloroplasts and Mitochondria[W

PubMed Central

Pesaresi, Paolo; Masiero, Simona; Eubel, Holger; Braun, Hans-Peter; Bhushan, Shashi; Glaser, Elzbieta; Salamini, Francesco; Leister, Dario

2006-01-01

Arabidopsis thaliana mutants prors1-1 and -2 were identified on the basis of a decrease in effective photosystem II quantum yield. Mutations were localized to the 5′-untranslated region of the nuclear gene PROLYL-tRNA SYNTHETASE1 (PRORS1), which acts in both plastids and mitochondria. In prors1-1 and -2, PRORS1 expression is reduced, along with protein synthesis in both organelles. PRORS1 null alleles (prors1-3 and -4) result in embryo sac and embryo development arrest. In mutants with the leaky prors1-1 and -2 alleles, transcription of nuclear genes for proteins involved in photosynthetic light reactions is downregulated, whereas genes for other chloroplast proteins are upregulated. Downregulation of nuclear photosynthetic genes is not associated with a marked increase in the level of reactive oxygen species in leaves and persists in the dark, suggesting that the transcriptional response is light and photooxidative stress independent. The mrpl11 and prpl11 mutants are impaired in the mitochondrial and plastid ribosomal L11 proteins, respectively. The prpl11 mrpl11 double mutant, but neither of the single mutants, resulted in strong downregulation of nuclear photosynthetic genes, like that seen in leaky mutants for PRORS1, implying that, when organellar translation is perturbed, signals derived from both types of organelles cooperate in the regulation of nuclear photosynthetic gene expression. PMID:16517761

The Effect of Hydrostatic Pressure on Enrichments of Hydrocarbon Degrading Microbes From the Gulf of Mexico Following the Deepwater Horizon Oil Spill.

PubMed

Marietou, Angeliki; Chastain, Roger; Beulig, Felix; Scoma, Alberto; Hazen, Terry C; Bartlett, Douglas H

2018-01-01

The Deepwater Horizon oil spill was one of the largest and deepest oil spills recorded. The wellhead was located at approximately 1500 m below the sea where low temperature and high pressure are key environmental characteristics. Using cells collected 4 months following the Deepwater Horizon oil spill at the Gulf of Mexico, we set up Macondo crude oil enrichments at wellhead temperature and different pressures to determine the effect of increasing depth/pressure to the in situ microbial community and their ability to degrade oil. We observed oil degradation under all pressure conditions tested [0.1, 15, and 30 megapascals (MPa)], although oil degradation profiles, cell numbers, and hydrocarbon degradation gene abundances indicated greatest activity at atmospheric pressure. Under all incubations the growth of psychrophilic bacteria was promoted. Bacteria closely related to Oleispira antarctica RB-8 dominated the communities at all pressures. At 30 MPa we observed a shift toward Photobacterium , a genus that includes piezophiles. Alphaproteobacterial members of the Sulfitobacter , previously associated with oil-degradation, were also highly abundant at 0.1 MPa. Our results suggest that pressure acts synergistically with low temperature to slow microbial growth and thus oil degradation in deep-sea environments.

T-614, a novel immunomodulator, attenuates joint inflammation and articular damage in collagen-induced arthritis

PubMed Central

Du, Fang; Lü, Liang-jing; Fu, Qiong; Dai, Min; Teng, Jia-lin; Fan, Wei; Chen, Shun-le; Ye, Ping; Shen, Nan; Huang, Xin-fang; Qian, Jie; Bao, Chun-de

2008-01-01

Introduction T-614 is a novel oral antirheumatic agent for the treatment of rheumatoid arthritis. Whether it has immunomodulatory or disease-modifying properties and its mechanism of action are largely undetermined. Methods Rats with collagen-induced arthritis (CIA) were treated with T-614 (5 and 20 mg/kg) daily. Animals receiving methotrexate (1 mg/kg every 3 days) and the nonsteroidal anti-inflammatory agent nimesulide (10 mg/kg per day) were used as controls. A combination therapy group was treated with both T-614(10 mg/kg per day) and methotrexate (1 mg/kg every 3 days). Hind paw swelling was evaluated and radiographic scores calculated. Serum cytokine levels were assessed by Bio-plex analysis. Quantitative PCR was used to evaluate expression of mRNA for interferon-γ, IL-4 and IL-17. Serum IL-17 and anti-type II collagen antibodies (total IgG, IgG1, IgG2a, IgG2b and IgM) were measured using ELISA. Results Oral T-614 inhibited paw swelling and offered significant protection against arthritis-induced cartilage and bone erosion, comparable to the effects of methotrexate. CIA rats treated with T-614 exhibited decreases in both mRNA expression of IL-17 in peripheral blood mononuclear cells and lymph node cells, and circulating IL-17 in a dose-dependent manner. T-614 also reduced serum levels of tumor necrosis factor-α, IL-1β and IL-6. A synergistic effect was observed for the combination of methotrexate and T-614. In addition, T-614 (20 mg/kg per day) depressed production of anti-type II collagen antibodies and differentially affected levels of IgG2a subclasses in vivo, whereas IgM level was decreased without any change in the IgG1 level. Together, the findings presented here indicate that the novel agent T-614 has disease-modifying effects against experimental arthritis, as opposed to nimesulide. Conclusions Our data suggested that T-614 is an effective disease-modifying agent that can prevent bone/cartilage destruction and inflammation in in CIA rats. Combination with methotrexate markedly enhances the therapeutic effect of T-614. PMID:19019215

Drug repurposing: In-vitro anti-glycation properties of 18 common drugs

PubMed Central

Rasheed, Saima; Sánchez, Sara S.; Yousuf, Sammer; Honoré, Stella M.; Choudhary, M. Iqbal

2018-01-01

Drug repositioning or repurposing, i.e. identifying new indications for existing drugs, has gained increasing attention in the recent years. This approach enables the scientists to discover “new targets” for known drugs in a cost and time efficient manner. Glycation, the non-enzymatic reaction of sugars with proteins or nucleic acids to form early glycation (Amadori or fructosamine) products, is a key molecular basis of diabetic complications. Inhibiting the process of non-enzymatic protein glycation is one of the key strategies to prevent glycation-mediated diabetic complications. The present study focuses on the anti-glycation activity of 18 drugs, commonly used for the treatment of gastrointestinal, central nervous system, inflammatory diseases, bacterial infections, and gout. This study was carried out by using two in-vitro protein anti-glycation assay models. Results revealed that nimesulide (3), a non-steroidal anti-inflammatory drug, possesses a good anti-glycation activity in in-vitro BSA-MG and BSA-glucose glycation models with IC50 values of 330.56 ± 2.90, and 145.46 ± 16.35 μM, respectively. Phloroglucinol dihydrate (11), a drug used for the treatment of gastrointestinal diseases, showed a weak activity in BSA-MG glycation model (IC50 = 654.89 ± 2.50 μM), while it showed a good activity in BSA-glucose assay (IC50 = 148.23 ± 0.15 μM). Trimethylphloroglucinol (9), a drug used for the treatment of pain related to functional disorders of the digestive and biliary tracts, also showed a good antiglycation activity in BSA-MG model (IC50 = 321.15 ± 1.26 μM), while it was found to be inactive in in-vitro BSA-glucose assay (IC50 = 12.95% inhibition). These activities of drugs were compared with the anti-glycation activity of the standard, rutin (IC50 = 294.5 ± 1.50 μM in BSA-MG glycation model, and IC50 = 86.94 ± 0.24 μM in BSA- glucose model). Rest of the drugs exhibited a relatively weak antiglycation activity. This study identifies nimesulide (3), and phloroglucinol dihydrate (11) as new inhibitors of in-vitro protein glycation for further investigations as potential anti-diabetic agents. PMID:29300762

Human milk inactivates pathogens individually, additively, and synergistically.

PubMed

Isaacs, Charles E

2005-05-01

Breast-feeding can reduce the incidence and the severity of gastrointestinal and respiratory infections in the suckling neonate by providing additional protective factors to the infant's mucosal surfaces. Human milk provides protection against a broad array of infectious agents through redundancy. Protective factors in milk can target multiple early steps in pathogen replication and target each step with more than one antimicrobial compound. The antimicrobial activity in human milk results from protective factors working not only individually but also additively and synergistically. Lipid-dependent antimicrobial activity in milk results from the additive activity of all antimicrobial lipids and not necessarily the concentration of one particular lipid. Antimicrobial milk lipids and peptides can work synergistically to decrease both the concentrations of individual compounds required for protection and, as importantly, greatly reduce the time needed for pathogen inactivation. The more rapidly pathogens are inactivated the less likely they are to establish an infection. The total antimicrobial protection provided by human milk appears to be far more than can be elucidated by examining protective factors individually.

Diospyros lotus leaf and grapefruit stem extract synergistically ameliorate atopic dermatitis-like skin lesion in mice by suppressing infiltration of mast cells in skin lesions.

PubMed

Cho, Byoung Ok; Che, Denis Nchang; Yin, Hong Hua; Shin, Jae Young; Jang, Seon Il

2017-05-01

Atopic dermatitis, a chronic relapsing and pruritic inflammation of the skin also thought to be involved in, or caused by immune system destruction is an upsetting health problem due to its continuously increasing incidence especially in developed countries. Mast cell infiltration in atopic dermatitis skin lesions and its IgE-mediated activation releases various cytokines and chemokines that have been implicated in the pathogenesis of atopic dermatitis. This study was aimed at investigating synergistic anti-inflammatory, anti-pruritic and anti-atopic dermatitis effects of Diospyros lotus leaf extract (DLE) and Muscat bailey A grapefruit stem extract (GFSE) in atopic dermatitis-like induced skin lesions in mice. Combinations of DLE and GFSE inhibited TNF-α and IL-6 production more than DLE or GFSE in PMA plus calcium ionophore A23187-activated HMC-1 cells. DLE and GFSE synergistically inhibited compound 48/80-induced dermal infiltration of mast cells and reduced scratching behavior than DLE or GFSE. Furthermore, DLE and GFSE synergistically showed a stronger ameliorative effect in skin lesions by reducing clinical scores; dermal infiltration of mast cells; ear and dorsal skin thickness; serum IgE and IL-4 production in atopic dermatitis-like mice. Collectively, these results suggest that DLE and GFSE synergistically exhibit anti-atopic dermatitis effects in atopic dermatitis-like skin lesions in mice. Copyright © 2017. Published by Elsevier Masson SAS.

Stroke from Vasospasm due to Marijuana Use: Can Cannabis Synergistically with Other Medications Trigger Cerebral Vasospasm?

PubMed

Jamil, Marium; Zafar, Atif; Adeel Faizi, Syed; Zawar, Ifrah

2016-01-01

We present a case of imaging proven cerebral vasospasm causing ischemic stroke in a young patient chronically on buprenorphine-naloxone for heroin remission who started smoking cannabis on a daily basis. With cannabis legalization spreading across the states in the USA, it is important for physicians not only to be aware of cannabis reported association with cerebral vasospasm in some patients but also to be on the lookout for possible interacting medications that can synergistically affect cerebral vessels causing debilitating strokes.

Effects of pro-inflammatory cytokines, lipopolysaccharide and COX-2 mediators on human colonic neuromuscular function and epithelial permeability.

PubMed

Safdari, B K; Sia, T C; Wattchow, D A; Smid, S D

2016-07-01

Chronic colitis is associated with decreased colonic muscle contraction and loss of mucosal barrier function. Pro-inflammatory cytokines and bacterial lipopolysaccharide (LPS) are important in the generation and maintenance of inflammation. While colitis is associated with upregulated COX-2 -derived prostanoids and nitric oxide (NO), the direct activity of pro-inflammatory cytokines on human colonic neuromuscular function is less clear. This study investigated the effects of IBD-associated pro-inflammatory cytokines IL-17, TNF-α, IL-1β and LPS on human colonic muscle strip contractility, alone and following inhibition of COX-2 or nitric oxide production. In addition, human colonic epithelial Caco-2 cell monolayers were treated with LPS or COX-2 mediators including prostaglandins (PGE2, PGF2α) or their corresponding ethanolamides (PGE2-EA or PGF2α-EA) over 48h and trans-epithelial electrical resistance used to record permeability changes. Longitudinal muscle strips were obtained from healthy colonic resection margins and mounted in organ baths following IL-17, TNF-α, IL-1β and bacterial LPS incubations in an explant setting over 20h. Contraction in response to acetylcholine (ACh) was then measured, before and after either COX-2 inhibition (nimesulide; 10(-5)M) or nitric oxide synthase (NOS) inhibition (l-NNA; 10(-4)M). None of the cytokine or LPS explant incubations affected the potency or maximum cholinergic contraction in vitro, and subsequent COX-2 blockade with nimesulide revealed a significant but similar decrease in potency of ACh-evoked contraction in control, LPS and cytokine-incubated muscle strips. Pre-treatment with l-NNA provided no functional differences in the potency or maximum contractile responses to ACh in cytokine or LPS-incubated colonic longitudinal smooth muscle. Only PGE2 transiently increased Caco-2 monolayer permeability at 24h, while LPS (10μg/ml) increased permeability over 24-48h. These findings indicate that cholinergic contractility in the human colon can be decreased by the blockade of COX-2 generated excitatory prostanoids, but major pro-inflammatory cytokines or LPS do not alter the sensitivity or amplitude of this contraction ex vivo. While PGE2 transiently increase epithelial permeability, LPS generates a significant and sustained increase in permeability indicative of an important role on barrier function at the mucosal interface. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

Role of oxidants in DNA damage. Hydroxyl radical mediates the synergistic DNA damaging effects of asbestos and cigarette smoke.

PubMed Central

Jackson, J H; Schraufstatter, I U; Hyslop, P A; Vosbeck, K; Sauerheber, R; Weitzman, S A; Cochrane, C G

1987-01-01

The mechanism by which cigarette smoking and asbestos exposure synergistically increase the incidence of lung cancer is unknown. We hypothesized that cigarette smoke and asbestos might synergistically increase DNA damage. To test this hypothesis we exposed isolated bacteriophage PM2 DNA to cigarette smoke and/or asbestos, and assessed DNA strand breaks as an index of DNA damage. Our results supported our hypothesis. 78 +/- 12% of the DNA exposed to both cigarette smoke and asbestos developed strand breaks, while only 9.8 +/- 7.0 or 4.3 +/- 3.3% of the DNA exposed to cigarette smoke or asbestos, respectively, developed strand breaks under the conditions of the experiment. Our experimental evidence suggested that cigarette smoke and asbestos synergistically increased DNA damage by stimulating .OH formation. First, significant amounts of .OH were detected by electron paramagnetic resonance (EPR) in DNA mixtures containing both cigarette smoke and asbestos, but no .OH was detected in mixtures containing cigarette smoke alone or asbestos alone. Second, the .OH scavengers, dimethylsulfoxide (DMSO), mannitol, or Na benzoate decreased both .OH detection by EPR and strand breaks in DNA mixtures exposed to cigarette smoke and asbestos. Third, the H2O2 scavenger, catalase, and the iron chelators, 1,10-phenanthroline and desferrithiocin, decreased both .OH detection and strand breaks in DNA mixtures exposed to cigarette smoke and asbestos. These latter findings suggest that iron contained in asbestos may catalyze the formation of .OH from H2O2 generated by cigarette smoke. In summary, our study indicates that cigarette smoke and asbestos synergistically increase DNA damage and suggests that this synergism may involve .OH production. PMID:2821073

Pipecolic Acid Orchestrates Plant Systemic Acquired Resistance and Defense Priming via Salicylic Acid-Dependent and -Independent Pathways

PubMed Central

Bernsdorff, Friederike; Döring, Anne-Christin; Gruner, Katrin; Schuck, Stefan; Bräutigam, Andrea; Zeier, Jürgen

2016-01-01

We investigated the relationships of the two immune-regulatory plant metabolites, salicylic acid (SA) and pipecolic acid (Pip), in the establishment of plant systemic acquired resistance (SAR), SAR-associated defense priming, and basal immunity. Using SA-deficient sid2, Pip-deficient ald1, and sid2 ald1 plants deficient in both SA and Pip, we show that SA and Pip act both independently from each other and synergistically in Arabidopsis thaliana basal immunity to Pseudomonas syringae. Transcriptome analyses reveal that SAR establishment in Arabidopsis is characterized by a strong transcriptional response systemically induced in the foliage that prepares plants for future pathogen attack by preactivating multiple stages of defense signaling and that SA accumulation upon SAR activation leads to the downregulation of photosynthesis and attenuated jasmonate responses systemically within the plant. Whereas systemic Pip elevations are indispensable for SAR and necessary for virtually the whole transcriptional SAR response, a moderate but significant SA-independent component of SAR activation and SAR gene expression is revealed. During SAR, Pip orchestrates SA-dependent and SA-independent priming of pathogen responses in a FLAVIN-DEPENDENT-MONOOXYGENASE1 (FMO1)-dependent manner. We conclude that a Pip/FMO1 signaling module acts as an indispensable switch for the activation of SAR and associated defense priming events and that SA amplifies Pip-triggered responses to different degrees in the distal tissue of SAR-activated plants. PMID:26672068

Roles for both FtsA and the FtsBLQ subcomplex in FtsN-stimulated cell constriction in Escherichia coli.

PubMed

Liu, Bing; Persons, Logan; Lee, Lynda; de Boer, Piet A J

2015-03-01

Escherichia coli FtsN is a bitopic membrane protein that is essential for triggering active cell constriction. A small periplasmic subdomain ((E) FtsN) is required and sufficient for function, but its mechanism of action is unclear. We isolated extragenic (E) FtsN*-suppressing mutations that restore division in cells producing otherwise non-functional variants of FtsN. These mapped to the IC domain of FtsA in the cytoplasm and to small subdomains of the FtsB and FtsL proteins in the periplasm. All FtsB and FtsL variants allowed survival without (E) FtsN, but many then imposed a new requirement for interaction between the cytoplasmic domain of FtsN ((N) FtsN) and FtsA. Alternatively, variants of FtsA, FtsB or FtsL acted synergistically to allow cell division in the complete absence of FtsN. Strikingly, moreover, substitution of a single residue in FtsB (E56) proved sufficient to rescue ΔftsN cells as well. In FtsN(+) cells, (E) FtsN*-suppressing mutations promoted cell fission at an abnormally small cell size, and caused cell shape and integrity defects under certain conditions. This and additional evidence support a model in which FtsN acts on either side of the membrane to induce a conformational switch in both FtsA and the FtsBLQ subcomplex to de-repress septal peptidoglycan synthesis and membrane invagination. © 2014 John Wiley & Sons Ltd.

PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder

NASA Astrophysics Data System (ADS)

Brown, Anna; Patel, Siddharth; Ward, Carl; Lorenz, Anna; Ortiz, Mauren; Duross, Allison; Wieghardt, Fabian; Esch, Amanda; Otten, Elsje G.; Heiser, Laura M.; Korolchuk, Viktor I.; Sun, Conroy; Sarkar, Sovan; Sahay, Gaurav

2016-08-01

2-Hydroxy-propyl-β-cyclodextrin (HPβCD), a cholesterol scavenger, is currently undergoing Phase 2b/3 clinical trial for treatment of Niemann Pick Type C-1 (NPC1), a fatal neurodegenerative disorder that stems from abnormal cholesterol accumulation in the endo/lysosomes. Unfortunately, the extremely high doses of HPβCD required to prevent progressive neurodegeneration exacerbates ototoxicity, pulmonary toxicity and autophagy-based cellular defects. We present unexpected evidence that a poly (ethylene glycol) (PEG)-lipid conjugate enables cholesterol clearance from endo/lysosomes of Npc1 mutant (Npc1-/-) cells. Herein, we show that distearyl-phosphatidylethanolamine-PEG (DSPE-PEG), which forms 12-nm micelles above the critical micelle concentration, accumulates heavily inside cholesterol-rich late endosomes in Npc1-/- cells. This potentially results in cholesterol solubilization and leakage from lysosomes. High-throughput screening revealed that DSPE-PEG, in combination with HPβCD, acts synergistically to efflux cholesterol without significantly aggravating autophagy defects. These well-known excipients can be used as admixtures to treat NPC1 disorder. Increasing PEG chain lengths from 350 Da-30 kDa in DSPE-PEG micelles, or increasing DSPE-PEG content in an array of liposomes packaged with HPβCD, improved cholesterol egress, while Pluronic block copolymers capable of micelle formation showed slight effects at high concentrations. We postulate that PEG-lipid based nanocarriers can serve as bioactive drug delivery systems for effective treatment of lysosomal storage disorders.

Interleukin-7-induced Stat-5 acts in synergy with Flt-3 signaling to stimulate expansion of hematopoietic progenitor cells.

PubMed

Åhsberg, Josefine; Tsapogas, Panagiotis; Qian, Hong; Zetterblad, Jenny; Zandi, Sasan; Månsson, Robert; Jönsson, Jan-Ingvar; Sigvardsson, Mikael

2010-11-19

The development of lymphoid cells from bone marrow progenitors is dictated by interplay between internal cues such as transcription factors and external signals like the cytokines Flt-3 ligand and Il-7. These proteins are both of large importance for normal lymphoid development; however, it is unclear if they act in direct synergy to expand a transient Il-7R(+)Flt-3(+) population or if the collaboration is created through sequential activities. We report here that Flt-3L and Il-7 synergistically stimulated the expansion of primary Il-7R(+)Flt-3(+) progenitor cells and a hematopoietic progenitor cell line ectopically expressing the receptors. The stimulation resulted in a reduced expression of pro-apoptotic genes and also mediated survival of primary progenitor cells in vitro. However, functional analysis of single cells suggested that the anti-apoptotic effect was additive indicating that the synergy observed mainly depends on stimulation of proliferation. Analysis of downstream signaling events suggested that although Il-7 induced Stat-5 phosphorylation, Flt-3L caused activation of the ERK and AKT signaling pathways. Flt-3L could also drive proliferation in synergy with ectopically expressed constitutively active Stat-5. This synergy could be inhibited with either receptor tyrosine kinase or MAPK inhibitors suggesting that Flt-3L and Il-7 act in synergy by activation of independent signaling pathways to expand early hematopoietic progenitors.

CG200745, an HDAC inhibitor, induces anti-tumour effects in cholangiocarcinoma cell lines via miRNAs targeting the Hippo pathway.

PubMed

Jung, Dawoon E; Park, Soo Been; Kim, Kahee; Kim, Chanyang; Song, Si Young

2017-09-07

Cholangiocarcinoma is a devastating malignancy with fatal complications that exhibits low response and resistance to chemotherapy. Here, we evaluated the anticancer effects of CG200745, a novel histone deacetylase inhibitor, either alone or in combination with standard chemotherapy drugs in cholangiocarcinoma cells. CG200745 dose-dependently reduced the viability of cholangiocarcinoma cells in vitro and decreased tumour volume and weight in a xenograft model. Administering CG200745 along with other chemotherapeutic agents including gemcitabine, 5-fluorouracil (5-FU), cisplatin, oxaliplatin, or gemcitabine plus cisplatin further decreased cholangiocarcinoma cell viability, with a combination index < 1 that indicated synergistic action. CG200745 also enhanced the sensitivity of gemcitabine-resistant cells to gemcitabine and 5-FU, thereby decreasing cell viability and inducing apoptosis. This was accompanied by downregulation of YAP, TEAD4, TGF-β2, SMAD3, NOTCH3, HES5, Axl, and Gas6 and upregulation of the miRNAs miR-22-3p, miR-22-5p, miR-194-5p, miR-194-3p, miR-194-5p, miR-210-3p, and miR-509-3p. The Ingenuity Pathway Analysis revealed that CG200745 mainly targets the Hippo signalling pathway by inducing miR-509-3p expression. Thus, CG200745 inhibits cholangiocarcinoma growth in vitro and in vivo, and acts synergistically when administered in combination with standard chemotherapeutic agents, enabling dose reduction. CG200745 is therefore expected to improve the outcome of cholangiocarcinoma patients who exhibit resistance to conventional therapies.

Hedgehog signaling regulates nociceptive sensitization.

PubMed

Babcock, Daniel T; Shi, Shanping; Jo, Juyeon; Shaw, Michael; Gutstein, Howard B; Galko, Michael J

2011-09-27

Nociceptive sensitization is a tissue damage response whereby sensory neurons near damaged tissue enhance their responsiveness to external stimuli. This sensitization manifests as allodynia (aversive withdrawal to previously nonnoxious stimuli) and/or hyperalgesia (exaggerated responsiveness to noxious stimuli). Although some factors mediating nociceptive sensitization are known, inadequacies of current analgesic drugs have prompted a search for additional targets. Here we use a Drosophila model of thermal nociceptive sensitization to show that Hedgehog (Hh) signaling is required for both thermal allodynia and hyperalgesia following ultraviolet irradiation (UV)-induced tissue damage. Sensitization does not appear to result from developmental changes in the differentiation or arborization of nociceptive sensory neurons. Genetic analysis shows that Hh signaling acts in parallel to tumor necrosis factor (TNF) signaling to mediate allodynia and that distinct transient receptor potential (TRP) channels mediate allodynia and hyperalgesia downstream of these pathways. We also demonstrate a role for Hh in analgesic signaling in mammals. Intrathecal or peripheral administration of cyclopamine (CP), a specific inhibitor of Sonic Hedgehog signaling, blocked the development of analgesic tolerance to morphine (MS) or morphine antinociception in standard assays of inflammatory pain in rats and synergistically augmented and sustained morphine analgesia in assays of neuropathic pain. We demonstrate a novel physiological role for Hh signaling, which has not previously been implicated in nociception. Our results also identify new potential therapeutic targets for pain treatment. Copyright © 2011 Elsevier Ltd. All rights reserved.

Inhibition of Autophagy Potentiates Atorvastatin-Induced Apoptotic Cell Death in Human Bladder Cancer Cells in Vitro

PubMed Central

Kang, Minyong; Jeong, Chang Wook; Ku, Ja Hyeon; Kwak, Cheol; Kim, Hyeon Hoe

2014-01-01

Statins are cholesterol reduction agents that exhibit anti-cancer activity in several human cancers. Because autophagy is a crucial survival mechanism for cancer cells under stress conditions, cooperative inhibition of autophagy acts synergistically with other anti-cancer drugs. Thus, this study investigates whether combined treatment of atorvastatin and autophagy inhibitors results in enhancing the cytotoxic effects of atorvastatin, upon human bladder cancer cells, T24 and J82, in vitro. To measure cell viability, we performed the EZ-Cytox cell viability assay. We examined apoptosis by flow cytometry using annexin-V/propidium iodide (PI and western blot using procaspase-3 and poly (ADP-ribose) polymerase (PARP) antibodies. To examine autophagy activation, we evaluated the co-localization of LC3 and LysoTracker by immunocytochemistry, as well as the expression of LC3 and p62/sequestosome-1 (SQSTM1) by western blot. In addition, we assessed the survival and proliferation of T24 and J82 cells by a clonogenic assay. We found that atorvastatin reduced the cell viability of T24 and J82 cells via apoptotic cell death and induced autophagy activation, shown by the co-localization of LC3 and LysoTracker. Moreover, pharmacologic inhibition of autophagy significantly enhanced atorvastatin-induced apoptosis in T24 and J82 cells. In sum, inhibition of autophagy potentiates atorvastatin-induced apoptotic cell death in human bladder cancer cells in vitro, providing a potential therapeutic approach to treat bladder cancer. PMID:24815071

Evolution of cooperation on complex networks with synergistic and discounted group interactions

NASA Astrophysics Data System (ADS)

Zhou, Lei; Li, Aming; Wang, Long

2015-06-01

In the real world individuals often engage in group interactions and their payoffs are determined by many factors, including the typical nonlinear interactions, i.e., synergy and discounting. Previous literatures assume that individual payoffs are either synergistically enhanced or discounted with the additional cooperators. Such settings ignore the interplay of these two factors, which is in sharp contrast with the fact that they ubiquitously coexist. Here we investigate how the coexistence and periodical switching of synergistic and discounted group interactions affect the evolution of cooperation on various complex networks. We show that scale-free networks facilitate the emergence of cooperation in terms of fixation probability for group interactions. With nonlinear interactions the heterogeneity of the degree acts as a double-edged sword: below the neutral drift it is the best for cooperation while above the neutral drift it instead provides the least opportunity for cooperators to be fixed. The advantages of the heterogeneity fade as interactive attributes switch between synergy and discounting, which suggests that the heterogeneity of population structures cannot favor cooperators in group interactions even with simple nonlinear interactions. Nonetheless, scale-free networks always guarantee cooperators the fastest rate of fixation. Our work implies that even very simple nonlinear group interactions could greatly shape the fixation probability and fixation time of cooperators in structured populations indicated by complex networks.

Radon testing in rapid access lung clinics: an opportunity for secondary prevention.

PubMed

Smyth, R; Long, S; Wiseman, E; Sharpe, D; Breen, D; O'Regan, A

2017-05-01

Radon is a naturally occurring radioactive gas and a level 1 carcinogen. It acts synergistically with cigarette smoke to cause lung cancer. In Ireland, radon is estimated to be associated with 13 % of all lung cancers. Rapid access lung cancer clinics (RALC's) were established in the UK and Ireland to improve lung cancer management outcomes. There has been no attempt to date to provide advice on household radon exposure assessments in this setting. We performed a prospective feasibility study of radon assessment in our RALC to test the hypothesis that patients would avail of this service and that it would provide an opportunity for secondary prevention in at risk persons. We investigated household radon levels in consecutive patients who were newly referred with symptoms of lung cancer to the RALC in Galway University Hospital, Ireland over a 6-month period. Of 50 patients enrolled, 42 returned valid results. Overall 21 % of patients had radon levels recorded above the national reference level. Only 5 % of patients were aware of the association between radon gas and lung cancer. Smokers were significantly less likely to engage fully in radon testing. The development of RALC's offers a novel opportunity to integrate the concepts of radon exposure, cigarette smoking and the development of lung cancer, and to reinforce this message in the minds of at risk patients.

Modeling tandem AAG8-MEK inhibition in melanoma cells.

PubMed

Sun, Bing; Kawahara, Masahiro; Nagamune, Teruyuki

2014-06-01

Drug resistance presents a challenge to the treatment of cancer patients, especially for melanomas, most of which are caused by the hyperactivation of MAPK signaling pathway. Innate or acquired drug-resistant relapse calls for the investigation of the resistant mechanisms and new anti-cancer drugs to provide implications for the ultimate goal of curative therapy. Aging-associated gene 8 (AAG8, encoded by the SIGMAR1 gene) is a chaperone protein profoundly elaborated in neurology. However, roles of AAG8 in carcinogenesis remain unclear. Herein, we discover AAG8 antagonists as new MEK inhibitors in melanoma cells and propose a novel drug combination strategy for melanoma therapy by presenting the experimental evidences. We report that specific antagonism of AAG8, efficiently suppresses melanoma cell growth and migration through, at least in part, the inactivation of the RAS-CRAF-MEK signaling pathway. We further demonstrate that melanoma cells that are resistant to AAG8 antagonist harbor refractory CRAF-MEK activity. MEK acts as a central mediator for anti-cancer effects and also for the resistance mechanism, leading to our proposal of tandem AAG8-MEK inhibition in melanoma cells. Combination of AAG8 antagonist and very low concentration of a MEK inhibitor synergistically restricts the growth of drug-resistant cells. These data collectively pinpoint AAG8 as a potential target and delineate a promising drug combination strategy for melanoma therapy. © 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Ferroelectric Self-Poling, Switching, and Monoclinic Domain Configuration in BiFeO 3 Thin Films

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beekman, C.; Siemons, W.; Chi, M.

2016-05-23

Self-poling of ferroelectric films, i.e., a preferred, uniform direction of the ferroelectric polarization in as-grown samples is often observed yet poorly understood despite its importance for device applications. The multiferroic perovskite BiFeO 3, which crystallizes in two distinct structural polymorphs depending on applied epitaxial strain, is well known to exhibit self-poling. This study investigates the effect of self-poling on the monoclinic domain configuration and the switching properties of the two polymorphs of BiFeO 3 (R' and T') in thin films grown on LaAlO 3 substrates with slightly different La 0.3Sr 0.7MnO 3 buffer layers. Our study shows that the polarizationmore » state formed during the growth acts as “imprint” on the polarization and that switching the polarization away from this self-poled direction can only be done at the expense of the sample's monoclinic domain configuration. We observed reduction of the monoclinic domain size and found that it was largely reversible; hence, the domain size is restored when the polarization is switched back to its original orientation. This is a direct consequence of the growth taking place in the polar phase (below T c). Finally, switching the polarization away from the preferred configuration, in which defects and domain patterns synergistically minimize the system's energy, leads to a domain state with smaller (and more highly strained and distorted) monoclinic domains.« less

PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder

PubMed Central

Brown, Anna; Patel, Siddharth; Ward, Carl; Lorenz, Anna; Ortiz, Mauren; DuRoss, Allison; Wieghardt, Fabian; Esch, Amanda; Otten, Elsje G.; Heiser, Laura M.; Korolchuk, Viktor I.; Sun, Conroy; Sarkar, Sovan; Sahay, Gaurav

2016-01-01

2-Hydroxy-propyl-β-cyclodextrin (HPβCD), a cholesterol scavenger, is currently undergoing Phase 2b/3 clinical trial for treatment of Niemann Pick Type C-1 (NPC1), a fatal neurodegenerative disorder that stems from abnormal cholesterol accumulation in the endo/lysosomes. Unfortunately, the extremely high doses of HPβCD required to prevent progressive neurodegeneration exacerbates ototoxicity, pulmonary toxicity and autophagy-based cellular defects. We present unexpected evidence that a poly (ethylene glycol) (PEG)-lipid conjugate enables cholesterol clearance from endo/lysosomes of Npc1 mutant (Npc1−/−) cells. Herein, we show that distearyl-phosphatidylethanolamine-PEG (DSPE-PEG), which forms 12-nm micelles above the critical micelle concentration, accumulates heavily inside cholesterol-rich late endosomes in Npc1−/− cells. This potentially results in cholesterol solubilization and leakage from lysosomes. High-throughput screening revealed that DSPE-PEG, in combination with HPβCD, acts synergistically to efflux cholesterol without significantly aggravating autophagy defects. These well-known excipients can be used as admixtures to treat NPC1 disorder. Increasing PEG chain lengths from 350 Da-30 kDa in DSPE-PEG micelles, or increasing DSPE-PEG content in an array of liposomes packaged with HPβCD, improved cholesterol egress, while Pluronic block copolymers capable of micelle formation showed slight effects at high concentrations. We postulate that PEG-lipid based nanocarriers can serve as bioactive drug delivery systems for effective treatment of lysosomal storage disorders. PMID:27572704

Gibberellin Promotes Shoot Branching in the Perennial Woody Plant Jatropha curcas.

PubMed

Ni, Jun; Gao, Congcong; Chen, Mao-Sheng; Pan, Bang-Zhen; Ye, Kaiqin; Xu, Zeng-Fu

2015-08-01

Strigolactone (SL), auxin and cytokinin (CK) interact to regulate shoot branching. CK has long been considered to be the only key phytohormone to promote lateral bud outgrowth. Here we report that gibberellin also acts as a positive regulator in the control of shoot branching in the woody plant Jatropha curcas. We show that gibberellin and CK synergistically promote lateral bud outgrowth, and that both hormones influence the expression of putative branching regulators, J. curcas BRANCHED1 and BRANCHED2, which are key transcription factors maintaining bud dormancy. Moreover, treatment with paclobutrazol, an inhibitor of de novo gibberellin biosynthesis, significantly reduced the promotion of bud outgrowth by CK, suggesting that gibberellin is required for CK-mediated axillary bud outgrowth. In addition, SL, a plant hormone involved in the repression of shoot branching, acted antagonistically to both gibberellin and CK in the control of lateral bud outgrowth. Consistent with this, the expression of JcMAX2, a J. curcas homolog of Arabidopsis MORE AXILLARY GROWTH 2 encoding an F-box protein in the SL signaling pathway, was repressed by gibberellin and CK treatment. We also provide physiological evidence that gibberellin also induces shoot branching in many other trees, such as papaya, indicating that a more complicated regulatory network occurs in the control of shoot branching in some perennial woody plants. © The Author 2015. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists.

Identification of a Novel Splice Variant Isoform of TREM-1 in Human Neutrophil Granules.

PubMed

Baruah, Sankar; Keck, Kathy; Vrenios, Michelle; Pope, Marshall R; Pearl, Merideth; Doerschug, Kevin; Klesney-Tait, Julia

2015-12-15

Triggering receptor expressed on myeloid cells-1 (TREM-1) is critical for inflammatory signal amplification. Humans have two forms of TREM-1: a membrane receptor, associated with the adaptor DAP12, and a soluble receptor detected at times of infection. The membrane receptor isoform acts synergistically with the TLR pathway to promote cytokine secretion and neutrophil migration, whereas the soluble receptor functions as a counterregulatory molecule. In multiple models of sepsis, exogenous administration of soluble forms of TREM-1 attenuates inflammation and markedly improves survival. Despite intense interest in soluble TREM-1, both as a clinical predictor of survival and as a therapeutic tool, the origin of native soluble TREM-1 remains controversial. Using human neutrophils, we identified a 15-kDa TREM-1 isoform in primary (azurophilic) and secondary (specific) granules. Mass spectrometric analysis, ELISA, and immunoblot confirm that the 15-kDa protein is a novel splice variant form of TREM-1 (TREM-1sv). Neutrophil stimulation with Pseudomonas aeruginosa, LPS, or PAM(3)Cys4 resulted in degranulation and release of TREM-1sv. The addition of exogenous TREM-1sv inhibited TREM-1 receptor-mediated proinflammatory cytokine production. Thus, these data reveal that TREM-1 isoforms simultaneously activate and inhibit inflammation via the canonical membrane TREM-1 molecule and this newly discovered granular isoform, TREM-1sv. Copyright © 2015 by The American Association of Immunologists, Inc.

Lithium modulates the muscarinic facilitation of synaptic plasticity and theta-gamma coupling in the hippocampal-prefrontal pathway.

PubMed

Ruggiero, Rafael N; Rossignoli, Matheus T; Lopes-Aguiar, Cleiton; Leite, João P; Bueno-Junior, Lezio S; Romcy-Pereira, Rodrigo N

2018-06-01

Mood disorders are associated to functional unbalance in mesolimbic and frontal cortical circuits. As a commonly used mood stabilizer, lithium acts through multiple biochemical pathways, including those activated by muscarinic cholinergic receptors crucial for hippocampal-prefrontal communication. Therefore, here we investigated the effects of lithium on prefrontal cortex responses under cholinergic drive. Lithium-treated rats were anesthetized with urethane and implanted with a ventricular cannula for muscarinic activation, a recording electrode in the medial prefrontal cortex (mPFC), and a stimulating electrode in the intermediate hippocampal CA1. Either of two forms of synaptic plasticity, long-term potentiation (LTP) or depression (LTD), were induced during pilocarpine effects, which were monitored in real time through local field potentials. We found that lithium attenuates the muscarinic potentiation of cortical LTP (<20 min) but enhances the muscarinic potentiation of LTD maintenance (>80 min). Moreover, lithium treatment promoted significant cross-frequency coupling between CA1 theta (3-5 Hz) and mPFC low-gamma (30-55 Hz) oscillations. Interestingly, lithium by itself did not affect any of these measures. Thus, lithium pretreatment and muscarinic activation synergistically modulate the hippocampal-prefrontal connectivity. Because these alterations varied with time, oscillatory parameters, and type of synaptic plasticity, our study suggests that lithium influences prefrontal-related circuits through intricate dynamics, informing future experiments on mood disorders. Copyright © 2018. Published by Elsevier Inc.

Inhibition of warm ischemic injury to rat liver, pancreas, and heart grafts by controlling the nutritional status of both donor and recipient.

PubMed

Nishihara, V; Sumimoto, R; Fukuda, Y; Southard, J H; Asahara, T; Dohi, K

1997-01-01

In this study, we tested the effect of donor fasting with or without the use of an essential fatty acids deficiency (EFAD) diet in the recipient using rat heart, pancreas, and liver transplant models. We then compared the survivals, tumor necrosis factor alpha (TNF-alpha) response, and white cell accumulation in rats in order to clarify the mechanisms of the beneficial effect of donor fasting and recipient EFAD. It was found that when the grafts were obtained from fasted donors and then transplanted into fed recipients, the survival rate was significantly higher for all three grafts than for those obtained from fed rats and transplanted into fed rats. The best survival was seen for pancreas grafts obtained from fasted donors and then transplanted into EFAD recipients. TNF-alpha secretion was significantly suppressed in both fasted and EFAD rats, and both the total cell count and neutrophil count were suppressed in EFAD rats. These results clearly indicate that in addition to liver grafts, both heart and pancreas grafts obtained from fasted animals are more tolerant to warm ischemic injury. Furthermore, the combination of donor fasting and recipient EFAD acts synergistically to inhibit the post-transplantation inflammatory reaction (through decreased TNF-alpha secretion and white cell accumulation), thus resulting in an improved survival.

Osteoprotegerin and β2-Agonists Mitigate Muscular Dystrophy in Slow- and Fast-Twitch Skeletal Muscles.

PubMed

Dufresne, Sébastien S; Boulanger-Piette, Antoine; Frenette, Jérôme

2017-03-01

Our recent work showed that daily injections of osteoprotegerin (OPG)-immunoglobulin fragment complex (OPG-Fc) completely restore the function of fast-twitch extensor digitorum longus muscles in dystrophic mdx mice, a murine model of Duchenne muscular dystrophy. However, despite marked improvements, OPG-Fc was not as effective in preventing the loss of function of slow-twitch soleus and diaphragm muscles. Because β 2 -agonists enhance the function of slow- and fast-twitch dystrophic muscles and because their use is limited by their adverse effects on bone and cardiac tissues, we hypothesized that OPG-Fc, a bone and skeletal muscle protector, acts synergistically with β 2 -agonists and potentiates their positive effects on skeletal muscles. We observed that the content of β 2 -adrenergic receptors, which are mainly expressed in skeletal muscle, is significantly reduced in dystrophic muscles but is rescued by the injection of OPG-Fc. Most important, OPG-Fc combined with a low dose of formoterol, a member of a new generation of β 2 -agonists, histologically and functionally rescued slow-twitch dystrophic muscles. This combination of therapeutic agents, which have already been tested and approved for human use, may open up new therapeutic avenues for Duchenne muscular dystrophy and possibly other neuromuscular diseases. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

A D-octapeptide drug efflux pump inhibitor acts synergistically with azoles in a murine oral candidiasis infection model.

PubMed

Hayama, Kazumi; Ishibashi, Hiroko; Ishijima, Sanae A; Niimi, Kyoko; Tansho, Shigeru; Ono, Yasuo; Monk, Brian C; Holmes, Ann R; Harding, David R K; Cannon, Richard D; Abe, Shigeru

2012-03-01

Clinical management of patients undergoing treatment of oropharyngeal candidiasis with azole antifungals can be impaired by azole resistance. High-level azole resistance is often caused by the overexpression of Candida albicans efflux pump Cdr1p. Inhibition of this pump therefore represents a target for combination therapies that reverse azole resistance. We assessed the therapeutic potential of the D-octapeptide derivative RC21v3, a Cdr1p inhibitor, in the treatment of murine oral candidiasis caused by either the azole-resistant C. albicans clinical isolate MML611 or its azole-susceptible parental strain MML610. RC21v3, fluconazole (FLC), or a combination of both drugs were administered orally to immunosuppressed ICR mice at 3, 24, and 27 h after oral inoculation with C. albicans. FLC protected the mice inoculated with MML610 from oral candidiasis, but was only partially effective in MML611-infected mice. The co-application of RC21v3 (0.02 μmol per dose) potentiated the therapeutic performance of FLC for mice infected with either strain. It caused a statistically significant decrease in C. albicans cfu isolated from the oral cavity of the infected mice and reduced oral lesions. RC21v3 also enhanced the therapeutic activity of itraconazole against MML611 infection. These results indicate that RC21v3 in combination with azoles has potential as a therapy against azole-resistant oral candidiasis. © 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Modulation of the cyclin-dependent kinase inhibitor p21(WAF1/Cip1) gene by Zac1 through the antagonistic regulators p53 and histone deacetylase 1 in HeLa Cells.

PubMed

Liu, Pei-Yao; Chan, James Yi-Hsin; Lin, Hsiu-Chen; Wang, Sung-Ling; Liu, Shu-Ting; Ho, Ching-Liang; Chang, Li-Chien; Huang, Shih-Ming

2008-07-01

Zac1 is a novel seven-zinc finger protein which possesses the ability to bind specifically to GC-rich DNA elements. Zac1 not only promotes apoptosis and cell cycle arrest but also acts as a transcriptional cofactor for p53 and a number of nuclear receptors. Our previous study indicated that the enhancement of p53 activity by Zac1 is much more pronounced in HeLa cells compared with other cell lines tested. This phenomenon might be due to the coactivator effect of Zac1 on p53 and the ability of Zac1 to reverse E6 inhibition of p53. In the present study, we showed that Zac1 acted synergistically with either p53 or a histone deacetylase inhibitor, trichostatin A, to enhance p21(WAF1/Cip1) promoter activity. We showed that Zac1 physically interacted with some nuclear receptor corepressors such as histone deacetylase 1 (HDAC1) and mSin3a, and the induction of p21(WAF1/Cip1) gene and protein by Zac1 was suppressed by either overexpressing HDAC1 or its deacetylase-dead mutant. In addition, our data suggest that trichostatin A-induced p21(WAF1/Cip1) protein expression might be mediated through a p53-independent and HDAC deacetylase-independent pathway. Taken together, our data suggest that Zac1 might be involved in regulating the p21(WAF1/Cip1) gene and protein expression through its protein-protein interaction with p53 and HDAC1 in HeLa cells.

Study of colouring effect of herbal hair formulations on graying hair

PubMed Central

Singh, Vijender; Ali, Mohammed; Upadhyay, Sukirti

2015-01-01

Objective: To screen the hair colouring properties of hair colorants/ herbal hair colouring formulations. Materials and Methods: The dried aqueous herbal extracts of Gudhal leaves (Hibiscus rosa-sinensis), Jatamansi rhizome (Nardostachys jatamansi), Kuth roots (Saussurea lappa), Kattha (Acacia catechu), Amla dried fruit (Embelica officinalis), were prepared. Coffee powder (Coffea arabica) and Henna powder (Lowsonia inermis) were taken in the form of powder (# 40). Fourteen herbal hair colorants were prepared from these dried aqueous herbal extracts and powders. Activities of hair colorants were observed on sheep wool fibers. On the basis of the above observation six hair colorants were selected. These six formulations were taken for trials on human beings. Observation: The formulation coded HD-3 gave maximum colouring effect on sheep wool fibers as well as on human beings and percentage of acceptance among the volunteers were in the following order: HD- 3 > HD- 4 > HD-1 > HD-13 > HD-14 > HD-11. Results and Discussion: The remarkable results were obtained from five herbal hair colorants, viz., HD-1, HD- 3, HD- 4, HD-13 and HD-14 on sheep wool fibers and human beings. Formulation HD-3, having gudhal, jatamansi, kuth, kattha, amla, coffee and henna, was the maximum accepted formulation and suggested that these herbs in combination acts synergistically in hair colouring action. It also concluded that jatamansi, present in different hair colorants, was responsible to provide maximum blackening on hair PMID:26130937

Nitric oxide plays a role in stem cell niche homeostasis through its interaction with auxin.

PubMed

Sanz, Luis; Fernández-Marcos, María; Modrego, Abelardo; Lewis, Daniel R; Muday, Gloria K; Pollmann, Stephan; Dueñas, Montserrat; Santos-Buelga, Celestino; Lorenzo, Oscar

2014-12-01

Nitric oxide (NO) is a unique reactive nitrogen molecule with an array of signaling functions that modulates plant developmental processes and stress responses. To explore the mechanisms by which NO modulates root development, we used a pharmacological approach and NO-deficient mutants to unravel the role of NO in establishing auxin distribution patterns necessary for stem cell niche homeostasis. Using the NO synthase inhibitor and Arabidopsis (Arabidopsis thaliana) NO biosynthesis mutants (nitric oxide-associated1 [noa1], nitrate reductase1 [nia1] and nia2, and nia1 nia2 noa1), we show that depletion of NO in noa1 reduces primary root elongation and increases flavonol accumulation consistent with elevated reactive oxygen species levels. The elevated flavonols are required for the growth effect, because the transparent testa4 mutation reverses the noa1 mutant root elongation phenotype. In addition, noa1 and nia1 nia2 noa1 NO-deficient mutant roots display small root meristems with abnormal divisions. Concomitantly, auxin biosynthesis, transport, and signaling are perturbed. We further show that NO accumulates in cortex/endodermis stem cells and their precursor cells. In endodermal and cortical cells, the noa1 mutant acts synergistically to the effect of the wuschel-related homeobox5 mutation on the proximal meristem, suggesting that NO could play an important role in regulating stem cell decisions, which has been reported in animals. © 2014 American Society of Plant Biologists. All Rights Reserved.

WNT10B Functional Dualism: β-Catenin/Tcf-dependent Growth Promotion or Independent Suppression with Deregulated Expression in Cancer

PubMed Central

Yoshikawa, Hirohide; Matsubara, Kenichi; Zhou, Xiaoling; Okamura, Shu; Kubo, Takahiko; Murase, Yaeko; Shikauchi, Yuko; Esteller, Manel; Herman, James G.; Wei Wang, Xin

2007-01-01

We found aberrant DNA methylation of the WNT10B promoter region in 46% of primary hepatocellular carcinoma (HCC) and 15% of colon cancer samples. Three of 10 HCC and one of two colon cancer cell lines demonstrated low or no expression, and 5-aza-2′deoxycytidine reactivated WNT10B expression with the induction of demethylation, indicating that WNT10B is silenced by DNA methylation in some cancers, whereas WNT10B expression is up-regulated in seven of the 10 HCC cell lines and a colon cancer cell line. These results indicate that WNT10B can be deregulated by either overexpression or silencing in cancer. We found that WNT10B up-regulated β-catenin/Tcf activity. However, WNT10B-overexpressing cells demonstrated a reduced growth rate and anchorage-independent growth that is independent of the β-catenin/Tcf activation, because mutant β-catenin–transduced cells did not suppress growth, and dominant-negative hTcf-4 failed to alleviate the growth suppression by WNT10B. Although WNT10B expression alone inhibits cell growth, it acts synergistically with the fibroblast growth factor (FGF) to stimulate cell growth. WNT10B is bifunctional, one function of which is involved in β-catenin/Tcf activation, and the other function is related to the down-regulation of cell growth through a different mechanism. We suggest that FGF switches WNT10B from a negative to a positive cell growth regulator. PMID:17761539

Melanoma risk and survival among organ transplant recipients

PubMed Central

Robbins, Hilary A.; Clarke, Christina A.; Arron, Sarah T.; Tatalovich, Zaria; Kahn, Amy R.; Hernandez, Brenda Y.; Paddock, Lisa; Yanik, Elizabeth L.; Lynch, Charles F.; Kasiske, Bertram L.; Snyder, Jon; Engels, Eric A.

2015-01-01

Solid organ transplant recipients, who are medically immunosuppressed to prevent graft rejection, have increased melanoma risk, but risk factors and outcomes are incompletely documented. We evaluated melanoma incidence among 139,991 non-Hispanic white transplants using linked U.S. transplant-cancer registry data (1987–2010). We used standardized incidence ratios (SIRs) to compare incidence to the general population, and incidence rate ratios (IRRs) from multivariable Poisson models to assess risk factors. Separately, we compared post-melanoma survival among transplant recipients (N=182) and non-recipients (N=131,358) using multivariable Cox models. Among transplant recipients, risk of invasive melanoma (N=519) was elevated (SIR=2.20, 95%CI 2.01-2.39), especially for regional stage tumors (SIR=4.11, 95%CI 3.27–5.09). Risk of localized tumors was stable over time after transplantation, but higher with azathioprine maintenance therapy (IRR=1.35, 95%CI 1.03–1.77). Risk of regional/distant stage tumors peaked within 4 years following transplantation and increased with polyclonal antibody induction therapy (IRR=1.65, 95%CI 1.02–2.67). Melanoma-specific mortality was higher among transplant recipients than non-recipients (HR 2.98, 95%CI 2.26–3.93). Melanoma exhibits increased incidence and aggressive behavior under transplant-related immunosuppression. Some localized melanomas may result from azathioprine, which acts synergistically with ultraviolet radiation, while T-cell depleting induction therapies may promote late stage tumors. Our findings support sun safety practices and skin screening for transplant recipients. PMID:26270022

Environmental enrichment synergistically improves functional recovery by transplanted adipose stem cells in chronic hypoxic-ischemic brain injury.

PubMed

Seo, Jung Hwa; Kim, Hyongbum; Park, Eun Sook; Lee, Jong Eun; Kim, Dong Wook; Kim, Hyun Ok; Im, Sang Hee; Yu, Ji Hea; Kim, Ji Yeon; Lee, Min-Young; Kim, Chul Hoon; Cho, Sung-Rae

2013-01-01

We investigated the effects of environmental enrichment (EE) on the function of transplanted adipose stem cells (ASCs) and the combined effect of EE and ASC transplantation on neurobehavioral function in an animal model of chronic hypoxic-ischemic (HI) brain injury. HI brain damage was induced in 7-day-old mice by unilateral carotid artery ligation and exposure to hypoxia (8% O2 for 90 min). At 6 weeks of age, the mice were randomly injected with either ASCs or PBS into the striatum and were randomly assigned to either EE or standard cages (SC), comprising ASC-EE (n=18), ASC-SC (n=19), PBS-EE (n=12), PBS-SC (n=17), and untreated controls (n=23). Rotarod, forelimb-use asymmetry, and grip strength tests were performed to evaluate neurobehavioral function. The fate of transplanted cells and the levels of endogenous neurogenesis, astrocyte activation, and paracrine factors were also measured. As a result, EE and ASC transplantation synergistically improved rotarod latency, forelimb-use asymmetry, and grip strength compared to those of the other groups. The number of engrafted ASCs and βIII-tubulin(+) neurons derived from the transplanted ASCs was significantly higher in mice in EE than those in SC. EE and ASC transplantation also synergistically increased BrdU(+)βIII-tubulin(+) neurons, GFAP(+) astrocytic density, and fibroblast growth factor 2 (FGF2) level but not the level of CS-56(+) glial scarring in the striatum. In conclusion, EE and ASC transplantation synergistically improved neurobehavioral functions. The underlying mechanisms of this synergism included enhanced repair processes such as higher engraftment of the transplanted ASCs, increased endogenous neurogenesis and astrocytic activation coupled with upregulation of FGF2.

Development and validation of a stability-indicating capillary zone electrophoretic method for the assessment of entecavir and its correlation with liquid chromatographic methods.

PubMed

Dalmora, Sergio Luiz; Nogueira, Daniele Rubert; D'Avila, Felipe Bianchini; Souto, Ricardo Bizogne; Leal, Diogo Paim

2011-01-01

A stability-indicating capillary zone electrophoresis (CZE) method was validated for the analysis of entecavir in pharmaceutical formulations, using nimesulide as an internal standard. A fused-silica capillary (50 µm i.d.; effective length, 40 cm) was used while being maintained at 25°C; the applied voltage was 25 kV. A background electrolyte solution consisted of a 20 mM sodium tetraborate solution at pH 10. Injections were performed using a pressure mode at 50 mbar for 5 s, with detection at 216 nm. The specificity and stability-indicating capability were proven through forced degradation studies, evaluating also the in vitro cytotoxicity test of the degraded products. The method was linear over the concentration range of 1-200 µg mL(-1) (r(2) = 0.9999), and was applied for the analysis of entecavir in tablet dosage forms. The results were correlated to those of validated conventional and fast LC methods, showing non-significant differences (p > 0.05).

Fluorescent Heterodoped Nanotetrapods as Synergistically Enhancing Positive and Negative Magnetic Resonance Imaging Contrast Agents.

PubMed

Sharma, V K; Alipour, A; Soran-Erdem, Z; Kelestemur, Y; Aykut, Z G; Demir, H V

2016-05-18

In this work, we report Mn-Fe heterodoped ZnSe tetrapod nanocrystals (NCs) synthesized to synergistically enhance contrast in both T1- and T2-weighted magnetic resonance imaging (MRI). The proposed NCs were prepared using a customized heteroarchitecture such that the manganese (Mn) is confined in the core and iron (Fe) in the branches of the tetrapods. The elemental composition and profile of these NCs were studied using X-ray photoelectron spectroscopy, energy-dispersive X-ray spectroscopy, and inductively coupled plasma mass spectroscopy. Photoluminescence quantum yield of these heterodoped NCs in water is ∼30%. Magnetic measurements reveal the simultaneous presence of superparamagnetic and paramagnetic behavior in these NCs because of the coexistence of Mn(2+) and Fe(2+) dopants. Their potential as simultaneous positive and negative MRI contrast agents was demonstrated by relaxivity measurements and in vivo MRI. From the in vivo studies, we also found that these NCs (with a hydrodynamic diameter of 20 nm) are excreted from the body within 24 h after the injection. Therefore, these heterodoped tetrapods NCs, while being fluorescent and safe, hold great future as a synergistically enhancing dual-modal MRI contrast agent.

Do the honeybee pathogens Nosema ceranae and deformed wing virus act synergistically?

PubMed Central

Martin, Stephen J; Hardy, Jennifer; Villalobos, Ethel; Martín-Hernández, Raquel; Nikaido, Scott; Higes, Mariano

2013-01-01

The honeybee pathogens Nosema ceranae and deformed wing virus (DWV) cause the collapse of honeybee colonies. Therefore, it is plausible that these two pathogens act synergistically to increase colony losses, since N. ceranae causes damage to the mid-gut epithelial ventricular cells and actively suppresses the honeybees’ immune response, either of which could increase the virulence of viral pathogens within the bee. To test this hypothesis we exploited 322 Hawaiian honeybee colonies for which DWV prevalence and load is known. We determined via PCR that N. ceranae was present in 89–95% of these colonies, with no Nosema apis being detected. We found no significant difference in spore counts in colonies infected with DWV and those in which DWV was not detected, either on any of the four islands or across the entire honeybee population. Furthermore, no significant correlation between DWV loads (ΔCT levels) and N. ceranae spore counts was found, so these two pathogens are not acting synergistically. Although the Hawaiian honeybees have the highest known prevalence of N. ceranae in the world, with average number of spores been 2.7 million per bee, no acute Nosema related problems i.e. large-scale colony deaths, have been reported by Hawaiian beekeepers. PMID:23864563

Heat shock protein 47 and 65-kDa FK506-binding protein weakly but synergistically interact during collagen folding in the endoplasmic reticulum.

PubMed

Ishikawa, Yoshihiro; Holden, Paul; Bächinger, Hans Peter

2017-10-20

Collagen is the most abundant protein in the extracellular matrix in humans and is critical to the integrity and function of many musculoskeletal tissues. A molecular ensemble comprising more than 20 molecules is involved in collagen biosynthesis in the rough endoplasmic reticulum. Two proteins, heat shock protein 47 (Hsp47/ SERPINH1 ) and 65-kDa FK506-binding protein (FKBP65/ FKBP10 ), have been shown to play important roles in this ensemble. In humans, autosomal recessive mutations in both genes cause similar osteogenesis imperfecta phenotypes. Whereas it has been proposed that Hsp47 and FKBP65 interact in the rough endoplasmic reticulum, there is neither clear evidence for this interaction nor any data regarding their binding affinities for each other. In this study using purified endogenous proteins, we examined the interaction between Hsp47, FKBP65, and collagen and also determined their binding affinities and functions in vitro Hsp47 and FKBP65 show a direct but weak interaction, and FKBP65 prefers to interact with Hsp47 rather than type I collagen. Our results suggest that a weak interaction between Hsp47 and FKBP65 confers mutual molecular stability and also allows for a synergistic effect during collagen folding. We also propose that Hsp47 likely acts as a hub molecule during collagen folding and secretion by directing other molecules to reach their target sites on collagens. Our findings may explain why osteogenesis imperfecta-causing mutations in both genes result in similar phenotypes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Adhesion of human platelets to albumin is synergistically increased by lysophosphatidic acid and adrenaline in a donor-dependent fashion.

PubMed

Eriksson, Andreas C; Whiss, Per A; Nilsson, Ulrika K

2006-07-01

Lysophosphatidic acid (LPA) and adrenaline are weak platelet activators considered important for thrombus formation, and were previously shown to synergistically increase platelet aggregation. Here we investigate synergistic activation by LPA and adrenaline when measuring platelet adhesion. Platelet-rich plasma from healthy blood donors together with adrenaline and/or LPA were added to protein-coated microplates. Platelets were allowed to adhere and the amount of adhesion detected enzymatically. The LPA and adrenaline combination induced a synergistic increase of platelet adhesion to a normally non-adhesive albumin surface. The degree of synergy varied markedly between individuals; these variations could not be explained by age, gender, blood type or different amounts of platelets, oxidized low-density lipoprotein, insulin or glucose in plasma. There was a trend indicating increased synergistic effect for platelets sensitive to adrenaline stimulation. The synergistic effect was blocked by the alpha2-adrenoceptor antagonist yohimbine and inhibited by the ADP scavenger system creatine phosphate/creatine phosphokinase and antibodies against alphaIIbbeta3. Furthermore, platelets adhering to albumin after adrenaline and LPA treatment expressed P-selectin. In conclusion, LPA and adrenaline act synergistically to increase alphaIIbbeta3-mediated platelet adhesion to albumin, dependent on alpha2-adrenoceptor signalling and platelet secretion. We also confirm that synergistic platelet activation achieved with LPA and adrenaline is highly donor dependent.

Relation of gastric acid and pepsin secretion to serum gastrin levels in dogs given bombesin and gastrin-17.

PubMed

Hirschowitz, B I; Molina, E

1983-05-01

To quantitate bombesin stimulation of gastric acid and pepsin via release of gastrin, five gastric fistula dogs were given graded doses (60-1,250 pmol X kg-1 X h-1) of bombesin tetradecapeptide and 40-2,000 pmol X kg-1 X h-1 of synthetic gastrin-17 (G-17). Acid and pepsin output and serum gastrin were proportional to the dose of stimulant. The half-maximal dose of bombesin for gastrin release was 200 pmol X kg-1 X h-1. Bombesin-stimulated acid secretion related to serum gastrin concentrations was congruent with the G-17 curve, but with a maximum of only 62% of the G-17 maximum before declining by 27% despite higher serum gastrin levels. This suggested that bombesin stimulates acid secretion only via gastrin release and inhibits at higher doses by releasing another inhibitory peptide, most likely somatostatin, which is also released by bombesin. The same mechanism could apply to supramaximal inhibition of acid and pepsin seen with high doses of G-17. Because the pepsin curve related to serum gastrin was to the left of the G-17 curve, we concluded that another secretagogue released by bombesin acts synergistically with gastrin on pepsin secretion. Therefore, bombesin stimulates gastric secretion through gastrin release, but its effects are modified by peptides coreleased to a) increase pepsin output at low doses and b) limit the output of acid and pepsin to 50-60% of the G-17 maximum.

SPBP Is a Sulforaphane Induced Transcriptional Coactivator of NRF2 Regulating Expression of the Autophagy Receptor p62/SQSTM1

PubMed Central

Darvekar, Sagar Ramesh; Elvenes, Julianne; Brenne, Hanne Britt; Johansen, Terje; Sjøttem, Eva

2014-01-01

Organisms exposed to oxidative stress respond by orchestrating a stress response to prevent further damage. Intracellular levels of antioxidant agents increase, and damaged components are removed by autophagy induction. The KEAP1-NRF2 signaling pathway is the main pathway responsible for cell defense against oxidative stress and for maintaining the cellular redox balance at physiological levels. Sulforaphane, an isothiocyanate derived from cruciferous vegetables, is a potent inducer of KEAP1-NRF2 signaling and antioxidant response element driven gene expression. In this study, we show that sulforaphane enhances the expression of the transcriptional coregulator SPBP. The expression curve peaks 6–8 hours post stimulation, and parallels the sulforaphane-induced expression of NRF2 and the autophagy receptor protein p62/SQSTM1. Reporter gene assays show that SPBP stimulates the expression of p62/SQSTM1 via ARE elements in the promoter region, and siRNA mediated knock down of SPBP significantly decreases the expression of p62/SQSTM1 and the formation of p62/SQSTM1 bodies in HeLa cells. Furthermore, SPBP siRNA reduces the sulforaphane induced expression of NRF2, and the expression of the autophagy marker protein LC3B. Both these proteins contain ARE-like elements in their promoter regions. Over-expressed SPBP and NRF2 acts synergistically on the p62/SQSTM1 promoter and colocalize in nuclear speckles in HeLa cells. Collectively, these results suggest that SPBP is a coactivator of NRF2, and hence may be important for securing enhanced and sustained expression of NRF2 induced genes such as proteins involved in selective autophagy. PMID:24416372

Bactericidal effect of bovine lactoferrin, LFcin, LFampin and LFchimera on antibiotic-resistant Staphylococcus aureus and Escherichia coli.

PubMed

Flores-Villaseñor, Héctor; Canizalez-Román, Adrian; Reyes-Lopez, Magda; Nazmi, Kamram; de la Garza, Mireya; Zazueta-Beltrán, Jorge; León-Sicairos, Nidia; Bolscher, Jan G M

2010-06-01

Increased prevalence of antibiotic-resistant bacteria has become a major threat to the health sector worldwide due to their virulence, limited therapeutic options and distribution in both hospital and community settings. Discovery and development of new agents to combat antibiotic-resistant bacteria is thus needed. This study therefore aimed to evaluate the ability of bovine lactoferrin (LF), peptides from two antimicrobial domains lactoferricin B (LFcin17-30) and lactoferrampin (LFampin265-284) and a chimeric construct (LFchimera) containing both peptides, as potential bactericidal agents against clinical isolates of antibiotic-resistant Staphylococcus aureus and Escherichia coli. Results in kinetics of growth show that LF chimera and peptides inhibited the growth of both bacterial species. By confocal microscopy and flow cytometry it was observed that LF and FITC-labeled peptides are able to interact with these bacteria and cause membrane permeabilization, as monitored by propidium iodide staining, these effects were decreased by preincubation with lipopolysaccharide in E. coli. By electron microscopy, a clear cellular damage was observed in bacteria after treatments with LFchimera and peptides, suggesting that interaction and membrane disruption are probably involved as a mechanism of action. In conclusion, results show that LFchimera, LF and peptides have potential as bactericidal agents in the antibiotic-resistant strains of S. aureus and E. coli and also the work strongly suggest that LFcin17-30 and LFampin265-284 acts synergistically with antibiotics against multidrug resistant EPEC and MRSA in vitro.

Neonicotinoid pesticides and nutritional stress synergistically reduce survival in honey bees.

PubMed

Tosi, Simone; Nieh, James C; Sgolastra, Fabio; Cabbri, Riccardo; Medrzycki, Piotr

2017-12-20

The honey bee is a major pollinator whose health is of global concern. Declines in bee health are related to multiple factors, including resource quality and pesticide contamination. Intensive agricultural areas with crop monocultures potentially reduce the quality and quantity of available nutrients and expose bee foragers to pesticides. However, there is, to date, no evidence for synergistic effects between pesticides and nutritional stress in animals. The neonicotinoids clothianidin (CLO) and thiamethoxam (TMX) are common systemic pesticides that are used worldwide and found in nectar and pollen. We therefore tested if nutritional stress (limited access to nectar and access to nectar with low-sugar concentrations) and sublethal, field-realistic acute exposures to two neonicotinoids (CLO and TMX at 1/5 and 1/25 of LD 50 ) could alter bee survival, food consumption and haemolymph sugar levels. Bee survival was synergistically reduced by the combination of poor nutrition and pesticide exposure (-50%). Nutritional and pesticide stressors reduced also food consumption (-48%) and haemolymph levels of glucose (-60%) and trehalose (-27%). Our results provide the first demonstration that field-realistic nutritional stress and pesticide exposure can synergistically interact and cause significant harm to animal survival. These findings have implications for current pesticide risk assessment and pollinator protection. © 2017 The Author(s).

EHV-1 EICP22 protein sequences that mediate its physical interaction with the immediate-early protein are not sufficient to enhance the trans-activation activity of the IE protein.

PubMed

Derbigny, Wilbert A; Kim, Seong K; Jang, Hyung K; O'Callaghan, Dennis J

2002-03-20

The early 293 amino acid EICP22 protein (EICP22P) of equine herpesvirus 1 localizes within the nucleus and functions as an accessory regulatory protein (J. Virol. 68 (1994) 4329). Transient transfection assays indicated that although the EICP22P by itself only minimally trans-activates EHV-1 promoters, the EICP22P functions synergistically with the immediate-early protein (IEP) to enhance expression of EHV-1 early genes (J. Virol. 71 (1997) 1004). We previously showed that the EICP22 protein enhances the DNA-binding activity of the EHV-1 IEP and that it also physically interacts with the IEP (J. Virol. 74 (2000) 1425). In this communication, we employed transient trans-activation assays utilizing EICP22P deletion mutants to address whether the sequences required for EICP22P-IEP physical interactions are essential for EICP22P's ability to interact synergistically with the IEP. Assays employing various classes of the EHV-1 promoters fused to the chloramphenicol acetyl-transferase (CAT) reporter gene indicated that: (1) neither full length nor any of the EICP22P mutants tested was able to overcome repression of the IE promoter elicited by the IEP, (2) the full-length EICP22P interacted synergistically with the IEP to trans-activate the early and late promoters tested, and (3) all of the EICP22P mutants, including those that were able to physically interact with IEP and itself, failed to function synergistically with the IEP to trans-activate representative EHV-1 early and late promoters. The results suggest that EICP22P sequences required for its interaction with the IE protein are not sufficient to mediate its synergistic effect on the trans-activation function of the IEP. The possible explanations as to why sequences in addition to those that mediate EICP22P-IEP interaction and EICP22P self-interactions are essential for the synergistic function of EICP22P are discussed.

A small stress protein acts synergistically with trehalose to confer desiccation tolerance on mammalian cells.

PubMed

Ma, Xiaocui; Jamil, Kamran; Macrae, Thomas H; Clegg, James S; Russell, Joseph M; Villeneuve, Tania S; Euloth, Michelle; Sun, Yu; Crowe, John H; Tablin, Fern; Oliver, Ann E

2005-08-01

The ability to desiccate mammalian cells while maintaining a high degree of viability would be very important in many areas of biological science, including tissue engineering, cell transplantation, and biosensor technologies. Certain proteins and sugars found in animals capable of surviving desiccation might aid this process. We report here that human embryonic kidney (293H) cells transfected with the gene for the stress protein p26 from Artemia and loaded with trehalose showed a sharp increase in survival during air-drying. Further, we find vacuum-drying greatly improved the ability of the cells to survive, and that the physical shape and structure of the cellular sample had a large influence on recovery following rehydration. Cells suspended in a rounded droplet survived desiccation markedly better than those spread as a thin film. Finally, we used alamarBlue to monitor cellular metabolism and Hema 3 to assess colony formation after vacuum-drying. AlamarBlue fluorescence indicated that the transfected 293H cells expressing p26 (E11'L) grew much better than the control 293H cells. In fact, immediate survival and colony formation in E11'L cells increased as much as 34-fold compared with control cells when the samples were dried to a water content of 0.2 g H2O/g dry weight, as measured by gravimetric analysis. These results indicate that p26 improves cell survival following drying and rehydration, and suggest that dry storage of mammalian cells is a likely possibility in the future.

Current hypotheses for the evolution of sex and recombination.

PubMed

Hartfield, Matthew; Keightley, Peter D

2012-06-01

The evolution of sex is one of the most important and controversial problems in evolutionary biology. Although sex is almost universal in higher animals and plants, its inherent costs have made its maintenance difficult to explain. The most famous of these is the twofold cost of males, which can greatly reduce the fecundity of a sexual population, compared to a population of asexual females. Over the past century, multiple hypotheses, along with experimental evidence to support these, have been put forward to explain widespread costly sex. In this review, we outline some of the most prominent theories, along with the experimental and observational evidence supporting these. Historically, there have been 4 classes of theories: the ability of sex to fix multiple novel advantageous mutants (Fisher-Muller hypothesis); sex as a mechanism to stop the build-up of deleterious mutations in finite populations (Muller's ratchet); recombination creating novel genotypes that can resist infection by parasites (Red Queen hypothesis); and the ability of sex to purge bad genomes if deleterious mutations act synergistically (mutational deterministic hypothesis). Current theoretical and experimental evidence seems to favor the hypothesis that sex breaks down selection interference between new mutants, or it acts as a mechanism to shuffle genotypes in order to repel parasitic invasion. However, there is still a need to collect more data from natural populations and experimental studies, which can be used to test different hypotheses. © 2012 ISZS, Blackwell Publishing and IOZ/CAS.

Pipecolic Acid Orchestrates Plant Systemic Acquired Resistance and Defense Priming via Salicylic Acid-Dependent and -Independent Pathways.

PubMed

Bernsdorff, Friederike; Döring, Anne-Christin; Gruner, Katrin; Schuck, Stefan; Bräutigam, Andrea; Zeier, Jürgen

2016-01-01

We investigated the relationships of the two immune-regulatory plant metabolites, salicylic acid (SA) and pipecolic acid (Pip), in the establishment of plant systemic acquired resistance (SAR), SAR-associated defense priming, and basal immunity. Using SA-deficient sid2, Pip-deficient ald1, and sid2 ald1 plants deficient in both SA and Pip, we show that SA and Pip act both independently from each other and synergistically in Arabidopsis thaliana basal immunity to Pseudomonas syringae. Transcriptome analyses reveal that SAR establishment in Arabidopsis is characterized by a strong transcriptional response systemically induced in the foliage that prepares plants for future pathogen attack by preactivating multiple stages of defense signaling and that SA accumulation upon SAR activation leads to the downregulation of photosynthesis and attenuated jasmonate responses systemically within the plant. Whereas systemic Pip elevations are indispensable for SAR and necessary for virtually the whole transcriptional SAR response, a moderate but significant SA-independent component of SAR activation and SAR gene expression is revealed. During SAR, Pip orchestrates SA-dependent and SA-independent priming of pathogen responses in a FLAVIN-DEPENDENT-MONOOXYGENASE1 (FMO1)-dependent manner. We conclude that a Pip/FMO1 signaling module acts as an indispensable switch for the activation of SAR and associated defense priming events and that SA amplifies Pip-triggered responses to different degrees in the distal tissue of SAR-activated plants. © 2016 American Society of Plant Biologists. All rights reserved.

Determination of pharmaceuticals in groundwater collected in five cemeteries' areas (Portugal).

PubMed

Paíga, P; Delerue-Matos, C

2016-11-01

There are growing public attention and concern about the possibility of ecosystem and human health effects from pharmaceuticals in environment. Several types of environmental samples were target of studies by the scientific community, namely drinking water, groundwater, surface water (river, ocean), treated water (influent and effluent), soils, and sediments near to Wastewater Treatment Plants or near to others potential sources of contaminations. Normally, studies in the cemeteries areas are for historical and architectural research and questions of the potential risk for adverse impact of cemeteries in environment have never received enough attention. However, this risk may exist when cemeteries are placed in areas that are vulnerable to contamination. The objective of the present work was the determination of pharmaceuticals (nonsteroidal anti-inflammatory/analgesics, antibiotics and psychiatric drugs) in groundwater samples collected inside of the cemeteries areas. Acetaminophen, salicylic acid, ibuprofen, ketoprofen, nimesulide, carbamazepine, fluoxetine, and sertraline were the pharmaceuticals achieved in the analysed samples. None of the studied antibiotics were detected. The highest concentration was obtained for salicylic acid (in the range of 33.7 to 71.0ng/L) and carbamazepine (between 20.0 and 22.3ng/L), respectively. By the cluster analysis similarity between carbamazepine and fluoxetine was achieved. Copyright © 2016. Published by Elsevier B.V.

Plant Natural Products Calycosin and Gallic Acid Synergistically Attenuate Neutrophil Infiltration and Subsequent Injury in Isoproterenol-Induced Myocardial Infarction: A Possible Role for Leukotriene B4 12-Hydroxydehydrogenase?

PubMed Central

Cheng, Yuanyuan; Tse, Hung Fat; Le, X. Chris; Rong, Jianhui

2015-01-01

Leukotriene B4 12-hydroxydehydrogenase (LTB4DH) catalyzes the oxidation of proinflammatory LTB4 into less bioactive 12-oxo-LTB4. We recently discovered that LTB4DH was induced by two different natural products in combination. We previously isolated gallic acid from Radix Paeoniae through a bioactivity-guided fractionation procedure. The purpose of this study is to test the hypothesis that LTB4DH inducers may suppress neutrophil-mediated inflammation in myocardial infarction. We first isolated the active compound(s) from another plant, Radix Astragali, by the similar strategy. By evaluating LTB4DH induction, we identified calycosin and formononetin from Radix Astragali by HPLC-ESI-MS technique. We confirmed that gallic acid and commercial calycosin or formononetin could synergistically induce LTB4DH expression in HepG2 cells and human neutrophils. Moreover, calycosin and gallic acid attenuated the effects of LTB4 on the survival and chemotaxis of neutrophil cell culture. We further demonstrated that calycosin and gallic acid synergistically suppressed neutrophil infiltration and protected cardiac integrity in the isoproterenol-induced mice model of myocardial infarction. Calycosin and gallic acid dramatically suppressed isoproterenol-induced increase in myeloperoxidase (MPO) activity and malondialdehyde (MDA) level. Collectively, our results suggest that LTB4DH inducers (i.e., calycosin and gallic acid) may be a novel combined therapy for the treatment of neutrophil-mediated myocardial injury. PMID:26265982

SAHA and S116836, a novel tyrosine kinase inhibitor, synergistically induce apoptosis in imatinib-resistant chronic myelogenous leukemia cells

PubMed Central

Bu, Qiangui; Cui, Lijing; Li, Juan; Du, Xin; Zou, Waiyi; Ding, Ke; Pan, Jingxuan

2014-01-01

Limited treatment options are available for chronic myelogenous leukemia (CML) patients who develop imatinib mesylate (IM) resistance. Here we proposed a novel combination regimen, a co-administration of S116836, a novel small molecule multi-targeted tyrosine kinase inhibitor that was synthesized by rational design, and histone deacetylases inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA), to overcome IM resistance in CML. S116836 at low concentrations used in the present study mildly downregulates auto-tyrosine phosphorylation of Bcr-Abl. SAHA, an FDA-approved HDACi drug, at 1 μM has modest anti-tumor activity in treating CML. However, we found a synergistic interaction between SAHA and S116836 in Bcr-Abl-positive CML cells that were sensitive or resistant to IM. Exposure of KBM5 and KBM5-T315I cells to minimal or non-toxic concentrations of SAHA and S116836 synergistically reduced cell viability and induced cell death. Co-treatment with SAHA and S116838 repressed the expressions of anti-apoptosis proteins, such as Mcl-1 and XIAP, but promoted Bim expression and mitochondrial damage. Of importance, treatment with both drugs significantly reduced cell viability of primary human CML cells, as compared with either agent alone. Taken together, our findings suggest that SAHA exerts synergistically with S116836 at a non-toxic concentration to promote apoptosis in the CML, including those resistant to imatinib or dasatinib. PMID:24759597

Olea europaea leaf extract and bevacizumab synergistically exhibit beneficial efficacy upon human glioblastoma cancer stem cells through reducing angiogenesis and invasion in vitro.

PubMed

Tezcan, Gulcin; Taskapilioglu, Mevlut Ozgur; Tunca, Berrin; Bekar, Ahmet; Demirci, Hilal; Kocaeli, Hasan; Aksoy, Secil Ak; Egeli, Unal; Cecener, Gulsah; Tolunay, Sahsine

2017-06-01

Patients with glioblastoma multiforme (GBM) that are cancer stem-cell-positive (GSC [+]) essentially cannot benefit from anti-angiogenic or anti-invasive therapy. In the present study, the potential anti-angiogenic and anti-invasive effects of Olea europaea (olive) leaf extract (OLE) were tested using GSC (+) tumours. OLE (2mg/mL) caused a significant reduction in tumour weight, vascularisation, invasiveness and migration (p=0.0001, p<0.001, p=0.004; respectively) that was associated with reducing the expression of VEGFA, MMP-2 and MMP-9. This effect was synergistically increased in combination with bevacizumab. Therefore, our current findings may contribute to research on drugs that inhibit the invasiveness of GBM. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Characterization of the Impaired Glucose Homeostasis Produced in C57BL/6 Mice by Chronic Exposure to Arsenic and High-Fat Diet

PubMed Central

Paul, David S.; Walton, Felecia S.; Saunders, R. Jesse

2011-01-01

Background: Type 2 diabetes is characterized by glucose intolerance and insulin resistance. Obesity is the leading cause of type 2 diabetes. Growing evidence suggests that chronic exposure to inorganic arsenic (iAs) also produces symptoms consistent with diabetes. Thus, iAs exposure may further increase the risk of diabetes in obese individuals. Objectives: Our goal was to characterize diabetogenic effects of iAs exposure and high-fat diet (HFD) in weaned C57BL/6 mice. Methods: Mice were fed HFD or low-fat diet (LFD) while exposed to iAs in drinking water (25 or 50 ppm As) for 20 weeks; control HFD and LFD mice drank deionized water. Body mass and adiposity were monitored throughout the study. We measured glucose and insulin levels in fasting blood and in blood collected during oral glucose tolerance tests (OGTT) to evaluate the diabetogenic effects of the treatment. Results: Control mice fed HFD accumulated more fat, had higher fasting blood glucose, and were more insulin resistant than were control LFD mice. However, these diabetes indicators decreased with iAs intake in a dose-dependent manner. OGTT showed impaired glucose tolerance for both control and iAs-treated HFD mice compared with respective LFD mice. Notably, glucose intolerance was more pronounced in HFD mice treated with iAs despite a significant decrease in adiposity, fasting blood glucose, and insulin resistance. Conclusions: Our data suggest that iAs exposure acts synergistically with HFD-induced obesity in producing glucose intolerance. However, mechanisms of the diabetogenic effects of iAs exposure may differ from the mechanisms associated with the obesity-induced type 2 diabetes. PMID:21592922

The glucose sensor Snf1 and the transcription factors Msn2 and Msn4 regulate transcription of the vacuolar iron importer gene CCC1 and iron resistance in yeast.

PubMed

Li, Liangtao; Kaplan, Jerry; Ward, Diane M

2017-09-15

The budding yeast Saccharomyces cerevisiae stores iron in the vacuole, which is a major resistance mechanism against iron toxicity. One key protein involved in vacuolar iron storage is the iron importer Ccc1, which facilitates iron entry into the vacuole. Transcription of the CCC1 gene is largely regulated by the binding of iron-sulfur clusters to the activator domain of the transcriptional activator Yap5. Additional evidence, however, suggests that Yap5-independent transcriptional activation of CCC1 also contributes to iron resistance. Here, we demonstrate that components of the signaling pathway involving the low-glucose sensor Snf1 regulate CCC1 transcription and iron resistance. We found that SNF1 deletion acts synergistically with YAP5 deletion to regulate CCC1 transcription and iron resistance. A kinase-dead mutation of Snf1 lowered iron resistance as did deletion of SNF4 , which encodes a partner protein of Snf1. Deletion of all three alternative partners of Snf1 encoded by SIT1 , SIT2 , and GAL83 decreased both CCC1 transcription and iron resistance. The Snf1 complex is known to activate the general stress transcription factors Msn2 and Msn4. We show that Msn2 and Msn4 contribute to Snf1-mediated CCC1 transcription. Of note, SNF1 deletion in combination with MSN2 and MSN4 deletion resulted in additive effects on CCC1 transcription, suggesting that other activators contribute to the regulation of CCC1 transcription. In conclusion, we show that yeast have developed multiple transcriptional mechanisms to regulate Ccc1 expression and to protect against high cytosolic iron toxicity. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Microbial decomposition of keratin in nature-a new hypothesis of industrial relevance.

PubMed

Lange, Lene; Huang, Yuhong; Busk, Peter Kamp

2016-03-01

Discovery of keratin-degrading enzymes from fungi and bacteria has primarily focused on finding one protease with efficient keratinase activity. Recently, an investigation was conducted of all keratinases secreted from a fungus known to grow on keratinaceous materials, such as feather, horn, and hooves. The study demonstrated that a minimum of three keratinases is needed to break down keratin, an endo-acting, an exo-acting, and an oligopeptide-acting keratinase. Further, several studies have documented that disruption of sulfur bridges of the keratin structure acts synergistically with the keratinases to loosen the molecular structure, thus giving the enzymes access to their substrate, the protein structure. With such complexity, it is relevant to compare microbial keratin decomposition with the microbial decomposition of well-studied polymers such as cellulose and chitin. Interestingly, it was recently shown that the specialized enzymes, lytic polysaccharide monoxygenases (LPMOs), shown to be important for breaking the recalcitrance of cellulose and chitin, are also found in keratin-degrading fungi. A holistic view of the complex molecular self-assembling structure of keratin and knowledge about enzymatic and boosting factors needed for keratin breakdown have been used to formulate a hypothesis for mode of action of the LPMOs in keratin decomposition and for a model for degradation of keratin in nature. Testing such hypotheses and models still needs to be done. Even now, the hypothesis can serve as an inspiration for designing industrial processes for keratin decomposition for conversion of unexploited waste streams, chicken feather, and pig bristles into bioaccessible animal feed.

Inhibition of Bovine Viral Diarrhea Virus RNA Synthesis by Thiosemicarbazone Derived from 5,6-Dimethoxy-1-Indanone▿

PubMed Central

Castro, Eliana F.; Fabian, Lucas E.; Caputto, María E.; Gagey, Dolores; Finkielsztein, Liliana M.; Moltrasio, Graciela Y.; Moglioni, Albertina G.; Campos, Rodolfo H.; Cavallaro, Lucía V.

2011-01-01

In the present work, we described the activity of the thiosemicarbazone derived from 5,6-dimethoxy-1-indanone (TSC), which we previously characterized as a new compound that inhibits bovine viral diarrhea virus (BVDV) infection. We showed that TSC acts at a point of time that coincides with the onset of viral RNA synthesis and that it inhibits the activity of BVDV replication complexes (RCs). Moreover, we have selected five BVDV mutants that turned out to be highly resistant to TSC but still susceptible to ribavirin (RBV). Four of these resistant mutants carried an N264D mutation in the viral RNA-dependent RNA polymerase (RdRp). The remaining mutant showed an A392E mutation within the same protein. Some of these mutants replicated slower than the wild-type (wt) virus in the absence of TSC, whereas others showed a partial reversion to the wt phenotype over several passages in the absence of the compound. The docking of TSC in the crystal structure of the BVDV RdRp revealed a close contact between the indane ring of the compound and several residues within the fingers domain of the enzyme, some hydrophobic contacts, and hydrogen bonds with the thiosemicarbazone group. Finally, in the mutated RdRp from resistant BVDV, these interactions with TSC could not be achieved. Interestingly, TSC inhibited BVDV replication in cell culture synergistically with RBV. In conclusion, TSC emerges as a new nonnucleoside inhibitor of BVDV RdRp that is synergistic with RBV, a feature that turns it into a potential compound to be evaluated against hepatitis C virus (HCV). PMID:21430053

Next-generation proteasome inhibitor oprozomib synergizes with modulators of the unfolded protein response to suppress hepatocellular carcinoma.

PubMed

Vandewynckel, Yves-Paul; Coucke, Céline; Laukens, Debby; Devisscher, Lindsey; Paridaens, Annelies; Bogaerts, Eliene; Vandierendonck, Astrid; Raevens, Sarah; Verhelst, Xavier; Van Steenkiste, Christophe; Libbrecht, Louis; Geerts, Anja; Van Vlierberghe, Hans

2016-06-07

Hepatocellular carcinoma (HCC) responds poorly to conventional systemic therapies. The first-in-class proteasome inhibitor bortezomib has been approved in clinical use for hematologic malignancies and has shown modest activity in solid tumors, including HCC. However, a considerable proportion of patients fail to respond and experience important adverse events. Recently, the next-generation orally bioavailable irreversible proteasome inhibitor oprozomib was developed. Here, we assessed the efficacy of oprozomib and its effects on the unfolded protein response (UPR), a signaling cascade activated through the ATF6, PERK and IRE1 pathways by accumulation of unfolded proteins in the endoplasmic reticulum, in HCC. The effects of oprozomib and the role of the UPR were evaluated in HCC cell lines and in diethylnitrosamine-induced and xenograft mouse models for HCC. Oprozomib dose-dependently reduced the viability and proliferation of human HCC cells. Unexpectedly, oprozomib-treated cells displayed diminished cytoprotective ATF6-mediated signal transduction as well as unaltered PERK and IRE1 signaling. However, oprozomib increased pro-apoptotic UPR-mediated protein levels by prolonging their half-life, implying that the proteasome acts as a negative UPR regulator. Supplementary boosting of UPR activity synergistically improved the sensitivity to oprozomib via the PERK pathway. Oral oprozomib displayed significant antitumor effects in the orthotopic and xenograft models for HCC, and importantly, combining oprozomib with different UPR activators enhanced the antitumor efficacy by stimulating UPR-induced apoptosis without cumulative toxicity. In conclusion, next-generation proteasome inhibition by oprozomib results in dysregulated UPR activation in HCC. This finding can be exploited to enhance the antitumor efficacy by combining oprozomib with clinically applicable UPR activators.

On the composite response of the MLT to major sudden stratospheric warming events with elevated stratopause

NASA Astrophysics Data System (ADS)

Limpasuvan, Varavut; Orsolini, Yvan J.; Chandran, Amal; Garcia, Rolando R.; Smith, Anne K.

2016-05-01

Based on a climate-chemistry model (constrained by reanalyses below ~50 km), the zonal-mean composite response of the mesosphere and lower thermosphere (MLT) to major sudden stratospheric warming events with elevated stratopauses demonstrates the role of planetary waves (PWs) in driving the mean circulation in the presence of gravity waves (GWs), helping the polar vortex recover and communicating the sudden stratospheric warming (SSW) impact across the equator. With the SSW onset, strong westward PW drag appears above 80 km primarily from the dissipation of wave number 1 perturbations with westward period of 5-12 days, generated from below by the unstable westward polar stratospheric jet that develops as a result of the SSW. The filtering effect of this jet also allows eastward propagating GWs to saturate in the winter MLT, providing eastward drag that promotes winter polar mesospheric cooling. The dominant PW forcing translates to a net westward drag above the eastward mesospheric jet, which initiates downwelling over the winter pole. As the eastward polar stratospheric jet returns, this westward PW drag persists above 80 km and acts synergistically with the return of westward GW drag to drive a stronger polar downwelling that warms the pole adiabatically and helps reform the stratopause at an elevated altitude. With the polar wind reversal during the SSW onset, the westward drag by the quasi-stationary PW in the winter stratosphere drives an anomalous equatorial upwelling and cooling that enhance tropical stratospheric ozone. Along with equatorial wind anomalies, this ozone enhancement subsequently amplifies the migrating semidiurnal tide amplitude in the winter midlatitudes.

The synergistic necrohemorrhagic action of Clostridium perfringens perfringolysin and alpha toxin in the bovine intestine and against bovine endothelial cells

PubMed Central

2013-01-01

Bovine necrohemorrhagic enteritis is a major cause of mortality in veal calves. Clostridium perfringens is considered as the causative agent, but there has been controversy on the toxins responsible for the disease. Recently, it has been demonstrated that a variety of C. perfringens type A strains can induce necrohemorrhagic lesions in a calf intestinal loop assay. These results put forward alpha toxin and perfringolysin as potential causative toxins, since both are produced by all C. perfringens type A strains. The importance of perfringolysin in the pathogenesis of bovine necrohemorrhagic enteritis has not been studied before. Therefore, the objective of the current study was to evaluate the role of perfringolysin in the development of necrohemorrhagic enteritis lesions in calves and its synergism with alpha toxin. A perfringolysin-deficient mutant, an alpha toxin-deficient mutant and a perfringolysin alpha toxin double mutant were less able to induce necrosis in a calf intestinal loop assay as compared to the wild-type strain. Only complementation with both toxins could restore the activity to that of the wild-type. In addition, perfringolysin and alpha toxin had a synergistic cytotoxic effect on bovine endothelial cells. This endothelial cell damage potentially explains why capillary hemorrhages are an initial step in the development of bovine necrohemorrhagic enteritis. Taken together, our results show that perfringolysin acts synergistically with alpha toxin in the development of necrohemorrhagic enteritis in a calf intestinal loop model and we hypothesize that both toxins act by targeting the endothelial cells. PMID:23782465

Atorvastatin acts synergistically with N-acetyl cysteine to provide therapeutic advantage against Fas-activated erythrocyte apoptosis during chronic arsenic exposure in rats.

PubMed

Biswas, Debabrata; Sen, Gargi; Sarkar, Avik; Biswas, Tuli

2011-01-01

Arsenic is an environmental toxicant that reduces the lifespan of circulating erythrocytes during chronic exposure. Our previous studies had indicated involvement of hypercholesterolemia and reactive oxygen species (ROS) in arsenic-induced apoptotic death of erythrocytes. In this study, we have shown an effective recovery from arsenic-induced death signaling in erythrocytes in response to treatment with atorvastatin (ATV) and N-acetyl cysteine (NAC) in rats. Our results emphasized on the importance of cholesterol in the promotion of ROS-mediated Fas signaling in red cells. Arsenic-induced activation of caspase 3 was associated with phosphatidylserine exposure on the cell surface and microvesiculation of erythrocyte membrane. Administration of NAC in combination with ATV, proved to be more effective than either of the drugs alone towards the rectification of arsenic-mediated disorganization of membrane structural integrity, and this could be linked with decreased ROS accumulation through reduced glutathione (GSH) repletion along with cholesterol depletion. Moreover, activation of caspase 3 was capable of promoting aggregation of band 3 with subsequent binding of autologous IgG and opsonization by C3b that led to phagocytosis of the exposed cells by the macrophages. NAC-ATV treatment successfully amended these events and restored lifespan of erythrocytes from the exposed animals almost to the control level. This work helped us to identify intracellular membrane cholesterol enrichment and GSH depletion as the key regulatory points in arsenic-mediated erythrocyte destruction and suggested a therapeutic strategy against Fas-activated cell death related to enhanced cholesterol and accumulation of ROS. Copyright © 2010 Elsevier Inc. All rights reserved.

Synergistically enhanced transdermal permeation and topical analgesia of tetracaine gel containing menthol and ethanol in experimental and clinical studies.

PubMed

Fang, Chao; Liu, Yi; Ye, Xun; Rong, Zheng-xing; Feng, Xue-mei; Jiang, Chan-bing; Chen, Hong-zhuan

2008-03-01

The aim of this study is to observe the synergistically enhanced percutaneous penetration and skin analgesia of tetracaine gel containing menthol and ethanol through experimental and clinical studies. Four anesthetic gels containing 4% tetracaine in carbomer vehicle named T-gel (containing no menthol or ethanol), 5%M/T-gel (containing 5% menthol), 70%E/T-gel (containing 70% ethanol, an optimal concentration for antiseptic), and 5%M+70%E/T-gel (containing both 5% menthol and 70% ethanol), respectively, were fabricated. The in vitro mouse skin permeation was investigated using a Franz diffusion cell. The mouse skin morphology was examined by a scanning electron microscope. The in vivo skin analgesic effect in mice was evaluated using the von Frey tests. To determine the efficacy of tetracaine gels for managing the pain in human volunteers, a paralleled, double-blinded, placebo-controlled, randomized controlled trial design combined with verbal pain scores (VPS) was performed. The combination of menthol and ethanol (5%M+70%E/T-gel) conferred significantly higher tetracaine diffusion across full-thickness mouse skin than 5%M/T-gel, 70%E/T-gel, and T-gel. The ultra structure changes of mouse skin stratum corneum treated with 5%M+70%E/T-gel were more marked compared with those of any other tetracaine gel. von Frey tests in mice showed a synergistically enhanced effect of menthol and ethanol on the analgesia of tetracaine gel. The mean VPS were significantly lower for volunteers treated with 5%M+70%E/T-gel than those receiving other gels or the EMLA cream. 5%M+70%E/T-gel possessed the shortest anesthesia onset time, the longest anesthesia duration and the strongest anesthesia efficacy. Seventy percent ethanol in 5%M+70%E/T-gel not only improved the analgesic efficacy of the tetracaine gel through synergistically enhanced percutaneous permeation with menthol but also served as an antiseptic agent keeping drug application site from infection. 5%M+70%E/T-gel is a potential topical anesthesia preparation for clinical use.

Cost-effective three dimensional Ag/polymer dyes/graphene-carbon spheres hybrids for high performance nonenzymatic sensor and its application in living cell H2O2 detection.

PubMed

Lu, Baoping; Yuan, Xuna; Ren, Yuehong; Shi, Qinghua; Wang, Song; Dong, Jinlong; Nan, Ze-Dong

2018-05-03

We describe a facile method to synthesize a new type of catalyst by electrodepositing Ag nanocrystals (AgNCs) on the different polymer dyes, Poly (methylene blue) (PMB) or Poly (4-(2-Pyridylazo)-Resorcinol) (PAR) modified graphene‑carbon spheres (GS) hybrids. The self-assembled GS take dual advantages of carbon spheres and graphene. Carbon spheres acts as nano-spacers prevent the aggregation of graphene and guarantee the fast electron transfer of GS. Secondly, polymerized dyes used here are beneficial for AgNCs growing as a linker. The effects of dyes on the growth habits, morphologies and catalytic properties for AgNCs were investigated. A novel electrochemical nonenzymatic sensor for hydrogen peroxide (H 2 O 2 ) detection is fabricated based on the Ag/Polymer dyes/GS ternary composites modified glass carbon electrode (GCE) for the first time. It was found that the proposed electrodes, especially for Ag/PMB/GS/GCE, displayed a peculiar electrocatalytic activity towards H 2 O 2 reduction synergistically as compared to Ag/PAR/GS/GCE or Ag/GS/GCE alone. Ag/PMB/GS/GCE showed a linear response over the H 2 O 2 concentration range of 0.5 to 1112 μM. The detection limit and sensitivity is 0.15 μM and 400 μA mM -1  cm -2 , respectively. These outstanding results enable the practical application of Ag/PMB/GS/GCE for the H 2 O 2 tracking released from MCF-7 (human breast cancer cells) with satisfactory results. Copyright © 2018 Elsevier B.V. All rights reserved.

Synthetic Ligands of Cannabinoid Receptors Affect Dauer Formation in the Nematode Caenorhabditis elegans

PubMed Central

Reis Rodrigues, Pedro; Kaul, Tiffany K.; Ho, Jo-Hao; Lucanic, Mark; Burkewitz, Kristopher; Mair, William B.; Held, Jason M.; Bohn, Laura M.; Gill, Matthew S.

2016-01-01

Under adverse environmental conditions the nematode Caenorhabditis elegans can enter an alternate developmental stage called the dauer larva. To identify lipophilic signaling molecules that influence this process, we screened a library of bioactive lipids and found that AM251, an antagonist of the human cannabinoid (CB) receptor, suppresses dauer entry in daf-2 insulin receptor mutants. AM251 acted synergistically with glucose supplementation indicating that the metabolic status of the animal influenced the activity of this compound. Similarly, loss of function mutations in the energy-sensing AMP-activated kinase subunit, aak-2, enhanced the dauer-suppressing effects of AM251, while constitutive activation of aak-2 in neurons was sufficient to inhibit AM251 activity. Chemical epistasis experiments indicated that AM251 acts via G-protein signaling and requires the TGF-β ligand DAF-7, the insulin peptides DAF-28 and INS-6, and a functional ASI neuron to promote reproductive growth. AM251 also required the presence of the SER-5 serotonin receptor, but in vitro experiments suggest that this may not be via a direct interaction. Interestingly, we found that other antagonists of mammalian CB receptors also suppress dauer entry, while the nonselective CB receptor agonist, O-2545, not only inhibited the activity of AM251, but also was able to promote dauer entry when administered alone. Since worms do not have obvious orthologs of CB receptors, the effects of synthetic CBs on neuroendocrine signaling in C. elegans are likely to be mediated via another, as yet unknown, receptor mechanism. However, we cannot exclude the existence of a noncanonical CB receptor in C. elegans. PMID:27172180

Mechanisms of action of sacubitril/valsartan on cardiac remodeling: a systems biology approach.

PubMed

Iborra-Egea, Oriol; Gálvez-Montón, Carolina; Roura, Santiago; Perea-Gil, Isaac; Prat-Vidal, Cristina; Soler-Botija, Carolina; Bayes-Genis, Antoni

2017-01-01

Sacubitril/Valsartan, proved superiority over other conventional heart failure management treatments, but its mechanisms of action remains obscure. In this study, we sought to explore the mechanistic details for Sacubitril/Valsartan in heart failure and post-myocardial infarction remodeling, using an in silico, systems biology approach. Myocardial transcriptome obtained in response to myocardial infarction in swine was analyzed to address post-infarction ventricular remodeling. Swine transcriptome hits were mapped to their human equivalents using Reciprocal Best (blast) Hits, Gene Name Correspondence, and InParanoid database. Heart failure remodeling was studied using public data available in gene expression omnibus (accession GSE57345, subseries GSE57338), processed using the GEO2R tool. Using the Therapeutic Performance Mapping System technology, dedicated mathematical models trained to fit a set of molecular criteria, defining both pathologies and including all the information available on Sacubitril/Valsartan, were generated. All relationships incorporated into the biological network were drawn from public resources (including KEGG, REACTOME, INTACT, BIOGRID, and MINT). An artificial neural network analysis revealed that Sacubitril/Valsartan acts synergistically against cardiomyocyte cell death and left ventricular extracellular matrix remodeling via eight principal synergistic nodes. When studying each pathway independently, Valsartan was found to improve cardiac remodeling by inhibiting members of the guanine nucleotide-binding protein family, while Sacubitril attenuated cardiomyocyte cell death, hypertrophy, and impaired myocyte contractility by inhibiting PTEN. The complex molecular mechanisms of action of Sacubitril/Valsartan upon post-myocardial infarction and heart failure cardiac remodeling were delineated using a systems biology approach. Further, this dataset provides pathophysiological rationale for the use of Sacubitril/Valsartan to prevent post-infarct remodeling.

Sorafenib enhances proteasome inhibitor-mediated cytotoxicity via inhibition of unfolded protein response and keratin phosphorylation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Honma, Yuichi; Harada, Masaru, E-mail: msrharada@med.uoeh-u.ac.jp

2013-08-15

Hepatocellular carcinoma (HCC) is highly resistant to conventional systemic therapies and prognosis for advanced HCC patients remains poor. Recent studies of the molecular mechanisms responsible for tumor initiation and progression have identified several potential molecular targets in HCC. Sorafenib is a multi-kinase inhibitor shown to have survival benefits in advanced HCC. It acts by inhibiting the serine/threonine kinases and the receptor type tyrosine kinases. In preclinical experiments sorafenib had anti-proliferative activity in hepatoma cells and it reduced tumor angiogenesis and increased apoptosis. Here, we demonstrate for the first time that the cytotoxic mechanisms of sorafenib include its inhibitory effects onmore » protein ubiquitination, unfolded protein response (UPR) and keratin phosphorylation in response to endoplasmic reticulum (ER) stress. Moreover, we show that combined treatment with sorafenib and proteasome inhibitors (PIs) synergistically induced a marked increase in cell death in hepatoma- and hepatocyte-derived cells. These observations may open the way to potentially interesting treatment combinations that may augment the effect of sorafenib, possibly including drugs that promote ER stress. Because sorafenib blocked the cellular defense mechanisms against hepatotoxic injury not only in hepatoma cells but also in hepatocyte-derived cells, we must be careful to avoid severe liver injury. -- Graphical abstract: Display Omitted -- Highlights: •We examined the cytotoxic mechanisms of sorafenib in hepatoma cells. •Sorafenib induces cell death via apoptotic and necrotic fashion. •Sorafenib inhibits protein ubiquitination and unfolded protein response. •Autophagy induced by sorafenib may affect its cytotoxicity. •Sorafenib inhibits keratin phosphorylation and cytoplasmic inclusion formation.« less

Synergistic bactericidal activity of chlorhexidine-loaded, silver-decorated mesoporous silica nanoparticles.

PubMed

Lu, Meng-Meng; Wang, Qiu-Jing; Chang, Zhi-Min; Wang, Zheng; Zheng, Xiao; Shao, Dan; Dong, Wen-Fei; Zhou, Yan-Min

2017-01-01

Combination of chlorhexidine (CHX) and silver ions could engender synergistic bactericidal effect and improve the bactericidal efficacy. It is highly desired to develop an efficient carrier for the antiseptics codelivery targeting infection foci with acidic microenvironment. In this work, monodisperse mesoporous silica nanoparticle (MSN) nanospheres were successfully developed as an ideal carrier for CHX and nanosilver codelivery through a facile and environmentally friendly method. The CHX-loaded, silver-decorated mesoporous silica nanoparticles (Ag-MSNs@CHX) exhibited a pH-responsive release manner of CHX and silver ions simultaneously, leading to synergistically antibacterial effect against both gram-positive Staphylococcus aureus and gram-negative Escherichia coli . Moreover, the effective antibacterial concentration of Ag-MSNs@CHX showed less cytotoxicity on normal cells. Given their synergistically bactericidal ability and good biocompatibility, these nanoantiseptics might have effective and broad clinical applications for bacterial infections.

Synthetic Ligands of Cannabinoid Receptors Affect Dauer Formation in the Nematode Caenorhabditis elegans.

PubMed

Reis Rodrigues, Pedro; Kaul, Tiffany K; Ho, Jo-Hao; Lucanic, Mark; Burkewitz, Kristopher; Mair, William B; Held, Jason M; Bohn, Laura M; Gill, Matthew S

2016-06-01

Under adverse environmental conditions the nematode Caenorhabditis elegans can enter an alternate developmental stage called the dauer larva. To identify lipophilic signaling molecules that influence this process, we screened a library of bioactive lipids and found that AM251, an antagonist of the human cannabinoid (CB) receptor, suppresses dauer entry in daf-2 insulin receptor mutants. AM251 acted synergistically with glucose supplementation indicating that the metabolic status of the animal influenced the activity of this compound. Similarly, loss of function mutations in the energy-sensing AMP-activated kinase subunit, aak-2, enhanced the dauer-suppressing effects of AM251, while constitutive activation of aak-2 in neurons was sufficient to inhibit AM251 activity. Chemical epistasis experiments indicated that AM251 acts via G-protein signaling and requires the TGF-β ligand DAF-7, the insulin peptides DAF-28 and INS-6, and a functional ASI neuron to promote reproductive growth. AM251 also required the presence of the SER-5 serotonin receptor, but in vitro experiments suggest that this may not be via a direct interaction. Interestingly, we found that other antagonists of mammalian CB receptors also suppress dauer entry, while the nonselective CB receptor agonist, O-2545, not only inhibited the activity of AM251, but also was able to promote dauer entry when administered alone. Since worms do not have obvious orthologs of CB receptors, the effects of synthetic CBs on neuroendocrine signaling in C. elegans are likely to be mediated via another, as yet unknown, receptor mechanism. However, we cannot exclude the existence of a noncanonical CB receptor in C. elegans. Copyright © 2016 Rodrigues et al.

Fasting triggers hypothermia, and ambient temperature modulates its depth in Japanese quail Coturnix japonica.

PubMed

Ben-Hamo, Miriam; Pinshow, Berry; McCue, Marshall D; McWilliams, Scott R; Bauchinger, Ulf

2010-05-01

We tested three hypotheses regarding the cues that elicit facultative hypothermia in Japanese quail (Coturnix japonica): H(1)) Ambient temperature (T(a)), alone, influences the onset and depth of hypothermia; H(2)) Fasting, alone, influences the onset and depth of hypothermia; H(3)) T(a) acts synergistically with fasting to shape the use of hypothermia. Eight quail were maintained within their thermoneutral zone (TNZ) at 32.6+/-0.2 degrees C, and eight below their lower critical temperature (T(lc)) at 12.7+/-3.0 degrees C. All quail entered hypothermia upon food deprivation, even quail kept within their TNZ. Body temperature (T(b)) decreased more (38.36+/-0.53 degrees C vs. 39.57+/-0.57 degrees C), body mass (m(b)) loss was greater (21.0+/-7.20 g vs.12.8+/-2.62g), and the energy saved by using hypothermia was greater (25.18-45.01% vs. 7.98-28.06%) in low the T(a) treatment than in TNZ treatment. Interestingly, the depth of hypothermia was positively correlated with m(b) loss in the low T(a) treatment, but not in TNZ treatment. Our data support H(3), that both thermoregulatory costs and body energy reserves are proximate cues for entry into hypothermia in quail. This outcome is not surprising below the T(lc). However, the quail kept at their TNZ also responded to food deprivation by entering hypothermia with no apparent dependence on m(b) loss. Therefore inputs, other than thermoregulatory costs and body condition, must serve as cues to enter hypothermia. Consequently, we address the role that tissue sparing may play in the physiological 'decision' to employ hypothermia. Copyright 2009 Elsevier Inc. All rights reserved.

Inhibition of bovine viral diarrhea virus RNA synthesis by thiosemicarbazone derived from 5,6-dimethoxy-1-indanone.

PubMed

Castro, Eliana F; Fabian, Lucas E; Caputto, María E; Gagey, Dolores; Finkielsztein, Liliana M; Moltrasio, Graciela Y; Moglioni, Albertina G; Campos, Rodolfo H; Cavallaro, Lucía V

2011-06-01

In the present work, we described the activity of the thiosemicarbazone derived from 5,6-dimethoxy-1-indanone (TSC), which we previously characterized as a new compound that inhibits bovine viral diarrhea virus (BVDV) infection. We showed that TSC acts at a point of time that coincides with the onset of viral RNA synthesis and that it inhibits the activity of BVDV replication complexes (RCs). Moreover, we have selected five BVDV mutants that turned out to be highly resistant to TSC but still susceptible to ribavirin (RBV). Four of these resistant mutants carried an N264D mutation in the viral RNA-dependent RNA polymerase (RdRp). The remaining mutant showed an A392E mutation within the same protein. Some of these mutants replicated slower than the wild-type (wt) virus in the absence of TSC, whereas others showed a partial reversion to the wt phenotype over several passages in the absence of the compound. The docking of TSC in the crystal structure of the BVDV RdRp revealed a close contact between the indane ring of the compound and several residues within the fingers domain of the enzyme, some hydrophobic contacts, and hydrogen bonds with the thiosemicarbazone group. Finally, in the mutated RdRp from resistant BVDV, these interactions with TSC could not be achieved. Interestingly, TSC inhibited BVDV replication in cell culture synergistically with RBV. In conclusion, TSC emerges as a new nonnucleoside inhibitor of BVDV RdRp that is synergistic with RBV, a feature that turns it into a potential compound to be evaluated against hepatitis C virus (HCV).

The application of computer modeling to health effect research

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, R.S.H.

1996-12-31

In the United States, estimates show that more than 30,000 hazardous waste disposal sites exist, not including military installations, U.S. Department of Energy nuclear facilities, and hundreds and thousands of underground fuel storage tanks; these sites undoubtedly have their own respective hazardous waste chemical problems. When so many sites contain hazardous chemicals, how does one study the health effects of the chemicals at these sites? There could be many different answers, but none would be perfect. For an area as complex and difficult as the study of chemical mixtures associated with hazardous waste disposal sites, there are no perfect approachesmore » and protocols. Human exposure to chemicals, be it environmental or occupational, is rarely, if ever, limited to a single chemical. Therefore, it is essential that we consider multiple chemical effects and interactions in our risk assessment process. Systematic toxicity testing of chemical mixtures in the environment or workplace that uses conventional toxicology methodologies is highly impractical because of the immense numbers of mixtures involved. For example, about 600,000 chemicals are being used in our society. Just considering binary chemical mixtures, this means that there could be 600,000 x 599,999/2 = 359,999,400,000 pairs of chemicals. Assuming that only one in a million of these pairs of chemicals acts synergistically or has other toxicologic interactions, there would still be 359,999 binary chemical mixtures possessing toxicologic interactions. Moreover, toxicologic interactions undoubtedly exist among chemical mixtures with three or more component chemicals; the number of possible combinations for these latter mixtures is almost infinite. These are astronomically large numbers with respect to systematic toxicity testing. 22 refs., 5 figs., 1 tab.« less

Oxidized low-density lipoprotein acts synergistically with beta-glycerophosphate to induce osteoblast differentiation in primary cultures of vascular smooth muscle cells.

PubMed

Bear, Mackenzie; Butcher, Martin; Shaughnessy, Stephen G

2008-09-01

Previous studies have localized osteoblast specific markers to sites of calcified atherosclerotic lesions. We therefore decided to use an established in vitro model of vascular calcification in order to confirm earlier reports of oxidized low-density lipoprotein (oxLDL) promoting the osteogenic differentiation of vascular smooth muscle cells. Treatment of primary bovine aortic smooth muscle cells (BASMCs) with beta-glycerophosphate was found to induce a time-dependent increase in osteoblast differentiation. In contrast, no effect was seen when BASMCs were cultured in the presence of oxLDL alone. However, when the BASMCs were cultured in the presence of both beta-glycerophosphate and oxLDL, beta-glycerophosphate's ability to induce osteoblast differentiation was significantly enhanced. In an attempt to resolve the mechanism by which this effect was occurring, we examined the effect of beta-glycerophosphate and oxLDL on several pathways known to be critical to the differentiation of osteoblasts. Surprisingly, beta-glycerophosphate alone was found to enhance Osterix (Osx) expression by inducing both Smad 1/5/8 activation and Runx2 expression. In contrast, oxLDL did not affect either Smad 1/5/8 activation or Runx2 activation but rather, it enhanced both beta-glycerophosphate-induced Osx expression and osteoblast differentiation in an extracellular signal-regulated kinase 1 and 2 (Erk 1 and 2) -dependent manner. When taken together, these findings suggest a plausible mechanism by which oxLDL may promote osteogenic differentiation and vascular calcification in vivo. J. Cell. Biochem. 105: 185-193, 2008. (c) 2008 Wiley-Liss, Inc. (c) 2008 Wiley-Liss, Inc.

Hybrid Membrane System for Industrial Water Reuse

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

2016-08-01

This factsheet describes a project that developed and demonstrated a new hybrid system for industrial wastewater treatment that synergistically combines a forward osmosis system with a membrane distillation technology and is powered by waste heat.

Dihydroartemisinin and Curcumin Synergistically Induce Apoptosis in SKOV3 Cells Via Upregulation of MiR-124 Targeting Midkine.

PubMed

Zhao, Jiaojiao; Pan, Yuchen; Li, Xiujun; Zhang, Xuefang; Xue, Yaxian; Wang, Tingting; Zhao, Shuli; Hou, Yayi

2017-01-01

Women with advanced ovarian carcinoma are less likely to receive platinum-based chemotherapy and surgery due to a greater risk of cytotoxicity and poorer outcomes. We attempted to improve a promising therapy against ovarian cancer by using a combination of dihydroartemisinin (DHA) and curcumin (Cur). Human ovarian cancer SKOV3 cells were treated with DHA, Cur alone, or a combination of both. The viability of SKOV3 cells was measured by Cell Counting Kit-8 (CCK-8) and a colony formation assay. The cell cycle and apoptosis of SKOV3 cells were monitored by flow cytometry. The mRNA and protein expression levels of target genes were respectively examined by qRT-PCR and western blot. The biological effects of miR-124 on midkine (MK) were verified by a luciferase activity analysis. Combined treatment of DHA and Cur synergistically decreased cell viability, arrested cell cycle, and promoted apoptosis in SKOV3 cells. Moreover, it significantly attenuated the expression of oncogene MK and synergistically upregulated the expression of miR-124. Furthermore, miR-124 was verified to bind directly to the 3'-untranslated region of MK mRNA, resulting in mRNA degradation and reduced MK protein levels. The combination of DHA with Cur significantly inhibited tumor growth in xenograft nude mice without obvious toxicity. Co-treatment with DHA and Cur exhibited a synergistic anti-tumor effect on SKOV3 cells both in vitro and in vivo. © 2017 The Author(s). Published by S. Karger AG, Basel.

IL-17A Synergistically Enhances Bile Acid–Induced Inflammation during Obstructive Cholestasis

PubMed Central

O'Brien, Kate M.; Allen, Katryn M.; Rockwell, Cheryl E.; Towery, Keara; Luyendyk, James P.; Copple, Bryan L.

2014-01-01

During obstructive cholestasis, increased concentrations of bile acids activate ERK1/2 in hepatocytes, which up-regulates early growth response factor 1, a key regulator of proinflammatory cytokines, such as macrophage inflammatory protein 2 (MIP-2), which, in turn, exacerbates cholestatic liver injury. Recent studies have indicated that IL-17A contributes to hepatic inflammation during obstructive cholestasis, suggesting that bile acids and IL-17A may interact to regulate hepatic inflammatory responses. We treated mice with an IL-17A neutralizing antibody or control IgG and subjected them to bile duct ligation. Neutralization of IL-17A prevented up-regulation of proinflammatory cytokines, hepatic neutrophil accumulation, and liver injury, indicating an important role for IL-17A in neutrophilic inflammation during cholestasis. Treatment of primary mouse hepatocytes with taurocholic acid (TCA) increased the expression of MIP-2. Co-treatment with IL-17A synergistically enhanced up-regulation of MIP-2 by TCA. In contrast to MIP-2, IL-17A did not affect up-regulation of Egr-1 by TCA, indicating that IL-17A does not affect bile acid–induced activation of signaling pathways upstream of early growth response factor 1. In addition, bile acids increased expression of IL-23, a key regulator of IL-17A production in hepatocytes in vitro and in vivo. Collectively, these data identify bile acids as novel triggers of the IL-23/IL-17A axis and suggest that IL-17A promotes hepatic inflammation during cholestasis by synergistically enhancing bile acid–induced production of proinflammatory cytokines by hepatocytes. PMID:24012680

Antinociceptive interaction between spinal clonidine and lidocaine in the rat formalin test: an isobolographic analysis.

PubMed

Hao, S; Takahata, O; Iwasaki, H

2001-03-01

Clinical and basic science studies suggest that spinal alpha-2-adrenergic receptor agonists and local anesthetics produce analgesia, but interaction between alpha-2-adrenergic receptor agonists and local anesthetics in the persistent pain model has not been examined. In the present study, using isobolographic analysis, we investigated the antinociceptive interaction of intrathecal clonidine and lidocaine in the rat formalin test. Sprague-Dawley rats were implanted with chronic lumbar intrathecal catheters, and were tested for paw flinch by formalin injection. Biphasic painful behavior was counted. Intrathecal clonidine (3-12 nmol) was administered 15 min before formalin, and intrathecal lidocaine (375-1850 nmol) was administered 5 min before formalin. To examine the interaction of intrathecal clonidine and lidocaine, an isobolographic design was used. Spinal administration of clonidine produced dose-dependent suppression of the biphasic responses in the formalin test. Spinal lidocaine resulted in dose-dependent transient motor dysfunction and the motor dysfunction recovered to normal at 10-15 min after administration. Spinal lidocaine produced dose-dependent suppression of phase-2 activity in the formalin test. Isobolographic analysis showed that the combination of intrathecal clonidine and lidocaine synergistically reduced Phase-2 activity. We conclude that intrathecal clonidine synergistically interacts with lidocaine in reducing the nociceptive response in the formalin test. Preformalin administration of intrathecal clonidine and lidocaine dose-dependently produced antinociception in the formalin test. The combination of clonidine and lidocaine, synergistically produced suppression of nociceptive response in the persistent pain model.

The Effects of Direct and Indirect Speech Acts on Native English and ESL Speakers' Perception of Teacher Written Feedback

ERIC Educational Resources Information Center

Baker, Wendy; Hansen Bricker, Rachel

2010-01-01

This study explores how second language (L2) learners perceive indirect (hedging or indirect speech acts) and direct written teacher feedback. Though research suggests that indirect speech acts may be more difficult to interpret than direct speech acts ([Champagne, 2001] and [Holtgraves, 1999]), using indirect speech acts is often encouraged in…

A One Pot Synthesis of Novel Bioactive Tri-Substitute-Condensed-Imidazopyridines that Targets Snake Venom Phospholipase A2

PubMed Central

Anilkumar, Nirvanappa C.; Sundaram, Mahalingam S.; Mohan, Chakrabhavi Dhananjaya; Rangappa, Shobith; Bulusu, Krishna C.; Fuchs, Julian E.; Girish, Kesturu S.; Bender, Andreas; Basappa; Rangappa, Kanchugarakoppal S.

2015-01-01

Drugs such as necopidem, saripidem, alpidem, zolpidem, and olprinone contain nitrogen-containing bicyclic, condensed-imidazo[1,2-α]pyridines as bioactive scaffolds. In this work, we report a high-yield one pot synthesis of 1-(2-methyl-8-aryl-substitued-imidazo[1,2-α]pyridin-3-yl)ethan-1-onefor the first-time. Subsequently, we performed in silico mode-of-action analysis and predicted that the synthesized imidazopyridines targets Phospholipase A2 (PLA2). In vitro analysis confirmed the predicted target PLA2 for the novel imidazopyridine derivative1-(2-Methyl-8-naphthalen-1-yl-imidazo [1,2-α]pyridine-3-yl)-ethanone (compound 3f) showing significant inhibitory activity towards snake venom PLA2 with an IC50 value of 14.3 μM. Evidently, the molecular docking analysis suggested that imidazopyridine compound was able to bind to the active site of the PLA2 with strong affinity, whose affinity values are comparable to nimesulide. Furthermore, we estimated the potential for oral bioavailability by Lipinski's Rule of Five. Hence, it is concluded that the compound 3f could be a lead molecule against snake venom PLA2. PMID:26196520

48 CFR 52.249-10 - Default (Fixed-Price Construction).

Code of Federal Regulations, 2011 CFR

2011-10-01

... God or of the public enemy, (ii) acts of the Government in either its sovereign or contractual.... Examples of such causes include (i) acts of God or of the public enemy, (ii) acts of the Government in... of such causes include (i) acts of God or of the public enemy, (ii) acts of the Government in either...

A 3D Cloud-Construction Algorithm for the EarthCARE Satellite Mission

NASA Technical Reports Server (NTRS)

Barker, H. W.; Jerg, M. P.; Wehr, T.; Kato, S.; Donovan, D. P.; Hogan, R. J.

2011-01-01

This article presents and assesses an algorithm that constructs 3D distributions of cloud from passive satellite imagery and collocated 2D nadir profiles of cloud properties inferred synergistically from lidar, cloud radar and imager data.

Design and Performance of the Acts Gigabit Satellite Network High Data-Rate Ground Station

NASA Technical Reports Server (NTRS)

Hoder, Doug; Kearney, Brian

1995-01-01

The ACTS High Data-Rate Ground stations were built to support the ACTS Gigabit Satellite Network (GSN). The ACTS GSN was designed to provide fiber-compatible SONET service to remote nodes and networks through a wideband satellite system. The ACTS satellite is unique in its extremely wide bandwidth, and electronically controlled spot beam antennas. This paper discusses the requirements, design and performance of the RF section of the ACTS High Data-Rate Ground Stations and constituent hardware. The ACTS transponder systems incorporate highly nonlinear hard limiting. This introduced a major complexity in to the design and subsequent modification of the ground stations. A discussion of the peculiarities of the A CTS spacecraft transponder system and their impact is included.

Elements of a Plan-Based Theory of Speech Acts. Technical Report No. 141.

ERIC Educational Resources Information Center

Cohen, Philip R.; Perrault, C. Raymond

This report proposes that people often plan their speech acts to affect their listeners' beliefs, goals, and emotional states and that such language use can be modeled by viewing speech acts as operators in a planning system, allowing both physical and speech acts to be integrated into plans. Methodological issues of how speech acts should be…

Enhancer Variants Synergistically Drive Dysfunction of a Gene Regulatory Network In Hirschsprung Disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chatterjee, Sumantra; Kapoor, Ashish; Akiyama, Jennifer A.

Common sequence variants in cis-regulatory elements (CREs) are suspected etiological causes of complex disorders. We previously identified an intronic enhancer variant in the RET gene disrupting SOX10 binding and increasing Hirschsprung disease (HSCR) risk 4-fold. We now show that two other functionally independent CRE variants, one binding Gata2 and the other binding Rarb, also reduce Ret expression and increase risk 2- and 1.7-fold. By studying human and mouse fetal gut tissues and cell lines, we demonstrate that reduced RET expression propagates throughout its gene regulatory network, exerting effects on both its positive and negative feedback components. We also provide evidencemore » that the presence of a combination of CRE variants synergistically reduces RET expression and its effects throughout the GRN. These studies show how the effects of functionally independent non-coding variants in a coordinated gene regulatory network amplify their individually small effects, providing a model for complex disorders.« less

A gigantically increased ratio of electrical to thermal conductivity and synergistically enhanced thermoelectric properties in interface-controlled TiO2-RGO nanocomposites.

PubMed

Nam, Woo Hyun; Lim, Young Soo; Kim, Woochul; Seo, Hyeon Kook; Dae, Kyun Seong; Lee, Soonil; Seo, Won-Seon; Lee, Jeong Yong

2017-06-14

We report synergistically enhanced thermoelectric properties through the independently controlled charge and thermal transport properties in a TiO 2 -reduced graphene oxide (RGO) nanocomposite. By the consolidation of TiO 2 -RGO hybrid powder using spark plasma sintering, we prepared an interface-controlled TiO 2 -RGO nanocomposite where its grain boundaries are covered with the RGO network. Both the enhancement in electrical conductivity and the reduction in thermal conductivity were simultaneously achieved thanks to the beneficial effects of the RGO network, and detailed mechanisms are discussed. This led to the gigantic increase in the ratio of electrical to thermal conductivity by six orders of magnitude and also the synergistic enhancement in the thermoelectric figure of merit by two orders. Our results present a strategy for the realization of 'phonon-glass electron-crystals' through interface control using graphene in graphene hybrid thermoelectric materials.

Understanding gas adsorption in MOF-5/graphene oxide composite materials.

PubMed

Lin, Li-Chiang; Paik, Dooam; Kim, Jihan

2017-05-10

Metal-organic framework (MOF) and graphene oxide (GO) composite materials (MOF/GO) have been regarded as promising for separation applications due to their synergistically enhanced adsorption properties. Molecular-level understandings of these materials, however, remain unknown to date. In this study, molecular simulations were used, for the first time, to model these composite materials. Specifically, the composite MOF-5/GO material was modeled as stacks of sandwich-like layers on top of one another, consistent with experimental observations inferred from XRD and the SEM images. Simulations indicate that CO 2 and CH 4 bind strongly in the MOF/GO interface region, resulting in synergistically enhanced adsorption properties. To exploit the interface region, we found that in simulating linear alkanes, larger guest molecules show substantially improved adsorption properties in composites compared to the parent MOF-5 structure, illustrating that the performance of adsorption in these molecules will benefit the most from the MOF/GO composites.

Hsp90 N- and C-terminal double inhibition synergistically suppresses Bcr-Abl-positive human leukemia cells

PubMed Central

Chen, Xianling; Chen, Xiaole; Li, Ding; Fan, Yingjuan; Xu, Jianhua; Chen, Yuanzhong; Wu, Lixian

2017-01-01

Heat shock protein 90 (Hsp90) contains amino (N)–terminal domain, carboxyl(C)-terminal domain, and middle domains, which activate Hsp90 chaperone function cooperatively in tumor cells. One terminal occupancy might influence another terminal binding with inhibitor. The Bcr-Abl kinase is one of the Hsp90 clients implicated in the pathogenesis of chronic myeloid leukemia (CML). Present studies demonstrate that double inhibition of the N- and C-terminal termini can disrupt Hsp90 chaperone function synergistically, but not antagonistically, in Bcr-Abl-positive human leukemia cells. Furthermore, both the N-terminal inhibitor 17-AAG and the C-terminal inhibitor cisplatin (CP) have the capacity to suppress progenitor cells; however, only CP is able to inhibit leukemia stem cells (LSCs) significantly, which implies that the combinational treatment is able to suppress human leukemia in different mature states. PMID:28036294

Plac8 links oncogenic mutations to regulation of autophagy and is critical to pancreatic cancer progression

PubMed Central

Kinsey, Conan; Balakrishnan, Vijaya; O’Dell, Michael R.; Huang, Jing Li; Newman, Laurel; Whitney-Miller, Christa L.; Hezel, Aram F.; Land, Hartmut

2014-01-01

Summary Mutations in p53 and RAS potently cooperate in oncogenic transformation and correspondingly these genetic alterations frequently coexist in pancreatic ductal adenocarcinoma (PDA) and other human cancers. Previously we identified a set of genes synergistically activated by combined RAS and p53 mutations as frequent downstream mediators of tumorigenesis. Here, we show that the synergistically activated gene Plac8 is critical for pancreatic cancer growth. Silencing of Plac8 in cell lines suppresses tumor formation by blocking autophagy, a process essential for maintaining metabolic homeostasis in PDA, and genetic inactivation in an engineered mouse model inhibits PDA progression. We show that Plac8 is a critical regulator of the autophagic machinery, localizing to the lysosomal compartment and facilitating lysosome-autophagosome fusion. Plac8 thus provides a mechanistic link between primary oncogenic mutations and the induction of autophagy, a central mechanism of metabolic reprogramming, during PDA progression. PMID:24794439

Enhancer Variants Synergistically Drive Dysfunction of a Gene Regulatory Network In Hirschsprung Disease

DOE PAGES

Chatterjee, Sumantra; Kapoor, Ashish; Akiyama, Jennifer A.; ...

2016-09-29

Common sequence variants in cis-regulatory elements (CREs) are suspected etiological causes of complex disorders. We previously identified an intronic enhancer variant in the RET gene disrupting SOX10 binding and increasing Hirschsprung disease (HSCR) risk 4-fold. We now show that two other functionally independent CRE variants, one binding Gata2 and the other binding Rarb, also reduce Ret expression and increase risk 2- and 1.7-fold. By studying human and mouse fetal gut tissues and cell lines, we demonstrate that reduced RET expression propagates throughout its gene regulatory network, exerting effects on both its positive and negative feedback components. We also provide evidencemore » that the presence of a combination of CRE variants synergistically reduces RET expression and its effects throughout the GRN. These studies show how the effects of functionally independent non-coding variants in a coordinated gene regulatory network amplify their individually small effects, providing a model for complex disorders.« less

Probing the coagulation pathway with aptamers identifies combinations that synergistically inhibit blood clot formation

PubMed Central

Bompiani, Kristin M; Lohrmann, Jens L; Pitoc, George A; Frederiksen, James W; Mackensen, George B; Sullenger, Bruce A

2014-01-01

SUMMARY Coordinated enzymatic reactions regulate blood clot generation. To explore the contributions of various coagulation enzymes in this process, we utilized a panel of aptamers against factors VIIa, IXa, Xa, and prothrombin. Each aptamer dose-dependently inhibited clot formation, yet none was able to completely impede this process in highly procoagulant settings. However several combinations of two aptamers synergistically impaired clot formation. One extremely potent aptamer combination was able to maintain human blood fluidity even during extracorporeal circulation, a highly procoagulant setting encountered during cardiopulmonary bypass surgery. Moreover, this aptamer cocktail could be rapidly reversed with antidotes to restore normal hemostasis, indicating that even highly potent aptamer combinations can be rapidly controlled. These studies highlight the potential utility of using sets of aptamers to probe the functions of proteins in molecular pathways for research and therapeutic ends. PMID:25065530

Combination of arsenic and interferon-α inhibits expression of KSHV latent transcripts and synergistically improves survival of mice with primary effusion lymphomas.

PubMed

El Hajj, Hiba; Ali, Jihane; Ghantous, Akram; Hodroj, Dana; Daher, Ahmad; Zibara, Kazem; Journo, Chloé; Otrock, Zaher; Zaatari, Ghazi; Mahieux, Renaud; El Sabban, Marwan; Bazarbachi, Ali; Abou Merhi, Raghida

2013-01-01

Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphomas (PEL). PEL cell lines infected with KSHV, but negative for Epstein-Barr virus have a tumorigenic potential in non-obese diabetic/severe combined immunodeficient mice and result in efficient engraftment and formation of malignant ascites with notable abdominal distension, consistent with the clinical manifestations of PEL in humans. Using this preclinical mouse model, we demonstrate that the combination of arsenic trioxide and interferon-alpha (IFN) inhibits proliferation, induces apoptosis and downregulates the latent viral transcripts LANA-1, v-FLIP and v-Cyc in PEL cells derived from malignant ascites. Furthermore, this combination decreases the peritoneal volume and synergistically increases survival of PEL mice. These results provide a promising rationale for the therapeutic use of arsenic/IFN in PEL patients.

Combination of Arsenic and Interferon-α Inhibits Expression of KSHV Latent Transcripts and Synergistically Improves Survival of Mice with Primary Effusion Lymphomas

PubMed Central

El Hajj, Hiba; Ali, Jihane; Ghantous, Akram; Hodroj, Dana; Daher, Ahmad; Zibara, Kazem; Journo, Chloé; Otrock, Zaher; Zaatari, Ghazi; Mahieux, Renaud; El Sabban, Marwan; Bazarbachi, Ali; Abou Merhi, Raghida

2013-01-01

Background Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphomas (PEL). PEL cell lines infected with KSHV, but negative for Epstein-Barr virus have a tumorigenic potential in non-obese diabetic/severe combined immunodeficient mice and result in efficient engraftment and formation of malignant ascites with notable abdominal distension, consistent with the clinical manifestations of PEL in humans. Methodology/Principal Findings Using this preclinical mouse model, we demonstrate that the combination of arsenic trioxide and interferon-alpha (IFN) inhibits proliferation, induces apoptosis and downregulates the latent viral transcripts LANA-1, v-FLIP and v-Cyc in PEL cells derived from malignant ascites. Furthermore, this combination decreases the peritoneal volume and synergistically increases survival of PEL mice. Conclusion/Significance These results provide a promising rationale for the therapeutic use of arsenic/IFN in PEL patients. PMID:24250827

Chemically Tunable 2D Materials

DTIC Science & Technology

new opto-electronic silicon based 2D materials, (ii) new material coatings that can change color from transparent to blue chemically or with heat, and...conduction and transparency . Activities are integrated with in-situ fundamental investigation to synergistically develop a complete understanding in materials research.

Hedgehog signaling is synergistically enhanced by nutritional deprivation and ligand stimulation in human fibroblasts of Gorlin syndrome.

PubMed

Mizuochi, Hiromi; Fujii, Katsunori; Shiohama, Tadashi; Uchikawa, Hideki; Shimojo, Naoki

2015-02-13

Hedgehog signaling is a pivotal developmental pathway that comprises hedgehog, PTCH1, SMO, and GLI proteins. Mutations in PTCH1 are responsible for Gorlin syndrome, which is characterized by developmental defects and tumorigenicity. Although the hedgehog pathway has been investigated extensively in Drosophila and mice, its functional roles have not yet been determined in human cells. In order to elucidate the mechanism by which transduction of the hedgehog signal is regulated in human tissues, we employed human fibroblasts derived from three Gorlin syndrome patients and normal controls. We investigated GLI1 transcription, downstream of hedgehog signaling, to assess native signal transduction, and then treated fibroblasts with a recombinant human hedgehog protein with or without serum deprivation. We also examined the transcriptional levels of hedgehog-related genes under these conditions. The expression of GLI1 mRNA was significantly higher in Gorlin syndrome-derived fibroblasts than in control cells. Hedgehog stimulation and nutritional deprivation synergistically enhanced GLI1 transcription levels, and this was blocked more efficiently by vismodegib, a SMO inhibitor, than by the natural compound, cyclopamine. Messenger RNA profiling revealed the increased expression of Wnt signaling and morphogenetic molecules in these fibroblasts. These results indicated that the hedgehog stimulation and nutritional deprivation synergistically activated the hedgehog signaling pathway in Gorlin syndrome fibroblasts, and this was associated with increments in the transcription levels of hedgehog-related genes such as those involved in Wnt signaling. These fibroblasts may become a significant tool for predicting the efficacies of hedgehog molecular-targeted therapies such as vismodegib. Copyright © 2015 Elsevier Inc. All rights reserved.

Synergistic regulation of the acute phase protein SIP24/24p3 by glucocorticoid and pro-inflammatory cytokines.

PubMed

Liu, Quan-Sheng; Nilsen-Hamilton, Marit; Xiong, Si-Dong

2003-10-25

SIP24/24p3 is a secreted murine acute phase protein which has been speculated to play an anti-inflammatory role in vivo. Recently SIP24/24p3 has been found to be able to specifically induce apoptosis in leukocytes. By using (35)S metabolic labeling method, we studied the regulation of SIP24/24p3 by glucocorticoid and pro-inflammatory cytokines IL-6 and TNF-alpha in cultured Balb/c 3T3 and BNL cells. The following results were observed: (1) dexamethasone induced the expression of SIP24/24p3 in both Balb/c 3T3 and BNL cells, the induction was more significant in BNL cells; (2) dexamethasone and IL-6 synergistically induced the expression of SIP24/24p3 in both Balb/c 3T3 and BNL cells; (3) in Balb/c 3T3 cells dexamethasone and TNF-alpha acted synergistically to induce the expression of SIP24/24p3, whereas in BNL cells dexamethasone and TNF-alpha induced the expression of SIP24/24p3 in an additive manner; (4) dexamethasone and IL-6/TNF-alpha acted synergistically in Balb/c 3T3 cells and additively in BNL cells to induce the expression of SIP24/24p3. The inducibility of SIP24/24p3 by multiple factors will help to explain its highly specific expression in vivo. The difference in the expression patterns of SIP24/24p3 in different cell types is also suggestive to its expression and regulation in hepatic and extrahepatic tissues. Finally, the fact that SIP24/24p3 protein can be induced by both pro-inflammatory as well as anti-inflammatory factors is indicative of the important role of SIP24/24p3 in the entire acute phase response process.

Fibroblast growth factor and cyclic AMP (cAMP) synergistically activate gene expression at a cAMP response element.

PubMed Central

Tan, Y; Low, K G; Boccia, C; Grossman, J; Comb, M J

1994-01-01

Growth factors and cyclic AMP (cAMP) are known to activate distinct intracellular signaling pathways. Fibroblast growth factor (FGF) activates ras-dependent kinase cascades, resulting in the activation of MAP kinases, whereas cAMP activates protein kinase A. In this study, we report that growth factors and cAMP act synergistically to stimulate proenkephalin gene expression. Positive synergy between growth factor- and cAMP-activated signaling pathways on gene expression has not been previously reported, and we suggest that these synergistic interactions represent a useful model for analyzing interactions between these pathways. Transfection and mutational studies indicate that both FGF-dependent gene activation and cAMP-dependent gene activation require cAMP response element 2 (CRE-2), a previously characterized cAMP-dependent regulatory element. Furthermore, multiple copies of this element are sufficient to confer FGF regulation upon a minimal promoter, indicating that FGF and cAMP signaling converge upon transcription factors acting at CRE-2. Among many different ATF/AP-1 factors tested, two factors, ATF-3 and c-Jun, stimulate proenkephalin transcription in an FGF- or Ras-dependent fashion. Finally, we show that ATF-3 and c-Jun form heterodimeric complexes in SK-N-MC cells and that the levels of both proteins are increased in response to FGF but not cAMP. Together, these results indicate that growth factor- and cAMP-dependent signaling pathways converge at CRE-2 to synergistically stimulate gene expression and that ATF-3 and c-Jun regulate proenkephalin transcription in response to both growth factor- and cAMP-dependent intracellular signaling pathways. Images PMID:7935470

Lithium and an EPAC-specific inhibitor ESI-09 synergistically suppress pancreatic cancer cell proliferation and survival.

PubMed

Wang, Xinshuo; Luo, Cheng; Cheng, Xiaodong; Lu, Meiling

2017-07-01

Our previous studies showed that while lithium suppresses proliferation and induces apoptosis in pancreatic cancer cells, the inhibition of exchange proteins directly activated by cyclic adenosine monophosphate (cAMP) (EPAC)1 blocks pancreatic cancer cell migration and invasion. In this study, we further investigated the combinatory effects of lithium and EPAC-specific inhibitor (ESI)-09, an EPAC-specific inhibitor, on pancreatic cancer cell proliferation and viability, and explored whether lithium synergistically cooperates with EPAC inhibition in suppressing pancreatic cancer cell tumorigenicity. The cell viability of pancreatic cancer cell lines PANC-1 and MiaPaCa-2 was measured after 48 h of incubation with different dose combination of lithium and ESI-09. Flow cytometric analysis was carried out to further verify the impact of lithium and ESI-09 upon PANC-1 cell proliferation and apoptosis. To investigate the mechanism that the effects generated by lithium and ESI-09 on PANC-1 cells, the intracellular cAMP level was measured by an ELISA-based cAMP immunoassay. Our data showed that lithium and ESI-09 synergistically inhibit pancreatic cancer cell growth and survival. Furthermore, our results revealed a novel mechanism in which the synergism between lithium and ESI-09 is not mediated by the inhibitory effect of lithium toward GSK3β, but by lithium's ability to suppress cAMP/protein kinase A signaling. © The Author 2017. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Abscisic acid synergizes with rosiglitazone to improve glucose tolerance, down-modulate macrophage accumulation in adipose tissue: possible action of the cAMP/PKA/PPAR γ axis

PubMed Central

Guri, Amir J; Hontecillas, Raquel; Bassaganya-Riera, Josep

2010-01-01

Background & Aims Abscisic acid (ABA) is effective in preventing insulin resistance and obesity-related inflammation through a PPAR γ-dependent mechanism. The objective of this study was to assess the efficacy ABA in improving glucose homeostasis and suppress inflammation when administered in combination with rosiglitazone (Ros) and to determine whether PPAR γ activation by ABA is initiated via cAMP/protein kinase A (PKA) signaling. Methods Obese db/db mice were fed high-fat diets containing 0, 10, or 70 mg/kg Ros with and without racemic ABA (100 mg/kg) for 60 days. Glucose tolerance and fasting insulin levels were assessed at 6 and 8 weeks, respectively, and adipose tissue macrophage (ATM) infiltration was examined by flow cytometry. Gene expression was examined on white adipose tissue (WAT) and stromal vascular cells (SVCs) cultured with ABA, Ros, or an ABA/Ros combination. Results Both Ros and ABA improved glucose tolerance, and ABA decreased plasma insulin levels while having no effect on Ros-induced weight gain. ABA in combination with low-dose Ros (10 mg/kg; Roslo) synergistically inhibited ATM infiltration. Treatment of SVCs with Ros, ABA or ABA/Ros suppressed expression of the M1 marker CCL17. ABA and Ros synergistically increased PPAR γ activity and pretreatment with a cAMP-inhibitor or a PKA-inhibitor abrogated ABA-induced PPAR γ activation. Conclusions ABA and Ros act synergistically to modulate PPAR γ activity and macrophage accumulation in WAT and ABA enhances PPAR γ activity through a membrane-initiated mechanism dependent on cAMP/PKA signaling. PMID:20207056

43 CFR 5462.2 - Prohibited acts.

Code of Federal Regulations, 2013 CFR

2013-10-01

... § 5462.2 Prohibited acts. (a) The acts or omissions listed in paragraph (b) of this section apply only to... permit held by the purchaser responsible for such acts or omissions may be canceled. (b) The following activities are prohibited: (1) Cutting, removing, or otherwise damaging any timber, tree, or other vegetative...

Quantitative evaluation of a thrust vector controlled transport at the conceptual design phase

NASA Astrophysics Data System (ADS)

Ricketts, Vincent Patrick

The impetus to innovate, to push the bounds and break the molds of evolutionary design trends, often comes from competition but sometimes requires catalytic political legislature. For this research endeavor, the 'catalyzing legislation' comes in response to the rise in cost of fossil fuels and the request put forth by NASA on aircraft manufacturers to show reduced aircraft fuel consumption of +60% within 30 years. This necessitates that novel technologies be considered to achieve these values of improved performance. One such technology is thrust vector control (TVC). The beneficial characteristic of thrust vector control technology applied to the traditional tail-aft configuration (TAC) commercial transport is its ability to retain the operational advantage of this highly evolved aircraft type like cabin evacuation, ground operation, safety, and certification. This study explores if the TVC transport concept offers improved flight performance due to synergistically reducing the traditional empennage size, overall resulting in reduced weight and drag, and therefore reduced aircraft fuel consumption. In particular, this study explores if the TVC technology in combination with the reduced empennage methodology enables the TAC aircraft to synergistically evolve while complying with current safety and certification regulation. This research utilizes the multi-disciplinary parametric sizing software, AVD Sizing, developed by the Aerospace Vehicle Design (AVD) Laboratory. The sizing software is responsible for visualizing the total system solution space via parametric trades and is capable of determining if the TVC technology can enable the TAC aircraft to synergistically evolve, showing marked improvements in performance and cost. This study indicates that the TVC plus reduced empennage methodology shows marked improvements in performance and cost.

Simultaneous silencing of ACSL4 and induction of GADD45B in hepatocellular carcinoma cells amplifies the synergistic therapeutic effect of aspirin and sorafenib

PubMed Central

Xia, Hongping; Lee, Kee Wah; Chen, Jianxiang; Kong, Shik Nie; Sekar, Karthik; Deivasigamani, Amudha; Seshachalam, Veerabrahma Pratap; Goh, Brian Kim Poh; Ooi, London Lucien; Hui, Kam M

2017-01-01

Sorafenib is currently the only US Food and Drug Administration (FDA)-approved molecular inhibitor for the systemic therapy of advanced hepatocellular carcinoma (HCC). Aspirin has been studied extensively as an anti-inflammation, cancer preventive and therapeutic agent. However, the potential synergistic therapeutic effects of sorafenib and aspirin on advanced HCC treatment have not been well studied. Drug combination studies and their synergy quantification were performed using the combination index method of Chou-Talalay. The synergistic therapeutic effects of sorafenib and aspirin were evaluated using an orthotopic mouse model of HCC and comprehensive gene profiling analyses were conducted to identify key factors mediating the synergistic therapeutic effects of sorafenib and aspirin. Sorafenib was determined to act synergistically on HCC cells with aspirin in vitro. Using Hep3B and HuH7 HCC cells, it was demonstrated that sorafenib and aspirin acted synergistically to induce apoptosis. Mechanistic studies demonstrated that combining sorafenib and aspirin yielded significant synergistically anti-tumor effects by simultaneously silencing ACSL4 and the induction of GADD45B expression in HCC cells both in vitro and in the orthotopic HCC xenograft mouse model. Importantly, clinical evidence has independently corroborated that survival of HCC patients expressing ACSL4highGADD45Blow was significantly poorer compared to patients with ACSL4lowGADD45Bhigh, thus demonstrating the potential clinical value of combining aspirin and sorafenib for HCC patients expressing ACSL4highGADD45Blow. In conclusion, sorafenib and aspirin provide synergistic therapeutic effects on HCC cells that are achieved through simultaneous silencing of ACSL4 and induction of GADD45B expression. Targeting HCC with ACSL4highGADD45Blow expression with aspirin and sorafenib could provide potential synergistic therapeutic benefits. PMID:28900541

Combined Toxicity of Three Essential Oils Against Aedes aegypti (Diptera: Culicidae) Larvae.

PubMed

Muturi, Ephantus J; Ramirez, Jose L; Doll, Kenneth M; Bowman, Michael J

2017-11-07

Essential oils are potential alternatives to synthetic insecticides because they have low mammalian toxicity, degrade rapidly in the environment, and possess complex mixtures of bioactive constituents with multi-modal activity against the target insect populations. Twenty-one essential oils were initially screened for their toxicity against Aedes aegypti (L.) larvae and three out of the seven most toxic essential oils (Manuka, oregano, and clove bud essential oils) were examined for their chemical composition and combined toxicity against Ae. aegypti larvae. Manuka essential oil interacted synergistically with oregano essential oil and antagonistically with clove bud essential oil. GC-MS analysis revealed the presence of 21 components in Manuka essential oil and three components each in oregano and clove bud essential oils. Eugenol (84.9%) and eugenol acetate (9.6%) were the principal constituents in clove bud essential oil while carvacrol (75.8%) and m-isopropyltoluene (15.5%) were the major constituents in oregano essential oil. The major constituents in Manuka essential oil were calamenene (20%) and 3-dodecyl-furandione (11.4%). Manuka essential oil interacted synergistically with eugenol acetate and antagonistically with eugenol, suggesting that eugenol was a major contributor to the antagonistic interaction between Manuka and clove bud essential oils. In addition, Manuka interacted synergistically with carvacrol suggesting its contribution to the synergistic interaction between Manuka and oregano essential oils. These findings provide novel insights that can be used to develop new and safer alternatives to synthetic insecticides. Published by Oxford University Press on behalf of Entomological Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yamamoto, Yasuhiro; Fujita, Megumi; Koma, Hiromi

Highlights: {yields} A topoisomerase-I inhibitor, camptothecin, exhibited synergistically toxicity with 15d-PGJ{sub 2}. {yields} The combination of 15d-PGJ{sub 2} and a topoisomerase-II inhibitor, doxorubicine, did not cause synergistic cell growth inhibition. {yields} A PPAR{gamma} antagonist did not prevent Caki-2 from undergoing 15d-PGJ{sub 2}-induced cytotoxicity. {yields} The treatment of camptothecin combined with 15d-PGJ{sub 2} activated caspase-3 more than the separate treatment. -- Abstract: Renal cell carcinoma (RCC) is chemoresistant cancer. Although several clinical trials were conducted to explore effective medications, the chemoresistance of RCC has not yet been conquered. An endogenous ligand for peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}), 15-deoxy-{Delta}{sup 12,14}-prostaglandin J{sub 2} (15d-PGJ{submore » 2}), induces apoptosis in RCC. Here, we examined synergistic effects of several carcinostatics on the anti-tumor activity of 15d-PGJ{sub 2} in Caki-2 cell line by MTT assay. A topoisomerase-I inhibitor, camptothecin (CPT), exhibited synergistically toxicity with 15d-PGJ{sub 2}, but neither 5-fluorouracil nor cisplatin did. The combination of 15d-PGJ{sub 2} and a topoisomerase-II inhibitor, doxorubicine, did not cause synergistic cell growth inhibition. The synergistic effect of topoisomerase-I and II inhibitors was not also detected. A PPAR{gamma} antagonist, GW9662, did not prevent Caki-2 from undergoing 15d-PGJ{sub 2}-induced cytotoxicity. The treatment of CPT combined with 15d-PGJ{sub 2} activated caspase-3 more than the separate treatment. These results suggest that 15d-PGJ{sub 2} exhibited the anti-tumor activity synergistically with CPT independent of topoisomerase-II and PPAR{gamma}.« less

43 CFR 5462.2 - Prohibited acts.

Code of Federal Regulations, 2011 CFR

2011-10-01

... § 5462.2 Prohibited acts. (a) The acts or omissions listed in paragraph (b) of this section apply only to... permit held by the purchaser responsible for such acts or omissions may be canceled. (b) The following activities are prohibited: (1) Cutting, removing, or otherwise damaging any timber, tree, or other vegetative...

43 CFR 5462.2 - Prohibited acts.

Code of Federal Regulations, 2012 CFR

2012-10-01

... § 5462.2 Prohibited acts. (a) The acts or omissions listed in paragraph (b) of this section apply only to... permit held by the purchaser responsible for such acts or omissions may be canceled. (b) The following activities are prohibited: (1) Cutting, removing, or otherwise damaging any timber, tree, or other vegetative...

42 CFR 6.6 - Covered acts and omissions.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Covered acts and omissions. 6.6 Section 6.6 Public... CLAIMS ACT COVERAGE OF CERTAIN GRANTEES AND INDIVIDUALS § 6.6 Covered acts and omissions. (a) Only acts and omissions occurring on and after the effective date of the Secretary's determination under § 6.5...

14 CFR 1274.926 - Clean Air-Water Pollution Control Acts.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Clean Air-Water Pollution Control Acts. 1274... AGREEMENTS WITH COMMERCIAL FIRMS Other Provisions and Special Conditions § 1274.926 Clean Air-Water Pollution Control Acts. Clean Air-Water Pollution Control Acts July 2002 If this cooperative agreement or supplement...

Harmful situations, impure people: an attribution asymmetry across moral domains.

PubMed

Chakroff, Alek; Young, Liane

2015-03-01

People make inferences about the actions of others, assessing whether an act is best explained by person-based versus situation-based accounts. Here we examine people's explanations for norm violations in different domains: harmful acts (e.g., assault) and impure acts (e.g., incest). Across four studies, we find evidence for an attribution asymmetry: people endorse more person-based attributions for impure versus harmful acts. This attribution asymmetry is partly explained by the abnormality of impure versus harmful acts, but not by differences in the moral wrongness or the statistical frequency of these acts. Finally, this asymmetry persists even when the situational factors that lead an agent to act impurely are stipulated. These results suggest that, relative to harmful acts, impure acts are linked to person-based attributions. Copyright © 2014 Elsevier B.V. All rights reserved.

The cognitive roles of behavioral variability: idiosyncratic acts as the foundation of identity and as transitional, preparatory, and confirmatory phases.

PubMed

Eilam, David

2015-02-01

Behavior in obsessive compulsive disorder (OCD), in habitual daily tasks, and in sport and cultural rituals is deconstructed into elemental acts and categorized into common acts, performed by all individuals completing a similar task, and idiosyncratic acts, not performed by all individuals. Never skipped, common acts establish the pragmatic part of motor tasks. Repetitive performance of a few common acts renders rituals a rigid form, whereby common acts may serve as memes for cultural transmission. While idiosyncratic acts are not pragmatically necessary for task completion, they fulfill important cognitive roles. They form a long preparatory phase in tasks that involve high stakes, and a long confirmatory phase in OCD rituals. Idiosyncratic acts also form transitional phases between motor tasks, and are involved in establishing identity and preserving the flexibility necessary for adapting to varying circumstances. Behavioral variability, as manifested in idiosyncrasy, thus does not seem to be a noise or by-product of motor activity, but an essential cognitive component that has been preserved in the evolution of behavioral patterns, similar to the genetic variability in biology. Copyright © 2014 Elsevier Ltd. All rights reserved.

Shedding Light on Synergistic Chemical Genetic Connections with Machine Learning.

PubMed

Ekins, Sean; Siqueira-Neto, Jair Lage

2015-12-23

Machine learning can be used to predict compounds acting synergistically, and this could greatly expand the universe of available potential treatments for diseases that are currently hidden in the dark chemical matter. Copyright © 2015 Elsevier Inc. All rights reserved.

A Call for Research on Planned vs. Unplanned Suicidal Behavior

ERIC Educational Resources Information Center

Conner, Kenneth R.

2004-01-01

Unplanned acts of suicidal behavior involve little preparation or forethought whereas planned acts may be carefully conceived and implemented. Planned acts are associated with greater depression, hopelessness, and lethality, but there are meager data on other factors associated with planning. The prevention of planned and unplanned acts may…

14 CFR 1274.926 - Clean Air-Water Pollution Control Acts.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 5 2012-01-01 2012-01-01 false Clean Air-Water Pollution Control Acts...-Water Pollution Control Acts. Clean Air-Water Pollution Control Acts July 2002 If this cooperative... 91-604) and section 308 of the Federal Water Pollution Control Act, as amended (33 U.S.C. 1251 et seq...

Integrated Multimedia Modeling System Response to Regional Land Management Change

EPA Science Inventory

A multi-media system of nitrogen and co-pollutant models describing critical physical and chemical processes that cascade synergistically and competitively through the environment, the economy and society has been developed at the USEPA Office of research and development. It is ...

Traumatic Brain Injury in Adult Rats Causes Progressive Nigrostriatal Dopaminergic Cell Loss and Enhanced Vulnerability to the Pesticide Paraquat

PubMed Central

Hutson, Che Brown; Lazo, Carlos R.; Mortazavi, Farzad; Giza, Christopher C.; Hovda, David

2011-01-01

Abstract Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of nigrostriatal dopaminergic neurons and the accumulation of alpha-synuclein. Both traumatic brain injury (TBI) and pesticides are risk factors for PD, but whether TBI causes nigrostriatal dopaminergic cell loss in experimental models and whether it acts synergistically with pesticides is unknown. We have examined the acute and long-term effects of TBI and exposure to low doses of the pesticide paraquat, separately and in combination, on nigrostriatal dopaminergic neurons in adult male rats. In an acute study, rats received moderate TBI by lateral fluid percussion (LFP) injury, were injected with saline or paraquat (10 mg/kg IP) 3 and 6 days after LFP, were sacrificed 5 days later, and their brains processed for immunohistochemistry. TBI alone increased microglial activation in the substantia nigra, and caused a 15% loss of dopaminergic neurons ipsilaterally. Paraquat increased the TBI effect, causing a 30% bilateral loss of dopaminergic neurons, reduced striatal tyrosine hydroxylase (TH) immunoreactivity more than TBI alone, and induced alpha-synuclein accumulation in the substantia nigra pars compacta. In a long-term study, rats received moderate LFP, were injected with saline or paraquat at 21 and 22 weeks post-injury, and were sacrificed 4 weeks later. At 26 weeks post injury, TBI alone induced a 30% bilateral loss of dopaminergic neurons that was not exacerbated by paraquat. These data suggest that TBI is sufficient to induce a progressive degeneration of nigrostriatal dopaminergic neurons. Furthermore, TBI and pesticide exposure, when occurring within a defined time frame, could combine to increase the PD risk. PMID:21644813

Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation

PubMed Central

Ambegaokar, Surendra S.; Jackson, George R.

2011-01-01

A functional genetic screen using loss-of-function and gain-of-function alleles was performed to identify modifiers of tau-induced neurotoxicity using the 2N/4R (full-length) isoform of wild-type human tau expressed in the fly retina. We previously reported eye pigment mutations, which create dysfunctional lysosomes, as potent modifiers; here, we report 37 additional genes identified from ∼1900 genes screened, including the kinases shaggy/GSK-3beta, par-1/MARK, CamKI and Mekk1. Tau acts synergistically with Mekk1 and p38 to down-regulate extracellular regulated kinase activity, with a corresponding decrease in AT8 immunoreactivity (pS202/T205), suggesting that tau can participate in signaling pathways to regulate its own kinases. Modifiers showed poor correlation with tau phosphorylation (using the AT8, 12E8 and AT270 epitopes); moreover, tested suppressors of wild-type tau were equally effective in suppressing toxicity of a phosphorylation-resistant S11A tau construct, demonstrating that changes in tau phosphorylation state are not required to suppress or enhance its toxicity. Genes related to autophagy, the cell cycle, RNA-associated proteins and chromatin-binding proteins constitute a large percentage of identified modifiers. Other functional categories identified include mitochondrial proteins, lipid trafficking, Golgi proteins, kinesins and dynein and the Hsp70/Hsp90-organizing protein (Hop). Network analysis uncovered several other genes highly associated with the functional modifiers, including genes related to the PI3K, Notch, BMP/TGF-β and Hedgehog pathways, and nuclear trafficking. Activity of GSK-3β is strongly upregulated due to TDP-43 expression, and reduced GSK-3β dosage is also a common suppressor of Aβ42 and TDP-43 toxicity. These findings suggest therapeutic targets other than mitigation of tau phosphorylation. PMID:21949350

Albendazole sensitizes cancer cells to ionizing radiation

PubMed Central

2011-01-01

Background Brain metastases afflict approximately half of patients with metastatic melanoma (MM) and small cell lung cancer (SCLC) and represent the direct cause of death in 60 to 70% of those affected. Standard of care remains ineffective in both types of cancer with the challenge of overcoming the blood brain barrier (BBB) exacerbating the clinical problem. Our purpose is to determine and characterize the potential of albendazole (ABZ) as a cytotoxic and radiosensitizing agent against MM and SCLC cells. Methods Here, ABZ's mechanism of action as a DNA damaging and microtubule disrupting agent is assessed through analysis of histone H2AX phosphorylation and cell cyle progression. The cytotoxicity of ABZ alone and in combination with radiation therapy is determined though clonogenic cell survival assays in a panel of MM and SCLC cell lines. We further establish ABZ's ability to act synergistically as a radio-sensitizer through combination index calculations and apoptotic measurements of poly (ADP-ribose) polymerase (PARP) cleavage. Results ABZ induces DNA damage as measured by increased H2AX phosphorylation. ABZ inhibits the growth of MM and SCLC at clinically achievable plasma concentrations. At these concentrations, ABZ arrests MM and SCLC cells in the G2/M phase of the cell cycle after 12 hours of treatment. Exploiting the notion that cells in the G2/M phase are the most sensitive to radiation therapy, we show that treatment of MM and SCLC cells treated with ABZ renders them more sensitive to radiation in a synergistic fashion. Additionally, MM and SCLC cells co-treated with ABZ and radiation exhibit increased apoptosis at 72 hours. Conclusions Our study suggests that the orally available antihelminthic ABZ acts as a potent radiosensitizer in MM and SCLC cell lines. Further evaluation of ABZ in combination with radiation as a potential treatment for MM and SCLC brain metastases is warranted. PMID:22094106

Attenuated stress response to acute restraint and forced swimming stress in arginine vasopressin 1b receptor subtype (Avpr1b) receptor knockout mice and wild-type mice treated with a novel Avpr1b receptor antagonist.

PubMed

Roper, J A; Craighead, M; O'Carroll, A-M; Lolait, S J

2010-11-01

Arginine vasopressin (AVP) synthesised in the parvocellular region of the hypothalamic paraventricular nucleus and released into the pituitary portal vessels acts on the 1b receptor subtype (Avpr1b) present in anterior pituitary corticotrophs to modulate the release of adrenocorticotrophic hormone (ACTH). Corticotrophin-releasing hormone is considered the major drive behind ACTH release; however, its action is augmented synergistically by AVP. To determine the extent of vasopressinergic influence in the hypothalamic-pituitary-adrenal axis response to restraint and forced swimming stress, we compared the stress hormone levels [plasma ACTH in both stressors and corticosterone (CORT) in restraint stress only] following acute stress in mutant Avpr1b knockout (KO) mice compared to their wild-type controls following the administration of a novel Avpr1b antagonist. Restraint and forced swimming stress-induced increases in plasma ACTH were significantly diminished in mice lacking a functional Avpr1b and in wild-type mice that had been pre-treated with Avpr1b antagonist. A corresponding decrease in plasma CORT levels was also observed in acute restraint-stressed knockout male mice, and in Avpr1b-antagonist-treated male wild-type mice. By contrast, plasma CORT levels were not reduced in acutely restraint-stressed female knockout animals, or in female wild-type animals pre-treated with Avpr1b antagonist. These results demonstrate that pharmacological antagonism or inactivation of Avpr1b causes a reduction in the hypothalamic-pituitary-adrenal (HPA) axis response, particularly ACTH, to acute restraint and forced swimming stress, and show that Avpr1b knockout mice constitute a model by which to study the contribution of Avpr1b to the HPA axis response to acute stressors. © 2010 The Authors. Journal of Neuroendocrinology © 2010 Blackwell Publishing Ltd.

Inhalation of progesterone inhibits chronic airway inflammation of mice exposed to ozone.

PubMed

Fei, Xia; Bao, Wuping; Zhang, Pengyu; Zhang, Xue; Zhang, Guoqing; Zhang, Yingying; Zhou, Xin; Zhang, Min

2017-05-01

Chronic ozone exposure leads to a model of mice with lung inflammation, emphysema and oxidative stress. Progesterone plays an important role in attenuating the neuroinflammation. We assume that progesterone will reduce the chronic airway inflammation exposed to ozone and evaluate whether combination of progesterone with glucocorticoids results in synergistic effects. C57/BL6 mice were exposed to ozone (2.5ppm, 3h) 12 times over 6 weeks, and were administered with progesterone (0.03 or 0.3mg/L; inhaled) alone or combined with budesonide (BUD) (0.2g/L) after each exposure until the tenth week. Mice were studied 24h after final exposure, cells and inflammatory mediators were assessed in bronchoalveolar lavage fluid (BALF) and lungs used for evaluation of glucocorticoids receptors (GR), p38 mitogen-activated protein kinase (MAPK) phosphorylation and nuclear transcription factor κB (NF-κB) activation. Exposure to ozone resulted in a marked lung neutrophilia. Moreover, in ozone-exposed group, the levels of oxidative stress-related interleukin (IL)-1β, IL-6, IL-8, IL-17A, activated NF-κB and p38MAPK, airway inflammatory cells infiltration density, mean linear intercept (Lm) were greatly increased, FEV 25 and glucocorticoids receptors (GR) were markedly decreased. Comparable to BUD, progesterone treatment dose-dependently led to a significant reduction of IL-1β, IL-6, IL-8, IL-17A, activated NF-κB and p38MAPK, and an increase of FEV 25 and GR. Progesterone combined with BUD resulted in dramatic changes, compared to monotherapy of BUD or progesterone. Therefore, these results demonstrate that chronic ozone exposure has profound airway inflammatory effects counteracted by progesterone and progesterone acts synergistically with glucocorticoids in attenuating the airway inflammation dose-dependently. Copyright © 2017 Elsevier Ltd. All rights reserved.

Aloe vera inhibits proliferation of human breast and cervical cancer cells and acts synergistically with cisplatin.

PubMed

Hussain, Arif; Sharma, Chhavi; Khan, Saniyah; Shah, Kruti; Haque, Shafiul

2015-01-01

Many of the anti-cancer agents currently used have an origin in natural sources including plants. Aloe vera is one such plant being studied extensively for its diverse health benefits, including cancer prevention. In this study, the cytotoxic potential of Aloe vera crude extract (ACE) alone or in combination with cisplatin in human breast (MCF-7) and cervical (HeLa) cancer cells was studied by cell viability assay, nuclear morphological examination and cell cycle analysis. Effects were correlated with modulation of expression of genes involved in cell cycle regulation, apoptosis and drug metabolism by RT-PCR. Exposure of cells to ACE resulted in considerable loss of cell viability in a dose- and time-dependent fashion, which was found to be mediated by through the apoptotic pathway as evidenced by changes in the nuclear morphology and the distribution of cells in the different phases of the cell cycle. Interestingly, ACE did not have any significant cytotoxicity towards normal cells, thus placing it in the category of safe chemopreventive agent. Further, the effects were correlated with the downregulation of cyclin D1, CYP 1A1, CYP 1A2 and increased expression of bax and p21 in MCF-7 and HeLa cells. In addition, low dose combination of ACE and cisplatin showed a combination index less than 1, indicating synergistic growth inhibition compared to the agents applied individually. In conclusion, these results signify that Aloe vera may be an effective anti-neoplastic agent to inhibit cancer cell growth and increase the therapeutic efficacy of conventional drugs like cispolatin. Thus promoting the development of plant-derived therapeutic agents appears warranted for novel cancer treatment strategies.

Novel inhibitory activity of the Staphylococcus aureus NorA efflux pump by a kaempferol rhamnoside isolated from Persea lingue Nees.

PubMed

Holler, Jes Gitz; Christensen, S Brøgger; Slotved, Hans-Christian; Rasmussen, Hasse B; Gúzman, Alfonso; Olsen, Carl-Erik; Petersen, Bent; Mølgaard, Per

2012-05-01

To isolate a plant-derived compound with efflux inhibitory activity towards the NorA transporter of Staphylococcus aureus. Bioassay-guided isolation was used, with inhibition of ethidium bromide efflux via NorA as a guide. Characterization of activity was carried out using MIC determination and potentiation studies of a fluoroquinolone antibiotic in combination with the isolated compound. Everted membrane vesicles of Escherichia coli cells enriched with NorA were prepared to study efflux inhibitory activity in an isolated manner. The ethanolic extract of Persea lingue was subjected to bioassay-guided fractionation and led to the isolation of the known compound kaempferol-3-O-α-L-(2,4-bis-E-p-coumaroyl)rhamnoside (compound 1). Evaluation of the dose-response relationship of compound 1 showed that ethidium bromide efflux was inhibited, with an IC(50) value of 2 μM. The positive control, reserpine, was found to have an IC(50) value of 9 μM. Compound 1 also inhibited NorA in enriched everted membrane vesicles of E. coli. Potentiation studies revealed that compound 1 at 1.56 mg/L synergistically increased the antimicrobial activity of ciprofloxacin 8-fold against a NorA overexpresser, and the synergistic activity was exerted at a fourth of the concentration necessary for reserpine. Compound 1 was not found to exert a synergistic effect on ciprofloxacin against a norA deletion mutant. The 2,3-coumaroyl isomer of compound 1 has been shown previously not to cause acute toxicity in mice at 20 mg/kg/day. Our results show that compound 1 acts through inhibition of the NorA efflux pump. Combination of compound 1 with subinhibitory concentrations of ciprofloxacin renders a wild-type more susceptible and a NorA overexpresser S. aureus susceptible.

Effect of Wave Reflection and Arterial Stiffness on the Risk of Development of Hypertension in Japanese Men.

PubMed

Tomiyama, Hirofumi; Komatsu, Shunsuke; Shiina, Kazuki; Matsumoto, Chisa; Kimura, Kazutaka; Fujii, Masatsune; Takahashi, Lisa; Chikamori, Taishiro; Yamashina, Akira

2018-05-08

We conducted analyses of repeated-measures data to examine whether pressure wave reflection acts additively or synergistically with arterial stiffness in the pathogenesis of hypertension. In 3172 middle-aged (42±9 years) healthy Japanese men without hypertension at the study baseline, systolic and diastolic blood pressures, brachial-ankle pulse wave velocity, and radial augmentation index were measured annually during a 9-year study period. Of these, 474 participants (15%) developed hypertension by the end of the study period. Binary logistic regression analysis demonstrated significant individual odds ratios for both baseline brachial-ankle pulse wave velocity and radial augmentation index for the development of hypertension. The rate of onset of hypertension during the study period was highest in the participant group with high values for both brachial-ankle pulse wave velocity and radial augmentation index at study baseline (262 of 965 participants: 27%). The generalized estimating equation analysis revealed that both radial augmentation index (estimate=0.06, SE=0.03, P =0.05) and brachial-ankle pulse wave velocity (estimate=0.07×10 -1 , SE=0.02×10 -1 , P <0.01) showed significant longitudinal association with new onset of hypertension, with no significant interaction. In Japanese men, abnormal wave reflection and increased arterial stiffness may be additively associated with the risk of new onset of hypertension. Abnormal wave reflection and elevated central blood pressure may be longitudinally associated with increase in arterial stiffness, and this longitudinal association may be a mechanism underlying the additive effect of these 2 variables on the risk of new onset of hypertension. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Highly Efficient Br-/NO3- Dual-Anion Electrolyte for Suppressing Charging Instabilities of Li-O2 Batteries.

PubMed

Xin, Xing; Ito, Kimihiko; Kubo, Yoshimi

2017-08-09

The main issues with Li-O 2 batteries are the high overpotential at the cathode and the dendrite formation at the anode during charging. Various types of redox mediators (RMs) have been proposed to reduce the charging voltage. However, the RMs tend to lose their activity during cycling owing to not only decomposition reactions but also undesirable discharge (shuttle effect) at the Li metal anode. Moreover, the dendrite growth of the Li metal anode is not resolved by merely adding RMs to the electrolytes. Here we report a simple yet highly effective method to reduce the charge overpotential while protecting the Li metal anode by incorporating LiBr and LiNO 3 in a tetraglyme solvent as the electrolyte for Li-O 2 cells. The Br - /Br 3 - couple acts as an RM to oxidize the discharge product Li 2 O 2 at the cathode, whereas the NO 3 - anion oxidizes the Li metal surface to prevent the shuttle reaction. In this work, we found that both anions work synergistically in the mixed Br - /NO 3 - electrolyte to dramatically suppress both parasitic reactions and dendrite formation by generating a solid Li 2 O thin film on the Li metal anode. As a result, the charge voltage was reduced to below 3.6 V over 40 cycles. The O 2 evolution during charging was more than 80% of the theoretical value, and CO 2 emission during charging was negligible. After cycling, the Li metal anode showed smooth surfaces with no indication of dendrite formation. These observations clearly demonstrate that the Br - /NO 3 - dual-anion electrolyte can solve the problems associated with both the overpotential at the cathode and the dendrite formation at the anode.

Inhibition and Dispersal of Pseudomonas aeruginosa Biofilms by Combination Treatment with Escapin Intermediate Products and Hydrogen Peroxide.

PubMed

Santiago, Ariel J; Ahmed, Marwa N A; Wang, Shu-Lin; Damera, Krishna; Wang, Binghe; Tai, Phang C; Gilbert, Eric S; Derby, Charles D

2016-09-01

Escapin is an l-amino acid oxidase that acts on lysine to produce hydrogen peroxide (H2O2), ammonia, and equilibrium mixtures of several organic acids collectively called escapin intermediate products (EIP). Previous work showed that the combination of synthetic EIP and H2O2 functions synergistically as an antimicrobial toward diverse planktonic bacteria. We initiated the present study to investigate how the combination of EIP and H2O2 affected bacterial biofilms, using Pseudomonas aeruginosa as a model. Specifically, we examined concentrations of EIP and H2O2 that inhibited biofilm formation or fostered disruption of established biofilms. High-throughput assays of biofilm formation using microtiter plates and crystal violet staining showed a significant effect from pairing EIP and H2O2, resulting in inhibition of biofilm formation relative to biofilm formation in untreated controls or with EIP or H2O2 alone. Similarly, flow cell analysis and confocal laser scanning microscopy revealed that the EIP and H2O2 combination reduced the biomass of established biofilms relative to that of the controls. Area layer analysis of biofilms posttreatment indicated that disruption of biomass occurs down to the substratum. Only nanomolar to micromolar concentrations of EIP and H2O2 were required to impact biofilm formation or disruption, and these concentrations are significantly lower than those causing bactericidal effects on planktonic bacteria. Micromolar concentrations of EIP and H2O2 combined enhanced P. aeruginosa swimming motility compared to the effect of either EIP or H2O2 alone. Collectively, our results suggest that the combination of EIP and H2O2 may affect biofilms by interfering with bacterial attachment and destabilizing the biofilm matrix. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Isolation of an Orally Active Insecticidal Toxin from the Venom of an Australian Tarantula

PubMed Central

Hardy, Margaret C.; Daly, Norelle L.; Mobli, Mehdi; Morales, Rodrigo A. V.; King, Glenn F.

2013-01-01

Many insect pests have developed resistance to existing chemical insecticides and consequently there is much interest in the development of new insecticidal compounds with novel modes of action. Although spiders have deployed insecticidal toxins in their venoms for over 250 million years, there is no evolutionary selection pressure on these toxins to possess oral activity since they are injected into prey and predators via a hypodermic needle-like fang. Thus, it has been assumed that spider-venom peptides are not orally active and are therefore unlikely to be useful insecticides. Contrary to this dogma, we show that it is possible to isolate spider-venom peptides with high levels of oral insecticidal activity by directly screening for per os toxicity. Using this approach, we isolated a 34-residue orally active insecticidal peptide (OAIP-1) from venom of the Australian tarantula Selenotypus plumipes. The oral LD50 for OAIP-1 in the agronomically important cotton bollworm Helicoverpa armigera was 104.2±0.6 pmol/g, which is the highest per os activity reported to date for an insecticidal venom peptide. OAIP-1 is equipotent with synthetic pyrethroids and it acts synergistically with neonicotinoid insecticides. The three-dimensional structure of OAIP-1 determined using NMR spectroscopy revealed that the three disulfide bonds form an inhibitor cystine knot motif; this structural motif provides the peptide with a high level of biological stability that probably contributes to its oral activity. OAIP-1 is likely to be synergized by the gut-lytic activity of the Bacillus thuringiensis Cry toxin (Bt) expressed in insect-resistant transgenic crops, and consequently it might be a good candidate for trait stacking with Bt. PMID:24039872

Graded hypoxia acts through a network of distributed peripheral oxygen chemoreceptors to produce changes in respiratory behaviour and plasticity.

PubMed

Janes, Tara A; Xu, Fenglian; Syed, Naweed I

2015-07-01

Respiratory behaviour relies critically upon sensory feedback from peripheral oxygen chemoreceptors. During environmental or systemic hypoxia, chemoreceptor input modulates respiratory central pattern generator activity to produce reflex-based increases in respiration and also shapes respiratory plasticity over longer timescales. The best-studied oxygen chemoreceptors are undoubtedly the mammalian carotid bodies; however, questions remain regarding this complex organ's role in shaping respiration in response to varying oxygen levels. Furthermore, many taxa possess distinct oxygen chemoreceptors located within the lungs, airways and cardiovasculature, but the functional advantage of multiple chemoreceptor sites is unclear. In this study, it is demonstrated that a distributed network of peripheral oxygen chemoreceptors exists in Lymnaea stagnalis and significantly modulates aerial respiration. Specifically, Lymnaea breath frequency and duration represent parameters that are shaped by interactions between hypoxic severity and its time-course. Using a combination of behaviour and electrophysiology approaches, the chemosensory pathways underlying hypoxia-induced changes in breath frequency/duration were explored. The current findings demonstrate that breath frequency is uniquely modulated by the known osphradial ganglion oxygen chemoreceptors during moderate hypoxia, while a newly discovered area of pneumostome oxygen chemoreception serves a similar function specifically during more severe hypoxia. Together, these findings suggest that multiple oxygen chemosensory sites, each with their own sensory and modulatory properties, act synergistically to form a functionally distributed network that dynamically shapes respiration in response to changing systemic or environmental oxygen levels. These distributed networks may represent an evolutionarily conserved strategy vis-à-vis respiratory adaptability and have significant implications for the understanding of fundamental respiratory control systems. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Serotonin and cholecystokinin synergistically stimulate rat vagal primary afferent neurones

PubMed Central

Li, Y; Wu, X Y; Owyang, C

2004-01-01

Recent studies indicate that cholecystokinin (CCK) and serotonin (5-hydroxytryptamine, 5-HT) act via vagal afferent fibres to mediate gastrointestinal functions. In the present study, we characterized the interaction between CCK and 5-HT in the vagal primary afferent neurones. Single neuronal discharges of vagal primary afferent neurones innervating the duodenum were recorded from rat nodose ganglia. Two groups of nodose ganglia neurones were identified: group A neurones responded to intra-arterial injection of low doses of cholecystokinin octapeptide (CCK-8; 10–60 pmol); group B neurones responded only to high doses of CCK-8 (120–240 pmol), and were also activated by duodenal distention. CCK-JMV-180, which acts as an agonist in high-affinity states and as an antagonist in low-affinity states, dose dependently stimulated group A neurones, but inhibited the effect of the high doses of CCK-8 on group B neurones. Duodenal perfusion of 5-HT evoked dose-dependent increases in nodose neuronal discharges. Some neurones that responded to 5-HT showed no response to either high or low doses of CCK-8. A separate group of nodose neurones that possessed high-affinity CCK type A (CCK-A) receptors also responded to luminal infusion of 5-HT. Further, a subthreshold dose of CCK-8 (i.e. 5 pmol) produced no measurable electrophysiological effects but it augmented the neuronal responses to 5-HT. This potentiation effect of CCK-8 was eliminated by CR 1409. From these results we concluded that the vagal nodose ganglion contains neurones that may possess only high- or low-affinity CCK-A receptors or 5-HT3 receptors. Some neurones that express high-affinity CCK-A receptors also express 5-HT3 receptors. Pre-exposure to luminal 5-HT may augment the subsequent response to a subthreshold dose of CCK. PMID:15235095

Temperature-specific competition between invasive mosquitofish and an endangered cyprinodontid fish.

PubMed

Carmona-Catot, Gerard; Magellan, Kit; García-Berthou, Emili

2013-01-01

Condition-specific competition is widespread in nature. Species inhabiting heterogeneous environments tend to differ in competitive abilities depending on environmental stressors. Interactions between these factors can allow coexistence of competing species, which may be particularly important between invasive and native species. Here, we examine the effects of temperature on competitive interactions between invasive mosquitofish, Gambusia holbrooki, and an endemic Iberian toothcarp, Aphanius iberus. We compare the tendency to approach heterospecifics and food capture rates between these two species, and examine differences between sexes and species in aggressive interactions, at three different temperatures (19, 24 and 29°C) in three laboratory experiments. Mosquitofish exhibit much more aggression than toothcarp. We show that mosquitofish have the capacity to competitively displace toothcarp through interference competition and this outcome is more likely at higher temperatures. We also show a reversal in the competitive hierarchy through reduced food capture rate by mosquitofish at lower temperatures and suggest that these two types of competition may act synergistically to deprive toothcarp of food at higher temperatures. Males of both species carry out more overtly aggressive acts than females, which is probably related to the marked sexual dimorphism and associated mating systems of these two species. Mosquitofish may thus impact heavily on toothcarp, and competition from mosquitofish, especially in warmer summer months, may lead to changes in abundance of the native species and displacement to non-preferred habitats. Globally increasing temperatures mean that highly invasive, warm-water mosquitofish may be able to colonize environments from which they are currently excluded through reduced physiological tolerance to low temperatures. Research into the effects of temperature on interactions between native and invasive species is thus of fundamental importance.

Attenuated Stress Response to Acute Restraint and Forced Swimming Stress in Arginine Vasopressin 1b Receptor Subtype (Avpr1b) Receptor Knockout Mice and Wild-Type Mice Treated with a Novel Avpr1b Receptor Antagonist

PubMed Central

Roper, J A; Craighead, M; O’Carroll, A-M; Lolait, S J

2010-01-01

Arginine vasopressin (AVP) synthesised in the parvocellular region of the hypothalamic paraventricular nucleus and released into the pituitary portal vessels acts on the 1b receptor subtype (Avpr1b) present in anterior pituitary corticotrophs to modulate the release of adrenocorticotrophic hormone (ACTH). Corticotrophin-releasing hormone is considered the major drive behind ACTH release; however, its action is augmented synergistically by AVP. To determine the extent of vasopressinergic influence in the hypothalamic-pituitary-adrenal axis response to restraint and forced swimming stress, we compared the stress hormone levels [plasma ACTH in both stressors and corticosterone (CORT) in restraint stress only] following acute stress in mutant Avpr1b knockout (KO) mice compared to their wild-type controls following the administration of a novel Avpr1b antagonist. Restraint and forced swimming stress-induced increases in plasma ACTH were significantly diminished in mice lacking a functional Avpr1b and in wild-type mice that had been pre-treated with Avpr1b antagonist. A corresponding decrease in plasma CORT levels was also observed in acute restraint-stressed knockout male mice, and in Avpr1b-antagonist-treated male wild-type mice. By contrast, plasma CORT levels were not reduced in acutely restraint-stressed female knockout animals, or in female wild-type animals pre-treated with Avpr1b antagonist. These results demonstrate that pharmacological antagonism or inactivation of Avpr1b causes a reduction in the hypothalamic-pituitary-adrenal (HPA) axis response, particularly ACTH, to acute restraint and forced swimming stress, and show that Avpr1b knockout mice constitute a model by which to study the contribution of Avpr1b to the HPA axis response to acute stressors. PMID:20846299

Wingless, decapentaplegic and EGF receptor signaling pathways interact to specify dorso-ventral pattern in the adult abdomen of Drosophila.

PubMed

Kopp, A; Blackman, R K; Duncan, I

1999-08-01

Adult abdominal segments of Drosophila are subdivided along the dorso-ventral axis into a dorsal tergite, a ventral sternite and ventro-lateral pleural cuticle. We report that this pattern is largely specified during the pupal stage by Wingless (Wg), Decapentaplegic (Dpp) and Drosophila EGF Receptor (DER) signaling. Expression of wg and dpp is activated at the posterior edge of the anterior compartment by Hedgehog signaling. Within this region, wg and dpp are expressed in domains that are mutually exclusive along the dorso-ventral axis: wg is expressed in the sternite and medio-lateral tergite, whereas dpp expression is confined to the pleura and the dorsal midline. Neither gene is expressed in the lateral tergite. Shirras and Couso (1996, Dev. Biol. 175, 24-36) have shown that tergite and sternite cell fates are specified by Wg signaling. We find that DER acts synergistically with Wg to promote tergite and sternite identities, and that Wg and DER activities are opposed by Dpp signaling, which promotes pleural identity. Wg and Dpp interact antagonistically at two levels. First, their expression is confined to complementary domains by mutual transcriptional repression. Second, Wg and Dpp compete directly with one another by exerting opposite effects on cell fate. DER signaling does not affect the expression of wg or dpp, indicating that it interacts with Wg and Dpp at the level of cell fate determination. Within the tergite, the requirements for Wg and DER function are roughly complementary: Wg is required mainly in the medial region, whereas DER is most important laterally. Finally, we show that Dpp signaling at the dorsal midline controls dorso-ventral patterning within the tergite by promoting pigmentation in the medial region.

Influence of Human Sera on the In Vitro Activity of the Echinocandin Caspofungin (MK-0991) against Aspergillus fumigatus

PubMed Central

Chiller, Tom; Farrokhshad, Kouros; Brummer, Elmer; Stevens, David A.

2000-01-01

There have been several reports that the activity of echinocandin antifungal agents is not affected or decreased in the presence of human sera. It is known that these drugs are bound >80% in animal and human sera. The activity of the echinocandin caspofungin (MK-0991), a 1,3-β-d-glucan synthase inhibitor, against Aspergillus fumigatus with and without human sera was studied. Conidia of A. fumigatus in microtest plate wells formed germlings after overnight culture in RPMI 1640. Caspofungin was then added with or without serum, and the germlings were incubated at 37°C for 24 h. Human serum (5%) in RPMI 1640 alone did not significantly inhibit the growth of A. fumigatus in vitro. Caspofungin in RPMI 1640 exhibited dose-dependent inhibition, with concentrations of 0.1 and 0.05 μg/ml inhibiting 24.9% +/− 10.4% and 11.7% +/− 3.6%, respectively (n = 10; P < 0.01). The addition of 5% human serum to caspofungin at 0.1 or 0.05 μg/ml increased the inhibition to 78.6% +/− 5.8% or 58.3% +/− 19.2%, respectively (n = 10; P < 0.01 versus controls and versus the drug without serum). Lower concentrations of serum also potentiated drug activity. The effect of human sera was further seen when using caspofungin that had lost activity (e.g., by storage) against A. fumigatus at 0.1 μg/ml. Inactive caspofungin alone demonstrated no significant inhibition of hyphal growth, whereas the addition of 5% human serum to the inactive drug showed 83% +/− 16.5% inhibition (n = 5; P < 0.01). The restoration of activity of caspofungin was seen at concentrations as low as 0.05% human serum. In contrast to prior reports, this study suggests that human serum acts synergistically with caspofungin to enhance its inhibitory activity in vitro against A. fumigatus. PMID:11083631

In Vitro and In Vivo Enhancement of Chemoradiation Using the Oral PARP Inhibitor ABT-888 in Colorectal Cancer Cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shelton, Joseph W., E-mail: jwshelt@emory.edu; Waxweiler, Timothy V.; Landry, Jerome

2013-07-01

Purpose: Poly(ADP-ribose) polymerase plays a critical role in the recognition and repair of DNA single-strand breaks and double-strand breaks (DSBs). ABT-888 is an orally available inhibitor of this enzyme. This study seeks to evaluate the use of ABT-888 combined with chemotherapy and radiation therapy (RT) in colorectal carcinoma models. Methods and Materials: RT clonogenic assays were performed on HCT116 and HT29 cells treated with 5-fluorouracil, irinotecan, or oxaliplatin with or without ABT. The surviving fraction at 2 Gy and dose-modifying factor at 10% survival were analyzed. Synergism was assessed by isobologram analysis for combination therapies. γH2AX and neutral comet assaysmore » were performed to assess the effect of therapy on DSB formation/repair. In vivo assessments were made by use of HCT116 cells in a xenograft mouse model. Tumor growth delay was measured at a volume of 500 mm{sup 3}. Results: Both lines were radiosensitized by ABT alone, and ABT further increased chemotherapy dose-modifying factors to the 1.6 to 1.8 range. All combinations were synergistic (combination indices <0.9). ABT treatment significantly increased DSB after RT (γH2AX, 69% vs 43%; P=.017) and delayed repair. We found tumor growth delays of 7.22 days for RT; 11.90 days for RT and ABT; 13.5 days for oxaliplatin, RT, and ABT; 14.17 days for 5-fluorouracil, RT, and ABT; and 23.81 days for irinotecan, RT, and ABT. Conclusion: ABT-888 radiosensitizes at similar or higher levels compared with classic chemotherapies and acts synergistically with these chemotherapies to enhance RT effects. In vivo confirmation of these results indicates a potential role for combining its use with existing chemoradiation regimens.« less

43 CFR 5462.2 - Prohibited acts.

Code of Federal Regulations, 2014 CFR

2014-10-01

... § 5462.2 Prohibited acts. (a) The acts or omissions listed in paragraph (b) of this section apply only to... permit held by the purchaser responsible for such acts or omissions may be canceled. (b) The following activities are prohibited: (1) Cutting, removing, or otherwise damaging any timber, tree, or other vegetative...

Serotonin receptor and dendritic plasticity in the spinal cord mediated by chronic serotonergic pharmacotherapy combined with exercise following complete SCI in the adult rat.

PubMed

Ganzer, Patrick D; Beringer, Carl R; Shumsky, Jed S; Nwaobasi, Chiemela; Moxon, Karen A

2018-06-01

Severe spinal cord injury (SCI) damages descending motor and serotonin (5-HT) fiber projections leading to paralysis and serotonin depletion. 5-HT receptors (5-HTRs) subsequently upregulate following 5-HT fiber degeneration, and dendritic density decreases indicative of atrophy. 5-HT pharmacotherapy or exercise can improve locomotor behavior after SCI. One might expect that 5-HT pharmacotherapy acts on upregulated spinal 5-HTRs to enhance function, and that exercise alone can influence dendritic atrophy. In the current study, we assessed locomotor recovery and spinal proteins influenced by SCI and therapy. 5-HT, 5-HT 2A R, 5-HT 1A R, and dendritic densities were quantified both early (1 week) and late (9 weeks) after SCI, and also following therapeutic interventions (5-HT pharmacotherapy, bike therapy, or a combination). Interestingly, chronic 5-HT pharmacotherapy largely normalized spinal 5-HTR upregulation following injury. Improvement in locomotor behavior was not correlated to 5-HTR density. These results support the hypothesis that chronic 5-HT pharmacotherapy can mediate recovery following SCI, despite acting on largely normal spinal 5-HTR levels. We next assessed spinal dendritic plasticity and its potential role in locomotor recovery. Single therapies did not normalize the loss of dendritic density after SCI. Groups displaying significantly atrophied dendritic processes were rarely able to achieve weight supported open-field locomotion. Only a combination of 5-HT pharmacotherapy and bike therapy enabled significant open-field weigh-supported stepping, mediated in part by restoring spinal dendritic density. These results support the use of combined therapies to synergistically impact multiple markers of spinal plasticity and improve motor recovery. Copyright © 2018 Elsevier Inc. All rights reserved.

Anti-malarial activity and HS-SPME-GC-MS chemical profiling of Plinia cerrocampanensis leaf essential oil

PubMed Central

2014-01-01

Background Plinia cerrocampanensis is an endemic plant of Panama. The leaf essential oil of this plant has shown antibacterial activity. However, anti-malarial activity and chemical profiling by HS-SPME-GC-MS of this essential oil have not been reported before. Methods Anti-malarial activity of the essential oil (EO) was evaluated in vitro against chloroquine-sensitive HB3 and chloroquine-resistant W2 strains of Plasmodium falciparum. Synergistic effect of chloroquine and the EO on parasite growth was evaluated by calculating the combination index. A methodology involving headspace solid phase microextraction and gas chromatography-mass spectrometry (HS-SPME-GC-MS) was developed to investigate the composition of Plinia cerrocampanensis EO. Results Plinia cerrocampanensis EO showed a high anti-malarial activity and a synergistic interaction with chloroquine. The Plinia cerrocampanensis EO inhibited P. falciparum growth in vitro at an IC50 of 7.3 μg/mL. Chloroquine together with the EO decreased the IC50 of chloroquine from 0.1 μg/mL to 0.05 μg/mL, and of the EO from 7.3 μg/mL to 1.1 μg/mL. The measured combination index was 0.58, which clearly indicates that the EO acts synergistically with chloroquine. Since the EO maintained its inhibitory activity on the chloroquine-sensitive strain of the parasite, it could be acting by a different mechanism of action than chloroquine. The best HS-SPME-GC-MS analytical conditions were obtained when the temperature of extraction was 49°C, incubation time 14 min, and the time of extraction 10 min. This method allowed for the identification of 53 volatile constituents in the EO, including new compounds not reported earlier. Conclusions The anti-malarial activity exhibited by the Plinia cerrocampanensis EO may lend support for its possible use as an alternative for anti-malarial therapy. PMID:24410874

Interleukin-17 Promotes Neutrophil-Mediated Immunity by Activating Microvascular Pericytes and Not Endothelium

PubMed Central

Liu, Rebecca; Lauridsen, Holly M.; Amezquita, Robert A.; Pierce, Richard W.; Jane-wit, Dan; Fang, Caodi; Pellowe, Amanda S.; Kirkiles-Smith, Nancy C.; Gonzalez, Anjelica L.; Pober, Jordan S.

2016-01-01

A classical hallmark of acute inflammation is neutrophil infiltration of tissues, a multi-step process that involves sequential cell-cell interactions of circulating leukocytes with interleukin (IL)-1- or tumor necrosis factor-α (TNF)-activated microvascular endothelial cells (ECs) and pericytes (PCs) that form the wall of the postcapillary venules. The initial infiltrating cells accumulate perivascularly in close proximity to PCs. IL-17, a pro-inflammatory cytokine that acts on target cells via a heterodimeric receptor formed by IL-17RA and IL-17RC subunits, also promotes neutrophilic inflammation but its effects on vascular cells are less clear. We report that both cultured human ECs and PCs strongly express IL-17RC and, while neither cell type expresses much IL-17RA, PCs express significantly more than ECs. IL-17, alone or synergistically with TNF, significantly alters inflammatory gene expression in cultured human PCs but not ECs. RNA-seq analysis identifies many IL-17-induced transcripts in PCs encoding proteins known to stimulate neutrophil-mediated immunity. Conditioned media (CM) from IL-17-activated PCs, but not ECs, induce pertussis toxin-sensitive neutrophil polarization, likely mediated by PC-secreted chemokines, and also stimulate neutrophil production of pro-inflammatory molecules, including TNF, IL-1α, IL-1β, and IL-8. Furthermore, IL-17-activated PCs but not ECs can prolong neutrophil survival by producing G-CSF and GM-CSF, delaying the mitochondria outer membrane permeabilization and caspase 9 activation. Importantly, neutrophils exhibit enhanced phagocytic capacity after activation by CM from IL-17-treated PCs. We conclude that PCs, not ECs, are the major target of IL-17 within the microvessel wall and that IL-17-activated PCs can modulate neutrophil functions within the perivascular tissue space. PMID:27534549

In vitro toxicity of polycyclic aromatic hydrocarbons and halogenated aromatic hydrocarbons to cetacean cells and tissues

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carvan, M.J. III.

1993-01-01

Cetaceans bioaccumulate high aromatic hydrocarbon tissue residues, and elevated levels of PCB residues in tissues are proposed to have occurred concurrently with recent epizootic deaths of dolphins. The objectives of this study were: (1) to develop and characterize an epithelial cell line derived from dolphin tissues, (2) to investigate the effects of hydrocarbon pollutants on those cells, and (3) to analyze the toxicity of hydrocarbon pollutants on cetacean tissues in vitro. An epithelial cell line, Carvan dolphin kidney (CDK), isolated from a spontaneously aborted female bottlenose dolphin, Tursiops truncatus, grew rapidly. These cells were neither transformed nor immortal. Velocity sedimentationmore » analysis showed CDK cells contained nuclear aryl hydrocarbon receptor, suggestive of cytochrome P450 inducibility. BaP inhibited mitosis in CDK cells in a dose-dependent manner. Data indicate that CDK cells metabolize BaP, that BaP metabolites bind to cellular DNA initiating unscheduled DNA synthesis, and that the inhibition of cytochrome P450 metabolism decrease the BaP-associated inhibition of mitosis in dolphin cells. The data also suggest that TCDD acts synergistically to increase the levels of DNA damage by the procarcinogen BaP. Cetacean liver microsomes was isolated and evaluated for the presence of cytochrome P450 proteins by SDS-PAGE, apparent minimum molecular weight determination, and immunoblot analysis. P450 activity was induced in cetacean tissue samples and CDK cells by exposure in vitro to one of several cytochrome P450-inducing chemicals. The data suggest that cetacean tissues and cells can be utilized to study the in vitro induction of cytochrome P450, resultant metabolism of xenobiotic contaminants, and the subsequent cellular and molecular responses. However, the identity of specific P450 isozymes involved in this process will remain undetermined until monoclonal antibodies that recognize cetacean P450s can be generated.« less

aguA, the gene encoding an extracellular alpha-glucuronidase from Aspergillus tubingensis, is specifically induced on xylose and not on glucuronic acid.

PubMed

de Vries, R P; Poulsen, C H; Madrid, S; Visser, J

1998-01-01

An extracellular alpha-glucuronidase was purified and characterized from a commercial Aspergillus preparation and from culture filtrate of Aspergillus tubingensis. The enzyme has a molecular mass of 107 kDa as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and 112 kDa as determined by mass spectrometry, has a determined pI just below 5.2, and is stable at pH 6.0 for prolonged times. The pH optimum for the enzyme is between 4.5 and 6.0, and the temperature optimum is 70 degrees C. The alpha-glucuronidase is active mainly on small substituted xylo-oligomers but is also able to release a small amount of 4-O-methylglucuronic acid from birchwood xylan. The enzyme acts synergistically with endoxylanases and beta-xylosidase in the hydrolysis of xylan. The enzyme is N glycosylated and contains 14 putative N-glycosylation sites. The gene encoding this alpha-glucuronidase (aguA) was cloned from A. tubingensis. It consists of an open reading frame of 2,523 bp and contains no introns. The gene codes for a protein of 841 amino acids, containing a eukaryotic signal sequence of 20 amino acids. The mature protein has a predicted molecular mass of 91,790 Da and a calculated pI of 5.13. Multiple copies of the gene were introduced in A. tubingensis, and expression was studied in a highly overproducing transformant. The aguA gene was expressed on xylose, xylobiose, and xylan, similarly to genes encoding endoxylanases, suggesting a coordinate regulation of expression of xylanases and alpha-glucuronidase. Glucuronic acid did not induce the expression of aguA and also did not modulate the expression on xylose. Addition of glucose prevented expression of aguA on xylan but only reduced the expression on xylose.

Identification of 2'-deoxy-2'-fluorocytidine as a potent inhibitor of Crimean-Congo hemorrhagic fever virus replication using a recombinant fluorescent reporter virus.

PubMed

Welch, Stephen R; Scholte, Florine E M; Flint, Mike; Chatterjee, Payel; Nichol, Stuart T; Bergeron, Éric; Spiropoulou, Christina F

2017-11-01

Crimean-Congo hemorrhagic fever virus (CCHFV), a tick-borne orthonairovirus, causes a severe hemorrhagic disease in humans (Crimean-Congo hemorrhagic fever, CCHF). Currently, no vaccines are approved to prevent CCHF; treatment is limited to supportive care and the use of ribavirin, the therapeutic benefits of which remain unclear. CCHF is part of WHO's priority list of infectious diseases warranting further research and development. To aid in the identification of new antiviral compounds, we generated a recombinant CCHFV expressing a reporter protein, allowing us to quantify virus inhibition by measuring the reduction in fluorescence in infected cells treated with candidate compounds. The screening assay was readily adaptable to high-throughput screening (HTS) of compounds using Huh7 cells, with a signal-to-noise ratio of 50:1, and Z'-factors > 0.6 in both 96- and 384-well formats. A screen of candidate nucleoside analog compounds identified 2'-deoxy-2'-fluorocytidine (EC 50  = 61 ± 18 nM) as having 200 × the potency of ribavirin (EC 50  = 12.5 ± 2.6 μM), as well as 17 × the potency of T-705 (favipiravir), another compound with reported anti-CCHFV activity (EC 50  = 1.03 ± 0.16 μM). Furthermore, we also determined that 2'-deoxy-2'-fluorocytidine acts synergistically with T-705 to inhibit CCHFV replication without causing cytotoxicity. The incorporation of this reporter virus into the high-throughput screening assay described here will allow more rapid identification of effective therapeutic options to combat this emerging human pathogen. Published by Elsevier B.V.

CM363, a novel naphthoquinone derivative which acts as multikinase modulator and overcomes imatinib resistance in chronic myelogenous leukemia

PubMed Central

Díaz-Chico, Juan Carlos; McNaughton-Smith, Grant; Jiménez-Alonso, Sandra; Hueso-Falcón, Idaira; Montero, Juan Carlos; Blanco, Raquel; León, Javier; Rodríguez-González, Germán; Estévez-Braun, Ana; Pandiella, Atanasio; Díaz-Chico, Bonifacio Nicolás; Fernández-Pérez, Leandro

2017-01-01

Human Chronic Myelogenous Leukemia (CML) is a hematological stem cell disorder which is associated with activation of Bcr-Abl-Stat5 oncogenic pathway. Direct Bcr-Abl inhibitors are initially successful for the treatment of CML but over time many patients develop drug resistance. In the present study, the effects of CM363, a novel naphthoquinone (NPQ) derivative, were evaluated on human CML-derived K562 cells. CM363 revealed an effective cell growth inhibition (IC50 = 0.7 ± 0.5 μM) by inducing cancer cells to undergo cell cycle arrest and apoptosis. CM363 caused a dose- and time-dependent reduction of cells in G0/G1 and G2/M phases. This cell cycle arrest was associated with increased levels of cyclin E, pChk1 and pChk2 whereas CM363 downregulated cyclin B, cyclin D3, p27, pRB, Wee1, and BUBR1. CM363 increased the double-strand DNA break marker γH2AX. CM363 caused a time-dependent increase of annexin V-positive cells, DNA fragmentation and increased number of apoptotic nuclei. CM363 triggered the mitochondrial apoptotic pathway as reflected by a release of cytochrome C from mitochondria and induction of the cleavage of caspase-3 and -9, and PARP. CM363 showed multikinase modulatory effects through an early increased JNK phosphorylation followed by inhibition of pY-Bcrl-Abl and pY-Stat5. CM363 worked synergistically with imatinib to inhibit cell viability and maintained its activity in imatinib-resistant cells. Finally, CM363 (10 mg/Kg) suppressed the growth of K562 xenograft tumors in athymic mice. In summary, CM363 is a novel multikinase modulator that offers advantages to circumvent imanitib resistance and might be therapeutically effective in Bcrl-Abl-Stat5 related malignancies. PMID:27557509

aguA, the Gene Encoding an Extracellular α-Glucuronidase from Aspergillus tubingensis, Is Specifically Induced on Xylose and Not on Glucuronic Acid

PubMed Central

de Vries, Ronald P.; Poulsen, Charlotte H.; Madrid, Susan; Visser, Jaap

1998-01-01

An extracellular α-glucuronidase was purified and characterized from a commercial Aspergillus preparation and from culture filtrate of Aspergillus tubingensis. The enzyme has a molecular mass of 107 kDa as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and 112 kDa as determined by mass spectrometry, has a determined pI just below 5.2, and is stable at pH 6.0 for prolonged times. The pH optimum for the enzyme is between 4.5 and 6.0, and the temperature optimum is 70°C. The α-glucuronidase is active mainly on small substituted xylo-oligomers but is also able to release a small amount of 4-O-methylglucuronic acid from birchwood xylan. The enzyme acts synergistically with endoxylanases and β-xylosidase in the hydrolysis of xylan. The enzyme is N glycosylated and contains 14 putative N-glycosylation sites. The gene encoding this α-glucuronidase (aguA) was cloned from A. tubingensis. It consists of an open reading frame of 2,523 bp and contains no introns. The gene codes for a protein of 841 amino acids, containing a eukaryotic signal sequence of 20 amino acids. The mature protein has a predicted molecular mass of 91,790 Da and a calculated pI of 5.13. Multiple copies of the gene were introduced in A. tubingensis, and expression was studied in a highly overproducing transformant. The aguA gene was expressed on xylose, xylobiose, and xylan, similarly to genes encoding endoxylanases, suggesting a coordinate regulation of expression of xylanases and α-glucuronidase. Glucuronic acid did not induce the expression of aguA and also did not modulate the expression on xylose. Addition of glucose prevented expression of aguA on xylan but only reduced the expression on xylose. PMID:9440512

ACTS Experiments Program

NASA Technical Reports Server (NTRS)

Schertler, R. J.

1986-01-01

An overview of the ACTS Experiments Program is presented. ACTS is being developed and will flight test the advanced technologies associated with: a Ka-band multibeam antenna, onboard signal processing and switching as well as laser communications. A nominal 3 yr experiments program is planned. Through the experiments program, the capabilities of the ACTS system will be made available to U.S. industry, university and government experimenters to test, prove the feasibility and evaluate the key ACTS system technologies. Communication modes of operation using the baseband processor and microwave switch matrix are presented, along with the antenna coverage pattern. Potential experiment categories are also presented and briefly discussed. An overall schedule of activities associated with the experiments program is outlined. Results of the ACTS Experiments Program will provide information vital to successful industry implementation of ACTS technology in a future operational system.

14 CFR 1274.926 - Clean Air-Water Pollution Control Acts.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 5 2013-01-01 2013-01-01 false Clean Air-Water Pollution Control Acts...-Water Pollution Control Acts. Clean Air-Water Pollution Control Acts July 2002 If this cooperative... 91-604) and section 308 of the Federal Water Pollution Control Act, as amended (33 U.S.C. 1251 et seq...

14 CFR § 1274.926 - Clean Air-Water Pollution Control Acts.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 5 2014-01-01 2014-01-01 false Clean Air-Water Pollution Control Acts. Â...-Water Pollution Control Acts. Clean Air-Water Pollution Control Acts July 2002 If this cooperative... 91-604) and section 308 of the Federal Water Pollution Control Act, as amended (33 U.S.C. 1251 et seq...

14 CFR 1274.926 - Clean Air-Water Pollution Control Acts.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Clean Air-Water Pollution Control Acts...-Water Pollution Control Acts. Clean Air-Water Pollution Control Acts July 2002 If this cooperative... 91-604) and section 308 of the Federal Water Pollution Control Act, as amended (33 U.S.C. 1251 et seq...

Synergistic interaction of platelet derived growth factor (PDGF) with the surface of PLLA/Col/HA and PLLA/HA scaffolds produces rapid osteogenic differentiation.

PubMed

Raghavendran, Hanumantha Rao Balaji; Mohan, Saktiswaren; Genasan, Krishnamurithy; Murali, Malliga Raman; Naveen, Sangeetha Vasudevaraj; Talebian, Sepehr; McKean, Robert; Kamarul, Tunku

2016-03-01

Scaffolds with structural features similar to the extracellular matrix stimulate rapid osteogenic differentiation in favorable microenvironment and with growth factor supplementation. In this study, the osteogenic potential of electrospun poly-l-lactide/hydroxyapatite/collagen (PLLA/Col/HA, PLLA/HA and PLLA/Col) scaffolds were tested in vitro with the supplementation of platelet derived growth factor-BB (PDGF-BB). Cell attachment and topography, mineralization, extracellular matrix protein localization, and gene expression of the human mesenchymal stromal cells were compared between the fibrous scaffolds PLLA/Col/HA, PLLA/Col, and PLLA/HA. The levels of osteocalcin, calcium, and mineralization were significantly greater in the PLLA/Col/HA and PLLA/HA compared with PLLA/Col. High expression of fibronectin, intracellular adhesion molecule, cadherin, and collagen 1 (Col1) suggests that PLLA/Col/HA and PLLA/HA scaffolds had superior osteoinductivity than PLLA/Col. Additionally, osteopontin, osteocalcin, osterix, Runt-related transcription factor 2 (Runx2), and bone morphogenic protein (BMP2) expression were higher in PLLA/Col/HA and PLLA/HA compared with PLLA/Col. In comparison with PLLA/Col, the PLLA/Col/HA and PLLA/HA scaffolds presented a significant upregulation of the genes Runx2, Col 1, Integrin, osteonectin (ON), bone gamma-carboxyglutamic acid-containing protein (BGALP), osteopontin (OPN), and BMP2. The upregulation of these genes was further increased with PDGF-BB supplementation. These results show that PDGF-BB acts synergistically with PLLA/Col/HA and PLLA/HA to enhance the osteogenic differentiation potential. Therefore, this combination can be used for the rapid expansion of bone marrow stromal cells into bone-forming cells for tissue engineering. Copyright © 2015 Elsevier B.V. All rights reserved.

Temperature-Specific Competition between Invasive Mosquitofish and an Endangered Cyprinodontid Fish

PubMed Central

Carmona-Catot, Gerard; Magellan, Kit; García-Berthou, Emili

2013-01-01

Condition-specific competition is widespread in nature. Species inhabiting heterogeneous environments tend to differ in competitive abilities depending on environmental stressors. Interactions between these factors can allow coexistence of competing species, which may be particularly important between invasive and native species. Here, we examine the effects of temperature on competitive interactions between invasive mosquitofish, Gambusia holbrooki, and an endemic Iberian toothcarp, Aphanius iberus. We compare the tendency to approach heterospecifics and food capture rates between these two species, and examine differences between sexes and species in aggressive interactions, at three different temperatures (19, 24 and 29°C) in three laboratory experiments. Mosquitofish exhibit much more aggression than toothcarp. We show that mosquitofish have the capacity to competitively displace toothcarp through interference competition and this outcome is more likely at higher temperatures. We also show a reversal in the competitive hierarchy through reduced food capture rate by mosquitofish at lower temperatures and suggest that these two types of competition may act synergistically to deprive toothcarp of food at higher temperatures. Males of both species carry out more overtly aggressive acts than females, which is probably related to the marked sexual dimorphism and associated mating systems of these two species. Mosquitofish may thus impact heavily on toothcarp, and competition from mosquitofish, especially in warmer summer months, may lead to changes in abundance of the native species and displacement to non-preferred habitats. Globally increasing temperatures mean that highly invasive, warm-water mosquitofish may be able to colonize environments from which they are currently excluded through reduced physiological tolerance to low temperatures. Research into the effects of temperature on interactions between native and invasive species is thus of fundamental importance. PMID:23382951

Allosteric MEK1/2 Inhibitor Refametinib (BAY 86-9766) in Combination with Sorafenib Exhibits Antitumor Activity in Preclinical Murine and Rat Models of Hepatocellular Carcinoma12

PubMed Central

Schmieder, Roberta; Puehler, Florian; Neuhaus, Roland; Kissel, Maria; Adjei, Alex A; Miner, Jeffrey N; Mumberg, Dominik; Ziegelbauer, Karl; Scholz, Arne

2013-01-01

OBJECTIVE: The objectives of the study were to evaluate the allosteric mitogen-activated protein kinase kinase (MEK) inhibitor BAY 86-9766 in monotherapy and in combination with sorafenib in orthotopic and subcutaneous hepatocellular carcinoma (HCC) models with different underlying etiologies in two species. DESIGN: Antiproliferative potential of BAY 86-9766 and synergistic effects with sorafenib were studied in several HCC cell lines. Relevant pathway signaling was studied in MH3924a cells. For in vivo testing, the HCC cells were implanted subcutaneously or orthotopically. Survival and mode of action (MoA) were analyzed. RESULTS: BAY 86-9766 exhibited potent antiproliferative activity in HCC cell lines with half-maximal inhibitory concentration values ranging from 33 to 762 nM. BAY 86-9766 was strongly synergistic with sorafenib in suppressing tumor cell proliferation and inhibiting phosphorylation of the extracellular signal-regulated kinase (ERK). BAY 86-9766 prolonged survival in Hep3B xenografts, murine Hepa129 allografts, and MH3924A rat allografts. Additionally, tumor growth, ascites formation, and serum alpha-fetoprotein levels were reduced. Synergistic effects in combination with sorafenib were shown in Huh-7, Hep3B xenografts, and MH3924A allografts. On the signaling pathway level, the combination of BAY 86-9766 and sorafenib led to inhibition of the upregulatory feedback loop toward MEK phosphorylation observed after BAY 86-9766 monotreatment. With regard to the underlying MoA, inhibition of ERK phosphorylation, tumor cell proliferation, and microvessel density was observed in vivo. CONCLUSION: BAY 86-9766 shows potent single-agent antitumor activity and acts synergistically in combination with sorafenib in preclinical HCC models. These results support the ongoing clinical development of BAY 86-9766 and sorafenib in advanced HCC. PMID:24204195

Platelet factor 4/CXCL4 induces phagocytosis and the generation of reactive oxygen metabolites in mononuclear phagocytes independently of Gi protein activation or intracellular calcium transients.

PubMed

Pervushina, Olga; Scheuerer, Barbara; Reiling, Norbert; Behnke, Lars; Schröder, Jens-M; Kasper, Brigitte; Brandt, Ernst; Bulfone-Paus, Silvia; Petersen, Frank

2004-08-01

Platelet factor 4 (PF-4), a platelet-derived CXC chemokine, is known to prevent human monocytes from apoptosis and to promote differentiation of these cells into HLA-DR(-) macrophages. In this study, we investigated the role of PF-4 in the control of acute monocyte proinflammatory responses involved in the direct combat of microbial invaders. We show that PF-4 increases monocyte phagocytosis and provokes a strong formation of oxygen radicals but lacks a chemotactic activity in these cells. Compared with FMLP, PF-4-induced oxidative burst was later in its onset but was remarkably longer in its duration (lasting for up to 60 min). Furthermore, in PF-4-prestimulated cells, FMLP- as well as RANTES-induced burst responses became synergistically enhanced. As we could show, PF-4-mediated oxidative burst in monocytes does not involve Gi proteins, elevation of intracellular free calcium concentrations, or binding to CXCR3B, a novel PF-4 receptor recently discovered on endothelial cells. Moreover, we found that PF-4 acts on macrophages in a dual manner. On the one hand, very similar to GM-CSF or M-CSF, PF-4 treatment of monocytes generates macrophages with a high capacity for unspecific phagocytosis. On the other hand, short term priming of GM-CSF-induced human macrophages with PF-4 substantially increases their capability for particle ingestion and oxidative burst. A comparable effect was also observed in murine bone marrow-derived macrophages, indicating cross-reactivity of human PF-4 between both species. Taken together, PF-4 may play a crucial role in the induction and maintenance of an unspecific immune response.

Evaluation of Anti-Metastatic Potential of the Combination of Fisetin with Paclitaxel on A549 Non-Small Cell Lung Cancer Cells.

PubMed

Klimaszewska-Wiśniewska, Anna; Hałas-Wiśniewska, Marta; Grzanka, Alina; Grzanka, Dariusz

2018-02-27

The identification and development of new agents with a therapeutic potential as well as novel drug combinations are gaining the attention of scientists and clinicians as a plausible approach to improve therapeutic regimens for chemoresistant tumors. We have recently reported that the flavonoid fisetin (FIS), at physiologically attainable concentrations, acts synergistically with clinically achievable doses of paclitaxel (PTX) to produce growth inhibitory and pro-death effects on A549 human non-small cell lung cancer (NSCLC) cells. To further investigate a potential therapeutic efficacy of the combination of fisetin with paclitaxel, we decided to assess its impact on metastatic capability of A549 cells as well as its toxicity toward normal human lung fibroblast. Cell viability, cell migration, and invasion were measured by thiazolyl blue tetrazolium bromide (MTT) assay, wound healing assay, and Transwell chamber assay, respectively. The expression of metastasis-related genes was assessed with quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR). Actin and vimentin filaments were examined under the fluorescence microscope. The combination of FIS and PTX significantly reduced cancer cell migration and invasion, at least partially, through a marked rearrangement of actin and vimentin cytoskeleton and the modulation of metastasis-related genes. Most of these effects of the combination treatment were significantly greater than those of individual agents. Paclitaxel alone was even more toxic to normal cells than the combination of this drug with the flavonoid, suggesting that FIS may provide some protection against PTX-mediated cytotoxicity. The combination of FIS and PTX is expected to have a synergistic anticancer efficacy and a significant potential for the treatment of NSCLC, however, further in vitro and in vivo studies are required to confirm this preliminary evidence.

CASK interacts with PMCA4b and JAM-A on the Mouse Sperm Flagellum to Regulate Ca2+ Homeostasis and Motility1

PubMed Central

Aravindan, Rolands G.; Fomin, Victor P.; Naik, Ulhas P.; Modelski, Mark J.; Naik, Meghna U.; Galileo, Deni S.; Duncan, Randall L.; Martin-DeLeon, Patricia A.

2012-01-01

Deletion of the highly conserved gene for the major Ca2+ efflux pump, Plasma membrane calcium/calmodulin-dependent ATPase 4b (Pmca4b), in the mouse leads to loss of progressive and hyperactivated sperm motility and infertility. Here we first demonstrate that compared to wild-type (WT), Junctional adhesion molecule-A (Jam-A) null sperm, previously shown to have motility defects and an abnormal mitochondrial phenotype reminiscent of that seen in Pmca4b nulls, exhibit reduced (P<0.001) ATP levels, significantly (P<0.001) greater cytosolic Ca2+ concentration ([Ca2+]c) and ~10-fold higher mitochondrial sequestration, indicating Ca2+ overload. Investigating the mechanism involved, we used coimmunoprecipitation studies to show that CASK (Ca2+/calmodulin-dependent serine kinase), identified for the first time on the sperm flagellum where it co-localizes with both PMCA4b and JAM-A on the proximal principal piece, acts as a common interacting partner of both. Importantly, CASK binds alternatively and non-synergistically with each of these molecules via its single PDZ (PDS-95/Dlg/ZO-1) domain to either inhibit or promote efflux. In the absence of CASK-JAM-A interaction in Jam-A null sperm, CASK-PMCA4b interaction is increased, resulting in inhibition of PMCA4b’s enzymatic activity, consequent Ca2+ accumulation, and a ~6-fold over-expression of constitutively ATP-utilizing CASK, compared to WT. Thus, CASK negatively regulates PMCA4b by directly binding to it and JAM-A positively regulates it indirectly through CASK. The decreased motility is likely due to the collateral net deficit in ATP observed in nulls. Our data indicate that Ca2+ homeostasis in sperm is maintained by the relative ratios of CASK-PMCA4b and CASK-JAM-A interactions. PMID:22020416

Mapping the Interaction Site for a β-Scorpion Toxin in the Pore Module of Domain III of Voltage-gated Na+ Channels*

PubMed Central

Zhang, Joel Z.; Yarov-Yarovoy, Vladimir; Scheuer, Todd; Karbat, Izhar; Cohen, Lior; Gordon, Dalia; Gurevitz, Michael; Catterall, William A.

2012-01-01

Activation of voltage-gated sodium (Nav) channels initiates and propagates action potentials in electrically excitable cells. β-Scorpion toxins, including toxin IV from Centruroides suffusus suffusus (CssIV), enhance activation of NaV channels. CssIV stabilizes the voltage sensor in domain II in its activated state via a voltage-sensor trapping mechanism. Amino acid residues required for the action of CssIV have been identified in the S1-S2 and S3-S4 extracellular loops of domain II. The extracellular loops of domain III are also involved in toxin action, but individual amino acid residues have not been identified. We used site-directed mutagenesis and voltage clamp recording to investigate amino acid residues of domain III that are involved in CssIV action. In the IIISS2-S6 loop, five substitutions at four positions altered voltage-sensor trapping by CssIVE15A. Three substitutions (E1438A, D1445A, and D1445Y) markedly decreased voltage-sensor trapping, whereas the other two substitutions (N1436G and L1439A) increased voltage-sensor trapping. These bidirectional effects suggest that residues in IIISS2-S6 make both positive and negative interactions with CssIV. N1436G enhanced voltage-sensor trapping via increased binding affinity to the resting state, whereas L1439A increased voltage-sensor trapping efficacy. Based on these results, a three-dimensional model of the toxin-channel interaction was developed using the Rosetta modeling method. These data provide additional molecular insight into the voltage-sensor trapping mechanism of toxin action and define a three-point interaction site for β-scorpion toxins on NaV channels. Binding of α- and β-scorpion toxins to two distinct, pseudo-symmetrically organized receptor sites on NaV channels acts synergistically to modify channel gating and paralyze prey. PMID:22761417

CM363, a novel naphthoquinone derivative which acts as multikinase modulator and overcomes imatinib resistance in chronic myelogenous leukemia.

PubMed

Guerra, Borja; Martín-Rodríguez, Patricia; Díaz-Chico, Juan Carlos; McNaughton-Smith, Grant; Jiménez-Alonso, Sandra; Hueso-Falcón, Idaira; Montero, Juan Carlos; Blanco, Raquel; León, Javier; Rodríguez-González, Germán; Estévez-Braun, Ana; Pandiella, Atanasio; Díaz-Chico, Bonifacio Nicolás; Fernández-Pérez, Leandro

2017-05-02

Human Chronic Myelogenous Leukemia (CML) is a hematological stem cell disorder which is associated with activation of Bcr-Abl-Stat5 oncogenic pathway. Direct Bcr-Abl inhibitors are initially successful for the treatment of CML but over time many patients develop drug resistance. In the present study, the effects of CM363, a novel naphthoquinone (NPQ) derivative, were evaluated on human CML-derived K562 cells. CM363 revealed an effective cell growth inhibition (IC50 = 0.7 ± 0.5 μM) by inducing cancer cells to undergo cell cycle arrest and apoptosis. CM363 caused a dose- and time-dependent reduction of cells in G0/G1 and G2/M phases. This cell cycle arrest was associated with increased levels of cyclin E, pChk1 and pChk2 whereas CM363 downregulated cyclin B, cyclin D3, p27, pRB, Wee1, and BUBR1. CM363 increased the double-strand DNA break marker γH2AX. CM363 caused a time-dependent increase of annexin V-positive cells, DNA fragmentation and increased number of apoptotic nuclei. CM363 triggered the mitochondrial apoptotic pathway as reflected by a release of cytochrome C from mitochondria and induction of the cleavage of caspase-3 and -9, and PARP. CM363 showed multikinase modulatory effects through an early increased JNK phosphorylation followed by inhibition of pY-Bcrl-Abl and pY-Stat5. CM363 worked synergistically with imatinib to inhibit cell viability and maintained its activity in imatinib-resistant cells. Finally, CM363 (10 mg/Kg) suppressed the growth of K562 xenograft tumors in athymic mice. In summary, CM363 is a novel multikinase modulator that offers advantages to circumvent imanitib resistance and might be therapeutically effective in Bcrl-Abl-Stat5 related malignancies.

Inhibition of mTOR/eIF4E by anti-viral drug ribavirin effectively enhances the effects of paclitaxel in oral tongue squamous cell carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dai, Dehua; Chen, Hujie; Tang, Jing

Upregulation of eIF4E is associated with poor clinical outcome in many human cancers and represents a potential therapeutic target. However, the function of eIF4E remains unknown in oral tongue squamous cell carcinoma (OTSCC). In this work, we show that ribavirin, an anti-viral drug, effectively augments sensitivity of OTSCC cells to paclitaxel via inhibiting mTOR/eIF4E signaling pathway. Ribavirin dose-dependently inhibits proliferation and induces apoptosis in SCC-9 and CAL27 cells. Combination of ribavirin and paclitaxel are more effective in inhibiting proliferation and inducing apoptosis in OTSCC cells. Importantly, the in vivo efficacy of ribavirin and its synergism with paclitaxel is confirmed by two independentmore » OTSCC xenograft mouse models. Mechanistically, ribavirin significantly decreases mTOR/eIF4E signaling pathway in OTSCC cells via suppressing phosphorylation of Akt, mTOR, 4EBP1 and eIF4E. Overexpression of the phosphor-mimetic form of eIF4E (eIF4E S209D) but not the nonphosphorylatable form (eIF4E S209A) reverses the effects of ribavirin, confirming that eIF4E inhibition is the mechanism of action of ribavirin in OTSCC cells. In addition, eIF4E depletion significantly enhances the anti-proliferative and pro-apoptotic effects of paclitaxel, demonstrating the critical role of eIF4E in OTSCC cell response to paclitaxel. Our work is the first to demonstrate the efficacy of ribavirin as a single agent and synergism as combination with paclitaxel in OTSCC in vitro and in vivo. Our findings also demonstrate the therapeutic value of inhibiting eIF4E in OTSCC treatment. - Highlights: • Ribavirin effectively targets OTSCC in vitro and in vivo. • Ribavirin acts synergistically with paclitaxel in OTSCC cells. • Ribavirin inhibits Akt/mTOR/eIF4E signaling in OTSCC. • eIF4E inhibition sensitizes OTSCC cell response to paclitaxel.« less

Integrated Biorefineries with Engineered Microbes and High-value Co-products for Profitable Biofuels Production

USDA-ARS?s Scientific Manuscript database

Corn-based fuel ethanol production processes provide several advantages which could be synergistically applied to overcome limitations of biofuel processes based on lignocellulose. These include resources such as equipment, manpower, nutrients, water, and heat. The fact that several demonstration-...

The vitality, independence, and vigor in the elderly 2 study (VIVE2): design and methods

USDA-ARS?s Scientific Manuscript database

Background: Nutritional supplementation may potentiate the increase in skeletal muscle protein synthesis following exercise in healthy older individuals. Whether exercise and nutrition act synergistically to produce sustained changes in physical functioning and body composition has not been well stu...

Operational uses of ACTS technology

NASA Astrophysics Data System (ADS)

Gedney, Richard T.; Wright, David L.; Balombin, Joseph L.; Sohn, Philip Y.; Cashman, William F.; Stern, Alan L.; Golding, Len; Palmer, Larry

1992-03-01

The NASA Advanced Communications Technology Satellite (ACTS) provides the technologies for very high gain hopping spot beam antennas, on-board baseband routing and processing, and wideband (1 GHz) Ka-band transponders. A number of studies have recently been completed using the experience gained in developing the actual ACTS system hardware to quantify how well the ACTS technology can be used in future operational systems. This paper provides a summary of these study results including the spacecraft (S/C) weight per unit circuit for providing services by ACTS technologies as compared to present-day satellites. The uses of the ACTS technology discussed are for providing T1 VSAT mesh networks, aeronautical mobile communications, supervisory control and data acquisition (SCADA) services, and high data rate networks for supercomputer and other applications.

Darwin, Dogs and DNA: Freshman Writing about Biology.

ERIC Educational Resources Information Center

Grant, Michael C.; Pirrto, John

1994-01-01

Describes a successful interdepartmental program at a major research-oriented university that melds freshman writing with freshman biology. Extensive, repeated feedback on individual student writing projects from two instructors appears to work synergistically so that student learning is significantly enhanced. Particulars derived from five years…

Integrated Biorefineries with Engineered Microbes and High-value Co-products for Profitable Biofuels Production

USDA-ARS?s Scientific Manuscript database

First-generation (ie., corn-based) fuel ethanol production processes provide several advantages which could be synergistically applied to overcome limitations of second-generation biofuel processes from lignocellulose. These include resources such as equipment, manpower, nutrients, water, and heat....

Obsessive-compulsive disorder: a disorder of pessimal (non-functional) motor behavior.

PubMed

Zor, R; Keren, H; Hermesh, H; Szechtman, H; Mort, J; Eilam, D

2009-10-01

To determine whether in addition to repetitiveness, the motor rituals of patients with obsessive-compulsive disorder (OCD) involve reduced functionality due to numerous and measurable acts that are irrelevant and unnecessary for task completion. Comparing motor rituals of OCD patients with behavior of non-patient control individuals who were instructed to perform the same motor task. Obsessive-compulsive disorder behavior comprises abundant acts that were not performed by the controls. These acts seem unnecessary or even irrelevant for the task that the patients were performing, and therefore are termed 'non-functional'. Non-functional acts comprise some 60% of OCD motor behavior. Moreover, OCD behavior consists of short chains of functional acts bounded by long chains of non-functional acts. The abundance of irrelevant or unnecessary acts in OCD motor rituals represents reduced functionality in terms of task completion, typifying OCD rituals as pessimal behavior (antonym of optimal behavior).

16 CFR 1101.2. - Scope.

Code of Federal Regulations, 2010 CFR

2010-01-01

... four other acts the Commission administers (transferred acts). These transferred acts are the Flammable... (PPPA); the Federal Hazardous Substances Act, 15 U.S.C. 1261-1276 (FHSA); and the Refrigerator Safety...

Pragmatic Study of Directive Speech Acts in Stories in Alquran

ERIC Educational Resources Information Center

Santosa, Rochmat Budi; Nurkamto, Joko; Baidan, Nashruddin; Sumarlam

2016-01-01

This study aims at describing the directive speech acts in the verses that contain the stories in the Qur'an. Specifically, the objectives of this study are to assess the sub directive speech acts contained in the verses of the stories and the dominant directive speech acts. The research target is the verses ("ayat") containing stories…

ACTS propagation terminal update

NASA Technical Reports Server (NTRS)

Stutzman, Warren L.; Pratt, Tim

1992-01-01

The activities at Virginia Polytechnic Institute and State University in preparation for the February 1993 launch of ACTS are summarized. ACTS propagation terminals (APT) are being constructed to receive the 20 and 27.5 GHz ACTS beacon signals. Total power radiometers operating at the same frequencies are integrated into the terminal for use in level setting. Recent progress and plans for APT's are reported.

Acts of terrorism and mass violence targeting schools : Analysis and implications for preparedness in the USA.

PubMed

Schlegelmilch, Jeff; Petkova, Elisaveta; Martinez, Stephanie; Redlener, Irwin

2017-01-01

To enhance the preparedness of US schools to acts of terrorism and mass violence, the landscape of threats against schools must first be understood. This includes exploring the global trends of acts of terrorism against schools, as well as looking specifically at the history of terrorism and acts of mass violence against schools domestically. This paper conducts a review of two databases in order to look at the trends in acts of terrorism and mass violence carried out against schools, and provides recommendations for domestic school preparedness based on this information.

Quercetin and pioglitazone synergistically reverse endothelial dysfunction in isolated aorta from fructose-streptozotocin (F-STZ)-induced diabetic rats.

PubMed

Kunasegaran, Thubasni; Mustafa, Mohd Rais; Achike, Francis I; Murugan, Dharmani Devi

2017-03-15

Pioglitazone is an anti-diabetic drug with potential to cause adverse effects following prolonged use. This study, therefore, investigated the effects of combination treatment of a subliminal concentration of pioglitazone and quercetin, a potent antioxidant, on vascular reactivity of aorta isolated from fructose-streptozotocin (F-STZ)-induced diabetic rats. Relaxation to acetylcholine and sodium nitroprusside, and contraction to phenylephrine were tested in organ bath chambers following pre-incubation with vehicle (DMSO; 0.05%), quercetin (10-7 M), pioglitazone (10-7 M), or their combination (P+Q; 10-7 M each drug). Subliminal concentration of quercetin or pioglitazone did not alter the acetylcholine- induced relaxation nor the phenylephrine-induced contraction in both normal rat and diabetic F-STZ induced tissues. However, P+Q combination synergistically improved the impaired acetylcholine-induced relaxation and decreased the elevated phenylephrine-induced contraction in aortic rings from diabetic, but not in the normal rats. Neither mono nor combination treatment altered sodium nitroprusside-induced relaxation. The combination also synergistically decreased superoxide anion and increased nitric oxide production compared to the individual treatments in aorta from diabetic rats. Overall, these data demonstrated a synergistic effect, in which, a combination (P+Q; 10-7 M each drug) caused a significantly greater effect than 10-6 M of either agent in improving endothelial function of isolated diabetic aorta. In conclusion, a combination of subliminal concentrations of pioglitazone and quercetin is able to decrease oxidative stress and provide synergistic vascular protection in type 2 diabetes mellitus and thus the possibility of using quercetin as a supplement to pioglitazone in the treatment of diabetes with the goal of reducing pioglitazone toxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

Sigma-2 ligands and PARP inhibitors synergistically trigger cell death in breast cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

McDonald, Elizabeth S.; Mankoff, Julia; Makvandi, Mehran

The sigma-2 receptor is overexpressed in proliferating cells compared to quiescent cells and has been used as a target for imaging solid tumors by positron emission tomography. Recent work has suggested that the sigma-2 receptor may also be an effective therapeutic target for cancer therapy. Poly (ADP-ribose) polymerase (PARP) is a family of enzymes involved in DNA damage response. In this study, we looked for potential synergy of cytotoxicity between PARP inhibitors and sigma-2 receptor ligands in breast cancer cell lines. We showed that the PARP inhibitor, YUN3-6, sensitized mouse breast cancer cell line, EMT6, to sigma-2 receptor ligand (SV119,more » WC-26, and RHM-138) induced cell death determined by cell viability assay and colony forming assay. The PARP inhibitor, olaparib, sensitized tumor cells to a different sigma-2 receptor ligand SW43-induced apoptosis and cell death in human triple negative cell line, MDA-MB-231. Olaparib inhibited PARP activity and cell proliferation, and arrested cells in G2/M phase of the cell cycle in MDA-MB-231 cells. Subsequently cells became sensitized to SW43 induced cell death. In conclusion, the combination of sigma-2 receptor ligands and PARP inhibitors appears to hold promise for synergistically triggering cell death in certain types of breast cancer cells and merits further investigation. - Highlights: • PARPi, YUN3-6 and olaparib, and σ2 ligands, SV119 and SW43, were evaluated. • Mouse and human breast cancer cells, EMT6 and MDA-MB-231 respectively, were used. • YUN3-6 and SV119 synergistically triggered cell death in EMT6 cells. • Olaparib and SW43 additively triggered cell death in MDA-MB-231 cells. • Olaparib arrested cells in G2/M in MDA-MB-231 cells.« less

Combination of TS-021 with metformin improves hyperglycemia and synergistically increases pancreatic β-cell mass in a mouse model of type 2 diabetes.

PubMed

Tajima, Atsushi; Hirata, Takashi; Taniguchi, Kazuo; Kondo, Yukiko; Kato, Sota; Saito-Hori, Masako; Ishimoto, Tsuyoshi; Yamamoto, Koji

2011-10-24

The objectives of this study were to elucidate the effects of a potent dipeptidyl peptidase (DPP)-IV inhibitor, TS-021, combined with/without metformin on glycemic control and pathological changes in pancreatic islets in high-fat diet and streptozotocin-induced (HFD-STZ) diabetic mice. The anti-diabetic effects of TS-021 and/or metformin in HFD-STZ mice were examined in both acute and chronic treatment studies. In addition, we performed immunohistochemical analysis after repeated administration of TS-021 and/or metformin to HFD-STZ mice twice a day for 5 weeks. In the acute treatment study, TS-021 and/or metformin significantly improved glucose tolerance and glucagon-like peptide-1 (GLP-1) level, and TS-021 alone or in combination with metformin significantly increased the plasma insulin level after nutrient ingestion. In the chronic treatment study, TS-021 in combination with metformin significantly lowered the glycosylated hemoglobin level, plasma insulin level, and α-cell-to-β-cell area ratio in pancreatic islets. In particular, the combined treatment synergistically increased the insulin-positive area in pancreatic islets from 32.3% in diabetic mice treated with the vehicle to 51.1% (TS-021 alone, 35.3%; metformin alone, 30.6%). The present study demonstrated that the coadministration of TS-021 and metformin synergistically improved the islet morphology by increasing the circulating level of biologically active GLP-1, which is thought to result from two different mechanisms (namely, an increase in GLP-1 secretion and DPP-IV inhibition). These findings strongly support the rationale for combined treatment with DPP-IV inhibitors plus metformin in clinical practice by clearly demonstrating an anti-diabetic effect associated with the remarkable improvement in pancreatic β-cell morphology. Copyright © 2011 Elsevier Inc. All rights reserved.

Abscisic acid synergizes with rosiglitazone to improve glucose tolerance and down-modulate macrophage accumulation in adipose tissue: possible action of the cAMP/PKA/PPAR γ axis.

PubMed

Guri, Amir J; Hontecillas, Raquel; Bassaganya-Riera, Josep

2010-10-01

Abscisic acid (ABA) is effective in preventing insulin resistance and obesity-related inflammation through a PPAR γ-dependent mechanism. The objective of this study was to assess the efficacy ABA in improving glucose homeostasis and suppress inflammation when administered in combination with rosiglitazone (Ros) and to determine whether PPAR γ activation by ABA is initiated via cAMP/protein kinase A (PKA) signaling. Obese db/db mice were fed high-fat diets containing 0, 10, or 70 mg/kg Ros with and without racemic ABA (100 mg/kg) for 60 days. Glucose tolerance and fasting insulin levels were assessed at 6 and 8 weeks, respectively, and adipose tissue macrophage (ATM) infiltration was examined by flow cytometry. Gene expression was examined on white adipose tissue (WAT) and stromal vascular cells (SVCs) cultured with ABA, Ros, or an ABA/Ros combination. Both Ros and ABA improved glucose tolerance, and ABA decreased plasma insulin levels while having no effect on Ros-induced weight gain. ABA in combination with low-dose Ros (10 mg/kg; Roslo) synergistically inhibited ATM infiltration. Treatment of SVCs with Ros, ABA or ABA/Ros suppressed expression of the M1 marker CCL17. ABA and Ros synergistically increased PPAR γ activity and pretreatment with a cAMP-inhibitor or a PKA-inhibitor abrogated ABA-induced PPAR γ activation. ABA and Ros act synergistically to modulate PPAR γ activity and macrophage accumulation in WAT and ABA enhances PPAR γ activity through a membrane-initiated mechanism dependent on cAMP/PKA signaling. Copyright © 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Leptin and leucine synergistically regulate protein metabolism in C2C12 myotubes and mouse skeletal muscles.

PubMed

Mao, Xiangbing; Zeng, Xiangfang; Huang, Zhimin; Wang, Junjun; Qiao, Shiyan

2013-07-28

Leucine and leptin play important roles in regulating protein synthesis and degradation in skeletal muscles in vitro and in vivo. However, the objective of the present study was to determine whether leptin and leucine function synergistically in regulating protein metabolism of skeletal muscles. In the in vitro experiment, C2C12 myotubes were cultured for 2 h in the presence of 5 mm-leucine and/or 50 ng/ml of leptin. In the in vivo experiment, C57BL/6 and ob/ob mice were randomly assigned to be fed a non-purified diet supplemented with 3 % L-leucine or 2·04 % L-alanine (isonitrogenous control) for 14 d. Ob/ob mice were injected intraperitoneally with sterile PBS or recombinant mouse leptin (0·1 μg/g body weight) for 14 d. In C57BL/6 mice, dietary leucine supplementation increased (P< 0·05) plasma leptin, leptin receptor expression and protein synthesis in skeletal muscles, but reduced (P< 0·05) plasma urea and protein degradation in skeletal muscles. Dietary leucine supplementation and leptin injection increased the relative weight of the gastrocnemius and soleus muscles in ob/ob mice. Moreover, leucine and leptin treatments stimulated (P< 0·05) protein synthesis and inhibited (P< 0·05) protein degradation in C2C12 myotubes and skeletal muscles of ob/ob mice. There were interactions (P< 0·05) between the leucine and leptin treatments with regard to protein metabolism in C2C12 myotubes and soleus muscles of ob/ob mice but not in the gastrocnemius muscles of ob/ob mice. Collectively, these results suggest that leptin and leucine synergistically regulate protein metabolism in skeletal muscles both in vitro and in vivo.

Staurosporine synergistically potentiates the deoxycholate-mediated induction of COX-2 expression.

PubMed

Saeki, Tohru; Inui, Haruka; Fujioka, Saya; Fukuda, Suguru; Nomura, Ayumi; Nakamura, Yasushi; Park, Eun Young; Sato, Kenji; Kanamoto, Ryuhei

2014-08-01

Colorectal cancer is a major cause of cancer-related death in western countries, and thus there is an urgent need to elucidate the mechanism of colorectal tumorigenesis. A diet that is rich in fat increases the risk of colorectal tumorigenesis. Bile acids, which are secreted in response to the ingestion of fat, have been shown to increase the risk of colorectal tumors. The expression of cyclooxygenase (COX)-2, an inducible isozyme of cyclooxygenase, is induced by bile acids and correlates with the incidence and progression of cancers. In this study, we investigated the signal transduction pathways involved in the bile-acid-mediated induction of COX-2 expression. We found that staurosporine (sts), a potent protein kinase C (PKC) inhibitor, synergistically potentiated the deoxycholate-mediated induction of COX-2 expression. Sts did not increase the stabilization of COX-2 mRNA. The sts- and deoxycholate-mediated synergistic induction of COX-2 expression was suppressed by a membrane-permeable Ca(2+) chelator, a phosphoinositide 3-kinase inhibitor, a nuclear factor-κB pathway inhibitor, and inhibitors of canonical and stress-inducible mitogen-activated protein kinase pathways. Inhibition was also observed using PKC inhibitors, suggesting the involvement of certain PKC isozymes (η, θ, ι, ζ, or μ). Our results indicate that sts exerts its potentiating effects via the phosphorylation of p38. However, the effects of anisomycin did not mimic those of sts, indicating that although p38 activation is required, it does not enhance deoxycholate-induced COX-2 expression. We conclude that staurosporine synergistically enhances deoxycholate-induced COX-2 expression in RCM-1 colon cancer cells. © 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

14-3-3ζ and aPKC-ι synergistically facilitate epithelial-mesenchymal transition of cholangiocarcinoma via GSK-3β/snail signaling pathway

PubMed Central

He, Jun-chuang; Wang, Jian-ming; Schemmer, Peter; Ma, Chao-qun; Qian, Ya-wei; Yao, Wei; Zhang, Jian; Qi, Wei-peng; Fu, Yang; Feng, Wei; Yang, Tao

2016-01-01

Cholangiocarcinoma (CCA) invasion and metastasis are the primary causes of poor survival rates in patients. The epithelial-mesenchymal transition (EMT) is a crucial step in cancer invasion and metastasis. However, it is still unclear of the molecular mechanism. In this study, the expression of 14-3-3ζ and atypical protein kinase C-ι (aPKC-ι) was further detected in CCA tissues and cell lines. Meanwhile, we established the EMT model of CCA cells and investigated 14-3-3ζ and aPKC-ι co-regulatory effect on the EMT in vitro and in vivo. Further, we identified the downstream molecular glycogen synthase kinase 3 beta (GSK-3β)/Snail signalling pathway that contribute to regulating the EMT. Our data showed that the expression of 14-3-3ζ and aPKC-ι was synergistically increased in CCA tissues compared with adjacent noncancerous tissues and was intimately associated with differentiation and the tumour-node-metastasis (TNM) stage. Multivariate Cox regression analysis indicated that high 14-3-3ζ and aPKC-ι expression separately predicted a poor prognosis and were independent prognostic indicators in patients with CCA. The CO-IP experiment confirmed that the mutual binding relationship between 14-3-3ζ and aPKC-ι. Small interfering RNAs and siRNA rescue experiment demonstrated that 14-3-3ζ and aPKC-ι regulated each other. In addition, 14-3-3ζ and aPKC-ι pretreatment by si-RNA inhibit the phosphorylated GSK-3β and Snail expression during EMT. Meanwhile, silence of 14-3-3ζ or aPKC-ι suppressed CCA cells migration, metastasis and proliferation in vitro and in vivo. Our study demonstrates that 14-3-3ζ and aPKC-ι synergistically facilitate EMT of CCA via GSK-3β/Snail signalling pathway, and may be potential therapeutic target for CCA. PMID:27409422

Synergic carcinostatic effects of ascorbic acid and hyperthermia on Ehrlich ascites tumor cell.

PubMed

Saitoh, Y; Yoshimoto, T; Kato, S; Miwa, N

2015-06-01

In this study, we evaluated the carcinostatic effects of combined ascorbic acid (AsA) and a capacitive-resistive electric transfer (CRet) hyperthermic apparatus-induced hyperthermic treatment on Ehrlich ascites tumor (EAT) cells. EAT cells were exposed to various AsA (0-10 mM) concentrations for 1 h; they subsequently underwent CRet treatment for 15 min at 42 °C. Cell viability was assessed by the WST-8 assay 24 h after the combined treatment. Reactive oxygen species involvement was evaluated using catalase and tempol; caspase-3/7 activation was determined by their fluorescent substrates; cell proliferation were estimated by time-lapse observation. The effect on the cell cycle was analyzed by flow cytometry. Combined AsA and CRet treatment synergistically suppressed cell viability compared with either treatment alone, and these synergistically carcinostatic effects were evident even at noncytotoxic concentrations of AsA alone (≤ 2 mM). The carcinostatic effects of combined AsA and CRet treatment were attenuated in a dose-dependent manner by catalase addition, but not by the superoxide anion radical scavenger tempol. Time-lapse observation revealed that combined AsA and CRet treatment activated caspase-3/7 at 10-24 h after treatment, accompanied by significant cell growth suppression. Cell cycle analysis revealed that the rate of sub-G1-phase (apoptotic) cells was drastically increased at 12 h and 24 h, and that the G2/M-phase cells gradually increased at 6-24 h after treatment. These results indicate that combined AsA and CRet treatment synergistically inhibits EAT cell growth through G2/M arrest and apoptosis induction via H2O2 generation at lower AsA concentrations; this carcinostatic effect cannot be exerted by AsA alone.

14-3-3ζ and aPKC-ι synergistically facilitate epithelial-mesenchymal transition of cholangiocarcinoma via GSK-3β/Snail signaling pathway.

PubMed

Yang, Yan; Liu, Yan; He, Jun-Chuang; Wang, Jian-Ming; Schemmer, Peter; Ma, Chao-Qun; Qian, Ya-Wei; Yao, Wei; Zhang, Jian; Qi, Wei-Peng; Fu, Yang; Feng, Wei; Yang, Tao

2016-08-23

Cholangiocarcinoma (CCA) invasion and metastasis are the primary causes of poor survival rates in patients. The epithelial-mesenchymal transition (EMT) is a crucial step in cancer invasion and metastasis. However, it is still unclear of the molecular mechanism. In this study, the expression of 14-3-3ζ and atypical protein kinase C-ι (aPKC-ι) was further detected in CCA tissues and cell lines. Meanwhile, we established the EMT model of CCA cells and investigated 14-3-3ζ and aPKC-ι co-regulatory effect on the EMT in vitro and in vivo. Further, we identified the downstream molecular glycogen synthase kinase 3 beta (GSK-3β)/Snail signalling pathway that contribute to regulating the EMT. Our data showed that the expression of 14-3-3ζ and aPKC-ι was synergistically increased in CCA tissues compared with adjacent noncancerous tissues and was intimately associated with differentiation and the tumour-node-metastasis (TNM) stage. Multivariate Cox regression analysis indicated that high 14-3-3ζ and aPKC-ι expression separately predicted a poor prognosis and were independent prognostic indicators in patients with CCA. The CO-IP experiment confirmed that the mutual binding relationship between 14-3-3ζ and aPKC-ι. Small interfering RNAs and siRNA rescue experiment demonstrated that 14-3-3ζ and aPKC-ι regulated each other. In addition, 14-3-3ζ and aPKC-ι pretreatment by si-RNA inhibit the phosphorylated GSK-3β and Snail expression during EMT. Meanwhile, silence of 14-3-3ζ or aPKC-ι suppressed CCA cells migration, metastasis and proliferation in vitro and in vivo. Our study demonstrates that 14-3-3ζ and aPKC-ι synergistically facilitate EMT of CCA via GSK-3β/Snail signalling pathway, and may be potential therapeutic target for CCA.

Oxidized low-density lipoprotein and β-glycerophosphate synergistically induce endothelial progenitor cell ossification.

PubMed

Liu, Li; Liu, Zhi-zhong; Chen, Hui; Zhang, Guo-jun; Kong, Yu-hua; Kang, Xi-xiong

2011-12-01

To investigate the ability of ox-LDL to induce ossification of endothelial progenitor cells (EPCs) in vitro and explored whether oxidative stress, especially hypoxia inducible factor-1α (HIF-1α) and reactive oxygen species (ROS), participate in the ossific process. Rat bone marrow-derived endothelial progenitor cells (BMEPCs) were cultured in endothelial growth medium supplemented with VEGF (40 ng/mL) and bFGF (10 ng/mL). The cells were treated with oxidized low-density lipoprotein (ox-LDL, 5 μg/mL) and/or β-glycerophosphate (β-GP, 10 mmol/L). Calcium content and Von Kossa staining were used as the measures of calcium deposition. Ossific gene expression was determined using RT-PCR. The expression of osteocalcin (OCN) was detected with immunofluorescence. Alkaline phosphatase (ALP) activity was analyzed using colorimetric assay. Intercellular reactive oxygen species (ROS) were measured with flow cytometry. BMEPCs exhibited a spindle-like shape. The percentage of cells that expressed the cell markers of EPCs CD34, CD133 and kinase insert domain-containing receptor (KDR) were 46.2%±5.8%, 23.5%±4.0% and 74.3%±8.8%, respectively. Among the total cells, 78.3%±4.2% were stained with endothelial-specific fluorescence. Treatment of BMEPCs with ox-LDL significantly promoted calcium deposition, which was further significantly enhanced by co-treatment with β-GP. The same treatments significantly increased the gene expression of core-binding factor a-1 (cbfa-1) and OCN, while decreased the gene expression of osteoprotegerin (OPG). The treatments also significantly enhanced the activity of ALP, but did not affect the number of OCN(+) cells. Furthermore, the treatments significantly increased ROS and activated the hypoxia inducible factor-1α (HIF-1α). In all these effects, ox-LDL acted synergistically with β-GP. Ox-LDL and β-GP synergistically induce ossification of BMEPCs, in which an oxidizing mechanism is involved.

Harming ourselves and defiling others: what determines a moral domain?

PubMed

Chakroff, Alek; Dungan, James; Young, Liane

2013-01-01

Recent work has distinguished "harm" from "purity" violations, but how does an act get classified as belonging to a domain in the first place? We demonstrate the impact of not only the kind of action (e.g., harmful versus impure) but also its target (e.g., oneself versus another). Across two experiments, common signatures of harm and purity tracked with other-directed and self-directed actions, respectively. First, participants judged self-directed acts as primarily impure and other-directed acts as primarily harmful. Second, conservatism predicted harsher judgments of self-directed but not other-directed acts. Third, while participants delivered harsher judgments of intentional versus accidental acts, this effect was smaller for self-directed than other-directed acts. Finally, participants judged self-directed acts more harshly when focusing on the actor's character versus the action itself; other-directed acts elicited the opposite pattern. These findings suggest that moral domains are defined not only by the kind of action but also by the target of the action.

Synergistic induction of cytogenetic damage by the homo-aza-steroidal ester of p-bis(2-chloroethyl)aminophenylacetic acid in combination with caffeine in human lymphocytes in vitro and in Ehrlich ascites tumour cells in vivo.

PubMed

Petrou, C; Mourelatos, D; Dozi-Vassiliades, J; Catsoulacos, P

1990-02-01

We studied the effects of caffeine alone or in combination with homo-aza-steroidal ester of p-bis(2-chloroethyl)aminophenylacetic acid (ASE, NSC 290205) on the frequency of SCEs and lymphocyte proliferation kinetics. Caffeine was found to act synergistically with ASE on the induction of SCEs when the two components were administered in combination. Caffeine was also found to act synergistically with ASE in inducing cell-division delays. Enhanced cytogenetic damage by ASE was observed when Ehrlich ascites tumour cells (EAT cells) were exposed in vivo to caffeine. ASE alone or in combination with caffeine caused a dose-dependent increase in SCE rates and cell-division delays. SCEs were demonstrated in EAT-bearing mice, by the i.p. injection of BrdUrd adsorbed onto activated charcoal, 1 h after the i.p. injection of ASE and/or caffeine.

Soy isoflavone aglycone modulates a hematopoietic response in combination with soluble beta-glucan: SCG.

PubMed

Harada, Toshie; Masuda, Susumu; Arii, Masayuki; Adachi, Yoshiyuki; Nakajima, Mitsuhiro; Yadomae, Toshiro; Ohno, Naohito

2005-12-01

Soy isoflavone aglycones (IFAs) have a wide range of biological actions that suggest they may be of use in cancer prevention. On the other hand, a branched beta-glucan from Sparassis crispa (SCG) is a major 6-branched 1,3-beta-D-glucan in an edible/medicinal mushroom: Sparassis crispa showing antitumor activity. We have previously reported that both oral and intraperitoneal administration of SCG enhanced the hematopoietic response in cyclophosphamide (CY)-induced leukopenic mice. In this study, we investigated the hematopoietic response due to IFA in combination with SCG in CY-induced leukopenic mice. The oral administration of IFA in combination with SCG synergistically enhanced the number of white blood cells, and increased spleen weight. Analyzing the leukocyte population by flow cytometry, the combination of IFA and SCG increased the number of monocytes and granulocytes in the spleen. Taken together, the combination of IFA and SCG synergistically provides the hematopoietic responses that are enhanced over IFA or SCG alone.

Synergistically-enhanced ion track formation in pre-damaged strontium titanate by energetic heavy ions

DOE PAGES

Xue, Haizhou; Zarkadoula, Eva; Sachan, Ritesh; ...

2018-03-20

Latent ion tracks created by energetic heavy ions (12 MeV Ti to 946 MeV Au) in single crystal SrTiO 3 are investigated in this paper using Rutherford backscattering spectrometry and scanning transmission electron microscopy. The results demonstrate that pre-existing irradiation damage, introduced via elastic collision processes, interacts synergistically with the electronic energy deposition from energetic heavy ions to enhance formation of latent ion tracks. The average amorphous cross-section increases with the level of pre-damage and is linearly proportional to the electronic energy loss of the ions, with a slope dependent on the pre-damage level. For the highest energy ions (629more » MeV Xe and 946 MeV Au), the tracks are continuous over the pre-damaged depth, but become discontinuous beyond the pre-damaged region. Finally, this work provides new understanding and insights on ion-solid interactions that significantly impact the interpretation of latent track formation processes, models of amorphization, and the fabrication of electro-ceramic devices.« less

Synergistically-enhanced ion track formation in pre-damaged strontium titanate by energetic heavy ions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xue, Haizhou; Zarkadoula, Eva; Sachan, Ritesh

Latent ion tracks created by energetic heavy ions (12 MeV Ti to 946 MeV Au) in single crystal SrTiO 3 are investigated in this paper using Rutherford backscattering spectrometry and scanning transmission electron microscopy. The results demonstrate that pre-existing irradiation damage, introduced via elastic collision processes, interacts synergistically with the electronic energy deposition from energetic heavy ions to enhance formation of latent ion tracks. The average amorphous cross-section increases with the level of pre-damage and is linearly proportional to the electronic energy loss of the ions, with a slope dependent on the pre-damage level. For the highest energy ions (629more » MeV Xe and 946 MeV Au), the tracks are continuous over the pre-damaged depth, but become discontinuous beyond the pre-damaged region. Finally, this work provides new understanding and insights on ion-solid interactions that significantly impact the interpretation of latent track formation processes, models of amorphization, and the fabrication of electro-ceramic devices.« less

Done Wrong or Said Wrong? Young Children Understand the Normative Directions of Fit of Different Speech Acts

ERIC Educational Resources Information Center

Rakoczy, Hannes; Tomasello, Michael

2009-01-01

Young children use and comprehend different kinds of speech acts from the beginning of their communicative development. But it is not clear how they understand the conventional and normative structure of such speech acts. In particular, imperative speech acts have a world-to-word direction of fit, such that their fulfillment means that the world…

Low-dose ribavirin potentiates the antiviral activity of favipiravir against hemorrhagic fever viruses.

PubMed

Westover, Jonna B; Sefing, Eric J; Bailey, Kevin W; Van Wettere, Arnaud J; Jung, Kie-Hoon; Dagley, Ashley; Wandersee, Luci; Downs, Brittney; Smee, Donald F; Furuta, Yousuke; Bray, Mike; Gowen, Brian B

2016-02-01

Favipiravir is approved in Japan to treat novel or re-emerging influenza viruses, and is active against a broad spectrum of RNA viruses, including Ebola. Ribavirin is the only other licensed drug with activity against multiple RNA viruses. Recent studies show that ribavirin and favipiravir act synergistically to inhibit bunyavirus infections in cultured cells and laboratory mice, likely due to their different mechanisms of action. Convalescent immune globulin is the only approved treatment for Argentine hemorrhagic fever caused by the rodent-borne Junin arenavirus. We previously reported that favipiravir is highly effective in a number of small animal models of Argentine hemorrhagic fever. We now report that addition of low dose of ribavirin synergistically potentiates the activity of favipiravir against Junin virus infection of guinea pigs and another arenavirus, Pichinde virus infection of hamsters. This suggests that the efficacy of favipiravir against hemorrhagic fever viruses can be further enhanced through the addition of low-dose ribavirin. Copyright © 2015 Elsevier B.V. All rights reserved.

POLYCHLORINATED BIPHENYLS AND METHYLMERCURY ACT SYNERGISTICALLY TO REDUCE RAT BRAIN DOPAMINE CONTENT IN VITRO. (R825812)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Associations of Neighborhood and Family Factors with Trajectories of Physical and Social Aggression during Adolescence

ERIC Educational Resources Information Center

Karriker-Jaffe, Katherine J.; Foshee, Vangie A.; Ennett, Susan T.; Suchindran, Chirayath

2013-01-01

Adolescents develop within multiple contexts that synergistically influence their behavior and health. To understand the simultaneous influence of neighborhood and family contexts on adolescents, this study examined relationships of neighborhood socioeconomic disadvantage, neighborhood social disorganization, family conflict, parent-child bonding…

A BRIEF TARGETED REVIEW OF SUSCEPTIBILITY FACTORS, ENVIRONMENTAL EXPOSURES, ASHTMA INCIDENCE, AND RECOMMENDATIONS FOR FUTURE ASHTMA INCIDENCE RESEARCH

EPA Science Inventory

Genetics, obesity, age, and lifestyle are major susceptibility factors in the induction of asthma and can interact with environmental exposures either synergistically or antagonistically. Different environmental exposures that increase or decrease the likelihood of developing as...

Mud, Macrofauna and Microbes: An ode to benthic organism-abiotic interactions at varying scales

EPA Science Inventory

Benthic environments are dynamic habitats, subject to variable sources and rates of sediment delivery, reworking from the abiotic and biotic processes, and complex biogeochemistry. These activities do not occur in a vacuum, and interact synergistically to influence food webs, bi...

Synergies between climate anomalies and hydrological modifications facilitate estuarine biotic invasions.

PubMed

Winder, Monika; Jassby, Alan D; Mac Nally, Ralph

2011-08-01

Environmental perturbation, climate change and international commerce are important drivers for biological invasions. Climate anomalies can further increase levels of habitat disturbance and act synergistically to elevate invasion risk. Herein, we use a historical data set from the upper San Francisco Estuary to provide the first empirical evidence for facilitation of invasions by climate extremes. Invasive zooplankton species did not become established in this estuary until the 1970s when increasing propagule pressure from Asia coincided with extended drought periods. Hydrological management exacerbated the effects of post-1960 droughts and reduced freshwater inflow even further, increasing drought severity and allowing unusually extreme salinity intrusions. Native zooplankton experienced unprecedented conditions of high salinity and intensified benthic grazing, and life history attributes of invasive zooplankton were advantageous enough during droughts to outcompete native species and colonise the system. Extreme climatic events can therefore act synergistically with environmental perturbation to facilitate the establishment of invasive species. © 2011 Blackwell Publishing Ltd/CNRS.

Vibrio cholerae use pili and flagella synergistically to effect motility switching and conditional surface attachment

NASA Astrophysics Data System (ADS)

Utada, Andrew S.; Bennett, Rachel R.; Fong, Jiunn C. N.; Gibiansky, Maxsim L.; Yildiz, Fitnat H.; Golestanian, Ramin; Wong, Gerard C. L.

2014-09-01

We show that Vibrio cholerae, the causative agent of cholera, use their flagella and mannose-sensitive hemagglutinin (MSHA) type IV pili synergistically to switch between two complementary motility states that together facilitate surface selection and attachment. Flagellar rotation counter-rotates the cell body, causing MSHA pili to have periodic mechanical contact with the surface for surface-skimming cells. Using tracking algorithms at 5 ms resolution we observe two motility behaviours: ‘roaming', characterized by meandering trajectories, and ‘orbiting’, characterized by repetitive high-curvature orbits. We develop a hydrodynamic model showing that these phenotypes result from a nonlinear relationship between trajectory shape and frictional forces between pili and the surface: strong pili-surface interactions generate orbiting motion, increasing the local bacterial loiter time. Time-lapse imaging reveals how only orbiting mode cells can attach irreversibly and form microcolonies. These observations suggest that MSHA pili are crucial for surface selection, irreversible attachment, and ultimately microcolony formation.

SA1 and TRF1 synergistically bind to telomeric DNA and promote DNA-DNA pairing

NASA Astrophysics Data System (ADS)

Wang, Hong; Lin, Jiangguo; Countryman, Preston; Pan, Hai; Parminder Kaur Team; Robert Riehn Team; Patricia Opresko Team; Jane Tao Team; Susan Smith Team

Impaired telomere cohesion leads to increased aneuploidy and early onset of tumorigenesis. Cohesion is thought to occur through the entrapment of two DNA strands within tripartite cohesin ring(s), along with a fourth subunit (SA1/SA2). Surprisingly, cohesion rings are not essential for telomere cohesion, which instead requires SA1 and shelterin proteins including TRF1. However, neither this unique cohesion mechanism at telomeres or DNA-binding properties of SA1 is understood. Here, using single-molecule fluorescence imaging of quantum dot-labeled proteins on DNA we discover that while SA1 diffuses across multiple telomeric and non-telomeric regions, the diffusion mediated through its N-terminal domain is slower at telomeric regions. However, addition of TRF1 traps SA1 within telomeric regions, which form longer DNA-DNA pairing tracts than with TRF1 alone, as revealed by atomic force microscopy. Together, these experimental results and coarse-grained molecular dynamics simulations suggest that TRF1 and SA1 synergistically interact with DNA to support telomere cohesion without cohesin rings.

Cognitive function and unsafe driving acts during an on-road test among community-dwelling older adults with cognitive impairments.

PubMed

Hotta, Ryo; Makizako, Hyuma; Doi, Takehiko; Tsutsumimoto, Kota; Nakakubo, Sho; Makino, Keitaro; Shimada, Hiroyuki

2018-02-19

To examine the relationship between cognitive function and unsafe driving acts among community-dwelling older adults with cognitive impairments. Participants (n = 160) were older residents of Obu, Japan, aged ≥65 years with cognitive impairments. They regularly drove and were assessed for the number of unsafe driving acts without adequate verification during an on-road test. We also evaluated cognitive function (attention, executive function and processing speed). Other examined variables included demographics, driving characteristics and visual condition. Participants were classified into two groups according to the number of unsafe driving acts as follows: high group (≥4 unsafe driving acts) and low group (≤3 unsafe driving acts). The high group participants were older in age (P < 0.001) and obtained a lower score on the symbol digit substitution task (P = 0.002) than the low group. The number of unsafe driving acts showed modest significant positive correlations with age (r = 0.396, P < 0.001). The symbol digit substitution task score was significantly associated with the number of unsafe driving acts (β = -0.196, P < 0.05) after adjusting for age group. Processing speed was associated with unsafe driving acts that became worse with increasing age. Future study will be required to longitudinally examine the influence of processing speed on traffic accidents for those with cognitive impairments. Geriatr Gerontol Int 2018; ••: ••-••. © 2018 Japan Geriatrics Society.

Identification and isolation of the cyclooxygenase-2 inhibitory principle in Isatis tinctoria.

PubMed

Danz, H; Stoyanova, S; Wippich, P; Brattström, A; Hamburger, M

2001-07-01

Various extracts prepared from the traditional dye and medicinal plant Isatis tinctoria L. were submitted to a broad in vitro screening against 16 anti-inflammatory targets. Dichloromethane (DCM) extracts from dried leaves showed a marked cyclooxygenase (COX) inhibitory activity with a preferential effect on COX-2 catalysed prostaglandin synthesis. A supercritical fluid extraction (SFE) procedure employing CO2-modifier mixtures was developed by which the bioactivity profile and chromatographic fingerprint of the DCM extract could be reproduced. High-resolution activity directed on-line identification of the COX-2 inhibitory principle, using a combination of LC-DAD-MS with a microtitre-based bioassay, led to the identification of tryptanthrin (1) as the constituent responsible for essentially all COX-2 inhibitory activity in the crude extract. Following on-line identification, 1 was isolated at preparative scale and its structure confirmed by comparison with synthetic tryptanthrin. In an assay with lipopolysaccharide stimulated Mono Mac 6 cells, tryptanthrin (1) was of comparable potency (IC50 = 64 nM) than the preferential COX-2 inhibitors nimesulide (IC50 = 39 nM) and NS 398 (IC50 = 2 nM). The SFE extract and 1 showed no cytotoxicity in Mono Mac 6 and RAW 264.7 cells when tested at 100 microg/ml and 10 microM, respectively.

A toxicity assessment of 30 pharmaceuticals using Aliivibrio fischeri: a comparison of the acute effects of different formulations.

PubMed

Jacob, Raquel Sampaio; Santos, Lucilaine Valéria de Souza; de Souza, Ana Flávia Rodrigues; Lange, Liséte Celina

2016-11-01

Considerable quantities of different classes of drugs are consumed annually worldwide. These drugs, once disposed, often remain stable, even after conventional or advanced treatments. Although there have been a number of studies on the potential harm caused by drugs when released into the environment, few studies have investigated the toxicity of pharmaceutical excipients. In the present study, the acute toxicity of 30 drugs was tested to Aliivibrio fischeri. Ten different active ingredients were investigated, each in three distinct formulations: generic, similar and reference (brand drug). The aim of the study was to evaluate the harmful potential of drugs frequently sold in drugstores and to assess the contribution of excipients towards the observed acute toxicity. Within the 10 drugs evaluated, only one, dexchlorpheniramine maleate, was not toxic in any formulation. The toxicities of the three formulations were often different, even though the active ingredient has been the same. For some drugs, such as diazepam, glibenclamide, metformin, nimesulide, hydrochlorothiazide and simvastatin, only one or two of the three formulations tested were toxic to A. fischeri. These results highlight the toxicological potential of drug excipients, but not exclusively the toxicity of the active ingredients.

Deployment Guide

DTIC Science & Technology

1994-02-01

military administration). D. Notarial acts performed under 10 U.S.C. 5 1044a are legally effective as notarial acts for all purposes in all states...and to execute all necessary documents, instruments or papers and perform all acts necessary to carry out the foregoing. Clearing Quarters To effect ...attorney in fact to perform all necessary acts in the execution of the aforesaid authorization with the same validity as I could effect if personally

Evil acts not evil people: their characteristics and contexts.

PubMed

Horne, Michael

2008-11-01

The problem of evil has vexed philosophers and theologians for centuries and anthropologists, sociologists, psychoanalysts and analytical psychologists in more recent times. Numerous theories have been proposed but there is still little agreement on such basic questions as the nature of evil, what constitutes and motivates an evil act, and how we resolve conflicts between individuals and groups in which evil acts are being committed. I am proposing that evil should be used as an adjective, and not as a noun. As such it should be employed to qualify acts of persons rather than their character. This change would enable us to eschew foundational explanations of evil and, therefore, to examine evil acts in their contexts and so better discern their nature and motivation. I will contend that evil acts begin when an individual makes, or members of a group make, assertions about the 'naturalness' of their own acts and, correspondingly, the 'unnaturalness' of the acts of others. I will suggest that this results from the anxiety that ensues when they cannot adequately signify their experience of these acts. When this occurs, those so treated are dispossessed of their 'personhood', allowing members of the 'natural' group to violate their 'boundaries' with impunity. These violations can range from the relatively innocuous such as being ignored to the extreme such as genocide. I am asserting that all these acts should be termed evil as they derive from the same semiotic process of 'naturalizaton'. I will discuss ways of preventing individuals or groups from embarking on the process of 'naturalization' and describe the types of contexts that might reduce or eliminate the commission of evil acts by those already engaged in their perpetration. To demonstrate these ideas I will use examples from my personal experience, from analytic theory and from the 'troubles' in Northern Ireland.

Harm mediates the disgust-immorality link.

PubMed

Schein, Chelsea; Ritter, Ryan S; Gray, Kurt

2016-09-01

Many acts are disgusting, but only some of these acts are immoral. Dyadic morality predicts that disgusting acts should be judged as immoral to the extent that they seem harmful. Consistent with this prediction, 3 studies reveal that perceived harm mediates the link between feelings of disgust and moral condemnation-even for ostensibly harmless "purity" violations. In many cases, accounting for perceived harm completely eliminates the link between disgust and moral condemnation. Analyses also reveal the predictive power of anger and typicality/weirdness in moral judgments of disgusting acts. The mediation of disgust by harm holds across diverse acts including gay marriage, sex acts, and religious blasphemy. Revealing the endogenous presence and moral relevance of harm within disgusting-but-ostensibly harmless acts argues against modular accounts of moral cognition such as moral foundations theory. Instead, these data support pluralistic conceptions of harm and constructionist accounts of morality and emotion. Implications for moral cognition and the concept of "purity" are discussed. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Harming Ourselves and Defiling Others: What Determines a Moral Domain?

PubMed Central

Chakroff, Alek; Dungan, James; Young, Liane

2013-01-01

Recent work has distinguished “harm” from “purity” violations, but how does an act get classified as belonging to a domain in the first place? We demonstrate the impact of not only the kind of action (e.g., harmful versus impure) but also its target (e.g., oneself versus another). Across two experiments, common signatures of harm and purity tracked with other-directed and self-directed actions, respectively. First, participants judged self-directed acts as primarily impure and other-directed acts as primarily harmful. Second, conservatism predicted harsher judgments of self-directed but not other-directed acts. Third, while participants delivered harsher judgments of intentional versus accidental acts, this effect was smaller for self-directed than other-directed acts. Finally, participants judged self-directed acts more harshly when focusing on the actor’s character versus the action itself; other-directed acts elicited the opposite pattern. These findings suggest that moral domains are defined not only by the kind of action but also by the target of the action. PMID:24040245

50 CFR 648.161 - Bluefish Annual Catch Targets (ACTs).

Code of Federal Regulations, 2013 CFR

2013-10-01

... commercial and recreational sector-specific ACTs shall be less than or equal to the fishery level ACL. The... relative to ACTs in conjunction with any ACL performance review, as outlined in § 648.160(b)(1) through (3...

Oregon's ACTs, cross-jurisdictional collaboration and improved transportation planning.

DOT National Transportation Integrated Search

2009-01-01

The Oregon Transportation Commission (OTC) created Area Commissions on Transportation (ACTs) to improve coordination, help prioritize infrastructure investment, and provide input on statewide transportation issues. The structure of the ACTs is design...

A three-dimensional self-assembled SnS 2 -nano-dots@graphene hybrid aerogel as an efficient polysulfide reservoir for high-performance lithium–sulfur batteries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luo, Liu; Chung, Sheng-Heng; Manthiram, Arumugam

A free-standing self-assembled graphene aerogel embedded with SnS 2 nano-dots (SnS 2 -ND@G) is established as an efficient substrate for high-loading sulfur cathodes with synergistically physical and chemical polysulfide-trapping capability.

Chimeric phage lysins act synergistically with lysostaphin to kill mastitis causing staphylococcus aureus in murine mammary glands

USDA-ARS?s Scientific Manuscript database

Staphylococci cause bovine mastitis with Staphylococcus aureus being responsible for the majority of the mastitis-based losses to the dairy industry (up to $2 billion/annum). Treatment is primarily with antibiotics that are often ineffective and potentially contribute to resistance development. Bac...

Structural Truss Elements and Forces

ERIC Educational Resources Information Center

Troyer, Steve; Griffis, Kurt; Shackelford, Ray

2005-01-01

In the field of construction, most structures are supported by several groups of truss systems working together synergistically. A "truss" is a group of centered and balanced elements combined to carry a common load (Warner, 2003). Trusses provide strength against loads and forces within a structure. Though a complex field of study, structural…

Response of a One-Biosphere Nutrient Modeling System to Regional Land Use and Management Change

EPA Science Inventory

A multi-media system of nitrogen and co-pollutant models describing critical physical and chemical processes that cascade synergistically and competitively through the environment, the economy and society has been developed at the USEPA Office of Research and Development (see fig...

A three-dimensional self-assembled SnS 2 -nano-dots@graphene hybrid aerogel as an efficient polysulfide reservoir for high-performance lithium–sulfur batteries

DOE PAGES

Luo, Liu; Chung, Sheng-Heng; Manthiram, Arumugam

2018-01-01

A free-standing self-assembled graphene aerogel embedded with SnS 2 nano-dots (SnS 2 -ND@G) is established as an efficient substrate for high-loading sulfur cathodes with synergistically physical and chemical polysulfide-trapping capability.

Minocycline and N-acetylcysteine: A Synergistic Drug Combination to Treat Traumatic Brain Injury

DTIC Science & Technology

2013-10-01

Contract Number: W81XWH-10-2-0171 TITLE: Minocycline and...30September2012-29September2013 4. TITLE AND SUBTITLE Minocycline and N-acetylcysteine: a synergistic drug combination to treat...grantee previously found screened that the combination of minocycline (MINO) and N-acetyl cysteine (NAC) synergistically improved brain function when

ACTS data center

NASA Technical Reports Server (NTRS)

Syed, Ali; Vogel, Wolfhard J.

1993-01-01

Viewgraphs on ACTS Data Center status report are included. Topics covered include: ACTS Data Center Functions; data flow overview; PPD flow; RAW data flow; data compression; PPD distribution; RAW Data Archival; PPD Audit; and data analysis.

50 CFR 648.161 - Bluefish Annual Catch Targets (ACTs).

Code of Federal Regulations, 2014 CFR

2014-10-01

... commercial and recreational sector-specific ACTs shall be less than or equal to the fishery level ACL. The... relative to ACTs in conjunction with any ACL performance review, as outlined in § 648.160(b)(1) through (3...

Oregon's ACTs, cross-jurisdictional collaboration, and improved transportation planning.

DOT National Transportation Integrated Search

2009-01-01

The Oregon Transportation Commission (OTC) created Area Commissions on Transportation (ACTs) to improve : coordination, help prioritize infrastructure investment, and provide input on statewide transportation issues. The structure of : the ACTs is de...

ACTS propagation experiment discussion: Ka-band propagation measurements using the ACTS propagation terminal and the CSU-CHILL and Space Communications Technology Center Florida propagation program

NASA Technical Reports Server (NTRS)

Bringi, V. N.; Chandrasekar, V.; Mueller, Eugene A.; Turk, Joseph; Beaver, John; Helmken, Henry F.; Henning, Rudy

1993-01-01

Papers on Ka-band propagation measurements using the ACTS propagation terminal and the Colorado State University CHILL multiparameter radar and on Space Communications Technology Center Florida Propagation Program are discussed. Topics covered include: microwave radiative transfer and propagation models; NASA propagation terminal status; ACTS channel characteristics; FAU receive only terminal; FAU terminal status; and propagation testbed.

Advanced Communications Technology Satellite (ACTS): Four-Year System Performance

NASA Technical Reports Server (NTRS)

Acosta, Roberto J.; Bauer, Robert; Krawczyk, Richard J.; Reinhart, Richard C.; Zernic, Michael J.; Gargione, Frank

1999-01-01

The Advanced Communications Technology Satellite (ACTS) was conceived at the National Aeronautics and Space Administration (NASA) in the late 1970's as a follow-on program to ATS and CTS to continue NASA's long history of satellite communications projects. The ACTS project set the stage for the C-band satellites that started the industry, and later the ACTS project established the use of Ku-band for video distribution and direct-to-home broadcasting. ACTS, launched in September 1993 from the space shuttle, created a revolution in satellite system architecture by using digital communications techniques employing key technologies such as a fast hopping multibeam antenna, an on-board baseband processor, a wide-band microwave switch matrix, adaptive rain fade compensation, and the use of 900 MHz transponders operating at Ka-band frequencies. This paper describes the lessons learned in each of the key ACTS technology areas, as well as in the propagation investigations.

Design and implementation of an experiment scheduling system for the ACTS satellite

NASA Technical Reports Server (NTRS)

Ringer, Mark J.

1994-01-01

The Advanced Communication Technology Satellite (ACTS) was launched on the 12th of September 1993 aboard STS-51. All events since that time have proceeded as planned with user operations commencing on December 6th, 1993. ACTS is a geosynchronous satellite designed to extend the state of the art in communication satellite design and is available to experimenters on a 'time/bandwidth available' basis. The ACTS satellite requires the advance scheduling of experimental activities based upon a complex set of resource, state, and activity constraints in order to ensure smooth operations. This paper describes the software system developed to schedule experiments for ACTS.

40 CFR 8.11 - Prohibited acts, enforcement and penalties.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Prohibited acts, enforcement and penalties. 8.11 Section 8.11 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL ENVIRONMENTAL IMPACT ASSESSMENT OF NONGOVERNMENTAL ACTIVITIES IN ANTARCTICA § 8.11 Prohibited acts, enforcement and...

10 CFR 52.10 - Attacks and destructive acts.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 2 2010-01-01 2010-01-01 false Attacks and destructive acts. 52.10 Section 52.10 Energy... protection against the effects of— (a) Attacks and destructive acts, including sabotage, directed against the... deployment of weapons incident to U.S. defense activities. ...

Data collection with the ACTS propagation terminal

NASA Technical Reports Server (NTRS)

Remaklus, Will

1993-01-01

Viewgraphs on data collection with the ACTS propagation terminal are included. Topics covered include: DACS system overview; DACS board; APT data collection computer; APT software downloading; data storage for APT; and ACTS propagation experiment data flow.

Service offerings and interfaces for the ACTS network of earth stations

NASA Technical Reports Server (NTRS)

Coney, T. A.; Dobyns, T. R.; Chitre, D. M.; Lindstrom, R.

1988-01-01

The NASA Advanced Communications Technology Satellite (ACTS) will use a network of about 20 earth stations to operate as a Mode 1 network. This network will support two ACTS program objectives: to verify the technical performance of ACTS Mode 1 operation in GEO and to demonstrate the types and quality of services that can be provided by an ACTS Mode 1 communications system. The terrestrial interface design is a critical element in assuring that these network earth stations will meet the objectives. In this paper, the applicable terrestrial interface design requirements, the resulting interface specifications, and the associated terrestrial input/output hardware are discussed. A functional block diagram of a network earth station is shown.

50 CFR 648.161 - Bluefish Annual Catch Targets (ACTs).

Code of Federal Regulations, 2012 CFR

2012-10-01

... commercial and recreational sector-specific ACTs shall be less than or equal to the fishery level ACL. The... relative to ACTs in conjunction with any ACL performance review, as outlined in § 648.160(b)(1) through (3...

Commercialization of Advanced Communications Technology Satellite (ACTS) technology

NASA Astrophysics Data System (ADS)

Plecity, Mark S.; Strickler, Walter M.; Bauer, Robert A.

1996-03-01

In an on-going effort to maintain United States leadership in communication satellite technology, the National Aeronautics and Space Administration (NASA), led the development of the Advanced Communications Technology Satellite (ACTS). NASA's ACTS program provides industry, academia, and government agencies the opportunity to perform both technology and telecommunication service experiments with a leading-edge communication satellite system. Over 80 organizations are using ACTS as a multi server test bed to establish communication technologies and services of the future. ACTS was designed to provide demand assigned multiple access (DAMA) digital communications with a minimum switchable circuit bandwidth of 64 Kbps, and a maximum channel bandwidth of 900 MHZ. It can, therefore, provide service to thin routes as well as connect fiber backbones in supercomputer networks, across oceans, or restore full communications in the event of national or manmade disaster. Service can also be provided to terrestrial and airborne mobile users. Commercial applications of ACTS technologies include: telemedicine; distance education; Department of Defense operations; mobile communications, aeronautical applications, terrestrial applications, and disaster recovery. This paper briefly describes the ACTS system and the enabling technologies employed by ACTS including Ka-band hopping spot beams, on-board routing and switching, and rain fade compensation. When used in conjunction with a time division multiple access (TDMA) architecture, these technologies provide a higher capacity, lower cost satellite system. Furthermore, examples of completed user experiments, future experiments, and plans of organizations to commercialize ACTS technology in their own future offerings will be discussed.

Influence of the anti-inflammatory compound flosulide on granulocyte function.

PubMed

Zimmerli, W; Sansano, S; Wiesenberg-Böttcher, I

1991-10-24

Polymorphonuclear leukocytes (PMN) are involved in inflammatory reactions. It is thought that oxygen-derived free radicals released from activated PMN may participate in tissue damage during inflammation. We have shown that flosulide (6-(2,4-difluorophenoxy)-5-methylsulfonylamino-1-indanone ), a novel highly potent anti-inflammatory compound, inhibits superoxide production induced by N-formyl-Met-Leu-Phe (FMLP), C5a and PMA without impairing bacterial killing or chemotaxis. Flosulide (10(-5)-10(-7) M) was more potent in inhibiting the FMLP-induced respiratory burst of PMN than the structurally related compound nimesulide. FMLP-induced superoxide generation was also inhibited by two human flosulide metabolites. A good correlation between this in vitro effect and in vivo anti-inflammatory potency in rat adjuvant arthritis was found for flosulide and its metabolites. Indomethacin, piroxicam and ibuprofen did not inhibit the respiratory burst at 10(-5) M. FMLP receptor number was decreased by 36% in the presence of 10(-5) M flosulide. However, a 250-fold molar excess of flosulide could not displace labeled FMLP from the receptor. Inhibition of degranulation of primary and secondary granules was a common effect of all anti-inflammatory compounds tested. At a concentration of 10(-5) M, all drugs inhibited degranulation to about the same degree, independent of their in vivo anti-inflammatory activity.

Preparation and Characterization of Amylose Inclusion Complexes for Drug Delivery Applications.

PubMed

Carbinatto, Fernanda M; Ribeiro, Tatiana S; Colnago, Luiz Alberto; Evangelista, Raul Cesar; Cury, Beatriz S F

2016-01-01

Amylose complexes with nimesulide (NMS) and praziquantel (PZQ) were prepared by a simple and low cost method, so that high yield (>57%) and drug content (up to 68.16%) were achieved. The influence of drug:polymer ratio, temperature, and presence of palmitic acid on the complexes properties was evaluated. Differential scanning calorimetry, X-ray diffraction, and nuclear magnetic resonance data evidenced the drug-polymer interaction and the formation of inclusion complexes with semi-crystalline structures related to type II complexes. The drug release rates from complexes were lowered in acid media (pH 1.2) and phosphate buffer (pH 6.9). The presence of pancreatin promoted a significant acceleration of the release rates of both drugs, evidencing the enzymatic degradability of these complexes. The highest enzymatic resistance of PZQ1:30PA60°C complex makes the release time longer and the full release of PZQ in phosphate buffer with pancreatin occurred at 240 min, whereas the complexes with NMS and PZQ1:5PA90°C did it in 60 min. According to the Weibull model, the drug release process in media without enzyme occurred by complex mechanisms involving diffusion, swelling, and erosion. In media containing pancreatin, generally, the better correlation was with the first order, evidencing the acceleration of the release rates of drugs in the early stages of the test, due to enzymatic degradation.

10 CFR 52.10 - Attacks and destructive acts.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 2 2011-01-01 2011-01-01 false Attacks and destructive acts. 52.10 Section 52.10 Energy... protection against the effects of— (a) Attacks and destructive acts, including sabotage, directed against the... deployment of weapons incident to U.S. defense activities. ...

Asking what before we ask why: taxonomy, etiology, and rape.

PubMed

Baker, Katharine K

2003-06-01

This article presents a spectrum of sexual coersion. By looking at the social meaning of the different acts of coercion along the spectrum, the author suggests that most acts of sexual coercion can be classified as either rape (a sexual act with intent to do harm to the victim) or sex (a sexual act engaged in without any intent to harm the victim). Ironically, though, the author suggests that the most and least egregious acts of sexual aggression, that is, the acts we most readily identify as rape and the acts we are most reluctant to label rape are the ones that most easily evade explanation as either rape or sex.

One Hundred Intentional Acts of Kindness toward a Pregnant Woman: building reproductive social capital in Los Angeles.

PubMed

Jones, Loretta; Lu, Michael C; Lucas-Wright, Aziza; Dillon-Brown, Neysa; Broussard, Marsha; Wright, Kynna; Maidenberg, Molly; Norris, Keith; Ferré, Cynthia

2010-01-01

This article describes the development of an innovative community-based program, One Hundred Intentional Acts of Kindness toward a Pregnant Woman (100 Acts), which seeks to increase reproductive social capital for pregnant women in south and central Los Angeles communities. Reproductive social capital includes features such as networks, norms, and social trust that facilitate optimal reproductive health within a community. 100 Acts was designed and developed by the Healthy African American Families project, using community participatory methods, to increase local community and social network support for pregnant women. Dialog groups with pregnant women identified specific actions that families, friends, and strangers might do to support pregnancies. Participants primarily wanted emotional and instrumental support from family and friends. From strangers, they wanted respect for personal space and common courtesy. Based on these results, the 100 Acts was created for use in the Los Angeles community. 100 Acts encourages and engages active participation from community members in promoting healthy pregnancies. By seeking to increase community-level reproductive social capital, 100 Acts shifts the provision of social support during pregnancy from a high-risk approach to a population approach. 100 Acts also establishes new social norms about how pregnant women are valued, treated and respected.

22 CFR 1104.3 - Prohibited acts.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 2 2010-04-01 2010-04-01 true Prohibited acts. 1104.3 Section 1104.3 Foreign Relations INTERNATIONAL BOUNDARY AND WATER COMMISSION, UNITED STATES AND MEXICO, UNITED STATES SECTION PROTECTION OF ARCHAEOLOGICAL RESOURCES § 1104.3 Prohibited acts. (a) No person may excavate, remove, damage...

40 CFR 255.31 - Integration with other acts.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Integration with other acts. 255.31 Section 255.31 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES... Relationship to Other Programs § 255.31 Integration with other acts. The Governor shall integrate the...

10 CFR 490.603 - Prohibited acts.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 3 2012-01-01 2012-01-01 false Prohibited acts. 490.603 Section 490.603 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ALTERNATIVE FUEL TRANSPORTATION PROGRAM Investigations and Enforcement § 490.603 Prohibited acts. It is unlawful for any person to violate any provision of sections 501, 503(b...

50 CFR 300.156 - Prohibited acts.

Code of Federal Regulations, 2013 CFR

2013-10-01

.... Nationals Fishing in Russian Fisheries § 300.156 Prohibited acts. In addition to the prohibited acts... such vessel: (a) To fish for Russian fishery resources without a valid permit issued by the competent authorities of the Russian Federation. (b) To violate the provisions, conditions, and restrictions of an...

Early and middle adolescents' disclosure to parents about activities in different domains.

PubMed

Smetana, Judith G; Villalobos, Myriam; Tasopoulos-Chan, Marina; Gettman, Denise C; Campione-Barr, Nicole

2009-06-01

Disclosure, disclosure strategies, and justifications for nondisclosure for prudential, peer, multifaceted, and personal acts were assessed using a sorting task with 118 lower-middle class early and middle adolescents (Ms=12.77 and 15.68 years). Adolescents were less involved in prudential than other behaviors, although prudential behavior was greater among middle than early adolescents; adolescents disclosed more about prudential and personal than multifaceted and peer behaviors. Nondisclosure was primarily due to concerns about parental disapproval (for prudential acts), claims that acts were personal or not harmful (for personal acts), and their mixture (for peer and multifaceted acts). When concerned about parental disapproval, older adolescents fully disclosed less (and lied somewhat more) than younger adolescents, whereas adolescents primarily avoided discussing the issue when they viewed acts as personal. Full disclosure was associated with better relationships with parents and less depressed mood; lying was associated with more parental behavioral control over personal issues and poorer relationships with fathers.

10 CFR 52.10 - Attacks and destructive acts.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 2 2012-01-01 2012-01-01 false Attacks and destructive acts. 52.10 Section 52.10 Energy... protection against the effects of— (a) Attacks and destructive acts, including sabotage, directed against the... deployment of weapons incident to U.S. defense activities. ...

10 CFR 52.10 - Attacks and destructive acts.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 2 2014-01-01 2014-01-01 false Attacks and destructive acts. 52.10 Section 52.10 Energy... protection against the effects of— (a) Attacks and destructive acts, including sabotage, directed against the... deployment of weapons incident to U.S. defense activities. ...

Combining Content and Elements of Communication into an Upper-Level Biochemistry Course

ERIC Educational Resources Information Center

Whittington, Carli P.; Pellock, Samuel J.; Cunningham, Rebecca L.; Cox, James R.

2014-01-01

This report describes how a science communication module was incorporated into an advanced biochemistry course. Elements of communication were taught synergistically with biochemistry content in this course in an effort to expose students to a variety of effective oral communication strategies. Students were trained to use these established…

Transcriptional responses in honey bee larvae infected with chalkbrood fungus

USDA-ARS?s Scientific Manuscript database

Diseases and other stress factors working synergistically weaken honey bee health and may play a major role in the losses of bee populations in recent years. Among a large number of bee diseases, chalkbrood has been on the rise. We present here the experimental identification of honey bee genes that...

What Comes before Report Writing? Attending to Clinical Reasoning and Thinking Errors in School Psychology

ERIC Educational Resources Information Center

Wilcox, Gabrielle; Schroeder, Meadow

2015-01-01

Psychoeducational assessment involves collecting, organizing, and interpreting a large amount of data from various sources. Drawing upon psychological and medical literature, we review two main approaches to clinical reasoning (deductive and inductive) and how they synergistically guide diagnostic decision-making. In addition, we discuss how the…

The streptococcal phage SA2 and B30 endolysins act synergistically and kill mastitis causing streptococci in milk

USDA-ARS?s Scientific Manuscript database

Bovine mastitis results in billion dollar losses annually in the United States alone. Among the most relevant causative agents of this disease are members of the genus Streptococcus, particularly the species S. agalactiae (Group B Streptococcus; GBS), S. dysgalactiae (Group C; GCS), and S. uberis....

Concomitant consumption of lycopene and fish oil inhibits tumor growth and progression in a mouse xenograft model of colon cancer

USDA-ARS?s Scientific Manuscript database

Our previous report showed that concomitant supplementation of lycopene and eicosa-pentaenoic acid synergistically inhibited the proliferation of human colon cancer HT-29 cells in vitro. To validate our findings, the present study investigated whether consumption of lycopene and fish oil would help ...

Bowman-Birk inhibitor and genistein among soy compounds that synergistically inhibit nitric oxide and prostaglandin E2 pathways in lipopolysaccharide-induced macrophages

USDA-ARS?s Scientific Manuscript database

Inflammation has an important role in the development of chronic diseases. In this study, we evaluated the anti-inflammatory properties of eight soybean bioactive compounds using lipopolysaccharide-induced RAW 264.7 macrophages. Genistein, daidzein, mix isoflavone glucosides, saponin A group glyco...

Rapid detection method for fusaric acid-producing species of Fusarium by PCR

USDA-ARS?s Scientific Manuscript database

Fusaric acid is a mycotoxin produced by species of the fungus Fusarium and can act synergistically with other Fusarium toxins. In order to develop a specific detection method for fusaric acid-producing fungus, PCR prim¬ers were designed to amplify FUB10, a transcription factor gene in fusaric acid ...

Organizing for Effective Marketing Communications in Higher Education: Restructuring for Your Competitive Edge in Marketing.

ERIC Educational Resources Information Center

Sands, Gene C.; Smith, Rick J.

1999-01-01

Suggestions for restructuring marketing efforts within colleges and universities stress the institution's primary profit center: student recruitment and retention. Techniques such as continuous quality improvement and implementation of a task force concept are recommended as a way of synergistically employing all the institution's assets and…

Considerations in the weathering of wood-plastic composites

Treesearch

Nicole M. Stark

2007-01-01

During weathering, wood-plastic composites (WPCs) can fade and lose stiffness and strength. Weathering variables that induce these changes include exposure to UV light and water. Each variable degrades WPCs independently, but can also act synergistically. Recent efforts have highlighted the need to understand how WPCs weather, and to develop schemes for protection. The...

Fluorescence Spectrometric Determination of Drugs Containing α-Methylene Sulfone/Sulfonamide Functional Groups Using N-Methylnicotinamide Chloride as a Fluorogenic Agent.

PubMed

Elokely, Khaled M; Eldawy, Mohamed A; Elkersh, Mohamed A; El-Moselhy, Tarek F

2011-01-01

A simple spectrofluorometric method has been developed, adapted, and validated for the quantitative estimation of drugs containing α-methylene sulfone/sulfonamide functional groups using N(1)-methylnicotinamide chloride (NMNCl) as fluorogenic agent. The proposed method has been applied successfully to the determination of methyl sulfonyl methane (MSM) (1), tinidazole (2), rofecoxib (3), and nimesulide (4) in pure forms, laboratory-prepared mixtures, pharmaceutical dosage forms, spiked human plasma samples, and in volunteer's blood. The method showed linearity over concentration ranging from 1 to 150 μg/mL, 10 to 1000 ng/mL, 1 to 1800 ng/mL, and 30 to 2100 ng/mL for standard solutions of 1, 2, 3, and 4, respectively, and over concentration ranging from 5 to 150 μg/mL, 10 to 1000 ng/mL, 10 to 1700 ng/mL, and 30 to 2350 ng/mL in spiked human plasma samples of 1, 2, 3, and 4, respectively. The method showed good accuracy, specificity, and precision in both laboratory-prepared mixtures and in spiked human plasma samples. The proposed method is simple, does not need sophisticated instruments, and is suitable for quality control application, bioavailability, and bioequivalency studies. Besides, its detection limits are comparable to other sophisticated chromatographic methods.

10 CFR 52.10 - Attacks and destructive acts.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 2 2013-01-01 2013-01-01 false Attacks and destructive acts. 52.10 Section 52.10 Energy... protection against the effects of— (a) Attacks and destructive acts, including sabotage, directed against the... deployment of weapons incident to U.S. defense activities. ...

Ka-Band Propagation Studies using the ACTS Propagation Terminal and the CSU-CHILL Multiparameter Radar

NASA Technical Reports Server (NTRS)

Bringi, V. N.; Beaver, John

1996-01-01

One of the first experimental communications satellites using Ka-band technology is the NASA Advanced Communications Technology Satellite (ACTS). In September 1993, ACTS was deployed into a geostationary orbit near 100 degrees W longitude by the space shuttle Discovery. The ACTS system supports both communication and propagation experiments at the 20/30 GHz frequency bands. The propagation experiment involves multi-year attenuation measurements along the satellite-Earth slant path.

Surfactant-enhanced disinfection of the human norovirus surrogate, Tulane virus, with organic acids and surfactant

USDA-ARS?s Scientific Manuscript database

Combination treatments of surfactants and phenolic or short-chained organic acids (SCOA) may act synergistically or additively as sanitizers to inactive foodborne viruses and prevent outbreaks. The purpose of this study was to investigate the effect of gallic acid (GA), tannic acid (TA), p-coumaric ...

The Triumphant Triumvirate: Synergistically Realizing the Purposes of a University through a Core Management Course

ERIC Educational Resources Information Center

Kessler, Eric H.

2017-01-01

Core management courses bear a particularly challenging curricular as well as pedagogical burden insofar as they are typically the sole or primary vehicle for integrating management principles with larger university and school objectives. Compounding the challenge is that these very objectives are neither universally clear nor necessarily…

Interaction of visual and vestibular stimulation on spatial coordinates for eye movements in rabbits.

PubMed

Pettorossi, V E; Errico, P; Ferraresi, A; Minciotti, M; Barmack, N H

1998-07-01

Researchers investigated how vestibular and optokinetic signals alter the spatial transformation of the coordinate system that governs the spatial orientation of reflexive eye movements. Also examined were the effects of sensory stimulation when vestibular and optokinetic signals act synergistically and when the two signals are in conflict.

22 CFR 91.1 - Answering inquiries regarding tariff acts and customs regulations.

Code of Federal Regulations, 2010 CFR

2010-04-01

... customs regulations. 91.1 Section 91.1 Foreign Relations DEPARTMENT OF STATE LEGAL AND RELATED SERVICES IMPORT CONTROLS § 91.1 Answering inquiries regarding tariff acts and customs regulations. In replying to inquiries received from exporters, travelers, or other interested parties, concerning tariff acts or customs...

22 CFR 91.1 - Answering inquiries regarding tariff acts and customs regulations.

Code of Federal Regulations, 2013 CFR

2013-04-01

... customs regulations. 91.1 Section 91.1 Foreign Relations DEPARTMENT OF STATE LEGAL AND RELATED SERVICES IMPORT CONTROLS § 91.1 Answering inquiries regarding tariff acts and customs regulations. In replying to inquiries received from exporters, travelers, or other interested parties, concerning tariff acts or customs...

22 CFR 91.1 - Answering inquiries regarding tariff acts and customs regulations.

Code of Federal Regulations, 2014 CFR

2014-04-01

... customs regulations. 91.1 Section 91.1 Foreign Relations DEPARTMENT OF STATE LEGAL AND RELATED SERVICES IMPORT CONTROLS § 91.1 Answering inquiries regarding tariff acts and customs regulations. In replying to inquiries received from exporters, travelers, or other interested parties, concerning tariff acts or customs...

ACTS Battery and Solar Array Assembly On-Orbit Measured Performance

NASA Technical Reports Server (NTRS)

Hilderman, Don R.

2005-01-01

The Advanced Communications Technology Satellite (ACTS) is a NASA experimental communications satellite system designed to demonstrate on-orbit Ka-band communications and switching technologies that will be used by NASA and the commercial sector in the 21st century. The ACTS was launched on September 12, 1993, and has performed over 10 years of successful experimental operations. The purpose of this report is to describe the ACTS power subsystem and the ACTS solar array and battery assemblies located within the power subsystem and then to document on-orbit measured performance from launch to mission end on April 28, 2004. Solar array and battery performance data is presented, and respective conclusions are drawn. The total solar array power available to the spacecraft was measured each year at the same time, and battery voltage performance was measured twice per year at the same times during peak solar eclipse. At the highest spacecraft power demand, the ACTS uses approximately 1113 W of electrical power during the low-burstrate experiment to operate all six satellite subsystems. After 10 years of on-orbit operation, solar array available output power normal to the Sun measured 1508 W, which represents 395 W of excess margin. The ACTS batteries have successfully supported the ACTS experiment program for over 10 years and operated in excess of 900 charge and discharge cycles through 21 eclipse seasons.

28 CFR 501.3 - Prevention of acts of violence and terrorism.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Prevention of acts of violence and terrorism. 501.3 Section 501.3 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF JUSTICE GENERAL MANAGEMENT AND ADMINISTRATION SCOPE OF RULES § 501.3 Prevention of acts of violence and terrorism. (a) Upon...

Suicidal thoughts/acts and clinical correlates in patients with depressive disorders in Asians: results from the REAP-AD study.

PubMed

Park, Seon-Cheol; Lee, Min-Soo; Hahn, Sang Woo; Si, Tian-Mei; Kanba, Shigenobu; Chong, Mian-Yoon; Yoon, Chee Kok; Udomratn, Pichet; Tripathi, Adarsh; Sartorius, Norman; Shinfuku, Naotaka; Maramis, Margarita M; Park, Yong Chon

2016-12-01

Using data from the Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) study, we aimed to present the rates and clinical correlates of suicidal thoughts/acts in patients recruited from a total of 40 centres in 10 Asian countries/areas: China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Singapore, Taiwan, and Thailand. Data from 1122 patients with depressive disorders in the REAP-AD study were used. The ICD-10 was employed to diagnose depressive episodes and recurrent depressive disorder. The presence or absence of suicidal thoughts/acts and profile of other depressive symptoms was established using the National Institute for Health and Clinical Excellence guidelines for depression. Country/area differences in rates of suicidal thoughts/acts were evaluated with the χ2 test. In addition, depressive symptom profiles, other clinical characteristics, and patterns of psychotropic drug prescription in depressed patients with and without suicidal thoughts/acts were compared using analysis of covariance for continuous variables and logistic regression analysis for discrete variables to adjust the effects of covariates. The rates of suicidal thoughts/acts in 10 countries/areas varied from 12.8% in Japan to 36.3% in China. Patients with suicidal thoughts/acts presented more persistent sadness (adjusted odds ratio [aOR]=2.64, p<0.001), loss of interest (aOR=2.33, p<0.001), fatigue (aOR=1.58, p<0.001), insomnia (aOR=1.74, p<0.001), poor concentration (aOR=1.88, p<0.001), low self-confidence (aOR=1.78, p<0.001), poor appetite (aOR=2.27, p<0.001), guilt/self-blame (aOR=3.03, p<0.001), and use of mood stabilisers (aOR=1.79, p<0.001) than those without suicidal thoughts/acts. Suicidal thoughts/acts can indicate greater severity of depression, and are associated with a poorer response to antidepressants and increased burden of illness. Hence, suicidal thoughts/acts can provide a clinical index reflecting the clinical status of depressive disorders in Asians.

ACTS/TOS after release from Shuttle Discovery

NASA Technical Reports Server (NTRS)

1993-01-01

The Advanced Communications Technology Satellite (ACTS) with its Transfer Orbit Stage (TOS) is backdropped over the blue ocean following its release from the Earth-orbiting Space Shuttle Discovery. ACTS/TOS deploy was the first major task performed on the almost ten-day mission.

22 CFR 1104.3 - Prohibited acts.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 22 Foreign Relations 2 2014-04-01 2014-04-01 false Prohibited acts. 1104.3 Section 1104.3 Foreign Relations INTERNATIONAL BOUNDARY AND WATER COMMISSION, UNITED STATES AND MEXICO, UNITED STATES SECTION PROTECTION OF ARCHAEOLOGICAL RESOURCES § 1104.3 Prohibited acts. (a) No person may excavate, remove, damage...

10 CFR 490.603 - Prohibited acts.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 3 2011-01-01 2011-01-01 false Prohibited acts. 490.603 Section 490.603 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ALTERNATIVE FUEL TRANSPORTATION PROGRAM Investigations and Enforcement § 490.603 Prohibited acts. It is unlawful for any person to violate any provision of sections 501, 503(b...

10 CFR 490.603 - Prohibited acts.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 3 2013-01-01 2013-01-01 false Prohibited acts. 490.603 Section 490.603 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ALTERNATIVE FUEL TRANSPORTATION PROGRAM Investigations and Enforcement § 490.603 Prohibited acts. It is unlawful for any person to violate any provision of sections 501, 503(b...

50 CFR 300.156 - Prohibited acts.

Code of Federal Regulations, 2012 CFR

2012-10-01

.... Nationals Fishing in Russian Fisheries § 300.156 Prohibited acts. In addition to the prohibited acts... such vessel: (a) To fish for Russian fishery resources without a valid permit issued by the competent authorities of the Russian Federation. (b) To violate the provisions, conditions, and restrictions of an...

DCSS Semi-Annual Tire Conference. CATL Update

DTIC Science & Technology

2009-03-25

1 a/s, AP, PS X1.3.41 ACTS-CATL-T1-1/98-053 Durango All Terrain...1 a/s, A/t, AP, PS X1.3.109 ACTS-CATL-T1-1/98-053 Durango Radial XTR 1...a/s, a/t, AP, PS X1.3.110 ACTS-CATL-T1-1/98-053 Durango M/T 1 a/t

22 CFR 92.12 - Necessity for certification of notarial acts.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Necessity for certification of notarial acts. 92.12 Section 92.12 Foreign Relations DEPARTMENT OF STATE LEGAL AND RELATED SERVICES NOTARIAL AND... certificate; two or more distinct notarial acts should not be attested to by one certificate. [22 FR 10858...

25 CFR 101.8 - Environmental and Flood Disaster Acts.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false Environmental and Flood Disaster Acts. 101.8 Section 101... FROM THE REVOLVING LOAN FUND § 101.8 Environmental and Flood Disaster Acts. Loans will not be approved until there is assurance of compliance with any applicable provisions of the Flood Disaster Protection...

29 CFR 458.27 - Prohibited acts relating to subordinate body under trusteeship.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 2 2010-07-01 2010-07-01 false Prohibited acts relating to subordinate body under... of Conduct Trusteeships § 458.27 Prohibited acts relating to subordinate body under trusteeship. During any period when a subordinate body of a labor organization is in trusteeship, (a) the votes of...

28 CFR 501.3 - Prevention of acts of violence and terrorism.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Prevention of acts of violence and terrorism. 501.3 Section 501.3 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF JUSTICE GENERAL MANAGEMENT AND ADMINISTRATION SCOPE OF RULES § 501.3 Prevention of acts of violence and terrorism. (a) Upon...

28 CFR 501.3 - Prevention of acts of violence and terrorism.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Prevention of acts of violence and terrorism. 501.3 Section 501.3 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF JUSTICE GENERAL MANAGEMENT AND ADMINISTRATION SCOPE OF RULES § 501.3 Prevention of acts of violence and terrorism. (a) Upon...

Proceedings of the Twentieth NASA Propagation Experimenters Meeting (NAPEX XX) and the Advanced Communications Technology Satellite (ACTS) Propagation Studies Miniworkshop

NASA Technical Reports Server (NTRS)

Golshan, Nassar (Editor)

1996-01-01

The NASA Propagation Experimenters (NAPEX) Meeting and associated Advanced Communications Technology Satellite (ACTS) Propagation Studies Miniworkshop convene yearly to discuss studies supported by the NASA Propagation Program. Representatives from the satellite communications (satcom)industry, academia, and government with an interest in space-ground radio wave propagation have peer discussion of work in progress, disseminate propagation results, and interact with the satcom industry. NAPEX XX, in Fairbanks, Alaska, June 4-5, 1996, had three sessions: (1) "ACTS Propagation Study: Background, Objectives, and Outcomes," covered results from thirteen station-years of Ka-band experiments; (2) "Propagation Studies for Mobile and Personal Satellite Applications," provided the latest developments in measurement, modeling, and dissemination of propagation phenomena of interest to the mobile, personal, and aeronautical satcom industry; and (3)"Propagation Research Topics," covered a range of topics including space/ground optical propagation experiments, propagation databases, the NASA Propagation Web Site, and revision plans for the NASA propagation effects handbooks. The ACTS Miniworkshop, June 6, 1996, covered ACTS status, engineering support for ACTS propagation terminals, and the ACTS Propagation Data Center. A plenary session made specific recommendations for the future direction of the program.

Enzymatic hydrolysis of oil palm empty fruits bunch fiber using Celluclast® and Accellerase® BG for sugar production

NASA Astrophysics Data System (ADS)

Salleh, Noor Shafryna; Murad, Abdul Munir Abdul

2016-11-01

In this work, the ability of commercial Trichoderma reesei cellulases preparation, Celluclast® or in combination with Accellerase®BG β-glucosidase to hydrolyse pretreated oil palm empty fruit bunch (OPEFB) was evaluated. Celluclast® alone hydrolyzed OPEFB to produce 2.41±0.44 mg glucose per gram OPEFB. However, the production of glucose was significantly improved with supplementation of Accellerase®BG (8.12±0.93 mg/g). This result suggested that the endoglucanases and exoglucanases in Celluclast® and β-glucosidase in Accellerase®BG able to work synergistically to increase the production of glucose from OPEFB. In addition, the production of xylose was also improved by 30% when the enzyme mixture was used. The result suggested that the mixture of Celluclast® with Accellerase®BG work synergistically to improve the production of sugars by removing the inhibition by cellobiose for complete cellulose hydrolysis. The production of glucose and xylose from OPEFB wastes showed the potential of this biomass as the source of renewable energy and fine chemicals production in Malaysia.

Ethacrynic acid improves the antitumor effects of irreversible epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer

PubMed Central

Hu, YunLong; Chen, TingTing; Peng, BoYa; Gao, NingNing; Jin, ZhenChao; Jia, TieLiu; Zhang, Na; Wang, ZhuLin; Jin, GuangYi

2016-01-01

Prolonged treatment of breast cancer with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) often results in acquired resistance and a narrow therapeutic index. One strategy to improve the therapeutic effects of EGFR TKIs is to combine them with drugs used for other clinical indications. Ethacrynic acid (EA) is an FDA approved drug that may have antitumor effects and may enhance the cytotoxicity of chemotherapeutic agents by binding to glutathione and inhibiting WNT signaling. While the α,β-unsaturated-keto structure of EA is similar to that of irreversible TKIs, the mechanism of action of EA when combined with irreversible EGFR TKIs in breast cancer remains unknown. We therefore investigated the combination of irreversible EGFR TKIs and EA. We found that irreversible EGFR TKIs and EA synergistically inhibit breast cancer both in vitro and in vivo. The combination of EGFR TKIs and EA induces necrosis and cell cycle arrest and represses WNT/β-catenin signaling as well as MAPK-ERK1/2 signaling. We conclude that EA synergistically enhances the antitumor effects of irreversible EGFR TKIs in breast cancer. PMID:27487128

Induction of MAPK- and ROS-dependent autophagy and apoptosis in gastric carcinoma by combination of romidepsin and bortezomib.

PubMed

Hui, Kwai Fung; Yeung, Po Ling; Chiang, Alan K S

2016-01-26

Proteasome inhibitors and histone deacetylase (HDAC) inhibitors can synergistically induce apoptotic cell death in certain cancer cell types but their combinatorial effect on the induction of autophagy remains unknown. Here, we investigated the combinatorial effects of a proteasome inhibitor, bortezomib, and an HDAC inhibitor, romidepsin, on the induction of apoptotic and autophagic cell death in gastric carcinoma (GC) cells. Isobologram analysis showed that low nanomolar concentrations of bortezomib/romidepsin could synergistically induce killing of GC cells. The synergistic killing was due to the summative effect of caspase-dependent intrinsic apoptosis and caspase-independent autophagy. The autophagic cell death was dependent on the activation of MAPK family members (ERK1/2 and JNK), and generation of reactive oxygen species (ROS), but was independent of Epstein-Barr virus infection. In vivo, bortezomib/romidepsin also significantly induced apoptosis and autophagy in GC xenografts in nude mice. This is the first report demonstrating the potent effect of combination of HDAC and proteasome inhibitors on the induction of MAPK- and ROS-dependent autophagy in addition to caspase-dependent apoptosis in a cancer type.

A Synergistic Antiobesity Effect by a Combination of Capsinoids and Cold Temperature Through Promoting Beige Adipocyte Biogenesis

PubMed Central

Ohyama, Kana; Nogusa, Yoshihito; Shinoda, Kosaku; Suzuki, Katsuya

2016-01-01

Beige adipocytes emerge postnatally within the white adipose tissue in response to certain environmental cues, such as chronic cold exposure. Because of its highly recruitable nature and relevance to adult humans, beige adipocytes have gained much attention as an attractive cellular target for antiobesity therapy. However, molecular circuits that preferentially promote beige adipocyte biogenesis remain poorly understood. We report that a combination of mild cold exposure at 17°C and capsinoids, a nonpungent analog of capsaicin, synergistically and preferentially promotes beige adipocyte biogenesis and ameliorates diet-induced obesity. Gain- and loss-of-function studies show that the combination of capsinoids and cold exposure synergistically promotes beige adipocyte development through the β2-adrenoceptor signaling pathway. This synergistic effect on beige adipocyte biogenesis occurs through an increased half-life of PRDM16, a dominant transcriptional regulator of brown/beige adipocyte development. We document a previously unappreciated molecular circuit that controls beige adipocyte biogenesis and suggest a plausible approach to increase whole-body energy expenditure by combining dietary components and environmental cues. PMID:26936964

10 CFR 490.603 - Prohibited acts.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 3 2010-01-01 2010-01-01 false Prohibited acts. 490.603 Section 490.603 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ALTERNATIVE FUEL TRANSPORTATION PROGRAM Investigations and Enforcement § 490.603 Prohibited acts. It is unlawful for any person to violate any provision of sections 501, 503(b...

10 CFR 490.603 - Prohibited acts.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 3 2014-01-01 2014-01-01 false Prohibited acts. 490.603 Section 490.603 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ALTERNATIVE FUEL TRANSPORTATION PROGRAM Investigations and Enforcement § 490.603 Prohibited acts. It is unlawful for any person to violate any provision of sections 501, 503(b...

50 CFR 300.156 - Prohibited acts.

Code of Federal Regulations, 2010 CFR

2010-10-01

.... Nationals Fishing in Russian Fisheries § 300.156 Prohibited acts. In addition to the prohibited acts... such vessel: (a) To fish for Russian fishery resources without a valid permit issued by the competent authorities of the Russian Federation. (b) To violate the provisions, conditions, and restrictions of an...

50 CFR 300.156 - Prohibited acts.

Code of Federal Regulations, 2011 CFR

2011-10-01

.... Nationals Fishing in Russian Fisheries § 300.156 Prohibited acts. In addition to the prohibited acts... such vessel: (a) To fish for Russian fishery resources without a valid permit issued by the competent authorities of the Russian Federation. (b) To violate the provisions, conditions, and restrictions of an...

50 CFR 300.156 - Prohibited acts.

Code of Federal Regulations, 2014 CFR

2014-10-01

.... Nationals Fishing in Russian Fisheries § 300.156 Prohibited acts. In addition to the prohibited acts... such vessel: (a) To fish for Russian fishery resources without a valid permit issued by the competent authorities of the Russian Federation. (b) To violate the provisions, conditions, and restrictions of an...

22 CFR 91.1 - Answering inquiries regarding tariff acts and customs regulations.

Code of Federal Regulations, 2012 CFR

2012-04-01

... customs regulations. 91.1 Section 91.1 Foreign Relations DEPARTMENT OF STATE LEGAL AND RELATED SERVICES IMPORT CONTROLS § 91.1 Answering inquiries regarding tariff acts and customs regulations. In replying to inquiries received from exporters, travelers, or other interested parties, concerning tariff acts or customs...

Polymer-attached zanamivir inhibits synergistically both early and late stages of influenza virus infection

PubMed Central

Lee, Chia Min; Weight, Alisha K.; Haldar, Jayanta; Wang, Ling; Klibanov, Alexander M.; Chen, Jianzhu

2012-01-01

Covalently conjugating multiple copies of the drug zanamivir (ZA; the active ingredient in Relenza) via a flexible linker to poly-l-glutamine (PGN) enhances the anti-influenza virus activity by orders of magnitude. In this study, we investigated the mechanisms of this phenomenon. Like ZA itself, the PGN-attached drug (PGN-ZA) binds specifically to viral neuraminidase and inhibits both its enzymatic activity and the release of newly synthesized virions from infected cells. Unlike monomeric ZA, however, PGN-ZA also synergistically inhibits early stages of influenza virus infection, thus contributing to the markedly increased antiviral potency. This inhibition is not caused by a direct virucidal effect, aggregation of viruses, or inhibition of viral attachment to target cells and the subsequent endocytosis; rather, it is a result of interference with intracellular trafficking of the endocytosed viruses and the subsequent virus-endosome fusion. These findings both rationalize the great anti-influenza potency of PGN-ZA and reveal that attaching ZA to a polymeric chain confers a unique mechanism of antiviral action potentially useful for minimizing drug resistance. PMID:23185023

Synergistic growth inhibition in HL-60 cells by the combination of acyclic retinoid and vitamin K2.

PubMed

Kitagawa, Junichi; Hara, Takeshi; Tsurumi, Hisashi; Ninomiya, Soranobu; Ogawa, Kengo; Adachi, Seiji; Kanemura, Nobuhiro; Kasahara, Senji; Shimizu, Masahito; Moriwaki, Hisataka

2011-05-01

The aim of this study was to assess the effects of acyclic retinoid (ACR) and vitamin K(2) (VK(2)) in HL-60 cells. We used HL-60 cells, and the Trypan Blue dye exclusion method was used for cell proliferation assays. For detection of apoptosis, the Annexin V-binding capacity of treated cells was examined by flow cytometry. To evaluate the cell cycle, we used a FITC BrdU Flow KIT and flow cytometry. Total extracted and equivalent amounts of protein were examined by Western blotting using specific antibodies. ACR and VK(2) dose dependently inhibited the proliferation of HL-60 cells. These two agents in combination synergistically inhibited cell growth and induced apoptosis. VK(2) inhibited activation of the Ras/MAPK signaling pathway, and ACR plus VK(2) cooperatively inhibited phosphorylation of RXRα and the growth of HL-60 cells. Moreover, ACR and VK(2) induced increases in G0/G1 phase HL-60 cells, alone and synergistically in combination. The synergistic effects of ACR and VK(2) on HL-60 cells may provide a novel strategy for treating leukemia.

XMAP215 is a microtubule nucleation factor that functions synergistically with the γ-tubulin ring complex.

PubMed

Thawani, Akanksha; Kadzik, Rachel S; Petry, Sabine

2018-05-01

How microtubules (MTs) are generated in the cell is a major question in understanding how the cytoskeleton is assembled. For several decades, γ-tubulin has been accepted as the universal MT nucleator of the cell. Although there is evidence that γ-tubulin complexes are not the sole MT nucleators, identification of other nucleation factors has proven difficult. Here, we report that the well-characterized MT polymerase XMAP215 (chTOG/Msps/Stu2p/Alp14/Dis1 homologue) is essential for MT nucleation in Xenopus egg extracts. The concentration of XMAP215 determines the extent of MT nucleation. Even though XMAP215 and the γ-tubulin ring complex (γ-TuRC) possess minimal nucleation activity individually, together, these factors synergistically stimulate MT nucleation in vitro. The amino-terminal TOG domains 1-5 of XMAP215 bind to αβ-tubulin and promote MT polymerization, whereas the conserved carboxy terminus is required for efficient MT nucleation and directly binds to γ-tubulin. In summary, XMAP215 and γ-TuRC together function as the principal nucleation module that generates MTs in cells.

Synergistic anti-inflammatory effects of Nobiletin and Sulforaphane in lipopolysaccharide-stimulated RAW 264.7 cells

PubMed Central

Guo, Shanshan; Qiu, Peiju; Xu, Guang; Wu, Xian; Dong, Ping; Yang, Guanpin; Zheng, Jinkai; McClements, David Julian; Xiao, Hang

2012-01-01

Inflammation plays important roles in initiation and progress of many diseases including cancers in multiple organ sites. Herein, we investigated the anti-inflammatory effects of two dietary compounds, nobiletin (NBN) and sulforaphane (SFN) in combination. Non-cytotoxic concentrations of NBN, SFN, and their combinations were studied in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. The results showed that combined NBN and SFN treatments produced much stronger inhibitory effects on the production of nitric oxide (NO) than NBN or SFN alone at higher concentrations. These enhanced inhibitory effects were synergistic based on the isobologram analysis. Western blot analysis showed that combined NBN and SFN treatments synergistically decreased iNOS and COX-2 protein expression levels and induced heme oxygenase-1 (HO-1) protein expression. Real-time PCR analysis indicated that low doses of NBN and SFN in combination significantly suppressed LPS-induced upregulation of IL-1 mRNA levels, and synergistically increased HO-1 mRNA levels. Overall our results demonstrated that NBN and SFN in combination produced synergistic effects in inhibiting LPS-induced inflammation in RAW 264.7 cells. PMID:22335189

Advanced Communications Technology Satellite (ACTS) Experiments Program - A market-driven approach to government/industry cooperation

NASA Astrophysics Data System (ADS)

Olmstead, Dean A.; Schertler, Ronald R.; Randall, Laura A.

1992-03-01

The Advanced Communications Technology Satellite (ACTS), now under development and scheduled for launch in early 1993, is the current focus of NASA's commercial communications satellite program. The full power of the key technologies on ACTS can only be realized if industry assumes an active role in the conduct of experiments and demonstrations. This paper discusses the current market-driven rationale behind the ACTS Experiments Program activities aimed at getting industry involved - a rationale that addresses industry concerns and responds to industry inputs.

Proceedings of the Fourteenth NASA Propagation Experimenters Meeting (NAPEX 14) and the Advanced Communications Technology Satellite (ACTS) Propagation Studies Miniworkshop

NASA Technical Reports Server (NTRS)

Davarian, Faramaz (Editor)

1990-01-01

The NASA Propagation Experimenters Meeting (NAPEX), supported by the NASA Propagation Program, is convened annually to discuss studies made on radio wave propagation by investigators from domestic and international organizations. NAPEX XIV was held on May 11, 1990, at the Balcones Research Centers, University of Texas, Austin, Texas. The meeting was organized into two technical sessions: Satellite (ACTS) and the Olympus Spacecraft, while the second focused on the fixed and mobile satellite propagation studies and experiments. Following NAPEX XIV, the ACTS Miniworkshop was held at the Hotel Driskill, Austin, Texas, on May 12, 1990, to review ACTS propagation activities since the First ACTS Propagation Studies Workshop was held in Santa Monica, California, on November 28 and 29, 1989.

Ethacrynic acid improves the antitumor effects of irreversible epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer.

PubMed

Liu, Bing; Huang, XinPing; Hu, YunLong; Chen, TingTing; Peng, BoYa; Gao, NingNing; Jin, ZhenChao; Jia, TieLiu; Zhang, Na; Wang, ZhuLin; Jin, GuangYi

2016-09-06

Prolonged treatment of breast cancer with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) often results in acquired resistance and a narrow therapeutic index. One strategy to improve the therapeutic effects of EGFR TKIs is to combine them with drugs used for other clinical indications. Ethacrynic acid (EA) is an FDA approved drug that may have antitumor effects and may enhance the cytotoxicity of chemotherapeutic agents by binding to glutathione and inhibiting WNT signaling. While the α,β-unsaturated-keto structure of EA is similar to that of irreversible TKIs, the mechanism of action of EA when combined with irreversible EGFR TKIs in breast cancer remains unknown. We therefore investigated the combination of irreversible EGFR TKIs and EA. We found that irreversible EGFR TKIs and EA synergistically inhibit breast cancer both in vitro and in vivo. The combination of EGFR TKIs and EA induces necrosis and cell cycle arrest and represses WNT/β-catenin signaling as well as MAPK-ERK1/2 signaling. We conclude that EA synergistically enhances the antitumor effects of irreversible EGFR TKIs in breast cancer.

Impact of Phospholipids and Tocopherols on the Oxidative Stability of Soybean Oil-in-Water Emulsions.

PubMed

Samdani, Gautam K; McClements, D Julian; Decker, Eric A

2018-04-18

Phospholipids have been shown to act synergistically with tocopherols and delay lipid oxidation in bulk oil. The synergistic activity between phospholipids and tocopherols is due to the ability of amino-group-containing phospholipids (e.g., phosphatidylethanolamine (PE) and phosphatidylserine (PS)) to convert oxidized tocopherol back into tocopherols. This study shows the effect of PE and PS on the antioxidant activity of different tocopherol homologues in oil-in-water emulsions. Effect of emulsifier type on the interaction between tocopherols and phospholipids was also studied. δ-Tocopherol and PE exhibited greater antioxidant activity as compared to α-tocopherol and PE. PS displayed 1.5-3 times greater synergism than PE with Tween 20 as emulsifier whereas both PE and PS had a similar antioxidant activity in the presence of α-tocopherol when bovine serum albumin was used as the emulsifier. This study is the first to show that PE and PS can act synergistically with tocopherols to inhibit lipid oxidation in oil-in-water emulsions and can present a new clean label antioxidant strategy for food emulsions.

Enhancing the Antibiotic Antibacterial Effect by Sub Lethal Tellurite Concentrations: Tellurite and Cefotaxime Act Synergistically in Escherichia coli

PubMed Central

Molina-Quiroz, Roberto C.; Muñoz-Villagrán, Claudia M.; de la Torre, Erick; Tantaleán, Juan C.; Vásquez, Claudio C.; Pérez-Donoso, José M.

2012-01-01

The emergence of antibiotic-resistant pathogenic bacteria during the last decades has become a public health concern worldwide. Aiming to explore new alternatives to treat antibiotic-resistant bacteria and given that the tellurium oxyanion tellurite is highly toxic for most microorganisms, we evaluated the ability of sub lethal tellurite concentrations to strengthen the effect of several antibiotics. Tellurite, at nM or µM concentrations, increased importantly the toxicity of defined antibacterials. This was observed with both Gram negative and Gram positive bacteria, irrespective of the antibiotic or tellurite tolerance of the particular microorganism. The tellurite-mediated antibiotic-potentiating effect occurs in laboratory and clinical, uropathogenic Escherichia coli, especially with antibiotics disturbing the cell wall (ampicillin, cefotaxime) or protein synthesis (tetracycline, chloramphenicol, gentamicin). In particular, the effect of tellurite on the activity of the clinically-relevant, third-generation cephalosporin (cefotaxime), was evaluated. Cell viability assays showed that tellurite and cefotaxime act synergistically against E. coli. In conclusion, using tellurite like an adjuvant could be of great help to cope with several multi-resistant pathogens. PMID:22536386

Gum arabic and Fe²⁺ synergistically improve the heat and acid stability of norbixin at pH 3.0-5.0.

PubMed

Guan, Yongguang; Zhong, Qixin

2014-12-31

Thermal and acid stabilities of norbixin are challenges for its application as a food colorant. In this work, gum arabic and Fe(2+) were studied for the possibility to improve the thermal and acid stabilities of norbixin. Norbixin was dissolved at 0.004% w/v in deionized water with and without 0.2% w/v gum arabic and/or 0.15 mM ferrous chloride, adjusted to pH 3.0-5.0, and heated at 90 or 126 °C for 30 min. Before heating, norbixin precipitated at pH 3.0-4.0, which was prevented by gum arabic. The thermal stability of norbixin was improved by the combination of gum arabic and Fe(2+). Fluorescence analyses indicated the complex formation between norbixin and gum arabic with and without Fe(2+). Particle size and atomic force microscopy results suggested Fe(2+) and gum arabic synergistically prevented the aggregation of norbixin at acidic pH and during heating. It was hypothesized that the core of gum arabic-norbixin complexes was strengthened by Fe(2+) to enable the synergy.

Induction of MAPK- and ROS-dependent autophagy and apoptosis in gastric carcinoma by combination of romidepsin and bortezomib

PubMed Central

Hui, Kwai Fung; Yeung, Po Ling; Chiang, Alan K.S.

2016-01-01

Proteasome inhibitors and histone deacetylase (HDAC) inhibitors can synergistically induce apoptotic cell death in certain cancer cell types but their combinatorial effect on the induction of autophagy remains unknown. Here, we investigated the combinatorial effects of a proteasome inhibitor, bortezomib, and an HDAC inhibitor, romidepsin, on the induction of apoptotic and autophagic cell death in gastric carcinoma (GC) cells. Isobologram analysis showed that low nanomolar concentrations of bortezomib/romidepsin could synergistically induce killing of GC cells. The synergistic killing was due to the summative effect of caspase-dependent intrinsic apoptosis and caspase-independent autophagy. The autophagic cell death was dependent on the activation of MAPK family members (ERK1/2 and JNK), and generation of reactive oxygen species (ROS), but was independent of Epstein-Barr virus infection. In vivo, bortezomib/romidepsin also significantly induced apoptosis and autophagy in GC xenografts in nude mice. This is the first report demonstrating the potent effect of combination of HDAC and proteasome inhibitors on the induction of MAPK- and ROS-dependent autophagy in addition to caspase-dependent apoptosis in a cancer type. PMID:26683357

Combination of fluvastatin and losartan relieves atherosclerosis and macrophage infiltration in atherosclerotic plaques in rabbits

PubMed Central

Yang, Ya-pei; Dong, Qiu-li; Zhang, Xu-hong; Zhang, Yue-hui; Zhu, Li; Li, Shu-ying; Liu, Zhong-zhi; Xu, Hui; Wang, Nan; Jiang, Hong; Liu, Chun-xi; Liu, Xian-xi; Dong, Bo

2011-01-01

Aim: To investigate whether the combination of fluvastatin and losartan synergistically relieve atherosclerosis and plaque inflammation induced by a high-cholesterol diet in rabbits. Methods: Atherosclerosis was induced with a high-cholesterol diet for 3 months in 36 New Zealand white rabbits. The animals were randomly divided into model group, fluvastatin (10 mg·kg-1·d-1) group, losartan (25 mg·kg-1·d-1) group, and fluvastatin plus losartan group. After the 16-week treatments, the blood samples the animals were collected, and the thoracic aortas were examined immunohistochemically. The mRNA and protein expression levels of monocyte chemotactic protein-1 (MCP-1) were measured using RT-PCR and Western blot. Results: Compared to the treatment with losartan or fluvastatin alone, the combined treatment did not produce higher efficacy in reduction of blood cholesterol level. However, the combination did synergistically decrease the intimal and media thickness of thoracic aortas with significantly reduced macrophage infiltration and MCP-1 expression in the plaques. Conclusion: The combined treatment with losartan and fluvastatin significantly inhibited atherosclerotic progress and reduced inflammation associated with atherosclerotic plaques. PMID:21909126

Analysis of Major Genome Loci Underlying Artemisinin Resistance and pfmdr1 Copy Number in pre- and post-ACTs in Western Kenya

PubMed Central

Ngalah, Bidii S.; Ingasia, Luiser A.; Cheruiyot, Agnes C.; Chebon, Lorna J.; Juma, Dennis W.; Muiruri, Peninah; Onyango, Irene; Ogony, Jack; Yeda, Redemptah A.; Cheruiyot, Jelagat; Mbuba, Emmanuel; Mwangoka, Grace; Achieng, Angela O.; Ng'ang'a, Zipporah; Andagalu, Ben; Akala, Hoseah M.; Kamau, Edwin

2015-01-01

Genetic analysis of molecular markers is critical in tracking the emergence and/or spread of artemisinin resistant parasites. Clinical isolates collected in western Kenya pre- and post- introduction of artemisinin combination therapies (ACTs) were genotyped at SNP positions in regions of strong selection signatures on chromosome 13 and 14, as described in Southeast Asia (SEA). Twenty five SNPs were genotyped using Sequenom MassArray and pfmdr1 gene copy number by real-time PCR. Parasite clearance half-life and in vitro drug sensitivity testing were performed using standard methods. One hundred twenty nine isolates were successfully analyzed. Fifteen SNPs were present in pre-ACTs isolates and six in post-ACTs. None of the SNPs showed association with parasite clearance half-life. Post-ACTs parasites had significantly higher pfmdr1 copy number compared to pre-ACTs. Seven of eight parasites with multiple pfmdr1 were post-ACTs. When in vitro IC50s were compared for parasites with single vs. multiple gene copies, only amodiaquine and piperaquine reached statistical significance. Data showed SNPs on chromosome 13 and 14 had different frequency and trend in western Kenya parasites compared SEA. Increase in pfmdr1 gene copy is consistent with recent studies in African parasites. Data suggests genetic signature of artemisinin resistance in Africa might be different from SEA. PMID:25655315

10 CFR 50.13 - Attacks and destructive acts by enemies of the United States; and defense activities.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 1 2012-01-01 2012-01-01 false Attacks and destructive acts by enemies of the United States; and defense activities. 50.13 Section 50.13 Energy NUCLEAR REGULATORY COMMISSION DOMESTIC... the effects of (a) attacks and destructive acts, including sabotage, directed against the facility by...

A Data-Driven Conceptualization of Teacher Evaluation

ERIC Educational Resources Information Center

Namaghi, Seyyed Ali Ostovar

2010-01-01

Research perspectives on teacher evaluation present evaluators with a set of possible acts. Local evaluation systems, on the other hand, specify a permissible set of acts from the total universe. The acts specified within a given locality act as conditions for teacher action. Using the sampling and analytical procedures of grounded theory, this…

43 CFR 2522.1 - General acts authorizing extensions of time.

Code of Federal Regulations, 2012 CFR

2012-10-01

...) BUREAU OF LAND MANAGEMENT, DEPARTMENT OF THE INTERIOR LAND RESOURCE MANAGEMENT (2000) DESERT-LAND ENTRIES... of time for the submission of final proof by a desert-land claimant. Said Acts are the following... making desert-land proofs were authorized by the Acts of June 16, 1933 (48 Stat. 274; 43 U.S.C. 256a...

43 CFR 2522.1 - General acts authorizing extensions of time.

Code of Federal Regulations, 2014 CFR

2014-10-01

...) BUREAU OF LAND MANAGEMENT, DEPARTMENT OF THE INTERIOR LAND RESOURCE MANAGEMENT (2000) DESERT-LAND ENTRIES... of time for the submission of final proof by a desert-land claimant. Said Acts are the following... making desert-land proofs were authorized by the Acts of June 16, 1933 (48 Stat. 274; 43 U.S.C. 256a...

22 CFR 91.1 - Answering inquiries regarding tariff acts and customs regulations.

Code of Federal Regulations, 2011 CFR

2011-04-01

... customs regulations. 91.1 Section 91.1 Foreign Relations DEPARTMENT OF STATE LEGAL AND RELATED SERVICES IMPORT CONTROLS § 91.1 Answering inquiries regarding tariff acts and customs regulations. In replying to inquiries received from exporters, travelers, or other interested parties, concerning tariff acts or customs...

29 CFR 458.27 - Prohibited acts relating to subordinate body under trusteeship.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 29 Labor 2 2011-07-01 2011-07-01 false Prohibited acts relating to subordinate body under... of Conduct Trusteeships § 458.27 Prohibited acts relating to subordinate body under trusteeship. During any period when a subordinate body of a labor organization is in trusteeship, (a) the votes of...

Analogical acts as conceptual strategies in science, engineering and the humanities

NASA Technical Reports Server (NTRS)

Winkler, V. M.

1981-01-01

The composing models which operate by means of analogy are identified. The importance of analogical acts in the prewriting stage of the composing process is discussed. The relations between analogical acts and concept formation are explored. A basic correspondence between the analogical thinking employed in successful learning and analogical thinking as a composing strategy is discussed. Teaching analogical acts as conceptual strategies for exploring problems and generating the form and content of discourse is presented in support of the contention that writing is a unique mode of learning.

12 CFR 226.34 - Prohibited acts or practices in connection with credit subject to § 226.32.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 3 2010-01-01 2010-01-01 false Prohibited acts or practices in connection with... Certain Home Mortgage Transactions § 226.34 Prohibited acts or practices in connection with credit subject... consumer's current and reasonably expected income, employment, assets other than the collateral, current...

1 CFR 3.3 - Reproduction and certification of copies of acts and documents.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 1 General Provisions 1 2011-01-01 2011-01-01 false Reproduction and certification of copies of acts and documents. 3.3 Section 3.3 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER GENERAL SERVICES TO THE PUBLIC § 3.3 Reproduction and certification of copies of acts and documents. The...

Curses in Acts: Hearing the Apostles’ Words of Judgment Alongside ‘Magical’ Spell Texts

PubMed Central

Kent, Benedict H. M.

2017-01-01

Scholars of Luke–Acts have struggled to define the apostles’ proclamations of judgment on those who threatened the early Christian community. Ananias and Sapphira (Acts 4.32–5.11), Simon magus (8.4-25) and Bar-Jesus (13.4-12) all fall victim to the apostles’ words of power, yet scholars have typically shied away from categorizing their speeches as curses. Close analysis of the structure, style, phonaesthetic and dramatic aspects of the Greek texts suggests, however, that Luke indeed intends the apostles’ speeches to be heard as curses whilst simultaneously presenting them as legitimate acts of power. A comparison with Greek and Coptic ‘magical’ texts helps to place the curses of Acts in the context of cursing traditions in the wider ancient Mediterranean world. PMID:29278250

Smallest Coins of Marital Happiness.

ERIC Educational Resources Information Center

Kalyan-Masih, V.; And Others

People tend to have such lofty conceptions of love and marital happiness that little day-to-day simple acts of kindness are seldom considered. This study investigated specific, repetitive, small daily acts that strengthen marriage, and little acts that disturb a stable relationship. Participants (N=57) were individuals who had been happily married…

28 CFR 501.3 - Prevention of acts of violence and terrorism.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 28 Judicial Administration 2 2011-07-01 2011-07-01 false Prevention of acts of violence and terrorism. 501.3 Section 501.3 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF JUSTICE GENERAL MANAGEMENT AND ADMINISTRATION SCOPE OF RULES § 501.3 Prevention of acts of violence and terrorism. (a) Upon...

28 CFR 501.3 - Prevention of acts of violence and terrorism.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Prevention of acts of violence and terrorism. 501.3 Section 501.3 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF JUSTICE GENERAL MANAGEMENT AND ADMINISTRATION SCOPE OF RULES § 501.3 Prevention of acts of violence and terrorism. (a) Upon...

Intracellular trehalose and sorbitol synergistically promoting cell viability of a biocontrol yeast Pichia anomala for aflatoxin reduction

USDA-ARS?s Scientific Manuscript database

Pichia anomala WRL-076 was discovered by a visual screening bioassay for its antagonism against Aspergillus flavus. The yeast was shown to significantly inhibit aflatoxin production and the growth of A. flavus. P. anomala is a potential biocontrol agent for reduction of mycotoxin in the food chain...

Mixtures of wine, essential oils, and plant polyphenolics do not act synergistically against Escherichia coli O157 and Salmonella enterica

USDA-ARS?s Scientific Manuscript database

Red wine or fortified red wine formulations containing some various essential oils from oregano or thyme or their pure active components, and a mixture of plant extract powders from apple skin, green tea, and olive, were evaluated for inhibitory activity against the foodborne pathogens Escherichia c...

Bacterial associations with decaying wood : a review

Treesearch

C. A. Clausen

1996-01-01

Wood-inhabiting bacteria are associated with wood decay and may have an indirect influence on the decay process. Bacteria are able to affect wood permeability, attack wood structure, or work synergistically with other bacteria and soft-rot fungi to predispose wood to fungal attack. Bacteria that can inhabit chemically treated wood are recognized. The natural ability of...

Microbial networking in cancer: when two toxins collide.

PubMed

Tomkovich, Sarah; Jobin, Christian

2018-05-01

A recent study by Dejea et al. has demonstrated that two enterotoxigenic bacteria frequently associated with sporadic colorectal cancer, Bacteroides fragilis and pks+ Escherichia coli, are found together in biofilms on tissue from patients with familial adenomatous polyposis. In preclinical mouse models, these two bacteria and their corresponding toxins work synergistically to promote colon cancer.

Dissolved organic matter and aluminum oxide nanoparticles synergistically cause cellular responses in freshwater microalgae.

PubMed

Ye, Nan; Wang, Zhuang; Wang, Se; Fang, Hao; Wang, Degao

2018-06-07

This study investigated the impact of dissolved organic matters (DOM) on the ecological toxicity of aluminum oxide nanoparticles (Al 2 O 3 NPs) at a relatively low exposure concentration (1 mg L -1 ). The unicellular green alga Scenedesmus obliquus was exposed to Al 2 O 3 NP suspensions in the presence of DOM (fulvic acid) at various concentrations (1, 10, and 40 mg L -1 ). The results show that the presence of DOM elevated the growth inhibition toxicity of Al 2 O 3 NPs towards S. obliquus in a dose-dependent manner. Moreover, the combination of DOM at 40 mg L -1 and Al 2 O 3 NPs resulted in a synergistic effect. The relative contribution of Al-ions released from Al 2 O 3 NPs to toxicity was lower than 5%, indicating that the presence of the particles instead of the dissolved ions in the suspensions was the major toxicity sources, regardless of the presence of DOM. Furthermore, DOM at 10 and 40 mg L -1 and Al 2 O 3 NPs synergistically induced the upregulation of intercellular reactive oxygen species levels and superoxide dismutase activities. Analysis of the plasma malondialdehyde concentrations and the observation of superficial structures of S. obliquus indicated that the mixtures of DOM and Al 2 O 3 NPs showed no significant effect on membrane lipid peroxidation damage. In addition, the presence of both DOM and Al 2 O 3 NPs contributed to an enhancement in both the mitochondrial membrane potential and the cell membrane permeability (CMP) in S. obliquus. In particular, Al 2 O 3 NPs in the presence of 10 and 40 mg L -1 DOM caused a greater increase in CMP compared to Al 2 O 3 NPs and DOM alone treatments. In conclusion, these findings suggest that DOM at high concentrations and Al 2 O 3 NPs synergistically interrupted cell membrane functions and triggered subsequent growth inhibition toxicity.

Phenylbutyrate Is Bacteriostatic against Mycobacterium tuberculosis and Regulates the Macrophage Response to Infection, Synergistically with 25-Hydroxy-Vitamin D3.

PubMed

Coussens, Anna K; Wilkinson, Robert J; Martineau, Adrian R

2015-07-01

Adjunctive vitamin D treatment for pulmonary tuberculosis enhances resolution of inflammation but has modest effects on bacterial clearance. Sodium 4-phenylbutyrate (PBA) is in clinical use for a range of conditions and has been shown to synergise with vitamin D metabolites to upregulate cathelicidin antimicrobial peptide (CAMP) expression. We investigated whether clinically attainable plasma concentrations of PBA (0.4-4 mM) directly affect Mycobacterium tuberculosis (Mtb) growth and human macrophage and PBMC response to infection. We also tested the ability of PBA to enhance the immunomodulatory actions of the vitamin D metabolite 25(OH)D3 during infection and synergistically inhibit intracellular Mtb growth. PBA inhibited Mtb growth in broth with an MIC99 of 1 mM, which was reduced to 0.25 mM by lowering pH. During human macrophage infection, PBA treatment restricted Mtb uptake, phagocytic receptor expression and intracellular growth in a dose-dependent manner. PBA independently regulated CCL chemokine secretion and induced expression of the antimicrobial LTF (lactoferrin), the anti-inflammatory PROC (protein C) and multiple genes within the NLRP3 inflammasome pathway. PBA co-treatment with 25(OH)D3 synergistically modulated expression of numerous vitamin D-response genes, including CAMP, CYP24A1, CXCL10 and IL-37. This synergistic effect was dependent on MAPK signalling, while the effect of PBA on LTF, PROC and NLRP3 was MAPK-independent. During PBA and 25(OH)D3 co-treatment of human macrophages, in the absence of exogenous proteinase 3 (PR3) to activate cathelicidin, Mtb growth restriction was dominated by the effect of PBA, while the addition of PR3 enhanced growth restriction by 25(OH)D3 and PBA co-treatment. This suggests that PBA augments vitamin D-mediated cathelicidin-dependent Mtb growth restriction by human macrophages and independently induces antimicrobial and anti-inflammatory action. Therefore through both host-directed and bacterial-directed mechanisms PBA and vitamin D may prove an effective combinatorial adjunct therapy for tuberculosis to both resolve immunopathology and enhance bacterial clearance.

Structural simulation of adenosine phosphate via plumbagin and zoledronic acid competitively targets JNK/Erk to synergistically attenuate osteoclastogenesis in a breast cancer model

PubMed Central

Qiao, H; Wang, T-y; Yu, Z-f; Han, X-g; Liu, X-q; Wang, Y-g; Fan, Q-m; Qin, A; Tang, T-t

2016-01-01

The treatment of breast cancer-induced osteolysis remains a challenge in clinical settings. Here, we explored the effect and mechanism of combined treatment with zoledronic acid (ZA) and plumbagin (PL), a widely investigated component derived from Plumbago zeylanica, against breast cancer-induced osteoclastogenesis. We found that the combined treatment with PL and ZA suppressed cell viability of precursor osteoclasts and synergistically inhibited MDA-MB-231-induced osteoclast formation (combination index=0.28) with the abrogation of recombinant mouse receptor activator of nuclear factor-κB ligand (RANKL)-induced activation of NF-κB/MAPK (nuclear factor-κB/mitogen-activated protein kinase) pathways. Molecular docking suggested a putative binding area within c-Jun N-terminal kinase/extracellular signal-regulated kinase (JNK/Erk) protease active sites through the structural mimicking of adenosine phosphate (ANP) by the spatial combination of PL with ZA. A homogeneous time-resolved fluorescence assay further illustrated the direct competitiveness of the dual drugs against ANP docking to phosphorylated JNK/Erk, contributing to the inhibited downstream expression of c-Jun/c-Fos/NFATc-1 (nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1). Then, in vivo testing demonstrated that the combined administration of PL and ZA attenuated breast cancer growth in the bone microenvironment. Additionally, these molecules prevented the destruction of proximal tibia, with significant reduction of tartrate-resistant acid phosphatase (TRAcP)-positive osteoclast cells and potentiation of apoptotic cancer cells, to a greater extent when combined than when the drugs were applied independently. Altogether, the combination treatment with PL and ZA could significantly and synergistically suppress osteoclastogenesis and inhibit tumorigenesis both in vitro and in vivo by simulating the spatial structure of ANP to inhibit competitively phosphorylation of c-Jun N-terminal kinase/extracellular signal-regulated kinase (JNK/Erk). PMID:26866274

Moving Synergistically Acting Drug Combinations to the Clinic by Comparing Sequential versus Simultaneous Drug Administrations.

PubMed

Dinavahi, Saketh S; Noory, Mohammad A; Gowda, Raghavendra; Drabick, Joseph J; Berg, Arthur; Neves, Rogerio I; Robertson, Gavin P

2018-03-01

Drug combinations acting synergistically to kill cancer cells have become increasingly important in melanoma as an approach to manage the recurrent resistant disease. Protein kinase B (AKT) is a major target in this disease but its inhibitors are not effective clinically, which is a major concern. Targeting AKT in combination with WEE1 (mitotic inhibitor kinase) seems to have potential to make AKT-based therapeutics effective clinically. Since agents targeting AKT and WEE1 have been tested individually in the clinic, the quickest way to move the drug combination to patients would be to combine these agents sequentially, enabling the use of existing phase I clinical trial toxicity data. Therefore, a rapid preclinical approach is needed to evaluate whether simultaneous or sequential drug treatment has maximal therapeutic efficacy, which is based on a mechanistic rationale. To develop this approach, melanoma cell lines were treated with AKT inhibitor AZD5363 [4-amino- N -[(1 S )-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)piperidine-4-carboxamide] and WEE1 inhibitor AZD1775 [2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1 H -pyrazolo[3,4- d ]pyrimidin-3(2 H )-one] using simultaneous and sequential dosing schedules. Simultaneous treatment synergistically reduced melanoma cell survival and tumor growth. In contrast, sequential treatment was antagonistic and had a minimal tumor inhibitory effect compared with individual agents. Mechanistically, simultaneous targeting of AKT and WEE1 enhanced deregulation of the cell cycle and DNA damage repair pathways by modulating transcription factors p53 and forkhead box M1, which was not observed with sequential treatment. Thus, this study identifies a rapid approach to assess the drug combinations with a mechanistic basis for selection, which suggests that combining AKT and WEE1 inhibitors is needed for maximal efficacy. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Long non-coding RNA HOTAIR and STAT3 synergistically regulate the cervical cancer cell migration and invasion.

PubMed

Zhang, Yan; Cheng, Xiaoling; Liang, Hua; Jin, Zhenzhen

2018-04-25

Homeobox (HOX) transcript antisense RNA (HOTAIR) is a long intergenic non-coding RNA (lncRNA) that has been reported to be highly upregulated in several types of cancers. However, the role of HOTAIR in human cervical cancer is still unclear. We therefore investigated the expression and probable function of HOTAIR in cervical cancer cells. The expression of HOTAIR was examined in (HeLa, CaSki, ME-180, HT-3) and Human Cervical Epithelial Cells (HCerEpiC) by qRT-PCR. Transfection of si-NC, si-HOTAIR or si-STAT3 was carried out with the help of Lipofectamine 2000. The cell viability was assessed by CCK-8 assay. The cell migration and invasion was examined by wound healing and Boyden chamber assays. Protein expression was determined by western blotting. Our results showed that expression of HOTAIR was significantly upregulated in cervical cancer cells and inhibition of the expression of HOTAIR in HeLa cervical cancer cells resulted in suppression of cell proliferation, migration and invasion. Further, analysis of the promoter of HOTAIR, revealed that STAT3 could potentially regulate the activity of the HOTAIR in cervical cancer cells and inhibition of STAT3 had similar effects on the proliferation, migration and invasion of the cervical cancer cells as that of HOTAIR. Further, the suppression of STAT3 expression was associated with concomitant downregulation of IncRNA HOTAIR as indicated by the qRT-PCR. To unveil if STAT3 and HOTAIR have synergistic effects on the cell migration and invasion, si-STAT3 and si-HOTAIR were co-transformed into cervical HeLa cancer cells and it was observed that STAT3 and HOTAIR could synergistically inhibit the proliferation, migration and invasion of the cervical cancer cells. Taken together we conclude that HOTAIR and STAT3 synergistically regulate the proliferation, migration and invasion of cervical cancer cells. Copyright © 2018. Published by Elsevier B.V.

Phenylbutyrate Is Bacteriostatic against Mycobacterium tuberculosis and Regulates the Macrophage Response to Infection, Synergistically with 25-Hydroxy-Vitamin D₃

PubMed Central

Coussens, Anna K.; Wilkinson, Robert J.; Martineau, Adrian R.

2015-01-01

Adjunctive vitamin D treatment for pulmonary tuberculosis enhances resolution of inflammation but has modest effects on bacterial clearance. Sodium 4-phenylbutyrate (PBA) is in clinical use for a range of conditions and has been shown to synergise with vitamin D metabolites to upregulate cathelicidin antimicrobial peptide (CAMP) expression. We investigated whether clinically attainable plasma concentrations of PBA (0.4-4mM) directly affect Mycobacterium tuberculosis (Mtb) growth and human macrophage and PBMC response to infection. We also tested the ability of PBA to enhance the immunomodulatory actions of the vitamin D metabolite 25(OH)D3 during infection and synergistically inhibit intracellular Mtb growth. PBA inhibited Mtb growth in broth with an MIC99 of 1mM, which was reduced to 0.25mM by lowering pH. During human macrophage infection, PBA treatment restricted Mtb uptake, phagocytic receptor expression and intracellular growth in a dose-dependent manner. PBA independently regulated CCL chemokine secretion and induced expression of the antimicrobial LTF (lactoferrin), the anti-inflammatory PROC (protein C) and multiple genes within the NLRP3 inflammasome pathway. PBA co-treatment with 25(OH)D3 synergistically modulated expression of numerous vitamin D-response genes, including CAMP, CYP24A1, CXCL10 and IL-37. This synergistic effect was dependent on MAPK signalling, while the effect of PBA on LTF, PROC and NLRP3 was MAPK-independent. During PBA and 25(OH)D3 co-treatment of human macrophages, in the absence of exogenous proteinase 3 (PR3) to activate cathelicidin, Mtb growth restriction was dominated by the effect of PBA, while the addition of PR3 enhanced growth restriction by 25(OH)D3 and PBA co-treatment. This suggests that PBA augments vitamin D–mediated cathelicidin-dependent Mtb growth restriction by human macrophages and independently induces antimicrobial and anti-inflammatory action. Therefore through both host-directed and bacterial-directed mechanisms PBA and vitamin D may prove an effective combinatorial adjunct therapy for tuberculosis to both resolve immunopathology and enhance bacterial clearance. PMID:26133770

Estrogen and insulin-like growth factor 1 synergistically promote the development of lung adenocarcinoma in mice.

PubMed

Tang, Hexiao; Liao, Yongde; Xu, Liqiang; Zhang, Chao; Liu, Zhaoguo; Deng, Yu; Jiang, Zhixiao; Fu, Shengling; Chen, Zhenguang; Zhou, Sheng

2013-11-15

Estrogen receptor (ER) and insulin-like growth factor-1 receptor (IGF-1R) signaling are implicated in lung cancer progression. Based on their previous findings, the authors sought to investigate whether estrogen and IGF-1 act synergistically to promote lung adenocarcinoma (LADE) development in mice. LADE was induced with urethane in ovariectomized Kunming mice. Tumor-bearing mice were divided into seven groups: 17β-estradiol (E2), E2+fulvestrant (Ful; estrogen inhibitor), IGF-1, IGF-1+AG1024 (IGF-1 inhibitor), E2+IGF-1, E2+IGF-1+Ful+AG1024 and control groups. After 14 weeks, the mice were sacrificed, and then the tumor growth was determined. The expression of ERα/ERβ, IGF-1, IGF-1R and Ki67 was examined using tissue-microarray-immunohistochemistry, and IGF-1, p-ERβ, p-IGF-1R, p-MAPK and p-AKT levels were determined based on Western blot analysis. Fluorescence-quantitative polymerase chain reaction was used to detect the mRNA expression of ERβ, ERβ2 and IGF-1R. Tumors were found in 93.88% (46/49) of urethane-treated mice, and pathologically proven LADE was noted in 75.51% (37/49). In the E2+IGF-1 group, tumor growth was significantly higher than in the E2 group (p < 0.05), the IGF-1 group (p < 0.05) and control group (p < 0.05). Similarly, the expression of ERβ, p-ERβ, ERβ2, IGF-1, IGF-1R, p-IGF-1R, p-MAPK, p-AKT and Ki67 at the protein and/or mRNA levels was markedly higher in the ligand group than in the ligand + inhibitor groups (all p < 0.05). This study demonstrated for the first time that estrogen and IGF-1 act to synergistically promote the development of LADE in mice, and this may be related to the activation of the MAPK and AKT signaling pathways in which ERβ1, ERβ2 and IGF-1R play important roles. Copyright © 2013 UICC.

URANIUM EXTRACTION PROCESS USING SYNERGISTIC REAGENTS

DOEpatents

Schmitt, J.M.; Blake, C.A. Jr.; Brown, K.B.; Coleman, C.F.

1958-11-01

Improved methods are presented for recovering uranium values from aqueous solutions by organic solvent extraction. The improvement lies in the use, in combination, of two classes of organic compounds so that their extracting properties are enhanced synergistically. The two classes of organic compounds are dialkylphosphoric acid and certain neutral organophosphorus compounds such as trialkylphosphates, trialkylphosphonates, trlalkylphosphinates and trialkylphosphine oxides.

Oxidized low-density lipoprotein and β-glycerophosphate synergistically induce endothelial progenitor cell ossification

PubMed Central

Liu, Li; Liu, Zhi-zhong; Chen, Hui; Zhang, Guo-jun; Kong, Yu-hua; Kang, Xi-xiong

2011-01-01

Aim: To investigate the ability of ox-LDL to induce ossification of endothelial progenitor cells (EPCs) in vitro and explored whether oxidative stress, especially hypoxia inducible factor-1α (HIF-1α) and reactive oxygen species (ROS), participate in the ossific process. Methods: Rat bone marrow-derived endothelial progenitor cells (BMEPCs) were cultured in endothelial growth medium supplemented with VEGF (40 ng/mL) and bFGF (10 ng/mL). The cells were treated with oxidized low-density lipoprotein (ox-LDL, 5 μg/mL) and/or β-glycerophosphate (β-GP, 10 mmol/L). Calcium content and Von Kossa staining were used as the measures of calcium deposition. Ossific gene expression was determined using RT-PCR. The expression of osteocalcin (OCN) was detected with immunofluorescence. Alkaline phosphatase (ALP) activity was analyzed using colorimetric assay. Intercellular reactive oxygen species (ROS) were measured with flow cytometry. Results: BMEPCs exhibited a spindle-like shape. The percentage of cells that expressed the cell markers of EPCs CD34, CD133 and kinase insert domain-containing receptor (KDR) were 46.2%±5.8%, 23.5%±4.0% and 74.3%±8.8%, respectively. Among the total cells, 78.3%±4.2% were stained with endothelial-specific fluorescence. Treatment of BMEPCs with ox-LDL significantly promoted calcium deposition, which was further significantly enhanced by co-treatment with β-GP. The same treatments significantly increased the gene expression of core-binding factor a-1 (cbfa-1) and OCN, while decreased the gene expression of osteoprotegerin (OPG). The treatments also significantly enhanced the activity of ALP, but did not affect the number of OCN+ cells. Furthermore, the treatments significantly increased ROS and activated the hypoxia inducible factor-1α (HIF-1α). In all these effects, ox-LDL acted synergistically with β-GP. Conclusion: Ox-LDL and β-GP synergistically induce ossification of BMEPCs, in which an oxidizing mechanism is involved. PMID:22036865

Assessment & Commitment Tracking System (ACTS)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bryant, Robert A.; Childs, Teresa A.; Miller, Michael A.

2004-12-20

The ACTS computer code provides a centralized tool for planning and scheduling assessments, tracking and managing actions associated with assessments or that result from an event or condition, and "mining" data for reporting and analyzing information for improving performance. The ACTS application is designed to work with the MS SQL database management system. All database interfaces are written in SQL. The following software is used to develop and support the ACTS application: Cold Fusion HTML JavaScript Quest TOAD Microsoft Visual Source Safe (VSS) HTML Mailer for sending email Microsoft SQL Microsoft Internet Information Server

Poised to prosper? A cross-system comparison of climate change effects on native and non-native species performance

USDA-ARS?s Scientific Manuscript database

Climate change and biological invasions are primary threats to global biodiversity that may operate synergistically in the future. To date, the hypothesis that climate change will favor non-native species has been examined though local comparisons of single or few species. We took a meta-analytical ...

Towards subsidized malaria rapid diagnostic tests. Lessons learned from programmes to subsidise artemisinin-based combination therapies in the private sector: a review

PubMed Central

Lussiana, Cristina

2016-01-01

The idea of a private sector subsidy programme of artemisinin-based combination therapies (ACTs) was first proposed in 2004. Since then, several countries around the world have hosted pilot projects or programmes on subsidized ACTs and/or the Affordable Medicines Facility-malaria programme (AMFm). Overall the private sector subsidy programmes of ACTs have been effective in increasing availability of ACTs in the private sector and driving down average prices but struggled to crowd out antimalarial monotherapies. The results obtained from this ambitious strategy should inform policy makers in the designing of future interventions aimed to control malaria morbidity and mortality. Among the interventions recently proposed, a subsidy of rapid diagnostic tests (RDTs) in the private sector has been recommended by governments and international donors to cope with over-treatment with ACTs and to delay the emergence of resistance to artemisinin. In order to improve the cost-effectiveness of co-paid RDTs, we should build on the lessons we learned from almost 10 years of private sector subsidy programmes of ACTs in malaria-endemic countries. PMID:25862732

Selective Targeting of CTNNB1-, KRAS- or MYC-Driven Cell Growth by Combinations of Existing Drugs

PubMed Central

Uitdehaag, Joost C. M.; de Roos, Jeroen A. D. M.; van Doornmalen, Antoon M.; Prinsen, Martine B. W.; Spijkers-Hagelstein, Jill A. P.; de Vetter, Judith R. F.; de Man, Jos; Buijsman, Rogier C.; Zaman, Guido J. R.

2015-01-01

The aim of combination drug treatment in cancer therapy is to improve response rate and to decrease the probability of the development of drug resistance. Preferably, drug combinations are synergistic rather than additive, and, ideally, drug combinations work synergistically only in cancer cells and not in non-malignant cells. We have developed a workflow to identify such targeted synergies, and applied this approach to selectively inhibit the proliferation of cell lines with mutations in genes that are difficult to modulate with small molecules. The approach is based on curve shift analysis, which we demonstrate is a more robust method of determining synergy than combination matrix screening with Bliss-scoring. We show that the MEK inhibitor trametinib is more synergistic in combination with the BRAF inhibitor dabrafenib than with vemurafenib, another BRAF inhibitor. In addition, we show that the combination of MEK and BRAF inhibitors is synergistic in BRAF-mutant melanoma cells, and additive or antagonistic in, respectively, BRAF-wild type melanoma cells and non-malignant fibroblasts. This combination exemplifies that synergistic action of drugs can depend on cancer genotype. Next, we used curve shift analysis to identify new drug combinations that specifically inhibit cancer cell proliferation driven by difficult-to-drug cancer genes. Combination studies were performed with compounds that as single agents showed preference for inhibition of cancer cells with mutations in either the CTNNB1 gene (coding for β-catenin), KRAS, or cancer cells expressing increased copy numbers of MYC. We demonstrate that the Wnt-pathway inhibitor ICG-001 and trametinib acted synergistically in Wnt-pathway-mutant cell lines. The ERBB2 inhibitor TAK-165 was synergistic with trametinib in KRAS-mutant cell lines. The EGFR/ERBB2 inhibitor neratinib acted synergistically with the spindle poison docetaxel and with the Aurora kinase inhibitor GSK-1070916 in cell lines with MYC amplification. Our approach can therefore efficiently discover novel drug combinations that selectively target cancer genes. PMID:26018524

Proceedings of the Fifteenth NASA Propagation Experimenters Meeting (NAPEX 15) and the Advanced Communications Technology Satellite (ACTS) Propagation Studies Miniworkshop

NASA Technical Reports Server (NTRS)

Davarian, Faramaz (Editor)

1991-01-01

The NASA Propagation Experimenters Meeting (NAPEX), supported by the NASA Propagation Program, is convened annually to discuss studies made on radio wave propagation by investigators from domestic and international organizations. The meeting was organized into three technical sessions. The first session was dedicated to Olympus and ACTS studies and experiments, the second session was focused on the propagation studies and measurements, and the third session covered computer-based propagation model development. In total, sixteen technical papers and some informal contributions were presented. Following NAPEX 15, the Advanced Communications Technology Satellite (ACTS) miniworkshop was held on 29 Jun. 1991, to review ACTS propagation activities, with emphasis on ACTS hardware development and experiment planning. Five papers were presented.

32 CFR 644.554 - Insurance against loss or damages to buildings and improvements by fire or acts of God.

Code of Federal Regulations, 2013 CFR

2013-07-01

... and improvements by fire or acts of God. 644.554 Section 644.554 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Sale Procedure § 644.554 Insurance against loss or damages to buildings and improvements by fire or acts of God...

Threats and Acts of Intimate Partner Violence Reported by Users at Norwegian Women's Shelters

ERIC Educational Resources Information Center

Alsaker, Kjersti; Kristoffersen, Kjell; Moen, Bente E.; Baste, Valborg

2011-01-01

Women (n = 87) at women's shelters in Norway, a country of high welfare and gender equality, reported a multitude of severe threats and actual acts of physical, sexual and psychological violence. An individual threatening to kill his partner represented a significant increased risk for experiencing serious acts of violence, especially when the…

10 CFR 50.13 - Attacks and destructive acts by enemies of the United States; and defense activities.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 1 2011-01-01 2011-01-01 false Attacks and destructive acts by enemies of the United States; and defense activities. 50.13 Section 50.13 Energy NUCLEAR REGULATORY COMMISSION DOMESTIC... the effects of (a) attacks and destructive acts, including sabotage, directed against the facility by...

10 CFR 50.13 - Attacks and destructive acts by enemies of the United States; and defense activities.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 1 2014-01-01 2014-01-01 false Attacks and destructive acts by enemies of the United States; and defense activities. 50.13 Section 50.13 Energy NUCLEAR REGULATORY COMMISSION DOMESTIC... the effects of (a) attacks and destructive acts, including sabotage, directed against the facility by...

1 CFR 3.3 - Reproduction and certification of copies of acts and documents.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 1 General Provisions 1 2010-01-01 2010-01-01 false Reproduction and certification of copies of acts and documents. 3.3 Section 3.3 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER GENERAL SERVICES TO THE PUBLIC § 3.3 Reproduction and certification of copies of acts and documents. The...

43 CFR 2522.1 - General acts authorizing extensions of time.

Code of Federal Regulations, 2013 CFR

2013-10-01

...) BUREAU OF LAND MANAGEMENT, DEPARTMENT OF THE INTERIOR LAND RESOURCE MANAGEMENT (2000) DESERT-LAND ENTRIES... of time for the submission of final proof by a desert-land claimant. Said Acts are the following... making desert-land proofs were authorized by the Acts of June 16, 1933 (48 Stat. 274; 43 U.S.C. 256a...

22 CFR 92.5 - Acceptability of notarial acts under State or territorial law.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Acceptability of notarial acts under State or territorial law. 92.5 Section 92.5 Foreign Relations DEPARTMENT OF STATE LEGAL AND RELATED SERVICES NOTARIAL AND RELATED SERVICES Introduction § 92.5 Acceptability of notarial acts under State or territorial law...

10 CFR 50.13 - Attacks and destructive acts by enemies of the United States; and defense activities.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 1 2013-01-01 2013-01-01 false Attacks and destructive acts by enemies of the United States; and defense activities. 50.13 Section 50.13 Energy NUCLEAR REGULATORY COMMISSION DOMESTIC... the effects of (a) attacks and destructive acts, including sabotage, directed against the facility by...

43 CFR 2522.1 - General acts authorizing extensions of time.

Code of Federal Regulations, 2011 CFR

2011-10-01

...) BUREAU OF LAND MANAGEMENT, DEPARTMENT OF THE INTERIOR LAND RESOURCE MANAGEMENT (2000) DESERT-LAND ENTRIES... of time for the submission of final proof by a desert-land claimant. Said Acts are the following... making desert-land proofs were authorized by the Acts of June 16, 1933 (48 Stat. 274; 43 U.S.C. 256a...

1 CFR 15.4 - Reproduction and certification of copies of acts and documents.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 1 General Provisions 1 2011-01-01 2011-01-01 false Reproduction and certification of copies of... Reproduction and certification of copies of acts and documents. The Director of the Federal Register shall furnish to requesting agencies, at cost, reproductions or certified copies of original acts and documents...

1 CFR 3.3 - Reproduction and certification of copies of acts and documents.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 1 General Provisions 1 2012-01-01 2012-01-01 false Reproduction and certification of copies of acts and documents. 3.3 Section 3.3 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER GENERAL SERVICES TO THE PUBLIC § 3.3 Reproduction and certification of copies of acts and documents. The...

1 CFR 3.3 - Reproduction and certification of copies of acts and documents.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 1 General Provisions 1 2013-01-01 2012-01-01 true Reproduction and certification of copies of acts and documents. 3.3 Section 3.3 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER GENERAL SERVICES TO THE PUBLIC § 3.3 Reproduction and certification of copies of acts and documents. The...

1 CFR 3.3 - Reproduction and certification of copies of acts and documents.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 1 General Provisions 1 2014-01-01 2012-01-01 true Reproduction and certification of copies of acts and documents. 3.3 Section 3.3 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER GENERAL SERVICES TO THE PUBLIC § 3.3 Reproduction and certification of copies of acts and documents. The...

"Like Me": A Foundation for Social Cognition

ERIC Educational Resources Information Center

Meltzoff, Andrew N.

2007-01-01

Infants represent the acts of others and their own acts in commensurate terms. They can recognize cross-modal equivalences between acts they see others perform and their own felt bodily movements. This recognition of self-other equivalences in action gives rise to interpreting others as having similar psychological states such as perceptions and…

32 CFR 644.554 - Insurance against loss or damages to buildings and improvements by fire or acts of God.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 4 2010-07-01 2010-07-01 true Insurance against loss or damages to buildings and improvements by fire or acts of God. 644.554 Section 644.554 National Defense Department of... Procedure § 644.554 Insurance against loss or damages to buildings and improvements by fire or acts of God...

Virtuous acts as practical medical ethics: an empirical study.

PubMed

Little, Miles; Gordon, Jill; Markham, Pippa; Rychetnik, Lucie; Kerridge, Ian

2011-10-01

To examine the nature, scope and significance of virtues in the biographies of medical practitioners and to determine what kind of virtues are at play in their ethical behaviour and reflection. A case study involving 19 medical practitioners associated with the Sydney Medical School, using semi-structured narrative interviews. Narrative data were analysed using dialectical empiricism, constant comparison and iterative reformulation of research questions. Participants represented virtuous acts as centrally important in their moral assessments of both themselves and others. Acts appeared to be contextually virtuous, rather than expressions of stable character traits, and virtue was linked to acts that served to protect or enhance fundamental values attached to ontological security and human flourishing. Virtue ethics, in this sense, was the single most important ethical system for each of the participants. Virtue ethics, construed as the appraisal of acts in contexts of risk, danger or threat to foundational values, emerged as the 'natural' ethical approach for medical practitioners in this case study. Teaching medical ethics to students and graduates alike needs to accommodate the priority attached to virtuous acts. © 2011 Blackwell Publishing Ltd.

32 CFR 644.554 - Insurance against loss or damages to buildings and improvements by fire or acts of God.

Code of Federal Regulations, 2014 CFR

2014-07-01

... and improvements by fire or acts of God. 644.554 Section 644.554 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Sale Procedure § 644.554 Insurance against loss or damages to buildings and improvements by fire or acts of God...

Prevalence of malaria parasitemia and purchase of artemisinin-based combination therapies (ACTs) among drug shop clients in two regions in Tanzania with ACT subsidies.

PubMed

Briggs, Melissa A; Kalolella, Admirabilis; Bruxvoort, Katia; Wiegand, Ryan; Lopez, Gerard; Festo, Charles; Lyaruu, Pierre; Kenani, Mitya; Abdulla, Salim; Goodman, Catherine; Kachur, S Patrick

2014-01-01

Throughout Africa, many people seek care for malaria in private-sector drug shops where diagnostic testing is often unavailable. Recently, subsidized artemisinin-based combination therapies (ACTs), a first-line medication for uncomplicated malaria, were made available in these drug shops in Tanzania. This study assessed the prevalence of malaria among and purchase of ACTs by drug shop clients in the setting of a national ACT subsidy program and sub-national drug shop accreditation program. A cross-sectional survey of drug shop clients was performed in two regions in Tanzania, one with a government drug shop accreditation program and one without, from March-May, 2012. Drug shops were randomly sampled from non-urban districts. Shop attendants were interviewed about their education, training, and accreditation status. Clients were interviewed about their symptoms and medication purchases, then underwent a limited physical examination and laboratory testing for malaria. Malaria prevalence and predictors of ACT purchase were assessed using univariate analysis and multiple logistic regression. Amongst 777 clients from 73 drug shops, the prevalence of laboratory-confirmed malaria was 12% (95% CI: 6-18%). Less than a third of clients with malaria had purchased ACTs, and less than a quarter of clients who purchased ACTs tested positive for malaria. Clients were more likely to have purchased ACTs if the participant was <5 years old (aOR: 6.6; 95% CI: 3.9-11.0) or the shop attendant had >5 years, experience (aOR: 2.8; 95% CI: 1.2-6.3). Having malaria was only a predictor of ACT purchase in the region with a drug shop accreditation program (aOR: 3.4; 95% CI: 1.5-7.4). Malaria is common amongst persons presenting to drug shops with a complaint of fever. The low proportion of persons with malaria purchasing ACTs, and the high proportion of ACTs going to persons without malaria demonstrates a need to better target who receives ACTs in these drug shops.

To lie or not to lie: to whom and under what circumstances.

PubMed

Perkins, Serena A; Turiel, Elliot

2007-01-01

This research examined adolescents' judgments about lying to circumvent directives from parents or friends in the moral, personal, and prudential domains. One hundred and twenty-eight adolescents (12.1-17.3 years) were presented with situations in which an adolescent avoids a directive through deception. The majority of adolescents judged some acts as acceptable, including deception regarding parental directives to engage in moral violations and to restrict personal activities. Other acts of deception were judged as unacceptable, including deception of parents regarding prudential acts, as well as deception of friends in each domain. In addition, lying to conceal a misdeed was negatively evaluated. Most adolescents thought that directives from parents and friends to engage in moral violations or to restrict personal acts were not legitimate, whereas parental directives concerning prudential acts were seen as legitimate. Results indicate that adolescents value honesty, but sometimes subordinate it to moral and personal concerns in relationships of inequality.

Proceedings of the Seventeenth NASA Propagation Experimenters Meeting (NAPEX 17) and the Advanced Communications Technology Satellite (ACTS) Propagation Studies Miniworkshop

NASA Technical Reports Server (NTRS)

Davarian, Faramaz (Editor)

1993-01-01

The NASA Propagation Experimenters Meeting (NAPEX) is convened annually to discuss studies made on radio wave propagation by investors from domestic and international organizations. NAPEX 17 was held on 15 June 1993. The meeting was organized into two technical sessions. The first session was dedicated to slant path propagation studies and experiments. The second session focused on propagation studies for mobile and personal communications. Preceding NAPEX 17, the Advanced Communications Technology Satellite (ACTS) Propagation Studies Miniworkshop was held on 14 June 1993 to review ACTS propagation activities with emphasis on ACTS experiments status and data collection, processing, and exchange.

Advanced Communications Technology Satellite (ACTS): Design and on-orbit performance measurements

NASA Technical Reports Server (NTRS)

Gargione, F.; Acosta, R.; Coney, T.; Krawczyk, R.

1995-01-01

The Advanced Communications Technology Satellite (ACTS), developed and built by Lockheed Martin Astro space for the NASA Lewis Research Center, was launched in September 1993 on the shuttle STS 51 mission. ACTS is a digital experimental communications test bed that incorporates gigahertz bandwidth transponders operating at Ka band, hopping spot beams, on-board storage and switching, and dynamic rain fade compensation. This paper describes the ACTS enabling technologies, the design of the communications payload, the constraints imposed on the spacecraft bus, and the measurements conducted to verify the performance of the system in orbit.

26 CFR 53.4941(d)-2 - Specific acts of self-dealing.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 26 Internal Revenue 17 2011-04-01 2011-04-01 false Specific acts of self-dealing. 53.4941(d)-2...) MISCELLANEOUS EXCISE TAXES (CONTINUED) FOUNDATION AND SIMILAR EXCISE TAXES Taxes on Self-Dealing § 53.4941(d)-2 Specific acts of self-dealing. Except as provided in § 53.4941(d)-3 or § 53.4941(d)-4: (a) Sale or exchange...

32 CFR 644.554 - Insurance against loss or damages to buildings and improvements by fire or acts of God.

Code of Federal Regulations, 2012 CFR

2012-07-01

... and improvements by fire or acts of God. 644.554 Section 644.554 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Sale Procedure § 644.554 Insurance against loss or damages to buildings and improvements by fire or acts of God...

12 CFR 226.36 - Prohibited acts or practices in connection with credit secured by a consumer's principal dwelling.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 3 2010-01-01 2010-01-01 false Prohibited acts or practices in connection with...) Special Rules for Certain Home Mortgage Transactions § 226.36 Prohibited acts or practices in connection...) Misrepresentation of value of consumer's dwelling—(1) Coercion of appraiser. In connection with a consumer credit...

Adaptive Decision Aiding in Computer-Assisted Instruction: Adaptive Computerized Training System (ACTS).

ERIC Educational Resources Information Center

Hopf-Weichel, Rosemarie; And Others

This report describes results of the first year of a three-year program to develop and evaluate a new Adaptive Computerized Training System (ACTS) for electronics maintenance training. (ACTS incorporates an adaptive computer program that learns the student's diagnostic and decision value structure, compares it to that of an expert, and adapts the…

Prevalence of Malaria Parasitemia and Purchase of Artemisinin-Based Combination Therapies (ACTs) among Drug Shop Clients in Two Regions in Tanzania with ACT Subsidies

PubMed Central

Briggs, Melissa A.; Kalolella, Admirabilis; Bruxvoort, Katia; Wiegand, Ryan; Lopez, Gerard; Festo, Charles; Lyaruu, Pierre; Kenani, Mitya; Abdulla, Salim; Goodman, Catherine; Kachur, S. Patrick

2014-01-01

Background Throughout Africa, many people seek care for malaria in private-sector drug shops where diagnostic testing is often unavailable. Recently, subsidized artemisinin-based combination therapies (ACTs), a first-line medication for uncomplicated malaria, were made available in these drug shops in Tanzania. This study assessed the prevalence of malaria among and purchase of ACTs by drug shop clients in the setting of a national ACT subsidy program and sub-national drug shop accreditation program. Method and Findings A cross-sectional survey of drug shop clients was performed in two regions in Tanzania, one with a government drug shop accreditation program and one without, from March-May, 2012. Drug shops were randomly sampled from non-urban districts. Shop attendants were interviewed about their education, training, and accreditation status. Clients were interviewed about their symptoms and medication purchases, then underwent a limited physical examination and laboratory testing for malaria. Malaria prevalence and predictors of ACT purchase were assessed using univariate analysis and multiple logistic regression. Amongst 777 clients from 73 drug shops, the prevalence of laboratory-confirmed malaria was 12% (95% CI: 6–18%). Less than a third of clients with malaria had purchased ACTs, and less than a quarter of clients who purchased ACTs tested positive for malaria. Clients were more likely to have purchased ACTs if the participant was <5 years old (aOR: 6.6; 95% CI: 3.9–11.0) or the shop attendant had >5 years, experience (aOR: 2.8; 95% CI: 1.2–6.3). Having malaria was only a predictor of ACT purchase in the region with a drug shop accreditation program (aOR: 3.4; 95% CI: 1.5–7.4). Conclusion Malaria is common amongst persons presenting to drug shops with a complaint of fever. The low proportion of persons with malaria purchasing ACTs, and the high proportion of ACTs going to persons without malaria demonstrates a need to better target who receives ACTs in these drug shops. PMID:24732258