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Sample records for a27 protein synergizes

  1. ( sup 3 H)protein secretion in rat parotid gland: Substance P-. beta. -adrenergic synergism

    SciTech Connect

    Dreux, C.; Imhoff, V.; Rossignol, B. )

    1987-12-01

    In parotid fragment ({sup 3}H)protein, secretion induced by substance P was moderate, but strongly Ca dependent. However, secretion induced by isoproterenol was large and Ca independent. Potentiation of protein secretion was observed when substance P (SP) and isoproterenol (ISO) acted together. Addition of 10{sup {minus}8} M SP caused a shift to the left in the secretion dose-response curve caused by ISO, but did not enhance ISO-induced maximal response. The potentiating effect seems to be a postreceptor event, since it can be mimicked by forskolin (FK), known to induce directly cAMP accumulation, thus bypassing the {beta}-adrenergic receptor. The synergism described above was, therefore, investigated at the second messenger production level. Stimulation of parotid gland fragments by simultaneous addition of SP plus ISO or FK did not modify cAMP nor inositol trisphosphate (IP{sub 3}) accumulation induced independently by each secretagogue alone. The ionophore A23187 was also able to potentiate secretion induced by a {beta}-adrenergic agonist, this effect being totally abolished by external calcium omission, thus suggesting a role for external calcium in this potentiation phenomenon. These results suggest that the potentiation phenomenon observed is a postreceptor event that occurs at a step distal from the second messenger production.

  2. Protective Effect of Surfactant Protein D in Pulmonary Vaccinia Virus Infection: Implication of A27 Viral Protein

    PubMed Central

    Julien, Perino; Thielens, Nicole M.; Crouch, Erika; Spehner, Danièle; Crance, Jean-Marc; Favier, Anne-Laure

    2013-01-01

    Vaccinia virus (VACV) was used as a surrogate of variola virus (VARV) (genus Orthopoxvirus), the causative agent of smallpox, to study Orthopoxvirus infection. VARV is principally transmitted between humans by aerosol droplets. Once inhaled, VARV first infects the respiratory tract where it could encounter surfactant components, such as soluble pattern recognition receptors. Surfactant protein D (SP-D), constitutively present in the lining fluids of the respiratory tract, plays important roles in innate host defense against virus infection. We investigated the role of SP-D in VACV infection and studied the A27 viral protein involvement in the interaction with SP-D. Interaction between SP-D and VACV caused viral inhibition in a lung cell model. Interaction of SP-D with VACV was mediated by the A27 viral protein. Binding required Ca2+ and interactions were blocked in the presence of excess of SP-D saccharide ligands. A27, which lacks glycosylation, directly interacted with SP-D. The interaction between SP-D and the viral particle was also observed using electron microscopy. Infection of mice lacking SP-D (SP-D-/-) resulted in increased mortality compared to SP-D+/+ mice. Altogether, our data show that SP-D participates in host defense against the vaccinia virus infection and that the interaction occurs with the viral surface protein A27. PMID:23518578

  3. Co-expression and synergism analysis of Vip3Aa29 and Cyt2Aa3 insecticidal proteins from Bacillus thuringiensis.

    PubMed

    Yu, Xiumei; Liu, Tao; Sun, Zhiguang; Guan, Peng; Zhu, Jun; Wang, Shiquan; Li, Shuangcheng; Deng, Qiming; Wang, Lingxia; Zheng, Aiping; Li, Ping

    2012-04-01

    Vegetative insecticidal protein (Vip3) from Bacillus thuringiensis shows high activity against lepidopteran insects. Cytolytic δ-endotoxin (Cyt) also has high toxicity to dipteran larvae and synergism with other crystal proteins (Cry), but synergism between Cyt and Vip3 proteins has not been tested. We analyzed for synergism between Cyt2Aa3 and Vip3Aa29. Both cyt2Aa3 and vip3Aa29 genes were co-expressed in Escherichia coli strain BL21 carried on vector pCOLADuet-1. Vip3Aa29 showed insecticidal activity against Chilo suppressalis and Spodoptera exigua, with 50% lethal concentration (LC(50)) at 24.0 and 36.6 μg ml(-1), respectively. It could also inhibit Helicoverpa armigera growth, with 50% inhibition concentration at 22.6 μg ml(-1). While Cyt2Aa3 was toxic to Culex quinquefasciatus (LC(50): 0.53 μg ml(-1)) and Chironomus tepperi (LC(50): 36 μg ml(-1)), it did not inhibit C. suppressalis, S. exigua, and H. armigera. However, the co-expression of Cyt2Aa3 and Vip3Aa29 showed synergistic effect on C. suppressalis and S. exigua, and the individual activities were strengthened 3.35- and 4.34-fold, respectively. The co-expression had no synergism against C. tepperi and H. armigera, but exerted some antagonistic effect on Cx. quinquefasciatus. The synergism between Cyt2Aa and Vip3Aa was thus discovered for the first time, which confirmed that Cyt toxin can enhance the toxicity of other toxins against some non-target insects. By synergism analysis, the effectiveness of microbial insecticides can be verified.

  4. Crystal Structure of Vaccinia Viral A27 Protein Reveals a Novel Structure Critical for Its Function and Complex Formation with A26 Protein

    PubMed Central

    Hsieh, Fu-Lien; Ko, Tzu-Ping; Lin, Cheng-Tse; Ho, Meng-Ru; Wang, Iren; Hsu, Shang-Te Danny; Guo, Rey-Ting; Chang, Wen; Wang, Andrew H. J.

    2013-01-01

    Vaccinia virus envelope protein A27 has multiple functions and is conserved in the Orthopoxvirus genus of the poxvirus family. A27 protein binds to cell surface heparan sulfate, provides an anchor for A26 protein packaging into mature virions, and is essential for egress of mature virus (MV) from infected cells. Here, we crystallized and determined the structure of a truncated form of A27 containing amino acids 21–84, C71/72A (tA27) at 2.2 Å resolution. tA27 protein uses the N-terminal region interface (NTR) to form an unexpected trimeric assembly as the basic unit, which contains two parallel α-helices and one unusual antiparallel α-helix; in a serpentine way, two trimers stack with each other to form a hexamer using the C-terminal region interface (CTR). Recombinant tA27 protein forms oligomers in a concentration-dependent manner in vitro in gel filtration. Analytical ultracentrifugation and multi-angle light scattering revealed that tA27 dimerized in solution and that Leu47, Leu51, and Leu54 at the NTR and Ile68, Asn75, and Leu82 at the CTR are responsible for tA27 self-assembly in vitro. Finally, we constructed recombinant vaccinia viruses expressing full length mutant A27 protein defective in either NTR, CTR, or both interactions; the results demonstrated that wild type A27 dimer/trimer formation was impaired in NTR and CTR mutant viruses, resulting in small plaques that are defective in MV egress. Furthermore, the ability of A27 protein to form disulfide-linked protein complexes with A26 protein was partially or completely interrupted by NTR and CTR mutations, resulting in mature virion progeny with increased plasma membrane fusion activity upon cell entry. Together, these results demonstrate that A27 protein trimer structure is critical for MV egress and membrane fusion modulation. Because A27 is a neutralizing target, structural information will aid the development of inhibitors to block A27 self-assembly or complex formation against vaccinia virus

  5. Novel Irreversible Small Molecule Inhibitors of Replication Protein A Display Single Agent Activity and Synergize with Cisplatin

    PubMed Central

    Neher, Tracy M.; Bodenmiller, Diane; Fitch, Richard W.; Jalal, Shadia I.; Turchi, John J.

    2011-01-01

    Replication protein A (RPA) is a single-strand DNA-binding protein with essential roles in DNA replication, recombination and repair. RPA is necessary for the formation of the preincision complex which is required for proper incision of damaged DNA nucleotides during DNA repair. We have previously identified small molecule inhibitors (SMIs) with the ability to disrupt RPA binding activity to ssDNA. Further characterization of these RPA inhibitors was assessed using both lung and ovarian cancer cell lines. Lung cancer cell lines demonstrated increased apoptotic cell death following treatment with the SMI MCI13E, with IC50 values of ~5 μM. The A2780 ovarian cancer cell line and the p53-null lung cancer cell line H1299 were particularly sensitive to MCI13E treatment with IC50 values below 3 μM. Furthermore, a cell cycle effect was observed in lung cancer cell lines which resulted in a lengthening of either G1 or S-phases of the cell cycle following single agent treatment. Sequential treatment with MCI13E and cisplatin resulted in synergism. Overall these data suggest that decreasing RPA’s DNA binding activity via a SMI may disrupt RPA’s role in cell cycle regulation. Thus, RPA SMIs hold the potential to be used as single agent chemotherapeutics or in combination with current chemotherapeutic regimens to increase efficacy. PMID:21846830

  6. Multiple interferon stimulated genes synergize with the zinc finger antiviral protein to mediate anti-alphavirus activity.

    PubMed

    Karki, Sophiya; Li, Melody M H; Schoggins, John W; Tian, Suyan; Rice, Charles M; MacDonald, Margaret R

    2012-01-01

    The zinc finger antiviral protein (ZAP) is a host factor that mediates inhibition of viruses in the Filoviridae, Retroviridae and Togaviridae families. We previously demonstrated that ZAP blocks replication of Sindbis virus (SINV), the prototype Alphavirus in the Togaviridae family at an early step prior to translation of the incoming genome and that synergy between ZAP and one or more interferon stimulated genes (ISGs) resulted in maximal inhibitory activity. The present study aimed to identify those ISGs that synergize with ZAP to mediate Alphavirus inhibition. Using a library of lentiviruses individually expressing more than 350 ISGs, we screened for inhibitory activity in interferon defective cells with or without ZAP overexpression. Confirmatory tests of the 23 ISGs demonstrating the largest infection reduction in combination with ZAP revealed that 16 were synergistic. Confirmatory tests of all potentially synergistic ISGs revealed 15 additional ISGs with a statistically significant synergistic effect in combination with ZAP. These 31 ISGs are candidates for further mechanistic studies. The number and diversity of the identified ZAP-synergistic ISGs lead us to speculate that ZAP may play an important role in priming the cell for optimal ISG function.

  7. Methamphetamine and human immunodeficiency virus protein Tat synergize to destroy dopaminergic terminals in the rat striatum.

    PubMed

    Theodore, S; Cass, W A; Maragos, W F

    2006-02-01

    Dysfunction of the dopaminergic system accompanied by loss of dopamine in the striatum is a major feature of human immunodeficiency virus-1-associated dementia. Previous studies have shown that human immunodeficiency virus-1-associated dementia patients with a history of drug abuse have rapid neurological progression, prominent psychomotor slowing, more severe encephalitis and more severe dendritic and neuronal damage in the frontal cortex compared with human immunodeficiency virus-1-associated dementia patients without a history of drug abuse. In a previous study, we showed that methamphetamine and human immunodeficiency virus-1 protein Tat interact to produce a synergistic decline in dopamine levels in the rat striatum. The present study was carried out to understand the underlying cause for the loss of dopamine. Male Sprague-Dawley rats were administered saline, methamphetamine, Tat or Tat followed by methamphetamine 24 h later. Two and seven days later the animals were killed and tissue sections from striatum were processed for silver staining to examine terminal degeneration while sections from striatum and substantia nigra were processed for tyrosine hydroxylase immunoreactivity. Striatal tissue was also analyzed by Western blotting for tyrosine hydroxylase protein levels. Compared with controls, methamphetamine+Tat-treated animals showed extensive silver staining and loss of tyrosine hydroxylase immunoreactivity and protein levels in the ipsilateral striatum. There was no apparent loss of tyrosine hydroxylase in the substantia nigra. Markers for oxidative stress were significantly increased in striatal synaptosomes from Tat+methamphetamine group compared with controls. The results indicate that methamphetamine and Tat interact to produce an enhanced injury to dopaminergic nerve terminals in the striatum with sparing of the substantia nigra by a mechanism involving oxidative stress. These findings suggest a possible mode of interaction between methamphetamine

  8. A Chimeric HIV-1 gp120 Fused with Vaccinia Virus 14K (A27) Protein as an HIV Immunogen

    PubMed Central

    Vijayan, Aneesh; García-Arriaza, Juan; C. Raman, Suresh; Conesa, José Javier; Chichón, Francisco Javier; Santiago, César; Sorzano, Carlos Óscar S.; Carrascosa, José L.; Esteban, Mariano

    2015-01-01

    In the HIV vaccine field, there is a need to produce highly immunogenic forms of the Env protein with the capacity to trigger broad B and T-cell responses. Here, we report the generation and characterization of a chimeric HIV-1 gp120 protein (termed gp120-14K) by fusing gp120 from clade B with the vaccinia virus (VACV) 14K oligomeric protein (derived from A27L gene). Stable CHO cell lines expressing HIV-1 gp120-14K protein were generated and the protein purified was characterized by size exclusion chromatography, electron microscopy and binding to anti-Env antibodies. These approaches indicate that gp120-14K protein is oligomeric and reacts with a wide spectrum of HIV-1 neutralizing antibodies. Furthermore, in human monocyte-derived dendritic cells (moDCs), gp120-14K protein upregulates the levels of several proinflammatory cytokines and chemokines associated with Th1 innate immune responses (IL-1β, IFN-γ, IL-6, IL-8, IL-12, RANTES). Moreover, we showed in a murine model, that a heterologous prime/boost immunization protocol consisting of a DNA prime with a plasmid expressing gp120-14K protein followed by a boost with MVA-B [a recombinant modified vaccinia virus Ankara (MVA) expressing HIV-1 gp120, Gag, Pol and Nef antigens from clade B], generates stronger, more polyfunctional, and greater effector memory HIV-1-specific CD4+ and CD8+ T-cell immune responses, than immunization with DNA-gp120/MVA-B. The DNA/MVA protocol was superior to immunization with the combination of protein/MVA and the latter was superior to a prime/boost of MVA/MVA or protein/protein. In addition, these immunization protocols enhanced antibody responses against gp120 of the class IgG2a and IgG3, together favoring a Th1 humoral immune response. These results demonstrate that fusing HIV-1 gp120 with VACV 14K forms an oligomeric protein which is highly antigenic as it activates a Th1 innate immune response in human moDCs, and in vaccinated mice triggers polyfunctional HIV-1-specific adaptive

  9. Synergism and Antagonism between Bacillus thuringiensis Vip3A and Cry1 Proteins in Heliothis virescens, Diatraea saccharalis and Spodoptera frugiperda

    PubMed Central

    Lemes, Ana Rita Nunes; Davolos, Camila Chiaradia; Legori, Paula Cristina Brunini Crialesi; Fernandes, Odair Aparecido; Ferré, Juan; Lemos, Manoel Victor Franco; Desiderio, Janete Apparecida

    2014-01-01

    Second generation Bt crops (insect resistant crops carrying Bacillus thuringiensis genes) combine more than one gene that codes for insecticidal proteins in the same plant to provide better control of agricultural pests. Some of the new combinations involve co-expression of cry and vip genes. Because Cry and Vip proteins have different midgut targets and possibly different mechanisms of toxicity, it is important to evaluate possible synergistic or antagonistic interactions between these two classes of toxins. Three members of the Cry1 class of proteins and three from the Vip3A class were tested against Heliothis virescens for possible interactions. At the level of LC50, Cry1Ac was the most active protein, whereas the rest of proteins tested were similarly active. However, at the level of LC90, Cry1Aa and Cry1Ca were the least active proteins, and Cry1Ac and Vip3A proteins were not significantly different. Under the experimental conditions used in this study, we found an antagonistic effect of Cry1Ca with the three Vip3A proteins. The interaction between Cry1Ca and Vip3Aa was also tested on two other species of Lepidoptera. Whereas antagonism was observed in Spodoptera frugiperda, synergism was found in Diatraea saccharalis. In all cases, the interaction between Vip3A and Cry1 proteins was more evident at the LC90 level than at the LC50 level. The fact that the same combination of proteins may result in a synergistic or an antagonistic interaction may be an indication that there are different types of interactions within the host, depending on the insect species tested. PMID:25275646

  10. Synergism and antagonism between Bacillus thuringiensis Vip3A and Cry1 proteins in Heliothis virescens, Diatraea saccharalis and Spodoptera frugiperda.

    PubMed

    Lemes, Ana Rita Nunes; Davolos, Camila Chiaradia; Legori, Paula Cristina Brunini Crialesi; Fernandes, Odair Aparecido; Ferré, Juan; Lemos, Manoel Victor Franco; Desiderio, Janete Apparecida

    2014-01-01

    Second generation Bt crops (insect resistant crops carrying Bacillus thuringiensis genes) combine more than one gene that codes for insecticidal proteins in the same plant to provide better control of agricultural pests. Some of the new combinations involve co-expression of cry and vip genes. Because Cry and Vip proteins have different midgut targets and possibly different mechanisms of toxicity, it is important to evaluate possible synergistic or antagonistic interactions between these two classes of toxins. Three members of the Cry1 class of proteins and three from the Vip3A class were tested against Heliothis virescens for possible interactions. At the level of LC50, Cry1Ac was the most active protein, whereas the rest of proteins tested were similarly active. However, at the level of LC90, Cry1Aa and Cry1Ca were the least active proteins, and Cry1Ac and Vip3A proteins were not significantly different. Under the experimental conditions used in this study, we found an antagonistic effect of Cry1Ca with the three Vip3A proteins. The interaction between Cry1Ca and Vip3Aa was also tested on two other species of Lepidoptera. Whereas antagonism was observed in Spodoptera frugiperda, synergism was found in Diatraea saccharalis. In all cases, the interaction between Vip3A and Cry1 proteins was more evident at the LC90 level than at the LC50 level. The fact that the same combination of proteins may result in a synergistic or an antagonistic interaction may be an indication that there are different types of interactions within the host, depending on the insect species tested.

  11. Lysine biotinylation and methionine oxidation in the heat shock protein HSP60 synergize in the elimination of reactive oxygen species in human cell cultures.

    PubMed

    Li, Yong; Malkaram, Sridhar A; Zhou, Jie; Zempleni, Janos

    2014-04-01

    Previous studies suggest that the number of proteins containing covalently bound biotin is larger than previously thought. Here, we report the identity of some of these proteins. Using mass spectrometry, we discovered 108 novel biotinylation sites in the human embryonic kidney HEK293 cell proteome; members of the heat shock protein (HSP) superfamily were overrepresented among the novel biotinylated proteins. About half of the biotinylated proteins also displayed various degrees of methionine oxidation, which is known to play an important role in the defense against reactive oxygen species; for biotinylated HSPs, the percent of methionine sulfoxidation approached 100%. Protein structure analysis suggests that methionine sulfoxides localize in close physical proximity to the biotinylated lysines on the protein surface. Mass spectrometric analysis revealed that between one and five of the methionine residues in the C-terminal KEEKDPGMGAMGGMGGGMGGGMF motif are oxidized in HSP60. The likelihood of methionine sulfoxidation is higher if one of the adjacent lysine residues is biotinylated. Knockdown of HSP60 caused a 60% increase in the level of reactive oxygen species in fibroblasts cultured in biotin-sufficient medium. When HEK293 cells were transferred from biotin-sufficient medium to biotin-free medium, the level of reactive oxygen species increased by >9 times compared with baseline controls and a time-response relationship was evident. High levels of methionine sulfoxidation coincided with cell cycle arrest in the G0/G1 and S phases in biotin-depleted cells. We conclude that biotinylation of lysines synergizes with sulfoxidation of methionines in heat shock proteins such as HSP60 in the defense against reactive oxygen species. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Effects of opiates and HIV proteins on neurons: the role of ferritin heavy chain and a potential for synergism.

    PubMed

    Festa, Lindsay; Meucci, Olimpia

    2012-07-01

    Human immunodeficiency virus 1 (HIV-1) and its associated proteins can have a profound impact on the central nervous system. Co-morbid abuse of opiates, such as morphine and heroin, is often associated with rapid disease progression and greater neurological dysfunction. The mechanisms by which HIV proteins and opiates cause neuronal damage on their own and together are unclear. The emergence of ferritin heavy chain (FHC) as a negative regulator of the chemokine receptor CXCR4, a co-receptor for HIV, may prove to be important in elucidating the interaction between HIV proteins and opiates. This review summarizes our current knowledge of central nervous system damage inflicted by HIV and opiates, as well as the regulation of CXCR4 by opiate-induced changes in FHC protein levels. We propose that HIV proteins and opiates exhibit an additive or synergistic effect on FHC/CXCR4, thereby decreasing neuronal signaling and function.

  13. Dorzolamide synergizes the antitumor activity of mitomycin C against Ehrlich's carcinoma grown in mice: role of thioredoxin-interacting protein.

    PubMed

    Ali, Belal M; Zaitone, Sawsan A; Shouman, Samia A; Moustafa, Yasser M

    2015-12-01

    The antitumor activity of carbonic anhydrase (CA) inhibitors is attributed to their ability to induce a state of intracellular acidification. In fact, acidic intracellular pH was demonstrated to upregulate several tumor suppressor proteins and increase the activity of many chemotherapies. The present study aimed to investigate the antitumor activity of the CA inhibitor, dorzolamide, in combination with mitomycin C and to study the effect of these drugs on tumoral thioredoxin-interacting protein (TXNIP) as well as tumor cell proliferation and apoptosis. Solid tumors were induced by subcutaneous inoculation of Ehrlich's ascites carcinoma (EAC) cells in female mice. Mice were treated with dorzolamide (3, 10, or 30 mg/kg/day, i.p.) and/or mitomycin C (1 mg/kg, i.p.) weekly for 3 weeks. Treatment with mitomycin C increased TXNIP level in EAC solid tumors in mice. Likewise, treatment with dorzolamide upregulated TXNIP and p53 while downregulated bcl-2. Both drug therapies increased tumoral caspase 9, caspase 3, and PARP-1 cleavage in addition to decreasing the proliferative Ki-67-stained nuclear fraction. Indeed, a synergistic effect was detected between mitomycin C and dorzolamide. The current data demonstrated that the antitumor activity of mitomycin C and dorzolamide was, at least in part, mediated through stimulating tumoral expression of TXNIP and enhancing tumor apoptosis.

  14. High mobility group box 1 protein synergizes with lipopolysaccharide and peptidoglycan for nitric oxide production in mouse peritoneal macrophages in vitro.

    PubMed

    Chakraborty, Rituparna; Bhatt, Kunal H; Sodhi, Ajit

    2013-05-01

    Extracellular high mobility group box 1 (HMGB1) protein and nitric oxide (NO) has been credited with multiple inflammatory functions using in vivo and in vitro systems. Therefore, delineating their regulation may be an important therapeutic strategy for the treatment of sepsis. In the present study, it is demonstrated that recombinant HMGB1 (rHMGB1) synergizes with sub threshold concentration of TLR2 agonist (PGN; 1 μg/ml) as well as with TLR4 agonist (LPS; 1 ng/ml) to induce NO release in mouse peritoneal macrophages. The enhanced iNOS expression was also observed at the transcription and translational level. Co-incubation of macrophages with rHMGB1 with either PGN or LPS showed enhanced expression of TLR2, TLR4 and RAGE. TLR2, TLR4 or RAGE knockdown macrophages effectively inhibited the rHMGB1+PGN or LPS induced NO synergy. It was further observed that the JNK MAPK inhibitor SP600125 attenuated the PGN+rHMGB1 induced iNOS/NO synergy whereas p38 MAPK inhibitor SB908912 inhibited iNOS/NO synergy induced by LPS+rHMGB1. It was also observed that the activation of NF-κB is essential for the synergy as the pharmacological inhibition or siRNA knockdown of NF-κB (cRel) significantly reduced the rHMGB1+PGN or rHMGB1+LPS induced enhanced iNOS/NO expression. Altogether, the data suggests that the co-incubation of macrophages with rHMGB1 with either LPS or PGN induces the synergistic effect on iNOS expression and NO release by the upregulation of surface receptors (TLR2, TLR4 and RAGE) which in turn amplifies the MAPKs (p38 and JNK) and NF-κB activation and results in enhanced iNOS expression and NO production.

  15. Fas-activated serine/threonine kinase (FAST K) synergizes with TIA-1/TIAR proteins to regulate Fas alternative splicing.

    PubMed

    Izquierdo, José M; Valcárcel, Juan

    2007-01-19

    The factors and mechanisms that mediate the effects of intracellular signaling cascades on alternative pre-mRNA splicing are poorly understood. TIA-1 (T-cell intracellular antigen 1) and TIAR (TIA-1-related) proteins regulate alternative pre-mRNA splicing by promoting the use of suboptimal 5' splice sites followed by uridine-rich intronic enhancer sequences. These proteins promote, for example, inclusion of Fas receptor exon 6, which leads to an mRNA encoding a pro-apoptotic form of the receptor at the expense of the form that skips exon 6, which encodes an anti-apoptotic form. Fas-activated serine/threonine kinase (FAST K) is known to interact with and phosphorylate TIA-1. Here we have tested the possibility that FAST K influences alternative pre-mRNA splicing by affecting the activity of TIA-1/TIAR. Depletion of FAST K form Jurkat cells leads to skipping of exon 6 from endogenous Fas transcripts. Conversely, FAST K overexpression enhances exon 6 inclusion of Fas reporters transfected in HeLa cells. Consistent with the possibility that the effects of FAST K are mediated by changes in the function of TIA-1/TIAR, the effects of FAST K overexpression (i) are largely suppressed by depletion of TIA-1 and TIAR and (ii) are significantly compromised by mutation of a TIA-1/TIAR-responsive enhancer present downstream of exon 6 5' splice site. Furthermore, in vitro phosphorylation of TIA-1 by FAST K results in enhanced U1 snRNP recruitment. Interestingly, this enhancement is not due to increased binding of TIA-1 to the pre-mRNA. Taken together, the results connect Fas signaling with the activity of splicing factors that modulate Fas alternative splicing, suggesting the existence of an autoregulatory loop that could serve to amplify Fas responses.

  16. Development of Eco-friendly Soy Protein Isolate Films with High Mechanical Properties through HNTs, PVA, and PTGE Synergism Effect.

    PubMed

    Liu, Xiaorong; Song, Ruyuan; Zhang, Wei; Qi, Chusheng; Zhang, Shifeng; Li, Jianzhang

    2017-03-10

    This study was to develop novel soy protein isolate-based films for packaging using halloysite nanotubes (HNTs), poly-vinyl alcohol (PVA), and 1,2,3-propanetriol-diglycidyl-ether (PTGE). The structural, crystallinity, opacity, micromorphology, and thermal stability of the resultant SPI/HNTs/PVA/PTGE film were analyzed by the Attenuated total reflectance-Fourier transformed infrared (ATR-FTIR) spectroscopy, X-ray diffraction (XRD), UV-Vis spectrophotometry, scanning electron microscopy (SEM), and thermo-gravimetric analysis (TGA). The SPI/HNTs/PVA/PTGE film illustrated that HNTs were uniformly dispersed in the SPI matrix and the thermal stability of the film was enhanced. Furthermore, the tensile strength (TS) of the SPI/HNTs/PVA/PTGE film was increased by 329.3% and the elongation at the break (EB) remained unchanged. The water absorption (WA) and the moisture content (MC) were decreased by 5.1% and 10.4%, respectively, compared to the unmodified film. The results highlighted the synergistic effects of SPI, HNTs, PVA, and PTGE on the mechanical properties, water resistance, and thermal stability of SPI films, which showed excellent strength and flexibility. In short, SPI films prepared from HNTs, PVA, and PTGE showed considerable potential as packaging materials.

  17. Development of Eco-friendly Soy Protein Isolate Films with High Mechanical Properties through HNTs, PVA, and PTGE Synergism Effect

    PubMed Central

    Liu, Xiaorong; Song, Ruyuan; Zhang, Wei; Qi, Chusheng; Zhang, Shifeng; Li, Jianzhang

    2017-01-01

    This study was to develop novel soy protein isolate-based films for packaging using halloysite nanotubes (HNTs), poly-vinyl alcohol (PVA), and 1,2,3-propanetriol-diglycidyl-ether (PTGE). The structural, crystallinity, opacity, micromorphology, and thermal stability of the resultant SPI/HNTs/PVA/PTGE film were analyzed by the Attenuated total reflectance-Fourier transformed infrared (ATR-FTIR) spectroscopy, X-ray diffraction (XRD), UV-Vis spectrophotometry, scanning electron microscopy (SEM), and thermo-gravimetric analysis (TGA). The SPI/HNTs/PVA/PTGE film illustrated that HNTs were uniformly dispersed in the SPI matrix and the thermal stability of the film was enhanced. Furthermore, the tensile strength (TS) of the SPI/HNTs/PVA/PTGE film was increased by 329.3% and the elongation at the break (EB) remained unchanged. The water absorption (WA) and the moisture content (MC) were decreased by 5.1% and 10.4%, respectively, compared to the unmodified film. The results highlighted the synergistic effects of SPI, HNTs, PVA, and PTGE on the mechanical properties, water resistance, and thermal stability of SPI films, which showed excellent strength and flexibility. In short, SPI films prepared from HNTs, PVA, and PTGE showed considerable potential as packaging materials. PMID:28281634

  18. Development of Eco-friendly Soy Protein Isolate Films with High Mechanical Properties through HNTs, PVA, and PTGE Synergism Effect

    NASA Astrophysics Data System (ADS)

    Liu, Xiaorong; Song, Ruyuan; Zhang, Wei; Qi, Chusheng; Zhang, Shifeng; Li, Jianzhang

    2017-03-01

    This study was to develop novel soy protein isolate-based films for packaging using halloysite nanotubes (HNTs), poly-vinyl alcohol (PVA), and 1,2,3-propanetriol-diglycidyl-ether (PTGE). The structural, crystallinity, opacity, micromorphology, and thermal stability of the resultant SPI/HNTs/PVA/PTGE film were analyzed by the Attenuated total reflectance-Fourier transformed infrared (ATR-FTIR) spectroscopy, X-ray diffraction (XRD), UV-Vis spectrophotometry, scanning electron microscopy (SEM), and thermo-gravimetric analysis (TGA). The SPI/HNTs/PVA/PTGE film illustrated that HNTs were uniformly dispersed in the SPI matrix and the thermal stability of the film was enhanced. Furthermore, the tensile strength (TS) of the SPI/HNTs/PVA/PTGE film was increased by 329.3% and the elongation at the break (EB) remained unchanged. The water absorption (WA) and the moisture content (MC) were decreased by 5.1% and 10.4%, respectively, compared to the unmodified film. The results highlighted the synergistic effects of SPI, HNTs, PVA, and PTGE on the mechanical properties, water resistance, and thermal stability of SPI films, which showed excellent strength and flexibility. In short, SPI films prepared from HNTs, PVA, and PTGE showed considerable potential as packaging materials.

  19. A 27-mer oligonucleotide probe for the detection and measurement of the mRNA for uncoupling protein in brown adipose tissue of different species.

    PubMed

    Brander, F; Keith, J S; Trayhurn, P

    1993-01-01

    1. Data from rats, cattle, mice, rabbits and humans indicate considerable species heterogeneity in the sequence of the gene coding for the mitochondrial uncoupling protein (UCP) in brown adipose tissue. A 27-base sequence of an exon region of the gene is, however, identical in rats and cattle; in mice, rabbits, and humans this same region shows only a single base difference from the sequence in rats and cattle. 2. A 27-mer oligonucleotide (3'-TGGAAGGGCGACCTGTGGCGGTTTCAG-5') complementary to the conserved region of the rat and cattle UCP genes has been synthesized as a potential probe for UCP mRNA in widely differing species. 3. Northern blots of RNA from rat brown fat showed that the oligonucleotide hybridized with a 1.5 kbase mRNA, indicative of UCP mRNA. No hybridization was observed with RNA from white fat (subcutaneous, internal), liver, kidney, skeletal muscle, heart and brain. Acute cold-exposure of rats and mice led to an increase in UCP mRNA level, while streptozotocin-induced diabetes resulted in a decrease. 4. The oligonucleotide hybridized with a 1.5 (or 1.9) kbase mRNA from brown fat of rats, mice, golden hamsters, Djungarian hamsters, and newborn rabbits, pipistrelle bats, lambs, goats and red deer. 5. The 27-mer oligonucleotide provides a simple probe for UCP mRNA across a wide range of mammals, obviating any need to obtain species-specific cDNAs.

  20. A 27,000-D core of the Dictyostelium 34,000-D protein retains Ca(2+)- regulated actin cross-linking but lacks bundling activity

    PubMed Central

    1993-01-01

    Actin cross-linking proteins are important for formation of isotropic F- actin networks and anisotropic bundles of filaments in the cytoplasm of eucaryotic cells. A 34,000-D protein from the cellular slime mold Dictyostelium discoideum mediates formation of actin bundles in vitro, and is specifically incorporated into filopodia. The actin cross- linking activity of this protein is inhibited by the presence of micromolar calcium. A 27,000-D fragment obtained by digestion with alpha-chymotrypsin lacks the amino-terminal six amino acids and the carboxyl-terminal 7,000 D of the intact polypeptide. The 27,000-D fragment retains F-actin binding activity assessed by cosedimentation assays and by 125I-[F-actin] blot overlay technique, F-actin cross- linking activity as assessed by viscometry, and calcium binding activity. Ultrastructural analyses indicate that the 27,000-D fragment is deficient in the bundling activity characteristic of the intact 34,000-D protein. Actin filaments are aggregated into microdomains but not bundle in the presence of the 27,000-D fragment. A polarized light scattering assay was used to demonstrate that the 34,000-D protein increases the orientational correlation among F-actin filaments. The 27,000-D fragment does not increase the orientation of the actin filaments as assessed by this technique. A terminal segment(s) of the 34,000-D protein, lacking in the 27,000-D fragment, contributes significantly to the ability to cross-link actin filaments into bundles. PMID:8436589

  1. The vaccinia virus 14-kilodalton (A27L) fusion protein forms a triple coiled-coil structure and interacts with the 21-kilodalton (A17L) virus membrane protein through a C-terminal alpha-helix.

    PubMed

    Vázquez, M I; Rivas, G; Cregut, D; Serrano, L; Esteban, M

    1998-12-01

    The vaccinia virus 14-kDa protein (encoded by the A27L gene) plays an important role in the biology of the virus, acting in virus-to-cell and cell-to-cell fusions. The protein is located on the surface of the intracellular mature virus form and is essential for both the release of extracellular enveloped virus from the cells and virus spread. Sequence analysis predicts the existence of four regions in this protein: a structureless region from amino acids 1 to 28, a helical region from residues 29 to 37, a triple coiled-coil helical region from residues 44 to 72, and a Leu zipper motif at the C terminus. Circular dichroism spectroscopy, analytical ultracentrifugation, and chemical cross-linking studies of the purified wild-type protein and several mutant forms, lacking one or more of the above regions or with point mutations, support the above-described structural division of the 14-kDa protein. The two contiguous cysteine residues at positions 71 and 72 are not responsible for the formation of 14-kDa protein trimers. The location of hydrophobic residues at the a and d positions on a helical wheel and of charged amino acids in adjacent positions, e and g, suggests that the hydrophobic and ionic interactions in the triple coiled-coil helical region are involved in oligomer formation. This conjecture was supported by the construction of a three-helix bundle model and molecular dynamics. Binding assays with purified proteins expressed in Escherichia coli and cytoplasmic extracts from cells infected with a virus that does not produce the 14-kDa protein during infection (VVindA27L) show that the 21-kDa protein (encoded by the A17L gene) is the specific viral binding partner and identify the putative Leu zipper, the predicted third alpha-helix on the C terminus of the 14-kDa protein, as the region involved in protein binding. These findings were confirmed in vivo, following transfection of animal cells with plasmid vectors expressing mutant forms of the 14-kDa protein and

  2. Localization and dynamic expression of a 27.8 kDa receptor protein for lymphocystis disease virus infection in sea bass ( Lateolabrax japonicus) tissues

    NASA Astrophysics Data System (ADS)

    Wu, Ronghua; Sheng, Xiuzhen; Tang, Xiaoqian; Xing, Jing; Zhan, Wenbin

    2017-10-01

    Lymphocystis disease virus (LCDV) infects target cells by attaching to a 27.8 kDa receptor (27.8R) protein in flounder Paralichthys olivaceus, and anti-27.8R monoclonal antibodies (MAbs) have been developed. However, the 27.8R existence in tissues of sea bass ( Lateolabrax japonicus) and its role in LCDV infection have remained unclear. In this study, the results of western blotting demonstrated that the same 27.8R was shared by flounder and sea bass. LCDV-free sea bass individuals were intramuscularly injected with LCDV, and viral copies were detected in tissues from 3 h post infection and showed a time-dependent increase during 9 days infection. Distribution and synthesis of 27.8R in sea bass tissues were investigated by using anti-27.8R MAbs as probes. It was found that 27.8R was distributed in all the tested tissues. The levels of 27.8R protein were highest in gill and skin, then a bit lowly in stomach, head kidney and heart, followed by spleen, intestine, blood cells, gonad and liver, and least in kidney and brain in healthy sea bass. Upon LCDV infection, 27.8R synthesis was up-regulated in each tissue, and higher in the tissues with higher LCDV copies. The 27.8R and LCDV were detected in some peripheral blood leukocytes but not in red blood cells. These results suggested that 27.8R was widely distributed in sea bass tissues, and it served as a receptor and correlated with tissue tropism of LCDV infection. Furthermore, leukocytes had the potential of being a LCDV carrier and were responsible for a systemic infection of LCDV in sea bass.

  3. Prostaglandin E2 transactivates the colony-stimulating factor-1 receptor and synergizes with colony-stimulating factor-1 in the induction of macrophage migration via the mitogen-activated protein kinase ERK1/2.

    PubMed

    Digiacomo, Graziana; Ziche, Marina; Dello Sbarba, Persio; Donnini, Sandra; Rovida, Elisabetta

    2015-06-01

    Prostaglandin E2 (PGE2), a key mediator of immunity, inflammation, and cancer, acts through 4 G-protein-coupled E-prostanoid receptors (EPs 1-4). Crosstalk between EPs and receptor tyrosine kinases also occurs. Colony-stimulating factor-1 receptor (CSF-1R) is an RTK that sustains the survival, proliferation, and motility of monocytes/macrophages, which are an essential component of innate immunity and cancer development. The aim of this study was to investigate on a possible crosstalk between EP and CSF-1R. In BAC1.2F5 and RAW264.7 murine macrophages, CSF-1 (EC₅₀ = 18.1 and 10.2 ng/ml, respectively) and PGE2 (EC₅₀ = 1.5 and 5.5 nM, respectively) promoted migration. PGE2 induced rapid CSF-1R phosphorylation that was dependent on Src family kinases (SFKs). CSF-1R inhibition reduced PGE2-elicited ERK1/2 phosphorylation and macrophage migration, indicating that CSF-1R plays a role in PGE2-mediated immunoregulation. EP4 appeared responsible for functional PGE2/CSF-1R crosstalk. Furthermore, PGE2 synergized with CSF-1 in inducing ERK1/2 phosphorylation and macrophage migration. ERK1/2 inhibition completely blocked migration induced by the combination CSF-1/PGE2. CSF-1/PGE2 functional interaction with respect to migration also occurred in bone marrow-derived murine macrophages (EC₅₀ CSF-1, 6.7 ng/ml; EC₅₀ PGE2, 16.7 nM). These results indicated that PGE2 transactivates CSF-1R and synergizes with its signaling at ERK1/2 level in promoting macrophage migration. © FASEB.

  4. sHA 14-1, a stable and ROS-free antagonist against anti-apoptotic Bcl-2 proteins, bypasses drug resistances and synergizes cancer therapies in human leukemia cell

    PubMed Central

    Tian, Defeng; Das, Sonia Goutam Kumar; Doshi, Jignesh M.; Peng, Jun; Lin, Jialing; Xing, Chengguo

    2009-01-01

    HA 14-1, a small-molecule antagonist against anti-apoptotic Bcl-2 proteins, was demonstrated to induce selective cytotoxicity toward malignant cells and to overcome drug resistance. Due to its poor stability and the reactive oxygen species (ROS) generated by its decomposition, chemical modification of HA 14-1 is needed for its future development. We have synthesized a stabilized analog of HA 14-1 – sHA 14-1, which did not induce the formation of ROS. As expected for a putative antagonist against anti-apoptotic Bcl-2 proteins like HA 14-1, sHA 14-1 disrupted the binding interaction of a Bak BH3 peptide with Bcl-2 or Bcl-XL protein, inhibited the growth of tumor cells through the induction of apoptosis, and circumvented the drug resistance induced by the over-expression of anti-apoptotic Bcl-2 and Bcl-XL proteins. Interestingly, the impairment of extrinsic apoptotic pathway induced moderate resistance to sHA 14-1. The moderate resistance suggested that sHA 14-1 generated part of its apoptotic stress through the intrinsic pathway, possibly through its antagonism against anti-apoptotic Bcl-2 proteins. The resistance indicated that sHA 14-1 generated apoptotic stress through the extrinsic apoptotic pathway as well. The ability of sHA 14-1 to induce apoptotic stress through both pathways was further supported by the synergism of sHA 14-1 towards the cytotoxicities of Fas ligand and dexamethasone in Jurkat cells. Taken together, these findings suggest that sHA 14-1 may represent a promising candidate for the treatment of drug-resistant cancers either as a monotherapy or in combination with current cancer therapies. PMID:18037229

  5. Phosphorylation and ubiquitination of dynamin-related proteins (AtDRP3A/3B) synergically regulate mitochondrial proliferation during mitosis.

    PubMed

    Wang, Feng; Liu, Peng; Zhang, Quan; Zhu, Jian; Chen, Tong; Arimura, Shin-Ichi; Tsutsumi, Nobuhiro; Lin, Jinxing

    2012-10-01

    The balance between mitochondrial fission and fusion is disrupted during mitosis, but the mechanism governing this phenomenon in plant cells remains enigmatic. Here, we used mitochondrial matrix-localized Kaede protein (mt-Kaede) to analyze the dynamics of mitochondrial fission in BY-2 suspension cells. Analysis of the photoactivatable fluorescence of mt-Kaede suggested that the fission process is dominant during mitosis. This finding was confirmed by an electron microscopic analysis of the size distribution of mitochondria in BY-2 suspension cells at various stages. Cellular proteins interacting with Myc-tagged dynamin-related protein 3A/3B (AtDRP3A and AtDRP3B) were immunoprecipitated with anti-Myc antibody-conjugated beads and subsequently identified by microcapillary liquid chromatography-quadrupole time-of-flight mass spectrometry (CapLC Q-TOF) MS/MS. The identified proteins were broadly associated with cytoskeletal (microtubular), phosphorylation, or ubiquitination functions. Mitotic phosphorylation of AtDRP3A/AtDRP3B and mitochondrial fission at metaphase were inhibited by treatment of the cells with a CdkB/cyclin B inhibitor or a serine/threonine protein kinase inhibitor. The fate of AtDRP3A/3B during the cell cycle was followed by time-lapse imaging of the fluorescence of Dendra2-tagged AtDRP3A/3B after green-to-red photoconversion; this experiment showed that AtDRP3A/3B is partially degraded during interphase. Additionally, we found that microtubules are involved in mitochondrial fission during mitosis, and that mitochondria movement to daughter cell was limited as early as metaphase. Taken together, these findings suggest that mitotic phosphorylation of AtDRP3A/3B promotes mitochondrial fission during plant cell mitosis, and that AtDRP3A/3B is partially degraded at interphase, providing mechanistic insight into the mitochondrial morphological changes associated with cell-cycle transitions in BY-2 suspension cells. © 2012 The Authors. The Plant Journal

  6. Single concentration tests show synergism among Bacillus thuringiensis subsp. israelensis toxins against the malaria vector mosquito Anopheles albimanus.

    PubMed

    Fernández-Luna, María Teresa; Tabashnik, Bruce E; Lanz-Mendoza, Humberto; Bravo, Alejandra; Soberón, Mario; Miranda-Ríos, Juan

    2010-07-01

    Bioassays of insecticidal proteins from Bacillus thuringiensis subsp. israelensis with larvae of the malaria vector mosquito Anopheles albimanus showed that the cytolytic protein Cyt1Aa was not toxic alone, but it increased the toxicity of the crystalline proteins Cry4Ba and Cry11Aa. Synergism also occurred between Cry4Ba and Cry11Aa toxins. Whereas many previous analyses of synergism have been based on a series of toxin concentrations leading to comparisons between expected and observed values for the concentration killing 50% of insects tested (LC(50)), we describe and apply a method here that enables testing for synergism based on single concentrations of toxins.

  7. A synthetic M protein peptide synergizes with a CXC chemokine protease to induce vaccine-mediated protection against virulent streptococcal pyoderma and bacteremia.

    PubMed

    Pandey, Manisha; Langshaw, Emma; Hartas, Jon; Lam, Alfred; Batzloff, Michael R; Good, Michael F

    2015-06-15

    Infections caused by Streptococcus pyogenes (group A Streptococcus [GAS]) are highly prevalent in the tropics, in developing countries, and in the Indigenous populations of developed countries. These infections and their sequelae are responsible for almost 500,000 lives lost prematurely each year. A synthetic peptide vaccine (J8-DT) from the conserved region of the M protein has shown efficacy against disease that follows i.p. inoculation of bacteria. By developing a murine model for infection that closely mimics human skin infection, we show that the vaccine can protect against pyoderma and subsequent bacteremia caused by multiple GAS strains, including strains endemic in Aboriginal communities in the Northern Territory of Australia. However, the vaccine was ineffective against a hypervirulent cluster of virulence responder/sensor mutant GAS strain; this correlated with the strain's ability to degrade CXC chemokines, thereby preventing neutrophil chemotaxis. By combining J8-DT with an inactive form of the streptococcal CXC protease, S. pyogenes cell envelope proteinase, we developed a combination vaccine that is highly effective in blocking CXC chemokine degradation and permits opsonic Abs to kill the bacteria. Mice receiving the combination vaccine were strongly protected against pyoderma and bacteremia, as evidenced by a 100-1000-fold reduction in bacterial burden following challenge. To our knowledge, a vaccine requiring Abs to target two independent virulence factors of an organism is unique.

  8. MicroRNA-19b Downregulates Gap Junction Protein Alpha1 and Synergizes with MicroRNA-1 in Viral Myocarditis

    PubMed Central

    Lin, Junyi; Xue, Aimin; Li, Liliang; Li, Beixu; Li, Yuhua; Shen, Yiwen; Sun, Ning; Chen, Ruizhen; Xu, Hongfei; Zhao, Ziqin

    2016-01-01

    Viral myocarditis (VMC) is a life-threatening disease that leads to heart failure or cardiac arrhythmia. A large number of researches have revealed that mircroRNAs (miRNAs) participate in the pathological processes of VMC. We previously reported that miR-1 repressed the expression of gap junction protein α1 (GJA1) in VMC. In this study, miR-19b was found to be significantly upregulated using the microarray analysis in a mouse model of VMC, and overexpression of miR-19b led to irregular beating pattern in human cardiomyocytes derived from the induced pluripotent stem cells (hiPSCs-CMs). The upregulation of miR-19b was associated with decreased GJA1 in vivo. Furthermore, a miR-19b inhibitor increased, while its mimics suppressed the expression of GJA1 in HL-1 cells. When GJA1 was overexpressed, the miR-19b mimics-mediated irregular beating was reversed in hiPSCs-CMs. In addition, the effect of miR-19b on GJA1 was enhanced by miR-1 in a dose-dependent manner. These data suggest miR-19b contributes to irregular beating through regulation of GJA1 by cooperating with miR-1. Based on the present and our previous studies, it could be indicated that miR-19b and miR-1 might be critically involved in cardiac arrhythmia associated with VMC. PMID:27213338

  9. Selective affinity labeling of a 27-kDa integral membrane protein in rat liver and kidney with N-bromoacetyl derivatives of L-thyroxine and 3,5,3'-triiodo-L-thyronine

    SciTech Connect

    Koehrle, J.R.; Rasmussen, U.B.; Rokos, H.; Leonard, J.L.; Hesch, R.D. )

    1990-04-15

    125I-Labeled N-bromoacetyl derivatives of L-thyroxine and L-triiodothyronine were used as alkylating affinity labels to identify rat liver and kidney microsomal membrane proteins which specifically bind thyroid hormones. Affinity label incorporation was analyzed by ethanol precipitation and individual affinity labeled proteins were identified by autoradiography after separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions. Six to eight membrane proteins ranging in size from 17 to 84 kDa were affinity labeled by both bromoacetyl-L-thyroxine (BrAcT4) and bromoacetyl-L-triiodothyronine (BrAcT3). Affinity labeling was time- and temperature-dependent, and both reduced dithiols and detergents increased affinity labeling, predominantly in a 27-kDa protein(s). Up to 80% of the affinity label was associated with a 27-kDa protein (p27) under optimal conditions. Affinity labeling of p27 by 0.4 nM BrAc(125I)L-T4 was blocked by 0.1 microM of the alkylating ligands BrAcT4, BrAcT3, or 100 microM iodoacetate, by 10 microM concentrations of the non-alkylating, reversible ligands N-acetyl-L-thyroxine, 3,3',5'-triiodothyronine, 3,5-diiodosalicylate, and EMD 21388, a T4-antagonistic flavonoid. Neither 10 microM L-T4, nor 10 microM N-acetyltriiodothyronine or 10 microM L-triiodothyronine blocked affinity labeling of p27 or other affinity labeled bands. Affinity labeling of a 17-kDa band was partially inhibited by excess of the alkylating ligands BrAcT4, BrAcT3, and iodoacetate, but labeling of other minor bands was not blocked by excess of the competitors. BrAc(125I)T4 yielded higher affinity label incorporation than BrAc(125I)T3, although similar banding patterns were observed, except that BrAcT3 affinity labeled more intensely a 58,000-Da band in liver and a 53,000-55,000-Da band in kidney.

  10. Lethal Synergism between Influenza and Streptococcus pneumoniae

    PubMed Central

    Rudd, Jennifer M; Ashar, Harshini K; Chow, Vincent TK; Teluguakula, Narasaraju

    2016-01-01

    The devastating synergism of bacterial pneumonia with influenza viral infections left its mark on the world over the last century. Although the details of pathogenesis remain unclear, the synergism is related to a variety of factors including pulmonary epithelial barrier damage which exposes receptors that influence bacterial adherence and the triggering of an exaggerated innate immune response and cytokine storm, which further acts to worsen the injury. Several therapeutics and combination therapies of antibiotics, anti-inflammatories including corticosteroids and toll-like receptor modifiers, and anti-virals are being discussed. This mini review summarizes recent developments in unearthing the pathogenesis of the lethal synergism of pneumococcal co-infection following influenza, as well as addresses potential therapeutic options and combinations of therapies currently being evaluated. PMID:27981251

  11. Effects of 17beta-estradiol and testosterone on hepatic mRNA/protein levels and catalytic activities of CYP2M1, CYP2K1, and CYP3A27 in rainbow trout (Oncorhynchus mykiss).

    PubMed

    Buhler, D R; Miranda, C L; Henderson, M C; Yang, Y H; Lee, S J; Wang-Buhler, J L

    2000-10-15

    There is growing concern that exposure to chemicals in the environment can disrupt the endocrine systems of wildlife and humans, causing reproductive problems or other adverse effects. The expression of many cytochrome P450s (CYPs) is under hormonal control, hence, levels of these enzymes can be affected by exposure to endocrine-disrupting chemicals. Previous research has reported that treatment of fish and other animals with the estrogenic and androgenic hormones 17beta-estradiol (E2) and testosterone (T) alters the P450 content or enzyme activities in the treated animals. However, the results of many of these studies are either incomplete or in disagreement and in most cases the effect on specific P450 forms has not been determined. Therefore, to better understand the effects of gonadal hormones on the expression of P450s and their associated enzyme activities, it was of interest to undertake a comprehensive investigation of the transcriptional and translational expression of three constitutive hepatic P450s in the rainbow trout (Oncorhynchus mykiss) following hormone exposure. Accordingly, juvenile trout were injected intraperitoneally with propylene glycol vehicle and the most active estrogenic and androgenic hormones E2 (3 mg/kg) or T (3 mg/kg) on days 1, 4, 7, 13, and 15 and euthanized on day 19. After treatment with E2, hepatic microsomes showed significantly lower levels (percentage of control) in total P450 contents (52%), lauric acid hydroxylase (32%), and 6beta-progesterone hydroxylase activities (27%), [(3)H]aflatoxin-DNA binding (31%), and the protein levels of individual cytochrome P450s (CYPs) LMC1 (CYP2M1), LMC2, (CYP2K1), and LMC5 (CYP3A27) (average for three isoforms a reduction to 29% of control values) with only minor differences between sexes. Treatment with T had either no effect or resulted in small increases in total P450 in males (42%), in lauric acid hydroxylase in females (24%), and in 6beta-progesterone hydroxylase activity in males (21

  12. The Synergic Integrated Concepts of C2S

    DTIC Science & Technology

    2004-09-01

    manner, main intention or construction principle. The synergic integrated concept of the command and control system represents a definition and...trends comprise specifications of synergic integrated concepts for the command and control systems, particularly battlefield digitalisation and Network

  13. Investigation of synergism in binary mixtures of sweeteners.

    PubMed

    Schiffman, S S; Booth, B J; Carr, B T; Losee, M L; Sattely-Miller, E A; Graham, B G

    1995-01-01

    The purpose of the present study was to determine the presence and degree of synergism among all binary mixtures of 14 sweeteners varying in chemical structure. A trained panel evaluated binary combinations of the following sweeteners: three sugars (fructose, glucose, sucrose), two polyhydric alcohols (mannitol, sorbitol), two diterpenoid glycosides (rebaudioside-A, stevioside), two dipeptide derivatives (alitame, aspartame), one sulfamate (sodium cyclamate), one protein (thaumatin), two N-sulfonyl amides (acesulfame-K, sodium saccharin), and one dihydrochalcone (neohesperidin dihydrochalcone). Each sweetener was tested at three concentrations that were isosweet with 3%, 5%, and 7% sucrose. Two methods of analysis were performed to determine synergistic effects. In Method I, an ANOVA was performed for each intensity level to determine if the mean sweetness intensity ratings of each binary mixture were equal to nominal sweetness (i.e., additivity) or not equal to nominal sweetness (i.e., synergism or suppression). In Method II, an additional ANOVA was performed to determine if the sweetness intensity ratings of any given mixture were equal to or greater than the average of the sweetness ratings of the two pure components in that blend.

  14. Adsorption and synergism of cellobiohydrolase I and II of Trichoderma reesei during hydrolysis of microcrystalline cellulose

    SciTech Connect

    Medve, J.; Tjerneld, F. . Dept. of Biochemistry); Staahlberg, J. . Dept. of Molecular Biology)

    1994-11-05

    Hydrolysis of microcrystalline cellulose (Avicel) by cellobiohydrolase I and II (CBH I and II) from Trichoderma reesei has been studied. Adsorption and synergism of the enzymes were investigated. Experiments were performed at different temperatures and enzyme/substrate ratios using CBH I and CBH II alone and in reconstituted equimolar mixtures. Fast protein liquid chromatography (FPLC) analysis was found to be an accurate and reproducible method to follow the enzyme adsorption. A linear correlation was found between the conversion and the amount of adsorbed enzyme when Avicel was hydrolyzed by increasing amounts of CBH I and/or CBH II. CBH I had lower specific activity compared to CBH II although, over a wide concentration range, more CBH I was adsorbed than CBH II. Synergism between the cellobiohydrolases during hydrolysis of the amorphous fraction of Avicel showed a maximum as a function of total enzyme concentration. Synergism measured as a function of bound enzyme showed a continuous increase, which indicates that by decreasing the distance between the two enzymes the synergism is enhanced. The adsorption process for both enzymes was slow. Depending on the enzyme/substrate ratio it took 30--90 min to reach 95% of the equilibrium binding. The amount of bound enzyme decreased with increasing temperature. The two enzymes compete for the adsorption sites but also bind to specific sites. Stronger competition for adsorption sites was shown by CBH I.

  15. Synergism among ternary mixtures of fourteen sweeteners.

    PubMed

    Schiffman, S S; Sattely-Miller, E A; Graham, B G; Booth, B J; Gibes, K M

    2000-04-01

    The purpose of the present study was to determine the degree of synergism of sweet taste among ternary mixtures of 14 sweeteners. A trained panel evaluated ternary mixtures of 14 sweeteners varying in chemical structure and type. The ternary mixtures that were tested were limited to those in which the compounds comprising the mixture were synergistic in binary combinations, according to an earlier study. All sweeteners in the ternary mixtures were isointense with 2% sucrose, according to a previously developed formulae. Each self-mixture was also tested (e.g. 2% sucrose + 2% sucrose + 2% sucrose). The triad with the highest mean sweetness intensity rating was alitame-neohesperidin dihydrochalcone-rebaudioside-A (10.8). This represents an increase of 99.4% when compared with the average of the self-mixtures. While this is greater than the maximum of 74% increase found for binary mixtures, more dyadic combinations of sweeteners tested previously exhibited synergism than ternary combinations tested here. However, most ternary mixtures were synergistic (significantly greater than the average of the three self-mixtures) to some degree.

  16. Synergism between ipratropium and theophylline in asthma.

    PubMed Central

    Kreisman, H; Frank, H; Wolkove, N; Gent, M

    1981-01-01

    Ipratropium bromide is a bronchodilator whose effect has been compared with beta agonists but not with theophylline. Twelve asthmatics were given four two-week courses of the different combinations of ipratropium (40 micrograms in two puffs), theophylline capsules, and their corresponding placebos in a random, double-blind fashion. There was a significant increase in FEV1 and MMFR 60 minutes after theophylline was administered (p less than 0.05) when measured after one and two weeks of therapy. FEV1 and MMFR were significantly increased (p less than 0.05) 30 and 60 minutes after ipratropium inhalation and this increase was significantly greater when the patient had also been taking theophylline compared with placebo capsules (p less than 0.05). There was no toxicity associated with this combination. The synergism demonstrated may be related to the time sequence of drug administration, mechanical or cellular factors. PMID:6458919

  17. A synergic approach to terraforming Mars

    NASA Astrophysics Data System (ADS)

    Fogg, Martyn J.

    1992-08-01

    A two-stage terraforming scenario is outlined for Mars. The approach adopted differs from past methodology in two ways. It adopts a more conservative and plausible Martian volatile inventory. Possible planetary engineering solutions, including possible synergic use of terraforming techniques, are examined in detail. In the first stage, the Martian environment is modified to a state where it can support microbial and hardy plant life in approximately 200 years. While this step is conceptually similar to past scenarios, it differs greatly in detail. The second stage deals with the creation of conditions tolerable for human beings over a period of approximately 21,000 years. It is concluded that terraforming Mars is possible but not by the passive, or near-spontaneous, methods favored by some workers. A powerful industrial effort is required both on the planet's surface and in space as will be continuing technological intervention to stabilize the postterraformed regime.

  18. Antagonism and synergism between lead and zinc in amphibian larvae.

    PubMed

    Herkovits, J; Pérez-Coll, C S

    1991-01-01

    Lead and zinc effects on Bufo arenarum larval survival were studied in single and combined treatments. On a weight basis, lead is about twice as toxic as zinc. The antagonism or synergism between these heavy metals is dose-dependent.

  19. Synergism between hydrogen sulfide (H(2)S) and nitric oxide (NO) in vasorelaxation induced by stonustoxin (SNTX), a lethal and hypotensive protein factor isolated from stonefish Synanceja horrida venom.

    PubMed

    Liew, H C; Khoo, H E; Moore, P K; Bhatia, M; Lu, J; Moochhala, S M

    2007-04-10

    Stonustoxin (SNTX) is a 148 kDa, dimeric, hypotensive and lethal protein factor isolated from the venom of the stonefish Synanceja horrida. SNTX (10-320 ng/ml) progressively causes relaxation of endothelium-intact, phenylephrine (PE)-precontracted rat thoracic aortic rings. The SNTX-induced vasorelaxation was inhibited by L-N(G)-nitro arginine methyl ester (L-NAME), suggesting that nitric oxide (NO) contributes to the SNTX-induced response. Interestingly, D, L-proparglyglycine (PAG) and beta-cyano-L-alanine (BCA), irreversible and competitive inhibitors of cystathionine-gamma-lyase (CSE) respectively, also inhibited SNTX-induced vasorelaxation, indicating that H(2)S may also play a part in the effect of SNTX. The combined use of L-NAME with PAG or BCA showed that H(2)S and NO act synergistically in effecting SNTX-induced vasorelaxation.

  20. Developmental synergism of steroidal estrogens in sex determination.

    PubMed

    Bergeron, J M; Willingham, E; Osborn, C T; Rhen, T; Crews, D

    1999-02-01

    Gonadal sex in the red-eared slider turtle, Trachemys scripta, is determined by incubation temperature during embryonic development. Evidence suggests that temperature determines sex by influencing steroid hormone metabolism and/or sensitivity: steroidogenic enzyme inhibitors or exogenous sex steroid hormones and their man-made analogs override (or enhance) temperature effects on sex determination. Specifically, nonaromatizable androgens and aromatase inhibitors induce testis differentiation at female-producing temperatures, whereas aromatizable androgens and estrogens induce ovary differentiation at male-producing temperatures. Moreover, natural estrogens and temperature synergize to produce more females than would be expected if estrogens and temperature had purely additive effects on sex determination. In this study, we use sex reversal of turtle embryos incubated at a male-producing temperature to examine synergism among steroidal estrogens: estrone, 17ss-estradiol, and estriol. A low dose of 17ss-estradiol (200 ng) showed significant synergism when administered with a single low dose of estriol (10 ng). Likewise, a single low dose of estrone (250 ng) had a synergistic effect when combined with the same low dose of estriol (10 ng). We conclude that the weak natural estrogens estrone and 17ss-estradiol synergize with a low dose of the more potent estriol to reverse gonadal sex during the critical period of sexual differentiation. These results suggest that weak environmental estrogens may also synergize with stronger natural estrogens.

  1. Soluble amyloid beta-peptide and myelin basic protein strongly stimulate, alone and in synergism with combined proinflammatory cytokines, the expression of functional nitric oxide synthase-2 in normal adult human astrocytes.

    PubMed

    Chiarini, Anna; Dal Pra, Ilaria; Menapace, Lia; Pacchiana, Raffaella; Whitfield, James F; Armato, Ubaldo

    2005-11-01

    The accumulation of amyloid beta (Abeta)-peptides and their collection in fibrillar plaques in the human brain are believed to be responsible for Alzheimer's disease. The major neuron killers in the Alzheimer brain include proinflammatory cytokines and NO made by NOS-2 (inducible nitric oxide synthase-2). We have determined the effect of a soluble Abeta peptide, Abeta(1-40), on the expression of NOS-2 in astrocytes using a novel model system consisting of pure cultures of cells from adult human brains that, after the first three passages in vitro, become stably locked into the normal astrocytic phenotype like their counterparts in the adult human brain. Abeta(1-40) alone stimulated quiescent astrocytes to start expressing functional NOS-2 and dumping NO into the culture medium during the next 4 days. But adding three of the proinflammatory cytokines commonly produced in the Alzheimer brain--IFN-gamma, IL-1beta, and TNF-alpha--along with Abeta(1-40) more than trebled NOS-2 expression and doubled NO production. In view of the possibility of myelin breakdown in the Alzheimer brain, we also tested the capability of myelin basic protein (MBP) to stimulate NO production using human astrocytes. We found that MBP mimicked the ability of Abeta(1-40) to induce cells to release NO and adding the cytokine triad along with MBP more than doubled NO production and release. Thus, it appears that Abeta peptides and MBP can join forces with proinflammatory cytokines to enhance the NO-mediated killing of neurons in the Alzheimer brain.

  2. Synergism between soluble and dietary fiber bound antioxidants.

    PubMed

    Çelik, Ecem Evrim; Gökmen, Vural; Skibsted, Leif H

    2015-03-04

    This study investigates the synergism between antioxidants bound to dietary fibers (DF) of grains and soluble antioxidants of highly consumed beverages or their pure antioxidants. The interaction between insoluble fractions of grains containing bound antioxidants and soluble antioxidants was investigated using (i) a liposome-based system by measuring the lag phase before the onset of oxidation and (ii) an ESR-based system by measuring the reduction percentage of Fremy's salt radical. In both procedures, antioxidant capacities of DF-bound and soluble antioxidants were measured as well as their combinations, which were prepared at different ratios. The simple addition effects of DF-bound and soluble antioxidants were compared with measured values. The results revealed a clear synergism for almost all combinations in both liposome- and ESR-based systems. The synergism observed in DF-bound-soluble antioxidant system paints a promising picture considering the role of fiber in human gastrointestinal (GI) tract health.

  3. Tests of pesticidal synergism with young pheasants and Japanese quail

    USGS Publications Warehouse

    Kreitzer, J.F.; Spann, J.W.

    1973-01-01

    Thirteen pairs of chemicals involving 18 pesticides and two polychlorinated biphenyl preparations were each fed for 5 days to Japanese quail or ring-necked pheasant chicks 7 to 16 days of age. Malathion + EPN, and malathion + trichlorofon were moderately synergistic in tests with both species, whereas joint toxicities of the other chemicals tended to be additive. Comparisons with other studies of joint action of pesticides against mammals and insects suggest that the two species of birds tested are less susceptible to synergism than are mammals or insects. The results also suggest that the likelihood of a factor of synergism greater than three in birds is not great.

  4. C1-Cx revisited: intramolecular synergism in a cellulase.

    PubMed Central

    Din, N; Damude, H G; Gilkes, N R; Miller, R C; Warren, R A; Kilburn, D G

    1994-01-01

    Endoglucanase A (CenA) from the bacterium Cellulomonas fimi is composed of a catalytic domain and a nonhydrolytic cellulose-binding domain that can function independently. The individual domains interact synergistically in the disruption and hydrolysis of cellulose fibers. This intramolecular synergism is distinct from the well-known intermolecular synergism between individual cellulases. The catalytic domain corresponds to the hydrolytic Cx system and the cellulose-binding domain corresponds to the nonhydrolytic C1 system postulated by Reese et al. [Reese, E. T., Sui, R. G. H. & Levinson, H. S. (1950) J. Bacteriol. 59, 485-497] to be required for the hydrolysis of cellulose. PMID:7972069

  5. Enhance-Synergism and Suppression Effects in Multiple Regression

    ERIC Educational Resources Information Center

    Lipovetsky, Stan; Conklin, W. Michael

    2004-01-01

    Relations between pairwise correlations and the coefficient of multiple determination in regression analysis are considered. The conditions for the occurrence of enhance-synergism and suppression effects when multiple determination becomes bigger than the total of squared correlations of the dependent variable with the regressors are discussed. It…

  6. Enhance-Synergism and Suppression Effects in Multiple Regression

    ERIC Educational Resources Information Center

    Lipovetsky, Stan; Conklin, W. Michael

    2004-01-01

    Relations between pairwise correlations and the coefficient of multiple determination in regression analysis are considered. The conditions for the occurrence of enhance-synergism and suppression effects when multiple determination becomes bigger than the total of squared correlations of the dependent variable with the regressors are discussed. It…

  7. Peripheral synergism between tramadol and ibuprofen in the formalin test.

    PubMed

    Chavarria-Bolaños, Daniel; Perez-Urizar, José; Grandfils, Christian; Pozos-Guillén, Amaury

    2014-06-01

    Preclinical Research Analgesics with different mechanisms of action can be combined in order to obtain pharmacological synergism, employing lower doses of each agent, thus diminishing side effects. For instance, an atypical dual analgesic such as tramadol (TMD) and a nonsteroidal anti-inflammatory drug such as ibuprofen (IBU) are good candidates to be evaluated when combined and applied peripherally. The present study was conducted to evaluate possible local synergism between TMD and IBU when combined peripherally using the formalin test in rats. The effects of the individual analgesics and their combinations were evaluated simultaneously using a 5% formalin dilution. Dose-effect curves were determined for TMD (50-400 μg/paw) and IBU (1-100 μg/paw). Experimental effective doses were evaluated and isobolographic analyses were constructed to evaluate TMD-IBU combination synergism. Both drugs produced a dose-dependent analgesic effect when applied separately. Isobolographic analysis showed synergism during phase 1 (0-10 min) and phase 2 (15-60 min) when compared with theoretical doses (P < 0.05), with interaction indexes of 0.06 and 0.09, respectively. The present information supports the peripheral analgesic effect of TMD and IBU, especially when combined at appropriate doses.

  8. Drug activity and therapeutic synergism in cancer treatment.

    PubMed

    Carter, W H; Wampler, G L; Stablein, D M; Campbell, E D

    1982-08-01

    In work involving modeling of response surfaces to describe the effects of cancer chemotherapy treatments, it is important to define activity and therapeutic synergism in a statistically defensible manner. This requires the construction of confidence intervals around the estimated optimal treatment which has been achieved by use of an indirect method first proposed by Box and Hunter. Activity for a drug or a combination can be claimed at 100(1 - alpha)% level of confidence when the 100(1 - alpha)% confidence interval about the optimal treatment excludes a zero dose. Results of treatment of B16 melanoma and Lewis lung carcinoma with 3,4-dihydroxybenzohydroxamic acid are used to demonstrate this definition. Extensions of this concept lead to a statistically valid definition of therapeutic synergism. If the confidence region about the optimum combination of k drugs does not contact any of the k - 1 dimensional subspaces, then a k drug therapeutic synergism can be claimed. In the event that a k drug therapeutic synergism cannot be claimed, there may be subsets of the drugs which do combine with therapeutic synergy. These concepts are demonstrated by two- and three-drug combination experiments in L1210-bearing C57BL/6 x DBA/2 F1 (B6D2F1) mice. Razoxane and dacarbazine show therapeutic synergism at a 95% confidence level. A three-drug combination of 5-fluorouracil, Teniposide, and mitomycin C is considered. In this case, although the estimated optimum treatment includes 48.1 mg of 5-fluorouracil per kg, 15.9 mg of Teniposide per kg, and 3.9 mg of mitomycin C per kg, the confidence region generated failed to confirm at an 80% level of confidence that 5-fluorouracil was a necessary component of the best treatment.

  9. Optimization of synergism of a recombinant auxiliary activity 9 from Chaetomium globosum with cellulase in cellulose hydrolysis.

    PubMed

    Kim, In Jung; Nam, Ki Hyun; Yun, Eun Ju; Kim, Sooah; Youn, Hak Jin; Lee, Hee Jin; Choi, In-Geol; Kim, Kyoung Heon

    2015-10-01

    Auxiliary activity family 9 (AA9, formerly known as glycoside hydrolase family 61 or polysaccharide monooxygenase) is a group of fungal proteins that were recently found to have a significant synergism with cellulase in cellulose hydrolysis via the oxidative cleavage of glycosidic bonds of cellulose chains. In this study, we report the active expression of a recombinant fungal AA9 from Chaetomium globosum (CgAA9) in a bacterial host, Escherichia coli, and the optimization of its synergistic activity in cellulose hydrolysis by using cellulase. The recombinant CgAA9 (0.9 mg/g cellulose) exhibited 1.7-fold synergism in the hydrolysis of Avicel when incubated with 0.9 filter paper units of Celluclast 1.5 L/g cellulose. The first study of the active expression of AA9 using a bacterial host and its synergistic optimization could be useful for the industrial application of AA9 for the saccharification of lignocellulose.

  10. Molecular mechanism for the umami taste synergism

    PubMed Central

    Zhang, Feng; Klebansky, Boris; Fine, Richard M.; Xu, Hong; Pronin, Alexey; Liu, Haitian; Tachdjian, Catherine; Li, Xiaodong

    2008-01-01

    Umami is one of the 5 basic taste qualities. The umami taste of L-glutamate can be drastically enhanced by 5′ ribonucleotides and the synergy is a hallmark of this taste quality. The umami taste receptor is a heteromeric complex of 2 class C G-protein-coupled receptors, T1R1 and T1R3. Here we elucidate the molecular mechanism of the synergy using chimeric T1R receptors, site-directed mutagenesis, and molecular modeling. We propose a cooperative ligand-binding model involving the Venus flytrap domain of T1R1, where L-glutamate binds close to the hinge region, and 5′ ribonucleotides bind to an adjacent site close to the opening of the flytrap to further stabilize the closed conformation. This unique mechanism may apply to other class C G-protein-coupled receptors. PMID:19104071

  11. Molecular mechanism for the umami taste synergism.

    PubMed

    Zhang, Feng; Klebansky, Boris; Fine, Richard M; Xu, Hong; Pronin, Alexey; Liu, Haitian; Tachdjian, Catherine; Li, Xiaodong

    2008-12-30

    Umami is one of the 5 basic taste qualities. The umami taste of L-glutamate can be drastically enhanced by 5' ribonucleotides and the synergy is a hallmark of this taste quality. The umami taste receptor is a heteromeric complex of 2 class C G-protein-coupled receptors, T1R1 and T1R3. Here we elucidate the molecular mechanism of the synergy using chimeric T1R receptors, site-directed mutagenesis, and molecular modeling. We propose a cooperative ligand-binding model involving the Venus flytrap domain of T1R1, where L-glutamate binds close to the hinge region, and 5' ribonucleotides bind to an adjacent site close to the opening of the flytrap to further stabilize the closed conformation. This unique mechanism may apply to other class C G-protein-coupled receptors.

  12. Synergic effect of methanol and water on pine liquefaction.

    PubMed

    Zhao, Yun-Peng; Zhu, Wei-Wei; Wei, Xian-Yong; Fan, Xing; Cao, Jing-Pei; Dou, You-Quan; Zong, Zhi-Min; Zhao, Wei

    2013-08-01

    Pine liquefaction (PL) and re-liquefaction of its liquefaction residues in sub- and supercritical methanol, water or methanol/water mixed solvents (MWMSs) was investigated. The results show that isometric MWMS has the highest synergic effect on PL. Moreover, the total yield of bio-oil (BO) and conversion from pine and its residue both liquefied in the MWMS were obvious higher than those from PL in methanol (water) and re-liquefaction of its residue in water (methanol), suggesting that the interaction between the two solvents is responsible for synergic effect. This approach facilitates understanding the mechanism for biomass liquefaction in mixed solvents and developing efficient utilization process of biomass. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Mechanism and Synergism in Epithelial Fluid and Electrolyte Secretion

    PubMed Central

    Hong, Jeong Hee; Park, Seonghee; Shcheynikov, Nikolay; Muallem, Shmuel

    2014-01-01

    A central function of epithelia is the control of the volume and electrolyte composition of bodily fluids through vectorial transport of electrolytes and the obligatory H2O. In exocrine glands fluid and electrolyte secretion is carried out by both acinar and duct cells, with the portion of fluid secreted by each cell type vary among glands. All acinar cells secrete isotonic, plasma-like fluid, while the duct determines the final electrolyte composition of the fluid by absorbing most of the Cl− and secreting HCO3−. The key transporters mediating acinar fluid and electrolyte secretion are the basolateral Na+/K+/2Cl− cotransporter, the luminal Ca2+-activated Cl− channel ANO1 and basolateral and luminal Ca2+-activated K+ channels. Ductal fluid and HCO3− secretion are mediated by the basolateral membrane Na+-HCO3− cotransporter NBCe1-B and the luminal membrane Cl−/HCO3− exchanger slc26a6 and the Cl− channel CFTR. The function of the transporters is regulated by multiple inputs, which in the duct include major regulation by the WNK/SPAK pathway that inhibit secretion and the IRBIT/PP1 pathway that antagonize the effects of the WNK/SPAK pathway to both stimulate and coordinate the secretion. The function of these regulatory pathways in secretory glands acinar cells is yet to be examined. An important concept in biology is synergism among signaling pathways to generate the final physiological response that ensures regulation with high fidelity and guards against cell toxicity. While synergism is observed in all epithelial functions, the molecular mechanism mediating the synergism is not known. Recent work reveals a central role for IRBIT as a third messenger that integrates and synergizes the function of the Ca2+ and cAMP signaling pathways in activation of epithelial fluid and electrolyte secretion. These concepts are discussed in this review using secretion by the pancreatic and salivary gland ducts as model systems. PMID:24240699

  14. Endo-exo Synergism in Cellulose Hydrolysis Revisited*

    PubMed Central

    Jalak, Jürgen; Kurašin, Mihhail; Teugjas, Hele; Väljamäe, Priit

    2012-01-01

    Synergistic cooperation of different enzymes is a prerequisite for efficient degradation of cellulose. The conventional mechanistic interpretation of the synergism between randomly acting endoglucanases (EGs) and chain end-specific processive cellobiohydrolases (CBHs) is that EG-generated new chain ends on cellulose surface serve as starting points for CBHs. Here we studied the hydrolysis of bacterial cellulose (BC) by CBH TrCel7A and EG TrCel5A from Trichoderma reesei under both single-turnover and “steady state” conditions. Unaccountable by conventional interpretation, the presence of EG increased the rate constant of TrCel7A-catalyzed hydrolysis of BC in steady state. At optimal enzyme/substrate ratios, the “steady state” rate of synergistic hydrolysis became limited by the velocity of processive movement of TrCel7A on BC. A processivity value of 66 ± 7 cellobiose units measured for TrCel7A on 14C-labeled BC was close to the leveling off degree of polymerization of BC, suggesting that TrCel7A cannot pass through the amorphous regions on BC and stalls. We propose a mechanism of endo-exo synergism whereby the degradation of amorphous regions by EG avoids the stalling of TrCel7A and leads to its accelerated recruitment. Hydrolysis of pretreated wheat straw suggested that this mechanism of synergism is operative also in the degradation of lignocellulose. Although both mechanisms of synergism are used in parallel, the contribution of conventional mechanism is significant only at high enzyme/substrate ratios. PMID:22733813

  15. Chemokines and other GPCR ligands synergize in receptor-mediated migration of monocyte-derived immature and mature dendritic cells.

    PubMed

    Gouwy, Mieke; Struyf, Sofie; Leutenez, Lien; Pörtner, Noëmie; Sozzani, Silvano; Van Damme, Jo

    2014-03-01

    Dendritic cells (DCs) are potent antigen presenting cells, described as the initiators of adaptive immune responses. Immature monocyte-derived DCs (MDDC) showed decreased CD14 expression, increased cell surface markers DC-SIGN and CD1a and enhanced levels of receptors for the chemokines CCL3 (CCR1/CCR5) and CXCL8 (CXCR1/CXCR2) compared with human CD14⁺ monocytes. After further MDDC maturation by LPS, the markers CD80 and CD83 and the chemokine receptors CXCR4 and CCR7 were upregulated, whereas CCR1, CCR2 and CCR5 expression was reduced. CCL3 dose-dependently synergized with CXCL8 or CXCL12 in chemotaxis of immature MDDC. CXCL12 augmented the CCL3-induced ERK1/2 and Akt phosphorylation in immature MDDC, although the synergy between CCL3 and CXCL12 in chemotaxis of immature MDDC was dependent on the Akt signaling pathway but not on ERK1/2 phosphorylation. CCL2 also synergized with CXCL12 in immature MDDC migration. Moreover, two CXC chemokines not sharing receptors (CXCL12 and CXCL8) cooperated in immature MDDC chemotaxis, whereas two CC chemokines (CCL3 and CCL7) sharing CCR1 did not. Further, the non-chemokine G protein-coupled receptor ligands chemerin and fMLP synergized with respectively CCL7 and CCL3 in immature MDDC signaling and migration. Finally, CXCL12 and CCL3 did not cooperate, but CXCL12 synergized with CCL21 in mature MDDC chemotaxis. Thus, chemokine synergy in immature and mature MDDC migration is dose-dependently regulated by chemokines via alterations in their chemokine receptor expression pattern according to their role in immune responses.

  16. 17 CFR 260.7a-27 - Title of securities.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Title of securities. 260.7a-27 Section 260.7a-27 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 General Requirements As to Contents § 260.7a-27 Title of securities. Where the title...

  17. 17 CFR 260.7a-27 - Title of securities.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Title of securities. 260.7a-27 Section 260.7a-27 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 General Requirements As to Contents § 260.7a-27 Title of securities. Where the title...

  18. 17 CFR 260.7a-27 - Title of securities.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Title of securities. 260.7a-27 Section 260.7a-27 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 General Requirements As to Contents § 260.7a-27 Title of securities. Where the title...

  19. 17 CFR 260.7a-27 - Title of securities.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Title of securities. 260.7a-27 Section 260.7a-27 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 General Requirements As to Contents § 260.7a-27 Title of securities. Where the title...

  20. Bryostatin-1 synergizes with histone deacetylase inhibitors to reactivate HIV-1 from latency.

    PubMed

    Pérez, Moisés; de Vinuesa, Amaya García; Sanchez-Duffhues, Gonzalo; Marquez, Nieves; Bellido, M Luz; Muñoz-Fernandez, M Angeles; Moreno, Santiago; Castor, Trevor P; Calzado, Marco A; Muñoz, Eduardo

    2010-09-01

    The persistence of latent HIV-infected cellular reservoirs represents the major hurdle to virus eradication on patients treated with HAART. It has been suggested that successful depletion of such latent reservoirs will require a combination of therapeutic agents that can specifically and efficiently act on cells harboring latent HIV-1 provirus. Using Jurkat-LAT-GFP cells, a tractable model of HIV-1 latency, we have found that bryostatin -1 reactivates HIV-1 through a classical PKC-dependent pathway. Bryostatin-1 also activates MAPKs and NF-κB pathways and synergizes with HDAC inhibitors to reactivate HIV-1 from latency. Bryostatin-1 downregulates the expression of the HIV-1 co-receptors CD4 and CXCR4 and prevented de novo HIV-1 infection in susceptible cells. We applied proteomic methods to investigate major changes in protein expression in Jurkat-LAT-GFP under latency and reactivation conditions. We identified up-regulation of proteins that may be involved in the innate anti-HIV-1 response (NKEF-A and MHD2) and in different cell functions (i.e. cofilin-1 and transgelin-2) of the host cells. PKC agonists may represent a valuable pharmacological approach to purge latent HIV from cellular reservoirs and at the moment, the only clinically available PKC agonist is bryostatin-1. This drug has been tested in numerous clinical trials and its pharmacokinetics and toxicity in humans is well known. Moreover, bryostatin-1 potently synergizes with other HDAC inhibitors commonly used in the medical practice such as valproic acid. Therefore, bryostatin-1, alone or in combination with HDAC inhibitors, could be used in HAART treated patients to validate the hypothesis that reactivating HIV-1 from latency could purge HIV-1 reservoirs.

  1. Competition, professional synergism, and the geographic distribution of rural physicians.

    PubMed

    Connor, R A; Hillson, S D; Krawelski, J E

    1995-11-01

    This study provides a theoretical and empirical investigation of competition and synergism among physicians in rural areas. The results show that rural primary care physicians cluster together rather than distribute themselves evenly. This suggests that public policy makers and rural communities must take an active role to ensure provider availability in all rural areas. There is less clustering among subspecialists. The results also reveal a disturbing negative relationship between young children and physician availability in rural areas. Finally, the results provide strong evidence that the relationship between rural physicians and hospitals is synergistic.

  2. Asbestos as an air pollutant and synergism with smoking

    SciTech Connect

    Frank, A.L.

    1986-01-01

    For many years the health consequences of asbestos exposure, including an overall mortality experience of approximately 50% from cancer among occupationally exposed individuals, have been well documented worldwide. Less well appreciated are the lessons to be learned from data available concerning outdoor asbestos air pollution and, of perhaps greater concern, the risks in certain indoor environments contaminated by this useful mineral. The biologically complex issue of carcinogenic synergism has been clearly demonstrated for cigarette smoking, asbestos-exposed individuals. Prevention of cancer among those exposed to asbestos not only requires efforts to minimize such exposure, but also requires strong antismoking measures among those exposed.

  3. Melatonin synergizes the chemotherapeutic effect of 5-fluorouracil in colon cancer by suppressing PI3K/AKT and NF-κB/iNOS signaling pathways.

    PubMed

    Gao, Yue; Xiao, Xiangsheng; Zhang, Changlin; Yu, Wendan; Guo, Wei; Zhang, Zhifeng; Li, Zhenglin; Feng, Xu; Hao, Jiaojiao; Zhang, Kefang; Xiao, Bingyi; Chen, Miao; Huang, Wenlin; Xiong, Shunbin; Wu, Xiaojun; Deng, Wuguo

    2017-03-01

    5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents in colon cancer treatment, but has a narrow therapeutic index limited by its toxicity. Melatonin exerts antitumor activity in various cancers, but it has never been combined with 5-FU as an anticolon cancer treatment to improve the chemotherapeutic effect of 5-FU. In this study, we assessed such combinational use in colon cancer and investigated whether melatonin could synergize the antitumor effect of 5-FU. We found that melatonin significantly enhanced the 5-FU-mediated inhibition of cell proliferation, colony formation, cell migration and invasion in colon cancer cells. We also found that melatonin synergized with 5-FU to promote the activation of the caspase/PARP-dependent apoptosis pathway and induce cell cycle arrest. Further mechanism study demonstrated that melatonin synergized the antitumor effect of 5-FU by targeting the PI3K/AKT and NF-κB/inducible nitric oxide synthase (iNOS) signaling. Melatonin in combination with 5-FU markedly suppressed the phosphorylation of PI3K, AKT, IKKα, IκBα, and p65 proteins, promoted the translocation of NF-κB p50/p65 from the nuclei to cytoplasm, abrogated their binding to the iNOS promoter, and thereby enhanced the inhibition of iNOS signaling. In addition, pretreatment with a PI3K- or iNOS-specific inhibitor synergized the antitumor effects of 5-FU and melatonin. Finally, we verified in a xenograft mouse model that melatonin and 5-FU exerted synergistic antitumor effect by inhibiting the AKT and iNOS signaling pathways. Collectively, our study demonstrated that melatonin synergized the chemotherapeutic effect of 5-FU in colon cancer through simultaneous suppression of multiple signaling pathways. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Differential Roles of AC2 and AC4 of Cassava Geminiviruses in Mediating Synergism and Suppression of Posttranscriptional Gene Silencing

    PubMed Central

    Vanitharani, Ramachandran; Chellappan, Padmanabhan; Pita, Justin S.; Fauquet, Claude M.

    2004-01-01

    Posttranscriptional gene silencing (PTGS) in plants is a natural defense mechanism against virus infection. In mixed infections, virus synergism is proposed to result from suppression of the host defense mechanism by the viruses. Synergistic severe mosaic disease caused by simultaneous infection with isolates of the Cameroon strain of African cassava mosaic virus (ACMV-[CM]) and East African cassava mosaic Cameroon virus (EACMCV) in cassava and tobacco is characterized by a dramatic increase in symptom severity and a severalfold increase in viral-DNA accumulation by both viruses compared to that in singly infected plants. Here, we report that synergism between ACMV-[CM] and EACMCV is a two-way process, as the presence of the DNA-A component of ACMV-[CM] or EACMCV in trans enhanced the accumulation of viral DNA of EACMCV and ACMV-[CM], respectively, in tobacco BY-2 protoplasts. Furthermore, transient expression of ACMV-[CM] AC4 driven by the Cauliflower mosaic virus 35S promoter (p35S-AC4) enhanced EACMCV DNA accumulation by ∼8-fold in protoplasts, while p35S-AC2 of EACMCV enhanced ACMV-[CM] DNA accumulation, also by ∼8-fold. An Agrobacterium-based leaf infiltration assay determined that ACMV-[CM] AC4 and EACMCV AC2, the putative synergistic genes, were able to suppress PTGS induced by green fluorescent protein (GFP) and eliminated the short interfering RNAs associated with PTGS, with a correlated increase in GFP mRNA accumulation. In addition, we have identified AC4 of Sri Lankan cassava mosaic virus and AC2 of Indian cassava mosaic virus as suppressors of PTGS, indicating that geminiviruses evolved differently in regard to interaction with the host. The specific and different roles played by these AC2 and AC4 proteins of cassava geminiviruses in regulating anti-PTGS activity and their relation to synergism are discussed. PMID:15308741

  5. Lethal synergism between organic and inorganic wood preservatives via formation of an unusual lipophilic ternary complex

    SciTech Connect

    Sheng, Zhi-Guo; Li, Yan; Fan, Rui-Mei; Chao, Xi-Juan; Zhu, Ben-Zhan

    2013-02-01

    We have shown previously that exposing bacteria to wood preservatives pentachlorophenol (PCP) and copper-containing compounds together causes synergistic toxicity. However, it is not clear whether these findings also hold true in mammalian cells; and if so, what is the underlying molecular mechanism? Here we show that PCP and a model copper complex bis-(1,10-phenanthroline) cupric (Cu(OP){sub 2}), could also induce synergistic cytotoxicity in human liver cells. By the single crystal X-ray diffraction and atomic absorption spectroscopy assay, the synergism was found to be mainly due to the formation of a lipophilic ternary complex with unusual structural and composition characteristics and subsequent enhanced cellular copper uptake, which markedly promoted cellular reactive oxygen species (ROS) production, leading to apoptosis by decreasing mitochondrial membrane potential, increasing pro-apoptotic protein expression, releasing cytochrome c from mitochondria and activating caspase-3, and -9. Analogous results were observed with other polychlorinated phenols (PCPs) and Cu(OP){sub 2}. Synergistic cytotoxicity could be induced by PCP/Cu(OP){sub 2} via formation of an unusual lipophilic complex in HepG2 cells. The formation of ternary complexes with similar lipophilic character could be of relevance as a general mechanism of toxicity, which should be taken into consideration especially when evaluating the toxicity of environmental pollutants found at currently-considered non- or sub-toxic concentrations. -- Highlights: ► The combination of PCP/Cu(OP){sub 2} induces synergistic cytotoxicity in HepG2 cells. ► The synergism is mainly due to forming a lipophilic ternary complex between them. ► The formation of lipophilic ternary complex enhances cellular copper uptake. ► PCP/Cu(OP){sub 2} stimulates the cellular ROS production. ► The ROS promoted by PCP/Cu(OP){sub 2} induces mitochondria-dependent apoptosis.

  6. Molecular mechanisms regulating the synergism between IL-32γ and NOD for the activation of eosinophils.

    PubMed

    Wong, Chun-Kwok; Dong, Jie; Lam, Christopher Wai-Kei

    2014-04-01

    IL-32 is a proinflammatory cytokine associated with infections, autoimmune diseases, and allergic asthma. In the present study, we elucidated the synergistic effect of IL-32γ and NOD ligand on the activation of human eosinophils, principal effector cells for allergic inflammation, and the underlying mechanisms. Specific IL-32-binding protein, PR3, was found to localize on the cell surface and in the cytoplasm of eosinophils. IL-32γ was more capable of activating eosinophils than its isotype variant IL-32α and exhibited synergistic effect with NOD1 ligand iE-DAP and NOD2 ligand MDP on the induction of allergic inflammation-related IL-1β, TNF-α, and chemokines CXCL8, CCL3, and CCL4 (P<0.05). Moreover, IL-32γ and iE-DAP or MDP induced the significant up-regulation of the cell-surface expression of adhesion molecule CD18 and ICAM-1 on eosinophils. Synergism between IL-32γ and NOD ligands was dependent on the activation of intracellular caspase 1, ERKs, p38 MAPK, and NF-κB pathways in eosinophils. The further-enhanced CD18 and ICAM-1 expression and production of cytokines and chemokines were observed in eosinophils cocultured with human bronchial epithelial BEAS-2B cells. Furthermore, combined treatment of IL-32γ and NOD ligand could activate the release of eosinophil extracellular DNA traps, thereby implying the pathogen-defense mechanisms of eosinophils. Together, the above study provides pivotal immunological mechanisms by which bacterial infection-mediated activation of NOD1,2, together with IL-32γ, can synergize the activation of eosinophils interacting with bronchial epithelial cells.

  7. The Synergism between Belotecan and Cisplatin in Gastric Cancer

    PubMed Central

    Jung, Joo Young; Song, Sang Hyun; Kim, Tae-Young; Park, Jung Hyun; Jong, Hyun-Soon; Im, Seock-Ah; Kim, Tae-You; Kim, Noe Kyoung

    2006-01-01

    Purpose We wanted to demonstrate the anti-cancer effect and interaction between belotecan and cisplatin on gastric cancer cell line and we evaluated the mechanisms of this synergistic effect in vitro. Materials and Methods The growth inhibitory effect of belotocan and cisplatin against several gastric cancer cell lines (SNU-5, SNU-16 and SNU-601) was estimated by tetrazolium dye assay. The effect of a combination treatment was evaluated by the isobologram method. The biochemical mechanisms for the interaction between the drugs were analyzed by measuring the formation of DNA interstrand cross-links (ICLs) and DNA topo-I activity. Results Belotecan showed synergism with cisplatin for growth inhibitory effect on the gastric cancer cell lines SNU-5, and SNU-16, but this was subadditive on the SNU-601 cell line. The formation of DNA ICLs in SNU-16 cells by cisplatin was increased by combination with belotecan, but this was not affected in SNU-601 cells. The topo-I inhibition by belotecan was enhanced at high concentrations of cisplatin in SNU-16, but not in SNU-601 cells. Conclusion Belotecan and cisplatin show various combination effect against gastric cancer cells. The synergism between cisplatin and belotecan could be the result of one of the following mechanisms: the modulating effect of belotecan on the repair of cisplatin-induced DNA adducts and the enhancing effect of cisplatin on the belotecan-induced topo-I inhibitory effect. PMID:19771277

  8. Synergism in education: An innovative approach to practice teaching supervision

    NASA Astrophysics Data System (ADS)

    Mereni, Joseph Ibewuike

    1985-12-01

    The problem of effective teacher education is central to the pressing needs of Nigerian education at all levels. Scholars have identified many of them, including the general problems relating to the supervision, guidance, and evaluation of student-practice teaching. The purpose of this essay is briefly to describe an innovative approach undertaken by the Imo State School Board (Nigeria), in collaboration with the Ministry of Education, to resolve some of the problems identified. The underlying assumption is that the student teachers' internship is best conducted with closer collaboration, supervision, and guidance of the teachers. The study employed a theoretical framework synergism in education which integrated earlier studies by both American and Nigerian scholars. The concept of synergism has been defined as the combined healthy action of all `elements' of a system. Application of the theory showed how the State Ministry of Education, the State School Board, the Teacher Training Colleges and the Nigeria Union of Teachers of Imo State collectively resolved in 1980 the problems of inadequate supervisory personnel, high cost of student-teaching internship, and poor student assessment and evaluation. With the synergetic supervisory process, the functions of planning, changing, and decision-making about instructional improvement are shared, with a certain degree of power equalization, among the student teachers, supervisors, co-operating teachers, and the school executives.

  9. Oligomerization is a key step in Cyt1Aa membrane insertion and toxicity but not necessary to synergize Cry11Aa toxicity in Aedes aegypti larvae

    PubMed Central

    López-Diaz, Jazmin A.; Cantón, Pablo Emiliano; Gill, Sarjeet S.; Soberón, Mario; Bravo, Alejandra

    2014-01-01

    Summary Bacillus thuringiensis produces insecticidal Cry and Cyt proteins that are toxic to different insect orders. In addition, Cyt toxins also display haemolytic activity. Both toxins are pore-forming proteins that form oligomeric structures that insert into the target membrane to lyse cells. Cyt toxins play an important role in mosquitocidal activity since they synergize Cry toxins and are able to overcome resistance to Cry toxins. Cry and Cyt toxins interact by specific epitopes, and this interaction is important to induce the synergistic activity observed. It was proposed that Cyt toxins do not interact with protein receptors but directly interacting with the specific midgut cell lipids. Here, we analysed if oligomerization and membrane insertion of Cyt1Aa are necessary steps to synergize Cry11Aa toxicity. We characterized Cyt1Aa helix α-C mutants that were affected in oligomerization, in membrane insertion and also in haemolytic and insecticidal activities. However, these mutants were still able to synergize Cry11Aa toxicity indicating these steps are independent events of Cyt1Aa synergistic activity. Furthermore, the data indicate that formation of stable Cyt1Aa-oligomeric structure is a key step for membrane insertion, haemolysis and insecticidal activity. PMID:24112611

  10. Design of an enzyme cocktail consisting of different fungal platforms for efficient hydrolysis of sugarcane bagasse: Optimization and synergism studies.

    PubMed

    Méndez Arias, Johanna; Modesto, Luiz Felipe Amarante; Polikarpov, Igor; Pereira, Nei

    2016-09-01

    Lignocellulosic materials represent a very important and promising source of renewable biomass. In order to turn them into fermentable sugars, synergism among the different enzymes that carry out bioconversion of these materials is one of the main factors that should be considered. Experimental mixture design was performed to optimize the proportion of enzymes produced by native strains of Trichoderma harzianum IOC 3844, Penicillium funiculosum ATCC 11797, and Aspergillus niger ATCC 1004, resulting in a proportion of 15, 50, and 35%, respectively. This mixture was able to hydrolyze 25 g/L of pretreated sugarcane bagasse with 91% of yield after 48 h of enzymatic reaction. Synergism along the hydrolysis process, besides the influence of lignin, hemicellulose, and solids loading, were also studied. Response surface methodology (RSM) based on Central Composite Rotatable Design was used to optimize solids and protein loadings to increase glucose release and enzymatic hydrolysis yield. The optimum solid and protein loadings established with RSM were 196 g/L and 24 mg/g cellulose, respectively, and under these conditions (94.1 ± 8) g/L of glucose were obtained, corresponding to a hydrolysis yield of 64%. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1222-1229, 2016. © 2016 American Institute of Chemical Engineers.

  11. Synergic effects of tryptamine and octopamine on ophiuroid luminescence (Echinodermata).

    PubMed

    Vanderlinden, C; Mallefet, J

    2004-10-01

    In ophiuroids, bioluminescence is under nervous control. Previous studies have shown that acetylcholine is the main neurotransmitter triggering light emission in Amphipholis squamata and Amphiura filiformis. By contrast, none of the neurotransmitters tested so far induced luminescence in two other ophiuroid species, Ophiopsila aranea and Ophiopsila californica. The aim of this work was thus to investigate the putative involvement of two biogenic amines, tryptamine and octopamine, in light emission of three ophiuroid species. A. filiformis responds to both tryptamine and octopamine, mainly on its arm segments, while O. californica only responds to tryptamine stimulation. By contrast, tryptamine and octopamine do not seem to be involved in O. aranea luminescence control since none of these substances induced light emission in this species. The synergic effects of several other drugs with tryptamine and octopamine were also tested.

  12. AZDAST the new horizon in antimicrobial synergism detection.

    PubMed

    Ziaei-Darounkalaei, Navid; Ameri, Mehrdad; Zahraei-Salehi, Taghi; Ziaei-Darounkalaei, Omid; Mohajer-Tabrizi, Tahereh; Bornaei, Lotfollah

    2016-01-01

    The attempts via introducing many methods have been conducted to select the best antibiotic combination in the treatment of seriously ill patients. Operational or interpretational complexity or time-consuming along with sufficient accuracy led to postpone routine clinical use of these tests until today, despite the urgent need for them. By this study and proposed method, selection of the best double antibiotic synergistic combination against resistant pathogen is simply same as Kirby-Bauer antibiotic susceptibility test. It seems, precise and reliable results (very low coefficient of variation) will be introduced it as a routine accurate diagnostic doubled antimicrobial synergism test.•The objective of this study was to introduce a novel method in antibiotic interaction detection.•It demonstrates high sensitivity and accuracy.•Easy implementation by routine microbiology labs materials and equipment and so easy stand-alone interpretation seems to make it friendly test be able to replacing the previous methods.

  13. Terpenes from Copaifera demonstrated in vitro antiparasitic and synergic activity.

    PubMed

    Izumi, Erika; Ueda-Nakamura, Tânia; Veiga, Valdir F; Pinto, Angelo C; Nakamura, Celso Vataru

    2012-04-12

    To discover new possible therapies for Chagas' disease, we evaluated against all Trypanosoma cruzi life stages the in vitro trypanocidal and synergistic activity of terpenes isolated from Copaifera oleoresins collected in the Amazon and investigated their possible mechanism of action. Seven acid diterpenes and one sesquiterpene were tested. Terpenes promoted changes in oxidative metabolism followed by autophagic processes in the parasite cell leading to selective death. Furthermore, they were more effective against replicative forms, in particular amastigotes. A synergistic effect occurred. Cytotoxicity to erythrocytes and nucleated cells was moderate. This is the first study showing synergic activity between two terpenes against T. cruzi. Combinations of natural compounds can show high activity and may lead to new alternative treatments in the future.

  14. Ocean Warming–Acidification Synergism Undermines Dissolved Organic Matter Assembly

    PubMed Central

    Chen, Chi-Shuo; Anaya, Jesse M.; Chen, Eric Y-T; Farr, Erik; Chin, Wei-Chun

    2015-01-01

    Understanding the influence of synergisms on natural processes is a critical step toward determining the full-extent of anthropogenic stressors. As carbon emissions continue unabated, two major stressors—warming and acidification—threaten marine systems on several scales. Here, we report that a moderate temperature increase (from 30°C to 32°C) is sufficient to slow— even hinder—the ability of dissolved organic matter, a major carbon pool, to self-assemble to form marine microgels, which contribute to the particulate organic matter pool. Moreover, acidification lowers the temperature threshold at which we observe our results. These findings carry implications for the marine carbon cycle, as self-assembled marine microgels generate an estimated global seawater budget of ~1016 g C. We used laser scattering spectroscopy to test the influence of temperature and pH on spontaneous marine gel assembly. The results of independent experiments revealed that at a particular point, both pH and temperature block microgel formation (32°C, pH 8.2), and disperse existing gels (35°C). We then tested the hypothesis that temperature and pH have a synergistic influence on marine gel dispersion. We found that the dispersion temperature decreases concurrently with pH: from 32°C at pH 8.2, to 28°C at pH 7.5. If our laboratory observations can be extrapolated to complex marine environments, our results suggest that a warming–acidification synergism can decrease carbon and nutrient fluxes, disturbing marine trophic and trace element cycles, at rates faster than projected. PMID:25714090

  15. Ocean warming-acidification synergism undermines dissolved organic matter assembly.

    PubMed

    Chen, Chi-Shuo; Anaya, Jesse M; Chen, Eric Y-T; Farr, Erik; Chin, Wei-Chun

    2015-01-01

    Understanding the influence of synergisms on natural processes is a critical step toward determining the full-extent of anthropogenic stressors. As carbon emissions continue unabated, two major stressors--warming and acidification--threaten marine systems on several scales. Here, we report that a moderate temperature increase (from 30°C to 32°C) is sufficient to slow--even hinder--the ability of dissolved organic matter, a major carbon pool, to self-assemble to form marine microgels, which contribute to the particulate organic matter pool. Moreover, acidification lowers the temperature threshold at which we observe our results. These findings carry implications for the marine carbon cycle, as self-assembled marine microgels generate an estimated global seawater budget of ~1016 g C. We used laser scattering spectroscopy to test the influence of temperature and pH on spontaneous marine gel assembly. The results of independent experiments revealed that at a particular point, both pH and temperature block microgel formation (32°C, pH 8.2), and disperse existing gels (35°C). We then tested the hypothesis that temperature and pH have a synergistic influence on marine gel dispersion. We found that the dispersion temperature decreases concurrently with pH: from 32°C at pH 8.2, to 28°C at pH 7.5. If our laboratory observations can be extrapolated to complex marine environments, our results suggest that a warming-acidification synergism can decrease carbon and nutrient fluxes, disturbing marine trophic and trace element cycles, at rates faster than projected.

  16. HDAC and Proteasome Inhibitors Synergize to Activate Pro-Apoptotic Factors in Synovial Sarcoma

    PubMed Central

    Barrott, Jared J.; Yao, Ren Jie; Poulin, Neal M.; Brodin, Bertha A.; Jones, Kevin B.; Underhill, T. Michael; Nielsen, Torsten O.

    2017-01-01

    Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting its driving SS18-SSX fusion oncoprotein are currently available. Patients remain at high risk for early and late metastasis. A high-throughput drug screen consisting of over 900 tool compounds and epigenetic modifiers, representing over 100 drug classes, was undertaken in a panel of synovial sarcoma cell lines to uncover novel sensitizing agents and targetable pathways. Top scoring drug categories were found to be HDAC inhibitors and proteasomal targeting agents. We find that the HDAC inhibitor quisinostat disrupts the SS18-SSX driving protein complex, thereby reestablishing expression of EGR1 and CDKN2A tumor suppressors. In combination with proteasome inhibition, HDAC inhibitors synergize to decrease cell viability and elicit apoptosis. Quisinostat inhibits aggresome formation in response to proteasome inhibition, and combination treatment leads to elevated endoplasmic reticulum stress, activation of pro-apoptotic effector proteins BIM and BIK, phosphorylation of BCL-2, increased levels of reactive oxygen species, and suppression of tumor growth in a murine model of synovial sarcoma. This study identifies and provides mechanistic support for a particular susceptibility of synovial sarcoma to the combination of quisinostat and proteasome inhibition. PMID:28056055

  17. LYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunity.

    PubMed

    Proekt, Irina; Miller, Corey N; Jeanne, Marion; Fasano, Kayla J; Moon, James J; Lowell, Clifford A; Gould, Douglas B; Anderson, Mark S; DeFranco, Anthony L

    2016-10-03

    Studies of the genetic factors associated with human autoimmune disease suggest a multigenic origin of susceptibility; however, how these factors interact and through which tolerance pathways they operate generally remain to be defined. One key checkpoint occurs through the activity of the autoimmune regulator AIRE, which promotes central T cell tolerance. Recent reports have described a variety of dominant-negative AIRE mutations that likely contribute to human autoimmunity to a greater extent than previously thought. In families with these mutations, the penetrance of autoimmunity is incomplete, suggesting that other checkpoints play a role in preventing autoimmunity. Here, we tested whether a defect in LYN, an inhibitory protein tyrosine kinase that is implicated in systemic autoimmunity, could combine with an Aire mutation to provoke organ-specific autoimmunity. Indeed, mice with a dominant-negative allele of Aire and deficiency in LYN spontaneously developed organ-specific autoimmunity in the eye. We further determined that a small pool of retinal protein-specific T cells escaped thymic deletion as a result of the hypomorphic Aire function and that these cells also escaped peripheral tolerance in the presence of LYN-deficient dendritic cells, leading to highly destructive autoimmune attack. These findings demonstrate how 2 distinct tolerance pathways can synergize to unleash autoimmunity and have implications for the genetic susceptibility of autoimmune disease.

  18. Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity.

    PubMed

    Chamoto, Kenji; Chowdhury, Partha S; Kumar, Alok; Sonomura, Kazuhiro; Matsuda, Fumihiko; Fagarasan, Sidonia; Honjo, Tasuku

    2017-01-31

    Although immunotherapy by PD-1 blockade has dramatically improved the survival rate of cancer patients, further improvement in efficacy is required to reduce the fraction of less sensitive patients. In mouse models of PD-1 blockade therapy, we found that tumor-reactive cytotoxic T lymphocytes (CTLs) in draining lymph nodes (DLNs) carry increased mitochondrial mass and more reactive oxygen species (ROS). We show that ROS generation by ROS precursors or indirectly by mitochondrial uncouplers synergized the tumoricidal activity of PD-1 blockade by expansion of effector/memory CTLs in DLNs and within the tumor. These CTLs carry not only the activation of mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) but also an increment of their downstream transcription factors such as PPAR-gamma coactivator 1α (PGC-1α) and T-bet. Furthermore, direct activators of mTOR, AMPK, or PGC-1α also synergized the PD-1 blockade therapy whereas none of above-mentioned chemicals alone had any effects on tumor growth. These findings will pave a way to developing novel combinatorial therapies with PD-1 blockade.

  19. Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

    PubMed Central

    Chamoto, Kenji; Chowdhury, Partha S.; Kumar, Alok; Sonomura, Kazuhiro; Matsuda, Fumihiko; Fagarasan, Sidonia; Honjo, Tasuku

    2017-01-01

    Although immunotherapy by PD-1 blockade has dramatically improved the survival rate of cancer patients, further improvement in efficacy is required to reduce the fraction of less sensitive patients. In mouse models of PD-1 blockade therapy, we found that tumor-reactive cytotoxic T lymphocytes (CTLs) in draining lymph nodes (DLNs) carry increased mitochondrial mass and more reactive oxygen species (ROS). We show that ROS generation by ROS precursors or indirectly by mitochondrial uncouplers synergized the tumoricidal activity of PD-1 blockade by expansion of effector/memory CTLs in DLNs and within the tumor. These CTLs carry not only the activation of mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) but also an increment of their downstream transcription factors such as PPAR-gamma coactivator 1α (PGC-1α) and T-bet. Furthermore, direct activators of mTOR, AMPK, or PGC-1α also synergized the PD-1 blockade therapy whereas none of above-mentioned chemicals alone had any effects on tumor growth. These findings will pave a way to developing novel combinatorial therapies with PD-1 blockade. PMID:28096382

  20. Fibronectin EDA and CpG synergize to enhance antigen-specific Th1 and cytotoxic responses.

    PubMed

    Julier, Ziad; de Titta, Alexandre; Grimm, Alizée J; Simeoni, Eleonora; Swartz, Melody A; Hubbell, Jeffrey A

    2016-05-05

    Subunit vaccines, employing purified protein antigens rather than intact pathogens, require the addition of adjuvants for enhanced immunogenicity with a correct balance between strong activation of the immune system and low toxicity. Here we show that the endogenous (i.e., autologous) non-toxic TLR4 agonist extra domain A type III repeat of fibronectin (FNIII EDA) can synergize with the exogenous (i.e., bacterial), toxic-at-high-dose, TLR9 agonist CpG to induce efficient cellular immune responses while keeping the dose of CpG low. The efficacy of the combined TLR agonists, even at half-doses, led to stronger dendritic cell activation, enhanced cytotoxic T lymphocyte activation as well as stronger humoral response, compared to the individual agonists given at full doses. Immune cells induced after vaccination with the co-adjuvanted formulation could mediate tumor regression in an E.G7-OVA tumor model, and eradicate circulating hepatitis B virus (HBV) in a transgenic HBV model. Together, these results show that endogenous TLR agonists, such as variants of FNIII EDA, can synergize with exogenous TLR ligands, such as CpG, and strongly enhance cellular immune responses, while improving their safety profile. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. Synergism effects of pioglitazone and Urtica dioica extract in streptozotocin-induced nephropathy via attenuation of oxidative stress.

    PubMed

    Shokrzadeh, Mohammad; Sadat-Hosseini, Sara; Fallah, Marjan; Shaki, Fatemeh

    2017-05-01

    Hyperglycemia promotes oxidative stress that plays a crucial role in the pathogenesis of Diabetic nephropathy (DN). In this study, we investigated the synergism effects of hydroalcoholic extract of Urtica dioica and pioglitazone (PIO) on the prevention of DN in streptozotocin induced-diabetic mice. Forty-two mice were divided into six groups as follows: non-diabetic control group, DMSO group (as solvent), diabetic group and four treatment groups which received U. dioica, pioglitazone, U. dioica plus pioglitazone and vitE. Diabetes was induced by a single dose of streptozotocin (STZ) (200 mg/kg body wt, IP) diluted in citrate buffer (pH= 4.6). After 4 weeks treatment, all animals were anaesthetized and blood was collected for serum urea and creatinine levels assessment in plasma and kidney tissue were excised for evaluation of oxidative stress markers. Treatment with U. dioica significantly inhibited increase in serum urea and creatinine in plasma that were observed in diabetic mice. Furthermore, the elevated level of oxidative stress markers (glutathione oxidation, lipid peroxidation (LPO), protein carbonyl) in renal supernatant of diabetic mice was inhibited by U. dioica treatment. Interestingly, U. dioica promoted beneficial effects of PIO in reducing STZ-induced hyperglycemia, renal damage and oxidative stress markers. Our findings showed that PIO plus U. dioica have synergism protective effects against STZ-induced nephropathy that can be a candidate as a therapeutic approach in order to treatment of DN.

  2. Synergism effects of pioglitazone and Urtica dioica extract in streptozotocin-induced nephropathy via attenuation of oxidative stress

    PubMed Central

    Shokrzadeh, Mohammad; Sadat-hosseini, Sara; Fallah, Marjan; Shaki, Fatemeh

    2017-01-01

    Objective(s): Hyperglycemia promotes oxidative stress that plays a crucial role in the pathogenesis of Diabetic nephropathy (DN). In this study, we investigated the synergism effects of hydroalcoholic extract of Urtica dioica and pioglitazone (PIO) on the prevention of DN in streptozotocin induced-diabetic mice. Materials and Methods: Forty-two mice were divided into six groups as follows: non-diabetic control group, DMSO group (as solvent), diabetic group and four treatment groups which received U. dioica, pioglitazone, U. dioica plus pioglitazone and vitE. Diabetes was induced by a single dose of streptozotocin (STZ) (200 mg/kg body wt, IP) diluted in citrate buffer (pH= 4.6). After 4 weeks treatment, all animals were anaesthetized and blood was collected for serum urea and creatinine levels assessment in plasma and kidney tissue were excised for evaluation of oxidative stress markers. Results: Treatment with U. dioica significantly inhibited increase in serum urea and creatinine in plasma that were observed in diabetic mice. Furthermore, the elevated level of oxidative stress markers (glutathione oxidation, lipid peroxidation (LPO), protein carbonyl) in renal supernatant of diabetic mice was inhibited by U. dioica treatment. Interestingly, U. dioica promoted beneficial effects of PIO in reducing STZ-induced hyperglycemia, renal damage and oxidative stress markers. Conclusion: Our findings showed that PIO plus U. dioica have synergism protective effects against STZ-induced nephropathy that can be a candidate as a therapeutic approach in order to treatment of DN. PMID:28656084

  3. Identification of the Molecular Mechanism by which TLR Ligation and IFN-γ Synergize to Induce Mig

    PubMed Central

    Powell, Jonathan D.; Boodoo, Sada

    2004-01-01

    Monokine Induced by Interferon- (MIG), a CXC chemokine, is a potent inducer of T-cell chemotaxis and activation and has been implicated in the host response to viral infections and tumor immunity as well as in the pathogenesis of autoimmunity and transplant rejection. Although it is known that the Toll-Like Receptor-4 (TLR-4) ligand LPS synergizes with IFN-γ to induce MIG expression in macrophages, the molecular mechanisms responsible for the synergy have yet to be elucidated. We determined that the marked synergy between LPS and IFN-γ on MIG mRNA expression in mouse macrophages is a result of LPS-induced NF-κB and IFN-γ-induced STAT. The synergy was not dependent on new protein synthesis, was independent of TNF-α, and occurred at the level of gene transcription. We identified 2 NF-κB sites located at -154 and -129 of the MIG promoter proximal to the -responsive element that mediated this effect. Finally, we demonstrated that other TLR ligands (zymosan, double stranded RNA and CpG) synergized with IFN-γ to induce MIG in an NF-κB dependent fashion. These data emphasize the ability of bacterial and viral products to activate/modify immune responses and promote adaptive T cell immunity through the NF-κB pathway. PMID:15154616

  4. FIZ1 is expressed during photoreceptor maturation, and synergizes with NRL and CRX at rod-specific promoters in vitro.

    PubMed

    Mali, Raghuveer S; Zhang, Xiao; Hoerauf, Widmann; Doyle, Danielle; Devitt, Jeffrey; Loffreda-Wren, Janice; Mitton, Kenneth P

    2007-02-01

    FIZ1 (Flt-3 Interacting Zinc-finger) interacts and co-purifies with the rod-specific transcription factor NRL (Neural Retina Leucine zipper). We hypothesize that FIZ1 is part of an interface between cell-specific factors, like NRL, and more ubiquitous regulatory networks that vary the absolute expression levels of some rod-specific genes (i.e. Rhodopsin). As part of an ongoing exploration of FIZ1's role in neural retina, in vivo, we have taken the first look at FIZ1 expression in the developing mouse retina during the retinal maturation period. Using the normal C57B6 mouse as a model, multiple approaches were used including: immunoblotting, immunohistochemistry, and quantitative real-time PCR. Functional implications of FIZ1/NRL interaction, on NRL- and CRX-mediated activation of the Rhodopsin (Rho) and cGMP-phosphodiesterase beta-subunit gene (PDE6B) promoters, were examined by co-transfection assays. Immunoblot analysis revealed that FIZ1 protein levels were lowest in immature mouse neural retina (P0). FIZ1 concentration increased at least ten-fold as the neural retina matured to the adult state (P21 and later). Immunohistochemical comparison of immature post-natal and mature adult retina revealed increasing FIZ1 protein in photoreceptors, the inner plexiform layer, and the ganglion cell layer. Total retinal Fiz1 mRNA content increased as the neural retina matured. The expected increase in Rho mRNA level was also monitored as a genetic marker of photoreceptor maturation. In transient co-transfection assays of CV1 cells, FIZ1 synergized with NRL to activate transcription from the Rho and PDE6B gene promoters with some differences. In the case of the Rho promoter, FIZ1 synergized when both NRL and CRX were present. With the PDE6B promoter, FIZ1 synergized with NRL alone, and the inclusion of CRX decreased this synergy. These findings support previous evidence that FIZ1 is present in rod-photoreceptors (co-immunoprecipitation from nuclear-protein extracts with rod

  5. A PARP1-ERK2 synergism is required for the induction of LTP

    PubMed Central

    Visochek, L.; Grigoryan, G.; Kalal, A.; Milshtein-Parush, H.; Gazit, N.; Slutsky, I.; Yeheskel, A.; Shainberg, A.; Castiel, A.; Seger, R.; Langelier, M. F.; Dantzer, F.; Pascal, J. M.; Segal, M.; Cohen-Armon, M.

    2016-01-01

    Unexpectedly, a post-translational modification of DNA-binding proteins, initiating the cell response to single-strand DNA damage, was also required for long-term memory acquisition in a variety of learning paradigms. Our findings disclose a molecular mechanism based on PARP1-Erk synergism, which may underlie this phenomenon. A stimulation induced PARP1 binding to phosphorylated Erk2 in the chromatin of cerebral neurons caused Erk-induced PARP1 activation, rendering transcription factors and promoters of immediate early genes (IEG) accessible to PARP1-bound phosphorylated Erk2. Thus, Erk-induced PARP1 activation mediated IEG expression implicated in long-term memory. PARP1 inhibition, silencing, or genetic deletion abrogated stimulation-induced Erk-recruitment to IEG promoters, gene expression and LTP generation in hippocampal CA3-CA1-connections. Moreover, a predominant binding of PARP1 to single-strand DNA breaks, occluding its Erk binding sites, suppressed IEG expression and prevented the generation of LTP. These findings outline a PARP1-dependent mechanism required for LTP generation, which may be implicated in long-term memory acquisition and in its deterioration in senescence. PMID:27121568

  6. A PARP1-ERK2 synergism is required for the induction of LTP.

    PubMed

    Visochek, L; Grigoryan, G; Kalal, A; Milshtein-Parush, H; Gazit, N; Slutsky, I; Yeheskel, A; Shainberg, A; Castiel, A; Seger, R; Langelier, M F; Dantzer, F; Pascal, J M; Segal, M; Cohen-Armon, M

    2016-04-28

    Unexpectedly, a post-translational modification of DNA-binding proteins, initiating the cell response to single-strand DNA damage, was also required for long-term memory acquisition in a variety of learning paradigms. Our findings disclose a molecular mechanism based on PARP1-Erk synergism, which may underlie this phenomenon. A stimulation induced PARP1 binding to phosphorylated Erk2 in the chromatin of cerebral neurons caused Erk-induced PARP1 activation, rendering transcription factors and promoters of immediate early genes (IEG) accessible to PARP1-bound phosphorylated Erk2. Thus, Erk-induced PARP1 activation mediated IEG expression implicated in long-term memory. PARP1 inhibition, silencing, or genetic deletion abrogated stimulation-induced Erk-recruitment to IEG promoters, gene expression and LTP generation in hippocampal CA3-CA1-connections. Moreover, a predominant binding of PARP1 to single-strand DNA breaks, occluding its Erk binding sites, suppressed IEG expression and prevented the generation of LTP. These findings outline a PARP1-dependent mechanism required for LTP generation, which may be implicated in long-term memory acquisition and in its deterioration in senescence.

  7. Proneural and abdominal Hox inputs synergize to promote sensory organ formation in the Drosophila abdomen.

    PubMed

    Gutzwiller, Lisa M; Witt, Lorraine M; Gresser, Amy L; Burns, Kevin A; Cook, Tiffany A; Gebelein, Brian

    2010-12-15

    The atonal (ato) proneural gene specifies a stereotypic number of sensory organ precursors (SOP) within each body segment of the Drosophila ectoderm. Surprisingly, the broad expression of Ato within the ectoderm results in only a modest increase in SOP formation, suggesting many cells are incompetent to become SOPs. Here, we show that the SOP promoting activity of Ato can be greatly enhanced by three factors: the Senseless (Sens) zinc finger protein, the Abdominal-A (Abd-A) Hox factor, and the epidermal growth factor (EGF) pathway. First, we show that expression of either Ato alone or with Sens induces twice as many SOPs in the abdomen as in the thorax, and do so at the expense of an abdomen-specific cell fate: the larval oenocytes. Second, we demonstrate that Ato stimulates abdominal SOP formation by synergizing with Abd-A to promote EGF ligand (Spitz) secretion and secondary SOP recruitment. However, we also found that Ato and Sens selectively enhance abdominal SOP development in a Spitz-independent manner, suggesting additional genetic interactions between this proneural pathway and Abd-A. Altogether, these experiments reveal that genetic interactions between EGF-signaling, Abd-A, and Sens enhance the SOP-promoting activity of Ato to stimulate region-specific neurogenesis in the Drosophila abdomen. Copyright © 2010 Elsevier Inc. All rights reserved.

  8. Phellinus linteus extract induces autophagy and synergizes with 5-fluorouracil to inhibit breast cancer cell growth.

    PubMed

    Lee, Wen-Ying; Hsu, Keng-Fu; Chiang, Tai-An; Chen, Chee-Jen

    2015-01-01

    Phellinus linteus (PL) is a medicinal mushroom due to its several biological properties, including anticancer activity. However, the mechanisms of its anticancer effect remain to be elucidated. We evaluated the inhibitory effects of the ethanolic extract from the PL combined with 5-FU on MDA-MB-231 breast cancer cell line and to determine the mechanism of cell death. Individually, PL extract and 5-FU significantly inhibited the proliferation of MDA-MB-231 cells in a dose-dependent manner. PL extract (30 mg/mL) in combination with 5-FU (10 μg/mL) synergistically inhibited MDA-MB-231 cells by 1.8-fold. PL did not induce apoptosis, as demonstrated by the DNA fragmentation assay, the sub-G1 population, and staining with annexin V-FITC and propidium iodide. The exposure of MDA-MB-231 cells to PL extracts resulted in several confirmed characteristics of autophagy, including the appearance of autophagic vacuoles revealed by monodansylcadaverine staining, the formation of acidic vesicular organelles, autophagosome membrane association of microtubule-associated protein light chain 3 (LC3) characterized by cleavage of LC3 and its punctuate redistribution, and ultrastructural observation of autophagic vacuoles by transmission electron microscopy. We concluded that PL extracts synergized with low doses of 5-FU to inhibit triple-negative breast cancer cell growth and demonstrated that PL extract can induce autophagy-related cell death.

  9. Phenylacetate synergizes with retinoic acid in inducing the differentiation of human neuroblastoma cells.

    PubMed

    Sidell, N; Wada, R; Han, G; Chang, B; Shack, S; Moore, T; Samid, D

    1995-02-08

    Phenylacetate, a natural metabolite of phenylalanine which was originally described as a plant growth hormone, has recently gained attention as a possible differentiation inducer for a variety of human tumor cell types. This interest prompted us to assess the ability of sodium phenylacetate (NaPA) to promote the differentiation of human neuroblastoma cells, both alone and in combination with retinoic acid (RA), a known inducer of neuroblastoma differentiation and maturation. Using the LA-N-5 cell line, we have determined that NaPA can stimulate the differentiation of neuroblastoma cells, as evidenced by dose-dependent inhibition of cell proliferation, neurite outgrowth, increased acetylcholinesterase activity and reduction of N-myc expression. Furthermore, NaPA and RA synergized in inducing differentiation, in that combination treatment resulted in cessation of cell growth along with morphologic and biochemical changes indicative of the loss of malignant properties. We have determined that NaPA can markedly enhance mRNA levels of the nuclear RA receptor-beta (RAR beta) in LA-N-5 cells prior to morphologic or other phenotypic changes induced by this compound. This effect appeared to be distinct from the ability of NaPA to alter tumor cell lipid metabolism via inhibition of protein isoprenylation. Thus among its varied effects on LA-N-5 cells, NaPA appears to interact with the RA pathway at the nuclear level by up-regulating RAR beta expression.

  10. Evidence of cue synergism in termite corpse response behavior

    NASA Astrophysics Data System (ADS)

    Ulyshen, Michael D.; Shelton, Thomas G.

    2012-02-01

    Subterranean termites of the genus Reticulitermes are known to build walls and tubes and move considerable amounts of soil into wood but the causes of this behavior remain largely unexplored. In laboratory assays, we tested the hypothesis that Reticulitermes virginicus (Banks) would carry more sand into wooden blocks containing corpses compared to corpse-free controls. We further predicted that the corpses of predatory ants would elicit a stronger response than those of a benign beetle species or nestmates. As hypothesized, significantly more sand was carried into blocks containing corpses and this material was typically used to build partitions separating the dead from the rest of the colony. Contrary to expectations, however, this behavior did not vary among corpse types. We then tested the hypothesis that oleic acid, an unsaturated fatty acid released during arthropod decay and used by ants and other arthropod taxa in corpse recognition, would induce a similar building response in R. virginicus. To additionally determine the role of foreign objects in giving rise to this behavior, the experiment was carried out with and without imitation corpses (i.e., small glass beads). As predicted, oleic acid induced building (a tenfold increase) but only when applied to beads, suggesting strong synergism between tactile and chemical cues. Oleic acid also significantly reduced the amount of wood consumed by R. virginicus and may possess useful repellent properties.

  11. Synergism of Chinese Herbal Medicine: Illustrated by Danshen Compound.

    PubMed

    Su, Xuefeng; Yao, Zhuoting; Li, Shengting; Sun, He

    2016-01-01

    The primary therapeutic effects of Chinese herbal medicine (CHM) are based on the properties of each herb and the strategic combination of herbs in formulae. The herbal formulae are constructed according to Chinese medicine theory: the "Traditional Principles for Constructing Chinese Herbal Medicinal Formulae" and the "Principles of Combining Medicinal Substances." These principles of formulation detail how and why multiple medicinal herbs with different properties are combined together into a single formula. However, the concept of herbal synergism in CHM still remains a mystery due to lack of scientific data and modern assessment methods. The Compound Danshen Formula (CDF) is a validated formula that has been used to treat a variety of diseases for hundreds of years in China and other countries. The CDF will be employed to illustrate the theory and principle of Chinese herbal medicine formulation. The aim of this review is to describe how Chinese herbal medicinal formulae are constructed according to Chinese medicine theory and to illustrate with scientific evidence how Chinese herbs work synergistically within a formula, thereby supporting Chinese medicine theory and practice.

  12. Synergism of Chinese Herbal Medicine: Illustrated by Danshen Compound

    PubMed Central

    Su, Xuefeng; Yao, Zhuoting; Li, Shengting; Sun, He

    2016-01-01

    The primary therapeutic effects of Chinese herbal medicine (CHM) are based on the properties of each herb and the strategic combination of herbs in formulae. The herbal formulae are constructed according to Chinese medicine theory: the “Traditional Principles for Constructing Chinese Herbal Medicinal Formulae” and the “Principles of Combining Medicinal Substances.” These principles of formulation detail how and why multiple medicinal herbs with different properties are combined together into a single formula. However, the concept of herbal synergism in CHM still remains a mystery due to lack of scientific data and modern assessment methods. The Compound Danshen Formula (CDF) is a validated formula that has been used to treat a variety of diseases for hundreds of years in China and other countries. The CDF will be employed to illustrate the theory and principle of Chinese herbal medicine formulation. The aim of this review is to describe how Chinese herbal medicinal formulae are constructed according to Chinese medicine theory and to illustrate with scientific evidence how Chinese herbs work synergistically within a formula, thereby supporting Chinese medicine theory and practice. PMID:27190537

  13. Synergism between tramadol and parecoxib in the orofacial formalin test.

    PubMed

    Isiordia-Espinoza, Mario Alberto; Zapata-Morales, Juan Ramón; Castañeda-Santana, Demian Ismael; de la Rosa-Coronado, Maximiliano; Aragon-Martinez, Othoniel Hugo

    2015-05-01

    The aim of this study was to evaluate the interaction between tramadol and parecoxib in the orofacial formalin test. Tramadol (10, 31.6, 56, and 100 mg/kg ip) or parecoxib (31.6, 56, 100, and 178 mg/kg ip) were administered 10 min before formalin (2.5%) injection into the upper lip to characterize the dose-response curve of each individual drug in the orofacial pain test in mice. Once the dose-response curve of each drug was obtained, an experimental effective dose 50 (ED50 ) value was determined for each drug. The tramadol-parecoxib combination was evaluated in four different groups of animals. The isobolographic analysis and the interaction index were used to evaluate the nature of interaction between both drugs. The isobologram and the interaction index showed increased in the antinociceptive effect of the combination. The tramadol-parecoxib combination produces a synergism in the second phase of the orofacial formalin test. © 2015 Wiley Periodicals, Inc.

  14. New insights into the synergism of nucleoside analogs with radiotherapy.

    PubMed

    Lee, Michael W; Parker, William B; Xu, Bo

    2013-09-26

    Nucleoside analogs have been frequently used in combination with radiotherapy in the clinical setting, as it has long been understood that inhibition of DNA repair pathways is an important means by which many nucleoside analogs synergize. Recent advances in our understanding of the structure and function of deoxycytidine kinase (dCK), a critical enzyme required for the anti-tumor activity for many nucleoside analogs, have clarified the mechanistic role this kinase plays in chemo- and radio-sensitization. A heretofore unrecognized role of dCK in the DNA damage response and cell cycle machinery has helped explain the synergistic effect of these agents with radiotherapy. Since most currently employed nucleoside analogs are primarily activated by dCK, these findings lend fresh impetus to efforts focused on profiling and modulating dCK expression and activity in tumors. In this review we will briefly review the pharmacology and biochemistry of the major nucleoside analogs in clinical use that are activated by dCK. This will be followed by discussions of recent advances in our understanding of dCK activation via post-translational modifications in response to radiation and current strategies aimed at enhancing this activity in cancer cells.

  15. Novel synergic antidiabetic effects of Astragalus polysaccharides combined with Crataegus flavonoids via improvement of islet function and liver metabolism.

    PubMed

    Cui, Kai; Zhang, Shaobo; Jiang, Xin; Xie, Weidong

    2016-06-01

    The present study investigated the synergic effects and potential mechanisms of action of Astragalus polysaccharides (APS) combined with Crataegus flavonoids (CF) in the treatment of type 1 diabetes. Diabetes was induced by intraperitoneal injection of 100 mg/kg streptozotocin in mice. Normal and untreated diabetic control mice were used, and CF‑treated (200 mg/kg/day), APS‑treated (200 mg/kg/day), APS + CF (AC)‑treated (200 mg/kg/day of each) and metformin‑treated (200 mg/kg/day) diabetic mice were orally administrated the appropriate therapeutic agent for 4 weeks. The results demonstrated that AC treatment significantly reduced the fasting blood glucose, food and water intake in the diabetic mice. The AC group demonstrated increased serum insulin levels and islet cell function was restored. Furthermore, the AC‑treated mice demonstrated significant increases in the protein expression levels of pancreatic and duodenal homeobox‑1 and phosphorylated adenosine 5'‑monophosphate‑activated protein kinase in the pancreatic and liver tissue samples, respectively. In addition, AC significantly increased the mRNA expression levels of neurogenin 3, v‑maf musculoaponeurotic fibrosarcoma oncogene family, protein A and insulin, and simultaneously decreased the expressions of interleukin 6, tumor necrosis factor‑α and chemokine (C‑C motif) ligand 2 in the pancreatic islet cells of diabetic mice. The anti‑inflammatory activity of APS and the islet‑restoring effect of CF may contribute to the improvement of islet function. AC exerted greater antidiabetic effects compared with APS or CF treatments alone. These results indicated that AC treatment had a synergic antidiabetic effect, which may involve improvements in islet function and liver metabolism. These effects of AC may facilitate the treatment of type 1 or 2 diabetes, as these patients frequently experience impaired islet function and disordered extrapancreatic metabolism.

  16. Extracellular calcium stimulates DNA synthesis in synergism with zinc, insulin and insulin-like growth factor I in fibroblasts.

    PubMed

    Huang, J S; Mukherjee, J J; Chung, T; Crilly, K S; Kiss, Z

    1999-12-01

    In serum-starved mouse NIH 3T3 fibroblasts cultured in 1.8 mM Ca2+-containing medium, addition of 0.75-2 mM extra Ca2+ stimulated DNA synthesis in synergism with zinc (15-60 microM), insulin and insulin-like growth factor I. Extra Ca2+ stimulated phosphorylation/activation of p42/p44 mitogen-activated protein kinases by an initially (10 min) zinc-independent mechanism; however, insulin, and particularly zinc, significantly prolonged Ca2+-induced mitogen-activated protein kinase phosphorylation. In addition, extra Ca2+ activated p70 S6 kinase by a zinc-dependent mechanism and enhanced the stimulatory effect of zinc on choline kinase activity. Insulin and insulin-like growth factor I also commonly increased both p70 S6 kinase and choline kinase activities. In support of the role of the choline kinase product phosphocholine in the mediation of mitogenic Ca2+ effects, cotreatments with the choline kinase substrate choline (250 microM) and the choline kinase inhibitor hemicholinium-3 (2 mM) enhanced and inhibited, respectively, the combined stimulatory effect of extra Ca2+ (3.8 mM total) and zinc on DNA synthesis. In various human skin fibroblast lines, 1-2 mM extra Ca2+ also stimulated DNA synthesis in synergism with zinc and insulin. The results show that in various fibroblast cultures, high concentrations of extracellular Ca2+ can collaborate with zinc and certain growth factors to stimulate DNA synthesis. Considering the high concentration of extracellular Ca2+ in the dermal layer, Ca2+ may promote fibroblast growth during wound healing in concert with zinc, insulin growth factor-I insulin, and perhaps other growth factors.

  17. Will Synergizing Vaccination with Therapeutics Boost Measles Virus Eradication?

    PubMed Central

    Plemper, Richard K; Hammond, Anthea L

    2014-01-01

    Introduction Measles virus is a major human pathogen responsible for approximately 150,000 measles deaths annually. The disease is vaccine preventable and eradication of the virus is considered feasible in principle. However, a herd immunity exceeding 95% is required to prevent sporadic viral outbreaks in a population. Declining disease prevalence combined with public anxieties about vaccination safety has increased vaccine refusal especially in the European region, which has resulted in measles resurgence in some areas. Areas covered Here, we discuss whether synergizing effective measles therapeutics with vaccination could contribute to solving an endgame conundrum of measles elimination by accelerating the eradication effort. Based on an anticipated use for protection of high-risk contacts of confirmed measles cases through post-exposure prophylaxis, we identify key elements of the desirable drug profile, review current disease management strategies and the state of experimental inhibitor candidates, evaluate the risk associated with viral escape from inhibition, and consider the potential of measles therapeutics for the management of persistent viral infection of the CNS. Assuming a post-measles world with waning measles immunity, we contemplate the possible impact of therapeutics on controlling the threat imposed by closely related zoonotic pathogens of the same genus as measles virus. Expert opinion Efficacious therapeutics given for post-exposure prophylaxis of high-risk social contacts of confirmed index cases may aid measles eradication by closing herd immunity gaps due to vaccine refusal or failure in populations with overall good vaccination coverage. The envisioned primarily prophylactic application of measles therapeutics to a predominantly pediatric and/or adolescent patient population dictates the drug profile; the article must be safe and efficacious, orally available, shelf-stable at ambient temperature, and amenable to cost-effective manufacture

  18. Structural evidence for substrate-induced synergism and half-sites reactivity in biotin carboxylase

    PubMed Central

    Mochalkin, Igor; Miller, J. Richard; Evdokimov, Artem; Lightle, Sandra; Yan, Chunhong; Stover, Charles Ken; Waldrop, Grover L.

    2008-01-01

    Bacterial acetyl-CoA carboxylase is a multifunctional biotin-dependent enzyme that consists of three separate proteins: biotin carboxylase (BC), biotin carboxyl carrier protein (BCCP), and carboxyltransferase (CT). Acetyl-CoA carboxylase is a potentially attractive target for novel antibiotics because it catalyzes the first committed step in fatty acid biosynthesis. In the first half-reaction, BC catalyzes the ATP-dependent carboxylation of BCCP. In the second half-reaction, the carboxyl group is transferred from carboxybiotinylated BCCP to acetyl-CoA to produce malonyl-CoA. A series of structures of BC from several bacteria crystallized in the presence of various ATP analogs is described that addresses three major questions concerning the catalytic mechanism. The structure of BC bound to AMPPNP and the two catalytically essential magnesium ions resolves inconsistencies between the kinetics of active-site BC mutants and previously reported BC structures. Another structure of AMPPNP bound to BC shows the polyphosphate chain folded back on itself, and not in the correct (i.e., extended) conformation for catalysis. This provides the first structural evidence for the hypothesis of substrate-induced synergism, which posits that ATP binds nonproductively to BC in the absence of biotin. The BC homodimer has been proposed to exhibit half-sites reactivity where the active sites alternate or “flip-flop” their catalytic cycles. A crystal structure of BC showed the ATP analog AMPPCF2P bound to one subunit while the other subunit was unliganded. The liganded subunit was in the closed or catalytic conformation while the unliganded subunit was in the open conformation. This provides the first structural evidence for half-sites reactivity in BC. PMID:18725455

  19. Structural evidence for substrate-induced synergism and half-sites reactivity in biotin carboxylase

    SciTech Connect

    Mochalkin, Igor; Miller, J. Richard; Evdokimov, Artem; Lightle, Sandra; Yan, Chunhong; Stover, Charles Ken; Waldrop, Grover L.

    2008-10-24

    Bacterial acetyl-CoA carboxylase is a multifunctional biotin-dependent enzyme that consists of three separate proteins: biotin carboxylase (BC), biotin carboxyl carrier protein (BCCP), and carboxyltransferase (CT). Acetyl-CoA carboxylase is a potentially attractive target for novel antibiotics because it catalyzes the first committed step in fatty acid biosynthesis. In the first half-reaction, BC catalyzes the ATP-dependent carboxylation of BCCP. In the second half-reaction, the carboxyl group is transferred from carboxybiotinylated BCCP to acetyl-CoA to produce malonyl-CoA. A series of structures of BC from several bacteria crystallized in the presence of various ATP analogs is described that addresses three major questions concerning the catalytic mechanism. The structure of BC bound to AMPPNP and the two catalytically essential magnesium ions resolves inconsistencies between the kinetics of active-site BC mutants and previously reported BC structures. Another structure of AMPPNP bound to BC shows the polyphosphate chain folded back on itself, and not in the correct (i.e., extended) conformation for catalysis. This provides the first structural evidence for the hypothesis of substrate-induced synergism, which posits that ATP binds nonproductively to BC in the absence of biotin. The BC homodimer has been proposed to exhibit half-sites reactivity where the active sites alternate or 'flip-flop' their catalytic cycles. A crystal structure of BC showed the ATP analog AMPPCF{sub 2}P bound to one subunit while the other subunit was unliganded. The liganded subunit was in the closed or catalytic conformation while the unliganded subunit was in the open conformation. This provides the first structural evidence for half-sites reactivity in BC.

  20. The accessible cellulose surface influences cellulase synergism during the hydrolysis of lignocellulosic substrates.

    PubMed

    Hu, Jinguang; Gourlay, Keith; Arantes, Valdeir; Van Dyk, J S; Pribowo, Amadeus; Saddler, Jack N

    2015-03-01

    Effective enzymatic hydrolysis of insoluble cellulose requires the synergistic action of a suite of cellulase components. Most previous studies have only assessed cellulase synergism on model cellulosic substrates. When the actions of individual and combinations of cellulases (Cel7A, Cel6A, Cel7B, Cel5A) were assessed on various pretreated lignocellulosic substrates, Cel7A was shown to be the major contributor to overall cellulose hydrolysis, with the other enzymes synergistically enhancing its hydrolytic efficiency, at least partially, by facilitating Cel7A desorption (assessed by a double-sandwich enzyme-linked immunosorbent assay). When the influences of various substrate physicochemical characteristics on the effectiveness of enzyme synergism were assessed, a strong relationship was observed between cellulose accessibility (as determined by the cellulose binding module technique) and the degree of synergism, with greater synergy observed on the more disorganized/accessible cellulose surface.

  1. Synergism of cellulases from Trichoderma reesei in the degradation of cellulose

    SciTech Connect

    Henrissat, B.; Driguez, H.; Viet, C.; Schuelein, M.

    1985-08-01

    The action of cellobiohydrolases I and II (CBHI and CBHII) and endoglucanases I and II (EGI and EGII) purified from Trichoderma reesei was evaluated against various substrates. CBHI degraded the ..beta..-D-glucan from barley in a typical endo pattern. With cellulose substrates, the synergism between CBHI and endoglucanase I or II depended on the structural and ultrastructural features of the substrate. This effect, unrelated to endo-exo cooperation, was found with substrates of intermediate crystallinity whereas weak or no synergism was recorded with cellulose microcrystals or the soluble carboxy-methyl cellulose derivative. Synergistic degradation of cellulose was also recorded with mixtures of CBHI and CBHII. On the other hand, synergism between endoglucanases and CBHII followed the pattern expected for an endo-exo cooperation. These results presented support evidence for multiple types of cooperation between the cellulolytic enzymes. 30 references, 7 figures, 1 table.

  2. Enhanced activity of lysozyme-AgNP conjugate with synergic antibacterial effect without damaging the catalytic site of lysozyme.

    PubMed

    Ernest, Vinita; Gajalakshmi, Sekar; Mukherjee, Amitava; Chandrasekaran, Natarajan

    2014-10-01

    The conjugation of silver nanoparticles (AgNPs) with biomolecules such as oligosaccharides, DNA, proteins has attracted great attention of scientists recently. In this study, lysozyme-AgNP conjugates were evaluated for its synergic antimicrobial effect. AgNPs were synthesized and characterized using UV-Visible, X-ray diffraction analysis (XRD) and atomic force microscopy (AFM). AgNP (0-1 mM) was interacted with lysozyme for multi-spectrophotometric studies. Lysozyme was immobilized on AgNP at different ratios and the resulting nano-bio-conjugate was tested against Escherichia coli for potent synergic antibacterial effects. A surface plasmon peak at 420 nm confirmed the presence of AgNPs and spherical to oval-shaped AgNPs were observed by AFM. The particle size was calculated to be 25 nm by XRD analysis. The maximum immobilization efficiency (98%) was achieved at 0.01:1 ratio of enzyme:AgNP. UV-Visible and fluorescence spectral studies revealed the binding of AgNPs to lysozyme by the formation of ground-state complex and the binding parameters were calculated. Circular dichroism studies confirmed decrease by 11% in the α-helical and 29.32% in β-sheets of lysozyme upon AgNP interaction. FTIR spectra revealed the binding of AgNP through thiol (-SH) linkages of lysozyme. Our results showed that the antimicrobial activity of lysozyme-AgNP conjugate was enhanced up to 86% decrease in the cell growth. In summary, the immobilization of lysozyme on AgNP has yielded a nano-bio-conjugate with synergistic antibacterial properties.

  3. A synergic simulation-optimization approach for analyzing biomolecular dynamics in living organisms.

    PubMed

    Sadegh Zadeh, Kouroush

    2011-01-01

    A synergic duo simulation-optimization approach was developed and implemented to study protein-substrate dynamics and binding kinetics in living organisms. The forward problem is a system of several coupled nonlinear partial differential equations which, with a given set of kinetics and diffusion parameters, can provide not only the commonly used bleached area-averaged time series in fluorescence microscopy experiments but more informative full biomolecular/drug space-time series and can be successfully used to study dynamics of both Dirac and Gaussian fluorescence-labeled biomacromolecules in vivo. The incomplete Cholesky preconditioner was coupled with the finite difference discretization scheme and an adaptive time-stepping strategy to solve the forward problem. The proposed approach was validated with analytical as well as reference solutions and used to simulate dynamics of GFP-tagged glucocorticoid receptor (GFP-GR) in mouse cancer cell during a fluorescence recovery after photobleaching experiment. Model analysis indicates that the commonly practiced bleach spot-averaged time series is not an efficient approach to extract physiological information from the fluorescence microscopy protocols. It was recommended that experimental biophysicists should use full space-time series, resulting from experimental protocols, to study dynamics of biomacromolecules and drugs in living organisms. It was also concluded that in parameterization of biological mass transfer processes, setting the norm of the gradient of the penalty function at the solution to zero is not an efficient stopping rule to end the inverse algorithm. Theoreticians should use multi-criteria stopping rules to quantify model parameters by optimization.

  4. Tannerella forsythia GroEL induces inflammatory bone resorption and synergizes with interleukin-17.

    PubMed

    Jung, Y-J; Choi, Y-J; An, S-J; Lee, H-R; Jun, H-K; Choi, B-K

    2016-08-03

    Tannerella forsythia is a major periodontal pathogen, and T. forsythia GroEL is a molecular chaperone homologous to human heat-shock protein 60. Interleukin-17 (IL-17) has been implicated in the pathogenesis of periodontitis and several systemic diseases. This study investigated the potential of T. forsythia GroEL to induce inflammatory bone resorption and examined the cooperative effect of IL-17 and T. forsythia GroEL on inflammatory responses. Human gingival fibroblasts (HGFs) and periodontal ligament (PDL) fibroblasts were stimulated with T. forsythia GroEL and/or IL-17. Gene expression of IL-6, IL-8, and cyclooxygenase-2 (COX-2) and concentrations of IL-6, IL-8, and prostaglandin E2 (PGE2 ) were measured by real-time reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assays, respectively. After stimulation of MG63 cells with T. forsythia GroEL and/or IL-17, gene expression of osteoprotegerin (OPG) was examined. After subcutaneous injection of T. forsythia GroEL and/or IL-17 above the calvaria of BALB/c mice, calvarial bone resorption was assessed by micro-computed tomography and histological examination. Tannerella forsythia GroEL induced IL-6 and IL-8 production in HGFs and PDL cells, and IL-17 further promoted IL-6 and IL-8 production. Both T. forsythia GroEL and IL-17 synergistically increased PGE2 production and inhibited OPG gene expression. Calvarial bone resorption was induced by T. forsythia GroEL injection, and simultaneous injection of T. forsythia GroEL and IL-17 further increased bone resorption. These results suggest that T. forsythia GroEL is a novel virulence factor that can contribute to inflammatory bone resorption caused by T. forsythia and synergizes with IL-17 to exacerbate inflammation and bone resorption.

  5. p62/SQSTM1 synergizes with autophagy for tumor growth in vivo

    PubMed Central

    Wei, Huijun; Wang, Chenran; Croce, Carlo M.; Guan, Jun-Lin

    2014-01-01

    Autophagy is crucial for cellular homeostasis and plays important roles in tumorigenesis. FIP200 (FAK family-interacting protein of 200 kDa) is an essential autophagy gene required for autophagy induction, functioning in the ULK1–ATG13–FIP200 complex. Our previous studies showed that conditional knockout of FIP200 significantly suppressed mammary tumorigenesis, which was accompanied by accumulation of p62 in tumor cells. However, it is not clear whether FIP200 is also required for maintaining tumor growth and how the increased p62 level affects the growth in autophagy-deficient FIP200-null tumors in vivo. Here, we describe a new system to delete FIP200 in transformed mouse embryonic fibroblasts as well as mammary tumor cells following their transplantation and show that ablation of FIP200 significantly reduced growth of established tumors in vivo. Using similar strategies, we further showed that either p62 knockdown or p62 deficiency in established FIP200-null tumors dramatically impaired tumor growth. The stimulation of tumor growth by p62 accumulation in FIP200-null tumors is associated with the up-regulated activation of the NF-κB pathway by p62. Last, we showed that overexpression of the autophagy master regulator TFEBS142A increased the growth of established tumors, which correlated with the increased autophagy of the tumor cells. Together, our studies demonstrate that p62 and autophagy synergize to promote tumor growth, suggesting that inhibition of both pathways could be more effective than targeting either alone for cancer therapy. PMID:24888590

  6. Ibrutinib synergizes with MDM-2 inhibitors in promoting cytotoxicity in B chronic lymphocytic leukemia

    PubMed Central

    Melloni, Elisabetta; Rigolin, Gian Matteo; Casciano, Fabio; Arcidiacono, Maria Vittoria; Celeghini, Claudio; Cuneo, Antonio; Zauli, Giorgio; Secchiero, Paola

    2016-01-01

    Objective The aim of this study was to investigate the anti-leukemic activity of the Bruton tyrosine kinase inhibitor Ibrutinib in combination with the small molecule MDM-2 inhibitor Nutlin-3 in preclinical models. Methods The potential efficacy of the Ibrutinib/Nutlin-3 combination was evaluated in vitro in a panel of B leukemic cell lines (EHEB, JVM-2, JVM-3, MEC-1, MEC-2) and in primary B-chronic lymphocytic leukemia (B-CLL) patient samples, by assessing cell viability, cell cycle profile, apoptosis and intracellular pathway modulations. Validation of the combination therapy was assessed in a B leukemic xenograft mouse model. Results Ibrutinib exhibited variable anti-leukemic activity in vitro and the combination with Nutlin-3 synergistically enhanced the induction of apoptosis independently from the p53 status. Indeed, the Ibrutinib/Nutlin-3 combination was effective in promoting cytotoxicity also in primary B-CLL samples carrying 17p13 deletion and/or TP53 mutations, already in therapy with Ibrutinib. Molecular analyses performed on both B-leukemic cell lines as well as on primary B-CLL samples, while confirming the switch-off of the MAPK and PI3K pro-survival pathways by Ibrutinib, indicated that the synergism of action with Nutlin-3 was independent by p53 pathway and was accompanied by the activation of the DNA damage cascade signaling through the phosphorylation of the histone protein H2A.X. This observation was confirmed also in the JVM-2 B leukemic xenograft mouse model. Conclusions Taken together, our data emphasize that the Ibrutinib/Nutlin-3 combination merits to be further evaluated as a therapeutic option for B-CLL. PMID:27661115

  7. 75 FR 42743 - Synergics Roth Rock North Wind Energy, LLC; Supplemental Notice That Initial Market-Based Rate...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-22

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Synergics Roth Rock North Wind Energy, LLC; Supplemental Notice That Initial... supplemental notice in the above-referenced proceeding of Synergics Roth Rock North Wind Energy, LLC's...

  8. 75 FR 42744 - Synergics Roth Rock Wind Energy, LLC; Supplemental Notice That Initial Market-Based Rate Filing...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-22

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Synergics Roth Rock Wind Energy, LLC; Supplemental Notice That Initial... supplemental notice in the above-referenced proceeding of Synergics Roth Rock Wind Energy, LLC's application...

  9. Synergism Between Halide Binding and Proton Transport in a CLC-type Exchanger

    SciTech Connect

    Accardi,A.; Lobet, S.; Williams, C.; Miller, C.; Dutzler, R.

    2006-01-01

    The Cl{sup -}/H{sup +} exchange-transporter CLC-ec1 mediates stoichiometric transmembrane exchange of two Cl{sup -} ions for one proton. A conserved tyrosine residue, Y445, coordinates one of the bound Cl{sup -} ions visible in the structure of this protein and is located near the intersection of the Cl{sup -} and H{sup +} pathways. Mutants of this tyrosine were scrutinized for effects on the coupled transport of Cl{sup -} and H{sup +} determined electrophysiologically and on protein structure determined crystallographically. Despite the strong conservation of Y445 in the CLC family, substitution of F or W at this position preserves wild-type transport behavior. Substitution by A, E, or H, however, produces uncoupled proteins with robust Cl{sup -} transport but greatly impaired movement of H{sup +}+. The obligatory 2 Cl{sup -}/1 H{sup +} stoichiometry is thus lost in these mutants. The structures of all the mutants are essentially identical to wild-type, but apparent anion occupancy in the Cl{sup -} binding region correlates with functional H{sup +} coupling. In particular, as determined by anomalous diffraction in crystals grown in Br{sup -}, an electrophysiologically competent Cl{sup -} analogue, the well-coupled transporters show strong Br{sup -} electron density at the 'inner' and 'central' Cl{sup -} binding sites. However, in the uncoupled mutants, Br{sup -} density is absent at the central site, while still present at the inner site. An additional mutant, Y445L, is intermediate in both functional and structural features. This mutant clearly exchanges H{sup +} for Cl{sup -}, but at a reduced H{sup +}-to-Cl{sup -} ratio; likewise, both the central and inner sites are occupied by Br{sup -}, but the central site shows lower Br{sup -} density than in wild-type (or in Y445F,W). The correlation between proton coupling and central-site occupancy argues that halide binding to the central transport site somehow facilitates movement of H{sup +}, a synergism that is not

  10. Anti-vRE and anti-MRSA activities of new quinolones and their synergism with commercial antibiotics. Part 2.

    PubMed

    Sakagami, Yoshikazu; Komemushi, Sadao; Tsukamoto, Goro; Kondo, Hirosato; Yoshikawa, Akiko; Muraoka, Osamu

    2008-09-01

    Anti-VRE and anti-MRSA activities of new quinolone derivatives [The two quinolone derivatives are 8- [3-[(ethylamino) methyl]-1-pyrrodinyl] -7-fluoro-9, 1-[(N-methylimino)methano]-5-oxo-5H-thiazolo[3,2-a]quinolone-4-carboxylic acid (compound A) and 7-fluoro-8-morpholino-9,1-[(N-methylimino) methanol-5-oxo-5H-thiazolo [3,2-a] quinolone-4-carboxylic acid (compound B)] and their synergism with commercial antibiotics were investigated. Compound A exhibited potent antibacterial activity against VRE and MRSA among the five new quinolone compounds tested, and showed superior activity to pefloxacin, ofloxacin and levofloxacin, which are clinically in use these days. With respect to the anti-VRE activity, compound A showed synergism with fosfomycin (FOM), and partial synergism with ampicillin (ABPC), gentaicin (GM), minocycline (MINO) and vancomycin hydrochloride (VCM). Partial synergism in anti-VRE activity was also observed between compound B and GM, MINO, FOM and VCM. Compound A also showed synergism with MINO and FOM in anti-MASA activity. Partial synergism was observed with ABPC, GM and VCM. Synergism with ABPC was not detected in anti-MRSA activity. On the other hand, the synergism of compound B with FOM, and the partial synergisms with ABPC, GM and MINO were also found against MRSA. No synergism with ABPC was found against MRSA. These results suggested that compound A and B could possibly reduce the daily administration dose of these antibiotics in the treatment of nosocomial infections, and also reduce the possibility of the occurrence of nosocomial infections caused by VRE and/or MRSA.

  11. Synergizing nucleic acid aptamers with 1-dimensional nanostructures as label-free field-effect transistor biosensors.

    PubMed

    Lung Khung, Yit; Narducci, Dario

    2013-12-15

    Since the introduction by Gold et al. in 1990, nucleic acid aptamers had evolved to become a true contender in biosensors for protein and cell detections. Aptamers are short strands of synthetically designed DNA or RNA oligonucleotides that can be self-assembled into unique 3-dimensional structures and can bind to different proteins, cells or even small molecules at a high level of specificity and affinity. In recent years, there had been many reports in literature in using aptamers in place of conventional antibodies as capture biomolecules on the surface. This is mainly due to the better thermal stability properties and ease in production. Consequently, also these characteristics allowed the aptamers to find use in field effect transistors (FETs) based upon 1D nanostructured (1D-NS) as label-free biosensing. In terms of designing label-free platforms for biosensors applications, 1D-NS FET had been an attractive option due to reported high sensitivities toward protein targets arising from the large surface area for detection as well as to their label-free nature. Since the first aptamer-based 1D-NS FET biosensor had surfaced in 2005, there had been many more improvements in the overall design and sensitivity in recent years. In this review, the latest developments in synergizing these two interesting areas of research (aptamers and 1D-NS FET) will be discussed for a range of different nanowire types as well as for the detection results.

  12. Plant Essential Oils Synergize and Antagonize Toxicity of Different Conventional Insecticides against Myzus persicae (Hemiptera: Aphididae).

    PubMed

    Faraone, Nicoletta; Hillier, N Kirk; Cutler, G Christopher

    2015-01-01

    Plant-derived products can play an important role in pest management programs. Essential oils from Lavandula angustifolia (lavender) and Thymus vulgaris (thyme) and their main constituents, linalool and thymol, respectively, were evaluated for insecticidal activity and synergistic action in combination with insecticides against green peach aphid, Myzus persicae (Sulzer) (Hemiptera: Aphididae). The essential oils and their main constituents exerted similar insecticidal activity when aphids were exposed by direct sprays, but were non-toxic by exposure to treated leaf discs. In synergism experiments, the toxicity of imidacloprid was synergized 16- to 20-fold by L. angustifolia and T. vulgaris essential oils, but far less synergism occurred with linalool and thymol, indicating that secondary constituents of the oils were probably responsible for the observed synergism. In contrast to results with imidacloprid, the insecticidal activity of spirotetramat was antagonized by L. angustifolia and T. vulgaris essential oils, and linalool and thymol. Our results demonstrate the potential of plant essential oils as synergists of insecticides, but show that antagonistic action against certain insecticides may occur.

  13. Synergism of the carbon-heterocyclic thion composition in the process of polyethylene thermooxidation

    NASA Astrophysics Data System (ADS)

    Struk, V. A.; Oparin, D. A.; Medved', A. V.; Orlovskii, S. V.; Gritsevich, A. I.

    2000-05-01

    It is shown by the methods of IR spectroscopy and differential thermal analysis that heterocyclic thions of thiophthalone, isoindoline, and phthalazine systems can be effectively used as inhibitors of thermooxidation of low-pressure charge-filled polyethylene. The effect of synergism of the thion-charge complex has been revealed. The possible mechanism of the protective action of these thions is discussed.

  14. What Is Institutional Synergism? An Analysis of a Consortium of Health and Education Providers

    ERIC Educational Resources Information Center

    Sapadin, David; Carmel, Harvey

    1977-01-01

    The authors offer an operational definition of institutional integration and synergism, with reference to the Health and Education Council (a consortium of Essex Community College, Baltimore County Health Department, and Franklin Square Hospital). Key elements that appear to be essential to successful cooperative efforts are noted and described.…

  15. Plant Essential Oils Synergize and Antagonize Toxicity of Different Conventional Insecticides against Myzus persicae (Hemiptera: Aphididae)

    PubMed Central

    Faraone, Nicoletta; Hillier, N. Kirk; Cutler, G. Christopher

    2015-01-01

    Plant-derived products can play an important role in pest management programs. Essential oils from Lavandula angustifolia (lavender) and Thymus vulgaris (thyme) and their main constituents, linalool and thymol, respectively, were evaluated for insecticidal activity and synergistic action in combination with insecticides against green peach aphid, Myzus persicae (Sulzer) (Hemiptera: Aphididae). The essential oils and their main constituents exerted similar insecticidal activity when aphids were exposed by direct sprays, but were non-toxic by exposure to treated leaf discs. In synergism experiments, the toxicity of imidacloprid was synergized 16- to 20-fold by L. angustifolia and T. vulgaris essential oils, but far less synergism occurred with linalool and thymol, indicating that secondary constituents of the oils were probably responsible for the observed synergism. In contrast to results with imidacloprid, the insecticidal activity of spirotetramat was antagonized by L. angustifolia and T. vulgaris essential oils, and linalool and thymol. Our results demonstrate the potential of plant essential oils as synergists of insecticides, but show that antagonistic action against certain insecticides may occur. PMID:26010088

  16. Effects of methoprene and synergized pyrethrin aerosol applications on Tribolium castaneum (Herbst) populations

    USDA-ARS?s Scientific Manuscript database

    Experiments were performed to investigate the effects of horizontal transfer of the insect growth regulator (IGR) methoprene on confined populations of Tribolium castaneum (Herbst) either with or without hidden refugia. Multiple applications were made with the IGR alone or combined with synergized p...

  17. 78 FR 43889 - Synergizing Efforts in Standards Development for Cellular Therapies and Regenerative Medicine...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-22

    ... go to: https://collaboration.fda.gov/sesdctrmpworkshop/ . If you have never attended an Adobe Connect... HUMAN SERVICES Food and Drug Administration Synergizing Efforts in Standards Development for Cellular Therapies and Regenerative Medicine Products; Public Workshop AGENCY: Food and Drug Administration, HHS...

  18. Evaluation of synergized pyrethrin aerosol for control of Tribolium castaneum and Tribolium confusum (Coleoptera: Tenebrionidae)

    USDA-ARS?s Scientific Manuscript database

    Aerosol insecticides have been used in flour mill pest management programs, but there is limited information on their efficacy on different insect life stages. In this study, we evaluated the efficacy of synergized pyrethrin applied as an aerosol against eggs, larvae, pupae, and adults of the red fl...

  19. Influence of temperature and artificially-created physical barriers on the efficacy of synergized pyrethrin aerosol

    USDA-ARS?s Scientific Manuscript database

    Flour mills in the United States are utilizing synergized pyrethrin aerosol for management of stored product insects. However, the dispersal of the aerosol within a facility may be hampered by barriers created from machinery and other equipment that block dispersion. Additionally, seasonal temperatu...

  20. Efficacy of aerosol applications of methoprene and synergized pyrethrin against Tribolium castaneum adults and eggs

    USDA-ARS?s Scientific Manuscript database

    Experiments were performed to determine the efficacy of a single aerosol application of the insecticides methoprene and piperonyl butoxide-synergized pyrethrin, alone or in combination, and the insecticide carrier, Isopar M, against Tribolium castaneum (Herbst), the red flour beetle. The initial tes...

  1. Anopheles gambiae Cadherin AgCad1 Binds the Cry4Ba Toxin of Bacillus thuringiensis israelensis and a Fragment of AgCad1 Synergizes Toxicity†

    PubMed Central

    Hua, Gang; Zhang, Rui; Abdullah, Mohd Amir F.; Adang, Michael J.

    2009-01-01

    A midgut cadherin AgCad1 cDNA was cloned from Anopheles gambiae larvae and analyzed for its possible role as a receptor for the Cry4Ba toxin of Bacillus thuringiensis strain israelensis. The AgCad1 cadherin encodes a putative 1735-residue protein organized into an extracellular region of 11 cadherin repeats (CR) and a membrane-proximal extracellular domain (MPED). AgCad1 mRNA was detected in midgut of larvae by polymerase chain reaction (PCR). The AgCad1 protein was localized, by immunochemistry of sectioned larvae, predominately to the microvilli in posterior midgut. The localization of Cry4Ba binding was determined by the same technique, and toxin bound microvilli in posterior midgut. The AgCad1 protein was present in brush border membrane fractions prepared from larvae, and Cry4Ba toxin bound the same-sized protein on blots of those fractions. The AgCad1 protein was expressed transiently in Drosophila melanogaster Schneider 2 (S2) cells. 125I-Cry4Ba toxin bound AgCad1 from S2 cells in a competitive manner. Cry4Ba bound to beads extracted 200 kDa AgCad1 and a 29 kDa fragment of AgCad1 from S2 cells. A peptide containing the AgCad1 region proximal to the cell (CR11-MPED) was expressed in Escherichia coli. Although Cry4Ba showed limited binding to CR11-MPED, the peptide synergized the toxicity of Cry4Ba to larvae. AgCad1 in the larval brush border is a binding protein for Cry4Ba toxin. On the basis of binding results and CR11-MPED synergism of Cry4Ba toxicity, AgCad1 is probably a Cry4Ba receptor. PMID:18407662

  2. Isolation of Homogeneous Polysaccharide Monooxygenases from Fungal Sources and Investigation of Their Synergism with Cellulases when Acting on Cellulose.

    PubMed

    Bulakhov, A G; Gusakov, A V; Chekushina, A V; Satrutdinov, A D; Koshelev, A V; Matys, V Yu; Sinitsyn, A P

    2016-05-01

    Lytic polysaccharide monooxygenases (PMO) discovered several years ago are enzymes classified as oxidoreductases. In nature, they participate in microbial degradation of cellulose together with cellulases that belong to the hydrolytic type of enzymes (class of hydrolases). Three PMO from ascomycetes - Thielavia terrestris, Trichoderma reesei, and Myceliophthora thermophila - were isolated and purified to homogeneous state using various types of chromatography. The first two enzymes are recombinant proteins heterologously expressed by the Penicillium verruculosum fungus, while the third is a native PMO secreted by M. thermophila. When acting on microcrystalline cellulose, all these PMOs displayed synergism with the cellulase complex of the P. verruculosum fungus. Replacing 10% of cellulases (by protein concentration) with PMO in the presence of 6.25 mM gallic acid or 2.5 µM of cellobiose dehydrogenase from M. thermophila, used as electron donors for PMO, resulted in the 17-31% increase in the yield of reducing sugars after 24-48 h of the enzymatic reaction.

  3. Endometrial Adenocarcinoma in a 27-Year-Old Woman

    PubMed Central

    Fadhlaoui, Anis; Ben Hassouna, Jamel; Khrouf, Mohamed; Zhioua, Fethi; Chaker, Anis

    2010-01-01

    Background Endometrial adenocarcinoma usually occurs after menopause, but in 2%–14% of cases, it occurs in young patients (less than 40 years of age) who are eager to preserve their fertility. Its treatment includes hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy, and, in some cases, radiation therapy. Aim To describe a case of endometrial adenocarcinoma occurring in a young woman and to undertake a literature review of risk factors and therapeutic options proposed for young women wishing to preserve their fertility. Case We report a case of endometrial cancer in a 27-year-old woman treated for resistant menorrhagia and cared for in our department as well as in the Salah Azaiez Institute. Conclusion Endometrial adenocarcinoma rarely occurs in young women. In such cases, other therapeutic options can be proposed: progesterone therapy and LH-RH (Luteinzing-Hormone-Releasing-Hormone) agonists therapy in order to preserve fertility in younger patients. PMID:21769252

  4. A novel HSP90 inhibitor with reduced hepatotoxicity synergizes with radiotherapy to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer

    PubMed Central

    Albrecht, Valerie; Hennel, Roman; Brix, Nikko; Frey, Benjamin; Gaipl, Udo S.; Zuchtriegel, Gabriele; Reichel, Christoph A.; Blutke, Andreas; Schilling, Daniela; Multhoff, Gabriele; Li, Minglun; Niyazi, Maximilian; Friedl, Anna A.; Winssinger, Nicolas; Belka, Claus; Lauber, Kirsten

    2016-01-01

    The chaperone heat shock protein 90 (HSP90) crucially supports the maturation, folding, and stability of a variety of client proteins which are of pivotal importance for the survival and proliferation of cancer cells. Consequently, targeting of HSP90 has emerged as an attractive strategy of anti-cancer therapy, and it appears to be particularly effective in the context of molecular sensitization towards radiotherapy as has been proven in preclinical models of different cancer entities. However, so far the clinical translation has largely been hampered by suboptimal pharmacological properties and serious hepatotoxicity of first- and second-generation HSP90 inhibitors. Here, we report on NW457, a novel radicicol-derived member of the pochoxime family with reduced hepatotoxicity, how it inhibits the DNA damage response and how it synergizes with ionizing irradiation to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer in vitro and in vivo. PMID:27259245

  5. Endogenous Noxa Determines the Strong Proapoptotic Synergism of the BH3-Mimetic ABT-737 with Chemotherapeutic Agents in Human Melanoma Cells12

    PubMed Central

    Weber, Arnim; Kirejczyk, Zofia; Potthoff, Stephanie; Ploner, Christian; Häcker, Georg

    2009-01-01

    Human melanoma cells are very resistant to treatment with chemotherapeutic agents, and melanoma shows poor response to chemotherapeutic therapy. We describe a strong synergistic proapoptotic effect of the Bcl-2 family inhibitor ABT-737 and the standard antimelanoma drugs, namely, dacarbazine and fotemustine, and the experimental agent, imiquimod. Experiments with human melanoma cells, keratinocytes, and embryonic fibroblasts showed that all three agents activated the mitochondrial apoptosis pathway. ABT-737 on its own was ineffective in melanoma cells unless Mcl-1 was experimentally downregulated. However, ABT-737 strongly enhanced the proapoptotic activity of the chemotherapeutic drugs. Whereas cell death induction by all three agents involved the activity of both BH3-only proteins, Bim and Noxa, the combination with ABT-737 overcame the requirement for Bim. However, the synergism between ABT-737 and imiquimod or dacarbazine required endogenous Noxa, as demonstrated by experiments with Noxa-specific RNAi. Surprisingly, although Bim was activated, it was unable to replace Noxa. Studies of mitochondrial cytochrome c release using BH3 peptides confirmed that a main effect of dacarbazine, fotemustine, and imiquimod was to neutralize Mcl-1, thereby sensitizing mitochondria to the inhibition of other Bcl-2 family members through ABT-737. ABT-737 is thus a promising agent for combination therapy for human melanoma. Importantly, the efficacy of this therapy depends on endogenous Noxa, and the ability of chemotherapeutic drugs to activate Noxa may be a valuable predictor of their synergism with Bcl-2-targeting drugs. PMID:19412422

  6. Drug Synergism of Proteasome Inhibitors and Mitotane by Complementary Activation of ER Stress in Adrenocortical Carcinoma Cells.

    PubMed

    Kroiss, Matthias; Sbiera, Silviu; Kendl, Sabine; Kurlbaum, Max; Fassnacht, Martin

    2016-12-01

    Mitotane is the only drug approved for treatment of the orphan disease adrenocortical carcinoma (ACC) and was recently shown to be the first clinically used drug acting through endoplasmic reticulum (ER)-stress induced by toxic lipids. Since mitotane has limited clinical activity as monotherapy, we here study the potential of activating ER-stress through alternative pathways. The single reliable NCI-H295 cell culture model for ACC was used to study the impact MG132, bortezomib (BTZ) and carfilzomib (CFZ) on mRNA and protein expression of ER-stress markers, cell viability and steroid hormone secretion. We found all proteasome inhibitors alone to trigger expression of mRNA (spliced X-box protein 1, XBP1) and protein markers indicative of the inositol-requiring enzyme 1 (IRE1) dependent pathway of ER-stress but not phosphorylation of eukaryotic initiation factor 2α (eIF2α), a marker of the PRKR-like endoplasmic reticulum kinase (PERK)-dependent pathway. Whereas mitotane alone activated both pathways, combination of BTZ and CFZ with low-dose mitotane blocked mitotane-induced eIF2α phosphorylation but increased XBP1-mRNA splicing indicating that proteasome inhibitors can commit signalling towards a single ER-stress pathway in ACC cells. By applying the median effect model of drug combinations using cell viability as a read out, we determined significant drug synergism between mitotane and both BTZ and CFZ. In conclusion, combination of mitotane with activators of ER-stress through the unfolded protein response is synergistic in an ACC cell culture model. Since proteasome inhibitors are readily available clinically, they are attractive candidates to study for ACC treatment in clinical trials in combination with mitotane.

  7. Correction: Synergism between genome sequencing, tandem mass spectrometry and bio-inspired synthesis reveals insights into nocardioazine B biogenesis.

    PubMed

    Alqahtani, Norah; Porwal, Suheel K; James, Elle D; Bis, Dana M; Karty, Jonathan A; Lane, Amy L; Viswanathan, Rajesh

    2015-09-21

    Correction for 'Synergism between genome sequencing, tandem mass spectrometry and bio-inspired synthesis reveals insights into nocardioazine B biogenesis' by Norah Alqahtani et al., Org. Biomol. Chem., 2015, 13, 7177-7192.

  8. Phage-antibiotic synergism: a possible approach to combatting Pseudomonas aeruginosa.

    PubMed

    Knezevic, Petar; Curcin, Sanja; Aleksic, Verica; Petrusic, Milivoje; Vlaski, Ljiljana

    2013-01-01

    Pseudomonas aeruginosa is a highly resistant opportunistic pathogen and an important etiological agent of various types of infections. During the last decade, P. aeruginosa phages have been extensively examined as alternative antimicrobial agents. The aim of the study was to determine antimicrobial effectiveness of combining subinhibitory concentrations of gentamicin, ceftriaxone, ciprofloxacin or polymyxin B with P. aeruginosa-specific bacteriophages belonging to families Podoviridae and Siphoviridae. The time-kill curve method showed that a combination of bacteriophages and subinhibitory concentrations of ceftriaxone generally reduced bacterial growth, and synergism was proven for a Siphoviridae phage σ-1 after 300 min of incubation. The detected alteration in morphology after ceftriaxone application, resulting in cell elongation, along with its specific mode of action, seemed to be a necessary but was not a sufficient reason for phage-antibiotic synergism. The phenomenon offers an opportunity for future development of treatment strategies for potentially lethal infections caused by P. aeruginosa.

  9. Synergism by co-assembly at the origin of ion selectivity in liquid-liquid extraction

    SciTech Connect

    Dourdain, S.; Hofmeister, I.; Dufreche, J.F.; Turgis, R.; Pellet-Rostaing, S.; Zemb, T.; Pecheur, O.; Leydier, A.; Jestin, J.; Testard, F.

    2012-08-15

    In liquid-liquid extraction, synergism emerges when for a defined formulation of the solvent phase, there is an increase of distribution coefficients for some cations in a mixture. To characterize the synergistic mechanisms, we determine the free energy of mixed co-assembly in aggregates. Aggregation in any point of a phase diagram can be followed not only structurally by SANS, SAXS, and SLS, but also thermodynamically by determining the concentration of monomers coexisting with reverse aggregates. Using the industrially used couple HDEHP/TOPO forming mixed reverse aggregates, and the representative couple U/Fe, we show that there is no peculiarity in the aggregates microstructure at the maximum of synergism. Nevertheless, the free energy of aggregation necessary to form mixed aggregates containing extracted ions in their polar core is comparable to the transfer free energy difference between target and nontarget ions, as deduced from the synergistic selectivity peak. (authors)

  10. Hydractinia echinata test-system. IV. Toxic synergism of human pharmaceuticals in mixtures with iodoform.

    PubMed

    Chicu, Sergiu A; Schannen, Ladislaus; Putz, Mihai V; Simu, Georgeta-M

    2016-12-01

    The structure-toxicity relationships for a series of singular human stomatological pharmaceuticals preparations and in mixture with Iodoform on Hydractinia echinata were obtained and their synergism was analyzed through the Metamorphosis Reduction Concentration (MRC50) within the "Köln model". The differences manifested between the total and individual components of the samples and mixtures, associated with toxic versus non-toxic synergism, are dependent on three essential factors of synthesis (the nature, the concentration and the number) besides manifested isotoxicity of the given components. The method represents a practical alternative useful for the reduction of experimental tests on animal to the lowest possible level, in accordance to the '3Rs' (reduce, reuse and recycle) integrative concept.

  11. The synergism of nucleoside antibiotics combined with guanine 7-N-oxide against a rhabdovirus, infectious hematopoietic necrosis virus (IHNV).

    PubMed

    Hasobe, M; Saneyoshi, M; Isono, K

    1986-09-01

    Guanine 7-N-oxide was shown to have synergistic activity in combination with neplanocin A against a rhabdovirus, infectious hematopoietic necrosis virus (IHNV), as reported previously. We examined further the antiviral activity of guanine 7-N-oxide in combination with other nucleoside antibiotics against IHNV. Synergism was seen between guanine 7-N-oxide and D-eritadenine or cordycepin. It is considered that compounds inhibiting RNA methylation show synergism with guanine 7-N-oxide.

  12. Synergism in the desorption of polycyclic aromatic hydrocarbons from soil models by mixed surfactant solutions.

    PubMed

    Sales, Pablo S; Fernández, Mariana A

    2016-05-01

    This study investigates the effect of a mixed surfactant system on the desorption of polycyclic aromatic hydrocarbons (PAHs) from soil model systems. The interaction of a non-ionic surfactant, Tween 80, and an anionic one, sodium laurate, forming mixed micelles, produces several beneficial effects, including reduction of adsorption onto solid of the non-ionic surfactant, decrease in the precipitation of the fatty acid salt, and synergism to solubilize PAHs from solids compared with individual surfactants.

  13. Synergism between aminoglycosides and cephalosporins with antipseudomonal activity: interaction index and killing curve method.

    PubMed Central

    Hallander, H O; Dornbusch, K; Gezelius, L; Jacobson, K; Karlsson, I

    1982-01-01

    Combinations of gentamicin with cefotaxime, moxalactam, and ceftazidime were tested against 43 bacterial strains, most of them blood isolates. With an interaction index of less than or equal to 0.5 as borderline, synergism was demonstrated against 30 to 40% of the strains by the fractional inhibitory concentration index and against 50 to 70% by the fractional bactericidal concentration index. The reproducibility of the index was within +/- 0.2 for two-thirds of 40 repetitive assays and within +/- 0.4 to 0.5 for all of these assays. Similar results were obtained when netilmicin was substituted for gentamicin. The killing curve system for studying antibiotic synergism was standardized to give results comparable to those obtained with the interaction index. This was achieved when one-half of a previously determined minimum bactericidal concentration was used for single drugs and the amount of antibiotic was at least halved again when drugs were used in combination. An initial bacterial concentration of 10(5) to 10(6) colony-forming units per ml is recommended. Given these conditions, synergism could be defined as a 2-log 10 or more decrease in viable count given by both drugs together, as compared with the more active of the pair after 24 h. Prediction of killing curve results could then be obtained with the fractional bactericidal concentration index. When cephalosporins and gentamicin were combined from the start, the beta-lactam antibiotics were less susceptible to inactivation, as demonstrated in time-killing assays. If one of the antibiotics were added after 24 h, synergism was not demonstrable. The results indicate that the new cephalosporins may be advantageously combined with aminoglycosides. PMID:7181485

  14. Synergism of insecticides provides evidence of metabolic mechanisms of resistance in the obliquebanded leafroller Choristoneura rosaceana (Lepidoptera: Tortricidae).

    PubMed

    Ahmad, Mushtaq; Hollingworth, Robert M

    2004-05-01

    The interactions between six insecticides (indoxacarb, cypermethrin, chlorpyrifos, azinphosmethyl, tebufenozide and chlorfenapyr) and three potential synergists, (piperonyl butoxide (PBO), S,S,S-tributyl phosphorotrithioate (DEF) and diethyl maleate (DEM)) were studied by dietary exposure in a multi-resistant and a susceptible strain of the obliquebanded leafroller, Choristoneura rosaceana (Harris). The synergists did not produce appreciable synergism with most of the insecticides in the susceptible strain. Except for tebufenozide, PBO synergized all the insecticides to varying degrees in the resistant strain. A very high level of synergism by PBO was found with indoxacarb, which reduced the resistance level from 705- to 20-fold when PBO was administered alone and to around 10-fold when used in combination with DEF. DEF also synergized indoxacarb, cypermethrin, chlorpyrifos, azinphosmethyl and tebufenozide in the resistant strain. DEM produced synergism of indoxacarb, chlorpyrifos, azinphos-methyl and chlorfenapyr in the resistant strain. DEM was highly synergistic to cypermethrin, and to some extent to tebufenozide in both the susceptible and resistant strains equally, implying that detoxification by glutathione S-transferases was not a mechanism of resistance for these insecticides. The high level of synergism seen with DEM in the case of cypermethrin may be due to an increase in oxidative stress resulting from the removal of the antioxidant, glutathione. These studies indicate that enhanced detoxification, often mediated by cytochrome P-450 monooxygenases, but with probable esterase and glutathione S-transferase contributions in some cases, is the major mechanism imparting resistance to different insecticides in C. rosaceana.

  15. Opioid Mechanism Involvement in the Synergism Produced by the Combination of Diclofenac and Caffeine in the Formalin Model

    PubMed Central

    Flores-Ramos, José María; Díaz-Reval, M. Irene

    2013-01-01

    Analgesics can be administered in combination with caffeine for improved analgesic effectiveness in a process known as synergism. The mechanisms by which these combinations produce synergism are not yet fully understood. The aim of this study was to analyze whether the administration of diclofenac combined with caffeine produced antinociceptive synergism and whether opioid mechanisms played a role in this event. The formalin model was used to evaluate the antinociception produced by the oral administration of diclofenac, caffeine, or their combination. Opioid involvement was analyzed through intracerebroventricular (i.c.v.) administration of naloxone followed by the oral administration of the study drugs. Diclofenac presented a dose-dependent effect, with a mean effective dose (ED50) of 6.7 mg/kg. Caffeine presented an analgesic effect with a 17–36% range. The combination of subeffective doses of each of the two drugs presented the greatest synergism with an effect of 57.7 ± 5.6%. The maximal antinociceptive effect was obtained with the combination of 10.0 mg/kg diclofenac and 1.0 mg/kg of caffeine, with an effect of 76.7 ± 5.6%. The i.c.v. administration of naloxone inhibited the effect of diclofenac, both separately and combined. In conclusion, caffeine produces antinociceptive synergism when administered in combination with diclofenac, and this synergism is partially mediated by opioid mechanisms at the central level. PMID:27335871

  16. Prediction of Synergism from Chemical-Genetic Interactions by Machine Learning.

    PubMed

    Wildenhain, Jan; Spitzer, Michaela; Dolma, Sonam; Jarvik, Nick; White, Rachel; Roy, Marcia; Griffiths, Emma; Bellows, David S; Wright, Gerard D; Tyers, Mike

    2015-12-23

    The structure of genetic interaction networks predicts that, analogous to synthetic lethal interactions between non-essential genes, combinations of compounds with latent activities may exhibit potent synergism. To test this hypothesis, we generated a chemical-genetic matrix of 195 diverse yeast deletion strains treated with 4,915 compounds. This approach uncovered 1,221 genotype-specific inhibitors, which we termed cryptagens. Synergism between 8,128 structurally disparate cryptagen pairs was assessed experimentally and used to benchmark predictive algorithms. A model based on the chemical-genetic matrix and the genetic interaction network failed to accurately predict synergism. However, a combined random forest and Naive Bayesian learner that associated chemical structural features with genotype-specific growth inhibition had strong predictive power. This approach identified previously unknown compound combinations that exhibited species-selective toxicity toward human fungal pathogens. This work demonstrates that machine learning methods trained on unbiased chemical-genetic interaction data may be widely applicable for the discovery of synergistic combinations in different species. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Levamisole and cocaine synergism: a prevalent adulterant enhances cocaine's action in vivo

    PubMed Central

    Tallarida, Christopher S.; Egan, Erin; Alejo, Gissel D.; Raffa, Robert; Tallarida, Ronald J.; Rawls, Scott M.

    2014-01-01

    Levamisole is estimated by the Drug Enforcement Agency (DEA) to be present in about 80% of cocaine seized in the United States and linked to debilitating, and sometimes fatal, immunologic effects in cocaine abusers. One explanation for the addition of levamisole to cocaine is that it increases the amount of product and enhances profits. An alternative possibility, and one investigated here, is that levamisole alters cocaine's action in vivo. We specifically investigated effects of levamisole on cocaine's stereotypical and place-conditioning effects in an established invertebrate (planarian) assay. Acute exposure to levamisole or cocaine produced concentration-dependent increases in stereotyped movements. For combined administration of the two agents, isobolographic analysis revealed that the observed stereotypical response was enhanced relative to the predicted effect, indicating synergism for the interaction. In conditioned place preference (CPP) experiments, cocaine produced a significant preference shift; in contrast, levamisole was ineffective at all concentrations tested. For combination experiments, a submaximal concentration of cocaine produced CPP that was enhanced by inactive concentrations of levamisole, indicating synergism. The present results provide the first experimental evidence that levamisole enhances cocaine's action in vivo. Most important is the identification of synergism for the levamisole/cocaine interaction, which now requires further study in mammals. PMID:24440755

  18. Synergism between plant extract and antimicrobial drugs used on Staphylococcus aureus diseases.

    PubMed

    Betoni, Joyce Elaine Cristina; Mantovani, Rebeca Passarelli; Barbosa, Lidiane Nunes; Di Stasi, Luiz Claudio; Fernandes Junior, Ary

    2006-06-01

    Searches for substances with antimicrobial activity are frequent, and medicinal plants have been considered interesting by some researchers since they are frequently used in popular medicine as remedies for many infectious diseases. The aim of this study was to verify the synergism between 13 antimicrobial drugs and 8 plant extracts--"guaco" (Mikania glomerata), guava (Psidium guajava), clove (Syzygium aromaticum), garlic (Allium sativum), lemongrass (Cymbopogon citratus), ginger (Zingiber officinale), "carqueja" (Baccharis trimera), and mint (Mentha piperita)--against Staphylococcus aureus strains, and for this purpose, the disk method was the antimicrobial susceptibility test performed. Petri dishes were prepared with or without dilution of plant extracts at sub-inhibitory concentrations in Mueller-Hinton Agar (MHA), and the inhibitory zones were recorded in millimeters. In vitro anti-Staphylococcus aureus activities of the extracts were confirmed, and synergism was verified for all the extracts; clove, guava, and lemongrass presented the highest synergism rate with antimicrobial drugs, while ginger and garlic showed limited synergistic capacity.

  19. Levamisole and cocaine synergism: a prevalent adulterant enhances cocaine's action in vivo.

    PubMed

    Tallarida, Christopher S; Egan, Erin; Alejo, Gissel D; Raffa, Robert; Tallarida, Ronald J; Rawls, Scott M

    2014-04-01

    Levamisole is estimated by the Drug Enforcement Agency (DEA) to be present in about 80% of cocaine seized in the United States and linked to debilitating, and sometimes fatal, immunologic effects in cocaine abusers. One explanation for the addition of levamisole to cocaine is that it increases the amount of product and enhances profits. An alternative possibility, and one investigated here, is that levamisole alters cocaine's action in vivo. We specifically investigated effects of levamisole on cocaine's stereotypical and place-conditioning effects in an established invertebrate (planarian) assay. Acute exposure to levamisole or cocaine produced concentration-dependent increases in stereotyped movements. For combined administration of the two agents, isobolographic analysis revealed that the observed stereotypical response was enhanced relative to the predicted effect, indicating synergism for the interaction. In conditioned place preference (CPP) experiments, cocaine produced a significant preference shift; in contrast, levamisole was ineffective at all concentrations tested. For combination experiments, a submaximal concentration of cocaine produced CPP that was enhanced by inactive concentrations of levamisole, indicating synergism. The present results provide the first experimental evidence that levamisole enhances cocaine's action in vivo. Most important is the identification of synergism for the levamisole/cocaine interaction, which now requires further study in mammals.

  20. Synergism in binary mixture of surfactants 11. Mixtures containing mono- and disulfonated alkyl- and dialkyldiphenylethers

    SciTech Connect

    Rosen, M.J.; Zhen Huo Zhu; Tao Gao

    1993-04-01

    Interaction and synergism at 25C of some alkyl- and dialkyl-diphenylether mono- and disulfonates with a second surfactant containing a single hydrophilic and a single hydrophobic group (a nonionic, a betaine, or an amine oxide type of surfactant) in aqueous solutions containing swamping amounts of NaCl were studied by calculating interaction parameters from surface tension-concentration data. Attractive interaction in mixed monolayers at the aqueous solution/water interface increased in the order: monoalkyl monosulfonate (MAMS) < monoalkyl disulfonate (MADS) < dialkyl disulfonate (DADS). In mixed micelles, by contrast, the DADS interaction was always weaker than that of either the MAMS or MADS. This is believed to be due to greater steric inhibition of micelle formation by the DADS structure. As a result of these differences in interaction, the DADS (gemini-type) structure is more prone than the other two types of structures to show synergism in both surface tension reduction efficiency and effectiveness, and less prone to show synergism in mixed micelle formation.

  1. Synergism between mefloquine and artemisinin and its enhancement by retinol in Plasmodium falciparum in vitro.

    PubMed

    Kerschbaumer, Gerwald; Wernsdorfer, Gunther; Wiedermann, Ursula; Congpuong, Kanungnit; Sirichaisinthop, Jeeraphat; Wernsdorfer, Walther H

    2010-10-01

    Following the advent of mefloquine resistance in Plasmodium falciparum in Thailand in the 1990s, the combined treatment of falciparum malaria with artesunate and mefloquine was found to be highly effective in treating and curing the patients in the affected areas. Monitoring of the clinical-parasitological response and of the in vitro sensitivity of P. falciparum was systematically conducted in order to detect any signs of failure of this type of artemisinin-based combination treatment (ACT). In earlier observations the in vitro activity of artemisinin was found to be significantly enhanced when combined with retinol. The same applies to mefloquine. In order to check whether the synergism between artemisinin and mefloquine was maintained in the presence of retinol, the pharmacodynamic interaction of the three compounds was investigated in the western border area of Thailand. Successful parallel tests with mefloquine, artemisinin, retinol, mefloquine-artemisinin 5:1 as well as mefloquine-artemisinin (5:1) + retinol low, medium and high were obtained with 43 fresh parasite isolates. The retinol concentrations in the low, medium and high formulations corresponded to the 50th, 65th and 80th percentile of the physiological mean concentrations in the blood of healthy adults. The IC(50), IC(90) and IC(99) values for mefloquine alone showed a further increase over the data of 2008. In the combinations with artemisinin and retinol moderate synergism was observed at the IC(50), but synergism increased strongly at the IC(90) and the IC(99).

  2. How Cellulose Stretches: Synergism between Covalent and Hydrogen Bonding

    PubMed Central

    2014-01-01

    Cellulose is the most familiar and most abundant strong biopolymer, but the reasons for its outstanding mechanical performance are not well understood. Each glucose unit in a cellulose chain is joined to the next by a covalent C–O–C linkage flanked by two hydrogen bonds. This geometry suggests some form of cooperativity between covalent and hydrogen bonding. Using infrared spectroscopy and X-ray diffraction, we show that mechanical tension straightens out the zigzag conformation of the cellulose chain, with each glucose unit pivoting around a fulcrum at either end. Straightening the chain leads to a small increase in its length and is resisted by one of the flanking hydrogen bonds. This constitutes a simple form of molecular leverage with the covalent structure providing the fulcrum and gives the hydrogen bond an unexpectedly amplified effect on the tensile stiffness of the chain. The principle of molecular leverage can be directly applied to certain other carbohydrate polymers, including the animal polysaccharide chitin. Related but more complex effects are possible in some proteins and nucleic acids. The stiffening of cellulose by this mechanism is, however, in complete contrast to the way in which hydrogen bonding provides toughness combined with extensibility in protein materials like spider silk. PMID:24568640

  3. How cellulose stretches: synergism between covalent and hydrogen bonding.

    PubMed

    Altaner, Clemens M; Thomas, Lynne H; Fernandes, Anwesha N; Jarvis, Michael C

    2014-03-10

    Cellulose is the most familiar and most abundant strong biopolymer, but the reasons for its outstanding mechanical performance are not well understood. Each glucose unit in a cellulose chain is joined to the next by a covalent C-O-C linkage flanked by two hydrogen bonds. This geometry suggests some form of cooperativity between covalent and hydrogen bonding. Using infrared spectroscopy and X-ray diffraction, we show that mechanical tension straightens out the zigzag conformation of the cellulose chain, with each glucose unit pivoting around a fulcrum at either end. Straightening the chain leads to a small increase in its length and is resisted by one of the flanking hydrogen bonds. This constitutes a simple form of molecular leverage with the covalent structure providing the fulcrum and gives the hydrogen bond an unexpectedly amplified effect on the tensile stiffness of the chain. The principle of molecular leverage can be directly applied to certain other carbohydrate polymers, including the animal polysaccharide chitin. Related but more complex effects are possible in some proteins and nucleic acids. The stiffening of cellulose by this mechanism is, however, in complete contrast to the way in which hydrogen bonding provides toughness combined with extensibility in protein materials like spider silk.

  4. Differential Protection of Cry1Fa Toxin against Spodoptera frugiperda Larval Gut Proteases by Cadherin Orthologs Correlates with Increased Synergism

    PubMed Central

    Rahman, Khalidur; Abdullah, Mohd Amir F.; Ambati, Suresh; Taylor, Milton D.

    2012-01-01

    The Cry proteins produced by Bacillus thuringiensis (Bt) are the most widely used biopesticides effective against a range of crop pests and disease vectors. Like chemical pesticides, development of resistance is the primary threat to the long-term efficacy of Bt toxins. Recently discovered cadherin-based Bt Cry synergists showed the potential to augment resistance management by improving efficacy of Cry toxins. However, the mode of action of Bt Cry synergists is thus far unclear. Here we elucidate the mechanism of cadherin-based Cry toxin synergism utilizing two cadherin peptides, Spodoptera frugiperda Cad (SfCad) and Manduca sexta Cad (MsCad), which differentially enhance Cry1Fa toxicity to Spodoptera frugiperda neonates. We show that differential SfCad- and MsCad-mediated protection of Cry1Fa toxin in the Spodoptera frugiperda midgut correlates with differential Cry1Fa toxicity enhancement. Both peptides exhibited high affinity for Cry1Fa toxin and an increased rate of Cry1Fa-induced pore formation in S. frugiperda. However, only SfCad bound the S. frugiperda brush border membrane vesicle and more effectively prolonged the stability of Cry1Fa toxin in the gut, explaining higher Cry1Fa enhancement by this peptide. This study shows that cadherin fragments may enhance B. thuringiensis toxicity by at least two different mechanisms or a combination thereof: (i) protection of Cry toxin from protease degradation in the insect midgut and (ii) enhancement of pore-forming ability of Cry toxin. PMID:22081566

  5. Bactericide, Immunomodulating, and Wound Healing Properties of Transgenic Kalanchoe pinnata Synergize with Antimicrobial Peptide Cecropin P1 In Vivo

    PubMed Central

    Lebedeva, A. A.; Zakharchenko, N. S.; Trubnikova, E. V.; Medvedeva, O. A.; Masgutova, G. A.; Zylkova, M. V.; Buryanov, Y. I.; Belous, A. S.

    2017-01-01

    Procedure of manufacturing K. pinnata water extracts containing cecropin P1 (CecP1) from the formerly described transgenic plants is established. It included incubation of leaves at +4°C for 7 days, mechanical homogenization of leaves using water as extraction solvent, and heating at +70°C for inactivating plant enzymes. Yield of CecP1 (after heating and sterilizing filtration) was 0.3% of total protein in the extract. The water extract of K. pinnata + CecP1 exhibits favorable effect on healing of wounds infected with S. aureus (equal to Cefazolin) and with a combination of S. aureus with P. aeruginosa (better than Cefazolin). Wild-type K. pinnata extract exhibited evident microbicide activity against S. aureus with P. aeruginosa but it was substantially strengthened in K. pinnata + CecP1 extract. K. pinnata extracts (both wild-type and transgenic) did not exhibit general toxicity and accelerated wound recovery. Due to immunomodulating activity, wild-type K. pinnata extract accelerated granulation of the wound bed and marginal epithelialization even better than K. pinnata + CecP1 extract. Immunomodulating and microbicide activity of K. pinnata synergizes with microbicide activity of CecP1 accelerating elimination of bacteria. PMID:28326334

  6. Ganoderma lucidum Combined with the EGFR Tyrosine Kinase Inhibitor, Erlotinib Synergize to Reduce Inflammatory Breast Cancer Progression

    PubMed Central

    Suárez-Arroyo, Ivette J.; Rios-Fuller, Tiffany J.; Feliz-Mosquea, Yismeilin R.; Lacourt-Ventura, Mercedes; Leal-Alviarez, Daniel J.; Maldonado-Martinez, Gerónimo; Cubano, Luis A.; Martínez-Montemayor, Michelle M.

    2016-01-01

    The high incidence of resistance to Tyrosine Kinase Inhibitors (TKIs) targeted against EGFR and downstream pathways has increased the necessity to identify agents that may be combined with these therapies to provide a sustained response for breast cancer patients. Here, we investigate the therapeutic potential of Ganoderma lucidum extract (GLE) in breast cancer, focusing on the regulation of the EGFR signaling cascade when treated with the EGFR TKI, Erlotinib. SUM-149, or intrinsic Erlotinib resistant MDA-MB-231 cells, and a successfully developed Erlotinib resistant cell line, rSUM-149 were treated with increasing concentrations of Erlotinib, GLE, or their combination (Erlotinib/GLE) for 72h. Treatment effects were tested on cell viability, cell proliferation, cell migration and invasion. To determine tumor progression, severe combined immunodeficient mice were injected with SUM-149 cells and then treated with Erlotinib/GLE or Erlotinib for 13 weeks. We assessed the protein expression of ERK1/2 and AKT in in vitro and in vivo models. Our results show that GLE synergizes with Erlotinib to sensitize SUM-149 cells to drug treatment, and overcomes intrinsic and developed Erlotinib resistance. Also, Erlotinib/GLE decreases SUM-149 cell viability, proliferation, migration and invasion. GLE increases Erlotinib sensitivity by inactivating AKT and ERK signaling pathways in our models. We conclude that a combinatorial therapeutic approach may be the best way to increase prognosis in breast cancer patients with EGFR overexpressing tumors. PMID:26958085

  7. Bactericide, Immunomodulating, and Wound Healing Properties of Transgenic Kalanchoe pinnata Synergize with Antimicrobial Peptide Cecropin P1 In Vivo.

    PubMed

    Lebedeva, A A; Zakharchenko, N S; Trubnikova, E V; Medvedeva, O A; Kuznetsova, T V; Masgutova, G A; Zylkova, M V; Buryanov, Y I; Belous, A S

    2017-01-01

    Procedure of manufacturing K. pinnata water extracts containing cecropin P1 (CecP1) from the formerly described transgenic plants is established. It included incubation of leaves at +4°C for 7 days, mechanical homogenization of leaves using water as extraction solvent, and heating at +70°C for inactivating plant enzymes. Yield of CecP1 (after heating and sterilizing filtration) was 0.3% of total protein in the extract. The water extract of K. pinnata + CecP1 exhibits favorable effect on healing of wounds infected with S. aureus (equal to Cefazolin) and with a combination of S. aureus with P. aeruginosa (better than Cefazolin). Wild-type K. pinnata extract exhibited evident microbicide activity against S. aureus with P. aeruginosa but it was substantially strengthened in K. pinnata + CecP1 extract. K. pinnata extracts (both wild-type and transgenic) did not exhibit general toxicity and accelerated wound recovery. Due to immunomodulating activity, wild-type K. pinnata extract accelerated granulation of the wound bed and marginal epithelialization even better than K. pinnata + CecP1 extract. Immunomodulating and microbicide activity of K. pinnata synergizes with microbicide activity of CecP1 accelerating elimination of bacteria.

  8. A Two-Stage Dissociation System for Multilayer Imaging of Cancer Biomarker-Synergic Networks in Single Cells.

    PubMed

    Qian, Ruo-Can; Cao, Yue; Zhao, Li-Jun; Gu, Zhen; Long, Yi-Tao

    2017-04-18

    The monitoring of cancer biomarkers is crucial to the early detection of cancer. However, a limiting factor in biomarker analysis is the ability to obtain the multilayered information of various biomarker molecules located at different parts of cells from the plasma membrane to the cytoplasm. A two-stage dissociation nanoparticle system based on multifunctionalized polydopamine-coated gold nanoparticles (Au@PDA NPs) is reported, which allows for the two-stage imaging of cancer biomarkers in single cells. We demonstrate the feasibility of this strategy on sialic acids (SAs), p53 protein, and microRNA-21 (miRNA-21) in MCF-7 breast cancer cells by two custom-built probes. Furthermore, the multicolor fluorescence information extracted is used for the monitoring of biomarker expression changes under different drug combinations, which allows us to investigate the complex interactions between various cancer biomarkers and to describe the cancer biomarker-synergic networks in single cells. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Scutellaria barbata D. Don extract synergizes the antitumor effects of low dose 5-fluorouracil through induction of apoptosis and metabolism.

    PubMed

    Xu, Huanli; Yu, Jinmei; Sun, Yan; Xu, Xiaona; Li, Li; Xue, Ming; Du, Guanhua

    2013-07-15

    Traditional Chinese medicines have been recognized as a new source of anticancer drugs or chemotherapy adjuvant to enhance the efficacy of chemotherapy and to ameliorate the side effects. This study aimed to investigate the antitumor effects of combined Scutellaria barbata D. Don extract (SBE) and 5-FU treatment in vitro and in vivo and the potential mechanisms. SBE was prepared and analyzed by HPLC. Tumor growth inhibition both in vitro and in vivo, cell apoptosis, apoptosis related protein expressions (P53, bid, bax, bcl-2), caspase-3 activities and 5-FU related enzymes were assessed. SBE could significantly synergize the antitumor effects of low dose 5-FU both in vivo and in vitro. SBE could increase the apoptosis inducing effect of low dose 5-FU in both Bel-7402 and HCT-8 cells. Also, caspase-3 activities, P53 and bax expressions were significantly increased, while bid and bcl-2 expressions were significantly decreased in drug combination groups, compared with individual drug treatment groups. Furthermore, SBE could significantly decrease the mRNA levels of dihydropyrimidine dehydrogenase. These results showed that combined treatment with SBE and low dose 5-FU can significantly inhibit the tumor growth both in vitro and in vivo, which might be related with apoptosis and regulations of 5-FU metabolism.

  10. Synergic hypocholesterolaemic effect of n-3 PUFA and oestrogen by modulation of hepatic cholesterol metabolism in female rats.

    PubMed

    Oh, Yuna; Jin, Youri; Park, Yongsoon

    2015-12-14

    n-3 PUFA such as EPA and DHA as well as oestrogen have been reported to decrease blood levels of cholesterol, but their underlying mechanism is unclear. The purpose of this study was to determine the effects of the combination of n-3 PUFA supplementation and oestrogen injection on hepatic cholesterol metabolism. Rats were fed a modified AIN-93G diet with 0, 1 or 2 % n-3 PUFA (EPA+DHA) relative to the total energy intake for 12 weeks. Rats were surgically ovariectomised at week 8, and, after 1-week recovery, rats were injected with 17β-oestradiol-3-benzoate (E2) or maize oil for the last 3 weeks. Supplementation with n-3 PUFA and E2 injection significantly increased the ratio of the hepatic expression of phosphorylated AMP activated protein kinase (p-AMPK):AMP activated protein kinase (AMPK) and decreased sterol regulatory element-binding protein-2, 3-hydroxy-3-methylglutaryl coenzyme A reductase and proprotein convertase subtilisin/kexin type 9. Supplementation with n-3 PUFA increased hepatic expression of cholesterol 7α-hydroxylase (CYP7A1), sterol 12α-hydroxylase (CYP8B1) and sterol 27-hydroxylase (CYP27A1); however, E2 injection decreased CYP7A1 and CYP8B1 but not CYP27A1. Additionally, E2 injection increased hepatic expression of oestrogen receptor-α and β. In conclusion, n-3 PUFA supplementation and E2 injection had synergic hypocholesterolaemic effects by down-regulating hepatic cholesterol synthesis (n-3 PUFA and oestrogen) and up-regulating bile acid synthesis (n-3 PUFA) in ovariectomised rats.

  11. Naturally occurring antifungal agents against Zygosaccharomyces bailii and their synergism.

    PubMed

    Fujita, Ken-Ichi; Kubo, Isao

    2005-06-29

    Polygodial was found to exhibit a fungicidal activity against a food spoilage yeast, Zygosaccharomyces bailii, with the minimum fungicidal concentration (MFC) of 50 microg/mL (0.17 mM). The time-kill curve study showed that polygodial was fungicidal at any growth stage. The primary action of polygodial comes from its ability to disrupt the native membrane-associated function of integral proteins as nonionic surface active agents (surfactants) followed by a decrease in plasma membrane fluidity. The fungicidal activity of polygodial was increased 128-fold in combination with a sublethal amount (equivalent of 1/2 MFC) of anethole and vice versa relative to the fungicidal activity of anethole. The fungicidal activity of sorbic acid was enhanced 512-fold in combination with 1/2 MFC of polygodial. Conversely, the fungicidal activity of polygodial was enhanced 128-fold in combination with 1/2 MFC of sorbic acid.

  12. Nucks1 synergizes with Trp53 to promote radiation lymphomagenesis in mice

    DOE PAGES

    Yue, Yangbo; Leung, Stanley G.; Liu, Yueyong; ...

    2016-08-16

    NUCKS1 is a 27 kD vertebrate-specific protein, with a role in the DNA damage response. Here, we show that after 4 Gy total-body X-irradiation, Trp53+/- Nucks1+/- mice more rapidly developed tumors, particularly thymic lymphoma (TL), than Trp53+/- mice. TLs in both cohorts showed loss of heterozygosity (LOH) of the Trp53+ allele in essentially all cases. In contrast, LOH of the Nucks1+ allele was rare. Nucks1 expression correlated well with Nucks1 gene dosage in normal thymi, but was increased in the majority of TLs from Trp53+/- Nucks1+/- mice, suggesting that elevated Nucks1 message may be associated with progression towards malignancy inmore » vivo. Trp53+/- Nucks1+/- mice frequently succumbed to CD4- CD8- TLs harboring translocations involving Igh but not Tcra/d, indicating TLs in Trp53+/- Nucks1+/- mice mostly originated prior to the double positive stage and at earlier lineage than TLs in Trp53+/- mice. Monoclonal rearrangements at Tcrb were more prevalent in TLs from Trp53+/- Nucks1+/- mice, as was infiltration of primary TL cells to distant organs (liver, kidney and spleen). We propose that, in the context of Trp53 deficiency, wild type levels of Nucks1 are required to suppress radiation-induced TL, likely through the role of the NUCKS1 protein in the DNA damage response.« less

  13. Nucks1 synergizes with Trp53 to promote radiation lymphomagenesis in mice.

    PubMed

    Yue, Yangbo; Leung, Stanley G; Liu, Yueyong; Huang, Yurong; Grundt, Kirsten; Østvold, Anne-Carine; Jen, Kuang-Yu; Schild, David; Mao, Jian-Hua; Wiese, Claudia

    2016-09-20

    NUCKS1 is a 27 kD vertebrate-specific protein, with a role in the DNA damage response. Here, we show that after 4 Gy total-body X-irradiation, Trp53+/- Nucks1+/- mice more rapidly developed tumors, particularly thymic lymphoma (TL), than Trp53+/- mice. TLs in both cohorts showed loss of heterozygosity (LOH) of the Trp53+ allele in essentially all cases. In contrast, LOH of the Nucks1+ allele was rare. Nucks1 expression correlated well with Nucks1 gene dosage in normal thymi, but was increased in the majority of TLs from Trp53+/- Nucks1+/- mice, suggesting that elevated Nucks1 message may be associated with progression towards malignancy in vivo. Trp53+/- Nucks1+/- mice frequently succumbed to CD4- CD8- TLs harboring translocations involving Igh but not Tcra/d, indicating TLs in Trp53+/- Nucks1+/- mice mostly originated prior to the double positive stage and at earlier lineage than TLs in Trp53+/- mice. Monoclonal rearrangements at Tcrb were more prevalent in TLs from Trp53+/- Nucks1+/- mice, as was infiltration of primary TL cells to distant organs (liver, kidney and spleen). We propose that, in the context of Trp53 deficiency, wild type levels of Nucks1 are required to suppress radiation-induced TL, likely through the role of the NUCKS1 protein in the DNA damage response.

  14. Nucks1 synergizes with Trp53 to promote radiation lymphomagenesis in mice

    PubMed Central

    Yue, Yangbo; Leung, Stanley G.; Liu, Yueyong; Huang, Yurong; Grundt, Kirsten; Østvold, Anne-Carine; Jen, Kuang-Yu; Schild, David; Mao, Jian-Hua; Wiese, Claudia

    2016-01-01

    NUCKS1 is a 27 kD vertebrate-specific protein, with a role in the DNA damage response. Here, we show that after 4 Gy total-body X-irradiation, Trp53+/− Nucks1+/− mice more rapidly developed tumors, particularly thymic lymphoma (TL), than Trp53+/− mice. TLs in both cohorts showed loss of heterozygosity (LOH) of the Trp53+ allele in essentially all cases. In contrast, LOH of the Nucks1+ allele was rare. Nucks1 expression correlated well with Nucks1 gene dosage in normal thymi, but was increased in the majority of TLs from Trp53+/− Nucks1+/− mice, suggesting that elevated Nucks1 message may be associated with progression towards malignancy in vivo. Trp53+/− Nucks1+/− mice frequently succumbed to CD4- CD8- TLs harboring translocations involving Igh but not Tcra/d, indicating TLs in Trp53+/− Nucks1+/− mice mostly originated prior to the double positive stage and at earlier lineage than TLs in Trp53+/- mice. Monoclonal rearrangements at Tcrb were more prevalent in TLs from Trp53+/− Nucks1+/− mice, as was infiltration of primary TL cells to distant organs (liver, kidney and spleen). We propose that, in the context of Trp53 deficiency, wild type levels of Nucks1 are required to suppress radiation-induced TL, likely through the role of the NUCKS1 protein in the DNA damage response. PMID:27542204

  15. Sorafenib synergizes with metformin in NSCLC through AMPK pathway activation

    PubMed Central

    Groenendijk, Floris H; Mellema, Wouter W; van der Burg, Eline; Schut, Eva; Hauptmann, Michael; Horlings, Hugo M; Willems, Stefan M; van den Heuvel, Michel M; Jonkers, Jos; Smit, Egbert F; Bernards, René

    2015-01-01

    The multikinase inhibitor sorafenib is under clinical investigation for the treatment of many solid tumors, but in most cases, the molecular target responsible for the clinical effect is unknown. Furthermore, enhancing the effectiveness of sorafenib using combination strategies is a major clinical challenge. Here, we identify sorafenib as an activator of AMP-activated protein kinase (AMPK), in a manner that involves either upstream LKB1 or CAMKK2. We further show in a phase II clinical trial in KRAS mutant advanced non-small cell lung cancer (NSCLC) with single agent sorafenib an improved disease control rate in patients using the antidiabetic drug metformin. Consistent with this, sorafenib and metformin act synergistically in inhibiting cellular proliferation in NSCLC in vitro and in vivo. A synergistic effect of both drugs is also seen on phosphorylation of the AMPKα activation site. Our results provide a rationale for the synergistic antiproliferative effects, given that AMPK inhibits downstream mTOR signaling. These data suggest that the combination of sorafenib with AMPK activators could have beneficial effects on tumor regression by AMPK pathway activation. The combination of metformin or other AMPK activators and sorafenib could be tested in prospective clinical trials. PMID:25080865

  16. Modulation of DNA damage response and induction of apoptosis mediates synergism between doxorubicin and a new imidazopyridine derivative in breast and lung cancer cells.

    PubMed

    El-Awady, Raafat A; Semreen, Mohammad H; Saber-Ayad, Maha M; Cyprian, Farhan; Menon, Varsha; Al-Tel, Taleb H

    2016-01-01

    DNA damage response machinery (DDR) is an attractive target of cancer therapy. Modulation of DDR network may alter the response of cancer cells to DNA damaging anticancer drugs such as doxorubicin. The aim of the present study is to investigate the effects of a newly developed imidazopyridine (IAZP) derivative on the DDR after induction of DNA damage in cancer cells by doxorubicin. Cytotoxicity sulphrhodamine-B assay showed a weak anti-proliferative effect of IAZP alone on six cancer cell lines (MCF7, A549, A549DOX11, HepG2, HeLa and M8) and a normal fibroblast strain. Combination of IAZP with doxorubicin resulted in synergism in lung (A549) and breast (MCF7) cancer cells but neither in the other cancer cell lines nor in normal fibroblasts. Molecular studies revealed that synergism is mediated by modulation of DNA damage response and induction of apoptosis. Using constant-field gel electrophoresis and immunofluorescence detection of γ-H2AX foci, IAZP was shown to inhibit the repair of doxorubicin-induced DNA damage in A549 and MCF7 cells. Immunoblot analysis showed that IAZP suppresses the phosphorylation of the ataxia lelangiectasia and Rad3 related (ATR) protein, which is an important player in the response of cancer cells to chemotherapy-induced DNA damage. Moreover, IAZP augmented the doxorubicin-induced degradation of p21, activation of p53, CDK2, caspase 3/7 and phosphorylation of Rb protein. These effects enhanced doxorubicin-induced apoptosis in both cell lines. Our results indicate that IAZP is a promising agent that may enhance the cytotoxic effects of doxorubicin on some cancer cells through targeting the DDR. It is a preliminary step toward the clinical application of IAZP in combination with anticancer drugs and opens the avenue for the development of compounds targeting the DDR pathway that might improve the therapeutic index of anticancer drugs and enhance their cure rate.

  17. Characterization of a Viral Synergism in the Monocot Brachypodium distachyon Reveals Distinctly Altered Host Molecular Processes Associated with Disease1[C][W][OA

    PubMed Central

    Mandadi, Kranthi K.; Scholthof, Karen-Beth G.

    2012-01-01

    Panicum mosaic virus (PMV) and its satellite virus (SPMV) together infect several small grain crops, biofuel, and forage and turf grasses. Here, we establish the emerging monocot model Brachypodium (Brachypodium distachyon) as an alternate host to study PMV- and SPMV-host interactions and viral synergism. Infection of Brachypodium with PMV+SPMV induced chlorosis and necrosis of leaves, reduced seed set, caused stunting, and lowered biomass, more than PMV alone. Toward gaining a molecular understanding of PMV- and SPMV-affected host processes, we used a custom-designed microarray and analyzed global changes in gene expression of PMV- and PMV+SPMV-infected plants. PMV infection by itself modulated expression of putative genes functioning in carbon metabolism, photosynthesis, metabolite transport, protein modification, cell wall remodeling, and cell death. Many of these genes were additively altered in a coinfection with PMV+SPMV and correlated to the exacerbated symptoms of PMV+SPMV coinfected plants. PMV+SPMV coinfection also uniquely altered expression of certain genes, including transcription and splicing factors. Among the host defenses commonly affected in PMV and PMV+SPMV coinfections, expression of an antiviral RNA silencing component, SILENCING DEFECTIVE3, was suppressed. Several salicylic acid signaling components, such as pathogenesis-related genes and WRKY transcription factors, were up-regulated. By contrast, several genes in jasmonic acid and ethylene responses were down-regulated. Strikingly, numerous protein kinases, including several classes of receptor-like kinases, were misexpressed. Taken together, our results identified distinctly altered immune responses in monocot antiviral defenses and provide insights into monocot viral synergism. PMID:22961132

  18. A new synergic-assembly strategy towards three-dimensional (3D) hollow nanoarchitectures.

    PubMed

    Wu, Changzheng; Xie, Yi

    2008-12-01

    Large-scale synthesis and assembly of meso-, micro- and nanostructured building blocks with the desired orientations are of great interest for the next-generation nanoarchitecture design. On the consideration that the traditional synthetic methodologies for nanostructures often produce tangled nanounits, how to align the nanounits into the ordered orientation at high production yield is a great challenge to current methods. The present review describes a facile and controllable way to grow and assemble the 3D hollow nanoarchitectures, with the utilization of the synergic effects of hollowing process from the self-produced templates and the highly anisotropic growth of nanounits of the target materials in one-pot reaction. In this process, the building block nanounits spontaneously in-situ form owing to their highly anisotropic internal structure, while the self-produced templates act as the supporter and growth-direction guidance for the in-situ formed nanounits. Therefore, the whole assembly process is simple, controllable and without the complicated manipulations. Herein, in the light of the different kinds of self-produced templates involved in the assembly process, recent developments based on the new synergic-assembly strategy are reviewed according to the classifications: (1) self-produced gas bubble template strategy; (2) self-produced homogeneous solid template strategy; (3) self-produced heterogeneous solid template strategy. Notably, the synergic-assembly methodology described in this review provides a newly essential way to construct and assemble nanoarchitectures facilely and controllably, and is also a crucial step for the next-generation of nanoarchitecture design in the near future. In conclusion, the challenges and prospects for the future are discussed.

  19. In Vitro Synergism between Azithromycin or Terbinafine and Topical Antimicrobial Agents against Pythium insidiosum

    PubMed Central

    Itaqui, Sabrina R.; Verdi, Camila M.; Tondolo, Juliana S. M.; da Luz, Thaisa S.; Alves, Sydney H.; Santurio, Janio M.

    2016-01-01

    We describe here in vitro activity for the combination of azithromycin or terbinafine and benzalkonium, cetrimide, cetylpyridinium, mupirocin, triclosan, or potassium permanganate. With the exception of potassium permanganate, the remaining antimicrobial drugs were active and had an MIC90 between 2 and 32 μg∕ml. The greatest synergism was observed for the combination of terbinafine and cetrimide (71.4%). In vivo experimental evaluations will clarify the potential of these drugs for the topical treatment of lesions caused by Pythium insidiosum. PMID:27216049

  20. Synergization of silicone with developed crosslinking to soy-based polyurethane foam matrix

    NASA Astrophysics Data System (ADS)

    Elvistia Firdaus, Flora

    2014-06-01

    Flexible polyurethane foam obtained from reaction of soybased polyol with TDI:MDI (80:20), and surfactant. The goal of this research is to determine the synergization effect of silicone with low molecular alcohols; methanol and ethylene glycol (EG) in soy-polyurethane formula on holding moisture of foams to density, foam solutions capacity, and cellular morphology. The optimized of polyol was achieved by ratio of epoxide/methanol 1:6 (mol/mol), and epoxide/EG 1:3 (mol/mol). It was found silicone surfactant can minimize solution absorbency in polyurethane foam matrix.

  1. In Vitro Synergism between Azithromycin or Terbinafine and Topical Antimicrobial Agents against Pythium insidiosum.

    PubMed

    Itaqui, Sabrina R; Verdi, Camila M; Tondolo, Juliana S M; da Luz, Thaisa S; Alves, Sydney H; Santurio, Janio M; Loreto, Érico S

    2016-08-01

    We describe here in vitro activity for the combination of azithromycin or terbinafine and benzalkonium, cetrimide, cetylpyridinium, mupirocin, triclosan, or potassium permanganate. With the exception of potassium permanganate, the remaining antimicrobial drugs were active and had an MIC90 between 2 and 32 μg∕ml. The greatest synergism was observed for the combination of terbinafine and cetrimide (71.4%). In vivo experimental evaluations will clarify the potential of these drugs for the topical treatment of lesions caused by Pythium insidiosum. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  2. Relationship between the Level of Acquired Resistance to Gentamicin and Synergism with Amoxicillin in Enterococcus faecalis

    PubMed Central

    Aslangul, Elisabeth; Ruimy, Raymond; Chau, Françoise; Garry, Louis; Andremont, Antoine; Fantin, Bruno

    2005-01-01

    In enterococci, intrinsic low-level resistance to gentamicin does not abolish synergism with a cell wall-active antibiotic while high-level resistance due to acquired aminoglycoside-modifying enzymes does. To study the impact of intermediate levels of resistance to gentamicin (64 < MIC < 500 μg/ml), we selected in vitro three consecutive generations of mutants of Enterococcus faecalis JH2-2 with MICs of gentamicin at 128 μg/ml for G1-1477, 256 μg/ml for G2-1573, and 512 μg/ml for G3-1688. E. faecalis 102, which is highly resistant to gentamicin by enzymatic inactivation was used as control. In in vitro killing curves experiments, gentamicin concentrations allowing bactericidal activity and synergism in combination with amoxicillin increased from 4 μg/ml (1/16th the MIC), 16 μg/ml (one-eighth the MIC), 64 μg/ml (one-quarter the MIC), and 256 μg/ml (one-half the MIC) for strains JH2-2, G1-1477, G2-1573 and G3-1688, respectively. As expected, no bactericidal effect of the combination or synergism could be obtained with strain 102. In rabbits with aortic endocarditis caused by strain G1-1477 or G2-1573, combination therapy with amoxicillin and gentamicin was significantly more active than amoxicillin alone (P < 0.05) but not in those infected with the strains G3-1688 and 102. Thus, intermediate levels of resistance to gentamicin was not associated with a loss of a beneficial effect of the gentamicin-amoxicillin combination in vivo even though higher concentrations of gentamicin were necessary to achieve in vitro synergism. Therefore, the use of an MIC of 500 μg/ml as a clinical cutoff limit to predict in vivo benefit of the combination remains a simple and effective tool. PMID:16189091

  3. Proteins.

    ERIC Educational Resources Information Center

    Doolittle, Russell F.

    1985-01-01

    Examines proteins which give rise to structure and, by virtue of selective binding to other molecules, make genes. Binding sites, amino acids, protein evolution, and molecular paleontology are discussed. Work with encoding segments of deoxyribonucleic acid (exons) and noncoding stretches (introns) provides new information for hypotheses. (DH)

  4. Proteins.

    ERIC Educational Resources Information Center

    Doolittle, Russell F.

    1985-01-01

    Examines proteins which give rise to structure and, by virtue of selective binding to other molecules, make genes. Binding sites, amino acids, protein evolution, and molecular paleontology are discussed. Work with encoding segments of deoxyribonucleic acid (exons) and noncoding stretches (introns) provides new information for hypotheses. (DH)

  5. Protein

    USDA-ARS?s Scientific Manuscript database

    Proteins are the major structural and functional components of all cells in the body. They are macromolecules that comprise 1 or more chains of amino acids that vary in their sequence and length and are folded into specific 3-dimensional structures. The sizes and conformations of proteins, therefor...

  6. Enhancing the pH sensitivity by laterally synergic modulation in dual-gate electric-double-layer transistors

    SciTech Connect

    Liu, Ning; Hui Liu, Yang; Qiang Zhu, Li; Feng, Ping Shi, Yi; Wan, Qing

    2015-02-16

    The sensitivity of a standard ion-sensitive field-effect transistor is limited to be 59.2 mV/pH (Nernst limit) at room temperature. Here, a concept based on laterally synergic electric-double-layer (EDL) modulation is proposed in order to overcome the Nernst limit. Indium-zinc-oxide EDL transistors with two laterally coupled gates are fabricated, and the synergic modulation behaviors of the two asymmetric gates are investigated. A high sensitivity of ∼168 mV/pH is realized in the dual-gate operation mode. Laterally synergic modulation in oxide-based EDL transistors is interesting for high-performance bio-chemical sensors.

  7. Epiploic appendagitis in a 27-year-old man

    PubMed Central

    Uehara, Ryohei; Isomoto, Hajime; Yamaguchi, Naoyuki; Ohnita, Ken; Fujita, Fumihiko; Ichikawa, Tatsuki; Takeshima, Fuminao; Yamaguchi, Tetsuji; Uetani, Masataka; Nakao, Kazuhiko

    2011-01-01

    Summary Background Epiploic appendagitis is an ischemic infarction of an epiploic appendage caused by torsion or spontaneous thrombosis of the central draining vein. Epiploic appendagitis is self-limited without surgery, and it is imperative for clinicians to be familiar with this entity. Case Report A healthy 27-year-old man was admitted due to acute right lower quadrant abdominal pain. Physical examination showed focal abdominal tenderness with slight rebound tenderness. Laboratory tests showed leukocytosis and an increased serum C-reactive protein level. Computed tomography (CT) showed a fatty ovoid pericolonic mass measuring 12 mm in diameter, with a circumferential hyperdense ring that abutted on the ascending colon and was surrounded by ill-defined fat stranding with a hyperdense ring. These findings were diagnostic of primary epiploic appendagitis. The patient was given high-dose antibiotics due to the secondary inflammation involving the parietal peritoneum. Conclusions Epiploic appendagitis presents with an abrupt onset of focal abdominal pain and tenderness without significant guarding or rigidity; it is an uncommon and difficult diagnosis. With awareness of this condition, however, evaluation by CT can provide an accurate diagnosis of epiploic appendagitis, distinguishing it from conditions with clinically overlapping manifestations. PMID:21959616

  8. Enhanced synergism of antibiotics with zinc oxide nanoparticles against extended spectrum β-lactamase producers implicated in urinary tract infections

    NASA Astrophysics Data System (ADS)

    Bhande, Rashmi M.; Khobragade, C. N.; Mane, R. S.; Bhande, S.

    2013-01-01

    In this study, enhanced synergistic bioactivity of zinc oxide nanoparticles (ZnO NPs) with β-lactam antibiotics were evaluated against a panel of clinically isolated extended spectrum β-lactamase producers implicated in urinary tract infections. Chemically synthesized zinc oxide nanoparticles (15 nm) were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), high resolution transmittance electron microscopy (HR-TEM), selective area electron diffraction (SAED), X-ray photoelectron spectroscopy (XPS), and UV-Visible spectrophotometry techniques. The antimicrobial potency (10 ± 0.66, 12, 11.33 ± 1.10, and 0.7 ± 0.66 mm inhibiting zone) and minimum inhibitory concentrations (80, 60, 30, 50 μg/ml) of ZnO NPs were tested separately whereas time-kill and membrane leakage assays were evaluated in combination with ZnO NPs+ cefotaxime, ampicillin, ceftriaxone, cefepime against the β-lactamase producer strains of E. coli, K. pneumoniae, S. paucimobilis, and P. aeruginosa, respectively. Time-kill curve dynamics of ZnO NPs with β-lactam antibiotics revealed enhanced bactericidal activity (50, 85, 58, 50 % fold inhibition) by delaying the exponential and stationary phases of all isolates when tested separately. Posttime-kill effect was studied on cell membrane by assaying leakage of reducing sugars (130.2, 124.7, 137, and 115.8 μg/bacterial dry weight of 1 mg (μg/mg) and proteins (15, 10, 16, 18 μg/mg). These assays revealed that membrane leakage was due to synergism of ZnO NPs+ β-lactam antibiotics which successfully damage cell membrane thereby leading to death of all ESBL producers. The results demonstrate the utilization of ZnO NPs as a potentiator of β-lactam antibiotics and suggest the possibility to use nanoparticles in a combination therapy to treat UTI.

  9. TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts.

    PubMed

    Damiano, Vincenzo; Caputo, Rosa; Garofalo, Sonia; Bianco, Roberto; Rosa, Roberta; Merola, Gerardina; Gelardi, Teresa; Racioppi, Luigi; Fontanini, Gabriella; De Placido, Sabino; Kandimalla, Ekambar R; Agrawal, Sudhir; Ciardiello, Fortunato; Tortora, Giampaolo

    2007-07-24

    Synthetic agonists of Toll-like receptor 9 (TLR9), a class of agents that induce specific immune response, exhibit antitumor activity and are currently being investigated in cancer patients. Intriguingly, their mechanisms of action on tumor growth and angiogenesis are still incompletely understood. We recently discovered that a synthetic agonist of TLR9, immune modulatory oligonucleotide (IMO), acts by impairing epidermal growth factor receptor (EGFR) signaling and potently synergizes with anti-EGFR antibody cetuximab in GEO human colon cancer xenografts, whereas it is ineffective in VEGF-overexpressing cetuximab-resistant GEO cetuximab-resistant (GEO-CR) tumors. VEGF is activated by EGFR, and its overexpression causes resistance to EGFR inhibitors. Therefore, we used IMO and the anti-VEGF antibody bevacizumab as tools to study IMO's role on EGFR and angiogenesis and to explore its therapeutic potential in GEO, LS174T, and GEO-CR cancer xenografts. We found that IMO enhances the antibody-dependent cell-mediated cytotoxicity (ADCC) activity of cetuximab, that bevacizumab has no ADCC, and IMO is unable to enhance it. Nevertheless, the IMO-plus-bevacizumab combination synergistically inhibits the growth of GEO and LS174T as well as of GEO-CR tumors, preceded by inhibition of signaling protein expression, microvessel formation, and human, but not murine, VEGF secretion. Moreover, IMO inhibited the growth, adhesion, migration, and capillary formation of VEGF-stimulated endothelial cells. The antitumor activity was irrespective of the TLR9 expression on tumor cells. These studies demonstrate that synthetic agonists of TLR9 interfere with growth and angiogenesis also by EGFR- and ADCC-independent mechanisms affecting endothelial cell functions and provide a strong rationale to combine IMO with bevacizumab and EGFR inhibitory drugs in colon cancer patients.

  10. Unusual Synergism of Transferrin and Citrate in the Regulation of Ti(IV) Speciation, Transport, and Toxicity.

    PubMed

    Tinoco, Arthur D; Saxena, Manoj; Sharma, Shweta; Noinaj, Nicholas; Delgado, Yamixa; Quiñones González, Ernesto P; Conklin, Steven E; Zambrana, Nicole; Loza-Rosas, Sergio A; Parks, Timothy B

    2016-05-04

    Human serum transferrin (sTf) is a protein that mediates the transport of iron from blood to cells. Assisted by the synergistic anion carbonate, sTf transports Fe(III) by binding the metal ion in a closed conformation. Previous studies suggest sTf's role as a potential transporter of other metals such as titanium. Ti is a widely used metal in colorants, foods, and implants. A substantial amount of Ti is leached into blood from these implants. However, the fate of the leached Ti and its transport into the cells is not known. Understanding Ti interaction with sTf assumes a greater significance with our ever increasing exposure to Ti in the form of implants. On the basis of in vitro studies, it was speculated that transferrin can bind Ti(IV) assisted by a synergistic anion. However, the role and identity of the synergistic anion(s) and the conformational state in which sTf binds Ti(IV) are not known. Here we have solved the first X-ray crystal structure of a Ti(IV)-bound sTf. We find that sTf binds Ti(IV) in an open conformation with both carbonate and citrate as synergistic anions at the metal binding sites, an unprecedented role for citrate. Studies with cell lines suggest that Ti(IV)-sTf is transported into cells and that sTf and citrate regulate the metal's blood speciation and attenuate its cytotoxic property. Our results provide the first glimpse into the citrate-transferrin synergism in the regulation of Ti(IV) bioactivity and offers insight into the future design of Ti(IV)-based anticancer drugs.

  11. Relevance of anti-inflammatory and antioxidant activities of exemestane and synergism with sulforaphane for disease prevention

    PubMed Central

    Liu, Hua; Talalay, Paul

    2013-01-01

    Exemestane (6-methyleneandrosta-1,4-diene-3,17-dione) is a synthetic steroidal inhibitor of the aromatase reaction that catalyzes the terminal and rate-limiting step of the biosynthesis of estrogens. It is active clinically in preventing, delaying progression of, and treating mammary cancers, many of which are estrogen receptor-positive. A striking feature of the structure of exemestane is an extended system of conjugated Michael reaction functions, which is also characteristic of inducers of a broad network of chemoprotective genes regulated by the Keap1 (Kelch-like ECA-associated protein)/Nrf2 (nuclear factor E2-related factor 2)/ARE (antioxidant response element) signaling system. These genes are largely involved in xenobiotic metabolism and antioxidative and anti-inflammatory protection, as well as the synthesis and reduction of glutathione. We show here that exemestane transcriptionally activates NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO-1), typical chemoprotective gene products, in a wide variety of mouse, rat, and human cells. It protects several cell lines against oxidative toxicity of tert-butyl hydroperoxide and 4-hydroxynonenal, against free radical damage arising from hypoxia–reoxygenation, and against UVA radiation damage. Exemestane also inhibits the inflammatory increases in inducible nitric oxide synthase (iNOS) in mouse macrophages exposed to LPS (lipopolysaccharide), thereby resembling the isothiocyanate sulforaphane derived from broccoli. Remarkably, combinations of exemestane and sulforaphane act highly synergistically, and this property is also displayed by several other phytochemicals. Thus, exemestane has a wide range of previously unrecognized protective activities, probably unrelated to aromatase inhibition. Its potential for reducing the risk, not only of breast cancer, but also of other chronic diseases that arise from inflammation, oxidative stress, and DNA-damaging electrophiles, requires exploration

  12. TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts

    PubMed Central

    Damiano, Vincenzo; Caputo, Rosa; Garofalo, Sonia; Bianco, Roberto; Rosa, Roberta; Merola, Gerardina; Gelardi, Teresa; Racioppi, Luigi; Fontanini, Gabriella; De Placido, Sabino; Kandimalla, Ekambar R.; Agrawal, Sudhir; Ciardiello, Fortunato; Tortora, Giampaolo

    2007-01-01

    Synthetic agonists of Toll-like receptor 9 (TLR9), a class of agents that induce specific immune response, exhibit antitumor activity and are currently being investigated in cancer patients. Intriguingly, their mechanisms of action on tumor growth and angiogenesis are still incompletely understood. We recently discovered that a synthetic agonist of TLR9, immune modulatory oligonucleotide (IMO), acts by impairing epidermal growth factor receptor (EGFR) signaling and potently synergizes with anti-EGFR antibody cetuximab in GEO human colon cancer xenografts, whereas it is ineffective in VEGF-overexpressing cetuximab-resistant GEO cetuximab-resistant (GEO-CR) tumors. VEGF is activated by EGFR, and its overexpression causes resistance to EGFR inhibitors. Therefore, we used IMO and the anti-VEGF antibody bevacizumab as tools to study IMO's role on EGFR and angiogenesis and to explore its therapeutic potential in GEO, LS174T, and GEO-CR cancer xenografts. We found that IMO enhances the antibody-dependent cell-mediated cytotoxicity (ADCC) activity of cetuximab, that bevacizumab has no ADCC, and IMO is unable to enhance it. Nevertheless, the IMO-plus-bevacizumab combination synergistically inhibits the growth of GEO and LS174T as well as of GEO-CR tumors, preceded by inhibition of signaling protein expression, microvessel formation, and human, but not murine, VEGF secretion. Moreover, IMO inhibited the growth, adhesion, migration, and capillary formation of VEGF-stimulated endothelial cells. The antitumor activity was irrespective of the TLR9 expression on tumor cells. These studies demonstrate that synthetic agonists of TLR9 interfere with growth and angiogenesis also by EGFR- and ADCC-independent mechanisms affecting endothelial cell functions and provide a strong rationale to combine IMO with bevacizumab and EGFR inhibitory drugs in colon cancer patients. PMID:17636117

  13. Novel walnut peptide–selenium hybrids with enhanced anticancer synergism: facile synthesis and mechanistic investigation of anticancer activity

    PubMed Central

    Liao, Wenzhen; Zhang, Rong; Dong, Chenbo; Yu, Zhiqiang; Ren, Jiaoyan

    2016-01-01

    This contribution reports a facile synthesis of degreased walnut peptides (WP1)-functionalized selenium nanoparticles (SeNPs) hybrids with enhanced anticancer activity and a detailed mechanistic evaluation of its superior anticancer activity. Structural and chemical characterizations proved that SeNPs are effectively capped with WP1 via physical absorption, resulting in a stable hybrid structure with an average diameter of 89.22 nm. A panel of selected human cancer cell lines demonstrated high susceptibility toward WP1-SeNPs and displayed significantly reduced proliferative behavior. The as-synthesized WP1-SeNPs exhibited excellent selectivity between cancer cells and normal cells. The targeted induction of apoptosis in human breast adenocarcinoma cells (MCF-7) was confirmed by the accumulation of arrested S-phase cells, nuclear condensation, and DNA breakage. Careful investigations revealed that an extrinsic apoptotic pathway can be attributed to the cell apoptosis and the same was confirmed by activation of the Fas-associated with death domain protein and caspases 3, 8, and 9. In addition, it was also understood that intrinsic apoptotic pathways including reactive oxygen species generation, as well as the reduction in mitochondrial membrane potential, are also involved in the WP1-SeNP-induced apoptosis. This suggested the involvement of multiple apoptosis pathways in the anticancer activity. Our results indicated that WP1-SeNP hybrids with Se core encapsulated in a WP1 shell could be a highly effective method to achieve anticancer synergism. Moreover, the great potential exhibited by WP1-SeNPs could make them an ideal candidate as a chemotherapeutic agent for human cancers, especially for breast cancer. PMID:27143875

  14. A Naturally Occurring Plant Cysteine Protease Possesses Remarkable Toxicity against Insect Pests and Synergizes Bacillus thuringiensis Toxin

    PubMed Central

    Mohan, Srinidi; Ma, Peter W. K.; Williams, W. Paul; Luthe, Dawn S.

    2008-01-01

    When caterpillars feed on maize (Zea maize L.) lines with native resistance to several Lepidopteran pests, a defensive cysteine protease, Mir1-CP, rapidly accumulates at the wound site. Mir1-CP has been shown to inhibit caterpillar growth in vivo by attacking and permeabilizing the insect's peritrophic matrix (PM), a structure that surrounds the food bolus, assists in digestion and protects the midgut from microbes and toxins. PM permeabilization weakens the caterpillar defenses by facilitating the movement of other insecticidal proteins in the diet to the midgut microvilli and thereby enhancing their toxicity. To directly determine the toxicity of Mir1-CP, the purified recombinant enzyme was directly tested against four economically significant Lepidopteran pests in bioassays. Mir1-CP LC50 values were 1.8, 3.6, 0.6, and 8.0 ppm for corn earworm, tobacco budworm, fall armyworm and southwestern corn borer, respectively. These values were the same order of magnitude as those determined for the Bacillus thuringiensis toxin Bt-CryIIA. In addition to being directly toxic to the larvae, 60 ppb Mir1-CP synergized sublethal concentrations of Bt-CryIIA in all four species. Permeabilization of the PM by Mir1-CP probably provides ready access to Bt-binding sites on the midgut microvilli and increases its activity. Consequently, Mir1-CP could be used for controlling caterpillar pests in maize using non-transgenic approaches and potentially could be used in other crops either singly or in combination with Bt-toxins. PMID:18335057

  15. A combination of additives can synergically decrease acrylamide content in gingerbread without compromising sensory quality.

    PubMed

    Komprda, Tomáš; Pridal, Antonin; Mikulíková, Renata; Svoboda, Zdeněk; Cwiková, Olga; Nedomová, Šárka; Sýkora, Vladimír

    2017-02-01

    The present study tested whether replacement of the leavening agent ammonium carbonate by sodium hydrogen carbonate in combination with calcium cation and acidifying agent will synergically decrease acrylamide (AA) content in gingerbread. The type of leavening agent and the presence of Ca(2+) and citric acid accounted for 33.6%, 13.2% and 53.2% of the explained variability of the AA content, respectively (P < 0.01). The AA content in gingerbread produced with (NH4 )2 CO3 alone was 186.5 µg kg(-1) . Irrespective of other tested additives, NaHCO3 decreased (P < 0.05) AA content to 42% compared to (NH4 )2 CO3 . Combination of NaHCO3 + CaCl2 + citric acid in dough reduced (P < 0.05) AA content below the limit of detection (25 µg kg(-1) ). The AA content in gingerbread (y; µg kg(-1) ) decreased with an increasing number of additives used (x) according to the equation y = 158.8 - 47.94x (r(2) = 0.42; P < 0.0001). A comprehensive sensory analysis did not indicate any significant deterioration (P > 0.05) in the organoleptic quality of gingerbread produced using calcium cation and citric acid. The present study demonstrates that the combination of additives NaHCO3 /Ca(2+) /citric acid synergically decreases AA content in gingerbread without compromising the sensory quality. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

  16. Cosolubilization synergism occurrence in codesorption of PAH mixtures during surfactant-enhanced remediation of contaminated soil.

    PubMed

    Liang, Xujun; Guo, Chuling; Wei, Yanfu; Lin, Weijia; Yi, Xiaoyun; Lu, Guining; Dang, Zhi

    2016-02-01

    Surfactant-enhanced remediation (SER) has been widely applied in decontaminating PAH-polluted soil. Most researches focus on evaluating washing efficiency without considering pollutants' mutual interaction. This study aims to investigate cosolubilization effect between phenanthrene (Phe) and pyrene (Pyr) in nonionic surfactant Triton X-100 (TX100) solution on their codesorption performance from soil. Cosolubilization experiment showed that, when cosolubilized, solubility of Phe and Pyr in TX100 increased by 15.38% and 18.19%, respectively, as quantified by the deviation ratio of molar solubilization ratio in single and binary solute solubilization systems. The synergism may be due to the enlarged micelle volume caused by PAHs solubilized in the shell region of the micelle. The cosolubilization effect was further observed in the soil washing process. The strengthened TX100 solubilization capacity towards Phe and Pyr could increase the two PAHs' codesorption efficiency from soil, accompanied by synergistic extent of 6-15%. However, synergism in codesorption was weaker than that observed in the cosolubilization system, which may be related to surfactant loss to soil and PAH partition into soil organic matter and the sorbed surfactants. The improved remediation performance during codesorption of mixed PAHs implies the significance of combining PAHs' mutual interaction into evaluating SER, which may reduce the surfactant washing concentration and save remediation cost.

  17. An in silico erythropoiesis model rationalizing synergism between stem cell factor and erythropoietin.

    PubMed

    Phan, Tran Hong Ha; Saraf, Pritha; Kiparissides, Alexandros; Mantalaris, Athanasios; Song, Hao; Lim, Mayasari

    2013-11-01

    Stem cell factor (SCF) and erythropoietin (EPO) are two most recognized growth factors that play in concert to control in vitro erythropoiesis. However, exact mechanisms underlying the interplay of these growth factors in vitro remain unclear. We developed a mathematical model to study co-signaling effects of SCF and EPO utilizing the ERK1/2 and GATA-1 pathways (activated by SCF and EPO) that drive the proliferation and differentiation of erythroid progenitors. The model was simplified and formulated based on three key features: synergistic contribution of SCF and EPO on ERK1/2 activation, positive feedback effects on proliferation and differentiation, and cross-inhibition effects of activated ERK1/2 and GATA-1. The model characteristics were developed to correspond with biological observations made known thus far. Our simulation suggested that activated GATA-1 has a more dominant cross-inhibition effect and stronger positive feedback response on differentiation than the proliferation pathway, while SCF contributed more to the activation of ERK1/2 than EPO. A sensitivity analysis performed to gauge the dynamics of the system was able to identify the most sensitive model parameters and illustrated a contribution of transient activity in EPO ligand to growth factor synergism. Based on theoretical arguments, we have successfully developed a model that can simulate growth factor synergism observed in vitro for erythropoiesis. This hypothesized model can be applied to further computational studies in biological systems where synergistic effects of two ligands are seen.

  18. [Synergic effect of alprostadil injection and ginaton in treating sudden deafness].

    PubMed

    Jiang, Jiping; Wang, Shuyun; Tong, Kang

    2011-07-01

    To explore synergic effect of Alprostadil injection and ginaton in treating sudden deafness. ninety one patients with sudden deafness were divided into group A, group B and group C at random; 33 ears of group A were treated with 70 mg ginaton by vein, 30 ears of group B were treated with 10 microg Alprostadil injection by vein, 31 ears of group C were treated with 10 microg Alprostadil injection and ginaton by vein,once a day, the time of treatment is 14 days. the effective rate of group A is 60.61%, the effective rate of group B is 60.00%, the effective rate of group C is 87.09% the treating effect was significantly different in the group A and C (P < 0.05), it was significantly different in the group B and C (P < 0.05)). It is effective for Alprostadil injection and ginaton to treat sudden deafness, and it has significantly Synergic effect in treating sudden deafness with Alprostadil injection and ginaton.

  19. The synergic effects of mirror therapy and neuromuscular electrical stimulation for hand function in stroke patients.

    PubMed

    Yun, Gi Jeong; Chun, Min Ho; Park, Ji Young; Kim, Bo Ryun

    2011-06-01

    To investigate the synergic effects of mirror therapy and neuromuscular electrical stimulation (NMES) for hand function in stroke patients. Sixty patients with hemiparesis after stroke were included (41 males and 19 females, average age 63.3 years). Twenty patients had NMES applied and simultaneously underwent mirror therapy. Twenty patients had NMES applied only, and twenty patients underwent mirror therapy only. Each treatment was done five days per week, 30 minutes per day, for three weeks. NMES was applied on the surface of the extensor digitorum communis and extensor pollicis brevis for open-hand motion. Muscle tone, Fugl-Meyer assessment, and power of wrist and hand were evaluated before and after treatment. There were significant improvements in the Fugl-Meyer assessment score in the wrist, hand and coordination, as well as power of wrist and hand in all groups after treatment. The mirror and NMES group showed significant improvements in the Fugl-Meyer scores of hand, wrist, coordination and power of hand extension compared to the other groups. However, the power of hand flexion, wrist flexion, and wrist extension showed no significant differences among the three groups. Muscle tone also showed no significant differences in the three groups. Our results showed that there is a synergic effect of mirror therapy and NMES on hand function. Therefore, a hand rehabilitation strategy combined with NMES and mirror therapy may be more helpful for improving hand function in stroke patients than NMES or mirror therapy only.

  20. Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

    PubMed Central

    Stoyanova, Tanya; Riedinger, Mireille; Lin, Shu; Faltermeier, Claire M.; Smith, Bryan A.; Zhang, Kelvin X.; Going, Catherine C.; Goldstein, Andrew S.; Lee, John K.; Drake, Justin M.; Rice, Meghan A.; Hsu, En-Chi; Nowroozizadeh, Behdokht; Castor, Brandon; Orellana, Sandra Y.; Blum, Steven M.; Cheng, Donghui; Pienta, Kenneth J.; Reiter, Robert E.; Pitteri, Sharon J.; Huang, Jiaoti; Witte, Owen N.

    2016-01-01

    Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-specific mortality. Defining new mechanisms that can predict recurrence and drive lethal CRPC is critical. Here, we demonstrate that localized high-risk prostate cancer and metastatic CRPC, but not benign prostate tissues or low/intermediate-risk prostate cancer, express high levels of nuclear Notch homolog 1, translocation-associated (Notch1) receptor intracellular domain. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of prostate adenocarcinoma. These tumors display features of epithelial-to-mesenchymal transition, a cellular state associated with increased tumor aggressiveness. Consistent with its activation in clinical CRPC, tumors driven by Notch1 intracellular domain in combination with multiple pathways altered in prostate cancer are metastatic and resistant to androgen deprivation. Our study provides functional evidence that the Notch1 signaling axis synergizes with alternative pathways in promoting metastatic CRPC and may represent a new therapeutic target for advanced prostate cancer. PMID:27694579

  1. Protein

    MedlinePlus

    ... Search for: Harvard T.H. Chan School of Public Health Email People Departments Calendar Careers Give my.harvard ... Nutrition Source Harvard T.H. Chan School of Public Health > The Nutrition Source > What Should I Eat? > Protein ...

  2. Src Inhibition Can Synergize with Gemcitabine and Reverse Resistance in Triple Negative Breast Cancer Cells via the AKT/c-Jun Pathway

    PubMed Central

    Liu, Ming-Ming; Zhang, Jian; Tao, Zhong-Hua; Hu, Xi-Chun

    2016-01-01

    Purpose Gemcitabine-based chemotherapy remains one of the standards in management of metastatic breast cancer. However, intrinsic and acquired resistance to gemcitabine inevitably occurs. The aims of this study were to assess the efficacy of the combination of src inhibition and gemcitabine in gemcitabine-resistant breast cancer cells. Methods and Results By using colony formation, sphere forming, flow cytometry, cell counting kit-8 and transwell assays, 231/GEM-res (gemcitabine-resistant) cell line, which was 10 times more resistant, was shown to have elevated drug tolerance, enhanced proliferative and self-renewal abilities, compared with its parental cells. Inhibition of src by both saracatinib (AZD0530) and siRNA could partially reverse gemcitabine resistance and attenuate resistance-associated anti-apoptosis, migration and stem cell capacities. In addition, the combination of src inhibition and gemcitabine had synergistic antitumor effects. Western blot analysis revealed up-regulation of pro-apoptotic protein BAX, along with the down-regulation of anti-apoptotic proteins (BCL-XL, Survivin), migration associated proteins (p-FAK, MMP-3) and cancer stem cell (CSC) markers (CD44, Oct-4), which was probably mediated by AKT/c-Jun pathway. Conclusion In highly gemcitabine-resistant 231 cells, src inhibition can synergize with gemcitabine, reverse drug resistance, inhibit tumor growth/metastasis/stemness of cancer stem cells, possibly via the AKT/c-Jun pathway. PMID:28036386

  3. Protection and synergism by recombinant fowl pox vaccines expressing multiple genes from Marek's disease virus.

    PubMed

    Lee, Lucy E; Witter, R L; Reddy, S M; Wu, P; Yanagida, N; Yoshida, S

    2003-01-01

    Recombinant fowl poxviruses (rFPVs) were constructed to express genes from serotype 1 Marek's disease virus (MDV) coding for glycoproteins B, E, I, H, and UL32 (gB1, gE, gI, gH, and UL32). An additional rFPV was constructed to contain four MDV genes (gB1, gE, gI, and UL32). These rFPVs were evaluated for their ability to protect maternal antibody-positive chickens against challenge with highly virulent MDV isolates. The protection induced by a single rFPV/gB1 (42%) confirmed our previous finding. The protection induced by rFPV/gI (43%), rFPV/gB1UL32 (46%), rFPV/gB1gEgI (72%), and rFPV/gB1gEgIUL32 (70%) contributed to additional knowledge on MDV genes involved in protective immunity. In contrast, the rFPV containing gE, gH, or UL32 did not induce significant protection compared with turkey herpesvirus (HVT). Levels of protection by rFPV/gB1 and rFPV/gl were comparable with that of HVT. Only gB1 and gI conferred synergism in rFPV containing these two genes. Protection by both rFPV/gB1gEgI (72%) and rFPV/gB1gEgIUL32(70%) against Marek's disease was significantly enhanced compared with a single gB1 or gI gene (40%). This protective synergism between gB1 and gI in rFPVs may be the basis for better protection when bivalent vaccines between serotypes 2 and 3 were used. When rFPV/gB1gIgEUL32 + HVT were used as vaccine against Md5 challenge, the protection was significantly enhanced (94%). This synergism between rFPV/gB1gIgEUL32 and HVT indicates additional genes yet to be discovered in HVT may be responsible for the enhancement.

  4. Antibacterial activity of three newly-synthesized chalcones & synergism with antibiotics against clinical isolates of methicillin-resistant Staphylococcus aureus

    PubMed Central

    Božić, Dragana D.; Milenković, Marina; Ivković, Branka; Cirković, Ivana

    2014-01-01

    Background & objectives: Multidrug-resistance of methicillin-resistant Staphylococcus aureus (MRSA) is a serious therapeutical problem. Chalcones belong to a group of naturally occurring flavonoids, usually found in various plant species, and have potent antibacterial, antiviral and antifungal activities. The goal of this study was to evaluate the antibacterial effect of three newly-synthesized chalcones against clinical isolates of MRSA, and their synergism with β-lactam and non- β-lactam antibiotics. Methods: Antimicrobial activity of the three newly-synthesized chalcones was tested against 19 clinical isolates of MRSA and a laboratory control strain of MRSA (ATCC 43300). The synergism with β-lactams: cefotaxime (CFX), ceftriaxone (CTX), and non-β-lactam antibiotics: ciprofloxacin (CIP), gentamicin (GEN) and trimethoprim/sulphamethoxazole (TMP-SMX) was investigated by checkerboard method. Results: All evaluated compounds showed significant anti-MRSA activity with MIC values from 25-200 μg/ml. Observed synergism with antibiotics demonstrated that chalcones significantly enhanced the efficacy of CIP, GEN and TMP-SMX. Interpretation & conclusions: Our study demonstrated that three newly-synthesized chalcones exhibited significant anti-MRSA effect and synergism with non-β-lactam antibiotics. The most effective compound was 1,3-Bis-(2-hydroxy-phenyl)-propenone. Our results provide useful information for future research of possible application of chalcones in combination with conventional anti-MRSA therapy as promising new antimicrobial agents. PMID:25222788

  5. The promiscuous and synergic molecular interaction of polyphenols in bactericidal activity: an opportunity to improve the performance of antibiotics?

    PubMed

    Tomás-Menor, Laura; Barrajón-Catalán, Enrique; Segura-Carretero, Antonio; Martí, Nuria; Saura, Domingo; Menéndez, Javier A; Joven, Jorge; Micol, Vicente

    2015-03-01

    Plant polyphenols are a potential source of new antimicrobial molecules against bacteria because most newly developed antimicrobial agents do not improve the clinical management of infectious diseases. The potential synergism between the major polyphenolic compounds present in a Cistus salviifolius extract, which was characterized by HPLC-ESI-MS/MS, was investigated by the isobole method and the fractional inhibitory concentration index determination. Pairwise combinations of selected flavonoids and ellagitannins present in C. salviifolius extract were assayed against the in vitro growth of Staphylococcus aureus. Some combinations revealed synergic effects, resulting in a reduction of the minimum inhibitory concentration required to inhibit 50% growth (MIC50 ) up to 20 times lower as compared with the individual compounds. Some of the combinations exhibited MIC50 values close to drug potency level (0.5-1 µg/mL). Punicalagin and myricetin were the major contributors in the combinations. The proportion between the compounds in the synergic mixtures is crucial and may explain the superior antimicrobial activity displayed by this extract when compared with other botanical extracts. The rational optimization of these combinations could lead to the design of potent antimicrobial phytopharmaceuticals, which may improve the performance of current antibiotics, taking advantage of the multi-targeted and synergic molecular interactions of selected polyphenols.

  6. Saccharomyces cerevisiae Mixed Culture of Blackberry (Rubus ulmifolius L.) Juice: Synergism in the Aroma Compounds Production

    PubMed Central

    Ragazzo-Sánchez, Juan Arturo; Ortiz-Basurto, Rosa Isela; Luna-Solano, Guadalupe; Calderón-Santoyo, Montserrat

    2014-01-01

    Blackberry (Rubus sp.) juice was fermented using four different strains of Saccharomyces cerevisiae (Vitilevure-CM4457, Enoferm-T306, ICV-K1, and Greroche Rhona-L3574) recognized because of their use in the wine industry. A medium alcoholic graduation spirit (<6°GL) with potential to be produced at an industrial scale was obtained. Alcoholic fermentations were performed at 28°C, 200 rpm, and noncontrolled pH. The synergistic effect on the aromatic compounds production during fermentation in mixed culture was compared with those obtained by monoculture and physic mixture of spirits produced in monoculture. The aromatic composition was determined by HS-SPME-GC. The differences in aromatic profile principally rely on the proportions in aromatic compounds and not on the number of those compounds. The multivariance analysis, principal component analysis (PCA), and factorial discriminant analysis (DFA) permit to demonstrate the synergism between the strains. PMID:25506606

  7. Synergic effect of carbon black and short carbon fiber on shape memory polymer actuation by electricity

    NASA Astrophysics Data System (ADS)

    Leng, Jinsong; Lv, Haibao; Liu, Yanju; Du, Shanyi

    2008-11-01

    This paper presents a study on the effect of carbon black (CB) and short carbon fibers (SCFs) on shape memory polymer (SMP) actuation by applying electric current. The coexistence of CB and SCF electrically conductive networks, supporting each other, resulting in significant improvement of electrical properties, was supported by optical microscopy, while the roles of particulate and fibrous fillers were distinguished by scanning electron microscopy. In sequence, the volume resistivity curves of one filler systems and two fillers systems were figured out and compared. Moreover, experimental results substantiated that the actuation voltage of two-filler SMP composites' shape recovery was prominently lower in comparison with that of one-filler systems at the same filler content. Additional, the response of glass transition temperature (Tg) and thermomechanical properties to filler content and two fillers' synergic effect were characterized and illuminated experimentally.

  8. Gold(I)‐Mediated Thiourea Organocatalyst Activation: A Synergic Effect for Asymmetric Catalysis

    PubMed Central

    Izaga, Anabel

    2017-01-01

    Abstract Several group 11 metal complexes with chiral thiourea organocatalysts have been prepared and tested as organocatalysts. The promising results on the influence of metal‐assisted thiourea organocatalysts in the asymmetric Friedel–Crafts alkylation of indole with nitrostyrene are described. Better results with the metal complexes have been achieved because of the cooperative effects between the chiral thiourea and the metal. The synergic effect between both species is higher than the effect promoted by each one separately, especially for gold(I). These outcomes are attributed to a pioneering gold(I) activation of the thiourea catalysts, affording a more acidic and rigid catalytic complex than that provided by the thiourea alone. Furthermore, the use of the gold–thiourea organocatalyst allows reducing the catalyst loading to 1–3 mol %. This contribution could become an important starting point for further investigations opening a new line of research overlooked so far in the literature. PMID:28706568

  9. Synergic effect of tungstophosphoric acid and sonication for rapid synthesis of crystalline nanocellulose.

    PubMed

    Hamid, Sharifah Bee Abd; Zain, Siti Khadijah; Das, Rasel; Centi, Gabriele

    2016-03-15

    The utilization of sonication in combination with tungstophosphoric acid (PWA) catalyst reduces dramatically the time of operations from 30h to 10min by using an optimum sonication power of 225W. The basic cellulosic structure is maintained, allowing preparing high-quality nanocellulose. The size of the nanocellulose obtained was in the range from 15 to 35nm in diameter and several hundred nanometers in length, with a high crystallinity of about 88%. The nanocellulose shows a surface charge of -38.2mV which allows to obtaina stable colloidal suspension. The surface tension of the stable, swollen aqueous nanocellulose was close to that of water. These characteristics, together with the fast procedure allowed from the synergic combination of PWA and sonication, evidence the high potential of the proposed method for the industrial production of nanocellulose having the properties required in many applications.

  10. LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis.

    PubMed

    Zhu, Shizhen; Zhang, Xiaoling; Weichert-Leahey, Nina; Dong, Zhiwei; Zhang, Cheng; Lopez, Gonzalo; Tao, Ting; He, Shuning; Wood, Andrew C; Oldridge, Derek; Ung, Choong Yong; van Ree, Janine H; Khan, Amish; Salazar, Brittany M; Lummertz da Rocha, Edroaldo; Zimmerman, Mark W; Guo, Feng; Cao, Hong; Hou, Xiaonan; Weroha, S John; Perez-Atayde, Antonio R; Neuberg, Donna S; Meves, Alexander; McNiven, Mark A; van Deursen, Jan M; Li, Hu; Maris, John M; Look, A Thomas

    2017-09-11

    A genome-wide association study identified LMO1, which encodes an LIM-domain-only transcriptional cofactor, as a neuroblastoma susceptibility gene that functions as an oncogene in high-risk neuroblastoma. Here we show that dβh promoter-mediated expression of LMO1 in zebrafish synergizes with MYCN to increase the proliferation of hyperplastic sympathoadrenal precursor cells, leading to a reduced latency and increased penetrance of neuroblastomagenesis. The transgenic expression of LMO1 also promoted hematogenous dissemination and distant metastasis, which was linked to neuroblastoma cell invasion and migration, and elevated expression levels of genes affecting tumor cell-extracellular matrix interaction, including loxl3, itga2b, itga3, and itga5. Our results provide in vivo validation of LMO1 as an important oncogene that promotes neuroblastoma initiation, progression, and widespread metastatic dissemination. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Synergic Antibacterial Effect of Curcumin with Ampicillin; Free Drug Solutions in Comparison with SLN Dispersions

    PubMed Central

    Alihosseini, Faezeh; Azarmi, Shirzad; Ghaffari, Solmaz; Haghighat, Setareh; Rezayat Sorkhabadi, Seyed Mahdi

    2016-01-01

    Purpose: This study was designed to investigate benefit of using nanotechnology on increasing of synergic antibacterial effect of natural and chemical antibacterial agents. Methods: At first the MIC and MBC of Curcumin and Ampicillin as selected antibacterial agents was determined, after that Solid Lipid Nanoparticles (SLNs) of each active ingredients as well as Curcumin-Ampicillin loaded SLNs were prepared using high pressure homogenization technique. Characterization of prepared SLNs was done, then MIC, MBC and contact killing time were investigated for Curcumin-Ampicillin loaded SLNs in comparison with free Curcumin and Ampicillin solutions as well as Ampicillin and Curcumin SLNs. Results: Based on results nanoparticles with the size of 150 nm show much more decreased MIC and MBC when Ampicillin and Curcumin were loaded together on SLNs than solutions in which free Ampicillin and Curcumin were mixed. Conclusion: It seems that using nanotechnology could cause decrease the dosage of antibiotics and risk of having antibiotic resistance bacteria strains. PMID:27766232

  12. Saccharomyces cerevisiae mixed culture of blackberry (Rubus ulmifolius L.) juice: synergism in the aroma compounds production.

    PubMed

    Bautista-Rosales, Pedro Ulises; Ragazzo-Sánchez, Juan Arturo; Ruiz-Montañez, Gabriela; Ortiz-Basurto, Rosa Isela; Luna-Solano, Guadalupe; Calderón-Santoyo, Montserrat

    2014-01-01

    Blackberry (Rubus sp.) juice was fermented using four different strains of Saccharomyces cerevisiae (Vitilevure-CM4457, Enoferm-T306, ICV-K1, and Greroche Rhona-L3574) recognized because of their use in the wine industry. A medium alcoholic graduation spirit (<6°GL) with potential to be produced at an industrial scale was obtained. Alcoholic fermentations were performed at 28°C, 200 rpm, and noncontrolled pH. The synergistic effect on the aromatic compounds production during fermentation in mixed culture was compared with those obtained by monoculture and physic mixture of spirits produced in monoculture. The aromatic composition was determined by HS-SPME-GC. The differences in aromatic profile principally rely on the proportions in aromatic compounds and not on the number of those compounds. The multivariance analysis, principal component analysis (PCA), and factorial discriminant analysis (DFA) permit to demonstrate the synergism between the strains.

  13. Effect of synergism in the mechanics of multilayer designs. 2. synthesis of optimal acoustic systems

    NASA Astrophysics Data System (ADS)

    Urzhumtsev, Yu. S.; Babe, G. D.; Gusev, E. L.

    1985-07-01

    Use of the synergism effect in the mechanics of inhomogeneous systems, and algorithms constructed on the basis of the theory of optimal control makes it possible to synthesize multilayer designs that are optimum in terms of weight capacity, thermal stability, sound conduction, and sound insulation. The proposed approach to solution of the problem of the optimal design of multilayer acoustic systems makes it possible firstly to develop a rather effective method on the basis of this approach; this method reduces to a solution that is optimal in terms of the physical parameters of the layer materials, the layer thicknesses, and the number of layers; and, secondly, to establish a number of qualitative attributes of the parameters of optimal multilayer structures. This approach is also promising for the development of methods for the optimization of multilayer foundations and systems that dampen vibrational loadings, earthquake-resistant designs, and armor protection.

  14. Synergism and chemiluminescence of cerium ions and ruthenium complexes in the belousov-zhabotinskii reaction

    SciTech Connect

    Karavaev, A.D.; Kazakov, V.P.; Tolstikov, G.A.

    1986-04-01

    This paper studies chemiluminescence (CL) in the system BrO/sup -//sub 3/-CH/sub 2/ (COOH)/sub 2/ -Ce/sup 3 +/,4+-RuPbipy)/sub 3/ /SUP 2+,/ /sub 3/. The tests were carried out in a CL/sup 3/ unit that included a light-tight chamber, a photoelectron multiplier (FEU-97), a VS-22 high voltage power pack, and an EPPV-60M recording potentiometer. The synergism in chemiluminescence at low concentrations of ruthenium complex does not appear in the oscillation parameters. The periodic CL of this two-catalyst system may be a convenient chemical model for the study of combined chemical reactions in more complicated biochemiluminescent processes, such as that by which the firefly flashes in the dark.

  15. Synergic Antibacterial Effect of Curcumin with Ampicillin; Free Drug Solutions in Comparison with SLN Dispersions.

    PubMed

    Alihosseini, Faezeh; Azarmi, Shirzad; Ghaffari, Solmaz; Haghighat, Setareh; Rezayat Sorkhabadi, Seyed Mahdi

    2016-09-01

    Purpose: This study was designed to investigate benefit of using nanotechnology on increasing of synergic antibacterial effect of natural and chemical antibacterial agents. Methods: At first the MIC and MBC of Curcumin and Ampicillin as selected antibacterial agents was determined, after that Solid Lipid Nanoparticles (SLNs) of each active ingredients as well as Curcumin-Ampicillin loaded SLNs were prepared using high pressure homogenization technique. Characterization of prepared SLNs was done, then MIC, MBC and contact killing time were investigated for Curcumin-Ampicillin loaded SLNs in comparison with free Curcumin and Ampicillin solutions as well as Ampicillin and Curcumin SLNs. Results: Based on results nanoparticles with the size of 150 nm show much more decreased MIC and MBC when Ampicillin and Curcumin were loaded together on SLNs than solutions in which free Ampicillin and Curcumin were mixed. Conclusion: It seems that using nanotechnology could cause decrease the dosage of antibiotics and risk of having antibiotic resistance bacteria strains.

  16. Synergism between polyamines and ROS in the induction of Ca2+ and K+ fluxes in roots

    PubMed Central

    Pottosin, Igor; Velarde-Buendía, Ana-María; Zepeda-Jazo, Isaac; Dobrovinskaya, Oxana; Shabala, Sergey

    2012-01-01

    Stress conditions cause increases in ROS and polyamines levels, which are not merely collateral. There is increasing evidence for the ROS participation in signaling as well as for polyamine protective roles under stress. Polyamines and ROS, respectively, inhibit cation channels and induce novel cation conductance in the plasma membrane. Our new results indicate that polyamines and OH• also stimulate Ca2+ pumping across the root plasma membrane. Besides, polyamines potentiate the OH•-induced non-selective current and respective passive K+ and Ca2+ fluxes. In roots this synergism, however, is restricted to the mature zone, whereas in the distal elongation zone only the Ca2+ pump activation is observed. Remodeling the plasma membrane ion conductance by OH• and polyamines would impact K+ homeostasis and Ca2+ signaling under stress. PMID:22899073

  17. Synergism of herpes simplex virus and tobacco-specific N'-nitrosamines in cell transformation

    SciTech Connect

    Park, N.H.; Dokko, H.; Li, S.L.; Cherrick, H.M. )

    1991-03-01

    Previous studies indicate that herpes simplex virus (HSV) enhances the carcinogenic activity of smokeless tobacco and tobacco-related chemical carcinogens in animals. Since tobacco-specific N'-nitrosamines (TSNAs) such as N'-nitrosonornicotine (NNN) and 4-(N-methyl-N'-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are major chemical carcinogens of smokeless tobacco and are known to be responsible for the development of oral cancers in smokeless tobacco users, the combined effects of TSNAs and HSV in cell transformation were investigated. Exposure of cells to NNN or NNK followed by virus infection resulted in a significant enhancement of transformation frequency when compared with that observed with chemical carcinogens or virus alone. This study suggests that TSNAs and HSV can interact together and show synergism in cell transformation.

  18. Gold(I)-Mediated Thiourea Organocatalyst Activation: A Synergic Effect for Asymmetric Catalysis.

    PubMed

    Izaga, Anabel; Herrera, Raquel P; Gimeno, M Concepción

    2017-04-07

    Several group 11 metal complexes with chiral thiourea organocatalysts have been prepared and tested as organocatalysts. The promising results on the influence of metal-assisted thiourea organocatalysts in the asymmetric Friedel-Crafts alkylation of indole with nitrostyrene are described. Better results with the metal complexes have been achieved because of the cooperative effects between the chiral thiourea and the metal. The synergic effect between both species is higher than the effect promoted by each one separately, especially for gold(I). These outcomes are attributed to a pioneering gold(I) activation of the thiourea catalysts, affording a more acidic and rigid catalytic complex than that provided by the thiourea alone. Furthermore, the use of the gold-thiourea organocatalyst allows reducing the catalyst loading to 1-3 mol %. This contribution could become an important starting point for further investigations opening a new line of research overlooked so far in the literature.

  19. Synaptic mechanism for functional synergism between delta- and mu-opioid receptors

    PubMed Central

    Zhang, Zhi; Pan, Zhizhong Z.

    2010-01-01

    By sustained activation of mu-opioid receptors (MOR), chronic opioids cause analgesic tolerance, physical dependence and opioid addiction, common clinical problems for which an effective treatment is still lacking. Chronic opioids recruit delta-opioid receptors (DOR) to plasma membrane through exocytotic trafficking, but the role of this new DOR and its interaction with existing MOR in brain functions and in the clinical problems remains largely unknown. In this study, we investigated the mechanisms underlying synaptic and behavioral actions of chronic morphine-induced DOR and its interaction with MOR in Nucleus Raphe Magnus (NRM) neurons important for opioid analgesia. We found that the emerged DOR inhibited GABAergic IPSCs through both the phospholipase A2 (PLA2) and cAMP/PKA signaling pathways. MOR inhibition of IPSCs, normally mediated predominantly by the PLA2 pathway, was additionally mediated by the cAMP/PKA pathway, with MOR potency significantly increased after chronic morphine treatment. Isobologram analysis revealed a synergistic DOR-MOR interaction in their IPSC inhibition, which was dependent on upregulated activities of both the PLA2 and cAMP/PKA pathways. Furthermore, DOR and MOR agonists microinjected into the NRM in vivo also produced a PLA2–dependent synergism in their antinociceptive effects. These findings suggest that the cAMP/PKA pathway, upregulated by chronic opioids, becomes more important in the mechanisms of both MOR and DOR inhibition of GABA synaptic transmission after chronic opioid exposure, and DOR and MOR are synergic both synaptically and behaviorally in producing analgesic effects in a PLA2-dependent fashion, supporting the potential therapeutic use of DOR agonists in pain management under chronic opioid conditions. PMID:20357124

  20. Phene Synergism between Root Hair Length and Basal Root Growth Angle for Phosphorus Acquisition1[OPEN

    PubMed Central

    Miguel, Magalhaes Amade

    2015-01-01

    Shallow basal root growth angle (BRGA) increases phosphorus acquisition efficiency by enhancing topsoil foraging because in most soils, phosphorus is concentrated in the topsoil. Root hair length and density (RHL/D) increase phosphorus acquisition by expanding the soil volume subject to phosphorus depletion through diffusion. We hypothesized that shallow BRGA and large RHL/D are synergetic for phosphorus acquisition, meaning that their combined effect is greater than the sum of their individual effects. To evaluate this hypothesis, phosphorus acquisition in the field in Mozambique was compared among recombinant inbred lines of common bean (Phaseolus vulgaris) having four distinct root phenotypes: long root hairs and shallow basal roots, long root hairs and deep basal roots, short root hairs and shallow basal roots, and short root hairs and deep basal roots. The results revealed substantial synergism between BRGA and RHL/D. Compared with short-haired, deep-rooted phenotypes, long root hairs increased shoot biomass under phosphorus stress by 89%, while shallow roots increased shoot biomass by 58%. Genotypes with both long root hairs and shallow roots had 298% greater biomass accumulation than short-haired, deep-rooted phenotypes. Therefore, the utility of shallow basal roots and long root hairs for phosphorus acquisition in combination is twice as large as their additive effects. We conclude that the anatomical phene of long, dense root hairs and the architectural phene of shallower basal root growth are synergetic for phosphorus acquisition. Phene synergism may be common in plant biology and can have substantial importance for plant fitness, as shown here. PMID:25699587

  1. Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4

    PubMed Central

    Collins, Paul J.; McCully, Michelle L.; Martínez-Muñoz, Laura; Santiago, César; Wheeldon, James; Caucheteux, Stephan; Thelen, Sylvia; Cecchinato, Valentina; Laufer, Julia M.; Purvanov, Vladimir; Monneau, Yoan R.; Lortat-Jacob, Hugues; Legler, Daniel F.; Uguccioni, Mariagrazia; Thelen, Marcus; Piguet, Vincent; Mellado, Mario; Moser, Bernhard

    2017-01-01

    The chemokine receptor, CXC chemokine receptor 4 (CXCR4), is selective for CXC chemokine ligand 12 (CXCL12), is broadly expressed in blood and tissue cells, and is essential during embryogenesis and hematopoiesis. CXCL14 is a homeostatic chemokine with unknown receptor selectivity and preferential expression in peripheral tissues. Here, we demonstrate that CXCL14 synergized with CXCL12 in the induction of chemokine responses in primary human lymphoid cells and cell lines that express CXCR4. Combining subactive concentrations of CXCL12 with 100–300 nM CXCL14 resulted in chemotaxis responses that exceeded maximal responses that were obtained with CXCL12 alone. CXCL14 did not activate CXCR4-expressing cells (i.e., failed to trigger chemotaxis and Ca2+ mobilization, as well as signaling via ERK1/2 and the small GTPase Rac1); however, CXCL14 bound to CXCR4 with high affinity, induced redistribution of cell-surface CXCR4, and enhanced HIV-1 infection by >3-fold. We postulate that CXCL14 is a positive allosteric modulator of CXCR4 that enhances the potency of CXCR4 ligands. Our findings provide new insights that will inform the development of novel therapeutics that target CXCR4 in a range of diseases, including cancer, autoimmunity, and HIV.—Collins, P. J., McCully, M. L., Martínez-Muñoz, L., Santiago, C., Wheeldon, J., Caucheteux, S., Thelen, S., Cecchinato, V., Laufer, J. M., Purvanov, V., Monneau, Y. R., Lortat-Jacob, H., Legler, D. F., Uguccioni, M., Thelen, M., Piguet, V., Mellado, M., Moser, B. Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4. PMID:28360196

  2. Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4.

    PubMed

    Collins, Paul J; McCully, Michelle L; Martínez-Muñoz, Laura; Santiago, César; Wheeldon, James; Caucheteux, Stephan; Thelen, Sylvia; Cecchinato, Valentina; Laufer, Julia M; Purvanov, Vladimir; Monneau, Yoan R; Lortat-Jacob, Hugues; Legler, Daniel F; Uguccioni, Mariagrazia; Thelen, Marcus; Piguet, Vincent; Mellado, Mario; Moser, Bernhard

    2017-07-01

    The chemokine receptor, CXC chemokine receptor 4 (CXCR4), is selective for CXC chemokine ligand 12 (CXCL12), is broadly expressed in blood and tissue cells, and is essential during embryogenesis and hematopoiesis. CXCL14 is a homeostatic chemokine with unknown receptor selectivity and preferential expression in peripheral tissues. Here, we demonstrate that CXCL14 synergized with CXCL12 in the induction of chemokine responses in primary human lymphoid cells and cell lines that express CXCR4. Combining subactive concentrations of CXCL12 with 100-300 nM CXCL14 resulted in chemotaxis responses that exceeded maximal responses that were obtained with CXCL12 alone. CXCL14 did not activate CXCR4-expressing cells (i.e., failed to trigger chemotaxis and Ca(2+) mobilization, as well as signaling via ERK1/2 and the small GTPase Rac1); however, CXCL14 bound to CXCR4 with high affinity, induced redistribution of cell-surface CXCR4, and enhanced HIV-1 infection by >3-fold. We postulate that CXCL14 is a positive allosteric modulator of CXCR4 that enhances the potency of CXCR4 ligands. Our findings provide new insights that will inform the development of novel therapeutics that target CXCR4 in a range of diseases, including cancer, autoimmunity, and HIV.-Collins, P. J., McCully, M. L., Martínez-Muñoz, L., Santiago, C., Wheeldon, J., Caucheteux, S., Thelen, S., Cecchinato, V., Laufer, J. M., Purvanov, V., Monneau, Y. R., Lortat-Jacob, H., Legler, D. F., Uguccioni, M., Thelen, M., Piguet, V., Mellado, M., Moser, B. Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4. © The Author(s).

  3. Heavy metals species affect fungal-bacterial synergism during the bioremediation of fluoranthene.

    PubMed

    Ma, Xiao-Kui; Ding, Ning; Peterson, Eric Charles; Daugulis, Andrew J

    2016-09-01

    The co-occurrence of polycyclic aromatic hydrocarbons (PAHs) with heavy metals (HMs) is very common in contaminated soils, but the influence of HMs on fungal-bacterial synergism during PAH bioremediation has not been investigated. The bioremediation of fluoranthene-contaminated sand using co-cultures of Acremonium sp. P0997 and Bacillus subtilis showed increases of 109.4 and 9.8 % in degradation compared to pure bacterial and fungal cultures, respectively, removing 64.1 ± 1.4 % fluoanthene in total. The presence of Cu(2+) reduced fluoranthene removal to 53.7 ± 1.7 %, while inhibiting bacterial growth, and reducing translocation of bacteria on fungal hyphae by 49.5 %, in terms of the bacterial translocation ratio. Cu(2+) reduced bacterial diffusion by 46.8 and 31.9 %, as reflected by D (a bulk random motility diffusional coefficient) and D eff (the effective one-dimensional diffusion coefficient) compared to the control without HM supplementation, respectively. However, Mn(2+) resulted in a 78.2 ± 1.9 % fluoranthene degradation, representing an increase of 21.9 %, while enhancing bacterial growth and bacterial translocation on fungal hyphae, showing a 12.0 % increase in translocation ratio, with no observable impact on D and D eff. Hence, the presence of HMs has been shown to affect fungal-bacterial synergism in PAH degradation, and this effect differs with HM species.

  4. Synergism of the IGRs Methoprene and Pyriproxyfen Against Larval Cat Fleas (Siphonaptera: Pulicidae).

    PubMed

    Rust, Michael K; Lance, W; Hemsarth, H

    2016-05-01

    Insect growth regulators (IGRs) methoprene and pyriproxyfen are widely used as topical treatments to pets or applied to the indoor environment to control cat fleas, Ctenocephalides felis (Bouché). The toxicity of methoprene, pyriproxyfen, and combinations of both IGRs to cat flea larvae was determined. The LC50 of methoprene and pyriproxyfen applied to larval rearing medium was 0.39 and 0.19 ppm, respectively. Combinations of methoprene:pyriproxyfen in ratios of 1:1, 5:1, 10:1, and 20:1 produced LC50s of 0.06, 0.09, 0.19, and 0.13 ppm, respectively. The pyriproxyfen synergized the activity of methoprene as indicated by the combination indices (CI). The ratio of methoprene:pyriproxyfen (40:1) provided an LC50 of 0.42 ppm and the pyriproxyfen was not synergistic. Combinations of pyriproxyfen:methoprene in ratios of 5:1, 10:1, and 20:1 provided LC50s of 0.14, 0.20, 0.20 ppm, respectively, and the methoprene did not synergize the activity of pyriproxyfen. The dose-reduction indices (DRIs) indicated that the concentrations of IGRs in the combinations of methoprene:pyriproxyfen (ratios of 20:1 or less) could be reduced by at least one-third of the amount required by methoprene alone to provide similar larval mortality. Combinations of methoprene and pyriproxyfen may be effective in increasing the residual activity on pets and assist in reducing the likelihood of insecticide resistance developing to IGRs. © The Authors 2016. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. GCP-2/CXCL6 synergizes with other endothelial cell-derived chemokines in neutrophil mobilization and is associated with angiogenesis in gastrointestinal tumors

    SciTech Connect

    Gijsbers, Klara; Gouwy, Mieke; Struyf, Sofie; Wuyts, Anja; Proost, Paul; Opdenakker, Ghislain; Penninckx, Freddy; Ectors, Nadine; Geboes, Karel; Van Damme, Jo . E-mail: jozef.vandamme@rega.kuleuven.ac.be

    2005-02-15

    The precise role of chemokines in neovascularization during inflammation or tumor growth is not yet fully understood. We show here that the chemokines granulocyte chemotactic protein-2 (GCP-2/CXCL6), interleukin-8 (IL-8/CXCL8), and monocyte chemotactic protein-1 (MCP-1/CCL2) are co-induced in microvascular endothelial cells after stimulation with pro-inflammatory stimuli. In contrast with its weak proliferative effect on endothelial cells, GCP-2 synergized with MCP-1 in neutrophil chemotaxis. This synergy may represent a mechanism for tumor development and metastasis by providing efficient leukocyte infiltration in the absence of exogenous immune modulators. To mimic endothelial cell-derived GCP-2 in vivo, GCP-2 was intravenously injected and shown to provoke a dose-dependent systemic response, composed of an immediate granulopenia, followed by a profound granulocytosis. By immunohistochemistry, GCP-2 was further shown to be expressed by endothelial cells from human patients with gastrointestinal (GI) malignancies. GCP-2 staining correlated with leukocyte infiltration into the tumor and with the expression of the matrix metalloproteinase-9 (MMP-9/gelatinase B). Together with previous findings, these data suggest that the production of GCP-2 by endothelial cells within the tumor can contribute to tumor development through neovascularization due to endothelial cell chemotaxis and to tumor cell invasion and metastasis by attracting and activating neutrophils loaded with proteases that promote matrix degradation.

  6. Combination of single walled carbon nanotubes/graphene oxide with paclitaxel: a reactive oxygen species mediated synergism for treatment of lung cancer

    NASA Astrophysics Data System (ADS)

    Arya, Neha; Arora, Aditya; Vasu, K. S.; Sood, A. K.; Katti, Dhirendra S.

    2013-03-01

    Heterogeneity in tumors has led to the development of combination therapies that enable enhanced cell death. Previously explored combination therapies mostly involved the use of bioactive molecules. In this work, we explored a non-conventional strategy of using carbon nanostructures (CNs) [single walled carbon nanotube (SWNT) and graphene oxide (GO)] for potentiating the efficacy of a bioactive molecule [paclitaxel (Tx)] for the treatment of lung cancer. The results demonstrated enhanced cell death following combination treatment of SWNT/GO and Tx indicating a synergistic effect. In addition, synergism was abrogated in the presence of an anti-oxidant, N-acetyl cysteine (NAC), and was therefore shown to be reactive oxygen species (ROS) dependent. It was further demonstrated using bromodeoxyuridine (BrdU) incorporation assay that treatment with CNs was associated with enhanced mitogen associated protein kinase (MAPK) activation that was ROS mediated. Hence, these results for the first time demonstrated the potential of SWNT/GO as co-therapeutic agents with Tx for the treatment of lung cancer.Heterogeneity in tumors has led to the development of combination therapies that enable enhanced cell death. Previously explored combination therapies mostly involved the use of bioactive molecules. In this work, we explored a non-conventional strategy of using carbon nanostructures (CNs) [single walled carbon nanotube (SWNT) and graphene oxide (GO)] for potentiating the efficacy of a bioactive molecule [paclitaxel (Tx)] for the treatment of lung cancer. The results demonstrated enhanced cell death following combination treatment of SWNT/GO and Tx indicating a synergistic effect. In addition, synergism was abrogated in the presence of an anti-oxidant, N-acetyl cysteine (NAC), and was therefore shown to be reactive oxygen species (ROS) dependent. It was further demonstrated using bromodeoxyuridine (BrdU) incorporation assay that treatment with CNs was associated with enhanced

  7. Ag85B synergizes with ESAT-6 to induce efficient and long-term immunity of C57BL/6 mice primed with recombinant Bacille Calmette-Guerin

    PubMed Central

    Liu, Wei; Xu, Ying; Yan, Jingran; Shen, Hongbo; Yang, Enzhuo; Wang, Honghai

    2017-01-01

    The latest probable scenario in vaccination strategies is to prime one live attenuated vaccine candidate followed by boost dose of second vaccine candidate. In the present study, we primed the mice with a recombinant Bacille Calmette-Guerin (BCG) comprising Ag85B and ESAT-6 followed by boost doses of Ag85B, ESAT-6 and Ag85B-ESAT-6 fusion protein in the DDA adjuvant, separately. After boost doses of 8 and 12 weeks, the levels of antigen-stimulated T cells secreting interferon (IFN)-γ, the content of the IFN-γ, tumor necrosis factor-α and interleukin-4 in the splenocytes in vitro culture supernatant, the antigen-specific immunoglobulin (Ig)G titer from mouse serum, IgG subclass and the population of antigen-specific CD4+ and CD8+ T cells were detected. The present study showed that recombinant BCG along with boost doses of Ag85B or ESAT-6 individually did not induce efficient T-helper (Th) 1-type immune response. On the other hand, recombinant BCG with boost doses of Ag85B-ESAT-6 fusion protein enhanced longer lasting predominant Th1 immune response. This result suggested that Ag85B might synergize with ESAT-6 protein in order to produce better as well as effective immune response. Thus, the present study concluded recombinant BCG with boost doses of Ag85B-ESAT-6 fusion protein could be a good strategy to improve the immune protective efficacy. PMID:28123491

  8. Lovastatin induces apoptosis of ovarian cancer cells and synergizes with doxorubicin: potential therapeutic relevance

    PubMed Central

    2010-01-01

    Background Ovarian carcinoma is a rarely curable disease, for which new treatment options are required. As agents that block HMG-CoA reductase and the mevalonate pathway, the statin family of drugs are used in the treatment of hypercholesterolemia and have been shown to trigger apoptosis in a tumor-specific manner. Recent clinical trials show that the addition of statins to traditional chemotherapeutic strategies can increase efficacy of targeting statin-sensitive tumors. Our goal was to assess statin-induced apoptosis of ovarian cancer cells, either alone or in combination with chemotherapeutics, and then determine these mechanisms of action. Methods The effect of lovastatin on ovarian cancer cell lines was evaluated alone and in combination with cisplatin and doxorubicin using several assays (MTT, TUNEL, fixed PI, PARP cleavage) and synergy determined by evaluating the combination index. The mechanisms of action were evaluated using functional, molecular, and pharmacologic approaches. Results We demonstrate that lovastatin induces apoptosis of ovarian cancer cells in a p53-independent manner and synergizes with doxorubicin, a chemotherapeutic agent used to treat recurrent cases of ovarian cancer. Lovastatin drives ovarian tumor cell death by two mechanisms: first, by blocking HMG-CoA reductase activity, and second, by sensitizing multi-drug resistant cells to doxorubicin by a novel mevalonate-independent mechanism. This inhibition of drug transport, likely through inhibition of P-glycoprotein, potentiates both DNA damage and tumor cell apoptosis. Conclusions The results of this research provide pre-clinical data to warrant further evaluation of statins as potential anti-cancer agents to treat ovarian carcinoma. Many statins are inexpensive, off-patent generic drugs that are immediately available for use as anti-cancer agents. We provide evidence that lovastatin triggers apoptosis of ovarian cancer cells as a single agent by a mevalonate-dependent mechanism

  9. [The primary role of central region of HC-pro of potato Y potyvirus in synergism of plant viruses].

    PubMed

    Lu, R F; Li, W M; Wang, H Y; Guo, M; Peng, X X

    2001-05-01

    Five deleted mutants of HC-Pro gene of Chinese isolate of potato Y potyvirus (PVY-C) were obtained by PCR mutation, and their plant expression vectors were constructed. They were transformed into tobacco K326 (Nicotina tabacum cv. K326) mediated by Agrobacterium. PCR and Southern blot analysis revealed that PVY-C HC-Pro gene and its deleted mutants were integrated into tobacco genome, and Western blot analysis showed that they were all expressed in transgenic tobacco plants. Furthermore, infection test demonstrated that the central region of PVY-C HC-Pro can mediate synergism of PVY-C/cucumber mosaic cucumovirus (CMV) and PVY-C/potato X potexvirus (PVX), identifying that it is functional domain in synergism.

  10. Limitations of the rheological mucoadhesion method: the effect of the choice of conditions and the rheological synergism parameter.

    PubMed

    Hägerström, Helene; Edsman, Katarina

    2003-04-01

    This work demonstrates several limitations of the simple rheological method that is widely used to investigate mucoadhesion of polymer gels. We establish the importance of the choice of conditions and the synergism parameter for the results obtained in comparative studies. Dynamic rheological measurements were performed on gels based on four slightly different poly(acrylic acid) (Carbopol) polymers and their corresponding mixtures with porcine stomach mucin and bovine submaxillary gland mucin. The rationale for the comparison of the polymers had a large influence on the results obtained. The method does not give the same ranking order when two different comparison strategies are used. Moreover, we show that the results obtained are also sensitive to where in the 'rheological range' the comparison is made, e.g., at which value of G'. Positive values of the synergism parameters are, for example, only seen with weak gels. The choice of synergism parameter also has a bearing on the results obtained, and here we suggest a new refined relative parameter, the log ratio (log(G'(mix)/G'(p))). We also investigated the adhesion of the gel preparations to porcine nasal mucosa, using tensile strength measurements. Increased gel strength resulted in stronger adhesion, which is in contrast to the results from the rheological method, where the positive values of the synergism parameters were seen only with weak gels. On the basis of the limitations demonstrated and discussed, we recommend that the rheological method should not be used as a stand-alone method for the studying of mucoadhesive properties of polymer gels.

  11. A kinetic model of the synergism of endo- and exoglucanase and {beta}-glucosidase on hydrolysis of cellulose

    SciTech Connect

    Fujii, Michihiro; Homma, Taira; Ooshima, Kazuhisa; Taniguchi, Masayuki

    1991-12-31

    A kinetic model representing the synergistic action of the three components that compose cellulose on hydrolysis of solid cellulose particles is proposed. The model consists of three simultaneous differential equations: one representing the action of the endoenzyme, another representing the action of the exoenzyme, and the third representing the action of the {Beta}-glucosidase. A simultaneous solution of these three equations expresses the synergism. The experimental data fit the theory well.

  12. Tramadol and Tramadol+Caffeine Synergism in the Rat Formalin Test Are Mediated by Central Opioid and Serotonergic Mechanisms.

    PubMed

    Carrillo-Munguía, Norma; González-Trujano, Ma Eva; Huerta, Miguel; Trujillo, Xochitl; Díaz-Reval, M Irene

    2015-01-01

    Different analgesic combinations with caffeine have shown this drug to be capable of increasing the analgesic effect. Many combinations with nonsteroidal anti-inflammatory drugs (NSAIDs) have been carried out, but, in regard to opioids, only combinations with morphine and tramadol have been reported. The antinociceptive synergism mechanism of these combinations is not well understood. The purpose of the present study was to determine the participation of spinal and supraspinal opioidergic and serotonergic systems in the synergic effect of the tramadol+caffeine combination in the rat formalin test. At the supraspinal level, the opioid antagonist, naloxone, completely reversed the effect of the drug combination, whereas ketanserin, a 5-HT2 receptor antagonist, inhibited the effect by 60%; however, ondansetron, a 5-HT3 receptor antagonist, did not alter the combination effect. When the antagonists were intrathecally administered, there was a significant reduction in all tramadol-caffeine combination effects. With respect to tramadol alone, there was significant participation of the opioid system at the supraspinal level, whereas it was the serotonergic system that participated at the spinal level by means of the two receptors studied. In conclusion, the tramadol+caffeine combination synergically activated the opioid and serotonergic systems at the supraspinal level, as well as at the spinal level, to produce the antinociception.

  13. Management of five stored-product insects in wheat with pirimiphos-methyl and pirimiphos-methyl plus synergized pyrethrins.

    PubMed

    Huang, Fangneng; Subramanyam, Bhadriraju

    2005-04-01

    Hard red winter wheat was treated with pirimiphos-methyl at 4, 6 and 8 mg kg(-1), synergized pyrethrins at 0.38, 0.75, 1.13 and 1.5 mg kg(-1), and combinations of the two insecticides, to conduct laboratory bioassays against four beetle pests of stored grain, red flour beetle Tribolium castaneum (Herbst), rusty grain beetle Cryptolestes ferrugineus (Stephens), lesser grain borer Rhyzopertha dominica (F), and rice weevil Sitophilus oryzae (L), and one moth pest, Indianmeal moth Plodia interpunctella (Hubner). Beetle adults and P interpunctella larvae survived well on control wheat, producing a large number of progeny (65-1037 insects per container). Kernel damage in control wheat among the insect species ranged from 9 to 99%. On pirimiphos-methyl-treated wheat, mortality of R dominica adults was > or =72%, but that of the other beetle species and P interpunctella larvae was 100%. Progeny were not produced on pirimiphos-methyl-treated wheat, and the kernel damage was negligible (< or =1%). Synergized pyrethrins were ineffective against the five insect pests. Pirimiphos-methyl combined with synergized pyrethrins was not superior to pirimiphos-methyl alone against the five insect pests. Pirimiphos-methyl is not registered in the USA for use on wheat, but our results suggest that it could be a viable grain protectant at rates of 4-8 mg kg(-1).

  14. Tramadol and Tramadol+Caffeine Synergism in the Rat Formalin Test Are Mediated by Central Opioid and Serotonergic Mechanisms

    PubMed Central

    Carrillo-Munguía, Norma; González-Trujano, Ma. Eva; Huerta, Miguel; Trujillo, Xochitl; Díaz-Reval, M. Irene

    2015-01-01

    Different analgesic combinations with caffeine have shown this drug to be capable of increasing the analgesic effect. Many combinations with nonsteroidal anti-inflammatory drugs (NSAIDs) have been carried out, but, in regard to opioids, only combinations with morphine and tramadol have been reported. The antinociceptive synergism mechanism of these combinations is not well understood. The purpose of the present study was to determine the participation of spinal and supraspinal opioidergic and serotonergic systems in the synergic effect of the tramadol+caffeine combination in the rat formalin test. At the supraspinal level, the opioid antagonist, naloxone, completely reversed the effect of the drug combination, whereas ketanserin, a 5-HT2 receptor antagonist, inhibited the effect by 60%; however, ondansetron, a 5-HT3 receptor antagonist, did not alter the combination effect. When the antagonists were intrathecally administered, there was a significant reduction in all tramadol-caffeine combination effects. With respect to tramadol alone, there was significant participation of the opioid system at the supraspinal level, whereas it was the serotonergic system that participated at the spinal level by means of the two receptors studied. In conclusion, the tramadol+caffeine combination synergically activated the opioid and serotonergic systems at the supraspinal level, as well as at the spinal level, to produce the antinociception. PMID:26146627

  15. Bortezomib induces apoptosis and growth suppression in human medulloblastoma cells, associated with inhibition of AKT and NF-ĸB signaling, and synergizes with an ERK inhibitor.

    PubMed

    Yang, Fan; Jove, Veronica; Chang, Shirley; Hedvat, Michael; Liu, Lucy; Buettner, Ralf; Tian, Yan; Scuto, Anna; Wen, Wei; Yip, M L Richard; Van Meter, Timothy; Yen, Yun; Jove, Richard

    2012-04-01

    Medulloblastoma is the most common brain tumor in children. Here, we report that bortezomib, a proteasome inhibitor, induced apoptosis and inhibited cell proliferation in two established cell lines and a primary culture of human medulloblastomas. Bortezomib increased the release of cytochrome c to cytosol and activated caspase-9 and caspase-3, resulting in cleavage of PARP. Caspase inhibitor (Z-VAD-FMK) could rescue medulloblastoma cells from the cytotoxicity of bortezomib. Phosphorylation of AKT and its upstream regulator mTOR were reduced by bortezomib treatment in medulloblastoma cells. Bortezomib increased the expression of Bad and Bak, pro-apoptotic proteins, and p21Cip1 and p27Kip1, negative regulators of cell cycle progression, which are associated with the growth suppression and induction of apoptosis in these tumor cells. Bortezomib also increased the accumulation of phosphorylated IĸBα, and decreased nuclear translocation of NF-ĸB. Thus, NF-ĸB signaling and activation of its downstream targets are suppressed. Moreover, ERK inhibitors or downregulating ERK with ERK siRNA synergized with bortezomib on anticancer effects in medulloblastoma cells. Bortezomib also inhibited the growth of human medulloblastoma cells in a mouse xenograft model. These findings suggest that proteasome inhibitors are potentially promising drugs for treatment of pediatric medulloblastomas.

  16. Systematic chemical-genetic and chemical-chemical interaction datasets for prediction of compound synergism.

    PubMed

    Wildenhain, Jan; Spitzer, Michaela; Dolma, Sonam; Jarvik, Nick; White, Rachel; Roy, Marcia; Griffiths, Emma; Bellows, David S; Wright, Gerard D; Tyers, Mike

    2016-11-22

    The network structure of biological systems suggests that effective therapeutic intervention may require combinations of agents that act synergistically. However, a dearth of systematic chemical combination datasets have limited the development of predictive algorithms for chemical synergism. Here, we report two large datasets of linked chemical-genetic and chemical-chemical interactions in the budding yeast Saccharomyces cerevisiae. We screened 5,518 unique compounds against 242 diverse yeast gene deletion strains to generate an extended chemical-genetic matrix (CGM) of 492,126 chemical-gene interaction measurements. This CGM dataset contained 1,434 genotype-specific inhibitors, termed cryptagens. We selected 128 structurally diverse cryptagens and tested all pairwise combinations to generate a benchmark dataset of 8,128 pairwise chemical-chemical interaction tests for synergy prediction, termed the cryptagen matrix (CM). An accompanying database resource called ChemGRID was developed to enable analysis, visualisation and downloads of all data. The CGM and CM datasets will facilitate the benchmarking of computational approaches for synergy prediction, as well as chemical structure-activity relationship models for anti-fungal drug discovery.

  17. Biochemical basis of synergism between pathogenic fungus Metarhizium anisopliae and insecticide chlorantraniliprole in Locusta migratoria (Meyen).

    PubMed

    Jia, Miao; Cao, Guangchun; Li, Yibo; Tu, Xiongbing; Wang, Guangjun; Nong, Xiangqun; Whitman, Douglas W; Zhang, Zehua

    2016-06-22

    We challenged Locusta migratoria (Meyen) grasshoppers with simultaneous doses of both the insecticide chlorantraniliprole and the fungal pathogen, Metarhizium anisopliae. Our results showed synergistic and antagonistic effects on host mortality and enzyme activities. To elucidate the biochemical mechanisms that underlie detoxification and pathogen-immune responses in insects, we monitored the activities of 10 enzymes. After administration of insecticide and fungus, activities of glutathione-S-transferase (GST), general esterases (ESTs) and phenol oxidase (PO) decreased in the insect during the initial time period, whereas those of aryl acylamidase (AA) and chitinase (CHI) increased during the initial period and that of acetylcholinesterase (AChE) increased during a later time period. Activities of superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) decreased at a later time period post treatment. Interestingly, treatment with chlorantraniliprole and M. anisopliae relieved the convulsions that normally accompany M. anisopliae infection. We speculate that locust mortality increased as a result of synergism via a mechanism related to Ca(2+) disruption in the host. Our study illuminates the biochemical mechanisms involved in insect immunity to xenobiotics and pathogens as well as the mechanisms by which these factors disrupt host homeostasis and induce death. We expect this knowledge to lead to more effective pest control.

  18. Indirect cooperative effects leading to synergism in bimetallic homogeneous catalysts containing azolates as bridging ligands

    SciTech Connect

    Esteruelas, M.A.; Garcia, M.P.; Lopez, A.M.; Oro, L.A. )

    1991-01-01

    The binuclear compounds (H(CO)(PPh{sub 3}){sub 2}Ru({mu}-bim)Ir(COD)) (1) (bim = 2,2{prime}-biimidazolate, COD = 1,5-cyclooctadiene) and (H(CO)(PPh{sub 3}){sub 2}Ru({mu}-pz){sub 2}Ir(TFB)) (2) (pz = pyrazolate, TFB = tetrafluorobenzobarrelene) are more active catalysts for the hydrogenation of cyclohexene than the mononuclear parent compounds (RuH(Hbim)(CO)(PPh{sub 3}){sub 2}), (Ir(Hbim)(COD)), (RuH(pa)(CO)(Hpz)(PPh{sub 3}){sub 2}), and (Ir(TFB)(Hpz){sub 2})BF{sub 4}. In the presence of 1, the reaction rate is first order with respect to the concentration of 1 and cyclohexene, second order with respect to hydrogen pressure, and inversely proportional to the concentration of added phosphine. For the reaction catalyzed by 2, the experimental data are in accordance with a rate expression of the form {minus}d(cyclohexene)/dt = k(2)(cyclohexene)P(H{sub 2}) (P(H{sub 2}) = hydrogen pressure). On the basis of the kinetic results and experimental evidence, the origin of the catalytic synergism is assigned to indirect cooperative effects between the metallic centers of the binuclear complexes. The kinetic investigation of the hydrogenation of cyclohexene catalyzed by (Ir({mu}-pz)(TFB)){sub 2} (3) is also reported, suggesting that the full catalytic cycle involves binuclear species.

  19. Triethylenetetramine Synergizes with Pharmacologic Ascorbic Acid in Hydrogen Peroxide Mediated Selective Toxicity to Breast Cancer Cell

    PubMed Central

    Wang, Lianlian; Luo, Xiaofang; Li, Cong; Huang, Yubing; Xu, Ping; Lloyd-Davies, Laetitia H.; Delplancke, Thibaut; Peng, Chuan; Qi, Hongbo; Baker, Philip

    2017-01-01

    Breast cancer is characterized by overexpression of superoxide dismutase (SOD) and downregulation of catalase and more resistance to hydrogen peroxide (H2O2) than normal cells. Thus, relatively high H2O2 promotes breast cancer cell growth and proliferation. However, excessive intracellular H2O2 leads to death of breast cancer cells. In cancer cells, high level ascorbic acid (Asc) is able to be autoxidized and thus provides an electron to oxygen to generate H2O2. In the present study, we demonstrated that triethylenetetramine (TETA) enhances Asc autoxidation and thus elevates H2O2 production in MCF-7 cells. Furthermore, Asc/TETA combination significantly impaired cancer cell viability, while having much milder effects on normal cells, indicating Asc/TETA could be a promising therapy for breast cancer. Moreover, SOD1 and N-acetyl-L-cysteine failed to improve MCF-7 cells viability in the presence of Asc/TETA, while catalase significantly inhibited the cytotoxicity of Asc/TETA to breast cancer cells, strongly suggesting that the selective cytotoxicity of Asc/TETA to cancer cells is H2O2-dependent. In addition, Asc/TETA induces RAS/ERK downregulation in breast cancer cells. Animal studies confirmed that Asc/TETA effectively suppressed tumor growth in vivo. In conclusion, TETA synergizes pharmacologic Asc autoxidation and H2O2 overproduction in breast cancer cells, which suppresses RAS/ERK pathway and results in apoptosis. PMID:28280522

  20. Triethylenetetramine Synergizes with Pharmacologic Ascorbic Acid in Hydrogen Peroxide Mediated Selective Toxicity to Breast Cancer Cell.

    PubMed

    Wang, Lianlian; Luo, Xiaofang; Li, Cong; Huang, Yubing; Xu, Ping; Lloyd-Davies, Laetitia H; Delplancke, Thibaut; Peng, Chuan; Gao, Rufei; Qi, Hongbo; Tong, Chao; Baker, Philip

    2017-01-01

    Breast cancer is characterized by overexpression of superoxide dismutase (SOD) and downregulation of catalase and more resistance to hydrogen peroxide (H2O2) than normal cells. Thus, relatively high H2O2 promotes breast cancer cell growth and proliferation. However, excessive intracellular H2O2 leads to death of breast cancer cells. In cancer cells, high level ascorbic acid (Asc) is able to be autoxidized and thus provides an electron to oxygen to generate H2O2. In the present study, we demonstrated that triethylenetetramine (TETA) enhances Asc autoxidation and thus elevates H2O2 production in MCF-7 cells. Furthermore, Asc/TETA combination significantly impaired cancer cell viability, while having much milder effects on normal cells, indicating Asc/TETA could be a promising therapy for breast cancer. Moreover, SOD1 and N-acetyl-L-cysteine failed to improve MCF-7 cells viability in the presence of Asc/TETA, while catalase significantly inhibited the cytotoxicity of Asc/TETA to breast cancer cells, strongly suggesting that the selective cytotoxicity of Asc/TETA to cancer cells is H2O2-dependent. In addition, Asc/TETA induces RAS/ERK downregulation in breast cancer cells. Animal studies confirmed that Asc/TETA effectively suppressed tumor growth in vivo. In conclusion, TETA synergizes pharmacologic Asc autoxidation and H2O2 overproduction in breast cancer cells, which suppresses RAS/ERK pathway and results in apoptosis.

  1. Strong Delayed Interactive Effects of Metal Exposure and Warming: Latitude-Dependent Synergisms Persist Across Metamorphosis.

    PubMed

    Debecker, Sara; Dinh, Khuong V; Stoks, Robby

    2017-02-21

    As contaminants are often more toxic at higher temperatures, predicting their impact under global warming remains a key challenge for ecological risk assessment. Ignoring delayed effects, synergistic interactions between contaminants and warming, and differences in sensitivity across species' ranges could lead to an important underestimation of the risks. We addressed all three mechanisms by studying effects of larval exposure to zinc and warming before, during, and after metamorphosis in Ischnura elegans damselflies from high- and low-latitude populations. By integrating these mechanisms into a single study, we could identify two novel patterns. First, during exposure zinc did not affect survival, whereas it induced mild to moderate postexposure mortality in the larval stage and at metamorphosis, and very strongly reduced adult lifespan. This severe delayed effect across metamorphosis was especially remarkable in high-latitude animals, as they appeared almost insensitive to zinc during the larval stage. Second, the well-known synergism between metals and warming was manifested not only during the larval stage but also after metamorphosis, yet notably only in low-latitude damselflies. These results highlight that a more complete life-cycle approach that incorporates the possibility of delayed interactions between contaminants and warming in a geographical context is crucial for a more realistic risk assessment in a warming world.

  2. Synergism effects for Escherichia coli inactivation applying the combined ozone and chlorine disinfection method.

    PubMed

    de Souza, Jeanette Beber; Daniel, Luiz Antonio

    2011-01-01

    Water disinfection assays were carried out using ozone and chlorine in non-sequential steps--the individual method--and in sequential steps--the combined ozone/chlorine method. Escherichia coli strain ATCC 11229 was used as the indicator microorganism. For the assays using the individual method, the applied dosages of ozone were 2.0, 3.0 and 5.0 mg/L, and 2.0 and 5.0 mg/L of chlorine were used. For the assays applying the combined method, the dosages (dosage combination) were, in mg/L: 2.0 O3 + 2.0 Cl, 3.0 O3 + 2.0 Cl2, 5.0 O3 + 2.0 Cl2 and 2.0 O3 + 5.0 Cl2. The applied contact times were 5, 10, 15 and 20 minutes for the individual method as well as for the combined method. For all used dosages and contact times, E. coli inactivation was superior to the inactivation obtained in the individual method, indicating the occurrence of synergism for E. coli inactivation in the combined method.

  3. Diurnal change in trees as observed by optical and microwave sensors - The EOS Synergism Study

    NASA Technical Reports Server (NTRS)

    Way, Jobea; Mcdonald, Kyle; Paris, Jack; Dobson, Myron C.; Ulaby, Fawwaz T.; Weber, James A.; Ustin, Susan L.; Vanderbilt, Vern C.; Kasischke, Eric S.

    1991-01-01

    The EOS (Earth Observing System) Synergism Study examined the temporal variability of the optical and microwave backscatter due to diurnal change in canopy properties of interest to ecosystem modelers. The experiment was designed to address diurnal changes in canopy water status that relate to transpiration. Multispectral optical and multifrequency, multipolarization microwave measurements were acquired using boom-truck-based systems over a two-week period. Sensor and canopy properties were collected around the clock. The canopy studied was a walnut orchard in the San Joaquin Valley of California. The results demonstrate a large diurnal variation in the dielectric properties of the tree that in turn produces significant diurnal changes in the microwave backscatter. The results suggest that permanently orbiting spaceborne sensors such as those on EOS should be placed in orbits that are optimized for the individual sensor and need not be tied together by a tight simultaneity requirement on the order of minutes to hours for the purpose of monitoring ecosystem properties.

  4. Biomimetic biodegradable artificial antigen presenting cells synergize with PD-1 blockade to treat melanoma.

    PubMed

    Kosmides, A K; Meyer, R A; Hickey, J W; Aje, K; Cheung, K N; Green, J J; Schneck, J P

    2017-02-01

    Biomimetic materials that target the immune system and generate an anti-tumor responses hold promise in augmenting cancer immunotherapy. These synthetic materials can be engineered and optimized for their biodegradability, physical parameters such as shape and size, and controlled release of immune-modulators. As these new platforms enter the playing field, it is imperative to understand their interaction with existing immunotherapies since single-targeted approaches have limited efficacy. Here, we investigate the synergy between a PLGA-based artificial antigen presenting cell (aAPC) and a checkpoint blockade molecule, anti-PD1 monoclonal antibody (mAb). The combination of antigen-specific aAPC-based activation and anti-PD-1 mAb checkpoint blockade induced the greatest IFN-γ secretion by CD8+ T cells in vitro. Combination treatment also acted synergistically in an in vivo murine melanoma model to result in delayed tumor growth and extended survival, while either treatment alone had no effect. This was shown mechanistically to be due to decreased PD-1 expression and increased antigen-specific proliferation of CD8+ T cells within the tumor microenvironment and spleen. Thus, biomaterial-based therapy can synergize with other immunotherapies and motivates the translation of biomimetic combinatorial treatments.

  5. Diurnal change in trees as observed by optical and microwave sensors - The EOS Synergism Study

    NASA Technical Reports Server (NTRS)

    Way, Jobea; Mcdonald, Kyle; Paris, Jack; Dobson, Myron C.; Ulaby, Fawwaz T.; Weber, James A.; Ustin, Susan L.; Vanderbilt, Vern C.; Kasischke, Eric S.

    1991-01-01

    The EOS (Earth Observing System) Synergism Study examined the temporal variability of the optical and microwave backscatter due to diurnal change in canopy properties of interest to ecosystem modelers. The experiment was designed to address diurnal changes in canopy water status that relate to transpiration. Multispectral optical and multifrequency, multipolarization microwave measurements were acquired using boom-truck-based systems over a two-week period. Sensor and canopy properties were collected around the clock. The canopy studied was a walnut orchard in the San Joaquin Valley of California. The results demonstrate a large diurnal variation in the dielectric properties of the tree that in turn produces significant diurnal changes in the microwave backscatter. The results suggest that permanently orbiting spaceborne sensors such as those on EOS should be placed in orbits that are optimized for the individual sensor and need not be tied together by a tight simultaneity requirement on the order of minutes to hours for the purpose of monitoring ecosystem properties.

  6. Aplidin synergizes with cytosine arabinoside: functional relevance of mitochondria in Aplidin-induced cytotoxicity.

    PubMed

    Humeniuk, R; Menon, L G; Mishra, P J; Saydam, G; Longo-Sorbello, G S A; Elisseyeff, Y; Lewis, L D; Aracil, M; Jimeno, J; Bertino, J R; Banerjee, D

    2007-12-01

    Aplidin (plitidepsin) is a novel marine-derived antitumor agent presently undergoing phase II clinical trials in hematological malignancies and solid tumors. Lack of bone marrow toxicity has encouraged further development of this drug for treatment of leukemia and lymphoma. Multiple signaling pathways have been shown to be involved in Aplidin-induced apoptosis and cell cycle arrest in G1 and G2 phase. However, the exact mechanism(s) of Aplidin action remains to be elucidated. Here we demonstrate that mitochondria-associated or -localized processes are the potential cellular targets of Aplidin. Whole genome gene-expression profiling (GEP) revealed that fatty acid metabolism, sterol biosynthesis and energy metabolism, including the tricarboxylic acid cycle and ATP synthesis are affected by Aplidin treatment. Moreover, mutant MOLT-4, human leukemia cells lacking functional mitochondria, were found to be resistant to Aplidin. Cytosine arabinoside (araC), which also generates oxidative stress but does not affect the ATP pool, showed synergism with Aplidin in our leukemia and lymphoma models in vitro and in vivo. These studies provide new insights into the mechanism of action of Aplidin. The efficacy of the combination of Aplidin and araC is currently being evaluated in clinical phase I/II program for the treatment of patients with relapsed leukemia and high-grade lymphoma.

  7. Synergism between ethanolic extract of propolis (EEP) and anti-tuberculosis drugs on growth of mycobacteria.

    PubMed

    Scheller, S; Dworniczak, S; Waldemar-Klimmek, K; Rajca, M; Tomczyk, A; Shani, J

    1999-01-01

    Ethanolic extract of propolis exerts a strong anti-bacterial activity, in addition to antifungal, antiviral and antiprotozoal properties. In previous studies from these laboratories we have demonstrated that the intensity of the bactericidal activity of EEP is correlated with the virulence of the mycobacteria tested, and that EEP has a synergistic effect with antibiotics on growth of staphylococcus aureus. In the present study we investigated whether the same synergism and correlation exists between EEP and some anti-tuberculosis drugs on tuberculosis mycobacteria with different degrees of virulence. Six standard strains and 11 wild strains of mycobacteria were exposed for 30 days to EEP, with or without streptomycin, rifamycin, isoniazid or ethambutol. Out of the 17 strains, 8 were resistant to at least two standard antibiotics, and were considered "multi-resistant strains". The rest were either susceptible or resistant to only one of the antimycobacterial drugs. Antagonism was recorded only in one case, when Staphylococcus aureus were treated with a mixture of EEP and ethambutol, suggesting that a chemical bond could have been formed between this anti-tuberculosis antibiotic and one of the active components of the ethanol extract of propolis.

  8. Biochemical basis of synergism between pathogenic fungus Metarhizium anisopliae and insecticide chlorantraniliprole in Locusta migratoria (Meyen)

    PubMed Central

    Jia, Miao; Cao, Guangchun; Li, Yibo; Tu, Xiongbing; Wang, Guangjun; Nong, Xiangqun; Whitman, Douglas W.; Zhang, Zehua

    2016-01-01

    We challenged Locusta migratoria (Meyen) grasshoppers with simultaneous doses of both the insecticide chlorantraniliprole and the fungal pathogen, Metarhizium anisopliae. Our results showed synergistic and antagonistic effects on host mortality and enzyme activities. To elucidate the biochemical mechanisms that underlie detoxification and pathogen-immune responses in insects, we monitored the activities of 10 enzymes. After administration of insecticide and fungus, activities of glutathione-S-transferase (GST), general esterases (ESTs) and phenol oxidase (PO) decreased in the insect during the initial time period, whereas those of aryl acylamidase (AA) and chitinase (CHI) increased during the initial period and that of acetylcholinesterase (AChE) increased during a later time period. Activities of superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) decreased at a later time period post treatment. Interestingly, treatment with chlorantraniliprole and M. anisopliae relieved the convulsions that normally accompany M. anisopliae infection. We speculate that locust mortality increased as a result of synergism via a mechanism related to Ca2+ disruption in the host. Our study illuminates the biochemical mechanisms involved in insect immunity to xenobiotics and pathogens as well as the mechanisms by which these factors disrupt host homeostasis and induce death. We expect this knowledge to lead to more effective pest control. PMID:27328936

  9. The synergic role of collagen and citrate in stabilizing amorphous calcium phosphate precursors with platy morphology.

    PubMed

    Delgado-López, José Manuel; Bertolotti, Federica; Lyngsø, Jeppe; Pedersen, Jan Skov; Cervellino, Antonio; Masciocchi, Norberto; Guagliardi, Antonietta

    2017-02-01

    Bioinspired in vitro collagen mineralization experiments have been performed in the presence of citrate and the combined role of the two bone organic matrix components in controlling mineral formation was investigated for the first time. Mineralized and non-mineralized collagen fibrils have been in depth characterized by combining small- and wide-angle X-ray scattering (SAXS/WAXS) techniques with Atomic Force Microscopy (AFM) imaging. A synergic effect of collagen and citrate in driving the formation of long-term stable amorphous calcium phosphate (ACP) nanoparticles with platy morphology was found. AFM images on mineralized collagen fibrils revealed that some of the ACP nanoparticles were deposited on the intramolecular nanoscopic holes of collagen fibrils. Citrate is an important component of the bone organic matrix but its specific role in bone mineralization is presently unclear. In this work, bioinspired in vitro collagen mineralization experiments in the presence of citrate have been carried out and the combined role of collagen and citrate in controlling mineral formation has been addressed for the first time. Through X-ray scattering and Atomic Force Microscopy characterizations on mineralized and non-mineralized collagen fibrils, we have found that citrate in synergy with collagen stabilizes an amorphous calcium phosphate (ACP) phase with platy morphology over one week and controls its deposition on collagen fibrils. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  10. Synergism between two amphenicol of antibiotics, florfenicol and thiamphenicol, against Staphylococcus aureus.

    PubMed

    Wei, C-F; Chang, S-K; Shien, J-H; Kuo, H-C; Chen, W-Y; Chou, C-C

    2016-03-26

    Synergistic effects between the same class of antibiotics are rarely reported. In the current study, two amphenicols, namely florfenicol and thiamphenicol, exhibited both in vitro and in vivo synergism against clinical isolates ofStaphylococcus aureusfrom chickens, cattle and pigs. Checkerboard assays on 21S. aureusisolates showed that in 80 per cent of methicillin-susceptibleS. aureus(MSSA) and 82 per cent of methicillin-resistantS. aureus(MRSA) isolates tested, the minimal inhibitory concentration (MIC) of florfenicol could be reduced by 75 per cent (1/4 MIC) or more (up to 1/16 MIC) when combined with 1/2 MIC of thiamphenicol to exhibit antimicrobial activity comparable to the respective drugs at original strength (1×MIC). A synergistic effect (fractional inhibitory concentration index ≤0.5 or ≥2-log10decrease in colony-forming unit/ml in time-kill study) was evident against 30 per cent of MSSA and 45 per cent of MRSA strains tested. A study in mice revealed that the florfenicol/thiamphenicol combination at reduced dosages provided sufficient protection againstS. aureuschallenge. The possible mechanism warrants further study but likely includes the facilitated uptake of thiamphenicol via florfenicol action, and this facilitation was not limited to amphenicol class. The present study may offer new strategy for combination therapy and provide potential alternatives for effective treatment againstS. aureusinfections.

  11. Anti-Trichophyton Activity of Protocatechuates and Their Synergism with Fluconazole

    PubMed Central

    Gullo, Fernanda Patrícia; Sardi, Janaina de Cássia Orlandi; Costa-Orlandi, Caroline Barcelos; Sangalli-Leite, Fernanda; Scorzoni, Liliana; Regasini, Luis Octávio; Petrônio, Maicon Segalla; Souza, Patrícia Fernanda; Silva, Dulce Helena Siqueira; Mendes-Giannini, Maria José Soares

    2014-01-01

    Dermatophytosis and superficial mycosis are a major global public health problem that affects 20–25% of the world's population. The increase in fungal resistance to the commercially available antifungal agents, in conjunction with the limited spectrum of action of such drugs, emphasises the need to develop new antifungal agents. Natural products are attractive prototypes for antifungal agents due to their broad spectrum of biological activities. This study aimed to verify the antifungal activity of protocatechuic acid, 3,4-diacetoxybenzoic, and fourteen alkyl protocatechuates (3,4-dihydroxybenzoates) against Trichophyton rubrum and Trichophyton mentagrophytes and to further assess their activities when combined with fluconazole. Susceptibility and synergism assays were conducted as described in M38-A2 (CLSI), with modifications. Three strains of Trichophyton rubrum and three strains of Trichophyton mentagrophytes were used in this work. The pentyl, hexyl, heptyl, octyl, nonyl, and decyl protocatechuates showed great fungicidal effects, with minimum inhibitory concentration (MIC) values ranging from 0.97 to 7.8 mg/L. Heptyl showed a synergistic activity (FIC index = 0.49), reducing the MIC of fluconazole by fourfold. All substances tested were safe, especially the hexyl, heptyl, octyl, and nonyl compounds, all of which showed a high selectivity index, particularly in combination with fluconazole. These ester associations with fluconazole may represent a promising source of prototypes in the search for anti-Trichophyton therapeutic agents. PMID:25136374

  12. Synergism between endotoxin priming and exotoxin challenge in provoking severe vascular leakage in rabbit lungs.

    PubMed

    Schütte, H; Rosseau, S; Czymek, R; Ermert, L; Walmrath, D; Krämer, H J; Seeger, W; Grimminger, F

    1997-09-01

    Lipopolysaccharides (LPS) of gram-negative bacteria prime rabbit lungs for enhanced thromboxane-mediated vasoconstriction upon subsequent challenge with the exotoxin Escherichia coli hemolysin (HlyA) (Walmrath et al. J. Exp. Med. 1994;180:1437-1443). We investigated the impact of endotoxin priming and subsequent HlyA challenge on lung vascular permeability while maintaining constancy of capillary pressure. Rabbit lungs were perfused in a pressure-controlled mode in the presence of the thromboxane receptor antagonist BM 13.505, with continuous monitoring of flow. Perfusion for 180 min with 10 ng/ml LPS did not provoke vasoconstriction or alteration of capillary filtration coefficient (Kfc) values. HlyA (0.021 hemolytic units/ml) induced thromboxane release and a transient decrease in perfusion flow in the absence of significant changes in Kfc. Similar results were obtained when LPS and HlyA were coapplied simultaneously. However, when the HlyA challenge was undertaken after 180 min of LPS priming, a manifold increase in Kfc values was noted, with concomitant severe lung edema formation, although capillary pressure remained unchanged. Thus, endotoxin primes the lung vasculature to respond with a severe increase in vascular permeability to a subsequent low-dose application of HlyA. Such synergism between endotoxin priming and exotoxin challenge in provoking lung vascular leakage may contribute to the pathogenesis of respiratory failure in sepsis and severe lung infection.

  13. Synergism at clinically attainable concentrations of aminoglycoside and beta-lactam antibiotics.

    PubMed Central

    Hooton, T M; Blair, A D; Turck, M; Counts, G W

    1984-01-01

    We evaluated the in vitro synergistic activity at clinically attainable concentrations of combinations of aminoglycoside and beta-lactam antibiotics against 30 gentamicin-resistant clinical isolates of gram-negative bacilli. All 56 pairs of 4 aminoglycosides and 14 beta-lactams were evaluated. Combinations with amikacin demonstrated inhibitory synergistic activity in 29% of the assays, as compared with 22% for netilmicin (P = 0.018), 17% for gentamicin (P less than 0.001), and 13% for tobramycin (P less than 0.001). Among the beta-lactams, combinations with cefoperazone, ceftriaxone, or cefpiramide (SM-1652) demonstrated inhibitory synergistic activity most often (39, 38, and 35% of the assays, respectively) and with ceforanide, cefsulodin, and imipenem least often (less than or equal to 8% each). The most active combination was amikacin and ceftriaxone, with which 67% of the assays demonstrated inhibitory synergism. Isolates with high-level resistance to either antibiotic in a combination were unlikely to be inhibited synergistically by the combination. Further, combinations generally demonstrated little synergistic activity against isolates highly susceptible to beta-lactams. PMID:6517544

  14. Systematic chemical-genetic and chemical-chemical interaction datasets for prediction of compound synergism

    PubMed Central

    Wildenhain, Jan; Spitzer, Michaela; Dolma, Sonam; Jarvik, Nick; White, Rachel; Roy, Marcia; Griffiths, Emma; Bellows, David S.; Wright, Gerard D.; Tyers, Mike

    2016-01-01

    The network structure of biological systems suggests that effective therapeutic intervention may require combinations of agents that act synergistically. However, a dearth of systematic chemical combination datasets have limited the development of predictive algorithms for chemical synergism. Here, we report two large datasets of linked chemical-genetic and chemical-chemical interactions in the budding yeast Saccharomyces cerevisiae. We screened 5,518 unique compounds against 242 diverse yeast gene deletion strains to generate an extended chemical-genetic matrix (CGM) of 492,126 chemical-gene interaction measurements. This CGM dataset contained 1,434 genotype-specific inhibitors, termed cryptagens. We selected 128 structurally diverse cryptagens and tested all pairwise combinations to generate a benchmark dataset of 8,128 pairwise chemical-chemical interaction tests for synergy prediction, termed the cryptagen matrix (CM). An accompanying database resource called ChemGRID was developed to enable analysis, visualisation and downloads of all data. The CGM and CM datasets will facilitate the benchmarking of computational approaches for synergy prediction, as well as chemical structure-activity relationship models for anti-fungal drug discovery. PMID:27874849

  15. Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer

    PubMed Central

    Espey, Michael Graham; Chen, Ping; Chalmers, Brian; Drisko, Jeanne; Sun, Andrew Y.; Levine, Mark; Chen, Qi

    2012-01-01

    Conventional treatment approaches have had little impact on the course of pancreatic cancer, which has the highest fatality rate among cancers. Gemcitabine, the primary therapeutic agent for pancreatic carcinoma, produces minimal survival benefit as a single agent. Therefore, numerous efforts have focused on gemcitabine combination treatments. Using a ratio design, this study established that combining pharmacologically achievable concentrations of ascorbate with gemcitabine resulted in a synergistic cytotoxic response in eight pancreatic tumor cell lines. Sensitization was evident regardless of inherent gemcitabine resistance and epithelial–mesenchymal phenotype. Our analysis suggested that the promiscuous oxidative actions of H2O2 derived from pharmacologic ascorbate can culminate in synergism independent of the cancer cell's underlying phenotype and resistance to gemcitabine monotherapy. Gemcitabine–ascorbate combinations administered to mice bearing pancreatic tumor xenografts consistently enhanced inhibition of growth compared to gemcitabine alone, produced 50% growth inhibition in a tumor type not responsive to gemcitabine, and demonstrated a gemcitabine dose-sparing effect. These data support the testing of pharmacologic ascorbate in adjunctive treatments for cancers prone to high failure rates with conventional therapeutic regimens, such as pancreatic cancer. PMID:21402145

  16. A Newly Isolated Penicillium oxalicum 16 Cellulase with High Efficient Synergism and High Tolerance of Monosaccharide.

    PubMed

    Zhao, Xi-Hua; Wang, Wei; Tong, Bin; Zhang, Su-Ping; Wei, Dong-Zhi

    2016-01-01

    Compared to Trichoderma reesei RUT-C30 cellulase (Trcel), Penicillium oxalicum 16 cellulase (P16cel) from the fermentation supernatant produced a 2-fold higher glucose yield when degrading microcrystalline cellulose (MCC), possessed a 10-fold higher β-glucosidase (BGL) activity, but obtained somewhat lower other cellulase component activities. The optimal temperature and pH of β-1,4-endoglucanase, cellobiohydrolase, and filter paperase from P16cel were 50-60 °C and 4-5, respectively, but those of BGL reached 70 °C and 5. The cellulase cocktail of P16cel and Trcel had a high synergism when solubilizing MCC and generated 1.7-fold and 6.2-fold higher glucose yields than P16cel and Trcel at the same filter paperase loading, respectively. Additional low concentration of fructose enhanced the glucose yield during enzymatic hydrolysis of MCC; however, additional high concentration of monosaccharide (especially glucose) reduced cellulase activities and gave a stronger monosaccharide inhibition on Trcel. These results indicate that P16cel is a more excellent cellulase than Trcel.

  17. Development of the synergism between Fluxnet and global terrestrial remote sensing (Invited)

    NASA Astrophysics Data System (ADS)

    Running, S. W.

    2013-12-01

    Coordination of Fluxnet sites worldwide with new global remote sensing data products has emerged as one of the finest successes of international collaboration in global change science. The concept of an organized and quality controlled network of flux towers evolved in the early 1990s concurrently as the foundation of a new generation of earth observing satellites was being developed. The idea of linking the ground based flux towers with the remote sensing platforms developed in an array of meetings within the International Geosphere-Biosphere Program. Global remote sensing had an incentive to get connected to an international network of ground truth stations run by scientists, while fluxtower teams had the incentive of using the satellite based datasets for extrapolation of their tower measurements to broader regions. The new satellite datasets went beyond classic spectral vegetation indices to variables more relevant to the flux community such as for example; albedo, land surface temperature, Fraction of absorbed PAR, leaf area index, gross primary production and evapotranspiration. The credibility of these global ecosystem datasets has been dramatically improved by the synergism with Fluxnet.

  18. The electronic structure of alloxan monohydrate. Spectroscopic and density functional synergic approach

    NASA Astrophysics Data System (ADS)

    Elroby, Shaaban A.; Aziz, Saadullah G.; Hilal, Rifaat H.

    2017-02-01

    In the present communication, quantitative interpretation and assignments of the electronic absorption spectra, vibrational and one- and two-dimensional NMR spectra of alloxan, are detailed. A synergic analysis based on DFT and TD-DFT calculations and the experimental findings are performed. Attempt is made to relate these spectral findings to the electronic structure of alloxan. The computed electronic spectrum predicted three well defined bands. Natural transition orbital analysis indicate an intramolecular charge transfer from npπ orbital of the water oxygen atom resulting in the short wavelength nπ* at ∼200 nm. Furthermore, UV-photoabsorption cross section for alloxan and its monohydrate are simulated. The spectrum, composed of 10 excited states, was simulated with the nuclear ensemble approximation, sampling a Wigner distribution with 300 points. The FT-IR spectrum of alloxan, measured in the solid state as KBr pellets is reported and is computed at the DFT/B3LYP/6-311++G** level of theory. All observed vibrations are assigned. The 600 MHz one- and two-dimensional COSY, 1H NMR spectra of alloxan, measured in DMSO, are reported and analyzed and computed theoretically using the GIAO method. Hydrogen-bond interactions are responsible for remarkable downfield shift of 1H NMR peaks for alloxan.

  19. Radiation-thermal degradation of PE and PVC: Mechanism of synergism and dose rate effects

    NASA Astrophysics Data System (ADS)

    Clough, Roger L.; Gillen, Kenneth T.

    Polyethylene insulation and polyvinyl chloride jacketing materials that had been in use in a nuclear application were recently found to be substantially deteriorated. The damage had occurred under conditions where both the total estimated dose (about 2.5 Mrad) and the operating temperatures (about 43°C average) seemed relatively moderate. These results prompted us to initiate a program to study polyvinyl chloride and polyethylene degradation under conditions of combined γ-radiation and elevated temperature environments. A number of interesting aging effects were observed, including 1) a striking synergism between radiation and temperature and 2) strong dose-rate dependent effects which occur over a wide range of dose rates. The aging effects are explained in terms of a chain branching degradation mechanism involving thermally induced breakdown of peroxides which are formed in reactions initiated by the radiation. Evidence for this mechanism is derived from infrared spectra, from sequential radiation-elevated temperature experiments including experiments under inert atmosphere, from activation energy estimates and from a new technique involving treatment of intact samples with PH 3 for chemical reduction of peroxides. The results of our studies raise significant doubts about the utility of earlier compilations which purportedly serve as radiation life expectancy guides by indicating "tolerable radiation doses" for a variety of polymers.

  20. Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma.

    PubMed

    Beug, Shawn T; Beauregard, Caroline E; Healy, Cristin; Sanda, Tarun; St-Jean, Martine; Chabot, Janelle; Walker, Danielle E; Mohan, Aditya; Earl, Nathalie; Lun, Xueqing; Senger, Donna L; Robbins, Stephen M; Staeheli, Peter; Forsyth, Peter A; Alain, Tommy; LaCasse, Eric C; Korneluk, Robert G

    2017-02-15

    Small-molecule inhibitor of apoptosis (IAP) antagonists, called Smac mimetic compounds (SMCs), sensitize tumours to TNF-α-induced killing while simultaneously blocking TNF-α growth-promoting activities. SMCs also regulate several immunomodulatory properties within immune cells. We report that SMCs synergize with innate immune stimulants and immune checkpoint inhibitor biologics to produce durable cures in mouse models of glioblastoma in which single agent therapy is ineffective. The complementation of activities between these classes of therapeutics is dependent on cytotoxic T-cell activity and is associated with a reduction in immunosuppressive T-cells. Notably, the synergistic effect is dependent on type I IFN and TNF-α signalling. Furthermore, our results implicate an important role for TNF-α-producing cytotoxic T-cells in mediating the anti-cancer effects of immune checkpoint inhibitors when combined with SMCs. Overall, this combinatorial approach could be highly effective in clinical application as it allows for cooperative and complimentary mechanisms in the immune cell-mediated death of cancer cells.

  1. The mycotoxins deoxynivalenol and nivalenol show in vivo synergism on jejunum enterocytes apoptosis.

    PubMed

    Cheat, Sophal; Pinton, Philippe; Cossalter, Anne-Marie; Cognie, Juliette; Vilariño, Maria; Callu, Patrick; Raymond-Letron, Isabelle; Oswald, Isabelle P; Kolf-Clauw, Martine

    2016-01-01

    The mycotoxins deoxynivalenol (DON) and nivalenol (NIV), worldwide cereal contaminants, raise concerns for human and animal gut health, following exposure through contaminated food and feed. The aim of this work was to analyze the effects of DON and NIV, alone or associated, on the intestinal pig mucosa. Jejunal loops were used for testing DON and NIV individually and in combination (1:1) after a single exposure, for 24 h. For repeated exposure, piglets received a natural contaminated feed, with DON or with DON + NIV for 28 days. Histological investigations, proliferation and apoptosis assessments were conducted. Both experiments were concordant for the total-cell proliferation decreased at the villus tips after DON or DON + NIV at 10 μM acutely, or repeatedly, by 30-35% and 20-25%, respectively. In loops model, apoptotic enterocytes at villus tips increased dose-dependently after DON, NIV alone or DON + NIV in combination. The combination in loops at 10 μM showed higher effects on proliferation and apoptosis than DON alone, and synergism was shown for villus apoptotic enterocyte. These results are to be considered for NIV consumer risk assessment. Our results demonstrate the in vivo disruption of the intestinal balance proliferation/apoptosis explaining, at least partly, the disruption of intestinal barrier by these mycotoxins.

  2. Innate and Adaptive Immunity Synergize to Trigger Inflammation in the Mammary Gland

    PubMed Central

    Rainard, Pascal; Cunha, Patricia; Gilbert, Florence B.

    2016-01-01

    The mammary gland is able to detect and react to bacterial intrusion through innate immunity mechanisms, but mammary inflammation can also result from antigen-specific adaptive immunity. We postulated that innate and adaptive immune responses could synergize to trigger inflammation in the mammary gland. To test this hypothesis, we immunized cows with the model antigen ovalbumin and challenged the sensitized animals with either Escherichia coli lipopolysaccharide (LPS) as innate immunity agonist, ovalbumin as adaptive immunity agonist, or both agonists in three different udder quarters of lactating cows. There was a significant amplification of the initial milk leukocytosis in the quarters challenged with the two agonists compared to leukocytosis in quarters challenged with LPS or ovalbumin alone. This synergistic response occurred only with the cows that developed the ovalbumin-specific inflammatory response, and there were significant correlations between milk leukocytosis and production of IL-17A and IFN-γ in a whole-blood ovalbumin stimulation assay. The antigen-specific response induced substantial concentrations of IL-17A and IFN-γ in milk contrary to the response to LPS. Such a synergy at the onset of the reaction of the mammary gland suggests that induction of antigen-specific immune response with bacterial antigens could improve the initial immune response to infection, hence reducing the bacterial load and contributing to protection. PMID:27100324

  3. Synergisms among fire, land use, and climate change in the Amazon.

    PubMed

    Cochrane, Mark A; Laurance, William F

    2008-12-01

    The Amazon is being rapidly transformed by fire. Logging and forest fragmentation sharply elevate fire incidence by increasing forest desiccation and fuel loads, and forests that have experienced a low-intensity surface fire are vulnerable to far more catastrophic fires. Satellites typically detect thermal signatures from 40 000 to 50 000 separate fires in the Amazon each year, and this number could increase as new highways and infrastructure expand across the basin. Many are concerned that large-scale deforestation, by reducing regional evapotranspiration and creating moisture-trapping smoke plumes, will make the basin increasingly vulnerable to fire. The Amazon may also be affected by future global warming and atmospheric changes, although much remains uncertain. Most models suggest the basin will become warmer throughout this century, although there is no consensus about how precipitation will be affected. The most alarming scenarios project a permanent disruption of the El Niño-Southern Oscillation, leading to greatly increased drought or destructive synergisms between regional and global climate change in the Amazon.

  4. Alkaline pretreatment and the synergic effect of water and tetralin enhances the liquefaction efficiency of bagasse.

    PubMed

    Li, Zhixia; Cao, Jiangfei; Huang, Kai; Hong, Yaming; Li, Cunlong; Zhou, Xinxin; Xie, Ning; Lai, Fang; Shen, Fang; Chen, Congjin

    2015-02-01

    Bagasse liquefaction (BL) in water, tetralin, and water/tetralin mixed solvents (WTMS) was investigated, and effects of tetralin content in WTMS, temperature, and alkaline pretreatment of bagasse on liquefaction efficiency were studied. At 300°C, bagasse conversion in WTMS with tetralin content higher than 50 wt% was 86-87 wt%, whereas bagasse conversion in water or tetralin was 67 wt% or 84 wt%, respectively. Because the solid conversion from liquefaction in WTMS with tetralin content higher than 50 wt% was always higher than that in water or tetralin at temperatures between 250 and 300°C, a synergic effect between water and tetralin is suggested. Alkaline pretreatment of bagasse resulted in significantly higher conversion and heavy oil yield from BL in water or WTMS. The effect of deoxygenation by the present liquefaction method is demonstrated by lower oxygen contents (16.01-19.59 wt%) and higher heating values (31.9-34.8 MJ/kg) in the produced oils. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma

    PubMed Central

    Beug, Shawn T.; Beauregard, Caroline E.; Healy, Cristin; Sanda, Tarun; St-Jean, Martine; Chabot, Janelle; Walker, Danielle E.; Mohan, Aditya; Earl, Nathalie; Lun, Xueqing; Senger, Donna L.; Robbins, Stephen M.; Staeheli, Peter; Forsyth, Peter A.; Alain, Tommy; LaCasse, Eric C.; Korneluk, Robert G.

    2017-01-01

    Small-molecule inhibitor of apoptosis (IAP) antagonists, called Smac mimetic compounds (SMCs), sensitize tumours to TNF-α-induced killing while simultaneously blocking TNF-α growth-promoting activities. SMCs also regulate several immunomodulatory properties within immune cells. We report that SMCs synergize with innate immune stimulants and immune checkpoint inhibitor biologics to produce durable cures in mouse models of glioblastoma in which single agent therapy is ineffective. The complementation of activities between these classes of therapeutics is dependent on cytotoxic T-cell activity and is associated with a reduction in immunosuppressive T-cells. Notably, the synergistic effect is dependent on type I IFN and TNF-α signalling. Furthermore, our results implicate an important role for TNF-α-producing cytotoxic T-cells in mediating the anti-cancer effects of immune checkpoint inhibitors when combined with SMCs. Overall, this combinatorial approach could be highly effective in clinical application as it allows for cooperative and complimentary mechanisms in the immune cell-mediated death of cancer cells. PMID:28198370

  6. Impaired Synergic Control of Posture in Parkinson’s Patients without Postural Instability

    PubMed Central

    Falaki, Ali; Huang, Xuemei; Lewis, Mechelle M.; Latash, Mark L.

    2015-01-01

    Background Postural instability is one of most disabling motor symptoms in Parkinson’s disease. Indices of multi-muscle synergies are new measurements of movement and postural stability. Objectives Multi-muscle synergies stabilizing vertical posture were studied in Parkinson’s disease patients without clinical symptoms of postural instability (Hoehn-Yahr- ≤ II) and age-matched controls. We tested the hypothesis that both synergy indices during quiet standing and synergy adjustments to self-triggered postural perturbations would be reduced in patients. Methods Eleven Parkinson’s disease patients and 11 controls performed whole-body tasks while standing. Surface electromyography was used to quantify synergy indices stabilizing center of pressure shifts in the anterior-posterior direction during a load-release task. Results Parkinson’s disease patients showed a significantly lower percentage of variance in the muscle activation space accounted for by the first four principal components, significantly reduced synergy indices during steady state, and significantly reduced anticipatory synergy adjustments (a drop in the synergy index prior to the self-triggered unloading). Conclusions The study demonstrates for the first time that impaired synergic control in Parkinson’s disease can be quantified in postural tasks, even in patients without clinical manifestations of postural instability. Synergy measurements may provide a biomarker sensitive for early problems with postural stability in Parkinson’s disease. PMID:27004660

  7. Synergism of Alkaline Extract of the Leaves of Sasa senanensis Rehder and Antiviral Agents.

    PubMed

    Sakagami, Hiroshi; Fukuchi, Kunihiko; Kanamoto, Taisei; Terakubo, Shigemi; Nakashima, Hideki; Natori, Takenori; Suguro-Kitajima, Madoka; Oizumi, Hiroshi; Yasui, Toshikazu; Oizumi, Takaaki

    2016-01-01

    Previous studies have shown a much greater antiviral activity of alkaline extract of the leaves of Sasa senanensis Rehder (SE) against human immunodeficiency virus (HIV), compared to lignin precursors, tannins and flavonoids, suggesting its possible application to oral diseases. Systematic comparative study with herpes simplex virus (HSV) has been limited compared to that with HIV. In the present study, we investigated whether combination of SE with other popular antiviral agents further enhances their individual activity. Cell viability of mock-infected, HIV-infected and HSV-infected cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The antiviral activity was evaluated by the selectivity index, defined as the ratio of 50% cytotoxic concentration to 50% effective concentration. Synergy between SE and antiviral agents was evaluated by MacSynerg and CompuSyn software. SE showed potent anti-HIV activity, although its activity was two-orders lower than that of azidothymidine, 2',3'-dideoxycytidine dextran sulfate and curdlan sulfate. Combination of SE with these antiviral agents produced synergistic effects. Using a newly established MTT assay system for anti-HSV activity, SE and acyclovir were found to have synergistic anti-HSV activity. The present study suggests the possible efficacy of the clinical application of SE combined with antiviral agents. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  8. Synergism between Medihoney and Rifampicin against Methicillin-Resistant Staphylococcus aureus (MRSA)

    PubMed Central

    Müller, Patrick; Alber, Dagmar G.; Turnbull, Lynne; Schlothauer, Ralf C.; Carter, Dee A.; Whitchurch, Cynthia B.; Harry, Elizabeth J.

    2013-01-01

    Skin and chronic wound infections caused by highly antibiotic resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) are an increasing and urgent health problem worldwide, particularly with sharp increases in obesity and diabetes. New Zealand manuka honey has potent broad-spectrum antimicrobial activity, has been shown to inhibit the growth of MRSA strains, and bacteria resistant to this honey have not been obtainable in the laboratory. Combinational treatment of chronic wounds with manuka honey and common antibiotics may offer a wide range of advantages including synergistic enhancement of the antibacterial activity, reduction of the effective dose of the antibiotic, and reduction of the risk of antibiotic resistance. The aim of this study was to investigate the effect of Medihoney in combination with the widely used antibiotic rifampicin on S. aureus. Using checkerboard microdilution assays, time-kill curve experiments and agar diffusion assays, we show a synergism between Medihoney and rifampicin against MRSA and clinical isolates of S. aureus. Furthermore, the Medihoney/rifampicin combination stopped the appearance of rifampicin-resistant S. aureus in vitro. Methylglyoxal (MGO), believed to be the major antibacterial compound in manuka honey, did not act synergistically with rifampicin and is therefore not the sole factor responsible for the synergistic effect of manuka honey with rifampicin. Our findings support the idea that a combination of honey and antibiotics may be an effective new antimicrobial therapy for chronic wound infections. PMID:23469049

  9. Antagonism and synergism in Gardnerella vaginalis strains isolated from women with bacterial vaginosis.

    PubMed

    Teixeira, G S; Soares-Brandão, K L K; Branco, K M G R; Sampaio, J L M; Nardi, R M D; Mendonça, M; Almeida, R B; Farias, L M; Carvalho, M A R; Nicoli, J R

    2010-08-01

    Antagonistic and synergistic substances are important for interactions between micro-organisms associated with human body surfaces, either in healthy or in diseased conditions. In the present study, such compounds produced by Gardnerella vaginalis strains isolated from women with bacterial vaginosis (BV) were detected in vitro and the antagonistic ones were partially characterized. Among 11 G. vaginalis strains tested, all showed antagonistic activity against at least one of the 22 indicator bacteria assayed. Interestingly, for some of these strains, antagonism reverted to synergism, favouring one of the indicator strains (Peptostreptococcus anaerobius) when the growth medium was changed. Partial characterization of antagonistic substances suggested a bacteriocin-like chemical nature. Depending on growth conditions, G. vaginalis isolated from women with BV produced antagonistic or synergistic compounds for other bacterial components of the vaginal ecosystem. This is the first report to our knowledge of the production of antagonistic and/or synergistic substances by G. vaginalis. This ability may be a pivotal factor in understanding BV and the ecological role of this bacterium in the vaginal environment.

  10. Synergic Effects of Rehabilitation and Intravenous Infusion of Mesenchymal Stem Cells After Stroke in Rats.

    PubMed

    Sasaki, Yuichi; Sasaki, Masanori; Kataoka-Sasaki, Yuko; Nakazaki, Masahito; Nagahama, Hiroshi; Suzuki, Junpei; Tateyama, Daiki; Oka, Shinichi; Namioka, Takahiro; Namioka, Ai; Onodera, Rie; Mikami, Takeshi; Wanibuchi, Masahiko; Kakizawa, Masafumi; Ishiai, Sumio; Kocsis, Jeffery D; Honmou, Osamu

    2016-11-01

    Intravenous infusion of mesenchymal stem cells (MSCs) derived from adult bone marrow improves behavioral function in rat stroke models. Rehabilitation therapy through physical exercise also provides therapeutic efficacy for cerebral ischemia. The purpose of this study was to investigate whether synergic effects of daily rehabilitation and intravenous infusion of MSCs has therapeutic effects after stroke in rats. This was an experimental study. A permanent middle cerebral artery occlusion (MCAO) was induced by intraluminal vascular occlusion with a microfilament. Four experimental groups were studied: group 1 (vehicle only, n=10), group 2 (vehicle + exercise, n=10), group 3 (MSCs only, n=10), and group 4 (MSCs + exercise, n=10). Rat MSCs were intravenously infused at 6 hours after MCAO, and the rats received daily rehabilitation with treadmill running exercise for 20 minutes. Lesion size was assessed at 1, 14, and 35 days using magnetic resonance imaging. Functional outcome was assessed using the Limb Placement Test. Both combined therapy and MSC infusion reduced lesion volume, induced synaptogenesis, and elicited functional improvement compared with the groups without MSC infusion, but the effect was greater in the combined therapy group. A limitation of this study is that the results were limited to an animal model and cannot be generalized to humans. The data indicate that the combined therapy of daily rehabilitation and intravenous infusion of MSCs improved functional outcome in a rat MCAO model. © 2016 American Physical Therapy Association.

  11. HIF1alpha synergizes with glucocorticoids to promote BFU-E progenitor self-renewal.

    PubMed

    Flygare, Johan; Rayon Estrada, Violeta; Shin, Chanseok; Gupta, Sumeet; Lodish, Harvey F

    2011-03-24

    With the aim of finding small molecules that stimulate erythropoiesis earlier than erythropoietin and that enhance erythroid colony-forming unit (CFU-E) production, we studied the mechanism by which glucocorticoids increase CFU-E formation. Using erythroid burst-forming unit (BFU-E) and CFU-E progenitors purified by a new technique, we demonstrate that glucocorticoids stimulate the earliest (BFU-E) progenitors to undergo limited self-renewal, which increases formation of CFU-E cells > 20-fold. Interestingly, glucocorticoids induce expression of genes in BFU-E cells that contain promoter regions highly enriched for hypoxia-induced factor 1α (HIF1α) binding sites. This suggests activation of HIF1α may enhance or replace the effect of glucocorticoids on BFU-E self-renewal. Indeed, HIF1α activation by a prolyl hydroxylase inhibitor (PHI) synergizes with glucocorticoids and enhances production of CFU-Es 170-fold. Because PHIs are able to increase erythroblast production at very low concentrations of glucocorticoids, PHI-induced stimulation of BFU-E progenitors thus represents a conceptually new therapeutic window for treating erythropoietin-resistant anemia.

  12. BCR and Endosomal TLR Signals Synergize to Increase AID Expression and Establish Central B Cell Tolerance.

    PubMed

    Kuraoka, Masayuki; Snowden, Pilar B; Nojima, Takuya; Verkoczy, Laurent; Haynes, Barton F; Kitamura, Daisuke; Kelsoe, Garnett

    2017-02-14

    Activation-induced cytidine deaminase (AID) is required to purge autoreactive immature and transitional-1 (immature/T1) B cells at the first tolerance checkpoint, but how AID selectively removes self-reactive B cells is unclear. We now show that B cell antigen receptor (BCR) and endosomal Toll-like receptor (TLR) signals synergize to elicit high levels of AID expression in immature/T1 B cells. This synergy is restricted to ligands for endocytic TLR and requires phospholipase-D activation, endosomal acidification, and MyD88. The first checkpoint is significantly impaired in AID- or MyD88-deficient mice and in mice doubly heterozygous for AID and MyD88, suggesting interaction of these factors in central B cell tolerance. Moreover, administration of chloroquine, an inhibitor of endosomal acidification, results in a failure to remove autoreactive immature/T1 B cells in mice. We propose that a BCR/TLR pathway coordinately establishes central tolerance by hyper-activating AID in immature/T1 B cells that bind ligands for endosomal TLRs.

  13. Evaluation of synergized pyrethrin aerosol for control of Tribolium castaneum and Tribolium confusum (Coleoptera: Tenebrionidae).

    PubMed

    Kharel, Kabita; Arthur, Frank H; Zhu, Kun Yan; Campbell, James F; Subramanyam, Bhadriraju

    2014-02-01

    Aerosol insecticides are being used in flour mill pest management programs, but there is limited information on their efficacy on different insect life stages. In this study, we evaluated the efficacy of synergized pyrethrin applied as an aerosol against eggs, larvae, pupae, and adults of the red flour beetle, Tribolium castaneum (Herbst), and the confused flour beetle, Tribolium confusum Jacquelin du Val. Effects of direct and indirect exposure were evaluated by exposing each life stage to the aerosol and then transferring to untreated flour, transferring untreated insects to treated flour, or exposing both the insects and the flour to the aerosol. The aerosol produced >88% mortality of both species and all life stages when insects were directly treated and transferred to either treated or untreated flour. Mortality was significantly reduced when insects were either treated together with flour or untreated insects were transferred to treated flour (indirect exposure to the aerosol). Larvae and adults of both species were more tolerant compared with eggs and pupae. Recovery of moribund adults in the indirect exposure treatments was greater compared with recovery of moribund insects in the direct exposure treatments. Good sanitation before aerosol application could facilitate direct exposure of insects and thus increase aerosol efficacy inside flour mills.

  14. Synergisms between microbial pathogens in plant disease complexes: a growing trend

    PubMed Central

    Lamichhane, Jay Ram; Venturi, Vittorio

    2015-01-01

    Plant diseases are often thought to be caused by one species or even by a specific strain. Microbes in nature, however, mostly occur as part of complex communities and this has been noted since the time of van Leeuwenhoek. Interestingly, most laboratory studies focus on single microbial strains grown in pure culture; we were therefore unaware of possible interspecies and/or inter-kingdom interactions of pathogenic microbes in the wild. In human and animal infections, it is now being recognized that many diseases are the result of multispecies synergistic interactions. This increases the complexity of the disease and has to be taken into consideration in the development of more effective control measures. On the other hand, there are only a few reports of synergistic pathogen–pathogen interactions in plant diseases and the mechanisms of interactions are currently unknown. Here we review some of these reports of synergism between different plant pathogens and their possible implications in crop health. Finally, we briefly highlight the recent technological advances in diagnostics as these are beginning to provide important insights into the microbial communities associated with complex plant diseases. These examples of synergistic interactions of plant pathogens that lead to disease complexes might prove to be more common than expected and understanding the underlying mechanisms might have important implications in plant disease epidemiology and management. PMID:26074945

  15. Synergism between ammonia and phenols for Hybomitra tabanids in northern and temperate Canada.

    PubMed

    Mihok, S; Lange, K

    2012-09-01

    Baits for tabanids (Diptera: Tabanidae) were tested in the Northwest Territories (60 °N) and Ontario (45 °N) using Nzi traps. Tests targeted ammonia, phenols/cow urine and octenol. About 200 000 tabanids were captured in 15 experiments with a maximum capture of 4182 in one trap in 1 day. In the Northwest Territories, phenols, urine and octenol were effective single baits for only some species. At both locations, adding ammonia to an unbaited or an octenol-baited trap had no effect on catches. By contrast, catches were increased for several species when ammonia was combined with phenols or urine. In Ontario, including ammonia in various baits increased catches by 1.5- to 3.4-fold relative to octenol alone for three Hybomitra and one Tabanus species. Synergism between ammonia and phenols was clearly demonstrated for the dominant Hybomitra species in Ontario (Hybomitra lasiophthalma), but not for the dominant species in the Northwest Territories (Hybomitra epistates). In five other northern Hybomitra species, baits of ammonia and/or octenol in combination with phenols resulted in a 1.7- to 4.1-fold increase in catch relative to an unbaited trap. Further tests of ammonia as a synergist for biting flies may prove useful in, for example, tsetse, which respond strongly to phenols.

  16. Synergism of herbicide toxicity by 5-aminolevulinic acid is related to physiological and ultra-structural disorders in crickweed (Malachium aquaticum L.).

    PubMed

    Xu, Ling; Zhang, Wenfang; Ali, Basharat; Islam, Faisal; Zhu, Jinwen; Zhou, Weijun

    2015-11-01

    Selection of effective herbicides to control weeds has been one of the major objectives of scientists. This study determines the differential tolerance or susceptibility of crickweed (Malachium aquaticum L.) to various concentration combinations of 5-aminolevulinic acid (ALA) (1, 10 and 100mg/L) and propyl 4-(2-(4,6-dimethoxypyrimidin-2-yloxy)benzylamino)benzoate (ZJ0273) (100, 200, and 500mg/L). ALA was applied as pre- and post-treatment alone or in combination with ZJ0273. Results showed that ZJ0273 stress alone imposed negative effects on M. aquaticum seedling's growth, net photosynthetic rates and SPAD values, and the rate of decline was consistently increased with the increase in ZJ0273 concentration. The ZJ0273 treatment showed a gradual decrease in the activities of antioxidant enzymes peroxidase (POD), superoxide dismutase (SOD), and ascorbate peroxidase (APX), and increase in the accumulation of malondialdehyde (MDA). Changes in chloroplast swelling, increased number of plastoglobuli, disruption of thylakoid, disintegrated mitochondria and turbid nucleoplasm were noticed. Moreover, SDS-PAGE analysis of total proteins revealed that herbicide stress in the leaves was associated with the decrease or disappearance of some protein bands. Further, two-dimensional gel electrophoresis (2-DE) results showed that proteins in different spots were classified into three types for M. aquaticum. These results indicate that the combined treatment of ALA and ZJ0273 synergizes the herbicide toxicity which is different from its independent effects on M. aquaticum and thus, could improve weed control efficacy. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Treatment of Dropped Nucleus with a 27-Gauge Twin Duty Cycle Vitreous Cutter.

    PubMed

    Watanabe, Akira; Tsuzuki, Akane; Arai, Kota; Gekka, Tamaki; Tsuneoka, Hiroshi

    2016-01-01

    We report herein a method for the treatment of dropped nucleus during cataract surgery with a 27-gauge twin duty cycle (TDC) vitreous cutter. When a TDC vitreous cutter is used, suction flow volume is maintained even when the cutter is driven at a high speed. This enables an Emery-Little grade 3 nucleus that had been difficult to treat with a conventional 27-gauge cutter to be successfully excised using only a vitreous cutter, with no intra- or postoperative complications. A dropped lens during cataract surgery of up to moderate hardness can be removed using a TDC cutter alone with a 27-gauge cutter system.

  18. Treatment of Dropped Nucleus with a 27-Gauge Twin Duty Cycle Vitreous Cutter

    PubMed Central

    Watanabe, Akira; Tsuzuki, Akane; Arai, Kota; Gekka, Tamaki; Tsuneoka, Hiroshi

    2016-01-01

    We report herein a method for the treatment of dropped nucleus during cataract surgery with a 27-gauge twin duty cycle (TDC) vitreous cutter. When a TDC vitreous cutter is used, suction flow volume is maintained even when the cutter is driven at a high speed. This enables an Emery-Little grade 3 nucleus that had been difficult to treat with a conventional 27-gauge cutter to be successfully excised using only a vitreous cutter, with no intra- or postoperative complications. A dropped lens during cataract surgery of up to moderate hardness can be removed using a TDC cutter alone with a 27-gauge cutter system. PMID:26889159

  19. Nucks1 synergizes with Trp53 to promote radiation lymphomagenesis in mice

    SciTech Connect

    Yue, Yangbo; Leung, Stanley G.; Liu, Yueyong; Huang, Yurong; Grundt, Kirsten; Østvold, Anne-Carine; Jen, Kuang-Yu; Schild, David; Mao, Jian-Hua; Wiese, Claudia

    2016-08-16

    NUCKS1 is a 27 kD vertebrate-specific protein, with a role in the DNA damage response. Here, we show that after 4 Gy total-body X-irradiation, Trp53+/- Nucks1+/- mice more rapidly developed tumors, particularly thymic lymphoma (TL), than Trp53+/- mice. TLs in both cohorts showed loss of heterozygosity (LOH) of the Trp53+ allele in essentially all cases. In contrast, LOH of the Nucks1+ allele was rare. Nucks1 expression correlated well with Nucks1 gene dosage in normal thymi, but was increased in the majority of TLs from Trp53+/- Nucks1+/- mice, suggesting that elevated Nucks1 message may be associated with progression towards malignancy in vivo. Trp53+/- Nucks1+/- mice frequently succumbed to CD4- CD8- TLs harboring translocations involving Igh but not Tcra/d, indicating TLs in Trp53+/- Nucks1+/- mice mostly originated prior to the double positive stage and at earlier lineage than TLs in Trp53+/- mice. Monoclonal rearrangements at Tcrb were more prevalent in TLs from Trp53+/- Nucks1+/- mice, as was infiltration of primary TL cells to distant organs (liver, kidney and spleen). We propose that, in the context of Trp53 deficiency, wild type levels of Nucks1 are required to suppress radiation-induced TL, likely through the role of the NUCKS1 protein in the DNA damage response.

  20. Toxoplasmosis complications and novel therapeutic synergism combination of diclazuril plus atovaquone

    PubMed Central

    Oz, Helieh S.

    2014-01-01

    Toxoplasmosis is a major cause of foodborne disease, congenital complication, and morbidity. There is an urgent need for safe and effective therapies to encounter congenital and persisting toxoplasmosis. The hypothesis was: combination diclazuril plus atovaquone to exert a novel therapeutic synergy to prevent toxoplasmosis syndromes. Methods: Pregnant dams were treated with diclazuril and atovaquone monotherapy or combination therapy and infected i.p with Toxoplasma tachyzoites. Results: Infected dams developed severe toxoplasmosis associated syndrome with increases in the abdominal adiposity surrounding uteri, gansterointestinal and other internal organs and excessive weight gain. Numerous organisms along with infiltration of inflammatory cells were detected scattered into adipose tissues. Combination therapy (p < 0.01) and to a lesser extent diclazuril (p < 0.05) protected dams from inflammatory fat and excess weight gains. This was consistent with pancreatitis development in infected dams (versus normal p < 0.05) with infiltration of inflammatory cells, degeneration and necrosis of pancreatic cells followed by the degeneration and loss of islets. Combination and monotherapy protected dams from these inflammatory and pathological aspects of pancreatitis. Infected dams exhibited severe colitis, and colonic tissues significantly shortened in length. Brush border epithelial cells were replaced with infiltration of lymphocytes, granulocytes, and microabscess formations into cryptic microstructures. Combination therapy synergistically preserved colonic structure and normalized pathological damages (p < 0.001) and to a lesser degree diclazuril monotherapy protected dams from colitis (p < 0.05) and gastrointestinal toxoplasmosis. Other complications included severe splenitis (p < 0.001) and hepatitis (p < 0.001) which were normalized with combination therapy. Conclusion: Combination diclazuril plus atovaquone was safe and with a novel therapeutic synergism protected

  1. Direct in situ observation of synergism between cellulolytic enzymes during the biodegradation of crystalline cellulose fibers.

    PubMed

    Wang, Jingpeng; Quirk, Amanda; Lipkowski, Jacek; Dutcher, John R; Clarke, Anthony J

    2013-12-03

    High-resolution atomic force microscopy (AFM) was used to image the real-time in situ degradation of crystalline by three types of T. reesei cellulolytic enzymes-TrCel6A, TrCel7A, and TrCel7B-and their mixtures. TrCel6A and TrCel7A are exo-acting cellobiohydrolases processing cellulose fibers from the nonreducing and reducing ends, respectively. TrCel7B is an endoglucanase that hydrolyzes amorphous cellulose within fibers. When acting alone on native cellulose fibers, each of the three enzymes is incapable of significant degradation. However, mixtures of two enzymes exhibited synergistic effects. The degradation effects of this synergism depended on the order in which the enzymes were added. Faster hydrolysis rates were observed when TrCel7A (exo) was added to fibers pretreated first with TrCel7B (endo) than when adding the enzymes in the opposite order. Endo-acting TrCel7B removed amorphous cellulose, softened and swelled the fibers, and exposed single microfibrils, facilitating the attack by the exo-acting enzymes. AFM images revealed that exo-acting enzymes processed the TrCel7B-pretreated fibers preferentially from one specific end (reducing or nonreducing). The most efficient (almost 100%) hydrolysis was observed with the mixture of the three enzymes. In this mixture, TrCel7B softened the fiber and TrCel6A and TrCel7A were directly observed to process it from the two opposing ends. This study provides high-resolution direct visualization of the nature of the synergistic relation between T. reesei exo- and endo-acting enzymes digesting native crystalline cellulose.

  2. 21st Century Extravehicular Activities: Synergizing Past and Present Training Methods for Future Spacewalking Success

    NASA Technical Reports Server (NTRS)

    Moore, Sandra K.; Gast, Matthew A.

    2009-01-01

    Neil Armstrong's understated words, "That's one small step for man, one giant leap for mankind." were spoken from Tranquility Base forty years ago. Even today, those words resonate in the ears of millions, including many who had yet to be born when man first landed on the surface of the moon. By their very nature, and in the the spirit of exploration, extravehicular activities (EVAs) have generated much excitement throughout the history of manned spaceflight. From Ed White's first space walk in June of 1965, to the first steps on the moon in 1969, to the expected completion of the International Space Station (ISS), the ability to exist, live and work in the vacuum of space has stood as a beacon of what is possible. It was NASA's first spacewalk that taught engineers on the ground the valuable lesson that successful spacewalking requires a unique set of learned skills. That lesson sparked extensive efforts to develop and define the training requirements necessary to ensure success. As focus shifted from orbital activities to lunar surface activities, the required skill-set and subsequently the training methods, changed. The requirements duly changed again when NASA left the moon for the last time in 1972 and have continued to evolve through the Skylab, Space Shuttle; and ISS eras. Yet because the visits to the moon were so long ago, NASA's expertise in the realm of extra-terrestrial EVAs has diminished. As manned spaceflight again shifts its focus beyond low earth orbit, EVA success will depend on the ability to synergize the knowledge gained over 40+ years of spacewalking to create a training method that allows a single crewmember to perform equally well, whether performing an EVA on the surface of the Moon, while in the vacuum of space, or heading for a rendezvous with Mars. This paper reviews NASA's past and present EVA training methods and extrapolates techniques from both to construct the basis for future EVA astronaut training.

  3. Comparative Toxicities and Synergism of Apple Orchard Pesticides to Apis mellifera (L.) and Osmia cornifrons (Radoszkowski)

    PubMed Central

    Biddinger, David J.; Robertson, Jacqueline L.; Mullin, Chris; Frazier, James; Ashcraft, Sara A.; Rajotte, Edwin G.; Joshi, Neelendra K.; Vaughn, Mace

    2013-01-01

    The topical toxicities of five commercial grade pesticides commonly sprayed in apple orchards were estimated on adult worker honey bees, Apis mellifera (L.) (Hymenoptera: Apidae) and Japanese orchard bees, Osmia cornifrons (Radoszkowski) (Hymenoptera: Megachilidae). The pesticides were acetamiprid (Assail 30SG), λ-cyhalothrin (Warrior II), dimethoate (Dimethoate 4EC), phosmet (Imidan 70W), and imidacloprid (Provado 1.6F). At least 5 doses of each chemical, diluted in distilled water, were applied to freshly-eclosed adult bees. Mortality was assessed after 48 hr. Dose-mortality regressions were analyzed by probit analysis to test the hypotheses of parallelism and equality by likelihood ratio tests. For A. mellifera, the decreasing order of toxicity at LD50 was imidacloprid, λ-cyhalothrin, dimethoate, phosmet, and acetamiprid. For O. cornifrons, the decreasing order of toxicity at LD50 was dimethoate, λ-cyhalothrin, imidacloprid, acetamiprid, and phosmet. Interaction of imidacloprid or acetamiprid with the fungicide fenbuconazole (Indar 2F) was also tested in a 1∶1 proportion for each species. Estimates of response parameters for each mixture component applied to each species were compared with dose-response data for each mixture in statistical tests of the hypothesis of independent joint action. For each mixture, the interaction of fenbuconazole (a material non-toxic to both species) was significant and positive along the entire line for the pesticide. Our results clearly show that responses of A. mellifera cannot be extrapolated to responses of O.cornifrons, and that synergism of neonicotinoid insecticides and fungicides occurs using formulated product in mixtures as they are commonly applied in apple orchards. PMID:24039783

  4. Synergic interactions between 2-deoxy-D-glucose and Candida saitoana enhances citrus green mould control.

    PubMed

    Arras, G; Pani, G; Molinu, M G; Dore, A; Venditti, T; Petretto, A; Marceddu, S; D'Hallewin, G

    2010-01-01

    The activity of 2-deoxy-D-gLucose (2-DG) alone or in combination with a biocontrol yeast (Candida saitoana, strain 8C) was evaluated in vitro and in vivo against citrus green mould (Penicillium digitatum Sacc.). The in vitro assays were performed on amended potato dextrose agar (PDA) containing 0, 1.5, 3.0, 6.0, 15.0, 30.0 or 60.0 mM of 2-DG. P. digitatum conidia were sown on the amended media and growth inhibition occurred starting from 6.0 mM. A nearly total inhibition of the growth and spore germination occurred with 60.0 mM of 2-DG. The antagonist was not affected by any of the 2-DG concentrations employed and the amended plates resulted well colonized within 2 d post-treatment. In vivo assays were carried out with 'Hamlin' oranges, inoculated with P. digitatum 24 h before treating with: the antagonist; the above reported concentrations of 2-DG, or by combining the two treatments. Seven days post-treatment the inhibition activity exerted by 3.0, 6.0, 15.0, 30.0 and 60.0 mM of 2-DG combined with the yeast was 15, 37, 42, 63 and 84%, respectively. While that exerted by the antagonist was 22% and that by the different concentrations of 2-DG were 7, 11, 27, 42 and 57%, respectively. Compared to single treatments, the co-application significantly and in a synergic mode improved the control of decay. Alterations to the hyphae were observed by SEM when the pathogen was cultured on amended media and into the wounds of inoculated oranges.

  5. Synergized antimicrobial activity of eugenol incorporated polyhydroxybutyrate films against food spoilage microorganisms in conjunction with pediocin.

    PubMed

    Narayanan, Aarthi; Neera; Mallesha; Ramana, Karna Venkata

    2013-07-01

    Biopolymers and biopreservatives produced by microorganisms play an essential role in food technology. Polyhydroxyalkanoates and bacteriocins produced by bacteria are promising components to safeguard the environment and for food preservation applications. Polyhydroxybutyrate (PHB)-based antimicrobial films were prepared incorporating eugenol, from 10 to 200 μg/g of PHB. The films were evaluated for antimicrobial activity against foodborne pathogens, spoilage bacteria, and fungi such as Staphylococcus aureus, Escherichia coli, Salmonella typhimurium, Bacillus cereus, Aspergillus flavus, Aspergillus niger, Penicillium sp., and Rhizopus sp. The synergistic antimicrobial activity of the films in the presence of crude pediocin was also investigated. The broth system containing pediocin (soluble form) as well as antimicrobial PHB film demonstrated an extended lag phase and a significant growth reduction at the end of 24 h against the bacteria. Crude pediocin alone could not elicit antifungal activity, while inhibition of growth and sporulation were observed in the presence of antimicrobial PHB film containing eugenol (80 μg/g) until 7 days in the case of molds, i.e., A. niger, A. flavus, Penicillium sp., and Rhizopus sp. in potato dextrose broth. In the present study, we identified that use of pediocin containing broth in conjunction with eugenol incorporated PHB film could function in synergized form, providing effective hurdle toward food contaminating microorganisms. Furthermore, tensile strength, percent crystallinity, melting point, percent elongation to break, glass transition temperature, and seal strength of the PHB film with and without eugenol incorporation were investigated. The migration of eugenol on exposure to different liquid food simulants was also analyzed using Fourier transform infrared spectroscopy. The study is expected to provide applications for pediocin in conjunction with eugenol containing PHB film to enhance the shelf life of foods in the

  6. Unsaturated cuticular hydrocarbons synergize responses to sex attractant pheromone in the yellow peach moth, Conogethes punctiferalis.

    PubMed

    Xiao, Wei; Matsuyama, Shigeru; Ando, Tetsu; Millar, Jocelyn G; Honda, Hiroshi

    2012-09-01

    Four trienyl hydrocarbons, (Z3, Z6, Z9)-tricosatriene (Z3, Z6, Z9-23:HC), (Z3, Z6, Z9)-pentacosatriene (Z3, Z6, Z9-25:HC), (Z3, Z6, Z9)-heptacosatriene (Z3, Z6, Z9-27:HC), and (Z3, Z6, Z9)-nonacosatriene (Z3, Z6, Z9-29:HC) were identified in a non-polar fraction of the body wax of male and female yellow peach moth, Conogethes punctiferalis. The relative amounts and ratios of these hydrocarbons differed between sexes. In females, the ratios in body wax and pheromone gland extracts were similar, with lesser amounts found in gland extracts. Synergistic effects of these hydrocarbons when added to the known aldehyde pheromone components were assessed in wind tunnel tests. A blend of (E)-10-hexadecenal (E10-16: Ald) and (Z)-10-hexadecenal (Z10-16: Ald) elicited upwind flight and orientation of males to the pheromone source, but arriving males did not remain close to source for very long. Among the hydrocarbons identified, only Z3, Z6, Z9-23:HC enhanced the activity of the aldehyde blend by increasing the time spent close to the source and the number of source contacts. Z3, Z6, Z9-23:HC and (Z9)-heptacosene (Z9-27:HC) also increased close-range responses to the aldehyde blend. The activity of the aldehyde blend plus these two hydrocarbons was similar to that of crude pheromone extract. Positive dose-response relationships between the aldehyde blend and two hydrocarbon mixtures were found. The lowest doses that elicited synergism were 10(-1) female equivalents (of body wax extracts) for the two hydrocarbons, and 10(-2) female equivalents for the total unsaturated hydrocarbon mixture.

  7. SYNERGISM FROM COMBINED IMMUNOLOGIC AND PHARMACOLOGIC INHIBITION OF HER2 IN VIVO

    PubMed Central

    Morse, Michael A.; Wei, Junping; Hartman, Zachary; Xia, Wenle; Ren, Xiu-Rong; Lei, Gangjun; Barry, William T.; Osada, Takuya; Hobeika, Amy C.; Peplinski, Sharon; Jiang, Haixiang; Devi, Gayathri R.; Chen, Wei; Spector, Neil; Amalfitano, Andrea; Lyerly, H. Kim; Clay, Timothy M.

    2009-01-01

    The monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib improve the clinical outcome of patients with HER2-overexpressing breast cancer. However, the majority of metastatic cancers will eventually progress suggesting the need for other therapies. Because HER2 overexpression persists, we hypothesized that the anti-HER2 immune response induced by cancer vaccines would be an effective strategy for treating trastuzumab and lapatinib-refractory tumors. Furthermore, we hypothesized that the antibody response could synergize with lapatinib to enhance tumor inhibition. We developed a recombinant adenoviral vector expressing a kinase-inactive HER2 (Ad-HER2-ki) to use as a cancer vaccine. Vaccine-induced polyclonal HER2-specific anti-serum was analyzed for receptor internalization and signaling effects alone and in combination with lapatinib. Ad-HER2-ki vaccine induced potent T cell and antibody responses in mice and the vaccine-induced polyclonal HER2-specific anti-serum mediated receptor internalization and degradation much more effectively than trastuzumab. Our in vitro studies demonstrated that HER2-vaccine induced antibodies effectively caused a decrease in HER2 expression, but when combined with lapatinib caused significant inhibition of HER2 signaling, decreased pERK and pAKT levels, and reduced breast tumor cell proliferation. In addition, a known mechanism of resistance to lapatinib, induction of survivin, was inhibited. The combination of Ad-HER2-ki plus lapatinib also showed superior anti-tumor efficacy in vivo. Based on these results, we feel clinical studies using this approach to target HER2-overexpressing breast cancer, including trastuzumab- and lapatinib-resistant tumors is warranted. PMID:19856307

  8. Selenium nanoparticles as a carrier of 5-fluorouracil to achieve anticancer synergism.

    PubMed

    Liu, Wen; Li, Xiaoling; Wong, Yum-Shing; Zheng, Wenjie; Zhang, Yibo; Cao, Wenqiang; Chen, Tianfeng

    2012-08-28

    A simple method for preparing 5-fluorouracil surface-functionalized selenium nanoparticles (5FU-SeNPs) with enhanced anticancer activity has been demonstrated in the present study. Spherical SeNPs were capped with 5FU through formation of Se-O and Se-N bonds and physical adsorption, leading to the stable structure of the conjugates. 5FU surface decoration significantly enhanced the cellular uptake of SeNPs through endocytosis. A panel of five human cancer cell lines was shown to be susceptible to 5FU-SeNPs, with IC(50) values ranging from 6.2 to 14.4 μM. Despite this potency, 5FU-SeNP possesses great selectivity between cancer and normal cells. Induction of apoptosis in A375 human melanoma cells by 5FU-SeNPs was evidenced by accumulation of sub-G1 cell population, DNA fragmentation, and nuclear condensation. The contribution of the intrinsic apoptotic pathway to the cell apoptosis was confirmed by activation of caspase-9 and depletion of mitochondrial membrane potential. Pretreatment of cells with a general caspase inhibitor z-VAD-fmk significantly prevented 5FU-SeNP-induced apoptosis, indicating that 5FU-SeNP induced caspase-dependent apoptosis in A375 cells. Furthermore, 5FU-SeNP-induced apoptosis was found dependent on ROS generation. Our results suggest that the strategy to use SeNPs as a carrier of 5FU could be a highly efficient way to achieve anticancer synergism. 5FU-SeNPs may be a candidate for further evaluation as a chemopreventive and chemotherapeutic agent for human cancers, especially melanoma.

  9. Synergism between exposure to mercury and use of iodine supplements on thyroid hormones in pregnant women

    SciTech Connect

    Llop, Sabrina; Lopez-Espinosa, Maria-Jose; Murcia, Mario; Alvarez-Pedrerol, Mar; Vioque, Jesús; Aguinagalde, Xabier; Julvez, Jordi; and others

    2015-04-15

    Objective: To evaluate the association between mercury exposure and thyroid-stimulating hormone (TSH), total triiodothyronine (TT3) and free thyroxine (FT4) levels during pregnancy as well as to explore if there is any synergic action between mercury and intake of iodine from different sources. Methods: The study population was 1407 pregnant women participating in the Spanish INMA birth cohort study. Total mercury concentrations were analyzed in cord blood. Thyroid hormones (THs) were measured in serum samples collected at 13.2±1.5 weeks of gestation. The association between mercury and TH levels was evaluated with multivariate linear regression models. Effect modification caused by iodine intake from supplements and diet was also evaluated. Results: The geometric means of TSH, TT3, FT4 and mercury were 1.1 μU/L, 2.4 nmol/L, 10.5 pmol/L and 7.7 μg/L, respectively. Mercury levels were marginally significantly associated with TT3 (β: −0.05; 95%CI: −0.10, 0.01), but were neither associated with TSH nor FT4. The inverse association between mercury and TT3 levels was stronger among the iodine supplement consumers (−0.08; 95%CI: −0.15, −0.02, interaction p-value=0.07). The association with FT4 followed the same pattern, albeit not significant. Conclusion: Prenatal mercury exposure was inversely associated with TT3 levels among women who took iodine supplements during pregnancy. These results could be of public health concern, although further research is needed. - Highlights: • We studied the relationship between mercury and thyroid hormones among pregnant. • Mercury was marginally significantly associated with TT3, but not with TSH or FT4. • This association was stronger among the iodine supplement. • These results could be of public health concern, but further research is needed.

  10. The synergism of natural compounds in the pursuit of safe and healthier food.

    PubMed

    Szczepaniak, S; Polanska, M; Van Assche, A; Moloney, R; Willems, K A

    2011-01-01

    Food producers apply modern processing techniques and use a variety of preservative additives to guarantee safe food and a longer shelflife. Regrettably many of these impact the sensory characteristics of the foodstuffs, such as colour, texture, and flavour, which can result in low consumer acceptance. Additionally, strategies used to reduce growth of spoilage and pathogenic bacteria are not selective enough and may inactivate also desired microbiota. Food is usually overdosed with antimicrobials that are supplemented 'just in case.' Consequently, food producers are searching for natural preservation methods that are not harmful to humans. Nature offers a wide spectrum of biologically active (phyto) chemicals that can be used as potential natural preservatives. Compounds with bacterial growth-limiting properties are detected in all parts of plants, including their leaves, flowers, fruits, roots, etc. These are mostly acids, alcohols, medium and long-chain organic acids, terpenic compounds, and their derivatives. This study focused on the effectiveness of plant extracts, i.e., synergism between terpenoids and medium chain fatty acids in cured cooked meat. Bacterial strains that were tested include typical members of the spoilage microflora in vacuum (Lactobacillus curvatus) and MA-packed meats (Brochothrix thermosphacta). These were isolated and identified in a separate study. L. curvatus was observed to be very resistant against either terpenoids or fatty acids when used separately, whereas its growth was strongly inhibited when both chemicals were combined. Growth of B. thermosphacta was significantly inhibited when antimicrobial compounds were solely applied, whereas a blend of terpenoids and fatty acids showed an almost bactericidal effect.

  11. Toxoplasmosis complications and novel therapeutic synergism combination of diclazuril plus atovaquone.

    PubMed

    Oz, Helieh S

    2014-01-01

    Toxoplasmosis is a major cause of foodborne disease, congenital complication, and morbidity. There is an urgent need for safe and effective therapies to encounter congenital and persisting toxoplasmosis. The hypothesis was: combination diclazuril plus atovaquone to exert a novel therapeutic synergy to prevent toxoplasmosis syndromes. Pregnant dams were treated with diclazuril and atovaquone monotherapy or combination therapy and infected i.p with Toxoplasma tachyzoites. Infected dams developed severe toxoplasmosis associated syndrome with increases in the abdominal adiposity surrounding uteri, gansterointestinal and other internal organs and excessive weight gain. Numerous organisms along with infiltration of inflammatory cells were detected scattered into adipose tissues. Combination therapy (p < 0.01) and to a lesser extent diclazuril (p < 0.05) protected dams from inflammatory fat and excess weight gains. This was consistent with pancreatitis development in infected dams (versus normal p < 0.05) with infiltration of inflammatory cells, degeneration and necrosis of pancreatic cells followed by the degeneration and loss of islets. Combination and monotherapy protected dams from these inflammatory and pathological aspects of pancreatitis. Infected dams exhibited severe colitis, and colonic tissues significantly shortened in length. Brush border epithelial cells were replaced with infiltration of lymphocytes, granulocytes, and microabscess formations into cryptic microstructures. Combination therapy synergistically preserved colonic structure and normalized pathological damages (p < 0.001) and to a lesser degree diclazuril monotherapy protected dams from colitis (p < 0.05) and gastrointestinal toxoplasmosis. Other complications included severe splenitis (p < 0.001) and hepatitis (p < 0.001) which were normalized with combination therapy. Combination diclazuril plus atovaquone was safe and with a novel therapeutic synergism protected dams and fetuses from

  12. Synergism and foaming properties in mixed nonionic/fatty acid soap surfactant systems.

    PubMed

    Theander, Katarina; Pugh, Robert J

    2003-11-01

    The synergism and foaming behavior of a mixed surfactant system consisting of a nonionic surfactant (polyethoxylated alkyl ether C(n)E(m)) and a fatty acid soap (sodium oleate) were studied. The micellar interaction parameter (the beta-parameter) was determined from the cmc following the approach of Rubingh's regular solution theory. For both the C(12)E(6)/sodium oleate and the C(14)E(6)/sodium oleate mixtures, the results indicate a fairly strong attractive interaction (negative beta-values), which were in agreement with previous data reported for other nonionic/anionic surfactant systems. The characteristics of the foam produced from the surfactants were evaluated using a glass column equipped with a series of electrodes measuring the conductance of the foam, which enabled the water content of the foam to be determined. From these measurements, since the total foam volume was almost the same for all concentrations and surfactants, we compared the amount of liquid in the foam produced under dynamic foaming and the ability of the foam to entrain the liquid after the airflow was switched-off (static foam stability). The amount of liquid in the foam 100 s after the air was switched-off followed the order NaOl > C(12)E(6) > C(14)E(6). Also, the mixtures had the same foam volumes as the pure surfactants at the same concentration. However, both mixtures had higher concentrations of liquid in the foam when the mole fraction of the nonionic surfactant in the mixed surfactant system was greater than about >0.3 in the solution.

  13. 21st Century extravehicular activities: Synergizing past and present training methods for future spacewalking success

    NASA Astrophysics Data System (ADS)

    Moore, Sandra K.; Gast, Matthew A.

    2010-10-01

    Neil Armstrong's understated words, "That's one small step for man, one giant leap for mankind" were spoken from Tranquility Base forty years ago. Even today, those words resonate in the ears of millions, including many who had yet to be born when man first landed on the surface of the moon. By their very nature, and in the true spirit of exploration, extravehicular activities (EVAs) have generated much excitement throughout the history of manned spaceflight. From Ed White's first spacewalk in the June of 1965, to the first steps on the moon in 1969, to the expected completion of the International Space Station (ISS), the ability to exist, live and work in the vacuum of space has stood as a beacon of what is possible. It was NASA's first spacewalk that taught engineers on the ground the valuable lesson that successful spacewalking requires a unique set of learned skills. That lesson sparked extensive efforts to develop and define the training requirements necessary to ensure success. As focus shifted from orbital activities to lunar surface activities, the required skill set and subsequently the training methods changed. The requirements duly changed again when NASA left the moon for the last time in 1972 and have continued to evolve through the SkyLab, Space Shuttle, and ISS eras. Yet because the visits to the moon were so long ago, NASA's expertise in the realm of extra-terrestrial EVAs has diminished. As manned spaceflight again shifts its focus beyond low earth orbit, EVA's success will depend on the ability to synergize the knowledge gained over 40+ years of spacewalking to create a training method that allows a single crewmember to perform equally well, whether performing an EVA on the surface of the Moon, while in the vacuum of space, or heading for a rendezvous with Mars. This paper reviews NASA's past and present EVA training methods and extrapolates techniques from both to construct the basis for future EVA astronaut training.

  14. WHO water quality standards Vs Synergic effect(s) of fluoride, heavy metals and hardness in drinking water on kidney tissues

    NASA Astrophysics Data System (ADS)

    Wasana, Hewa M. S.; Perera, Gamage D. R. K.; Gunawardena, Panduka De S.; Fernando, Palika S.; Bandara, Jayasundera

    2017-02-01

    Despite WHO standards, waterborne diseases among the human being are rising alarmingly. It is known that the prolong exposure to contaminated water has major impact on public health. The effect of chemical contaminations in drinking water on human being is found to be chronic rather than acute and hence can be defined “consumption of contaminated drinking water could be a silent killer”. As the WHO recommended water quality standards are only for individual element and synergic effects of trace metals and anions have not been considered, investigation of synergic effects of trace metals and anions and their effect on human being is of prime important research. By an animal trial, we investigated the synergic effect(s) of heavy metals, aluminium, arsenic, fluoride and hardness in drinking water on kidney tissues of mice. Our investigation strongly suggests existing of a synergic effect especially among Cd, F and hardness of water which could lead to severe kidney damage in mice, even at WHO maximum recommended levels. Hence, the synergic effect(s) of trace metals, fluoride and hardness present in drinking water should be investigated meticulously when stipulating the water quality at WHO maximum recommended levels.

  15. Farnesyltransferase inhibitor R115777 (Zarnestra, Tipifarnib) synergizes with paclitaxel to induce apoptosis and mitotic arrest and to inhibit tumor growth of multiple myeloma cells.

    PubMed

    Zhu, Kuichun; Gerbino, Elvira; Beaupre, Darrin M; Mackley, Paul A; Muro-Cacho, Carlos; Beam, Craig; Hamilton, Andrew D; Lichtenheld, Mathias G; Kerr, William G; Dalton, William; Alsina, Melissa; Sebti, Saïd M

    2005-06-15

    Despite major advances, multiple myeloma (MM) remains an incurable malignancy. Recently we have found that disease stabilization was achieved in 64% of patients with advanced MM treated with the farnesyltransferase inhibitor R115777 (Zarnestra) in a phase 2 clinical trial. In order to enhance R115777 antitumor activity in MM, we examined the combination of this novel agent with other anticancer drugs in MM cell lines. In this study, R115777 was found to synergize with paclitaxel and docetaxel, but not with other chemotherapy agents, including doxorubicin, 5-fluorouracil, cisplastin, melphalan, mitoxantrone, and dexamethasone. R115777 synergized with paclitaxel to inhibit MM cell proliferation and to induce apoptosis. Synergism in the induction of apoptosis was accompanied by increase in cytochrome c release and caspase-3 activation. Furthermore, flow cytometry analysis also showed that paclitaxel and R115777 synergized to induce G(2)/M cell-cycle arrest. Importantly, synergism was observed in taxane- and R115777-resistant MM cells. In the human severe combined immunodeficient (SCID-hu) bone model of myeloma growth, the ability of paclitaxel to inhibit tumor growth in vivo was enhanced by R115777. Combination of paclitaxel or docetaxel with R115777 in the treatment of MM cells from patients with multiple myeloma was more beneficial than treatment with single agents. Our results provide the basis for combination therapy clinical trials with paclitaxel or docetaxel with R115777 in MM patients.

  16. WHO water quality standards Vs Synergic effect(s) of fluoride, heavy metals and hardness in drinking water on kidney tissues.

    PubMed

    Wasana, Hewa M S; Perera, Gamage D R K; Gunawardena, Panduka De S; Fernando, Palika S; Bandara, Jayasundera

    2017-02-14

    Despite WHO standards, waterborne diseases among the human being are rising alarmingly. It is known that the prolong exposure to contaminated water has major impact on public health. The effect of chemical contaminations in drinking water on human being is found to be chronic rather than acute and hence can be defined "consumption of contaminated drinking water could be a silent killer". As the WHO recommended water quality standards are only for individual element and synergic effects of trace metals and anions have not been considered, investigation of synergic effects of trace metals and anions and their effect on human being is of prime important research. By an animal trial, we investigated the synergic effect(s) of heavy metals, aluminium, arsenic, fluoride and hardness in drinking water on kidney tissues of mice. Our investigation strongly suggests existing of a synergic effect especially among Cd, F and hardness of water which could lead to severe kidney damage in mice, even at WHO maximum recommended levels. Hence, the synergic effect(s) of trace metals, fluoride and hardness present in drinking water should be investigated meticulously when stipulating the water quality at WHO maximum recommended levels.

  17. WHO water quality standards Vs Synergic effect(s) of fluoride, heavy metals and hardness in drinking water on kidney tissues

    PubMed Central

    Wasana, Hewa M. S.; Perera, Gamage D. R. K.; Gunawardena, Panduka De S.; Fernando, Palika S.; Bandara, Jayasundera

    2017-01-01

    Despite WHO standards, waterborne diseases among the human being are rising alarmingly. It is known that the prolong exposure to contaminated water has major impact on public health. The effect of chemical contaminations in drinking water on human being is found to be chronic rather than acute and hence can be defined “consumption of contaminated drinking water could be a silent killer”. As the WHO recommended water quality standards are only for individual element and synergic effects of trace metals and anions have not been considered, investigation of synergic effects of trace metals and anions and their effect on human being is of prime important research. By an animal trial, we investigated the synergic effect(s) of heavy metals, aluminium, arsenic, fluoride and hardness in drinking water on kidney tissues of mice. Our investigation strongly suggests existing of a synergic effect especially among Cd, F and hardness of water which could lead to severe kidney damage in mice, even at WHO maximum recommended levels. Hence, the synergic effect(s) of trace metals, fluoride and hardness present in drinking water should be investigated meticulously when stipulating the water quality at WHO maximum recommended levels. PMID:28195172

  18. Active ingredients in cade oil that synergize attractiveness of alpha-ionol to male Bactrocera latifrons (Diptera: Tephritidae).

    PubMed

    McQuate, Grant T; Keum, Young Soo; Sylva, Charmaine D; Li, Qing X; Jang, Eric B

    2004-06-01

    Cade oil, a commercially available essential oil produced by destructive distillation of juniper, Juniperus oxycedrus L., twigs, is known to synergize the attractancy of alpha-ionol to male Bactrocera latifrons (Hendel). Through chemical fractionation and outdoor olfactometer-based bioassays, seven compounds in cade oil were identified that potentially could provide some level of synergism. Tests with sterile laboratory flies showed that four of the seven compounds (eugenol, isoeugenol, 2-methoxy-4-ethylphenol, and 2-methoxy-4-propylphenol), together with a closely related compound not found in cade oil, 2-methoxy-4-methylphenol, are capable of synergizing the attractiveness of alpha-ionol to male B. latifrons under field conditions. The similarity in structures of these five synergistic compounds shows that there is a response to a core 2-methoxyphenol structure, with fly response little affected by some variation in the composition of the side chain on the number 4 carbon. Because identified synergists were structurally similar, only one compound, eugenol, was selected for further field studies. In an 8-wk weathering test, using released sterile flies, traps baited with alpha-ionol + eugenol had catches comparable with catches at traps baited with alpha-ionol + cade oil, with catches generally increased with a higher eugenol loading. For both eugenol and cade oil, catches tended to be better when these synergists were deployed on separate wicks from the alpha-ionol. Eugenol and alpha-ionol, however, were unable to provide attraction comparable with that of cade oil and alpha-ionol in tests with wild fly populations.

  19. Short, Synthetic Cationic Peptides Have Antibacterial Activity against Mycobacterium smegmatis by Forming Pores in Membrane and Synergizing with Antibiotics

    PubMed Central

    Gupta, Kajal; Singh, Sameer; van Hoek, Monique L.

    2015-01-01

    Multicellular organisms are constantly exposed to a multitude of pathogenic microbes. Infection is inhibited in vivo by the innate and adaptive immune system. Mycobacterium species have emerged that are resistant to most antibiotics. We identified several naturally occurring cationic antimicrobial peptides that were active at low micromolar concentrations against Mycobacterium smegmatis. Human-derived cathelicidin LL-37 is well characterized and studied against M. smegmatis; we compared LL-37 with Chinese cobra-derived cathelicidin NA-CATH and mouse cathelicidin (mCRAMP). Two synthetic 11-residue peptides (ATRA-1A and ATRA-2) containing variations of a repeated motif within NA-CATH were tested for their activity against M. smegmatis along with a short synthetic peptide derivative from the human beta-defensin hBD3 (hBD3-Pep4). We hypothesized that these smaller synthetic peptides may demonstrate antimicrobial effectiveness with shorter length (and at less cost), making them strong potential candidates for development into broad-spectrum antimicrobial compounds or use in combination with antibiotics. These peptides have antimicrobial activity with EC50 ranging from 0.05 to 1.88 μg/mL against Mycobacterium smegmatis. The ATRA-1A short peptide was found to be the most effective antimicrobial peptide (AMP) (EC50 = 0.05 μg/mL). High bactericidal activity correlated with bacterial membrane depolarization and permeabilization activities. The efficacy of the peptides was further analyzed through Minimal Inhibitory Concentration (MIC) assays. The MICs were determined by the microdilution method. The peptide mCRAMP showed the best MIC activity at 15.6 μg/mL. Neither of the effective short synthetic peptides demonstrated synergy with the antibiotic rifampicin, although both demonstrated synergy with the cyclic peptide antibiotic polymyxin B. The peptides LL-37 and mCRAMP displayed synergism with rifampicin in MIC assays, whereas antibiotic polymyxin B displayed synergism

  20. Serum amyloid A1α induces paracrine IL-8/CXCL8 via TLR2 and directly synergizes with this chemokine via CXCR2 and formyl peptide receptor 2 to recruit neutrophils.

    PubMed

    De Buck, Mieke; Berghmans, Nele; Pörtner, Noëmie; Vanbrabant, Lotte; Cockx, Maaike; Struyf, Sofie; Opdenakker, Ghislain; Proost, Paul; Van Damme, Jo; Gouwy, Mieke

    2015-12-01

    Cell migration depends on the ability of leukocytes to sense an external gradient of chemotactic proteins produced during inflammation. These proteins include chemokines, complement factors, and some acute phase proteins, such as serum amyloid A. Serum amyloid A chemoattracts neutrophils, monocytes, and T lymphocytes via its G protein-coupled receptor formyl peptide receptor 2. We demonstrate that serum amyloid A1α more potently chemoattracts neutrophils in vivo than in vitro. In contrast to CD14(+) monocytes, no rapid (within 2 h) induction of interleukin-8/CXC chemokine ligand 8 or macrophage-inflammatory protein-1α/CC chemokine ligand 3 was observed in purified human neutrophils after stimulation of the cells with serum amyloid A1α or lipopolysaccharide. Moreover, interleukin-8/CXC chemokine ligand 8 induction in monocytes by serum amyloid A1α was mediated by toll-like receptor 2 and was inhibited by association of serum amyloid A1α with high density lipoprotein. This indicates that the potent chemotactic response of neutrophils toward intraperitoneally injected serum amyloid A1α is indirectly enhanced by rapid induction of chemokines in peritoneal cells, synergizing in a paracrine manner with serum amyloid A1α. We observed direct synergy between IL-8/CXC chemokine ligand 8 and serum amyloid A1α, but not lipopolysaccharide, in chemotaxis and shape change assays with neutrophils. Furthermore, the selective CXC chemokine receptor 2 and formyl peptide receptor 2 antagonists, SB225002 and WRW4, respectively, blocked the synergy between IL-8/CXC chemokine ligand 8 and serum amyloid A1α in neutrophil chemotaxis in vitro, indicating that for synergy their corresponding G protein-coupled receptors are required. Additionally, SB225002 significantly inhibited serum amyloid A1α-mediated peritoneal neutrophil influx. Taken together, endogenous (e.g., IL-1β) and exogenous (e.g., lipopolysaccharide) inflammatory mediators induce primary chemoattractants such as

  1. PPAR-α and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal.

    PubMed

    Lee, Hsiang-Ying; Gao, Xiaofei; Barrasa, M Inmaculada; Li, Hu; Elmes, Russell R; Peters, Luanne L; Lodish, Harvey F

    2015-06-25

    Many acute and chronic anaemias, including haemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anaemia, are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production. Treatment of these anaemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently, we showed that glucocorticoids specifically stimulate self-renewal of an early erythroid progenitor, burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells. Here we show that activation of the peroxisome proliferator-activated receptor α (PPAR-α) by the PPAR-α agonists GW7647 and fenofibrate synergizes with the glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34(+) peripheral blood progenitors, with a new and effective culture system being used for the human cells that generates normal enucleated reticulocytes. Although Ppara(-/-) mice show no haematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-α agonists facilitate recovery of wild-type but not Ppara(-/-) mice from PHZ-induced acute haemolytic anaemia. We also show that PPAR-α alleviates anaemia in a mouse model of chronic anaemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-α co-occupies many chromatin sites with GR; when activated by PPAR-α agonists, additional PPAR-α is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPAR-α agonists in stimulating self-renewal of early erythroid

  2. Ethanol and cocaine: environmental place conditioning, stereotypy and synergism in planarians

    PubMed Central

    Tallarida, Christopher S.; Bires, Kristopher; Avershal, Jacob; Tallarida, Ronald J.; Seo, Stephanie; Rawls, Scott M.

    2015-01-01

    More than 90% of individuals who use cocaine also report concurrent ethanol use, but only a few studies, all conducted with vertebrates, have investigated pharmacodynamic interactions between ethanol and cocaine. Planaria, a type of flatworm often considered to have the simplest ‘brain’, is an invertebrate species especially amenable to the quantification of drug-induced behavioral responses and identification of conserved responses. Here, we investigated stereotypical and environmental place conditioning (EPC) effects of ethanol administered alone and in combination with cocaine. Planarians displayed concentration-related increases in C-shape movements following exposure to ethanol (0.01 – 1%) (maximal effect: 9.9 ± 1.1 C-shapes/5 min at 0.5%) or cocaine (0.1 – 5 mM) (maximal effect: 42.8 ± 4.1 C-shapes/5 min at 5 mM). For combined administration, cocaine (0.1 – 5 mM) were tested with submaximal ethanol concentrations (0.01, 0,1%), the observed effect for the combination was enhanced compared to its predicted effect, indicating synergism for the interaction. The synergy with ethanol was specific for cocaine, as related experiments revealed that combinations of ethanol and nicotine did not result in synergy. For EPC experiments, ethanol (0.0001 – 1%) concentration-dependently increased EPC, with significant environmental shifts detected at 0.01 and 1%. Cocaine (0.001 – 1 μM) produced an inverted U-shaped concentration-effect curve, with a significant environmental shift observed at 0.01 μM. For combined exposure, variable cocaine concentrations (0.001 – 1 μM) were administered with a statistically ineffective concentration of ethanol (0.0001%). For each concentration of cocaine, the environmental shift was enhanced by ethanol, with significance detected at 1 μM. Cocaethylene, a metabolite of cocaine and ethanol, also produced C-shapes and EPC. Lidocaine (0.001 – 10 μM), an anesthetic and analog of cocaine, did not produce EPC or C

  3. Ethanol and cocaine: environmental place conditioning, stereotypy, and synergism in planarians.

    PubMed

    Tallarida, Christopher S; Bires, Kristopher; Avershal, Jacob; Tallarida, Ronald J; Seo, Stephanie; Rawls, Scott M

    2014-09-01

    More than 90% of individuals who use cocaine also report concurrent ethanol use, but only a few studies, all conducted with vertebrates, have investigated pharmacodynamic interactions between ethanol and cocaine. Planaria, a type of flatworm often considered to have the simplest 'brain,' is an invertebrate species especially amenable to the quantification of drug-induced behavioral responses and identification of conserved responses. Here, we investigated stereotypical and environmental place conditioning (EPC) effects of ethanol administered alone and in combination with cocaine. Planarians displayed concentration-related increases in C-shaped movements following exposure to ethanol (0.01-1%) (maximal effect: 9.9±1.1 C-shapes/5 min at 0.5%) or cocaine (0.1-5 mM) (maximal effect: 42.8±4.1 C-shapes/5 min at 5 mM). For combined administration, cocaine (0.1-5 mM) was tested with submaximal ethanol concentrations (0.01, 0.1%); the observed effect for the combination was enhanced compared to its predicted effect, indicating synergism for the interaction. The synergy with ethanol was specific for cocaine, as related experiments revealed that combinations of ethanol and nicotine did not result in synergy. For EPC experiments, ethanol (0.0001-1%) concentration-dependently increased EPC, with significant environmental shifts detected at 0.01 and 1%. Cocaine (0.001-1 μM) produced an inverted U-shaped concentration-effect curve, with a significant environmental shift observed at 0.01 μM. For combined exposure, variable cocaine concentrations (0.001-1 μM) were administered with a statistically ineffective concentration of ethanol (0.0001%). For each concentration of cocaine, the environmental shift was enhanced by ethanol, with significance detected at 1 μM. Cocaethylene, a metabolite of cocaine and ethanol, also produced C-shapes and EPC. Lidocaine (0.001-10 μM), an anesthetic and analog of cocaine, did not produce EPC or C-shaped movements. Evidence from planarians

  4. Synergism between carvacrol or thymol increases the antimicrobial efficacy of soy sauce with no sensory impact.

    PubMed

    Moon, Hyeree; Rhee, Min Suk

    2016-01-18

    Here, we examined the antimicrobial effects of soy sauce containing essential oils (EOs) against Escherichia coli O157:H7, Salmonella Typhimurium, and Listeria monocytogenes at 22°C and 4°C. To screen a variety of combined effects, soy sauce was mixed with six different EOs (carvacrol, thymol, eugenol, trans-cinnamaldehyde, β-resorcylic acid, and vanillin), each at a concentration of 1mM for 10 min. None of the oils showed bactericidal activity when used alone. Soy sauce combined with carvacrol and thymol induced the greatest antibacterial activity against all tested bacteria; therefore, these oils were further tested at 0.25, 0.5, and 1mM (0.0039%, 0.0078%, and 0.0157%) for 1, 5, and 10 min at 4°C and 22°C. In addition, sensory evaluation of soy sauce containing each EO at 0.25, 0.5, 1, and 2mM was performed using the nine point hedonic test. Carvacrol or thymol (1mM) eliminated all the test bacteria (initial population, 7.0-7.5logCFU/ml) in 1-5 min at 22°C and within 10 min at 4°C. L. monocytogenes was slightly more tolerant at 4°C, which may be attributable to the ability of the cell membrane to adapt to low temperatures. The sensory scores for soy sauce containing EOs were not significantly different from that of soy sauce without EOs (P>0.05). The stability of EO efficacy in soy sauce was also verified. These results suggest that carvacrol and thymol act synergistically with other factors present in soy sauce to increase antimicrobial activity against major foodborne pathogens at both 4°C and 22°C. The synergism may be attributable to the combination of factors (mainly high salt concentration and low pH imparted by organic acids) present in soy sauce and the membrane attacking properties of carvacrol and thymol. This method will facilitate the production of microbiologically safe soy sauce, soy sauce-based marinades, and various marinated foods. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Molecular mechanism of antioxidant synergism of tocotrienols and carotenoids in palm oil.

    PubMed

    Schroeder, Maria T; Becker, Eleonora Miquel; Skibsted, Leif H

    2006-05-03

    . Regeneration of carotenes by the phenols also explains the synergism in liposomes. In the laser flash photolysis experiments, gamma-T3 was also found to be faster in regenerating carotenes than alpha-T3 and alpha-T.

  6. Synergized resmethrin and corticosterone alter the chicken's response to west nile virus

    SciTech Connect

    Jankowski, Mark David; Franson, J Christian; Mostl, Erich; Porter, Warren P; Hofmeister, Erik K

    2009-01-01

    Debate concerning arbovirus control strategies remains contentious because concern regarding the relative risk of viral infection and environmental toxicant exposure is high but inadequately characterized. Taking this into account, mosquito control agencies employ aerial insecticides only after arbovirus surveillance data indicate high local mosquito-infection-rates. Successfully mitigating the risk of adult-mosquito-control insecticides ('adulticides') to non-target species such as humans, domestic animals, fish, beneficial insects and wildlife, while increasing their efficacy to reduce arbovirus outbreak intensity requires targeted scientific data from animal toxicity studies and environmental monitoring activities. Wild birds are an important reservoir host for WNv and are potentially exposed to insecticides used for mosquito control. However, no risk assessments have evaluated whether insecticides augment or extend the potential transmissibility of West Nile virus (WNv) in birds. In order to augment existing resmethrin risk assessments, we aimed to determine whether synergized resmethrin (SR) may cause chickens to develop an elevated or extended WN viremia and if subacute stress may affect its immunotoxicity. We distributed 40 chickens into four groups then exposed them prior to and during WNv infection with SR (50 {mu}g/l resmethrin + 150 {mu}g/l piperonyl butoxide) and/or 20 mg/I corticosterone (CORT) in their drinking-water. Corticosterone was given for 10 continuous days and SR was given for 3 alternate days starting the 3rd day of CORT exposure, then chickens were subcutaneously inoculated with WNv on the 5th day of CORT treatment. Compared to controls, CORT treatment extended and elevated viremia, enhanced WNv-specific antibody and increased the percentage of birds that shed oral virus, whereas SR treatment extended viremia, depressed WNv-specific IgG, and increased the percentage of CORT-treated birds that shed oral virus. Corticosterone and SR

  7. Advantage of a Broad Focal Zone in SWL: Synergism Between Squeezing and Shear

    NASA Astrophysics Data System (ADS)

    Sapozhnikov, Oleg A.; Bailey, Michael R.; Maxwell, Adam D.; MacConaghy, Brian; Cleveland, Robin O.; McAteer, James A.; Crum, Lawrence A.

    2007-04-01

    on the distal end but not with the point on the proximal end. In both cases, squeezing was the same, so if squeezing were dominant, both stones should have broken. But the pointed front edge prevents the shear wave. The squeezing wave and its product — the shear wave — are both needed and work synergistically in a way explained by the model. Conclusions: A broad focus enhances the synergism of squeezing and shear waves without altering cavitation's effects, and thus accelerates stone fracture in SWL.

  8. Rapid Fire Damage Assessment by Using a Synergic Approach with Radar and Optical Data

    NASA Astrophysics Data System (ADS)

    Cadau, Enrico G.; Burini, Alessandro; Putignano, Cosimo; Goryl, Philippe; Gascon, Ferran; Miranda, Nuno; Laur, Henri

    2010-12-01

    burnt trunks). By means of multi-temporal SAR observation, it is possible to assess fire damage (burnt surface and burnt biomass estimation) and to monitor the forest regrown. A synergic approach of automatic rapid mapping fire scars is presented by the use of high-resolution optical imagery (ALOS-AVNIR, SPOT-5) and C and L band radar images (single and dual-pol) applied on the major forest fires occurred in Sardinia during the 2009 summer season.

  9. PPARα and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal

    PubMed Central

    Lee, Hsiang-Ying; Gao, Xiaofei; Barrasa, M. Inmaculada; Li, Hu; Elmes, Russell R.; Peters, Luanne L.; Lodish, Harvey F.

    2015-01-01

    Summary Many acute and chronic anemias, including hemolysis, sepsis, and genetic bone marrow failure diseases such as Diamond-Blackfan Anemia (DBA), are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production 1,2,3–5,6,7,8,9. Treatment of these anemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently we showed that glucocorticoids specifically stimulate self-renewal of the early erythroid progenitor, the burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells 10,11. Here we demonstrate that activation of the peroxisome proliferator-activated receptor alpha (PPARα) by PPARα agonists, GW7647 and fenofibrate, synergizes with glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures both of mouse fetal liver BFU-Es and of mobilized human adult CD34+ peripheral blood progenitors, the latter employing a new and effective culture system that generates normal enucleated reticulocytes. While PPARα−/− mice show no hematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPARα agonists facilitate recovery of wild-type mice, but not PPARα−/− mice, from PHZ-induced acute hemolytic anemia. We also showed that PPARα alleviates anemia in a mouse model of chronic anemia. Finally, both in control and corticosteroid-treated BFU-E cells PPARα co-occupies many chromatin sites with GR; when activated by PPARα agonists, additional PPARα is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPARα agonists in stimulating self

  10. DSCOVR: A New Perspective for Earth Observations from Space. Synergism and Complementarity with Existing Platforms

    NASA Astrophysics Data System (ADS)

    Valero, F. P.

    2011-12-01

    The Sun-Earth Lagrange points L-1 and L-2 mark positions where the gravitational pull of the Earth and Sun precisely equals the centripetal force required to rotate with the Earth about the Sun with the same orbital period as the Earth. Therefore, a satellite maintained at one of these Lagrange points would keep the same relative position to the Sun and the Earth and be able to observe most points on the planet as the Earth rotates during the day. L-1 and L-2 are of particular interest because a satellite at either location can easily be maintained near the Sun-Earth line and views the entire daytime hemisphere from L-1 and the entire nighttime hemisphere from L-2. Since L-1 and L-2 are in the ecliptic plane, synoptic, high temporal-resolution observations would be obtained as every point on the planet, including both polar regions, transits from sunrise to sunset (L-1) or from sunset to sunrise (L-2). In summary, a pair of deep-space observatories, one at L-1 (daytime) and one at L-2 (nighttime), could acquire minute by minute climate quality data for essentially every point on Earth, all observations simultaneously for the whole planet. Such unique attributes are incorporated in the Deep Space Climate Observatory (DSCOVR) that will systematically observe climate drivers (radiation, aerosols, ozone, clouds, oxygen A-band) from L-1 in ways not possible but synergistically complementary with platforms in Low Earth Orbit (LEO) or Geostationary Earth Orbit (GEO). The combination of Solar Lagrange Points (located in the ecliptic plane) GEO (located in the equatorial plane) and LEO platforms would certainly provide a powerful observational tool as well as enriched data sets for Earth sciences. Such synergism is greatly enhanced when one considers the potential of utilizing LEO, GEO, and Lagrange point satellites as components of an integrated observational system. For example, satellites at L-1 and L-2 will view the Earth plus the Moon while simultaneously having in

  11. Apple volatiles synergize the response of codling moth to pear ester.

    PubMed

    El-Sayed, Ashraf M; Cole, Lyn; Revell, John; Manning, Lee-Anne; Twidle, Andrew; Knight, Alan L; Bus, Vincent G M; Suckling, David M

    2013-05-01

    Codling moth, Cydia pomonella L. (Lepidoptera: Tortricidae), is a major cosmopolitan pest of apple and other pome fruits. Ethyl (E,Z)-2,4-decadienoate (pear ester) has been identified as a host-derived kairomone for female and male codling moths. However, pear ester has not performed similarly in different fruit production areas in terms of the relative magnitude of moth catch, especially the proportion of females caught. Our work was undertaken to identify host volatiles from apples, and to investigate whether these volatiles can be used to enhance the efficacy of host kairomone pear ester for monitoring female and male codling moths. Volatiles from immature apple trees were collected in the field using dynamic headspace sampling during the active period of codling moth flight. Using gas chromatography-electroantennogram detector (GC/EAD) analysis, six compounds elicited responses from antennae of females. These compounds were identified by GC/mass spectrometry (MS) and comparisons to authentic standards as nonanal, (E)-4,8-dimethyl-1,3,7-nonatriene, methyl salicylate, decanal, (Z,E)-α-farnesene, and (E,E)-α-farnesene. When the EAD-active compounds were tested individually in the field, no codling moths were caught except for a single male with decanal. However, addition of (E)-4,8-dimethyl-1,3,7-nonatriene, methyl salicylate, decanal, or (E,E)-α-farnesene to pear ester in a binary mixture enhanced the efficacy of pear ester for attracting female codling moths compared to pear ester alone. Addition of the 6-component blend to the pear ester resulted in a significant increase in the number of males attracted, and enhanced the females captured compared to pear ester alone; the number of males and females caught was similar to that with the pear ester plus acetic acid combination lure. Our results demonstrate that it is possible to synergize the response of codling moth to host kairomone by using other host volatiles. The new apple-pear ester host kairomone blend

  12. Synergic Effect of Active Sites in Zinc-Modified ZSM-5 Zeolites as Revealed by High-Field Solid-State NMR Spectroscopy.

    PubMed

    Qi, Guodong; Wang, Qiang; Xu, Jun; Trébosc, Julien; Lafon, Olivier; Wang, Chao; Amoureux, Jean-Paul; Deng, Feng

    2016-12-19

    Understanding the nature of active sites in metal-supported catalysts is of great importance towards establishing their structure-property relationships. The outstanding catalytic performance of metal-supported catalysts is frequently ascribed to the synergic effect of different active sites, which is however not well spectroscopically characterized. Herein, we report the direct detection of surface Zn species and (1) H-(67) Zn internuclear interaction between Zn(2+) ions and Brønsted acid sites on Zn-modified ZSM-5 zeolites by high-field solid-state NMR spectroscopy. The observed promotion of C-H bond activation of methane is rationalized by the enhanced Brønsted acidity generated by synergic effects arising from the spatial proximity/interaction between Zn(2+) ions and Brønsted acidic protons. The concentration of synergic active sites is determined by (1) H-(67) Zn double-resonance solid-state NMR spectroscopy.

  13. Synergism of MSC-secreted HGF and VEGF in stabilising endothelial barrier function upon lipopolysaccharide stimulation via the Rac1 pathway.

    PubMed

    Yang, Yi; Chen, Qi-Hong; Liu, Ai-Ran; Xu, Xiu-Ping; Han, Ji-Bin; Qiu, Hai-Bo

    2015-12-16

    Mesenchymal stem cells (MSCs) stabilise endothelial barrier function in acute lung injury via paracrine hepatocyte growth factor (HGF). Vascular endothelial growth factor (VEGF), which is secreted by MSCs, is another key regulator of endothelial permeability; however, its role in adjusting permeability remains controversial. In addition, whether an interaction occurs between HGF and VEGF, which are secreted by MSCs, is not completely understood. We introduced a co-cultured model of human pulmonary microvascular endothelial cells (HPMECs) and MSC conditioned medium (CM) collected from MSCs after 24 h of hypoxic culture. The presence of VEGF and HGF in the MSC-CM was neutralised by anti-VEGF and anti-HGF antibodies, respectively. To determine the roles and mechanisms of MSC-secreted HGF and VEGF, we employed recombinant humanised HGF and recombinant humanised VEGF to co-culture with HPMECs. Additionally, we employed the RhoA inhibitor C3 transferase and the Rac1 inhibitor NSC23766 to inhibit the activities of RhoA and Rac1 in HPMECs treated with MSC-CM or VEGF/HGF with the same dosage as in the MSC-CM. Then, endothelial paracellular and transcellular permeability was detected. VE-cadherin, occludin and caveolin-1 protein expression in HPMECs was measured by western blot. Adherens junction proteins, including F-actin and VE-cadherin, were detected by immunofluorescence. MSC-CM treatment significantly decreased lipopolysaccharide-induced endothelial paracellular and transcellular permeability, which was significantly inhibited by pretreatment with HGF antibody or with both VEGF and HGF antibodies. Furthermore, MSC-CM treatment increased the expression of the endothelial intercellular adherence junction proteins VE-cadherin and occludin and decreased the expression of caveolin-1 protein. MSC-CM treatment also decreased endothelial apoptosis and induced endothelial cell proliferation; however, the effects of MSC-CM treatment were inhibited by pretreatment with HGF

  14. Synergism between insecticides permethrin and propoxur occurs through activation of presynaptic muscarinic negative feedback of acetylcholine release in the insect central nervous system.

    PubMed

    Corbel, Vincent; Stankiewicz, Maria; Bonnet, Julien; Grolleau, Françoise; Hougard, Jean Marc; Lapied, Bruno

    2006-07-01

    Although synergism between pesticides has been widely documented, the physiological mechanisms by which an insecticide synergizes another remains unclear. Toxicological and electrophysiological studies were carried out on two susceptible pest species (the mosquito Culex quinquefasciatus and the cockroach Periplaneta americana) to understand better the physiological process involved in pyrethroid and carbamate interactions. Larval bioassays were conducted with the susceptible reference strain SLAB of C. quinquefasciatus to assess the implication of multi-function oxidases and non-specific esterases in insecticide detoxification and synergism. Results showed that the general theory of synergism (competition between pesticides for a common detoxification enzyme) was unlikely to occur in the SLAB strain since the level of synergy recorded between permethrin and propoxur was unchanged in the presence of piperonyl butoxide and tribufos, two inhibitors of oxidases and esterases, respectively (synergism ratios were similar with and without synergists). We also showed that addition of a sub-lethal concentration of nicotine significantly increased the toxicity of permethrin and propoxur at the lower range of the dose-mortality regression lines, suggesting the manifestation of important physiological disruptions at synaptic level. The effects of both permethrin and propoxur were studied on the cercal-afferent giant-interneuron synapses in the terminal abdominal ganglion of the cockroach P. americana using the single-fibre oil-gap method. We demonstrated that permethrin and propoxur increased drastically the ACh concentration within the synaptic cleft, which thereby stimulated a negative feedback of ACh release. Atropine, a muscarinic receptor antagonist, reversed the effect of permethrin and propoxur mixtures. This demonstrates the implication of the presynaptic muscarinic receptors in the negative feedback regulation process and in synergism. Based on these findings, we

  15. Oridonin synergizes with Nutlin-3 in osteosarcoma cells by modulating the levels of multiple Bcl-2 family proteins.

    PubMed

    Wang, Xiao-Hui; Zhang, Shu-Feng; Bao, Jun-Tao; Liu, Fu-Yun

    2017-06-01

    The small-molecule inhibitors of p53-murine double minute 2 interaction, such as Nutlin-3, are effective against cancers bearing wild-type p53. However, murine double minute 2 inhibitors often are unable to completely eliminate solid tumor cells. To address this issue, we investigated the anticancer effects of Nutlin-3 in combination with Oridonin in osteosarcoma cells. We found that Oridonin at sub-toxic concentrations synergistically enhanced Nutlin-3-mediated cell viability inhibition in wild-type p53 U2OS and SJSA-1, but not in p53-mutant MNNG/HOS and in null-p53 Saos-2 osteosarcoma cell lines. Importantly, in the presence of Oridonin, Nutlin-3 could completely abolish cell viability in the wild-type p53 osteosarcoma cell lines. Western blotting analysis showed that Oridonin treatment rapidly and distinctly increased the levels of all three forms of Bim and also markedly reduced the levels of Bcl-2 and Bcl-xl in osteosarcoma cells. Western blotting analysis further showed that Oridonin considerably enhanced Nutlin-3-triggered activation of caspases-9 and -3 and poly(ADP-ribose) polymerase cleavage. Flow cytometry assay showed that Oridonin significantly enhanced Nutlin-3-mediated apoptosis in wild-type p53 osteosarcoma cells. Overall, our results suggest that the combined treatment of Nutlin-3 plus Oridonin may offer a novel therapeutic strategy for osteosarcoma.

  16. NFAT5/STAT3 interaction mediates synergism of high salt with IL-17 towards induction of VEGF-A expression in breast cancer cells.

    PubMed

    Amara, Suneetha; Alotaibi, Dalal; Tiriveedhi, Venkataswarup

    2016-08-01

    Chronic inflammation has been considered an important player in cancer proliferation and progression. High salt (sodium chloride) levels have been considered a potent inducer of chronic inflammation. In the present study, the synergistic role of high salt with interleukin (IL)-17 towards induction of the inflammatory and angiogenic stress factor vascular endothelial growth factor (VEGF)-A was investigated. Stimulation of MCF-7 breast cancer cells with high salt (0.2 M NaCl) and sub-minimal IL-17 (1 ng/ml) enhanced the expression of VEGF-A (2.9 and 2.6-fold, respectively, P<0.05) compared with untreated cells. Furthermore, co-treatment with both high salt and sub-minimal IL-17 led to a 5.9-fold increase in VEGF-A expression (P<0.01), thus suggesting a synergistic role of these factors. VEGF-A promoter analysis and specific small interfering RNA knock-down of transcription factors revealed that high salt induced VEGF-A expression through nuclear factor of activated T-cells (NFAT)5, while IL-17 induced VEGF-A expression via signal transducer and activator of transcription (STAT)3 signaling mechanisms. Treatment of normal human aortic endothelial cells with the supernatant of activated MCF-7 cells enhanced cell migration and induced expression of migration-specific factors, including vascular cell adhesion protein, β1 integrin and cluster of differentiation 31. These data suggest that high salt levels synergize with pro-inflammatory IL-17 to potentially induce cancer progression and metastasis through VEGF-A expression. Therefore, low-salt diet, anti-NFAT5 and anti-STAT3 therapies may provide novel avenues for enhanced efficiency of the current cancer therapy.

  17. Critical Role of the Neonatal Fc Receptor (FcRn) in the Pathogenic Action of Antimitochondrial Autoantibodies Synergizing with Anti-desmoglein Autoantibodies in Pemphigus Vulgaris.

    PubMed

    Chen, Yumay; Chernyavsky, Alex; Webber, Robert J; Grando, Sergei A; Wang, Ping H

    2015-09-25

    Pemphigus vulgaris (PV) is a life-long, potentially fatal IgG autoantibody-mediated blistering disease targeting mucocutaneous keratinocytes (KCs). PV patients develop pathogenic anti-desmoglein (Dsg) 3 ± 1 and antimitochondrial antibodies (AMA), but it remained unknown whether and how AMA enter KCs and why other cell types are not affected in PV. Therefore, we sought to elucidate mechanisms of cell entry, trafficking, and pathogenic action of AMA in PV. We found that PVIgGs associated with neonatal Fc receptor (FcRn) on the cell membrane, and the PVIgG-FcRn complexes entered KCs and reached mitochondria where they dissociated. The liberated AMA altered mitochondrial membrane potential, respiration, and ATP production and induced cytochrome c release, although the lack or inactivation of FcRn abolished the ability of PVIgG to reach and damage mitochondria and to cause detachment of KCs. The assays of mitochondrial functions and keratinocyte adhesion demonstrated that although the pathobiological effects of AMA on KCs are reversible, they become irreversible, leading to epidermal blistering (acantholysis), when AMA synergize with anti-Dsg antibodies. Thus, it appears that AMA enter a keratinocyte in a complex with FcRn, become liberated from the endosome in the cytosol, and are trafficked to the mitochondria, wherein they trigger pro-apoptotic events leading to shrinkage of basal KCs uniquely expressing FcRn in epidermis. During recovery, KCs extend their cytoplasmic aprons toward neighboring cells, but anti-Dsg antibodies prevent assembly of nascent desmosomes due to steric hindrance, thus rendering acantholysis irreversible. In conclusion, FcRn is a common acceptor protein for internalization of AMA and, perhaps, for PV autoantibodies to other intracellular antigens, and PV is a novel disease paradigm for investigating and elucidating the role of FcRn in this autoimmune disease and possibly other autoimmune diseases.

  18. NFAT5/STAT3 interaction mediates synergism of high salt with IL-17 towards induction of VEGF-A expression in breast cancer cells

    PubMed Central

    Amara, Suneetha; Alotaibi, Dalal; Tiriveedhi, Venkataswarup

    2016-01-01

    Chronic inflammation has been considered an important player in cancer proliferation and progression. High salt (sodium chloride) levels have been considered a potent inducer of chronic inflammation. In the present study, the synergistic role of high salt with interleukin (IL)-17 towards induction of the inflammatory and angiogenic stress factor vascular endothelial growth factor (VEGF)-A was investigated. Stimulation of MCF-7 breast cancer cells with high salt (0.2 M NaCl) and sub-minimal IL-17 (1 ng/ml) enhanced the expression of VEGF-A (2.9 and 2.6-fold, respectively, P<0.05) compared with untreated cells. Furthermore, co-treatment with both high salt and sub-minimal IL-17 led to a 5.9-fold increase in VEGF-A expression (P<0.01), thus suggesting a synergistic role of these factors. VEGF-A promoter analysis and specific small interfering RNA knock-down of transcription factors revealed that high salt induced VEGF-A expression through nuclear factor of activated T-cells (NFAT)5, while IL-17 induced VEGF-A expression via signal transducer and activator of transcription (STAT)3 signaling mechanisms. Treatment of normal human aortic endothelial cells with the supernatant of activated MCF-7 cells enhanced cell migration and induced expression of migration-specific factors, including vascular cell adhesion protein, β1 integrin and cluster of differentiation 31. These data suggest that high salt levels synergize with pro-inflammatory IL-17 to potentially induce cancer progression and metastasis through VEGF-A expression. Therefore, low-salt diet, anti-NFAT5 and anti-STAT3 therapies may provide novel avenues for enhanced efficiency of the current cancer therapy. PMID:27446373

  19. Staurosporine, but not Ro 31-8220, induces interleukin 2 production and synergizes with interleukin 1alpha in EL4 thymoma cells.

    PubMed Central

    Mahon, T M; Matthews, J S; O'Neill, L A

    1997-01-01

    Protein kinase C (PKC) has been implicated in interleukin 1 (IL1) signal transduction in a number of cellular systems, either as a key event in IL1 action or as a negative regulator. Here we have examined the effects of two PKC inhibitors, staurosporine and the more selective agent Ro 31-8220, on IL1 responses in the murine thymoma line EL4.NOB-1. A 1 h pulse of staurosporine was found to strongly potentiate the induction of IL2 by IL1alpha in these cells. In contrast, neither a pulse nor prolonged incubation with Ro 31-8220 affected the response to IL1alpha. Both agents blocked the response to PMA, however. A 1 h pulse of staurosporine was also found to induce IL2 production on its own, activate the transcription factor nuclear factor kappaB (NFkappaB) and increase the expression of a NFkappaB-linked reporter gene. It synergized with IL1alpha in all of these responses. Ro 31-8220 was again without effect, although both staurosporine and Ro 31-8220 blocked the activation of NFkappaB by PMA. Finally, staurosporine caused the translocation of PKC-alpha and -epsilon, and to a lesser extent PKC-beta, but not PKC-θ or -zeta, from the cytosol to the membrane, although a similar effect was observed with Ro 31-8220. The results suggest that PKC is not involved in IL1alpha signalling in EL4 cells. Furthermore, the potentiating effect of staurosporine on IL1alpha action does not involve PKC inhibition, and is likely to be at the level of NFkappaB activation. PMID:9224627

  20. Critical Role of the Neonatal Fc Receptor (FcRn) in the Pathogenic Action of Antimitochondrial Autoantibodies Synergizing with Anti-desmoglein Autoantibodies in Pemphigus Vulgaris*

    PubMed Central

    Chen, Yumay; Chernyavsky, Alex; Webber, Robert J.; Grando, Sergei A.; Wang, Ping H.

    2015-01-01

    Pemphigus vulgaris (PV) is a life-long, potentially fatal IgG autoantibody-mediated blistering disease targeting mucocutaneous keratinocytes (KCs). PV patients develop pathogenic anti-desmoglein (Dsg) 3 ± 1 and antimitochondrial antibodies (AMA), but it remained unknown whether and how AMA enter KCs and why other cell types are not affected in PV. Therefore, we sought to elucidate mechanisms of cell entry, trafficking, and pathogenic action of AMA in PV. We found that PVIgGs associated with neonatal Fc receptor (FcRn) on the cell membrane, and the PVIgG-FcRn complexes entered KCs and reached mitochondria where they dissociated. The liberated AMA altered mitochondrial membrane potential, respiration, and ATP production and induced cytochrome c release, although the lack or inactivation of FcRn abolished the ability of PVIgG to reach and damage mitochondria and to cause detachment of KCs. The assays of mitochondrial functions and keratinocyte adhesion demonstrated that although the pathobiological effects of AMA on KCs are reversible, they become irreversible, leading to epidermal blistering (acantholysis), when AMA synergize with anti-Dsg antibodies. Thus, it appears that AMA enter a keratinocyte in a complex with FcRn, become liberated from the endosome in the cytosol, and are trafficked to the mitochondria, wherein they trigger pro-apoptotic events leading to shrinkage of basal KCs uniquely expressing FcRn in epidermis. During recovery, KCs extend their cytoplasmic aprons toward neighboring cells, but anti-Dsg antibodies prevent assembly of nascent desmosomes due to steric hindrance, thus rendering acantholysis irreversible. In conclusion, FcRn is a common acceptor protein for internalization of AMA and, perhaps, for PV autoantibodies to other intracellular antigens, and PV is a novel disease paradigm for investigating and elucidating the role of FcRn in this autoimmune disease and possibly other autoimmune diseases. PMID:26260795

  1. Rosiglitazone synergizes the neuroprotective effects of valproic acid against quinolinic acid-induced neurotoxicity in rats: targeting PPARγ and HDAC pathways.

    PubMed

    Mishra, Jitendriya; Chaudhary, Tanya; Kumar, Anil

    2014-08-01

    Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder which affects medium spiny GABAergic neurons mainly in the striatum. Oxidative damage, neuro-inflammation, apoptosis, protein aggregation, and signaling of neurotrophic factors are some of the common cellular pathways involved in HD. Quinolinic acid (QA) causes excitotoxicity by stimulating N-methyl-D-aspartate receptors via calcium overload leading to neurodegeneration. Neuroprotective potential of peroxisome proliferator activated receptor-γ (PPARγ) agonists and histone deacetylase (HDAC) inhibitors have been well documented in experimental models of neurodegenerative disorders; however, their exact mechanisms are not clear. Therefore, present study has been designed to explore possible neuroprotective mechanism of valproic acid (VPA) and its interaction with rosiglitazone against QA induced HD-like symptoms in rats. Single bilateral intrastriatal QA (200 nmol/2 μl saline) administration significantly caused motor incoordination, memory impairment, oxidative damage, mitochondrial dysfunction (complex I, II, II and IV), cellular alterations [tumor necrosis factor-alpha (TNF-α), caspase-3, brain derived neurotrophic factor, acetylcholinesterase], and striatal neurodegeneration as compared to sham group. Treatment with rosiglitazone (5, 10 mg/kg) and VPA (100, 200 mg/kg) for 21 days significantly attenuated these behavioral, biochemical, and cellular alterations as compared to control (QA 200 nmol) group. However, VPA (100 mg/kg) treatment in combination with rosiglitazone (5 mg/kg) for 21 days synergized their neuroprotective effect, which was significant as compared to their effects per se in QA-treated animals. The present study provides an evidence of possible interplay of PPARγ agonists and HDAC inhibitors as a novel therapeutic strategy in the management of HD.

  2. Protection by sigma-1 receptor agonists is synergic with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments.

    PubMed

    Maurice, Tangui

    2016-01-01

    Drugs activating the sigma-1 (σ1) chaperone protein are anti-amnesic and neuroprotective in neurodegenerative pathologies like Alzheimer's disease (AD). Since these so-called σ1 receptor (σ1R) agonists modulate cholinergic and glutamatergic systems in a variety of physiological responses, we addressed their putative additive/synergistic action in combination with cholinergic or glutamatergic drugs. The selective σ1 agonist PRE-084, or the non-selective σ1 drug ANAVEX2-73 was combined with the acetylcholinesterase inhibitor donepezil or the NMDA receptor antagonist memantine in the nontransgenic mouse model of AD-like memory impairments induced by intracerebroventricular injection of oligomeric Aβ25-35 peptide. Two behavioral tests, spontaneous alternation and passive avoidance response, were used in parallel and both protective and symptomatic effects were examined. After determination of the minimally active doses for each compound, the combinations were tested and the combination index (CI) calculated. Combinations between the σ1 agonists and donepezil showed a synergic protective effect, with CI<1, whereas the combinations with memantine showed an antagonist effect, with CI>1. Symptomatic effects appeared only additive for all combinations, with CI=1. A pharmacological analysis of the PRE-084+donepezil combination revealed that the synergy could be due to an inter-related mechanism involving α7 nicotinic ACh receptors and σ1R. These results demonstrated that σ1 drugs do not only offer a protective potential alone but also in combination with other therapeutic agents. The nature of neuromodulatory molecular chaperone of the σ1R could eventually lead to synergistic combinations.

  3. The novel Akt inhibitor API-1 induces c-FLIP degradation and synergizes with TRAIL to augment apoptosis independent of Akt inhibition.

    PubMed

    Li, Bo; Ren, Hui; Yue, Ping; Chen, Mingwei; Khuri, Fadlo R; Sun, Shi-Yong

    2012-04-01

    API-1 (pyrido[2,3-d]pyrimidines) is a novel small-molecule inhibitor of Akt, which acts by binding to Akt and preventing its membrane translocation and has promising preclinical antitumor activity. In this study, we reveal a novel function of API-1 in regulation of cellular FLICE-inhibitory protein (c-FLIP) levels and TRAIL-induced apoptosis, independent of Akt inhibition. API-1 effectively induced apoptosis in tested cancer cell lines including activation of caspase-8 and caspase-9. It reduced the levels of c-FLIP without increasing the expression of death receptor 4 (DR4) or DR5. Accordingly, it synergized with TRAIL to induce apoptosis. Enforced expression of ectopic c-FLIP did not attenuate API-1-induced apoptosis but inhibited its ability to enhance TRAIL-induced apoptosis. These data indicate that downregulation of c-FLIP mediates enhancement of TRAIL-induced apoptosis by API-1 but is not sufficient for API-1-induced apoptosis. API-1-induced reduction of c-FLIP could be blocked by the proteasome inhibitor MG132. Moreover, API-1 increased c-FLIP ubiquitination and decreased c-FLIP stability. These data together suggest that API-1 downregulates c-FLIP by facilitating its ubiquitination and proteasome-mediated degradation. Because other Akt inhibitors including API-2 and MK2206 had minimal effects on reducing c-FLIP and enhancement of TRAIL-induced apoptosis, it is likely that API-1 reduces c-FLIP and enhances TRAIL-induced apoptosis independent of its Akt-inhibitory activity. 2012 AACR

  4. All-trans retinoic acid synergizes with FLT3 inhibition to eliminate FLT3/ITD+ leukemia stem cells in vitro and in vivo

    PubMed Central

    Ma, Hayley S.; Greenblatt, Sarah M.; Shirley, Courtney M.; Duffield, Amy S.; Bruner, J. Kyle; Li, Li; Nguyen, Bao; Jung, Eric; Aplan, Peter D.; Ghiaur, Gabriel; Jones, Richard J.

    2016-01-01

    FMS-like tyrosine kinase 3 (FLT3)-mutant acute myeloid leukemia (AML) portends a poor prognosis, and ineffective targeting of the leukemic stem cell (LSC) population remains one of several obstacles in treating this disease. All-trans retinoic acid (ATRA) has been used in several clinical trials for the treatment of nonpromyelocytic AML with limited clinical activity observed. FLT3 tyrosine kinase inhibitors (TKIs) used as monotherapy also achieve limited clinical responses and are thus far unable to affect cure rates in AML patients. We explored the efficacy of combining ATRA and FLT3 TKIs to eliminate FLT3/internal tandem duplication (ITD)+ LSCs. Our studies reveal highly synergistic drug activity, preferentially inducing apoptosis in FLT3/ITD+ cell lines and patient samples. Colony-forming unit assays further demonstrate decreased clonogenicity of FLT3/ITD+ cells upon treatment with ATRA and TKI. Most importantly, the drug combination depletes FLT3/ITD+ LSCs in a genetic mouse model of AML, and prolongs survival of leukemic mice. Furthermore, engraftment of primary FLT3/ITD+ patient samples is reduced in mice following treatment with FLT3 TKI and ATRA in combination, with evidence of cellular differentiation occurring in vivo. Mechanistically, we provide evidence that the synergism of ATRA and FLT3 TKIs is at least in part due to the observation that FLT3 TKI treatment upregulates the antiapoptotic protein Bcl6, limiting the drug’s apoptotic effect. However, cotreatment with ATRA reduces Bcl6 expression to baseline levels through suppression of interleukin-6 receptor signaling. These studies provide evidence of the potential of this drug combination to eliminate FLT3/ITD+ LSCs and reduce the rate of relapse in AML patients with FLT3 mutations. PMID:27103744

  5. Synergism between hydrogen peroxide and seventeen acids against five agri-food-borne fungi and one yeast strain.

    PubMed

    Martin, H; Maris, P

    2012-12-01

    The objective of this study was to evaluate fungicidal efficacy of hydrogen peroxide administered in combination with 17 mineral and organic acids authorized for use in the food industry. The assays were performed on a 96-well microplate using a microdilution technique based on the checkerboard titration method. The six selected strains (one yeast and five fungi) were reference strains and strains representative of contaminating fungi found in the food industry. Each synergistic hydrogen peroxide/acid combination found after fifteen minutes contact time at 20 °C in distilled water was then tested in conditions simulating four different use conditions. Twelve combinations were synergistic in distilled water, eleven of these remained synergistic with one or more of the four mineral and organic interfering substances selected. Hydrogen peroxide/formic acid combination remained effective against four strains and was never antagonistic against the other two fungi. Combinations with propionic acid and acetic acid stayed synergistic against two strains. Those with oxalic acid and lactic acid kept their synergism only against Candida albicans. No synergism was detected against Penicillium cyclopium. Synergistic combinations of disinfectants were revealed, among them the promising hydrogen peroxide/formic acid combination. A rapid screening method developed in our laboratory for bacteria was adapted to fungi and used to reveal the synergistic potential of disinfectants and/or sanitizers combinations. © 2012 The Society for Applied Microbiology.

  6. Synergism between PGC-1α and estrogen in the survival of endometrial cancer cells via the mitochondrial pathway

    PubMed Central

    Yang, Hui; Yang, Rui; Liu, Hao; Ren, Zhongqian; Kong, Fanfei; Li, Da; Ma, Xiaoxin

    2016-01-01

    Accumulating evidence shows that peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is involved in the progression of hormone-related cancers, and there may exist an association between estrogen and PGC-1α. Notably, emerging evidence has led to considerable interest in the role of PGC-1α in endometrial cancer development. However, whether the synergism exists between PGC-1α and estrogen for regulating mitochondrial function to promote the development of endometrial cancer remains largely unknown. Here, we show that: 1) knockdown of PGC-1α attenuates the survival of endometrial cancer cells by inducing cell apoptosis through the mitochondrial pathway; 2) estrogen remedies the PGC-1α efficiency-induced decline of endometrial cancer cell viability; and 3) estrogen modulates the mitochondrial function to inhibit the PGC-1α deficiency-induced apoptosis in endometrial cancer cells. Collectively, these results demonstrated that the synergism between PGC-1α and estrogen was required for the survival of endometrial cancer cells, which was dependent on the mitochondrial pathway. PMID:27418839

  7. Polyphenolic Secondary Metabolites Synergize the Activity of Commercial Antibiotics against Clinical Isolates of β-Lactamase-producing Klebsiella pneumoniae.

    PubMed

    Dey, Diganta; Ghosh, Subhalakshmi; Ray, Ratnamala; Hazra, Banasri

    2016-02-01

    Emergence of worldwide antimicrobial resistance prompted us to study the resistance modifying potential of plant-derived dietary polyphenols, mainly caffeic acid, ellagic acid, epigallocatechin-3-gallate (EGCG) and quercetin. These compounds were studied in logical combination with clinically significant antibiotics (ciprofloxacin/gentamicin/tetracycline) against Klebsiella pneumoniae, after conducting phenotypic screening of a large number of clinical isolates and selecting the relevant strains possessing extended-spectrum β-lactamase (ESBL) and K. pneumoniae carbapenemase (KPC)-type carbapenemase enzymes only. The study demonstrated that EGCG and caffeic acid could synergize the activity of tested antibiotics within a major population of β-lactamase-producing K. pneumoniae. In spectrofluorimetric assay, ~17-fold greater ciprofloxacin accumulation was observed within K. pneumoniae cells pre-treated with EGCG in comparison with the untreated control, indicating its ability to synergize ciprofloxacin to restrain active drug-efflux. Further, electron micrograph of ESBL-producing K. pneumoniae clearly demonstrated the prospective efficacy of EGCG towards biofilm degradation. Copyright © 2015 John Wiley & Sons, Ltd.

  8. Synergism between southern rice black-streaked dwarf virus and rice ragged stunt virus enhances their insect vector acquisition.

    PubMed

    Li, Shu; Wang, Han; Zhou, Guohui

    2014-07-01

    Southern rice black-streaked dwarf virus (SRBSDV), a tentative species in the genus Fijivirus, family Reoviridae, is a novel rice virus transmitted by the white-backed planthopper (Sogatella furcifera). Since its discovery in 2001, SRBSDV has spread rapidly throughout eastern and southeastern Asia and caused large rice losses in China and Vietnam. Rice ragged stunt virus (RRSV) (genus Oryzavirus, family Reoviridae) is a common rice virus vectored by the brown planthopper (Nilaparvata lugens). RRSV is also widely distributed in eastern and southeastern Asia but has not previously caused serious problems in China owing to its low incidence. With SRBSDV's spread, however, RRSV has become increasingly common in China, and is frequently found in co-infection with SRBSDV. In this study, we show that SRBSDV and RRSV interact synergistically, the first example of synergism between plant viruses in the family Reoviridae. Rice plants co-infected with both viruses displayed enhanced stunting, earlier symptoms, and higher virus titers compared with singly infected plants. Furthermore, white-backed and brown planthoppers acquired SRBSDV and RRSV, respectively, from co-infected plants at higher rates. We propose that increased RRSV incidence in Chinese fields is partly due to synergism between SRBSDV and RRSV.

  9. Impacts of albumin synergized with hydroxyethyl starch on early microvascular albumin leakage after major abdominal surgery in rabbits.

    PubMed

    Li, Weiming; Xu, Pengyuan; Cen, Yunyun; Sun, Dali; Yang, Ting; Xu, Qingwen; Li, Shumin; Li, Yijun; Ding, Bo

    2017-02-01

    To investigate the impacts of albumin synergized with hydroxyethyl starch (HES) on early microvascular albumin leakage after major abdominal surgery in rabbits. Forty male Japanese rabbits were randomly divided into four groups: the control group, the saline group, the albumin group, and the Syn group (hydroxyethyl starch+albumin). The latter three groups were performed gastrectomy plus resection of pancreatic body and tail and splenectomy. The serum albumin concentration was detected before and 48h after surgery, and the conditions of mesenteric microvascular leakage in these 4 groups were observed under microscope 48 h after surgery to calculate the leakage rate. Compared with the saline group, the albumin group and the Syn group exhibited significantly increased serum albumin concentrations 48h after surgery (P<0.05). The albumin leakage rate was the most obvious in the albumin group, followed by the saline group, while that in the Syn group was the minimal, and there existed significant differences among these groups (P<0.05) . Simple administration of albumin in the early stage after major abdominal surgery could increase the albumin leakage, while the synergization of albumin and hydroxyethyl starch could reduce the albumin leakage.

  10. Prehension Synergies in the Grasps With Complex Friction Patterns: Local Versus Synergic Effects and the Template Control

    PubMed Central

    Niu, Xun; Latash, Mark L.; Zatsiorsky, Vladimir M.

    2010-01-01

    We studied adjustments of digit forces to changes in the friction. The subjects held a handle statically in a three-digit grasp. The friction under each digit was either high or low, resulting in eight three-element friction sets (such grasps were coined the grasps with complex friction pattern). The total load was also manipulated. It was found that digit forces were adjusted not only to the supported load and local friction, but also to friction at other digits (synergic effects). When friction under a digit was low, its tangential force decreased and the normal force increased (local effects). The synergic effects were directed to maintain the equilibrium of the handle. The relation between the individual digit forces and loads agreed with the triple-product model: fin=ki(2)ki(1)L, where fin is normal force of digit i, L is the load (newtons), ki(1) is a dimensionless coefficient representing sharing the total tangential force among the digits (Σki(1)=1.0), and ki(2) is a coefficient representing the relation between the tangential and normal forces of digit i (the overall friction equivalent, OFE). At each friction set, the central controller selected the grasping template—a three-element array of ki(2)ki(1) products—and then scaled the template with the load magnitude. PMID:17493928

  11. Prehension synergies in the grasps with complex friction patterns: local versus synergic effects and the template control.

    PubMed

    Niu, Xun; Latash, Mark L; Zatsiorsky, Vladimir M

    2007-07-01

    We studied adjustments of digit forces to changes in the friction. The subjects held a handle statically in a three-digit grasp. The friction under each digit was either high or low, resulting in eight three-element friction sets (such grasps were coined the grasps with complex friction pattern). The total load was also manipulated. It was found that digit forces were adjusted not only to the supported load and local friction, but also to friction at other digits (synergic effects). When friction under a digit was low, its tangential force decreased and the normal force increased (local effects). The synergic effects were directed to maintain the equilibrium of the handle. The relation between the individual digit forces and loads agreed with the triple-product model: f(i)(n) = k(i)((2))k(i)((1))L, where f(i)(n) is normal force of digit i, L is the load (newtons), k(i)((1)) is a dimensionless coefficient representing sharing the total tangential force among the digits (summation operator k(i)((1)) = 1.0), and k(i)((2)) is a coefficient representing the relation between the tangential and normal forces of digit i (the overall friction equivalent, OFE). At each friction set, the central controller selected the grasping template -- a three-element array of k(i)((2))k(i)((1)) products -- and then scaled the template with the load magnitude.

  12. System-level Study on Synergism and Antagonism of Active Ingredients in Traditional Chinese Medicine by Using Molecular Imprinting Technology

    PubMed Central

    Chen, Tengfei; Gu, Jiangyong; Zhang, Xinzhuang; Ma, Yimin; Cao, Liang; Wang, Zhenzhong; Chen, Lirong; Xu, Xiaojie; Xiao, Wei

    2014-01-01

    In this work, synergism and antagonism among active ingredients of traditional Chinese medicine (TCM) were studied at system-level by using molecular imprinting technology. Reduning Injection (RDNI), a TCM injection, was widely used to relieve fever caused by viral infection diseases in China. Molecularly imprinted polymers (MIPs) synthesized by sol-gel method were used to separate caffeic acid (CA) and analogues from RDNI without affecting other compounds. It can realize the preparative scale separation. The inhibitory effects of separated samples of RDNI and sample combinations in prostaglandin E2 biosynthesis in lipopolysaccharide-induced RAW264.7 cells were studied. The combination index was calculated to evaluate the synergism and antagonism. We found that components which had different scaffolds can produce synergistic anti-inflammatory effect inside and outside the RDNI. Components which had similar scaffolds exhibited the antagonistic effect, and the antagonistic effects among components could be reduced to some extent in RDNI system. The results indicated MIPs with the characteristics of specific adsorption ability and large scale preparation can be an effective approach to study the interaction mechanism among active ingredients of complex system such as TCM at system-level. And this work would provide a new idea to study the interactions among active ingredients of TCM. PMID:25418048

  13. Synergism between Enantiomers Creates Species-Specific Pheromone Blends and Minimizes Cross-Attraction for Two Species of Cerambycid Beetles.

    PubMed

    Meier, Linnea R; Zou, Yunfan; Millar, Jocelyn G; Mongold-Diers, Judith A; Hanks, Lawrence M

    2016-11-01

    Research over the last decade has revealed extensive parsimony among pheromones within the large insect family Cerambycidae, with males of many species producing the same, or very similar aggregation pheromones. Among some species in the subfamily Cerambycinae, interspecific attraction is minimized by temporal segregation, and/or by minor pheromone components that synergize attraction of conspecifics or inhibit attraction of heterospecifics. Less is known about pheromone-based mechanisms of reproductive isolation among species in the largest subfamily, the Lamiinae. Here, we present evidence that the pheromone systems of two sympatric lamiine species consist of synergistic blends of enantiomers of (E)-6,10-dimethyl-5,9-undecadien-2-ol (fuscumol) and the structurally related (E)-6,10-dimethyl-5,9-undecadien-2-yl acetate (fuscumol acetate), as a mechanism by which species-specific blends of pheromone components can minimize interspecific attraction. Male Astylidius parvus (LeConte) were found to produce (R)- and (S)-fuscumol + (R)-fuscumol acetate + geranylacetone, whereas males of Lepturges angulatus (LeConte) produced (R)- and (S)-fuscumol acetate + geranylacetone. Field experiments confirmed that adult beetles were attracted only by their species-specific blend of the enantiomers of fuscumol and fuscumol acetate, respectively, and not to the individual enantiomers. Because other lamiine species are known to produce single enantiomers or blends of enantiomers of fuscumol and/or fuscumol acetate, synergism between enantiomers, or inhibition by enantiomers, may be a widespread mechanism for forming species-specific pheromone blends in this subfamily.

  14. 22 CFR 41.82 - Certain parents and children of section 101(a)(27)(I) special immigrants. [Reserved

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Certain parents and children of section 101(a)(27)(I) special immigrants. 41.82 Section 41.82 Foreign Relations DEPARTMENT OF STATE VISAS VISAS... Nonimmigrants § 41.82 Certain parents and children of section 101(a)(27)(I) special immigrants....

  15. 22 CFR 41.82 - Certain parents and children of section 101(a)(27)(I) special immigrants. [Reserved

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Certain parents and children of section 101(a)(27)(I) special immigrants. 41.82 Section 41.82 Foreign Relations DEPARTMENT OF STATE VISAS VISAS... Nonimmigrants § 41.82 Certain parents and children of section 101(a)(27)(I) special immigrants....

  16. 22 CFR 41.82 - Certain parents and children of section 101(a)(27)(I) special immigrants. [Reserved

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Certain parents and children of section 101(a)(27)(I) special immigrants. 41.82 Section 41.82 Foreign Relations DEPARTMENT OF STATE VISAS VISAS... Nonimmigrants § 41.82 Certain parents and children of section 101(a)(27)(I) special immigrants....

  17. 22 CFR 41.82 - Certain parents and children of section 101(a)(27)(I) special immigrants. [Reserved

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Certain parents and children of section 101(a)(27)(I) special immigrants. 41.82 Section 41.82 Foreign Relations DEPARTMENT OF STATE VISAS VISAS... Nonimmigrants § 41.82 Certain parents and children of section 101(a)(27)(I) special immigrants....

  18. 22 CFR 41.82 - Certain parents and children of section 101(a)(27)(I) special immigrants. [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Certain parents and children of section 101(a)(27)(I) special immigrants. 41.82 Section 41.82 Foreign Relations DEPARTMENT OF STATE VISAS VISAS... Nonimmigrants § 41.82 Certain parents and children of section 101(a)(27)(I) special immigrants....

  19. Synergic effects of 10°/s constant rotation and rotating background on visual cognitive processing

    NASA Astrophysics Data System (ADS)

    He, Siyang; Cao, Yi; Zhao, Qi; Tan, Cheng; Niu, Dongbin

    accelerated the early process of visual cognition. There is a synergic effect between the effects of constant low-speed rotation and rotating speed of the background. Under certain conditions, they both served to facilitate the visual cognitive processing, and it had been started at the stage when extrastriate cortex perceiving the visual signal. Under the condition of constant low-speed rotation in higher cognitive load tasks, the rapid rotation of the background enhanced the magnitude of the signal transmission in the visual path, making signal to noise ratio increased and a higher signal to noise ratio is clearly in favor of target perception and recognition. This gave rise to the hypothesis that higher cognitive load tasks with higher top-down control had more power in counteracting the inhibition effect of higher velocity rotation background. Acknowledgements: This project was supported by National Natural Science Foundation of China (No. 30670715) and National High Technology Research and Development Program of China (No.2007AA04Z254).

  20. Synergism in immunotoxicological effects due to repeated combined administration of arsenic and lead in mice.

    PubMed

    Bishayi, B; Sengupta, M

    2006-03-01

    evident from the decrease in myeloperoxidase release in multimetal group from that in control. That the structural integrity of splenic macrophages is decreased in the multimetal exposed group is also evident from the enhanced percentage of DNA fragmentation after multimetal exposure, suggesting apoptotic death of splenic macrophage. Intracellular viable bacteria in the splenic macrophage from multimetal exposed group was 89.16 +/- 3.54% while that from control group was 49.19 +/- 1.16%, whereas single metal exposed groups showed a bacterial viability of 69.6 +/- 2.45% and 71.71 +/- 1.89% in arsenic and lead treated groups respectively. What is essentially noteworthy from the observed results is that lead and arsenic causes a greater immunotoxic effect when administered together as multimetal than when singly administered. Simultaneous exposure to lead and arsenic appears to be additive as is further established from the isobologram constructed by plotting the concentration of arsenic against the concentration of lead at which effect (in this case myeloperoxidase release) remained constant, a convex line showing synergism was demonstrated. The present study reports a definite synergistic trend of immunotoxicity during simultaneous exposure to arsenic and lead, that is, a multimetal challenge, as compared to the effects of independent exposure to them.

  1. Designing α-helical peptides with enhanced synergism and selectivity against Mycobacterium smegmatis: Discerning the role of hydrophobicity and helicity.

    PubMed

    Khara, Jasmeet Singh; Lim, Fang Kang; Wang, Ying; Ke, Xi-Yu; Voo, Zhi Xiang; Yang, Yi Yan; Lakshminarayanan, Rajamani; Ee, Pui Lai Rachel

    2015-12-01

    Recently, we reported on a series of short amphipathic α-helical peptides, comprising the backbone sequence (LLKK)2, with the ability to kill susceptible and drug-resistant Mycobacterium tuberculosis. In this study, the effect of key physicochemical parameters including hydrophobicity and helicity of α-helical peptides on anti-mycobacterial activity and synergism with rifampicin was investigated. The most hydrophobic analogue, W(LLKK)2W, displayed low selectivity against mycobacteria while peptides with intermediate hydrophobicity were shown to be equally active, yet significantly less toxic. Furthermore, proline substitution impeded the formation of stable amphipathic structures, rendering P(LLKK)2P as one of the least active analogues. Terminal capping with isoleucine was found to promote α-helical folding and the resultant peptide demonstrated the highest selectivity and minimal cytotoxicity against mammalian macrophages. Flow cytometric analysis revealed that enhancements in hydrophobicity and α-helicity increased the rate and extent of peptide-mediated membrane permeabilization. This finding corroborated the hypothesis that synergism between the peptides and rifampicin was likely mediated via peptide-induced pore formation. The rapid, concentration-dependent membrane depolarization, leakage of intracellular ATP and calcein release from PE/PG LUVs supported the membrane-lytic mechanism of action of the peptides. Together, these findings suggest that hydrophobicity and α-helicity significantly impact anti-mycobacterial activity and optimization of both parameters is necessary to develop synthetic analogues with superior selectivity indices and enhanced synergistic potential with conventional antibiotics. There is an urgent clinical need for the discovery of new antimicrobials, effective not just for drug susceptible, but also rapidly emerging drug-resistant TB. Recently, we reported on a series of short amphipathic α-helical peptides, comprising the

  2. Separation and pre-concentration of glucocorticoids in water samples by ionic liquid supported vortex-assisted synergic microextraction and HPLC determination.

    PubMed

    Qin, Hui; Li, Bi; Liu, Mou Sheng; Yang, Ya Ling

    2013-04-01

    We have developed a synergic microextraction procedure based on ionic liquid for the pre-concentration and determination of glucocorticoids in water samples. Using nonionic surfactant Triton X-100 (TX-100) as synergic reagent, 1-butyl-3-methylimidazolium hexa-fluorophosphate accomplished extraction rapidly without heating in water bath. One key property of ionic liquids that highlights their potential is their wide liquid temperature range. The improved extraction was named as ionic liquid supported vortex-assisted synergic microextraction. Compared with the traditional liquid-liquid extraction and cloud point extraction, ionic liquid supported vortex-assisted synergic microextraction was accomplished in 8 min with considerably high recovery. The proposed method greatly improved the sensitivity of HPLC for the determination of glucocorticoids. The results obtained indicated a good linearity with the correlation coefficient of 0.997 over the range of 0.6-300 ng/mL and high sensitivity with LODs of 4.11, 9.19, and 7.50 ng/mL for hydrocortisone butyrate, beclomethasone dipropionate, and nandrolone phenylpropionate, respectively. The RSD of the method was 1.57-1.81% (n = 6) with enrichment factor of 99.85, and good recovery (≥97.24%). The method was successfully applied to the determination of glucocorticoids in mineral water, water of Dianchi lake, and tap water samples.

  3. Western spruce budworm outbreaks did not increase fire risk over the last three centuries: A dendrochronological analysis of inter-disturbance synergism

    Treesearch

    Aquila Flower; Daniel G. Gavin; Emily K. Heyerdahl; Russell A. Parsons; Gregory M. Cohn

    2014-01-01

    Insect outbreaks are often assumed to increase the severity or probability of fire occurrence through increased fuel availability, while fires may in turn alter susceptibility of forests to subsequent insect outbreaks through changes in the spatial distribution of suitable host trees. However, little is actually known about the potential synergisms between these...

  4. Synergism between the potato glycoalkaloids alpha-chaconine and alpha-solanine in inhibition of snail feeding.

    PubMed

    Smith, D B; Roddick, J G; Jones, J L

    2001-05-01

    Snails (Helix aspersa L.) were fed filter paper treated with the potato glycoalkaloids, alpha-solanine and alpha-chaconine, singly or together. In pure form, both glycoalkaloids deterred feeding, with chaconine being the more active compound. In combination, authentic solanine and chaconine interacted synergistically in their inhibition of feeding. The antifeedant activities of methanolic extracts of tuber peel of the potato varieties Majestic and Sharpe's Express presented via filter paper discs did not differ significantly from those of authentic glycoalkaloid solutions of comparable concentration and ratio. In contrast, feeding inhibition by diluted tuber peel extracts of the variety Homeguard was greater than that elicited by comparable authentic glycoalkaloid solutions suggesting additional inhibitory compound(s) in the peel of this variety. Comparison of data from peel extracts of all three potato varieties and authentic glycoalkaloids indicated that the level of feeding inhibition by the extracts was, at least in part, a consequence of a synergism between solanine and chaconine.

  5. Synthesis, antifungal activity of caffeic acid derivative esters, and their synergism with fluconazole and nystatin against Candida spp.

    PubMed

    Sardi, Janaína de Cássia Orlandi; Gullo, Fernanda Patrícia; Freires, Irlan Almeida; Pitangui, Nayla de Souza; Segalla, Maicon Petrônio; Fusco-Almeida, Ana Marisa; Rosalen, Pedro Luiz; Regasini, Luís Octávio; Mendes-Giannini, Maria José Soares

    2016-12-01

    We tested the antifungal potential of caffeic acid and 8 of its derivative esters against Candidaalbicans ATCC 90028 and 9 clinical isolatesand carried out a synergism assay with fluconazole and nystatin. Propyl caffeate (C3) showed the best antifungal activity against the tested strains. When in combination, C3 markedly reduced the MIC of fluconazole and nystatin with synergistic effect up to 64-fold. Finally, C3 showed a high IC50 value and selective indexagainst oral keratinocytes, demonstrating low toxicity against this cell type and selectivity for yeast cells. Further research should confirm its antifungal potential for development of combined therapy to treat C. albicans infections. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Antimicrobial activity, synergism and inhibition of germ tube formation by Crocus sativus-derived compounds against Candida spp.

    PubMed

    Carradori, Simone; Chimenti, Paola; Fazzari, Marina; Granese, Arianna; Angiolella, Letizia

    2016-01-01

    The limited arsenal of synthetic antifungal agents and the emergence of resistant Candida strains have prompted the researchers towards the investigation of naturally occurring compounds or their semisynthetic derivatives in order to propose new innovative hit compounds or new antifungal combinations endowed with reduced toxicity. We explored the anti-Candida effects, for the first time, of two bioactive compounds from Crocus sativus stigmas, namely crocin 1 and safranal, and some semisynthetic derivatives of safranal obtaining promising biological results in terms of minimum inhibitory concentration/minimum fungicidal concentration (MIC/MFC) values, synergism and reduction in the germ tube formation. Safranal and its thiosemicarbazone derivative 5 were shown to display good activity against Candida spp.

  7. Synergism between NOAA-AVHRR and Meteosat data for studying vegetation development in semi-arid West Africa

    NASA Technical Reports Server (NTRS)

    Justice, C. O.; Dugdale, G.; Narracott, A. S.; Townshend, J. R. G.; Kumar, M.

    1991-01-01

    Rainfall estimates, based on cold cloud duration estimated from Meteosat data, are compared with vegetation development depicted by data of the normalized difference vegetation index (NDVI) from the NOAA AVHRR for part of the Sahel. Decadal data from the 1985 and 1986 growing seasons are examined to determine the synergism of the datasets for rangeland monitoring. There is a general correspondence between the two datasets with a marked lag between rainfall and NDVI of between 10 and 20 days. This time lag is particularly noticeable at the beginning of the rainy season and in the more northern areas where rainfall is the limiting factor for growth. Principal component analysis was used to examine deviations from the general relationship between rainfall and the NDVI. Areas of low NDVI values for a given input of rainfall were identified: at a regional scale, they give an indication o areas of low production potential and possible degradation of ecosystems.

  8. Trajectories of maternal depression: a 27-year population-based prospective study.

    PubMed

    Najman, J M; Plotnikova, M; Williams, G M; Alati, R; Mamun, A A; Scott, J; Wray, N; Clavarino, A M

    2017-02-01

    To identify distinct trajectories of depression experienced by a population-based sample of women over a 27-year period and to assess the validity of the derived trajectories. The Mater University of Queensland Study of Pregnancy is a birth cohort study which commenced in 1981. Women (N = 6753) were interviewed at their first clinic visit, at 6 months, then 5, 14, 21 and 27 years after the birth of their child, using the Delusions Symptoms - States Inventory. Some 3561 (52.7%) women were followed up at 27 years, with 3337 (49.4%) of the sample completing the Composite International Diagnostic Interview (CIDI). Depression trajectories over a 27-year period were identified using Latent Class Growth Modelling (LCGM). LCGM was used to identify respondents with similar patterns of depression over a 27-year period. At the 27-year follow-up women who completed the CIDI, were stratified according to their trajectory group membership. Three trajectory groups, each with different life-course patterns of depression were identified. The low/no symptoms of depression trajectory group comprised 48.4% of women. The mid-depression group (41.7%) had a consistent pattern of occasional symptoms of depression. The high/escalating trajectory group comprised 9.9% of the women in the study. We then examined each trajectory group based on their completion of the CIDI at the 27-year follow-up. Using the CIDI, 27.0% of women in the study had met the DSM-IV criteria for lifetime ever depression by their mean age of 46.5 years. The responses to the CIDI differed greatly for each of the trajectory groups, suggesting that the trajectories validly reflect different life histories of depression. The high/escalating trajectory group had an earlier age of first onset, more frequent episodes, longer duration of each episode of depression and experienced higher levels of impairment for their episodes of depression. For the high symptoms trajectory group, clinically significant depression is estimated

  9. Synergism between elevated pCO2 and temperature on the Antarctic sea ice diatom Nitzschia lecointei

    NASA Astrophysics Data System (ADS)

    Torstensson, A.; Hedblom, M.; Andersson, J.; Andersson, M. X.; Wulff, A.

    2013-04-01

    Polar oceans are particularly susceptible to ocean acidification and warming. Diatoms play a significant role in sea ice biogeochemistry and provide an important food source to grazers in ice-covered oceans, especially during early spring. However, the ecophysiology of ice living organisms has received little attention in terms of ocean acidification. In this study, the synergism between temperature and partial pressure of CO2 (pCO2) was investigated in relationship to the optimal growth temperature of the Antarctic sea ice diatom Nitzschia lecointei. Diatoms were kept in cultures at controlled levels of pCO2 (∼390 and ∼960 μatm}) and temperature (-1.8 and 2.5 °C) for 14 days. Synergism between temperature and pCO2 was detected in growth rate and acyl lipid fatty acid content. Carbon enrichment only promoted (3%) growth rate closer to the optimal growth, but not at the control temperature (-1.8 °C). Optimal growth rate was observed around 5 °C in a separate experiment. Polyunsaturated fatty acids (PUFA) comprised up to 98% of the total acyl lipid fatty acid pool at -1.8 °C. However, the total content of fatty acids was reduced by 39% at elevated pCO2, but only at the control temperature. PUFAs were reduced by 30% at high pCO2. Effects of carbon enrichment may be different depending on ocean warming scenario or season, e.g. reduced food quality for higher trophic levels during spring. Synergy between temperature and pCO2 may be particularly important in polar areas since a narrow thermal window generally limits cold-water organisms.

  10. Plant viral synergism: the potyviral genome encodes a broad-range pathogenicity enhancer that transactivates replication of heterologous viruses.

    PubMed Central

    Pruss, G; Ge, X; Shi, X M; Carrington, J C; Bowman Vance, V

    1997-01-01

    Synergistic viral diseases of higher plants are caused by the interaction of two independent viruses in the same host and are characterized by dramatic increases in symptoms and in accumulation of one of the coinfecting viruses. In potato virus X (PVX)/potyviral synergism, increased pathogenicity and accumulation of PVX are mediated by the expression of potyviral 5' proximal sequences encoding P1, the helper component proteinase (HC-Pro), and a fraction of P3. Here, we report that the same potyviral sequence (termed P1/HC-Pro) enhances the pathogenicity and accumulation of two other heterologous viruses: cucumber mosaic virus and tobacco mosaic virus. In the case of PVX-potyviral synergism, we show that the expression of the HC-Pro gene product, but not the RNA sequence itself, is sufficient to induce the increase in PVX pathogenicity and that both P1 and P3 coding sequences are dispensable for this aspect of the synergistic interaction. In protoplasts, expression of the potyviral P1/HC-Pro region prolongs the accumulation of PVX (-) strand RNA and transactivates expression of a reporter gene from a PVX subgenomic promoter. Unlike the synergistic enhancement of PVX pathogenicity, which requires only expression of HC-Pro, the enhancement of PVX (-) strand RNA accumulation in protoplasts is significantly greater when the entire P1/HC-Pro sequence is expressed. These results indicate that the potyviral P1/HC-Pro region affects a step in disease development that is common to a broad range of virus infections and suggest a mechanism involving transactivation of viral replication. PMID:9212462

  11. Phenobarbital induction and chemical synergism demonstrate the role of UDP-glucuronosyltransferases in detoxification of naphthalophos by Haemonchus contortus larvae.

    PubMed

    Kotze, Andrew C; Ruffell, Angela P; Ingham, Aaron B

    2014-12-01

    We used an enzyme induction approach to study the role of detoxification enzymes in the interaction of the anthelmintic compound naphthalophos with Haemonchus contortus larvae. Larvae were treated with the barbiturate phenobarbital, which is known to induce the activity of a number of detoxification enzymes in mammals and insects, including cytochromes P450 (CYPs), UDP-glucuronosyltransferases (UDPGTs), and glutathione (GSH) S-transferases (GSTs). Cotreatment of larvae with phenobarbital and naphthalophos resulted in a significant increase in the naphthalophos 50% inhibitory concentration (IC50) compared to treatment of larvae with the anthelmintic alone (up to a 28-fold increase). The phenobarbital-induced drug tolerance was reversed by cotreatment with the UDPGT inhibitors 5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine, probenecid, and sulfinpyrazone. Isobologram analysis of the interaction of 5-nitrouracil with naphthalophos in phenobarbital-treated larvae clearly showed the presence of strong synergism. The UDPGT inhibitors 5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine, and probenecid also showed synergistic effects with non-phenobarbital-treated worms (synergism ratio up to 3.2-fold). This study indicates that H. contortus larvae possess one or more UDPGT enzymes able to detoxify naphthalophos. In highlighting the protective role of this enzyme group, this study reveals the potential for UDPGT enzymes to act as a resistance mechanism that may develop under drug selection pressure in field isolates of this species. In addition, the data indicate the potential for a chemotherapeutic approach utilizing inhibitors of UDPGT enzymes as synergists to increase the activity of naphthalophos against parasitic worms and to combat detoxification-mediated drug resistance if it arises in the field. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  12. Phenobarbital Induction and Chemical Synergism Demonstrate the Role of UDP-Glucuronosyltransferases in Detoxification of Naphthalophos by Haemonchus contortus Larvae

    PubMed Central

    Ruffell, Angela P.; Ingham, Aaron B.

    2014-01-01

    We used an enzyme induction approach to study the role of detoxification enzymes in the interaction of the anthelmintic compound naphthalophos with Haemonchus contortus larvae. Larvae were treated with the barbiturate phenobarbital, which is known to induce the activity of a number of detoxification enzymes in mammals and insects, including cytochromes P450 (CYPs), UDP-glucuronosyltransferases (UDPGTs), and glutathione (GSH) S-transferases (GSTs). Cotreatment of larvae with phenobarbital and naphthalophos resulted in a significant increase in the naphthalophos 50% inhibitory concentration (IC50) compared to treatment of larvae with the anthelmintic alone (up to a 28-fold increase). The phenobarbital-induced drug tolerance was reversed by cotreatment with the UDPGT inhibitors 5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine, probenecid, and sulfinpyrazone. Isobologram analysis of the interaction of 5-nitrouracil with naphthalophos in phenobarbital-treated larvae clearly showed the presence of strong synergism. The UDPGT inhibitors 5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine, and probenecid also showed synergistic effects with non-phenobarbital-treated worms (synergism ratio up to 3.2-fold). This study indicates that H. contortus larvae possess one or more UDPGT enzymes able to detoxify naphthalophos. In highlighting the protective role of this enzyme group, this study reveals the potential for UDPGT enzymes to act as a resistance mechanism that may develop under drug selection pressure in field isolates of this species. In addition, the data indicate the potential for a chemotherapeutic approach utilizing inhibitors of UDPGT enzymes as synergists to increase the activity of naphthalophos against parasitic worms and to combat detoxification-mediated drug resistance if it arises in the field. PMID:25288079

  13. Caffeine synergizes with another coffee component to increase plasma GCSF: linkage to cognitive benefits in Alzheimer's mice.

    PubMed

    Cao, Chuanhai; Wang, Li; Lin, Xiaoyang; Mamcarz, Malgorzata; Zhang, Chi; Bai, Ge; Nong, Jasson; Sussman, Sam; Arendash, Gary

    2011-01-01

    Retrospective and prospective epidemiologic studies suggest that enhanced coffee/caffeine intake during aging reduces risk of Alzheimer's disease (AD). Underscoring this premise, our studies in AD transgenic mice show that long-term caffeine administration protects against cognitive impairment and reduces brain amyloid-β levels/deposition through suppression of both β- and γ-secretase. Because coffee contains many constituents in addition to caffeine that may provide cognitive benefits against AD, we examined effects of caffeinated and decaffeinated coffee on plasma cytokines, comparing their effects to caffeine alone. In both AβPPsw+PS1 transgenic mice and non-transgenic littermates, acute i.p. treatment with caffeinated coffee greatly and specifically increased plasma levels of granulocyte-colony stimulating factor (GCSF), IL-10, and IL-6. Neither caffeine solution alone (which provided high plasma caffeine levels) or decaffeinated coffee provided this effect, indicating that caffeine synergized with some as yet unidentified component of coffee to selectively elevate these three plasma cytokines. The increase in GCSF is particularly important because long-term treatment with coffee (but not decaffeinated coffee) enhanced working memory in a fashion that was associated only with increased plasma GCSF levels among all cytokines. Since we have previously reported that long-term GCSF treatment enhances cognitive performance in AD mice through three possible mechanisms (e.g., recruitment of microglia from bone marrow, synaptogenesis, and neurogenesis), the same mechanisms could be complimentary to caffeine's established ability to suppress Aβ production. We conclude that coffee may be the best source of caffeine to protect against AD because of a component in coffee that synergizes with caffeine to enhance plasma GCSF levels, resulting in multiple therapeutic actions against AD.

  14. Honokiol synergizes chemotherapy drugs in multidrug resistant breast cancer cells via enhanced apoptosis and additional programmed necrotic death.

    PubMed

    Tian, Wei; Deng, Yongchuan; Li, Ling; He, Haifei; Sun, Jie; Xu, Dong

    2013-02-01

    Multidrug resistance (MDR) is a major challenge in cancer therapy. Apoptosis tolerance is one of the key mechanisms of MDR. Honokiol, a small-molecule pharmacologically active component, exhibits competent cytotoxicity in a variety of human cancer cells through apoptosis and other forms of programmed cell death (such as programmed necrosis). Although much work has been done on its antitumor effects, little attention has been paid on systemic evaluation of efficacy of honokiol combined with other chemotherapeutic agents, especially in drug‑resistant cell lines. Here, we systematically and quantitatively assess its combinational effect with different chemotherapeutic agents using the combination index (CI) equation. We found that honokiol synergized with chemotherapeutic agents both in sensitive and resistant, solid and non-solid (MCF-7, HL-60, MCF-7/ADR and HL-60/ADR) cell lines. Honokiol (40 µg/ml) induced necrotic cell death in MCF-7/ADR cells with characterized morphological and biochemical features. Co-incubation with honokiol and etoposide (VP-16) activated a complex death modality, which was composed of necrotic cell death and apoptosis. This dual-death pathway was shut down when pretreated with pan-caspase inhibitor (z-VAD-fmk) and cyclophilin D inhibitor (cyclosporin A). Western blot analysis results proved that honokiol also enhanced VP-16-induced apoptosis potentially via blocking nuclear factor‑κB (NF-κB) activation. Our data for the first time quantitatively demonstrate that honokiol synergizes frequently-used chemotherapeutic agents via enhanced apoptosis and additional programmed necrotic death. These findings indicate a promising way to circumvent MDR and apoptosis tolerance.

  15. Luteolin synergizes the antitumor effects of 5-fluorouracil against human hepatocellular carcinoma cells through apoptosis induction and metabolism.

    PubMed

    Xu, Huanli; Yang, Tao; Liu, Xiaohui; Tian, Ye; Chen, Xiaoliang; Yuan, Ru; Su, Shuonan; Lin, Xiukun; Du, Guanhua

    2016-01-01

    Some compounds derived from Chinese medicine have demonstrated great prospective roles in sensitization to chemotherapy. This study aimed to investigate the combination of luteolin and 5-fluorouracil on proliferations of hepatocellular carcinoma cells and the potential mechanisms. The antitumor effects of luteolin, 5-fluorouracil, and their combinations were detected by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium/phenazine methosulfate assay, and isobole method was used to evaluate drug combinations. CellTiter-Blue and Caspase-Glo 3/7 assay were used for assessment of cell viability and apoptosis after treatment with luteolin, 5-fluorouracil and their combinations. Cell cycle distributions and apoptosis were detected by PI staining, Hoechst 33342 staining and FITC-Annexin V/PI staining. Bcl-2, bax, p53 and PARP expressions were determined by Western blot. Furthermore, mRNA levels of 5-fluorouracil metabolism related enzymes were detected by RT-PCR. Drug combination study showed that luteolin could synergize the antitumor effects of 5-fluorouracil at different dose ratios (luteolin: 5-fluorouracil=10:1, 20:1, 40:1) against HepG2 and Bel7402 cells. Cell viability and cell apoptosis analysis showed that the synergistic growth inhibition caused by combined luteolin and 5-fluorouracil was closely related to apoptosis. Further mechanism studies showed that the synergistic effects of drug combinations were related with enhanced bax/bcl-2 ratios and p53 expressions, and induced PARP cleavage. Also, combined luteolin and 5-fluorouracil could significantly decrease the dihydropyrimidine dehydrogenase. These results showed that luteolin could synergize the antitumor effects of 5-fluorouracil on HepG2 and Bel7402 cells, which might be related with apoptosis and regulation of 5-fluorouracil metabolism. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. A case of iloperidone overdose in a 27-year-old man with cocaine abuse

    PubMed Central

    Amon, Jin; Stephen, Elsa; El-Mallakh, Rif S

    2016-01-01

    Introduction: Iloperidone is a recently introduced antipsychotic medication. It is approved for the treatment of schizophrenia. There are no published reports of iloperidone overdosage, but there are eight cases that have been reported to the US Food and Drug Administration. Case report: A case of a 27-year-old man who took 84 mg of iloperidone while also smoking cocaine is described. He developed a prolonged QTc (527 ms) without arrhythmias and respiratory failure with mandated respiratory support. He ultimately recovered without sequelae. Discussion: The information regarding previous cases of toxicity on the US Food and Drug Administration website is incomplete. However, there were no fatalities due to iloperidone over-ingestion. Prolongation of the QTc may be a common feature. PMID:27570623

  17. A case of iloperidone overdose in a 27-year-old man with cocaine abuse.

    PubMed

    Amon, Jin; Stephen, Elsa; El-Mallakh, Rif S

    2016-01-01

    Iloperidone is a recently introduced antipsychotic medication. It is approved for the treatment of schizophrenia. There are no published reports of iloperidone overdosage, but there are eight cases that have been reported to the US Food and Drug Administration. A case of a 27-year-old man who took 84 mg of iloperidone while also smoking cocaine is described. He developed a prolonged QTc (527 ms) without arrhythmias and respiratory failure with mandated respiratory support. He ultimately recovered without sequelae. The information regarding previous cases of toxicity on the US Food and Drug Administration website is incomplete. However, there were no fatalities due to iloperidone over-ingestion. Prolongation of the QTc may be a common feature.

  18. Preliminary Analysis of a 27.5 mm Period Undulator for the MBA Lattice

    SciTech Connect

    Abliz, M.; Grimmer, J.

    2016-07-27

    The magnetic design of a 27.5 mm period undulator was performed for the APS MBA Lattice. One purpose of the magnetic design was to decrease the magnetic force in order to operate the undulator successfully at a smaller gap compared to the existing 27 mm undulator at the APS. As a result, the magnetic force is decreased by about 18% at a gap of 11 mm and the total volume of the magnet and the pole is decreased by approximately 22% with the new model. The calculated effective field with the new model was 172 G higher than the existing 27-mm period undulator with a gap of 11 mm. The calculated field roll-off with the new optimized model is within the requirements of the MBA, in the range of ± 5 mm.

  19. Hereditary spherocytosis in a 27-year-old woman: case report.

    PubMed

    Hassan, A; Babadoko, A A; Isa, A H; Abunimye, P

    2009-01-01

    Hereditary spherocytosis (HS) is a familial hemolytic disorder with marked heterogeneity of clinical features, ranging from an asymptomatic condition to a fulminant hemolytic anemia. Although a positive family history of spherocytosis increases the risk for this disorder, it may be sporadic in some cases. In severe cases the disorder may be detected in early childhood, but in mild cases it may go unnoticed until later in adult life. A 27-year-old Nigerian woman presented with mild anemia, jaundice, splenomegaly and a history of multiple blood transfusion. Blood film showed about 70% spherocytes, reticulocytosis of 6.5%, increased osmotic fragility test and a negative direct antiglobulin test. She was managed conservatively on nutritional supplements and a significant regression of symptoms after 6 months was achieved.

  20. A 27-locus STR assay to meet all United States and European law enforcement agency standards.

    PubMed

    Schumm, James W; Gutierrez-Mateo, Cristina; Tan, Eugene; Selden, Richard

    2013-11-01

    Different national and international agencies have selected specific STR sets for forensic database use. To enhance database comparison across national and international borders, a 27-locus multiplex system was developed comprising all 15 STR loci of the European standard set, the current 13 STR loci of the CODIS core, the proposed 22 STR loci of the expanded CODIS core, 4 additional commonly used STR loci, and the amelogenin locus. Development required iterative primer design to resolve primer-related artifacts, amplicon sizing, and locus-to-locus balance issues. The 19.5-min assay incorporated newly developed six-dye chemistry analyzed using a novel microfluidic electrophoresis instrument capable of simultaneous detection and discrimination of 8 or more fluorescent dyes. The 27-locus multiplex offers the potential for a new international STR standard permitting laboratories in any jurisdiction to use a single reaction to determine profiles for loci they typically generate plus an expanded common STR profiling set of global interest.

  1. Supervillin binding to myosin II and synergism with anillin are required for cytokinesis

    PubMed Central

    Smith, Tara C.; Fridy, Peter C.; Li, Yinyin; Basil, Shruti; Arjun, Sneha; Friesen, Ryan M.; Leszyk, John; Chait, Brian T.; Rout, Michael P.; Luna, Elizabeth J.

    2013-01-01

    Cytokinesis, the process by which cytoplasm is apportioned between dividing daughter cells, requires coordination of myosin II function, membrane trafficking, and central spindle organization. Most known regulators act during late cytokinesis; a few, including the myosin II–binding proteins anillin and supervillin, act earlier. Anillin's role in scaffolding the membrane cortex with the central spindle is well established, but the mechanism of supervillin action is relatively uncharacterized. We show here that two regions within supervillin affect cell division: residues 831–1281, which bind central spindle proteins, and residues 1–170, which bind the myosin II heavy chain (MHC) and the long form of myosin light-chain kinase. MHC binding is required to rescue supervillin deficiency, and mutagenesis of this site creates a dominant-negative phenotype. Supervillin concentrates activated and total myosin II at the furrow, and simultaneous knockdown of supervillin and anillin additively increases cell division failure. Knockdown of either protein causes mislocalization of the other, and endogenous anillin increases upon supervillin knockdown. Proteomic identification of interaction partners recovered using a high-affinity green fluorescent protein nanobody suggests that supervillin and anillin regulate the myosin II and actin cortical cytoskeletons through separate pathways. We conclude that supervillin and anillin play complementary roles during vertebrate cytokinesis. PMID:24088567

  2. Synergism between arsenite and proteasome inhibitor MG132 over cell death in myeloid leukaemic cells U937 and the induction of low levels of intracellular superoxide anion

    SciTech Connect

    Lombardo, Tomás; Cavaliere, Victoria; Costantino, Susana N.; Kornblihtt, Laura; Alvarez, Elida M.; Blanco, Guillermo A.

    2012-02-01

    Increased oxygen species production has often been cited as a mechanism determining synergism on cell death and growth inhibition effects of arsenic-combined drugs. However the net effect of drug combination may not be easily anticipated solely from available knowledge of drug-induced death mechanisms. We evaluated the combined effect of sodium arsenite with the proteasome inhibitor MG132, and the anti-leukaemic agent CAPE, on growth-inhibition and cell death effect in acute myeloid leukaemic cells U937 and Burkitt's lymphoma-derived Raji cells, by the Chou–Talalay method. In addition we explored the association of cytotoxic effect of drugs with changes in intracellular superoxide anion (O{sub 2}{sup −}) levels. Our results showed that combined arsenite + MG132 produced low levels of O{sub 2}{sup −} at 6 h and 24 h after exposure and were synergic on cell death induction in U937 cells over the whole dose range, although the combination was antagonistic on growth inhibition effect. Exposure to a constant non-cytotoxic dose of 80 μM hydrogen peroxide together with arsenite + MG132 changed synergism on cell death to antagonism at all effect levels while increasing O{sub 2}{sup −} levels. Arsenite + hydrogen peroxide also resulted in antagonism with increased O{sub 2}{sup −} levels in U937 cells. In Raji cells, arsenite + MG132 also produced low levels of O{sub 2}{sup −} at 6 h and 24 h but resulted in antagonism on cell death and growth inhibition. By contrast, the combination arsenite + CAPE showed high levels of O{sub 2}{sup −} production at 6 h and 24 h post exposure but resulted in antagonism over cell death and growth inhibition effects in U937 and Raji cells. We conclude that synergism between arsenite and MG132 in U937 cells is negatively associated to O{sub 2}{sup −} levels at early time points after exposure. -- Highlights: ► Arsenic combined cytotoxic and anti-proliferative effects by Chou–Talalay method. ► Cytotoxic effect associated

  3. Extracellular acidification synergizes with PDGF to stimulate migration of mouse embryo fibroblasts through activation of p38MAPK with a PTX-sensitive manner

    SciTech Connect

    An, Caiyan; Sato, Koichi; Wu, Taoya; Bao, Muqiri; Bao, Liang; Tobo, Masayuki; Damirin, Alatangaole

    2015-05-01

    The elucidation of the functional mechanisms of extracellular acidification stimulating intracellular signaling pathway is of great importance for developing new targets of treatment for solid tumors, and inflammatory disorders characterized by extracellular acidification. In the present study, we focus on the regulation of extracellular acidification on intracellular signaling pathways in mouse embryo fibroblasts (MEFs). We found extracellular acidification was at least partly involved in stimulating p38MAPK pathway through PTX-sensitive behavior to enhance cell migration in the presence or absence of platelet-derived growth factor (PDGF). Statistical analysis showed that the actions of extracellular acidic pH and PDGF on inducing enhancement of cell migration were not an additive effect. However, we also found extracellular acidic pH did inhibit the viability and proliferation of MEFs, suggesting that extracellular acidification stimulates cell migration probably through proton-sensing mechanisms within MEFs. Using OGR1-, GPR4-, and TDAG8-gene knock out technology, and real-time qPCR, we found known proton-sensing G protein-coupled receptors (GPCRs), transient receptor potential vanilloid subtype 1 (TRPV1), and acid-sensing ion channels (ASICs) were unlikely to be involved in the regulation of acidification on cell migration. In conclusion, our present study validates that extracellular acidification stimulates chemotactic migration of MEFs through activation of p38MAPK with a PTX-sensitive mechanism either by itself, or synergistically with PDGF, which was not regulated by the known proton-sensing GPCRs, TRPV1, or ASICs. Our results suggested that others proton-sensing GPCRs or ion channels might exist in MEFs, which mediates cell migration induced by extracellular acidification in the presence or absence of PDGF. - Highlights: • Acidic pH and PDGF synergize to stimulate MEFs migration via Gi/p38MAPK pathway. • Extracellular acidification inhibits the

  4. Lymphocyte activation by OKT3: cyclosporine sensitivity and synergism with phorbol ester.

    PubMed Central

    Kay, J E; Benzie, C R

    1986-01-01

    Lymphocyte activation by the mitogenic monoclonal antibody OKT3 is less effective than activation by mitogenic lectins such as phytohaemagglutinin (PHA) and concanavalin A (Con A). Activation by OKT3 is also very sensitive to inhibition by cyclosporine (CSA), which selectively inhibits Ca2+-activated steps in the activation process. In addition, the magnitude of the OKT3 response can be raised to that seen with mitogenic lectins by coincubation with phorbol esters (which activate protein kinase C). These observations suggest that OKT3 may deliver efficiently the Ca2+ signal involved in the initiation of lymphocyte activation, and that the comparatively weak overall response is due to a failure to generate a second signal, probably the activation of protein kinase C, as efficiently as the mitogenic lectins. PMID:3485075

  5. PARP Inhibitors Synergize With Loss of Checkpoint Control to Kill Mammary Carcinoma Cells

    DTIC Science & Technology

    2011-06-01

    D ow nloaded from induced ATM activation was PARP1- dependent , we deter- mined the impact of inhibiting ATM function on drug combination lethality...compensatory increase in CHK1 phosphorylation, which was also ATM - dependent . Together, the data in Figs. 1 and 2 demonstrate that CHK1 inhibitor-mediated...dominant-negative CHK1 protein, UCN-01 and AZD7762- induced activation of ERK1/2 was dependent on inhibition of CHK1; furthermore, expression of dominant

  6. DAX1 Overexpression in Pediatric Adrenocortical Tumors: A Synergic Role with SF1 in Tumorigenesis.

    PubMed

    de Sousa, G R V; Soares, I C; Faria, A M; Domingues, V B; Wakamatsu, A; Lerario, A M; Alves, V A F; Zerbini, M C N; Mendonca, B B; Fragoso, M C B V; Latronico, A C; Almeida, M Q

    2015-08-01

    DAX1 transcription factor is a key determinant of adrenogonadal development, acting as a repressor of SF1 targets in steroidogenesis. It was recently demonstrated that DAX1 regulates pluripotency and differentiation in murine embryonic stem cells. In this study, we investigated DAX1 expression in adrenocortical tumors (ACTs) and correlated it with SF1 expression and clinical parameters. DAX1 and SF1 protein expression were assessed in 104 ACTs from 34 children (25 clinically benign and 9 malignant) and 70 adults (40 adenomas and 30 carcinomas). DAX1 gene expression was studied in 49 ACTs by quantitative real-time PCR. A strong DAX1 protein expression was demonstrated in 74% (25 out of 34) and 24% (17 out of 70) of pediatric and adult ACTs, respectively (χ(2)=10.1, p=0.002). In the pediatric group, ACTs with a strong DAX1 expression were diagnosed at earlier ages than ACTs with weak expression [median 1.2 (range, 0.5-4.5) vs. 2.2 (0.9-9.4), p=0.038]. DAX1 expression was not associated with functional status in ACTs. Interestingly, a positive correlation was observed between DAX1 and SF1 protein expression in both pediatric and adult ACTs (r=0.55 for each group separately; p<0.0001). In addition, DAX1 gene expression was significantly correlated with SF1 gene expression (p<0.0001, r=0.54). In conclusion, DAX1 strong protein expression was more frequent in pediatric than in adult ACTs. Additionally, DAX1 and SF1 expression positively correlated in ACTs, suggesting that these transcription factors might cooperate in adrenocortical tumorigenesis. © Georg Thieme Verlag KG Stuttgart · New York.

  7. Path-averaged Rainfall Estimation Using a 27 GHz Microwave Link: Preliminary Results

    NASA Astrophysics Data System (ADS)

    Bijkerk, A.; Stricker, H.; Uijlenhoet, R.

    2003-04-01

    Between May and July 1999 a 27 GHz microwave link has been operated over a 5 km path between the towns of Rhenen and Wageningen in The Netherlands. The instrument, which was built at Eindhoven University of Technology, measures the power arriving at the receiving antenna with a frequency of 18 Hz (i.e. 18 samples per second). During dry weather conditions, it can be used as a microwave scintillometer, i.e. the (turbulent) fluxes of sensible and latent heat can be estimated from the variance of the received power fluctuations. Here we focus on the use of the instrument during rainy conditions, where it can be used to measure the path-integrated attenuation of the microwave signal due to intervening rain between the transmitting and the receiving antenna. Owing to the fact that the specific attenuation at this particular microwave frequency (in dB/km) is closely proportional to the rainfall rate (in mm/h), this instrument is well suited for path-averaged rainfall estimation. This parameter is highly relevant for various hydrological and meteorological applications. We present preliminary analyses for several rainfall events during the mentioned period, where we have compared the path-averaged rainfall estimates from the microwave link with rainfall measurements from a co-located line configuration of six tipping bucket rain gauges.

  8. Spatial temperature control with a 27 MHz current source interstitial hyperthermia system.

    PubMed

    Kaatee, R S; Crezee, H; Kanis, B P; Lagendijk, J J; Levendag, P C; Visser, A G

    1997-01-01

    This article gives an overview of the properties of a 27 MHz current source interstitial hyperthermia system, affecting temperature uniformity. Applicators can be inserted in standard flexible afterloading catheters. Maximum temperatures are measured with seven-point constantan-manganin thermocouple probes inside each applicator. Temperature can be controlled automatically using a simple control algorithm. Three-dimensional power absorption and thermal models for inhomogeneous tissues are available to optimize applicator geometry and phase configuration. Properties of the interstitial heating system have been verified both in phantom experiments and in in vivo treatments of rhabdomyosarcomas implanted in the flank of a rat. An experiment with four electrodes in one catheter proves that longitudinal control of the specific absorption rate (SAR) is feasible. Local cooling applied by cold water circulation through a catheter perpendicular to the afterloading catheter could be compensated by independent control of electrode power. Furthermore, comparison of two different phase configurations using four dual electrode applicators shows that the SAR distribution can be manipulated significantly, utilizing the phase of the electrodes. Finally, the temperature can be controlled safely and model calculations are in fair agreement with the measurements. The features of the 27 MHz current source interstitial hyperthermia system enable spatial temperature control at approximately 1.5 cm.

  9. Cavitation erosion - corrosion behaviour of ASTM A27 runner steel in natural river water

    NASA Astrophysics Data System (ADS)

    Tôn-Thât, L.

    2014-03-01

    Cavitation erosion is still one of the most important degradation modes in hydraulic turbine runners. Part of researches in this field focuses on finding new materials, coatings and surface treatments to improve the resistance properties of runners to this phenomenon. However, only few studies are focused on the deleterious effect of the environment. Actually, in some cases a synergistic effect between cavitation erosion mechanisms and corrosion kinetics can establish and increase erosion rate. In the present study, the cavitation erosion-corrosion behaviour of ASTM A27 steel in natural river water is investigated. This paper state the approach which has been used to enlighten the synergy between both phenomena. For this, a 20 kHz vibratory test according ASTM G32 standard is coupled to an electrochemical cell to be able to follow the different corrosion parameters during the tests to get evidence of the damaging mechanism. Moreover, mass losses have been followed during the exposure time. The classical degradation parameters (cumulative weight loss and erosion rate) are determined. Furthermore, a particular effort has been implemented to determine the evolution of surface damages in terms of pitting, surface cracking, material removal and surface corrosion. For this, scanning electron microscopy has been used to link the microstructure to the material removal mechanisms.

  10. Investigation of surfactant/cosurfactant synergism impact on ibuprofen solubilization capacity and drug release characteristics of nonionic microemulsions.

    PubMed

    Djekic, Ljiljana; Primorac, Marija; Filipic, Slavica; Agbaba, Danica

    2012-08-20

    The current study investigates the performances of the multicomponent mixtures of nonionic surfactants regarding the microemulsion stabilisation, drug solubilization and in vitro drug release kinetic. The primary surfactant was PEG-8 caprylic/capric glycerides (Labrasol). The cosurfactants were commercially available mixtures of octoxynol-12 and polysorbate 20 without or with the addition of PEG-40 hydrogenated castor oil (Solubilisant gamma 2421 and Solubilisant gamma 2429, respectively). The oil phase of microemulsions was isopropyl myristate. Phase behaviour study of the pseudo-ternary systems Labrasol/cosurfactant/oil/water at surfactant-to-cosurfactant weight ratios (K(m)) 40:60, 50:50 and 60:40, revealed a strong synergism in the investigated tensides mixtures for stabilisation of microemulsions containing up to 80% (w/w) of water phase at surfactant +cosurfactant-to-oil weight ratio (SCoS/O) 90:10. Solubilization of a model drug ibuprofen in concentration common for topical application (5%, w/w) was achieved at the water contents below 50% (w/w). Drug free and ibuprofen-loaded microemulsions M1-M6, containing 45% (w/w) of water phase, were prepared and characterized by polarized light microscopy, conductivity, pH, rheological and droplet size measurements. In vitro ibuprofen release kinetics from the microemulsions was investigated using paddle-over-enhancer cell method and compared with the commercial 5% (w/w) ibuprofen hydrogel product (Deep Relief, Mentholatum Company Ltd., USA). The investigated microemulsions were isotropic, low viscous Bingham-type liquids with the pH value (4.70-6.61) suitable for topical application. The different efficiency of the tensides mixtures for microemulsion stabilisation was observed, depending on the cosurfactant type and K(m) value. Solubilisant gamma 2429 as well as higher K(m) (i.e., lower relative content of the cosurfactant) provided higher surfactant/cosurfactant synergism. The drug molecules were predominantly

  11. Physicobiochemical synergism through gene therapy and functional tissue engineering for in vitro chondrogenesis.

    PubMed

    Salzmann, Gian M; Nuernberger, Benedikt; Schmitz, Philipp; Anton, Martina; Stoddart, Martin J; Grad, Sibylle; Milz, Stefan; Tischer, Thomas; Vogt, Stephan; Gansbacher, Bernd; Imhoff, Andreas B; Alini, Mauro

    2009-09-01

    Mechanical and chemical stimulation have been shown to enhance in vitro chondrogenesis. The aim of this study was to analyze and compare combined physicobiochemical effects. Bovine articular chondrocytes were retrovirally transduced to express bone morphogenetic protein-2 (BMP-2) or left as naïve controls. Cells were seeded in three-dimensional polyurethane scaffolds and further cultured under static conditions or exposed to dynamic compression and shear in a joint-specific bioreactor. Four groups: control (A), load (B), BMP-2-infected (C), and BMP-2-infected plus load (D) were analyzed for DNA and glycosaminoglycan (GAG) content; collagen I, II, and X; aggrecan, (cartilage oligomeric protein (COMP), superficial zone protein, matrix metalloproteinase (MMP)-3; MMP-13 mRNA; histology; and immunohistochemistry at 7, 21, and 35 days post-seeding. Synergistic effects (D) were higher than the sum of the individual treatments (B and C) for GAG/DNA, collagen II, and COMP. Histology revealed a functional organization in D including an intense safranin O staining in C and D superior to that in A and B. Immunostaining for collagen II and aggrecan was detected in C and D and was strongest in D. The results show that both stimuli augment in vitro chondrogenesis better than in controls. Biochemical manipulation proved to be predominantly more effective than load, and synergistic effects were demonstrated.

  12. The Proteomic Investigation of Chromatin Functional Domains Reveals Novel Synergisms among Distinct Heterochromatin Components*

    PubMed Central

    Soldi, Monica; Bonaldi, Tiziana

    2013-01-01

    Chromatin is a highly dynamic, well-structured nucleoprotein complex of DNA and proteins that controls virtually all DNA transactions. Chromatin dynamicity is regulated at specific loci by the presence of various associated proteins, histones, post-translational modifications, histone variants, and DNA methylation. Until now the characterization of the proteomic component of chromatin domains has been held back by the challenge of enriching distinguishable, homogeneous regions for subsequent mass spectrometry analysis. Here we describe a modified protocol for chromatin immunoprecipitation combined with quantitative proteomics based on stable isotope labeling by amino acids in cell culture to identify known and novel histone modifications, variants, and complexes that specifically associate with silent and active chromatin domains. Our chromatin proteomics strategy revealed unique functional interactions among various chromatin modifiers, suggesting new regulatory pathways, such as a heterochromatin-specific modulation of DNA damage response involving H2A.X and WICH, both enriched in silent domains. Chromatin proteomics expands the arsenal of tools for deciphering how all the distinct protein components act together to enforce a given region-specific chromatin status. PMID:23319141

  13. Synergism between elevated pCO2 and temperature on the Antarctic sea ice diatom Nitzschia lecointei

    NASA Astrophysics Data System (ADS)

    Torstensson, A.; Hedblom, M.; Andersson, J.; Andersson, M. X.; Wulff, A.

    2013-10-01

    Polar oceans are particularly susceptible to ocean acidification and warming. Diatoms play a significant role in sea ice biogeochemistry and provide an important food source to grazers in ice-covered oceans, especially during early spring. However, the ecophysiology of ice-living organisms has received little attention in terms of ocean acidification. In this study, the synergism between temperature and partial pressure of CO2 (pCO2) was investigated in relationship to the optimal growth temperature of the Antarctic sea ice diatom Nitzschia lecointei. Diatoms were kept in cultures at controlled levels of pCO2 (∼390 and ∼960 μatm) and temperature (-1.8 and 2.5 °C) for 14 days. Synergism between temperature and pCO2 was detected in growth rate and acyl lipid fatty acid (FA) content. Optimal growth rate was observed around 5 °C in a separate experiment. Carbon enrichment only promoted (6%) growth rate closer to the optimal growth, but not at the control temperature (-1.8 °C). At -1.8 °C and at ∼960 μatm pCO2, the total FA content was reduced relative to the ∼390 μatm treatment, although no difference between pCO2 treatments was observed at 2.5 °C. A large proportion (97%) of the total FAs comprised on average of polyunsaturated fatty acids (PUFA) at -1.8 °C. Cellular PUFA content was reduced at ∼960 relative to ∼390 μatm pCO2. Effects of carbon enrichment may be different depending on ocean warming scenario or season, e.g. reduced cellular FA content in response to elevated CO2 at low temperatures only, reflected as reduced food quality for higher trophic levels. Synergy between warming and acidification may be particularly important in polar areas since a narrow thermal window generally limits cold-water organisms.

  14. Observing lowermost tropospheric ozone pollution with a new multispectral synergic approach of IASI infrared and GOME-2 ultraviolet satellite measurements

    NASA Astrophysics Data System (ADS)

    Cuesta, Juan; Foret, Gilles; Dufour, Gaëlle; Eremenko, Maxim; Coman, Adriana; Gaubert, Benjamin; Beekmann, Matthias; Liu, Xiong; Cai, Zhaonan; Von Clarmann, Thomas; Spurr, Robert; Flaud, Jean-Marie

    2014-05-01

    Tropospheric ozone is currently one of the air pollutants posing greatest threats to human health and ecosystems. Monitoring ozone pollution at the regional, continental and global scale is a crucial societal issue. Only spaceborne remote sensing is capable of observing tropospheric ozone at such scales. The spatio-temporal coverage of new satellite-based instruments, such as IASI or GOME-2, offer a great potential for monitoring air quality by synergism with regional chemistry-transport models, for both inter-validation and full data assimilation. However, current spaceborne observations using single-band either UV or IR measurements show limited sensitivity to ozone in the atmospheric boundary layer, which is the major concern for air quality. Very recently, we have developed an innovative multispectral approach, so-called IASI+GOME-2, which combines IASI and GOME-2 observations, respectively in the IR and UV. This unique multispectral approach has allowed the observation of ozone plumes in the lowermost troposphere (LMT, below 3 km of altitude) over Europe, for the first time from space. Our first analyses are focused on typical ozone pollution events during the summer of 2009 over Europe. During these events, LMT ozone plumes at different regions are produced photo-chemically in the boundary layer, transported upwards to the free troposphere and also downwards from the stratosphere. We have analysed them using IASI+GOME-2 observations, in comparison with single-band methods (IASI, GOME-2 and OMI). Only IASI+GOME-2 depicts ozone plumes located below 3 km of altitude (both over land and ocean). Indeed, the multispectral sensitivity in the LMT is greater by 40% and it peaks at 2 to 2.5 km of altitude over land, thus at least 0.8 to 1 km below that for all single-band methods. Over Europe during the summer of 2009, IASI+GOME-2 shows 1% mean bias and 21% precision for direct comparisons with ozonesondes and also good agreement with CHIMERE model simulations

  15. Satellite observation of lowermost tropospheric ozone by multispectral synergism of IASI thermal infrared and GOME-2 ultraviolet measurements over Europe

    NASA Astrophysics Data System (ADS)

    Cuesta, J.; Eremenko, M.; Liu, X.; Dufour, G.; Cai, Z.; Hoepfner, M.; von Clarmann, T.; Sellitto, P.; Foret, G.; Gaubert, B.; Beekmann, M.; Orphal, J. J.; Chance, K.; Spurr, R. J.; Flaud, J.

    2013-12-01

    Lowermost tropospheric ozone is a major factor determining air quality, which directly affects human health in megacities and causes damages to ecosystems. Monitoring tropospheric ozone is a key societal issue which can be addressed at the regional scale by spaceborne observation. However, current satellite retrievals of tropospheric ozone using uncoupled either ultraviolet (UV) or thermal infrared (TIR) observations show limited sensitivity to ozone at the lowermost troposphere (LMT, up to 3 km asl of altitude above sea level), which is the major concern for air quality. In this framework, we have developed a new multispectral approach for observing lowermost tropospheric ozone from space by synergism of atmospheric TIR radiances observed by IASI and earth UV reflectances measured by GOME-2. Both instruments are onboard the series of MetOp satellites (in orbit since 2006 and expected until 2022) and their scanning capabilities offer global coverage every day, with a relatively fine ground pixel resolution (12-km-diameter pixels spaced by 25 km for IASI at nadir). Our technique uses altitude-dependent Tikhonov-Phillips-type constraints, which optimize sensitivity to lower tropospheric ozone. It integrates the VLIDORT and KOPRA radiative transfer codes for simulating UV reflectance and TIR radiance, respectively. We have used our method to analyze real observations over Europe during an ozone pollution episode in the summer of 2009. The results show that the multispectral synergism of IASI (TIR) and GOME-2 (UV) enables the observation of the spatial distribution of ozone plumes in the LMT, in good agreement with the CHIMERE regional chemistry-transport model. In this case study, when high ozone concentrations extend vertically above 3 km asl, they are similarly observed over land by both the multispectral and IASI retrievals. On the other hand, ozone plumes located below 3 km asl are only clearly depicted by the multispectral retrieval (both over land and over ocean

  16. Synergism between baltergin metalloproteinase and Ba SPII RP4 PLA2 from Bothrops alternatus venom on skeletal muscle (C2C12) cells.

    PubMed

    Bustillo, Soledad; Gay, Claudia C; García Denegri, María E; Ponce-Soto, Luis A; Bal de Kier Joffé, Elisa; Acosta, Ofelia; Leiva, Laura C

    2012-02-01

    Acute muscle damage, myonecrosis, is one of the main characteristics of envenoming by Bothrops genus. In this in vitro study we investigated the role of a metalloproteinase (baltergin) and an acidic phospholipase A2 (Ba SPII RP4) in the cytotoxicity exhibited by Bothrops alternatus venom. Baltergin metalloproteinase purified from the venom exerted a toxic effect on C2C12 myoblast cells (CC50: 583.34 μg/mL) which involved morphological alterations compatible with apoptosis/anoikis. On the contrary, the most abundant PLA2 isolated from this venom did not exhibit cytotoxicity at times and doses tested. However, when myoblasts were treated with both enzymes together, synergic activity was demonstrated. Neutralization of the venom with specific antibodies (IgG anti-baltergin and IgG anti-PLA2) confirmed this synergism. Copyright © 2011 Elsevier Ltd. All rights reserved.

  17. Synergism between wild-type Bacillus thuringiensis subsp. israelensis and B. sphaericus strains: a study based on isobolographic analysis and histopathology.

    PubMed

    Sreshty, M Asha Latha; Kumar, K Pranay; Murty, U S N

    2011-04-01

    Prevention is the best resistance management strategy in integrated vector control programs. Combined use of insecticides of different classes that interact synergistically and show multi-site actions within the insect is recognized as a potential key strategy to be implemented even before the onset of resistance. The present study is aimed at harvesting the benefits of synergism between the wild-type Bacillus thuringiensis subsp. israelensis-H14 (Bti) and Bacillus sphaericus-2362 (Bs) strains by evaluating six different combinations of mixtures toxic to Aedes and Culex mosquito larvae. Isobolographic analysis was performed to distinguish the synergistic combinations of Bti and Bs, followed by determination of the degree of synergism through synergy and improvement factors. Furthermore, the speed of activity of Bs when combined with Bti is studied by histopathological investigations on the fate of midgut muscles of mosquito larvae upon exposure to individual wild-type strains as well as their mixtures.

  18. The Synergic Effects of Crocus Sativus L. and Low Frequency Electromagnetic Field on VEGFR2 Gene Expression in Human Breast Cancer Cells

    PubMed Central

    Mousavi, Marzieh; Baharara, Javad; Shahrokhabadi, Khadijeh

    2014-01-01

    Background Angiogenesis, which is required for embryonic development and many physiological events, plays crucial role in many pathological conditions such as tumor growth and metastasis. Recent studies indicate anticancer and antitumor properties of saffron against human cancers. Many processes are affected by Electromagnetic Field (EMF) and its effect on proliferation and gene expression were examined. In this experimental study, the synergic effects of saffron and EMF on VEGFR2 gene expression in MCF7 cells were investigated. Methods Saffron was extracted using freeze dryer. MCF7 cells were grown in RPMI 1640 medium supplemented with 10% FBS and incubated at 37°C with 5% CO2. After 24 hr cells were treated with saffron extract at concentrations of 100, 200, 400 and 800 µg/ml. Forty eight hr after treatment all flasks were exposed with EMF (50 Hz, 0.004 T). Then total RNA was extracted and cDNA was synthetized using specific primer. Synthetized products were analyzed by Real Time PCR to determine expression level of VEGFR2. Data were analyzed by SPSS (ANOVA & Tukey). Results Critical inhibitory effect on VEGFR2 gene expression was 20% at 400 µg/ml. Synergic use of EMF and saffron extract showed most reduction (38%) at 100 µg/ml. On the other hand synergic use of 200, 400 and 800 µg/ml saffron aqua extract and EMF decline noticeably the VEGFR2 level of gene expression to 29, 35 and 36%, respectively. EMF itself also reduced VEGFR2 up to 25% in comparison with control group which is remarkable at p < 0.001. Conclusion Results indicate a decrease in the expression of vascular endothelial growth factor receptor in the treated samples with saffron extract compared to control. This reduction in VEGFR2 level induced by synergic treatment of saffron and EMF which reveals induction of inhibitory effects of saffron on angiogenesis and could be also considered as a promising chemotherapeutic agent in breast cancer treatment. PMID:24834315

  19. Interaction of prostanoid EP₃ and TP receptors in guinea-pig isolated aorta: contractile self-synergism of 11-deoxy-16,16-dimethyl PGE₂.

    PubMed

    Jones, R L; Woodward, D F

    2011-01-01

    Surprisingly high contractile activity was reported for 11-deoxy-16,16-dimethyl prostaglandin E₂ (DX-DM PGE₂) on pig cerebral artery when used as a selective EP₃ receptor agonist. This study investigated the selectivity profile of DX-DM PGE₂, focusing on the interaction between its EP₃ and TP (thromboxane A₂-like) agonist activities. Contraction of guinea-pig trachea (EP₁ system) and aorta (EP₃ and TP systems) was measured in conventional organ baths. Strong contraction of guinea-pig aorta to sulprostone and 17-phenyl PGE₂ (EP₃ agonists) was only seen under priming with a second contractile agent such as phenylephrine, histamine or U-46619 (TP agonist). In contrast, DX-DM PGE₂ induced strong contraction, which on the basis of treatment with (DG)-3ap (EP₃ antagonist) and/or BMS-180291 (TP antagonist) was attributed to self-synergism arising from co-activation of EP₃ and TP receptors. EP₃/TP self-synergism also accounted for contraction induced by PGF(2α) and its analogues (+)-cloprostenol and latanoprost-FA. DX-DM PGE₂ also showed significant EP₁ agonism on guinea-pig trachea as defined by the EP₁ antagonists SC-51322, (ONO)-5-methyl-1 and AH-6809, although AH-6809 exhibited poor specificity at concentrations ≥3 µM. EP₃/TP self-synergism, as seen with PGE/PGF analogues in this study, may confound EP₃ agonist potency comparisons and the characterization of prostanoid receptor systems. The competitive profile of a TP antagonist may be distorted by variation in the silent/overt contraction profile of the EP₃ system in different studies. The relevance of self-synergism to in vivo actions of natural prostanoid receptor agonists is discussed. © 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.

  20. Growth factor and ultrasound-assisted bioreactor synergism for human mesenchymal stem cell chondrogenesis

    PubMed Central

    Thakurta, Sanjukta Guha; Budhiraja, Gaurav

    2015-01-01

    Ultrasound at 5.0 MHz was noted to be chondro-inductive, with improved SOX-9 gene and COL2A1 protein expression in constructs that allowed for cell-to-cell contact. To achieve tissue-engineered cartilage using macroporous scaffolds, it is hypothesized that a combination of ultrasound at 5.0 MHz and transforming growth factor-β3 induces human mesenchymal stem cell differentiation to chondrocytes. Expression of miR-145 was used as a metric to qualitatively assess the efficacy of human mesenchymal stem cell conversion. Our results suggest that in group 1 (no transforming growth factor-β3, no ultrasound), as anticipated, human mesenchymal stem cells were not efficiently differentiated into chondrocytes, judging by the lack of decrease in the level of miR-145 expression. Human mesenchymal stem cells differentiated into chondrocytes in group 2 (transforming growth factor-β3, no ultrasound) and group 3 (transforming growth factor-β3, ultrasound) with group 3 having a 2-fold lower miR-145 when compared to group 2 at day 7, indicating a higher conversion to chondrocytes. Transforming growth factor-β3–induced chondrogenesis with and without ultrasound stimulation for 14 days in the ultrasound-assisted bioreactor was compared and followed by additional culture in the absence of growth factors. The combination of growth factor and ultrasound stimulation (group 3) resulted in enhanced COL2A1, SOX-9, and ACAN protein expression when compared to growth factor alone (group 2). No COL10A1 protein expression was noted. Enhanced cell proliferation and glycosaminoglycan deposition was noted with the combination of growth factor and ultrasound stimulation. These results suggest that ultrasound at 5.0 MHz could be used to induce chondrogenic differentiation of mesenchymal stem cells for cartilage tissue engineering. PMID:25610590

  1. Arsenic trioxide (ATO) and MEK1 inhibition synergize to induce apoptosis in acute promyelocytic leukemia cells.

    PubMed

    Lunghi, P; Tabilio, A; Lo-Coco, F; Pelicci, P G; Pelicci, P; Bonati, A

    2005-02-01

    Recent studies suggest that components of the prosurvival signal transduction pathways involving the Ras-mitogen-activated protein kinase (MAPK) can confer an aggressive, apoptosis-resistant phenotype to leukemia cells. In this study, we report that acute promyelocytic leukemia (APL) cells exploit the Ras-MAPK activation pathway to phosphorylate at Ser112 and to inactivate the proapoptotic protein Bad, delaying arsenic trioxide (ATO)-induced apoptosis. Both in APL cell line NB4 and in APL primary blasts, the inhibition of extracellular signal-regulated kinases 1/2 (ERK1/2) and Bad phosphorylation by MEK1 inhibitors enhanced apoptosis in ATO-treated cells. We isolated an arsenic-resistant NB4 subline (NB4-As(R)), which showed stronger ERK1/2 activity (2.7-fold increase) and Bad phosphorylation (2.4-fold increase) compared to parental NB4 cells in response to ATO treatment. Upon ATO exposure, both NB4 and NB4-As(R) cell lines doubled protein levels of the death antagonist Bcl-xL, but the amount of free Bcl-xL that did not heterodimerize with Bad was 1.8-fold greater in NB4-As(R) than in the parental line. MEK1 inhibitors dephosphorylated Bad and inhibited the ATO-induced increase of Bcl-xL, overcoming ATO resistance in NB4-As(R). These results may provide a rationale to develop combined or sequential MEK1 inhibitors plus ATO therapy in this clinical setting.

  2. Geranylgeranylacetone and volatile anesthetic-induced cardiac protection synergism is dependent on caveolae and caveolin-3.

    PubMed

    Tsutsumi, Yasuo M; Tsutsumi, Rie; Horikawa, Yousuke T; Sakai, Yoko; Hamaguchi, Eisuke; Kitahata, Hiroshi; Kasai, Asuka; Kambe, Noriko; Tanaka, Katsuya

    2014-10-01

    Pharmacological preconditioning, including that with geranylgeranylacetone (GGA) and volatile anesthetics, has been shown to confer cardiac protection from ischemia/reperfusion injury although the mechanisms for this protection are poorly understood. Caveolins, integral membrane proteins that act as scaffolding proteins in caveolar membranes, localize molecules involved in cardiac protection. We have tested the hypothesis that caveolin-3 (Cav-3), the predominant isoform in cardiac myocytes, is essential for the synergistic effect observed between GGA and volatile anesthetics. Mice were randomly assigned to receive GGA, isoflurane [0.5 and 1.0 minimum alveolar concentration (MAC)], or GGA + isoflurane (0.5 MAC). An in vivo mouse model of ischemia/reperfusion injury was tested in wild-type and Cav-3 knockout mice, and the infarct size was determined. Biochemical assays were also performed in excised hearts. Geranylgeranylacetone and therapeutic isoflurane (1.0 MAC) independently reduced infarct size (31.6 ± 6.1 and 28.0 ± 5.0% of the area at risk, respectively; n = 10) as compared to the controls (45.8 ± 9.4%; n = 10). The combination GGA + sub-therapeutic isoflurane (0.5 MAC) further decreased the infarct size to 19.3 ± 5.1% (n = 10). Preconditioning [GGA, isoflurane (1.0 MAC), and GGA + isoflurane] increased the amount of Cav-3 protein in the discontinuous sucrose-gradient buoyant fractions. Additionally, cardiac protection was not observed in Cav-3 knockout mice following the administration of GGA, isoflurane, and GGA + isoflurane. Combined administration of GGA + isoflurane had a synergistic effect, enhancing the protection against myocardial infarction to a greater extent than either drug alone. This beneficial effect is mediated by Cav-3 expression.

  3. Combination of the CCL5-Derived Peptide R4.0 with Different HIV-1 Blockers Reveals Wide Target Compatibility and Synergic Cobinding to CCR5

    PubMed Central

    Secchi, Massimiliano; Vassena, Lia; Morin, Sébastien; Schols, Dominique

    2014-01-01

    R4.0, a synthetic CCL5/RANTES-derived peptide, exerts potent anti-HIV-1 activity via its nonactivating interaction with CCR5, the major HIV-1 coreceptor. CCR5 chronic activation may promote undesirable inflammatory effects and enhance viral infection; thus, receptor antagonism is a necessary requisite. HIV-1 gp120, CCL5, and maraviroc dock on CCR5 by sharing two receptor sites: the N terminus and the second extracellular loop. In combination studies, R4.0, CCL5, and maraviroc exhibited concomitant interactions with CCR5 and promoted synergic inhibition of HIV-1 in acute-infection assays. Furthermore, various degrees of additive/synergic HIV-1 inhibition were observed when R4.0 was tested in combination with drugs and lead compounds directed toward different viral targets (gp120, gp41, reverse transcriptase, and protease). In combination with tenofovir, R4.0 provides cross-clade synergic inhibition of primary HIV-1 isolates. Remarkably, an in vitro-generated maraviroc-resistant R5 HIV-1 strain was inhibited by R4.0 comparably to the wild-type strain, suggesting the presence of viral resistance barriers similar to those reported for CCL5. Overall, R4.0 appears to be a promising lead peptide with potential for combination in anti-HIV-1 therapy and in microbicide development to prevent sexual HIV-1 transmission. PMID:25114130

  4. Synergism from combinations of tris(benzimidazole) monochloroplatinum(II) chloride with capsaicin, quercetin, curcumin and cisplatin in human ovarian cancer cell lines.

    PubMed

    Arzuman, Laila; Beale, Philip; Chan, Charles; Yu, Jun Q; Huq, Fazlul

    2014-10-01

    In the present study, synergism in activity from the sequenced combinations of monofunctional platinum tris(benzimidazole)monochloroplatinum(II) chloride (coded as LH4) with capsaicin, quercetin, curcumin and cisplatin was investigated as a function of sequence of administration in a number of human ovarian tumor models. Cellular accumulations of platinum and the levels of platinum-DNA binding were also determined for the 0/0 h and 4/0 sequences of administration. LH4 was found to be more active against the resistant A2780(cisR) and A2780(ZD0473R) cell lines than the parent A2780 cell line. As applied to combinations of LH4 with phytochemicals capsaicin, quercetin and curcumin, bolus administration was found to be most synergistic in both the parent A2780 and the resistant A2780(cisR) cell lines. For the combinations of LH4 with cisplatin, additiveness was observed in both the resistant cell lines but mild synergism was observed in the parent cell line. Greater activity of designed monofunctional platinum LH4 against resistant tumor models and synergism from combinations with phytochemicals indicate that the compound has the potential for development as a novel platinum-based anticancer drug.

  5. Combination of the CCL5-derived peptide R4.0 with different HIV-1 blockers reveals wide target compatibility and synergic cobinding to CCR5.

    PubMed

    Secchi, Massimiliano; Vassena, Lia; Morin, Sébastien; Schols, Dominique; Vangelista, Luca

    2014-10-01

    R4.0, a synthetic CCL5/RANTES-derived peptide, exerts potent anti-HIV-1 activity via its nonactivating interaction with CCR5, the major HIV-1 coreceptor. CCR5 chronic activation may promote undesirable inflammatory effects and enhance viral infection; thus, receptor antagonism is a necessary requisite. HIV-1 gp120, CCL5, and maraviroc dock on CCR5 by sharing two receptor sites: the N terminus and the second extracellular loop. In combination studies, R4.0, CCL5, and maraviroc exhibited concomitant interactions with CCR5 and promoted synergic inhibition of HIV-1 in acute-infection assays. Furthermore, various degrees of additive/synergic HIV-1 inhibition were observed when R4.0 was tested in combination with drugs and lead compounds directed toward different viral targets (gp120, gp41, reverse transcriptase, and protease). In combination with tenofovir, R4.0 provides cross-clade synergic inhibition of primary HIV-1 isolates. Remarkably, an in vitro-generated maraviroc-resistant R5 HIV-1 strain was inhibited by R4.0 comparably to the wild-type strain, suggesting the presence of viral resistance barriers similar to those reported for CCL5. Overall, R4.0 appears to be a promising lead peptide with potential for combination in anti-HIV-1 therapy and in microbicide development to prevent sexual HIV-1 transmission.

  6. Organophosphorus insecticides synergize pyrethroids in the resistant strain of cotton bollworm, Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) from West Africa.

    PubMed

    Martin, Thibaud; Ochou, Ochou G; Vaissayre, Maurice; Fournier, Didier

    2003-04-01

    Helicoverpa armigera (Hübner) populations from West Africa recently developed resistance to pyrethroid insecticides through enhanced metabolism by mixed-function oxidases. The combination index method was used to study the synergism of pyrethroids by organophosphorus insecticides. Several mixtures of insecticides currently registered to control cotton pest complex in West Africa were tested, including: cypermethrin/ethion, cypermethrin/profenofos, deltamethrin/ triazophos, deltamethrin/chlorpyriphos, cyfluthrin/chlorpyriphos, and betacyfluthrin/chlorpyriphos. In the resistant strain, the organophosphorus insecticides significantly increased the toxicity of pyrethroids suppressing the resistance effect, either by additive or synergistic effects. Significant synergism was shown for the following mixtures: cypermethrin/ethion, deltamethrin/triazophos, and deltamethrin/chlorpyriphos. The use of synergism from these insecticide mixtures should prove to be an additional tool in the overall resistance management strategy because the pyrethroid resistance in H. armigera from West Africa is not yet stable, decreasing between cotton seasons and increasing with treatments. In absence of selection, the susceptibility of H. armigera to insecticides should be restored.

  7. Higher education and psychological distress: a 27-year prospective cohort study in Sweden.

    PubMed

    Brännlund, Annica; Hammarström, Anne

    2014-03-01

    Research identifies a positive link between education and a reduction of psychological distress, but few studies have analysed the long-term impact of education on psychological distress. This study followed the same cohort for 27 years, investigating the association between education and adult psychological distress. Further, it discuss whether the link can be understood through the mediating mechanisms of social and labour-market resources, furthermore, if the mechanisms operate differently for men and women. A 27-year prospective cohort study was performed at ages 16, 18, 21, 30 and 43. The cohort consisted of all students (n = 1083, of which 1001 are included in this study) in their final year of compulsory school in Sweden. Data were collected through comprehensive questionnaires (response rate 96.4%), and analysed with OLS regression, with psychological distress at age 21, 30 and 43 as dependent variable. Baseline psychological distress, measures of social and labour-market resources, and possible educational selection factors were used as independent variables. To compare the overall magnitude of educational differences, a kappa index was calculated. A positive relation between higher education and less psychological distress was found. When becoming older this relation weakens and a link between social and labour-market resources and psychological distress is observed, indicating that education in a long-term perspective operates through the suggested mechanisms. Additionally, the mechanisms work somewhat differently for men than for women: labour-market resources were significant for men and social resources were important for women. higher education is positively linked to less psychological distress, and the link can somewhat be understood through the mechanisms of social and labour-market resources.

  8. Evolution of gender representation among Canadian OTL-HNS residents: a 27-year analysis.

    PubMed

    Chorfi, Sarah; Schwartz, Joseph S; Verma, Neil; Young, Meredith; Joseph, Lawrence; Nguyen, Lily H P

    2017-08-29

    The proportion of females enrolling into medical schools has been growing steadily. However, the representation of female residents among individual specialties has shown considerable variation. The purpose of this study was to compare the trends of gender representation in Otolaryngology - Head and Neck Surgery (OTL-HNS) residency programs with other specialty training programs in Canada. In order to contextualize these findings, a second phase of analysis examined the success rate of applicants of different genders to OTL-HNS residency programs. Anonymized data were obtained from the Canadian Residency Matching Service (CaRMS) and from the Canadian Post-M.D. Education Registry (CAPER) from 1988 to 2014. The differences in gender growth rates were compared to other subspecialty programs of varying size. Descriptive analysis was used to examine gender representation among OTL-HNS residents across years, and to compare these trends with other specialties. Bayesian hierarchical models were fit to analyze the growth in program rates in OTL-HNS based on gender. CaRMS and CAPER data over a 27 year period demonstrated that OTL-HNS has doubled its female representation from 20% to 40% between 1990 and 1994 and 2010-2014. The difference in annual growth rate of female representation versus male representation in OTL-HNS over this time period was 2.7%, which was similar to other large specialty programs and surgical subspecialties. There was parity in success rates of female and male candidates ranking OTL-HNS as their first choice specialty for most years. Female representation in Canadian OTL-HNS residency programs is steadily increasing over the last 27 years. Large variation in female applicant acceptance rates was observed across Canadian universities, possibly attributable to differences in student body or applicant demographics. Factors influencing female medical student career selection to OTL-HNS require further study to mitigate disparities in gender

  9. Protein Dependent Activation of the Unfolded Protein Response (UPR) Enables Prostate Cancer Development and a Druggable Target for Advance Prostate Cancer Therapy

    DTIC Science & Technology

    2016-10-01

    protein synthesis upon oncogenic insult is poorly understood. We showed that prostate cancer initiation and maintenance, following combined loss of the...survival. Specifically, we have employed a novel genetic mouse model coupling PTEN loss with MYC overexpression in the prostate and we observe that...overexpression of Myc in the prostate synergizes with PTEN loss to dramatically stimulate the PERK and IRE1 signaling arms of the UPR pathway, which

  10. MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors.

    PubMed

    Knorr, K L B; Schneider, P A; Meng, X W; Dai, H; Smith, B D; Hess, A D; Karp, J E; Kaufmann, S H

    2015-12-01

    MLN4924 (pevonedistat), an inhibitor of the Nedd8 activating enzyme (NAE), has exhibited promising clinical activity in acute myelogenous leukemia (AML). Here we demonstrate that MLN4924 induces apoptosis in AML cell lines and clinical samples via a mechanism distinct from those observed in other malignancies. Inactivation of E3 cullin ring ligases (CRLs) through NAE inhibition causes accumulation of the CRL substrate c-Myc, which transactivates the PMAIP1 gene encoding Noxa, leading to increased Noxa protein, Bax and Bak activation, and subsequent apoptotic changes. Importantly, c-Myc knockdown diminishes Noxa induction; and Noxa siRNA diminishes MLN4924-induced killing. Because Noxa also neutralizes Mcl-1, an anti-apoptotic Bcl-2 paralog often upregulated in resistant AML, further experiments have examined the effect of combining MLN4924 with BH3 mimetics that target other anti-apoptotic proteins. In combination with ABT-199 or ABT-263 (navitoclax), MLN4924 exerts a synergistic cytotoxic effect. Collectively, these results provide new insight into MLN4924-induced engagement of the apoptotic machinery that could help guide further exploration of MLN4924 for AML.

  11. Study on the synergic effect of natural compounds on the microbial quality decay of packed fish hamburger.

    PubMed

    Corbo, M R; Speranza, B; Filippone, A; Granatiero, S; Conte, A; Sinigaglia, M; Del Nobile, M A

    2008-10-31

    The effectiveness of natural compounds in slowing down the microbial quality decay of refrigerated fish hamburger is addressed in this study. In particular, the control of the microbiological spoilage by combined use of three antimicrobials, and the determination of their optimal composition to extend the fish hamburger Microbiological Stability Limit (MAL) are the main objectives of this work. Thymol, grapefruit seed extract (GFSE) and lemon extract were tested for monitoring the cell growth of the main fish spoilage microorganisms (Pseudomonas fluorescens, Photobacterium phosphoreum and Shewanella putrefaciens), inoculated in fish hamburgers, and the growth of mesophilic and psychrotrophic bacteria. A Central Composite Design (CCD) was developed to highlight a possible synergic effect of the above natural compounds. Results showed an increase in the MAL value for hamburgers mixed with the antimicrobial compounds, compared to the control sample. The optimal antimicrobial compound composition, which corresponds to the maximal MAL value determined in this study, is: 110 mgL(-1) of thymol, 100 mgL(-1) of GFSE and 120 mgL(-1) of lemon extract. The presence of the natural compounds delay the sensorial quality decay without compromising the flavor of the fish hamburgers.

  12. Gingerol Synergizes the Cytotoxic Effects of Doxorubicin against Liver Cancer Cells and Protects from Its Vascular Toxicity.

    PubMed

    Al-Abbasi, Fahad A; Alghamdi, Eman A; Baghdadi, Mohammed A; Alamoudi, Abdulmohsin J; El-Halawany, Ali M; El-Bassossy, Hany M; Aseeri, Ali H; Al-Abd, Ahmed M

    2016-07-08

    Hydroxyphenylalkanes and diarylheptanoids possess potential therapeutic value in different pathophysiological conditions, such as malignancy. In the current study, naturally isolated hydroxyphenylalkane and diarylheptanoid compounds were investigated for potential chemo-modulatory effects in addition to potential vascular protective roles with doxorubicin. Diarylheptanoids showed stronger antioxidant effects, in comparison to hydroxyphenylalkanes, as demonstrated by DPPH assay and amelioration of CCl₄-induced disturbed intracellular GSH/GSSG balance. Shogaol and 4'-methoxygingerol showed considerable cytotoxic effects against HCT116, HeLa, HepG2 and MCF7 cells, with IC50 values ranging from 3.1 to 19.4 µM. Gingerol significantly enhanced the cytotoxic profile of doxorubicin against HepG₂ and Huh7, cells decreasing its IC50s by 10- and 4-fold, respectively. Cell cycle distribution was studied using DNA cytometry. Doxorubicin alone induced cell accumulation at S-phase and G₂/M-phase, while in combination with gingerol it significantly induced cell cycle arrest at the G₂/M-phase. Additionally, the vascular protective effect of gingerol against doxorubicin (10 µM) was examined on isolated aortic rings. Co-incubation with 6-gingerol (30 µM) completely blocked the exaggerated vasoconstriction and impaired vascular relaxation induced by doxorubicin. In conclusion, despite its relatively weak antioxidant properties, gingerol protected from DOX-induced vascular damage, apparently not through a ROS scavenging mechanism. Besides, gingerol synergized the cytotoxic effects of DOX against liver cancer cells without influencing the cellular pharmacokinetics.

  13. Melatonin synergizes with citalopram to induce antidepressant-like behavior and to promote hippocampal neurogenesis in adult mice.

    PubMed

    Ramírez-Rodríguez, Gerardo; Vega-Rivera, Nelly Maritza; Oikawa-Sala, Julián; Gómez-Sánchez, Ariadna; Ortiz-López, Leonardo; Estrada-Camarena, Erika

    2014-05-01

    Adult hippocampal neurogenesis is affected in some neuropsychiatric disorders such as depression. Numerous evidence indicates that plasma levels of melatonin are decreased in depressed patients. Also, melatonin exerts positive effects on the hippocampal neurogenic process and on depressive-like behavior. In addition, antidepressants revert alterations of hippocampal neurogenesis present in models of depression following a similar time course to the improvement of behavior. In this study, we analyzed the effects of both, citalopram, a widely used antidepressant, and melatonin in the Porsolt forced swim test. In addition, we investigated the potential antidepressant role of the combination of melatonin and citalopram (MLTCITAL), its type of pharmacological interaction on depressive behavior, and its effect on hippocampal neurogenesis. Here, we found decreased immobility behavior in mice treated with melatonin (<14-33%) and citalopram (<17-30%). Additionally, the MLTCITAL combination also decreased immobility (<22-35%) in comparison with control mice, reflecting an antidepressant-like effect after 14 days of treatment. Moreover, MLTCITAL decreased plasma corticosterone levels (≤13%) and increased cell proliferation (>29%), survival (>39%), and the absolute number of -associated new neurons (>53%) in the dentate gyrus of the hippocampus. These results indicate that the MLTCITAL combination exerts synergism to induce an antidepressant-like action that could be related to the modulation of adult hippocampal neurogenesis. This outcome opens the opportunity of using melatonin to promote behavioral benefits and hippocampal neurogenesis in depression and also supports the use of the MLTCITAL combination as an alternative to treat depression.

  14. Capsaicin synergizes with camptothecin to induce increased apoptosis in human small cell lung cancers via the calpain pathway.

    PubMed

    Friedman, Jamie R; Perry, Haley E; Brown, Kathleen C; Gao, Ying; Lin, Ju; Stevenson, Cathyrn D; Hurley, John D; Nolan, Nicholas A; Akers, Austin T; Chen, Yi Charlie; Denning, Krista L; Brown, Linda G; Dasgupta, Piyali

    2017-04-01

    Small cell lung cancer (SCLC) is characterized by excellent initial response to chemotherapy and radiation therapy with a majority of the patients showing tumor shrinkage and even remission. However, the challenge with SCLC therapy is that patients inevitably relapse and subsequently do not respond to the first line treatment. Recent clinical studies have investigated the possibility of camptothecin-based combination therapy as first line treatment for SCLC patients. Conventionally, camptothecin is used for recurrent SCLC and has poor survival outcomes. Therefore, drugs which can improve the therapeutic index of camptothecin should be valuable for SCLC therapy. Extensive evidence shows that nutritional compounds like capsaicin (the spicy compound of chili peppers) can improve the anti-cancer activity of chemotherapeutic drugs in both cell lines and animal models. Statistical analysis shows that capsaicin synergizes with camptothecin to enhance apoptosis of human SCLC cells. The synergistic activity of camptothecin and capsaicin is observed in both classical and variant SCLC cell lines and, in vivo, in human SCLC tumors xenotransplanted on chicken chorioallantoic membrane (CAM) models. The synergistic activity of capsaicin and camptothecin are mediated by elevation of intracellular calcium and the calpain pathway. Our data foster hope for novel nutrition based combination therapies in SCLC.

  15. Sarcopenia and physical independence in older adults: the independent and synergic role of muscle mass and muscle function

    PubMed Central

    dos Santos, Leandro; Cyrino, Edilson S.; Antunes, Melissa; Santos, Diana A.

    2016-01-01

    Abstract Background The loss of skeletal muscle mass (MM) or muscle function (MF) alone increases the risk for losing physical independence in older adults. We aimed to examine the independent and synergic associations of low MM and low MF, both criteria of sarcopenia, with the risk for losing projected physical independence in later life (+90 years old). Methods Cross‐sectional analyses were conducted in 3493 non‐institutionalized older adults (1166 males). Physical independence was assessed with a 12‐item composite physical function scale. Logistic regression was used to estimate the odds‐ratio (OR) for being at risk for losing physical independence. Results Approximately 30% of the participants were at risk for losing physical independence at 90 years of age. Independent analysis demonstrated that participants with low MM had 1.65 (95%CI: 1.27–2.31) increased odds for being at risk for losing physical independence and participants with low MF had 6.19 (95%CI 5.08–7.53) increased odds for being at risk. Jointly, having a low MM and a low MF increased the risk for losing physical independence to 12.28 (95%CI 7.95 to 18.96). Conclusions Although low MM represents a risk factor for losing physical independence, low MF seems to play a more dominant role in this relationship, with the presence of both sarcopenia criteria representing a substantial risk for losing physical independence in later life. PMID:27897417

  16. Synergic effect of oral contraceptives, GSTP1 polymorphisms, and high-risk HPV infection in development of cervical lesions.

    PubMed

    Chagas, B S; Gurgel, A P A D; Paiva Júnior, S S L; Lima, R C P; Cordeiro, M N; Moura, R R; Coelho, A V C; Nascimento, K C G; Silva Neto, J C; Crovella, S; Freitas, A C

    2017-08-17

    Human papillomavirus (HPV) infection is considered a risk factor for cervical cancer. Even if the high-risk HPV (HR-HPV) infection is necessary, environmental co-factors and genetic susceptibility also play an important role in cervical cancer development. In this study, a possible association of rs1695 GSTP1 polymorphisms, HR-HPV infection, and oral contraceptive use with cancer lesion development in women was investigated. The study population comprised 441 Brazilian women from the Northeast region including 98 HPV-infected women with high-grade squamous intraepithelial lesions, 77 HPV-infected women with low-grade squamous intraepithelial lesions, and 266 HPV-negative women with no lesion, used as a control. Our data did not show a significant association between the GSTP1 polymorphism A/G (rs1695) and any HPV-related cervical abnormalities. However, considering the use of oral contraceptives, the GSTP1 rs1695 polymorphism was associated with higher susceptibility to the development of cervical lesions in HR-HPV-infected women. Our study suggests a synergic effect of oral contraceptive use, GSTP1 polymorphisms, and HR-HPV infection in the development of cervical lesions. Together, these risk factors may induce neoplastic transformation of the cervical squamous epithelium, setting conditions for secondary genetic events leading to cervical cancer.

  17. The synergic antitumor effects of paclitaxel and temozolomide co-loaded in mPEG-PLGA nanoparticles on glioblastoma cells.

    PubMed

    Xu, Yuanyuan; Shen, Ming; Li, Yiming; Sun, Ying; Teng, Yanwei; Wang, Yi; Duan, Yourong

    2016-04-12

    To get better chemotherapy efficacy, the optimal synergic effect of Paclitaxel (PTX) and Temozolomide (TMZ) on glioblastoma cells lines was investigated. A dual drug-loaded delivery system based on mPEG-PLGA nanoparticles (NPs) was developed to potentiate chemotherapy efficacy for glioblastoma. PTX/TMZ-NPs were prepared with double emulsification solvent evaporation method and exhibited a relatively uniform diameter of 206.3 ± 14.7 nm. The NPs showed sustained release character. Cytotoxicity assays showed the best synergistic effects were achieved when the weight ratios of PTX to TMZ were 1:5 and 1:100 on U87 and C6 cells, respectively. PTX/TMZ-NPs showed better inhibition effect to U87 and C6 cells than single drug NPs or free drugs mixture. PTX/TMZ-NPs (PTX: TMZ was 1:5(w/w)) significantly inhibited the tumor growth in the subcutaneous U87 mice model. These results indicate that coordinate administration of PTX and TMZ combined with NPs is an efficient method for glioblastoma.

  18. High metabolic demand in neural tissues: Information and control theory perspectives on the synergism between rate and stability.

    PubMed

    Wallace, Rodrick

    2016-11-21

    Evolutionary process has been selected for inherently unstable systems in higher animals that can react swiftly to changing patterns of threat or opportunity, for example blood pressure, the immune response, and gene expression. However, these require continual strict regulation: uncontrolled blood pressure is fatal, immune cells can attack 'self' tissues, and improper gene expression triggers developmental disorders. Consciousness in particular demands high rates of metabolic free energy to both operate and regulate the fundamental biological machinery: both the 'stream of consciousness' and the 'riverbanks' that confine it to useful realms are constructed and reconstructed moment-by-moment in response to highly dynamic internal and environmental circumstances. We develop powerful necessary conditions models for such phenomena based on the Data Rate Theorem linking control and information theories in the context of inherent instability. The synergism between conscious action and its regulation underlies the ten-fold higher rate of metabolic energy consumption in human neural tissues and implies a close, culturally modulated relation between sleep disorders and certain psychopathologies.

  19. Triclosan Demonstrates Synergic Effect with Amphotericin B and Fluconazole and Induces Apoptosis-Like Cell Death in Cryptococcus neoformans

    PubMed Central

    Movahed, Elaheh; Tan, Grace Min Yi; Munusamy, Komathy; Yeow, Tee Cian; Tay, Sun Tee; Wong, Won Fen; Looi, Chung Yeng

    2016-01-01

    Objectives: Cryptococcus neoformans is an opportunistic fungus that causes fatal meningoencephalitis especially in AIDS patients. There is an increasing need for discovery of new anti-cryptococcal drugs due to emergence of resistance cases in recent years. In this study, we aim to elucidate the antifungal effect of triclosan against C. neoformans. Methods: Minimal inhibitory concentration (MIC) of triclosan in different C. neoformans strains was first examined. The in vitro interactions between triclosan and two standard anti-fungal drugs (amphotericin B and fluconazole) were further evaluated by microdilution checkerboard assay. Mechanism of triclosan fungicidal activity was then investigated by viewing the cell morphology under transmission electron microscope. Results: We reported that triclosan potently inhibited the growth of C. neoformans. A combination of triclosan with amphotericin B or with fluconazole enhanced their fungicidal effects. Triclosan-treated C. neoformans displayed characteristics such as nuclear chromatin condensation, extensive intracellular vacuolation and mitochondrial swelling, indicating that triclosan triggered apoptosis-like cell death. Conclusion: In summary, our report suggests triclosan as an independent drug or synergent for C. neoformans treatment. PMID:27047474

  20. The synergic effect of regular exercise and resveratrol on kainate-induced oxidative stress and seizure activity in mice.

    PubMed

    Kim, Hee-jae; Kim, Il-Kon; Song, Wook; Lee, Jin; Park, Sok

    2013-01-01

    The synergic effect of regular exercise and resveratrol, a polyphenolic compound with potent antioxidant activity, was investigated against kainate-induced seizures and oxidative stress in mice. After 6 weeks of swimming training, the total body weight decreased and the blood concentration of lactate stabilized statistically in comparison with the sedentary mice, indicate that the training program increased the aerobic resistance of mice. Kainate (30 mg/kg) evoked seizure activity 5 min after injection, and seizure activity was measured seizure rating scores every 5 min up to 2 h. As previously well known experiments, regular exercise and resveratrol (40 mg/kg, daily supplementation for 6 weeks) have an inhibitory effect on kainate-induced seizure activity and oxidative stress. In particularly, a synergistic cooperation of regular exercise and resveratrol was observed in seizure activity, mortality and oxidative stress especially in SOD activity. These results suggest that regular exercise along with an anti-convulsant agent such as resveratrol could be a more efficient method for the prevention of seizure development than exercise alone.

  1. Synergism and Rules of the new Combination drug Yiqijiedu Formulae (YQJD) on Ischemic Stroke based on amino acids (AAs) metabolism

    PubMed Central

    Gao, Jian; Chen, Chang; Chen, Jian-Xin; Wen, Li-Mei; Yang, Geng-Liang; Duan, Fei-Peng; Huang, Zhi-Ying; Li, De-Feng; Yu, Ding-Rong; Yang, Hong-Jun; Li, Shao-Jing

    2014-01-01

    The use of combination drugs is considered to be a promising strategy to control complex diseases such as ischemic stroke. The detection of metabolites has been used as a versatile tool to reveal the potential mechanism of diverse diseases. In this study, the levels of 12 endogenous AAs were simultaneously determined quantitatively in the MCAO rat brain using RRLC-QQQ method. Seven AAs were chosen as the potential biomarkers, and using PLS-DA analysis, the effects of the new combination drug YQJD, which is composed of ginsenosides, berberine, and jasminoidin, on those 7 AAs were evaluated. Four AAs, glutamic acid, homocysteine, methionine, and tryptophan, which changed significantly in the YQJD-treated groups compared to the vehicle groups (P < 0.05), were identified and designated as the AAs to use to further explore the synergism of YQJD. The result of a PCA showed that the combination of these three drugs exhibits the strongest synergistic effect compared to other combination groups and that ginsenosides might play a pivotal role, especially when combined with jasminoidin. We successfully explored the synergetic mechanism of multi-component and provided a new method for evaluating the integrated effects of combination drugs in the treatment of complex diseases. PMID:24889025

  2. Green tea extract as food antioxidant. Synergism and antagonism with α-tocopherol in vegetable oils and their colloidal systems.

    PubMed

    Yin, Jie; Becker, Eleonora Miquel; Andersen, Mogens L; Skibsted, Leif H

    2012-12-15

    The antioxidant effects of α-tocopherol (TOH) in combination with green tea extract (GTE), the green tea polyphenol (-)-epicatechin (EC) or the isomeric (+)-catechin (C), were investigated using different lipid systems based on high linoleic sunflower oil: bulk oil, o/w-emulsion and a phosphatidylcholine-based liposome system. Both polyphenols as well as TOH were efficient antioxidants in all systems when used alone, as detected by the formation of free radicals and conjugated dienes and by oxygen consumption. Strong synergistic effect was found for the combination of TOH and GTE in a methyl linoleate o/w-emulsion and in the pure bulk oil, while only an additive effect was observed in a liposome system. The synergism was already evident for the tendency for radical formation in the bulk oil as detected by electron spin resonance (ESR) spectroscopy. On the contrary, combinations of TOH with either EC or C showed clear synergistic effects in both heterogeneous systems, but antagonistic or additive effects in bulk oil. GTE may accordingly be used to protect both vegetable oils and their emulsions against oxidation through enhancement of the activity of their endogenous antioxidants, while GTE is less efficient in the protection of phospholipids as in liposomes.

  3. Antioxidant activity of amino acids in soybean oil at frying temperature: Structural effects and synergism with tocopherols.

    PubMed

    Hwang, Hong-Sik; Winkler-Moser, Jill K

    2017-04-15

    The purpose of this study was to evaluate amino acids as natural antioxidants for frying. Twenty amino acids were added to soybean oil heated to 180°C, and the effects of amino acid structure on the antioxidant activity were investigated. Amino acids containing a thiol, a thioether, or an extra amine group such as arginine, cysteine, lysine, methionine, and tryptophan had the strongest antioxidant activities. At 5.5mM, these amino acids had stronger antioxidant activities than 0.02% (1.1mM) tert-butylhydroquinone (TBHQ). A functional group such as an amide, carboxylic acid, imidazole, or phenol appeared to negatively affect amino acid antioxidant activity. Synergism between amino acids and tocopherols was demonstrated, and we found that this synergistic interaction may be mostly responsible for the antioxidant activity that was observed. In a frying study with potato cubes, 5.5mM l-methionine had significantly stronger antioxidant activity than 0.02% TBHQ. Published by Elsevier Ltd.

  4. The synergic antitumor effects of paclitaxel and temozolomide co-loaded in mPEG-PLGA nanoparticles on glioblastoma cells

    PubMed Central

    Li, Yiming; Sun, Ying; Teng, Yanwei; Wang, Yi; Duan, Yourong

    2016-01-01

    To get better chemotherapy efficacy, the optimal synergic effect of Paclitaxel (PTX) and Temozolomide (TMZ) on glioblastoma cells lines was investigated. A dual drug-loaded delivery system based on mPEG-PLGA nanoparticles (NPs) was developed to potentiate chemotherapy efficacy for glioblastoma. PTX/TMZ-NPs were prepared with double emulsification solvent evaporation method and exhibited a relatively uniform diameter of 206.3 ± 14.7 nm. The NPs showed sustained release character. Cytotoxicity assays showed the best synergistic effects were achieved when the weight ratios of PTX to TMZ were 1:5 and 1:100 on U87 and C6 cells, respectively. PTX/TMZ-NPs showed better inhibition effect to U87 and C6 cells than single drug NPs or free drugs mixture. PTX/TMZ-NPs (PTX: TMZ was 1:5(w/w)) significantly inhibited the tumor growth in the subcutaneous U87 mice model. These results indicate that coordinate administration of PTX and TMZ combined with NPs is an efficient method for glioblastoma. PMID:26956046

  5. Synergic Effect between Adsorption and Photocatalysis of Metal-Free g-C3N4 Derived from Different Precursors

    PubMed Central

    Xu, Huan-Yan; Wu, Li-Cheng; Zhao, Hang; Jin, Li-Guo; Qi, Shu-Yan

    2015-01-01

    Graphitic carbon nitride (g-C3N4) used in this work was obtained by heating dicyandiamide and melamine, respectively, at different temperatures. The differences of g-C3N4 derived from different precursors in phase composition, functional group, surface morphology, microstructure, surface property, band gap and specific surface area were investigated by X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, UV-visible diffuse reflection spectroscopy and BET surface area analyzer, respectively. The photocatalytic discoloration of an active cationic dye, Methylene Blue (MB) under visible-light irradiation indicated that g-C3N4 derived from melamine at 500°C (CN-M500) had higher adsorption capacity and better photocatalytic activity than that from dicyandiamide at 500°C (CN-D500), which was attributed to the larger surface area of CN-M500. MB discoloration ratio over CN-M500 was affected by initial MB concentration and photocatalyst dosage. After 120 min reaction time, the blue color of MB solution disappeared completely. Subsequently, based on the measurement of the surface Zeta potentials of CN-M500 at different pHs, an active anionic dye, Methyl Orange (MO) was selected as the contrastive target pollutant with MB to reveal the synergic effect between adsorption and photocatalysis. Finally, the photocatalytic mechanism was discussed. PMID:26565712

  6. Synergic Effect between Adsorption and Photocatalysis of Metal-Free g-C3N4 Derived from Different Precursors.

    PubMed

    Xu, Huan-Yan; Wu, Li-Cheng; Zhao, Hang; Jin, Li-Guo; Qi, Shu-Yan

    2015-01-01

    Graphitic carbon nitride (g-C3N4) used in this work was obtained by heating dicyandiamide and melamine, respectively, at different temperatures. The differences of g-C3N4 derived from different precursors in phase composition, functional group, surface morphology, microstructure, surface property, band gap and specific surface area were investigated by X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, UV-visible diffuse reflection spectroscopy and BET surface area analyzer, respectively. The photocatalytic discoloration of an active cationic dye, Methylene Blue (MB) under visible-light irradiation indicated that g-C3N4 derived from melamine at 500°C (CN-M500) had higher adsorption capacity and better photocatalytic activity than that from dicyandiamide at 500°C (CN-D500), which was attributed to the larger surface area of CN-M500. MB discoloration ratio over CN-M500 was affected by initial MB concentration and photocatalyst dosage. After 120 min reaction time, the blue color of MB solution disappeared completely. Subsequently, based on the measurement of the surface Zeta potentials of CN-M500 at different pHs, an active anionic dye, Methyl Orange (MO) was selected as the contrastive target pollutant with MB to reveal the synergic effect between adsorption and photocatalysis. Finally, the photocatalytic mechanism was discussed.

  7. A high-throughput small molecule screen identifies synergism between DNA methylation and Aurora kinase pathways for X reactivation.

    PubMed

    Lessing, Derek; Dial, Thomas O; Wei, Chunyao; Payer, Bernhard; Carrette, Lieselot L G; Kesner, Barry; Szanto, Attila; Jadhav, Ajit; Maloney, David J; Simeonov, Anton; Theriault, Jimmy; Hasaka, Thomas; Bedalov, Antonio; Bartolomei, Marisa S; Lee, Jeannie T

    2016-12-13

    X-chromosome inactivation is a mechanism of dosage compensation in which one of the two X chromosomes in female mammals is transcriptionally silenced. Once established, silencing of the inactive X (Xi) is robust and difficult to reverse pharmacologically. However, the Xi is a reservoir of >1,000 functional genes that could be potentially tapped to treat X-linked disease. To identify compounds that could reactivate the Xi, here we screened ∼367,000 small molecules in an automated high-content screen using an Xi-linked GFP reporter in mouse fibroblasts. Given the robust nature of silencing, we sensitized the screen by "priming" cells with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5azadC). Compounds that elicited GFP activity include VX680, MLN8237, and 5azadC, which are known to target the Aurora kinase and DNA methylation pathways. We demonstrate that the combinations of VX680 and 5azadC, as well as MLN8237 and 5azadC, synergistically up-regulate genes on the Xi. Thus, our work identifies a synergism between the DNA methylation and Aurora kinase pathways as being one of interest for possible pharmacological reactivation of the Xi.

  8. The synergism mechanism of Rhubarb Anthraquinones on constipation elucidated by comparative pharmacokinetics of Rhubarb extract between normal and diseased rats.

    PubMed

    Gong, Xiao-Hong; Li, Yan; Zhang, Ruo-Qi; Xie, Xiao-Fang; Peng, Cheng; Li, Yun-Xia

    2015-12-01

    In the study, it was hypothesized that Rhubarb Anthraquinones synergistically enhanced the purgative effect on constipation rat from the direct and indirect pathway at the same time. A validated HPLC method was successfully applied to elucidate the synergism mechanism from pharmacokinetics aspect after oral administration of Rhubarb extract with a dose of 0.25 g to normal and constipation rats. Comparison of the pharmacokinetic data of normal and constipation rats showed that there were significant differences (p < 0.05) in the main pharmacokinetic parameters. The C max and AUC of emodin in constipation rats were about ten times that of normal rats, while the t 1/2 was remarkably decreased (p < 0.05). However, a significant decrease (p < 0.05) in AUC value for aloe-emodin and rhein was observed in model group compared with normal group. The results may be attributed to the direct action of aloe-emodin and rhein on intestinal cell membranes and the indirect action of emodin on bowel movement through the adjustment by nervous system.

  9. Decolorization of reactive dark blue K-R by the synergism of fungus and bacterium using response surface methodology.

    PubMed

    Qu, Yuanyuan; Shi, Shengnan; Ma, Fang; Yan, Bin

    2010-11-01

    The objective of this study was to investigate the potential ability of decolorizing Reactive Dark Blue K-R by the synergism of fungal strain Penicillium sp. QQ and bacterial strain Exiguobacterium sp. TL. The optimal conditions for decolorization determined by response surface methodology (RSM) were as follows: 12.5% (w/v) of both strains QQ and TL, 0.19% (w/v) of glucose, 0.09% (w/v) of yeast extract, pH7.0, 37 degrees C and 200mg/L of initial dye concentration. It was shown that about 97% of 200mg/L K-R could be decolorized within 24h under these conditions. Besides, strains QQ and TL co-cultures could decolorize 10 kinds of azo dyes effectively and be still 60% color removal when salinity increased to 15%. And most of the tested metal ions showed little influence on the decolorization except for Ni(2+). The results demonstrated that strains QQ and TL co-cultures could be useful for the practical bioremediation. Copyright 2010 Elsevier Ltd. All rights reserved.

  10. A high-throughput small molecule screen identifies synergism between DNA methylation and Aurora kinase pathways for X reactivation

    PubMed Central

    Lessing, Derek; Dial, Thomas O.; Wei, Chunyao; Payer, Bernhard; Carrette, Lieselot L. G.; Kesner, Barry; Szanto, Attila; Jadhav, Ajit; Maloney, David J.; Simeonov, Anton; Theriault, Jimmy; Hasaka, Thomas; Bedalov, Antonio; Bartolomei, Marisa S.; Lee, Jeannie T.

    2016-01-01

    X-chromosome inactivation is a mechanism of dosage compensation in which one of the two X chromosomes in female mammals is transcriptionally silenced. Once established, silencing of the inactive X (Xi) is robust and difficult to reverse pharmacologically. However, the Xi is a reservoir of >1,000 functional genes that could be potentially tapped to treat X-linked disease. To identify compounds that could reactivate the Xi, here we screened ∼367,000 small molecules in an automated high-content screen using an Xi-linked GFP reporter in mouse fibroblasts. Given the robust nature of silencing, we sensitized the screen by “priming” cells with the DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (5azadC). Compounds that elicited GFP activity include VX680, MLN8237, and 5azadC, which are known to target the Aurora kinase and DNA methylation pathways. We demonstrate that the combinations of VX680 and 5azadC, as well as MLN8237 and 5azadC, synergistically up-regulate genes on the Xi. Thus, our work identifies a synergism between the DNA methylation and Aurora kinase pathways as being one of interest for possible pharmacological reactivation of the Xi. PMID:28182563

  11. Synergic effect of salinity and CO2 enrichment on growth and photosynthetic responses of the invasive cordgrass Spartina densiflora

    PubMed Central

    Mateos-Naranjo, Enrique; Redondo-Gómez, Susana; Álvarez, Rosario; Cambrollé, Jesús; Gandullo, Jacinto; Figueroa, M. Enrique

    2010-01-01

    Spartina densiflora is a C4 halophytic species that has proved to have a high invasive potential which derives from its clonal growth and its physiological plasticity to environmental factors, such as salinity. A greenhouse experiment was designed to investigate the synergic effect of 380 and 700 ppm CO2 at 0, 171, and 510 mM NaCl on the growth and the photosynthetic apparatus of S. densiflora by measuring chlorophyll fluorescence parameters, gas exchange and photosynthetic pigment concentrations. PEPC activity and total ash, sodium, potassium, calcium, magnesium, and zinc concentrations were determined, as well as the C/N ratio. Elevated CO2 stimulated growth of S. densiflora at 0 and 171 mM NaCl external salinity after 90 d of treatment. This growth enhancement was associated with a greater leaf area and improved leaf water relations rather than with variations in net photosynthetic rate (A). Despite the fact that stomatal conductance decreased in response to 700 ppm CO2 after 30 d of treatment, A was not affected. This response of A to elevated CO2 concentration might be explained by an enhanced PEPC carboxylation capacity. On the whole, plant nutrient concentrations declined under elevated CO2, which can be ascribed to the dilution effect caused by an increase in biomass and the higher water content found at 700 ppm CO2. Finally, CO2 and salinity had a marked overall effect on the photochemical (PSII) apparatus and the synthesis of photosynthetic pigments. PMID:20194923

  12. Enhanced proliferation of coronary endothelial cells in response to growth factors is synergized by hemodialysate compounds in vitro.

    PubMed

    Schönwald, D; Sixt, B; Machicao, F; Marx, E; Haedenkamp, G; Bertsch, S

    1991-01-01

    Using capillary endothelial cells from the coronary system of guinea pig heart, we have devised an in vitro assay suitable for measuring proliferative and growth-promoting effects mediated by drugs and growth factors. In this assay, hemodialysate and fractions isolated from it--consisting exclusively of low-molecular-weight compounds from calf blood--stimulate the proliferation of coronary endothelial cells. This effect is not a trivial nutritive one. Furthermore, in respect to the stimulation of proliferation, hemodialysate synergizes with epidermal growth factor, basic fibroblast growth factor, and endothelial cell growth factor, but not with insulin, which shows no proliferative effect in our system. From data obtained by analysis of hemodialysate fractions, it is deduced that the active compounds are strongly negatively charged oligosaccharides with a molecular weight of apparently 3000 Dalton. The synergistic effect of hemodialysate compounds on proliferation of endothelial cells as well as their previously demonstrated insulin-like activity is believed to explain the therapeutic efficacy of hemodialysate in cases of impaired wound healing and occlusive diseases.

  13. A Purine Analog Synergizes with Chloroquine (CQ) by Targeting Plasmodium falciparum Hsp90 (PfHsp90)

    PubMed Central

    Shahinas, Dea; Folefoc, Asongna; Taldone, Tony; Chiosis, Gabriela; Crandall, Ian; Pillai, Dylan R.

    2013-01-01

    Background Drug resistance, absence of an effective vaccine, and inadequate public health measures are major impediments to controlling Plasmodium falciparum malaria worldwide. The development of antimalarials to which resistance is less likely is paramount. To this end, we have exploited the chaperone function of P. falciparum Hsp90 (PfHsp90) that serves to facilitate the expression of resistance determinants. Methods The affinity and activity of a purine analogue Hsp90 inhibitor (PU-H71) on PfHsp90 was determined using surface plasmon resonance (SPR) studies and an ATPase activity assay, respectively. In vitro, antimalarial activity was quantified using flow cytometry. Interactors of PfHsp90 were determined by LC-MS/MS. In vivo studies were conducted using the Plasmodium berghei infection mouse model. Results PU-H71 exhibited antimalarial activity in the nanomolar range, displayed synergistic activity with chloroquine in vitro. Affinity studies reveal that the PfHsp90 interacts either directly or indirectly with the P. falciparum chloroquine resistance transporter (PfCRT) responsible for chloroquine resistance. PU-H71 synergized with chloroquine in the P.berghei mouse model of malaria to reduce parasitemia and improve survival. Conclusions We propose that the interaction of PfHsp90 with PfCRT may account for the observed antimalarial synergy and that PU-H71 is an effective adjunct for combination therapy. PMID:24098696

  14. Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance.

    PubMed

    Vukovic, Milica; Guitart, Amelie V; Sepulveda, Catarina; Villacreces, Arnaud; O'Duibhir, Eoghan; Panagopoulou, Theano I; Ivens, Alasdair; Menendez-Gonzalez, Juan; Iglesias, Juan Manuel; Allen, Lewis; Glykofrydis, Fokion; Subramani, Chithra; Armesilla-Diaz, Alejandro; Post, Annemarie E M; Schaak, Katrin; Gezer, Deniz; So, Chi Wai Eric; Holyoake, Tessa L; Wood, Andrew; O'Carroll, Dónal; Ratcliffe, Peter J; Kranc, Kamil R

    2015-12-14

    Leukemogenesis occurs under hypoxic conditions within the bone marrow (BM). Knockdown of key mediators of cellular responses to hypoxia with shRNA, namely hypoxia-inducible factor-1α (HIF-1α) or HIF-2α, in human acute myeloid leukemia (AML) samples results in their apoptosis and inability to engraft, implicating HIF-1α or HIF-2α as therapeutic targets. However, genetic deletion of Hif-1α has no effect on mouse AML maintenance and may accelerate disease development. Here, we report the impact of conditional genetic deletion of Hif-2α or both Hif-1α and Hif-2α at different stages of leukemogenesis in mice. Deletion of Hif-2α accelerates development of leukemic stem cells (LSCs) and shortens AML latency initiated by Mll-AF9 and its downstream effectors Meis1 and Hoxa9. Notably, the accelerated initiation of AML caused by Hif-2α deletion is further potentiated by Hif-1α codeletion. However, established LSCs lacking Hif-2α or both Hif-1α and Hif-2α propagate AML with the same latency as wild-type LSCs. Furthermore, pharmacological inhibition of the HIF pathway or HIF-2α knockout using the lentiviral CRISPR-Cas9 system in human established leukemic cells with MLL-AF9 translocation have no impact on their functions. We therefore conclude that although Hif-1α and Hif-2α synergize to suppress the development of AML, they are not required for LSC maintenance.

  15. The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells.

    PubMed

    Kerl, Kornelius; Ries, David; Unland, Rebecca; Borchert, Christiane; Moreno, Natalia; Hasselblatt, Martin; Jürgens, Heribert; Kool, Marcel; Görlich, Dennis; Eveslage, Maria; Jung, Manfred; Meisterernst, Michael; Frühwald, Michael

    2013-06-13

    Rhabdoid tumors are highly aggressive malignancies affecting infants and very young children. In many instances these tumors are resistant to conventional type chemotherapy necessitating alternative approaches. Proliferation assays (MTT), apoptosis (propidium iodide/annexin V) and cell cycle analysis (DAPI), RNA expression microarrays and western blots were used to identify synergism of the HDAC (histone deacetylase) inhibitor SAHA with fenretinide, tamoxifen and doxorubicin in rhabdoidtumor cell lines. HDAC1 and HDAC2 are overexpressed in primary rhabdoid tumors and rhabdoid tumor cell lines. Targeting HDACs in rhabdoid tumors induces cell cycle arrest and apoptosis. On the other hand HDAC inhibition induces deregulated gene programs (MYCC-, RB program and the stem cell program) in rhabdoid tumors. These programs are in general associated with cell cycle progression. Targeting these activated pro-proliferative genes by combined approaches of HDAC-inhibitors plus fenretinide, which inhibits cyclinD1, exhibit strong synergistic effects on induction of apoptosis. Furthermore, HDAC inhibition sensitizes rhabdoid tumor cell lines to cell death induced by chemotherapy. Our data demonstrate that HDAC inhibitor treatment in combination with fenretinide or conventional chemotherapy is a promising tool for the treatment of chemoresistant rhabdoid tumors.

  16. Synergism between macrolide antibiotics and the azole fungicide ketoconazole in growth inhibition testing of the green alga Pseudokirchneriella subcapitata.

    PubMed

    Yamagishi, Takahiro; Horie, Yoshifumi; Tatarazako, Norihisa

    2017-05-01

    Macrolide antibiotics and azole fungicides are detected widely in the aquatic environment as a result of their increased use in humans and animal livestock disease and their incomplete removal by wastewater treatment plants. In most cases, ecotoxicological tests are performed by using individual chemical substances, but because of the coexistence of a number of chemicals in the environment, organisms are exposed to many chemicals simultaneously. Therefore, it is important to evaluate effects of chemical interactions, adding to potential hazards of individual chemical. Here, we investigated the synergetic effects of combined chemicals (the azole fungicide ketoconazole and either of two macrolide antibiotics, erythromycin and clarithromycin) in growth inhibition testing using Pseudokirchneriella subcapitata according to OECD Test guideline 201. Combination index plots, isobolograms, and curve-shift analyses revealed that the combination of macrolide antibiotic and ketoconazole at various ratios resulted in strong synergism that enhanced growth inhibition of P. subcapitata, suggesting the necessity of investigating potential hazard of combined chemicals for regulatory purposes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Surface contact toxicity and synergism of several insecticides against different stages of the tropical bed bug, Cimex hemipterus (Hemiptera: Cimicidae).

    PubMed

    How, Yee-Fatt; Lee, Chow-Yang

    2011-06-01

    Five formulated insecticides (lambda-cyhalothrin at 10 mg m⁻², bifenthrin at 50 mg m⁻², fipronil at 10 mg m⁻², fenitrothion at 50 mg m⁻², imidacloprid at 5 mg m⁻²) and one active ingredient (DDT at 500 mg m⁻²) were evaluated using a surface contact method against early and late instars and adults of two strains of the tropical bed bug, Cimex hemipterus (F.). Synergism of lambda-cyhalothrin and fipronil using piperonyl butoxide (PBO) was also assessed. The order of susceptibility of different stages of bed bugs was as follows: early stage-lambda-cyhalothrin > bifenthrin = imidacloprid > fipronil > fenitrothion > DDT; late stage-lambda-cyhalothrin > bifenthrin > fenitrothion > imidacloprid > fipronil > DDT; adult-lambda-cyhalothrin > imidacloprid > bifenthrin > fenitrothion > fipronil > DDT. The late instars exhibited significantly higher LT₅₀ among the life stages. The addition of PBO to fipronil increased the susceptibility of the insects. Lambda-cyhalothrin, bifenthrin, fenitrothion and fipronil at the recommended application rates were effective against C. hemipterus. Although imidacloprid demonstrated good initial response against C. hemipterus, the insects showed substantial recovery 72 h post-treatment. The late instars (fourth and fifth instars) should be used as the model for toxicological evaluation. Copyright © 2011 Society of Chemical Industry.

  18. miR-27b synergizes with anticancer drugs via p53 activation and CYP1B1 suppression

    PubMed Central

    Mu, Wenjing; Hu, Chaobo; Zhang, Haibin; Qu, Zengqiang; Cen, Jin; Qiu, Zhixin; Li, Chao; Ren, Haozhen; Li, Yixue; He, Xianghuo; Shi, Xiaolei; Hui, Lijian

    2015-01-01

    Liver and kidney cancers are notorious for drug resistance. Due to the complexity, redundancy and interpatient heterogeneity of resistance mechanisms, most efforts targeting a single pathway were unsuccessful. Novel personalized therapies targeting multiple essential drug resistance pathways in parallel hold a promise for future cancer treatment. Exploiting the multitarget characteristic of microRNAs (miRNAs), we developed a new therapeutic strategy by the combinational use of miRNA and anticancer drugs to increase drug response. By a systems approach, we identified that miR-27b, a miRNA deleted in liver and kidney cancers, sensitizes cancer cells to a broad spectrum of anticancer drugs in vitro and in vivo. Functionally, miR-27b enhances drug response by activating p53-dependent apoptosis and reducing CYP1B1-mediated drug detoxification. Notably, miR-27b promotes drug response specifically in patients carrying p53-wild-type or CYP1B1-high signature. Together, we propose that miR-27b synergizes with anticancer drugs in a defined subgroup of liver and kidney cancer patients. PMID:25698578

  19. Expressions of multiple umami taste receptors in oral and gastrointestinal tissues, and umami taste synergism in chickens.

    PubMed

    Yoshida, Yuta; Kawabata, Yuko; Kawabata, Fuminori; Nishimura, Shotaro; Tabata, Shoji

    2015-10-23

    Umami taste is one of the five basic taste qualities, along with sweet, bitter, sour, and salty, and is elicited by some l-amino acids and their salts, including monopotassium l-glutamate (MPG). The unique characteristic of umami taste is that it is synergistically enhanced by 5'-ribonucleotides such as inosine 5'-monophosphate (IMP). Unlike the other four basic taste qualities, the presence of umami taste sense in avian species is not fully understood. In this study, we demonstrated the expression of multiple umami taste receptor candidates in oral and gastrointestinal tract tissues in chickens using RT-PCR analysis. We first showed the metabotropic glutamate receptors (mGluRs) expressed in these tissues. Furthermore, we examined the preference for umami taste in chickens, focusing on the synergistic effect of umami taste as determined by the two-feed choice test. We concluded that chickens preferred feed containing both added MPG and added IMP over feeds containing either added MPG or added IMP alone and over the control feed. These results suggest that the umami taste sense and synergism are conserved in chickens.

  20. Microaerophilic Symmetric Reductive Cleavage of Reactive Azo Dye-Remazole Brilliant Violet 5R by Consortium VIE6: Community Synergism.

    PubMed

    Shah, Binal; Jain, Kunal; Jiyani, Hardik; Mohan, Venkata; Madamwar, Datta

    2016-11-01

    The textile-dyeing industry is rated as one of the foremost industrial sectors that explodes large amount of pollutants to the environment. Reactive azo dye degradation, being a major constituent of these pollutants and perilous material, has been constantly receiving scientific attention. In textile industry, use of Remazole Brilliant Violet 5R (RBV5R) as reactive azo dyes is more frequent. Highly competent, RBV5R-degrading bacterial consortium VIE6 was developed from the soil of the Vatva Industrial Estate, Gujarat, India. Consortium VIE6 comprised of five bacterial strains Bacillus sp. DMB1, Staphylococcus sp. DMB2, Escherichia sp. DMB3, Enterococcus sp. DMB4, and Pseudomonas sp. DMB5. These strains convened a better decolorization efficiency between 200 and 1000 mg/L of dye concentration and were much stable at pH 6.5, 37 °C. Azoreductase, laccase, and lignin peroxidase activities of consortium showed significant variation throughout the degradation process indicating the different metabolic capabilities of the existing microflora. The community interactions and synergism were shown to facilitate the biotransformation of RBV5R by combination of various electron donors. Voltammograms revealed the variations in electron discharge properties which coincide with the dynamics of community derived using qPCR assays. The variation in catabolic capabilities of the individual strains was observed during active metabolism of RBV5R degradation pertaining to the aerobic and facultative functions.

  1. Antifungal activity of Coriandrum sativum essential oil, its mode of action against Candida species and potential synergism with amphotericin B.

    PubMed

    Silva, Filomena; Ferreira, Susana; Duarte, Andreia; Mendonça, Dina I; Domingues, Fernanda C

    2011-12-15

    The increasing incidence of drug-resistant pathogens and toxicity of existing antifungal compounds has drawn attention towards the antimicrobial activity of natural products. The aim of the present study was to evaluate the antifungal activity of coriander essential oil according to classical bacteriological techniques, as well as with flow cytometry. The effect of the essential oil upon germ tube formation, seen as an important virulence factor, and potential synergism with amphotericin B were also studied. Coriander essential oil has a fungicidal activity against the Candida strains tested with MLC values equal to the MIC value and ranging from 0.05 to 0.4% (v/v). Flow cytometric evaluation of BOX, PI and DRAQ5 staining indicates that the fungicidal effect is a result of cytoplasmic membrane damage and subsequent leakage of intracellular components such as DNA. Also, concentrations bellow the MIC value caused a marked reduction in the percentage of germ tube formation for C. albicans strains. A synergetic effect between coriander oil and amphotericin B was also obtained for C. albicans strains, while for C. tropicalis strain only an additive effect was observed. This study describes the antifungal activity of coriander essential oil on Candida spp., which could be useful in designing new formulations for candidosis treatment.

  2. Immunomodulating and Revascularizing Activity of Kalanchoe pinnata Synergize with Fungicide Activity of Biogenic Peptide Cecropin P1.

    PubMed

    Zakharchenko, N S; Belous, A S; Biryukova, Y K; Medvedeva, O A; Belyakova, A V; Masgutova, G A; Trubnikova, E V; Buryanov, Y I; Lebedeva, A A

    2017-01-01

    Previously transgenic Kalanchoe pinnata plants producing an antimicrobial peptide cecropin P1 (CecP1) have been reported. Now we report biological testing K. pinnata extracts containing CecP1 as a candidate drug for treatment of wounds infected with Candida albicans. The drug constitutes the whole juice from K. pinnata leaves (not ethanol extract) sterilized with nanofiltration. A microbicide activity of CecP1 against an animal fungal pathogen in vivo was demonstrated for the first time. However, a favorable therapeutic effect of the transgenic K. pinnata extract was attributed to a synergism between the fungicide activity of CecP1 and wound healing (antiscar), revascularizing, and immunomodulating effect of natural biologically active components of K. pinnata. A commercial fungicide preparation clotrimazole eliminated C. albicans cells within infected wounds in rats with efficiency comparable to CecP1-enriched K. pinnata extract. But in contrast to K. pinnata extract, clotrimazole did not exhibit neither wound healing activity nor remodeling of the scar matrix. Taken together, our results allow assumption that CecP1-enriched K. pinnata extracts should be considered as a candidate drug for treatment of dermatomycoses, wounds infected with fungi, and bedsores.

  3. Immunomodulating and Revascularizing Activity of Kalanchoe pinnata Synergize with Fungicide Activity of Biogenic Peptide Cecropin P1

    PubMed Central

    Zakharchenko, N. S.; Belous, A. S.; Medvedeva, O. A.; Belyakova, A. V.; Masgutova, G. A.; Trubnikova, E. V.; Buryanov, Y. I.; Lebedeva, A. A.

    2017-01-01

    Previously transgenic Kalanchoe pinnata plants producing an antimicrobial peptide cecropin P1 (CecP1) have been reported. Now we report biological testing K. pinnata extracts containing CecP1 as a candidate drug for treatment of wounds infected with Candida albicans. The drug constitutes the whole juice from K. pinnata leaves (not ethanol extract) sterilized with nanofiltration. A microbicide activity of CecP1 against an animal fungal pathogen in vivo was demonstrated for the first time. However, a favorable therapeutic effect of the transgenic K. pinnata extract was attributed to a synergism between the fungicide activity of CecP1 and wound healing (antiscar), revascularizing, and immunomodulating effect of natural biologically active components of K. pinnata. A commercial fungicide preparation clotrimazole eliminated C. albicans cells within infected wounds in rats with efficiency comparable to CecP1-enriched K. pinnata extract. But in contrast to K. pinnata extract, clotrimazole did not exhibit neither wound healing activity nor remodeling of the scar matrix. Taken together, our results allow assumption that CecP1-enriched K. pinnata extracts should be considered as a candidate drug for treatment of dermatomycoses, wounds infected with fungi, and bedsores. PMID:28695135

  4. Synergic effects of sugar and caffeine on insulin-mediated metabolomic alterations after an acute consumption of soft drinks.

    PubMed

    González-Domínguez, Raúl; Mateos, Rosa María; Lechuga-Sancho, Alfonso María; González-Cortés, José Joaquín; Corrales-Cuevas, Manuel; Rojas-Cots, Juan Alberto; Segundo, Carmen; Schwarz, Mónica

    2017-09-01

    High sugar consumption elicits numerous deleterious effects on health by inducing insulin resistance, which is closely associated with the development of metabolic disorders such as obesity or type-2 diabetes. Furthermore, there is also growing evidence that caffeine may play an important role in the regulation of insulin release and the appearance of related metabolic impairments. Thus, the aim of this work was to investigate the impact of acute sugar and caffeine intake on the metabolic health status by using a metabolomic multi-platform based on the combination of flow injection mass spectrometry and ultra-high performance liquid chromatography mass spectrometry. To this end, we performed a randomized, crossover and double-blind intervention study with different soft drinks from the same brand. Numerous metabolomic changes were detected in serum samples over time after the intake of sugar-sweetened beverages, including energy-related metabolites, amino acids and lipids, thus demonstrating the intense effects provoked by acute sugar consumption on the organism during 3 h of follow-up. However, the most significant findings were observed after the co-ingestion of caffeine, which could be indicative of a synergic effect of this psychostimulant on insulin-mediated perturbations. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. The synergic effect of HPV infection and epigenetic anomaly of the p16 gene in the development of cervical cancer.

    PubMed

    Ahmad, Arif; Raish, Mohammad; Shahid, Mohammad; Batra, Swaraj; Batra, Vineeta; Husain, Syed Akhtar

    2017-07-04

    Cervical cancer is the most common cancer in Indian women. Infection with a high-risk human papillomavirus (HR-HPV) is the greatest risk factor for developing cervical cancer. The genetic and epigenetic changes in the tumor suppressor p16 gene is play an important role in the development of cervical cancer. To evaluate the expression and promoter methylation of p16 gene in HR-HPV infected squamous cell carcinoma of the uterine cervix. To find out p16INK4a expression and methylation status 105 squamous cell carcinoma of the uterine cervix were investigated by using immunohistochemistry and Methylation Specific PCR techniques. HPV16/18 was amplified in 83.8% cases of the cervix. 80% of them were positive for HPV type 16, while only 3.8% were positive for HPV type 18. Promoter CpG island hypermethylation of p16 gene was detected in 20.9% tissue samples of cervical carcinoma. Of these hypermethylated samples 90.9% cases showed nil/very low p16INK4a expression (P= 0.001). Overexpression of p16INK4a was observed in 73.3% cases of HR-HPV infected squamous cell carcinoma of the cervix. An association between p16 methylation, expression, and HR-HPV infection suggested the compliance of HPV infection and aberration of p16 gene have a synergic effect on initiation and progression of cervical carcinoma.

  6. Synergic adsorption of Pb2 + and reactive dye — RB5 on two series of organomodified bentonites

    NASA Astrophysics Data System (ADS)

    Jović-Jovičić, N. P.; Milutinović-Nikolić, A. D.; Žunić, M. J.; Mojović, Z. D.; Banković, P. T.; Gržetić, I. A.; Jovanović, D. M.

    2013-07-01

    Two series of organobentonites (OBs) were synthesized from Na+-exchanged bentonite clay from Bogovina, Serbia. In the first series the starting material was modified using hexadecyltrimethylammonium (HDTMA+) ion in the amounts corresponding to 0.2, 0.5, 1.0 and 2.0 of the CEC value. The second series was obtained using quaternary alkyl ammonium cations (QAACs) with different alkyl chain lengths: hexadecyltrimethylammonium (HDTMA+), dodecyltrimethylammonium (DDTMA+) and tetramethylammonium (TMA+) ions. The synthesized OBs were characterized. The adsorption of anionic reactive dye Reactive Black 5 (RB5) and Pb2 + from single component solutions and their bi-component solution was investigated for both series of OBs. The adsorptive properties of the OBs were correlated to the amount and type of incorporated QAACs. The correlation was tested using different mathematical models and best fits were found. Experimental results showed that simultaneous adsorption of RB5 and Pb2 + exhibited synergic effect. The adsorption capacity for both RB5 and Pb2 + was higher in their bi-component solution than in single-component solutions. These results indicate the creation of new adsorption sites during the simultaneous adsorption.

  7. Boswellic acids synergize antitumor activity and protect against the cardiotoxicity of doxorubicin in mice bearing Ehrlich's carcinoma.

    PubMed

    Ali, Shimaa A; Zaitone, Sawsan A; Moustafa, Yasser M

    2015-08-01

    This study aimed to test whether boswellic acids add to the antitumor effects of doxorubicin against solid tumors of Ehrlich's ascites carcinoma (EAC) grown in mice, and to investigate the protective effects of boswellic acids against doxorubicin-induced cardiotoxicity. Sixty-four female Swiss albino mice bearing EAC solid tumors were distributed among 8 groups as follows: group 1, EAC control group; group 2, doxorubicin treatment group [mice were injected with doxorubicin (6 mg·(kg body mass)(-1)·week(-1)) for 3 weeks]; groups 3-5, these mice were treated with boswellic acids (125, 250, or 500 mg·kg(-1)·day(-1)), respectively; groups 6-8, these mice were treated with a combination of doxorubicin and boswellic acids (125, 250, or 500 mg·kg(-1)·day(-1)), respectively, for 3 weeks. The results indicated that boswellic acids synergized the antitumor activity of doxorubicin. Doxorubicin-treated mice showed elevated serum activities of lactate dehydrogenase and creatine kinase isoenzyme MB as well as cardiac malondialdehyde. Further, decreases in cardiac levels of reduced glutathione, superoxide dismutase, and catalase activities were observed. These effects were accompanied by an increase in cardiac expression of caspase 3. Thus, treatment with boswellic acids attenuated doxorubicin-evoked disturbances in the above-mentioned parameters, highlighting antioxidant and antiapoptotic activities. Therefore, boswellic acids could be potential candidates for ameliorating the cardiotoxicity of doxorubicin.

  8. PI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia

    PubMed Central

    Silveira, André Bortolini; Laranjeira, Angelo Brunelli Albertoni; Rodrigues, Gisele Olinto Libanio; Leal, Paulo César; Cardoso, Bruno António; Barata, João Taborda; Yunes, Rosendo Augusto; Zanchin, Nilson Ivo Tonin; Brandalise, Sílvia Regina; Yunes, José Andrés

    2015-01-01

    The PI3K pathway is frequently hyperactivated in primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Activation of the PI3K pathway has been suggested as one mechanism of glucocorticoid resistance in T-ALL, and patients harboring mutations in the PI3K negative regulator PTEN may be at increased risk of induction failure and relapse. By gene expression microarray analysis of T-ALL cells treated with the PI3K inhibitor AS605240, we identified Myc as a prominent downstream target of the PI3K pathway. A significant association was found between the AS605240 gene expression signature and that of glucocorticoid resistance and relapse in T-ALL. AS605240 showed anti-leukemic activity and strong synergism with glucocorticoids both in vitro and in a NOD/SCID xenograft model of T-ALL. In contrast, PI3K inhibition showed antagonism with methotrexate and daunorubicin, drugs that preferentially target dividing cells. This antagonistic interaction, however, could be circumvented by the use of correct drug scheduling schemes. Our data indicate the potential benefits and difficulties for the incorporation of PI3K inhibitors in T-ALL therapy. PMID:25869207

  9. Inactivation of Rb and E2f8 Synergizes To Trigger Stressed DNA Replication during Erythroid Terminal Differentiation

    PubMed Central

    Ghazaryan, Seda; Sy, Chandler; Hu, Tinghui; An, Xiuli; Mohandas, Narla; Fu, Haiqing; Aladjem, Mirit I.; Chang, Victor T.; Opavsky, Rene

    2014-01-01

    Rb is critical for promoting cell cycle exit in cells undergoing terminal differentiation. Here we show that during erythroid terminal differentiation, Rb plays a previously unappreciated and unorthodox role in promoting DNA replication and cell cycle progression. Specifically, inactivation of Rb in erythroid cells led to stressed DNA replication, increased DNA damage, and impaired cell cycle progression, culminating in defective terminal differentiation and anemia. Importantly, all of these defects associated with Rb loss were exacerbated by the concomitant inactivation of E2f8. Gene expression profiling and chromatin immunoprecipitation (ChIP) revealed that Rb and E2F8 cosuppressed a large array of E2F target genes that are critical for DNA replication and cell cycle progression. Remarkably, inactivation of E2f2 rescued the erythropoietic defects resulting from Rb and E2f8 deficiencies. Interestingly, real-time quantitative PCR (qPCR) on E2F2 ChIPs indicated that inactivation of Rb and E2f8 synergizes to increase E2F2 binding to its target gene promoters. Taken together, we propose that Rb and E2F8 collaborate to promote DNA replication and erythroid terminal differentiation by preventing E2F2-mediated aberrant transcriptional activation through the ability of Rb to bind and sequester E2F2 and the ability of E2F8 to compete with E2F2 for E2f-binding sites on target gene promoters. PMID:24865965

  10. Synergic effect of salinity and CO2 enrichment on growth and photosynthetic responses of the invasive cordgrass Spartina densiflora.

    PubMed

    Mateos-Naranjo, Enrique; Redondo-Gómez, Susana; Alvarez, Rosario; Cambrollé, Jesús; Gandullo, Jacinto; Figueroa, M Enrique

    2010-06-01

    Spartina densiflora is a C(4) halophytic species that has proved to have a high invasive potential which derives from its clonal growth and its physiological plasticity to environmental factors, such as salinity. A greenhouse experiment was designed to investigate the synergic effect of 380 and 700 ppm CO(2) at 0, 171, and 510 mM NaCl on the growth and the photosynthetic apparatus of S. densiflora by measuring chlorophyll fluorescence parameters, gas exchange and photosynthetic pigment concentrations. PEPC activity and total ash, sodium, potassium, calcium, magnesium, and zinc concentrations were determined, as well as the C/N ratio. Elevated CO(2) stimulated growth of S. densiflora at 0 and 171 mM NaCl external salinity after 90 d of treatment. This growth enhancement was associated with a greater leaf area and improved leaf water relations rather than with variations in net photosynthetic rate (A). Despite the fact that stomatal conductance decreased in response to 700 ppm CO(2) after 30 d of treatment, A was not affected. This response of A to elevated CO(2) concentration might be explained by an enhanced PEPC carboxylation capacity. On the whole, plant nutrient concentrations declined under elevated CO(2), which can be ascribed to the dilution effect caused by an increase in biomass and the higher water content found at 700 ppm CO(2). Finally, CO(2) and salinity had a marked overall effect on the photochemical (PSII) apparatus and the synthesis of photosynthetic pigments.

  11. Inactivation of Rb and E2f8 synergizes to trigger stressed DNA replication during erythroid terminal differentiation.

    PubMed

    Ghazaryan, Seda; Sy, Chandler; Hu, Tinghui; An, Xiuli; Mohandas, Narla; Fu, Haiqing; Aladjem, Mirit I; Chang, Victor T; Opavsky, Rene; Wu, Lizhao

    2014-08-01

    Rb is critical for promoting cell cycle exit in cells undergoing terminal differentiation. Here we show that during erythroid terminal differentiation, Rb plays a previously unappreciated and unorthodox role in promoting DNA replication and cell cycle progression. Specifically, inactivation of Rb in erythroid cells led to stressed DNA replication, increased DNA damage, and impaired cell cycle progression, culminating in defective terminal differentiation and anemia. Importantly, all of these defects associated with Rb loss were exacerbated by the concomitant inactivation of E2f8. Gene expression profiling and chromatin immunoprecipitation (ChIP) revealed that Rb and E2F8 cosuppressed a large array of E2F target genes that are critical for DNA replication and cell cycle progression. Remarkably, inactivation of E2f2 rescued the erythropoietic defects resulting from Rb and E2f8 deficiencies. Interestingly, real-time quantitative PCR (qPCR) on E2F2 ChIPs indicated that inactivation of Rb and E2f8 synergizes to increase E2F2 binding to its target gene promoters. Taken together, we propose that Rb and E2F8 collaborate to promote DNA replication and erythroid terminal differentiation by preventing E2F2-mediated aberrant transcriptional activation through the ability of Rb to bind and sequester E2F2 and the ability of E2F8 to compete with E2F2 for E2f-binding sites on target gene promoters.

  12. Cross-linked matrix rigidity and soluble retinoids synergize in nuclear lamina regulation of stem cell differentiation

    PubMed Central

    Ivanovska, Irena L.; Swift, Joe; Spinler, Kyle; Dingal, Dave; Cho, Sangkyun; Discher, Dennis E.

    2017-01-01

    Synergistic cues from extracellular matrix and soluble factors are often obscure in differentiation. Here the rigidity of cross-linked collagen synergizes with retinoids in the osteogenesis of human marrow mesenchymal stem cells (MSCs). Collagen nanofilms serve as a model matrix that MSCs can easily deform unless the film is enzymatically cross-linked, which promotes the spreading of cells and the stiffening of nuclei as both actomyosin assembly and nucleoskeletal lamin-A increase. Expression of lamin-A is known to be controlled by retinoic acid receptor (RAR) transcription factors, but soft matrix prevents any response to any retinoids. Rigid matrix is needed to induce rapid nuclear accumulation of the RARG isoform and for RARG-specific antagonist to increase or maintain expression of lamin-A as well as for RARG-agonist to repress expression. A progerin allele of lamin-A is regulated in the same manner in iPSC-derived MSCs. Rigid matrices are further required for eventual expression of osteogenic markers, and RARG-antagonist strongly drives lamin-A–dependent osteogenesis on rigid substrates, with pretreated xenografts calcifying in vivo to a similar extent as native bone. Proteomics-detected targets of mechanosensitive lamin-A and retinoids underscore the convergent synergy of insoluble and soluble cues in differentiation. PMID:28566555

  13. Linear Epitopes in Vaccinia Virus A27 Are Targets of Protective Antibodies Induced by Vaccination against Smallpox

    PubMed Central

    Kaever, Thomas; Matho, Michael H.; Meng, Xiangzhi; Crickard, Lindsay; Schlossman, Andrew; Xiang, Yan; Crotty, Shane; Peters, Bjoern

    2016-01-01

    ABSTRACT Vaccinia virus (VACV) A27 is a target for viral neutralization and part of the Dryvax smallpox vaccine. A27 is one of the three glycosaminoglycan (GAG) adhesion molecules and binds to heparan sulfate. To understand the function of anti-A27 antibodies, especially their protective capacity and their interaction with A27, we generated and subsequently characterized 7 murine monoclonal antibodies (MAbs), which fell into 4 distinct epitope groups (groups I to IV). The MAbs in three groups (groups I, III, and IV) bound to linear peptides, while the MAbs in group II bound only to VACV lysate and recombinant A27, suggesting that they recognized a conformational and discontinuous epitope. Only group I antibodies neutralized the mature virion in a complement-dependent manner and protected against VACV challenge, while a group II MAb partially protected against VACV challenge but did not neutralize the mature virion. The epitope for group I MAbs was mapped to a region adjacent to the GAG binding site, a finding which suggests that group I MAbs could potentially interfere with the cellular adhesion of A27. We further determined the crystal structure of the neutralizing group I MAb 1G6, as well as the nonneutralizing group IV MAb 8E3, bound to the corresponding linear epitope-containing peptides. Both the light and the heavy chains of the antibodies are important in binding to their antigens. For both antibodies, the L1 loop seems to dominate the overall polar interactions with the antigen, while for MAb 8E3, the light chain generally appears to make more contacts with the antigen. IMPORTANCE Vaccinia virus is a powerful model to study antibody responses upon vaccination, since its use as the smallpox vaccine led to the eradication of one of the world's greatest killers. The immunodominant antigens that elicit the protective antibodies are known, yet for many of these antigens, little information about their precise interaction with antibodies is available. In an

  14. Synergism between Hedgehog-GLI and EGFR signaling in Hedgehog-responsive human medulloblastoma cells induces downregulation of canonical Hedgehog-target genes and stabilized expression of GLI1.

    PubMed

    Götschel, Frank; Berg, Daniela; Gruber, Wolfgang; Bender, Christian; Eberl, Markus; Friedel, Myriam; Sonntag, Johanna; Rüngeler, Elena; Hache, Hendrik; Wierling, Christoph; Nietfeld, Wilfried; Lehrach, Hans; Frischauf, Annemarie; Schwartz-Albiez, Reinhard; Aberger, Fritz; Korf, Ulrike

    2013-01-01

    Aberrant activation of Hedgehog (HH) signaling has been identified as a key etiologic factor in many human malignancies. Signal strength, target gene specificity, and oncogenic activity of HH signaling depend profoundly on interactions with other pathways, such as epidermal growth factor receptor-mediated signaling, which has been shown to cooperate with HH/GLI in basal cell carcinoma and pancreatic cancer. Our experimental data demonstrated that the Daoy human medulloblastoma cell line possesses a fully inducible endogenous HH pathway. Treatment of Daoy cells with Sonic HH or Smoothened agonist induced expression of GLI1 protein and simultaneously prevented the processing of GLI3 to its repressor form. To study interactions between HH- and EGF-induced signaling in greater detail, time-resolved measurements were carried out and analyzed at the transcriptomic and proteomic levels. The Daoy cells responded to the HH/EGF co-treatment by downregulating GLI1, PTCH, and HHIP at the transcript level; this was also observed when Amphiregulin (AREG) was used instead of EGF. We identified a novel crosstalk mechanism whereby EGFR signaling silences proteins acting as negative regulators of HH signaling, as AKT- and ERK-signaling independent process. EGFR/HH signaling maintained high GLI1 protein levels which contrasted the GLI1 downregulation on the transcript level. Conversely, a high-level synergism was also observed, due to a strong and significant upregulation of numerous canonical EGF-targets with putative tumor-promoting properties such as MMP7, VEGFA, and IL-8. In conclusion, synergistic effects between EGFR and HH signaling can selectively induce a switch from a canonical HH/GLI profile to a modulated specific target gene profile. This suggests that there are more wide-spread, yet context-dependent interactions, between HH/GLI and growth factor receptor signaling in human malignancies.

  15. Synergism between Hedgehog-GLI and EGFR Signaling in Hedgehog-Responsive Human Medulloblastoma Cells Induces Downregulation of Canonical Hedgehog-Target Genes and Stabilized Expression of GLI1

    PubMed Central

    Götschel, Frank; Berg, Daniela; Gruber, Wolfgang; Bender, Christian; Eberl, Markus; Friedel, Myriam; Sonntag, Johanna; Rüngeler, Elena; Hache, Hendrik; Wierling, Christoph; Nietfeld, Wilfried; Lehrach, Hans; Frischauf, Annemarie; Schwartz-Albiez, Reinhard; Aberger, Fritz; Korf, Ulrike

    2013-01-01

    Aberrant activation of Hedgehog (HH) signaling has been identified as a key etiologic factor in many human malignancies. Signal strength, target gene specificity, and oncogenic activity of HH signaling depend profoundly on interactions with other pathways, such as epidermal growth factor receptor-mediated signaling, which has been shown to cooperate with HH/GLI in basal cell carcinoma and pancreatic cancer. Our experimental data demonstrated that the Daoy human medulloblastoma cell line possesses a fully inducible endogenous HH pathway. Treatment of Daoy cells with Sonic HH or Smoothened agonist induced expression of GLI1 protein and simultaneously prevented the processing of GLI3 to its repressor form. To study interactions between HH- and EGF-induced signaling in greater detail, time-resolved measurements were carried out and analyzed at the transcriptomic and proteomic levels. The Daoy cells responded to the HH/EGF co-treatment by downregulating GLI1, PTCH, and HHIP at the transcript level; this was also observed when Amphiregulin (AREG) was used instead of EGF. We identified a novel crosstalk mechanism whereby EGFR signaling silences proteins acting as negative regulators of HH signaling, as AKT- and ERK-signaling independent process. EGFR/HH signaling maintained high GLI1 protein levels which contrasted the GLI1 downregulation on the transcript level. Conversely, a high-level synergism was also observed, due to a strong and significant upregulation of numerous canonical EGF-targets with putative tumor-promoting properties such as MMP7, VEGFA, and IL-8. In conclusion, synergistic effects between EGFR and HH signaling can selectively induce a switch from a canonical HH/GLI profile to a modulated specific target gene profile. This suggests that there are more wide-spread, yet context-dependent interactions, between HH/GLI and growth factor receptor signaling in human malignancies. PMID:23762360

  16. Toward RNA nanoparticle vaccines: synergizing RNA and inorganic nanoparticles to achieve immunopotentiation.

    PubMed

    DeLong, Robert K; Curtis, Chandler B

    2017-03-01

    Traditionally, vaccines have been composed of live attenuated or killed microorganisms. Alternatively, individual protein subunits or other molecular components of the microorganism can serve as the antigen and trigger an antibody response by the immune system. The immune system is a coordinated molecular and cellular response that works in concert to check the spread of infection. In the past decade, there has been much progress on DNA vaccines. DNA vaccination includes using the coding segments of a viral or bacterial genome to generate an immune response. However, the potential advantage of combining an RNA molecule with inorganic nanoparticle delivery should be considered, with the goal to achieve immuno-synergy between the two and to overcome some of the current limitations of DNA vaccines and traditional vaccines. WIREs Nanomed Nanobiotechnol 2017, 9:e1415. doi: 10.1002/wnan.1415 For further resources related to this article, please visit the WIREs website. © 2016 Wiley Periodicals, Inc.

  17. Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing.

    PubMed

    Arulanandam, Rozanne; Batenchuk, Cory; Varette, Oliver; Zakaria, Chadi; Garcia, Vanessa; Forbes, Nicole E; Davis, Colin; Krishnan, Ramya; Karmacharya, Raunak; Cox, Julie; Sinha, Anisha; Babawy, Andrew; Waite, Katherine; Weinstein, Erica; Falls, Theresa; Chen, Andrew; Hamill, Jeff; De Silva, Naomi; Conrad, David P; Atkins, Harold; Garson, Kenneth; Ilkow, Carolina; Kærn, Mads; Vanderhyden, Barbara; Sonenberg, Nahum; Alain, Tommy; Le Boeuf, Fabrice; Bell, John C; Diallo, Jean-Simon

    2015-03-30

    In this study, we show that several microtubule-destabilizing agents used for decades for treatment of cancer and other diseases also sensitize cancer cells to oncolytic rhabdoviruses and improve therapeutic outcomes in resistant murine cancer models. Drug-induced microtubule destabilization leads to superior viral spread in cancer cells by disrupting type I IFN mRNA translation, leading to decreased IFN protein expression and secretion. Furthermore, microtubule-destabilizing agents specifically promote cancer cell death following stimulation by a subset of infection-induced cytokines, thereby increasing viral bystander effects. This study reveals a previously unappreciated role for microtubule structures in the regulation of the innate cellular antiviral response and demonstrates that unexpected combinations of approved chemotherapeutics and biological agents can lead to improved therapeutic outcomes.

  18. Synergic Impact of Vascular Calcification and Low Autonomic Tone in Mortality of Hemodialysis Patients.

    PubMed

    Ng, Hwee-Yeong; Hsueh, Shu-Kai; Lee, Yueh-Ting; Chiou, Terry Ting-Yu; Huang, Pei-Chen; Lee, Chien-Te

    2017-06-22

    Both cardiovascular calcification and autonomic dysfunction are frequently encountered in hemodialysis patients. We aimed to investigate the relationship between cardiovascular calcification and heart rate variability (HRV) and their influence on long-term outcome. Seventy-eight hemodialysis patients underwent echocardiogram and radiography of the pelvis and hands to identify valvular and vascular calcification. HRV was evaluated using a commercial machine. Based on the average, the patients were divided into higher and lower subgroups of high frequency (HF) and low frequency (LF) respectively. Patients with higher LF were younger and were found to have a lower proportion of diabetes. Their hemoglobin, albumin, and bone morphogenic protein (BMP)-7 levels were significantly higher and both high-sensitive C-reactive protein (hs-CRP) and osteoprotegerin levels were lower (all p < 0.05). In patients of the higher HF group, the proportion of diabetes was lower but they were found to have higher levels of BMP-7 and lower levels of hs-CRP, interleukin-6 (all p < 0.05). Significantly higher LF and HF were noted in patients without vascular calcification, but only hand artery (HA) calcification was negatively correlated with both LF and HF in multivariate analysis. Low LF and high hs-CRP were the independent predictors of mortality. Coexistence of low LF band and HA calcification was associated with the worse outcome. Abnormal autonomic nervous function was closely related to inflammation and mortality in hemodialysis patients. Calcification of HA was associated with autonomic dysfunction and patients with lower autonomic tone and HA calcification had the highest mortality rate in this population. © 2017 S. Karger AG, Basel.

  19. Synergism of Bacillus thuringiensis toxins by a fragment of a toxin-binding cadherin.

    PubMed

    Chen, Jiang; Hua, Gang; Jurat-Fuentes, Juan Luis; Abdullah, Mohd Amir; Adang, Michael J

    2007-08-28

    The insecticidal crystal proteins produced by Bacillus thuringiensis (Bt) are broadly used to control insect pests with agricultural importance. The cadherin Bt-R(1) is a binding protein for Bt Cry1A toxins in midgut epithelia of tobacco hornworm (Manduca sexta). We previously identified the Bt-R(1) region most proximal to the cell membrane (CR12-MPED) as the essential binding region required for Cry1Ab-mediated cytotoxicity. Here, we report that a peptide containing this region expressed in Escherichia coli functions as a synergist of Cry1A toxicity against lepidopteran larvae. Far-UV circular dichroism and (1)H-NMR spectroscopy confirmed that our purified CR12-MPED peptide mainly consisted of beta-strands and random coils with unfolded structure. CR12-MPED peptide bound brush border membrane vesicles with high affinity (K(d) = 32 nM) and insect midgut microvilli but did not alter Cry1Ab or Cry1Ac binding localization in the midgut. By BIAcore analysis we demonstrate that Cry1Ab binds CR12-MPED at high (9 nM)- and low (1 microM)-affinity sites. CR12-MPED-mediated Cry1A toxicity enhancement was significantly reduced when the high-affinity Cry1A-binding epitope ((1416)GVLTLNIQ(1423)) within the peptide was altered. Because the mixtures of low Bt toxin dose and CR12-MPED peptide effectively control target insect pests, our discovery has important implications related to the use of this peptide to enhance insecticidal activity of Bt toxin-based biopesticides and transgenic Bt crops.

  20. Synergism of Bacillus thuringiensis toxins by a fragment of a toxin-binding cadherin

    PubMed Central

    Chen, Jiang; Hua, Gang; Jurat-Fuentes, Juan Luis; Abdullah, Mohd Amir; Adang, Michael J.

    2007-01-01

    The insecticidal crystal proteins produced by Bacillus thuringiensis (Bt) are broadly used to control insect pests with agricultural importance. The cadherin Bt-R1 is a binding protein for Bt Cry1A toxins in midgut epithelia of tobacco hornworm (Manduca sexta). We previously identified the Bt-R1 region most proximal to the cell membrane (CR12-MPED) as the essential binding region required for Cry1Ab-mediated cytotoxicity. Here, we report that a peptide containing this region expressed in Escherichia coli functions as a synergist of Cry1A toxicity against lepidopteran larvae. Far-UV circular dichroism and 1H-NMR spectroscopy confirmed that our purified CR12-MPED peptide mainly consisted of β-strands and random coils with unfolded structure. CR12-MPED peptide bound brush border membrane vesicles with high affinity (Kd = 32 nM) and insect midgut microvilli but did not alter Cry1Ab or Cry1Ac binding localization in the midgut. By BIAcore analysis we demonstrate that Cry1Ab binds CR12-MPED at high (9 nM)- and low (1 μM)-affinity sites. CR12-MPED-mediated Cry1A toxicity enhancement was significantly reduced when the high-affinity Cry1A-binding epitope (1416GVLTLNIQ1423) within the peptide was altered. Because the mixtures of low Bt toxin dose and CR12-MPED peptide effectively control target insect pests, our discovery has important implications related to the use of this peptide to enhance insecticidal activity of Bt toxin-based biopesticides and transgenic Bt crops. PMID:17724346

  1. Sulfated glycosaminoglycans and glucosamine may synergize in promoting synovial hyaluronic acid synthesis.

    PubMed

    McCarty, M F; Russell, A L; Seed, M P

    2000-05-01

    High-molecular-weight hyaluronic acid (HA) produced by the synovium may function physiologically to aid preservation of cartilage structure and prevent arthritic pain; both the size and concentration of HA in synovial fluid are diminished in osteoarthritis (OA). Glucosamine therapy for OA can be expected to increase synovial HA production by providing rate-limiting substrate. In addition, certain sulfated glycosaminoglycans and polysaccharides - including chondroitin sulfate (CS), dermatan sulfate, and pentosan polysulfate - stimulate synovial HA production, apparently owing to a hormone-like effect triggered by the binding of these polymers to membrane proteins of synovial cells. Surprisingly, a significant proportion of orally administered CS is absorbed as intact polymers - apparently by pinocytosis. These considerations may rationalize clinical studies concluding that oral CS provides slow-onset but durable pain relief and functional improvement in OA. The possibility that oral glucosamine and CS may interact in a complementary or synergistic fashion to improve synovial fluid HA content in OA should be assessed in clinical studies, and the potential of adjunctive CS administration to improve the clinical response achievable with optimal intakes of glucosamine should likewise be evaluated. In light of the fact that the synovium virtually functions as a 'placenta' for cartilage, focusing on synovium as the target for therapeutic intervention in OA may be a rational strategy.

  2. Retinoic acid synergizes ATO-mediated cytotoxicity by precluding Nrf2 activity in AML cells

    PubMed Central

    Valenzuela, M; Glorieux, C; Stockis, J; Sid, B; Sandoval, J M; Felipe, K B; Kviecinski, M R; Verrax, J; Calderon, P Buc

    2014-01-01

    Background: Standard therapy for acute promyelocytic leukaemia (APL) includes retinoic acid (all-trans retinoic acid (ATRA)), which promotes differentiation of promyelocytic blasts. Although co-administration of arsenic trioxide (ATO) with ATRA has emerged as an effective option to treat APL, the molecular basis of this effect remains unclear. Methods: Four leukaemia cancer human models (HL60, THP-1, NBR4 and NBR4-R2 cells) were treated either with ATO alone or ATO plus ATRA. Cancer cell survival was monitored by trypan blue exclusion and DEVDase activity assays. Gene and protein expression changes were assessed by RT-PCR and western blot. Results: ATO induced an antioxidant response characterised by Nrf2 nuclear translocation and enhanced transcription of downstream target genes (that is, HO-1, NQO1, GCLM, ferritin). In cells exposed to ATO plus ATRA, the Nrf2 nuclear translocation was prevented and cytotoxicity was enhanced. HO-1 overexpression reversed partially the cytotoxicity by ATRA-ATO in HL60 cells. The inhibitory effects of ATRA on ATO-mediated responses were not observed in either the ATRA-resistant NB4-R2 cells or in NB4 cells pre-incubated with the RARα antagonist Ro-41-52-53. Conclusions: The augmented cytotoxicity observed in leukaemia cells following combined ATO-ATRA treatment is likely due to inhibition of Nrf2 activity, thus explaining the efficacy of combined ATO-ATRA treatment in the APL therapy. PMID:25003661

  3. The natural compound forskolin synergizes with dexamethasone to induce cell death in myeloma cells via BIM.

    PubMed

    Follin-Arbelet, Virginie; Misund, Kristine; Naderi, Elin Hallan; Ugland, Hege; Sundan, Anders; Blomhoff, Heidi Kiil

    2015-08-26

    We have previously demonstrated that activation of the cyclic adenosine monophosphate (cAMP) pathway kills multiple myeloma (MM) cells both in vitro and in vivo. In the present study we have investigated the potential of enhancing the killing of MM cell lines and primary MM cells by combining the cAMP-elevating compound forskolin with the commonly used MM therapeutic drugs melphalan, cyclophosphamide, doxorubicin, bortezomib and dexamethasone. We observed that forskolin potentiated the killing induced by all the tested agents as compared to treatment with the single agents alone. In particular, forskolin had a synergistic effect on the dexamethasone-responsive cell lines H929 and OM-2. By knocking down the proapoptotic BCL-2 family member BIM, we proved this protein to be involved in the synergistic induction of apoptosis by dexamethasone and forskolin. The ability of forskolin to maintain the killing of MM cells even at lower concentrations of the conventional agents suggests that forskolin may be used to diminish treatment-associated side effects. Our findings support a potential role of forskolin in combination with current conventional agents in the treatment of MM.

  4. Osteogenic differentiation of amniotic epithelial cells: synergism of pulsed electromagnetic field and biochemical stimuli.

    PubMed

    Wang, Qian; Wu, Wenchao; Han, Xiaoyu; Zheng, Ai; Lei, Song; Wu, Jiang; Chen, Huaiqing; He, Chengqi; Luo, Fengming; Liu, Xiaojing

    2014-08-11

    Pulsed electromagnetic field (PEMF) is a non-invasive physical therapy used in the treatment of fracture nonunion or delayed healing. PEMF can facilitate the osteogenic differentiation of bone marrow mesenchymal stem cells in vitro. Amniotic epithelial cells (AECs) have been proposed as a potential source of stem cells for cell therapy. However, whether PEMF could modulate the osteogenic differentiation of AECs is unknown. In the present study, the effects of PEMF on the osteogenic differentiation of AECs were investigated. AECs were isolated from amniotic membrane of human placenta by trypsin digestion and were induced by PEMF and/or osteo-induction medium. After 21 days we used real time RT-PCR and immunocytochemistry to study the expression of osteoblast markers. The signal transduction of osteogenesis was further investigated. The PEMF stimulation, or osteo-induction medium alone could induce osteogenic differentiation of AECs, as shown by expression of osteoblast specific genes and proteins including alkaline phosphatase and osteocalcin. Furthermore, a combination of PEMF and osteo-induction medium had synergy effects on osteogenic differentiation. In our study, the gene expression of BMP-2, Runx2, β-catenin, Nrf2, Keap1 and integrinβ1 were up-regulated in the osteogenic differentiation of AECs induced by PEMF and/or osteo-induction medium. Combined application of PEMF and osteo-induction medium is synergistic for the osteogenic differentiation of AECs. It might be a novel approach in the bone regenerative medicine.

  5. Combined inhibition of MEK and mTOR has a synergic effect on angiosarcoma tumorgrafts

    PubMed Central

    ANDERSEN, NICHOLAS J.; BOGUSLAWSKI, ELISSA B.; KUK, CYNTHIA Y.; CHAMBERS, CHRISTOPHER M.; DUESBERY, NICHOLAS S.

    2015-01-01

    Angiosarcoma (AS) is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. Using tumorgraft models, we previously showed that AS is sensitive to small-molecule inhibitors that target mitogen-activated/extracellular-signal-regulated protein kinase kinases 1 and 2 (MEK). The objective of this study was to identify drugs that combine with MEK inhibitors to more effectively inhibit AS growth. We examined the in vitro synergy between the MEK inhibitor PD0325901 and inhibitors of eleven common cancer pathways in melanoma cell lines and canine angiosarcoma cell isolates. Combination indices were calculated using the Chou-Talalay method. Optimized combination therapies were evaluated in vivo for toxicity and efficacy using canine angiosarcoma tumorgrafts. Among the drugs we tested, rapamycin stood out because it showed strong synergy with PD0325901 at nanomolar concentrations. We observed that angiosarcomas are insensitive to mTOR inhibition. However, treatment with nanomolar levels of mTOR inhibitor renders these cells as sensitive to MEK inhibition as a melanoma cell line with mutant BRAF. Similar results were observed in B-Raf wild-type melanoma cells as well as in vivo, where treatment of canine AS tumorgrafts with MEK and mTOR inhibitors was more effective than monotherapy. Our data show that a low dose of an mTOR inhibitor can dramatically enhance angiosarcoma and melanoma response to MEK inhibition, potentially widening the field of applications for MEK-targeted therapy. PMID:25955301

  6. Primary cutaneous tuberculosis in a 27-year-old medical intern from needle-stick injury: a case report.

    PubMed

    Karoney, Mercy Jelagat; Kaumbuki, Erastus Kanake; Koech, Mathew Kiptonui; Lelei, Lectary Kibor

    2015-01-01

    The authors report a case of cutaneous tuberculosis in a 27-year-old African male medical intern who contracted primary cutaneous from a needle-stick injury. Cultures of pus aspirated from the finger initially grew Staphylococcus aureus that led to a delay in the diagnosis.

  7. Loss of RASSF1A synergizes with deregulated RUNX2 signaling in tumorigenesis.

    PubMed

    van der Weyden, Louise; Papaspyropoulos, Angelos; Poulogiannis, George; Rust, Alistair G; Rashid, Mamunur; Adams, David J; Arends, Mark J; O'Neill, Eric

    2012-08-01

    The tumor suppressor gene RASSF1A is inactivated through point mutation or promoter hypermethylation in many human cancers. In this study, we conducted a Sleeping Beauty transposon-mediated insertional mutagenesis screen in Rassf1a-null mice to identify candidate genes that collaborate with loss of Rassf1a in tumorigenesis. We identified 10 genes, including the transcription factor Runx2, a transcriptional partner of Yes-associated protein (YAP1) that displays tumor suppressive activity through competing with the oncogenic TEA domain family of transcription factors (TEAD) for YAP1 association. While loss of RASSF1A promoted the formation of oncogenic YAP1-TEAD complexes, the combined loss of both RASSF1A and RUNX2 further increased YAP1-TEAD levels, showing that loss of RASSF1A, together with RUNX2, is consistent with the multistep model of tumorigenesis. Clinically, RUNX2 expression was frequently downregulated in various cancers, and reduced RUNX2 expression was associated with poor survival in patients with diffuse large B-cell or atypical Burkitt/Burkitt-like lymphomas. Interestingly, decreased expression levels of RASSF1 and RUNX2 were observed in both precursor T-cell acute lymphoblastic leukemia and colorectal cancer, further supporting the hypothesis that dual regulation of YAP1-TEAD promotes oncogenic activity. Together, our findings provide evidence that loss of RASSF1A expression switches YAP1 from a tumor suppressor to an oncogene through regulating its association with transcription factors, thereby suggesting a novel mechanism for RASSF1A-mediated tumor suppression. ©2012 AACR.

  8. The NAE inhibitor pevonedistat (MLN4924) synergizes with TNF-α to activate apoptosis.

    PubMed

    Wolenski, F S; Fisher, C D; Sano, T; Wyllie, S D; Cicia, L A; Gallacher, M J; Baker, R A; Kirby, P J; Senn, J J

    2015-01-01

    Predicting and understanding the mechanism of drug-induced toxicity is one of the primary goals of drug development. It has been hypothesized that inflammation may have a synergistic role in this process. Cell-based models provide an easily manipulated system to investigate this type of drug toxicity. Several groups have attempted to reproduce in vivo toxicity with combination treatment of pharmacological agents and inflammatory cytokines. Through this approach, synergistic cytotoxicity between the investigational agent pevonedistat (MLN4924) and TNF-α was identified. Pevonedistat is an inhibitor of the NEDD8-activating enzyme (NAE). Inhibition of NAE prevents activation of cullin-RING ligases, which are critical for proteasome-mediated protein degradation. TNF-α is a cytokine that is involved in inflammatory responses and cell death, among other biological functions. Treatment of cultured cells with the combination of pevonedistat and TNF-α, but not as single agents, resulted in rapid cell death. This cell death was determined to be mediated by caspase-8. Interestingly, the combination treatment of pevonedistat and TNF-α also caused an accumulation of the p10 protease subunit of caspase-8 that was not observed with cytotoxic doses of TNF-α. Under conditions where apoptosis was blocked, the mechanism of death switched to necroptosis. Trimerized MLKL was verified as a biomarker of necroptotic cell death. The synergistic toxicity of pevonedistat and elevated TNF-α was also demonstrated by in vivo rat studies. Only the combination treatment resulted in elevated serum markers of liver damage and single-cell hepatocyte necrosis. Taken together, the results of this work have characterized a novel synergistic toxicity driven by pevonedistat and TNF-α.

  9. Endothelial differentiation of amniotic fluid-derived stem cells: synergism of biochemical and shear force stimuli.

    PubMed

    Zhang, Ping; Baxter, Jason; Vinod, Kateki; Tulenko, Thomas N; Di Muzio, Paul J

    2009-11-01

    Human amniotic fluid-derived stem (AFS) cells possess several advantages over embryonic and adult stem cells, as evidenced by expression of both types of stem cell markers and ability to differentiate into cells of all three germ layers. Herein, we examine endothelial differentiation of AFS cells in response to growth factors, shear force, and hypoxia. We isolated human AFS cells from amniotic fluid samples (1-4 cc/specimen) obtained from patients undergoing amniocentesis at 15-18 weeks of gestation (n = 10). Isolates maintained in nondifferentiating medium expressed the stem cell markers CD13, CD29, CD44, CD90, CD105, OCT-4, and SSEA-4 through passage 8. After 3 weeks of culture in endothelial growth media-2 (EGM-2), the stem cells exhibited an endothelial-like morphology, formed cord-like structures when plated on Matrigel, and uptook acetylated LDL/lectin. Additionally, mRNA and protein levels of CD31 and von Willebrand factor (vWF) significantly increased in response to culture in EGM-2, with further up-regulation when stimulated by physiological levels (12 dyne/cm(2)) of shear force. Culture in hypoxic conditions (5% O(2)) resulted in significant expression of vascular endothelial growth factor (VEGF) and placental growth factor (PGF) mRNA. This study suggests that AFS cells, isolated from minute amounts of amniotic fluid, acquire endothelial cell characteristics when stimulated by growth factors and shear force, and produce angiogenic factors (VEGF, PGF, and hepatocyte growth factor [HGF]) in response to hypoxia. Thus, amniotic fluid represents a rich source of mesenchymal stem cells potentially suitable for use in cardiovascular regenerative medicine.

  10. In vitro studies of cutaneous retention of magnetic nanoemulsion loaded with zinc phthalocyanine for synergic use in skin cancer treatment

    NASA Astrophysics Data System (ADS)

    Primo, Fernando L.; Rodrigues, Marcilene M. A.; Simioni, Andreza R.; Bentley, Maria V. L. B.; Morais, Paulo C.; Tedesco, Antonio C.

    In this study was developed a new nano drug delivery system (NDDS) based on association of biodegradable surfactants with biocompatible magnetic fluid of maguemita citrate derivative. This formulation consists in a magnetic emulsion with nanostructured colloidal particles. Preliminary in vitro experiments showed that the formulation presents a great potential for synergic application in the topical release of photosensitizer drug (PS) and excellent target tissue properties in the photodynamic therapy (PDT) combined with hyperthermia (HPT) protocols. The physical chemistry characterization and in vitro assays were carried out by Zn(II) Phtalocyanine (ZnPc) photosensitizer incorporated into NDDS in the absence and the presence of magnetic fluid, showed good results and high biocompatibility. In vitro experiments were accomplished by tape-stripping protocols for quantification of drug association with different skin tissue layers. This technique is a classical method for analyses of drug release in stratum corneum and epidermis+ dermis skin layers. The NDDS formulations were applied directly in pig skin (tissue model) fixed in the cell's Franz device with receptor medium container with a PBS/EtOH 20% solution (10 mM, pH 7.4) at 37 °C. After 12 h of topical administration stratum corneum was removed from fifty tapes and the ZnPc retained was evaluated by solvent extraction in dimetil-sulphoxide under ultrasonic bath. These results indicated that magnetic nanoemulsion (MNE) increase the drug release on the deeper skin layers when compared with classical formulation in the absence of magnetic particles. This could be related with the increase of biocompatibility of NDDS due to the great affinity for the polar extracelullar matrix in the skin and also for the increase in the drug partition inside of corneocites wall.

  11. IL-17E synergizes with EGF and confers in vitro resistance to EGFR-targeted therapies in TNBC cells

    PubMed Central

    Merrouche, Yacine; Fabre, Joseph; Cure, Herve; Garbar, Christian; Fuselier, Camille; Bastid, Jeremy; Antonicelli, Frank; Al-Daccak, Reem; Bensussan, Armand; Giustiniani, Jerome

    2016-01-01

    Estrogen receptor-, progesterone receptor- and HER2-negative breast cancers, also known as triple-negative breast cancers (TNBCs), have poor prognoses and are refractory to current therapeutic agents, including epidermal growth factor receptor (EGFR) inhibitors. Resistance to anti-EGFR therapeutic agents is often associated with sustained kinase phosphorylation, which promotes EGFR activation and translocation to the nucleus and prevents these agents from acting on their targets. The mechanisms underlying this resistance have not been fully elucidated. In addition, the IL-17E receptor is overexpressed in TNBC tumors and is associated with a poor prognosis. We have previously reported that IL-17E promotes TNBC resistance to anti-mitotic therapies. Here, we investigated whether IL-17E promotes TNBC resistance to anti-EGFR therapeutic agents by exploring the link between the IL-17E/IL-17E receptor axis and EGF signaling. We found that IL-17E, similarly to EGF, activates the EGFR in TNBC cells that are resistant to EGFR inhibitors. It also activates the PYK-2, Src and STAT3 kinases, which are essential for EGFR activation and nuclear translocation. IL-17E binds its specific receptor, IL-17RA/IL17RB, on these TNBC cells and synergizes with the EGF signaling pathway, thereby inducing Src-dependent EGFR transactivation and pSTAT3 and pEGFR translocation to the nucleus. Collectively, our data indicate that the IL-17E/IL-17E receptor axis may underlie TNBC resistance to EGFR inhibitors and suggest that inhibiting IL-17E or its receptor in combination with EGFR inhibitor administration may improve TNBC management. PMID:27462789

  12. Synergic effect of salinity and zinc stress on growth and photosynthetic responses of the cordgrass, Spartina densiflora

    PubMed Central

    Redondo-Gómez, Susana; Andrades-Moreno, Luis; Mateos-Naranjo, Enrique; Parra, Raquel; Valera-Burgos, Javier; Aroca, Ricardo

    2011-01-01

    Spartina densiflora is a C4 halophytic species that has proved to have a high invasive potential which derives from its physiological plasticity to environmental factors, such as salinity. It is found in coastal marshes of south-west Spain, growing over sediments with between 1 mmol l−1 and 70 mmol l−1 zinc. A glasshouse experiment was designed to investigate the synergic effect of zinc from 0 mmol l−1 to 60 mmol l−1 at 0, 1, and 3% NaCl on the growth and the photosynthetic apparatus of S. densiflora by measuring chlorophyll fluorescence parameters and gas exchange, and its recovery after removing zinc. Antioxidant enzyme activities and total zinc, sodium, calcium, iron, magnesium, manganese, phosphorus, potassium, and nitrogen concentrations were also determined. Spartina densiflora showed the highest growth at 1 mmol l−1 zinc and 1% NaCl after 90 d of treatment; this enhanced growth was supported by the measurements of net photosynthetic rate (A). Furthermore, there was a stimulatory effect of salinity on accumulation of zinc in tillers of this species. Zinc concentrations >1 mmol l−1 reduced growth of S. densiflora, regardless of salinity treatments. This declining growth may be attributed to a decrease in A caused by diffusional limitation of photosynthesis, owing to the modification of the potassium/calcium ratio. Also, zinc and salinity had a marked overall effect on the photochemical (photosystem II) apparatus, partially mediated by the accumulation of H2O2 and subsequent oxidative damage. However, salinity favoured the recovery of the photosynthetic apparatus to the toxic action of zinc, and enhanced the nutrient uptake. PMID:21841175

  13. Cross-resistance and synergism bioassays suggest multiple mechanisms of pyrethroid resistance in western corn rootworm populations

    PubMed Central

    Souza, Dariane; Zukoff, Sarah N.; Meinke, Lance J.; Siegfried, Blair D.

    2017-01-01

    Recently, resistance to the pyrethroid bifenthrin was detected and confirmed in field populations of western corn rootworm, Diabrotica virgifera virgifera LeConte from southwestern areas of Nebraska and Kansas. As a first step to understand potential mechanisms of resistance, the objectives of this study were i) to assess adult mortality at diagnostic concentration-LC99 to the pyrethroids bifenthrin and tefluthrin as well as DDT, ii) estimate adult and larval susceptibility to the same compounds as well as the organophosphate methyl-parathion, and iii) perform synergism experiments with piperonyl butoxide (PBO) (P450 inhibitor) and S,S,S-tributyl-phosphorotrithioate (DEF) (esterase inhibitor) in field populations. Most of the adult field populations exhibiting some level of bifenthrin resistance exhibited significantly lower mortality to both pyrethroids and DDT than susceptible control populations at the estimated LC99 of susceptible populations. Results of adult dose-mortality bioassays also revealed elevated LC50 values for bifenthrin resistant populations compared to the susceptible control population with resistance ratios ranging from 2.5 to 5.5-fold for bifenthrin, 28 to 54.8-fold for tefluthrin, and 16.3 to 33.0 for DDT. These bioassay results collectively suggest some level of cross-resistance between the pyrethroids and DDT. In addition, both PBO and DEF reduced the resistance ratios for resistant populations although there was a higher reduction in susceptibility of adults exposed to PBO versus DEF. Susceptibility in larvae varied among insecticides and did not correlate with adult susceptibility to tefluthrin and DDT, as most resistance ratios were < 5-fold when compared to the susceptible population. These results suggest that both detoxifying enzymes and target site insensitivity might be involved as resistance mechanisms. PMID:28628635

  14. Synergic Adsorption-Biodegradation by an Advanced Carrier for Enhanced Removal of High-Strength Nitrogen and Refractory Organics.

    PubMed

    Ahmad, Muhammad; Liu, Sitong; Mahmood, Nasir; Mahmood, Asif; Ali, Muhammad; Zheng, Maosheng; Ni, Jinren

    2017-04-06

    Coking wastewater contains not only high-strength nitrogen but also toxic biorefractory organics. This study presents simultaneous removal of high-strength quinoline, carbon, and ammonium in coking wastewater by immobilized bacterial communities composed of a heterotrophic strain Pseudomonas sp. QG6 (hereafter referred as QG6), ammonia-oxidizing bacteria (AOB), and anaerobic ammonium oxidation bacteria (anammox). The bacterial immobilization was implemented with the help of a self-designed porous cubic carrier that created structured microenvironments including an inner layer adapted for anaerobic bacteria, a middle layer suitable for coaggregation of certain aerobic and anaerobic bacteria, and an outer layer for heterotrophic bacteria. By coating functional polyurethane foam (FPUF) with iron oxide nanoparticles (IONPs), the biocarrier (IONPs-FPUF) could provide a good outer-layer barrier for absorption and selective treatment of aromatic compounds by QG6, offer a conducive environment for anammox in the inner layer, and provide a mutualistic environment for AOB in the middle layer. Consequently, simultaneous nitrification and denitrification were reached with the significant removal of up to 322 mg L(-1) (98%) NH4, 311 mg L(-1) (99%) NO2, and 633 mg L(-1) (97%) total nitrogen (8 mg L(-1) averaged NO3 concentration was recorded in the effluent), accompanied by an efficient removal of chemical oxygen demand by 3286 mg L(-1) (98%) and 350 mg L(-1) (100%) quinoline. This study provides an alternative way to promote synergic adsorption and biodegradation with the help of a modified biocarrier that has great potential for treatment of wastewater containing high-strength carbon, toxic organic pollutants, and nitrogen.

  15. Folate-Hapten-Mediated Immunotherapy Synergizes with Vascular Endothelial Growth Factor Receptor Inhibitors in Treating Murine Models of Cancer.

    PubMed

    Bandara, N Achini; Bates, Cody D; Lu, Yingjuan; Hoylman, Emily K; Low, Philip S

    2017-03-01

    The overexpression of folate receptors (FR) on many human cancers has led to the development of folate-linked drugs for the imaging and therapy of FR-expressing cancers. In a recent phase I clinical trial of late-stage renal cell carcinoma patients, folate was exploited to deliver an immunogenic hapten, fluorescein, to FR(+) tumor cells in an effort to render the cancer cells more immunogenic. Although >50% of the patients showed prolonged stable disease, all patients eventually progressed, suggesting that the folate-hapten immunotherapy was insufficient by itself to treat the cancer. In an effort to identify a companion therapy that might augment the folate-hapten immunotherapy, we explored coadministration of two approved cancer drugs that had been previously shown to also stimulate the immune system. We report that sunitinib and axitinib (VEGF receptor inhibitors that simultaneously mitigate immune suppression) synergize with the folate-hapten-targeted immunotherapy to reduce tumor growth in three different syngeneic murine tumor models. We further demonstrate that the combination therapy not only enhances tumor infiltration of CD4(+) and CD8(+) effector cells, but surprisingly reduces tumor neovasculogenesis more than predicted. Subsequent investigation of the mechanism for this unexpected suppression of neovasculogenesis revealed that it is independent of elimination of any tumor cells, but instead likely derives from a reduction in the numbers of FR(+) tumor-associated macrophages and myeloid-derived suppressor cells, that is, immunosuppressive cells that release significant quantities of VEGF. These data suggest that a reduction in stromal cells of myeloid origin can inhibit tumor growth by suppressing neovasculogenesis. Mol Cancer Ther; 16(3); 461-8. ©2016 AACR.

  16. The synergic effect of glycyrrhizic acid and low frequency electromagnetic field on angiogenesis in chick chorioallantoic membrane

    PubMed Central

    Majidian Eydgahi, Shokat; Baharara, Javad; Zafar Balanezhad, Saeideh; Asadi Samani, Majid

    2015-01-01

    Objective: Much attention is paid to angiogenesis due to its mutual role in health and disease. Therefore, the effect of various chemical and physical agents on inhibition of this process has been recently studied. This study was conducted to investigate the synergic effect of glycyrrhizic acid and electromagnetic field on angiogenesis. Materials and Methods: In this experimental study, 44 Ross fertilized chicken eggs were randomly divided into four groups, one control and three experimental. Control group was kept with dimethyl sulfoxide on the eighth day, experimental group 1 treated with 200 gauss, 50 Hz electromagnetic field on the 10th day, experimental group 2 treated with 1 mg/ml glycyrrhizic acid on the eighth day, and experimental group 3 simultaneously treated with glycyrrhizic acid on the eighth day and electromagnetic field on the 10th day. On the 12th day, the images of chorioallantoic membrane samples were prepared using photostreomicroscope and the number and length of vessels were measured. Results: The mean number of vessels in the experimental groups 1 and 3 (29.31±3.60 and 27.43±4.61, respectively) was not significantly different from that in the control group (29.11±4.76) (p>0.05). The length of vessels in the experimental groups 1 and 3 (52.35±3.25 mm and 54.94±4.70 mm, respectively) decreased significantly (p<0.05) compared with the control group (61.79±6.46 mm). In experimental group 2, both length and number of vessels (54.53±5.85 mm and 23.96±3.94) decreased significantly compared with the control group (p<0.05). Conclusion: Electromagnetic field and glycyrrhizic acid separately led to inhibition of angiogenesis. However, use of electromagnetic field accompanied with glycyrrhizic acid not only did not increase but also decreased the inhibitory effect. PMID:26101751

  17. The synergic effect of glycyrrhizic acid and low frequency electromagnetic field on angiogenesis in chick chorioallantoic membrane.

    PubMed

    Majidian Eydgahi, Shokat; Baharara, Javad; Zafar Balanezhad, Saeideh; Asadi Samani, Majid

    2015-01-01

    Much attention is paid to angiogenesis due to its mutual role in health and disease. Therefore, the effect of various chemical and physical agents on inhibition of this process has been recently studied. This study was conducted to investigate the synergic effect of glycyrrhizic acid and electromagnetic field on angiogenesis. In this experimental study, 44 Ross fertilized chicken eggs were randomly divided into four groups, one control and three experimental. Control group was kept with dimethyl sulfoxide on the eighth day, experimental group 1 treated with 200 gauss, 50 Hz electromagnetic field on the 10th day, experimental group 2 treated with 1 mg/ml glycyrrhizic acid on the eighth day, and experimental group 3 simultaneously treated with glycyrrhizic acid on the eighth day and electromagnetic field on the 10th day. On the 12th day, the images of chorioallantoic membrane samples were prepared using photostreomicroscope and the number and length of vessels were measured. The mean number of vessels in the experimental groups 1 and 3 (29.31±3.60 and 27.43±4.61, respectively) was not significantly different from that in the control group (29.11±4.76) (p>0.05). The length of vessels in the experimental groups 1 and 3 (52.35±3.25 mm and 54.94±4.70 mm, respectively) decreased significantly (p<0.05) compared with the control group (61.79±6.46 mm). In experimental group 2, both length and number of vessels (54.53±5.85 mm and 23.96±3.94) decreased significantly compared with the control group (p<0.05). Electromagnetic field and glycyrrhizic acid separately led to inhibition of angiogenesis. However, use of electromagnetic field accompanied with glycyrrhizic acid not only did not increase but also decreased the inhibitory effect.

  18. Regional colon transit in patients with dys-synergic defaecation or slow transit in patients with constipation

    PubMed Central

    Nullens, Sara; Nelsen, Tyler; Camilleri, Michael; Burton, Duane; Eckert, Deborah; Iturrino, Johanna; Vazquez-Roque, Maria; Zinsmeister, Alan R

    2013-01-01

    Objective To differentiate dys-synergic defaecation (DD) from normal function and slow transit constipation (STC). Methods The medical records of 1411 patients evaluated by a single gastroenterologist over a 16-year period at a tertiary medical centre were reviewed. DD was characterised by anorectal manometry and balloon expulsion test. There were 390 patients with DD, and 61 with STC without DD. Transit data from 211 healthy individuals served as controls. The primary endpoints were overall colonic transit (geometric centre) at 24 h and 48 h (GC24 and GC48). Regional transit was measured as ascending colon half-emptying time (AC t1/2) and residual content in descending rectosigmoid colon and stool (DRS). Results Age and body mass index were similar in the STC and DD groups. DD was associated with smaller perineal descent and a greater difference in rectoanal pressure than STC. Both STC and DD were associated with lower GC24 and GC48 and slower AC t1/2 than controls. GC48 differentiated DD from healthy controls (p<0.001) and DD from STC (p=0.007). AC t1/2 values differentiated healthy controls from DD (p=0.006) and STC (p<0.001) and were associated with constipation (DD vs STC, p=0.007). The regional content of DRS at 48 h discriminated DD from STC (AUC=0.82) and stool content at 48 h, increasing the odds for DD over STC (OR per 5% in stool 2.4, 95% CI 1.1 to 5.5, p=0.03). Conclusions DD is associated with delayed overall colonic transit at 48 h and AC t1/2 compared with healthy controls. Regional scintigraphic transit profiles differentiate DD from STC and facilitate identification of a subgroup of patients with constipation. PMID:22180057

  19. Nanomolar Oxytocin Synergizes with Weak Electrical Afferent Stimulation to Activate the Locomotor CPG of the Rat Spinal Cord In Vitro

    PubMed Central

    Dose, Francesco; Zanon, Patrizia; Coslovich, Tamara; Taccola, Giuliano

    2014-01-01

    Synergizing the effect of afferent fibre stimulation with pharmacological interventions is a desirable goal to trigger spinal locomotor activity, especially after injury. Thus, to better understand the mechanisms to optimize this process, we studied the role of the neuropeptide oxytocin (previously shown to stimulate locomotor networks) on network and motoneuron properties using the isolated neonatal rat spinal cord. On motoneurons oxytocin (1 nM–1 μM) generated sporadic bursts with superimposed firing and dose-dependent depolarization. No desensitization was observed despite repeated applications. Tetrodotoxin completely blocked the effects of oxytocin, demonstrating the network origin of the responses. Recording motoneuron pool activity from lumbar ventral roots showed oxytocin mediated depolarization with synchronous bursts, and depression of reflex responses in a stimulus and peptide-concentration dependent fashion. Disinhibited bursting caused by strychnine and bicuculline was accelerated by oxytocin whose action was blocked by the oxytocin antagonist atosiban. Fictive locomotion appeared when subthreshold concentrations of NMDA plus 5HT were coapplied with oxytocin, an effect prevented after 24 h incubation with the inhibitor of 5HT synthesis, PCPA. When fictive locomotion was fully manifested, oxytocin did not change periodicity, although cycle amplitude became smaller. A novel protocol of electrical stimulation based on noisy waveforms and applied to one dorsal root evoked stereotypic fictive locomotion. Whenever the stimulus intensity was subthreshold, low doses of oxytocin triggered fictive locomotion although oxytocin per se did not affect primary afferent depolarization evoked by dorsal root pulses. Among the several functional targets for the action of oxytocin at lumbar spinal cord level, the present results highlight how small concentrations of this peptide could bring spinal networks to threshold for fictive locomotion in combination with other

  20. Drinking water quality and chronic kidney disease of unknown etiology (CKDu): synergic effects of fluoride, cadmium and hardness of water.

    PubMed

    Wasana, Hewa M S; Aluthpatabendi, Dharshani; Kularatne, W M T D; Wijekoon, Pushpa; Weerasooriya, Rohan; Bandara, Jayasundera

    2016-02-01

    High prevalence of chronic kidney disease of unknown etiology (CKDu) in some regions of the world is suspected mainly due to a toxin-mediated renal failure. We examined the incidence of CKDu and potable chemical water quality in a CKDu-affected region. This region has been identified as a high-risk zone for CKDu (location: latitude: 8.3500°-9.0000°, longitude: 80.3833°-81.3000°, North Central Province, NCP, Sri Lanka) by the World Health Organization (WHO). However, within this macro-region, small pockets of CKDu non-prevalence zones do exist; notably, the residents in those pockets consume spring water. Therefore, the drinking water quality of four areas, namely high-CKDu-prevalence areas (zone I), low-CKDu-prevalence area (zone II), the CKDu-free isolated pockets (zone III) and control areas (controls) were examined for F, Al, Cd, and As, and hardness and the statistical analysis were carried out to probe possible correlations among these parameters. The fluoride and hardness concentrations of water in zone III and control areas are much lower compared to zones I and II, and the water hardness is ~61 mg/L CaCO3. In zones I and II, the harness of drinking water is ~121-180 mg/L CaCO3; however, Al, Cd and As concentrations are almost comparable and below WHO recommendations. In most of the locations in zones I and II, the F concentration in drinking water is higher than the WHO recommendations. The peculiar distribution patterns of CKDu point to a synergic effect of trace elements in water for etiology of the disease.

  1. IL-17E synergizes with EGF and confers in vitro resistance to EGFR-targeted therapies in TNBC cells.

    PubMed

    Merrouche, Yacine; Fabre, Joseph; Cure, Herve; Garbar, Christian; Fuselier, Camille; Bastid, Jeremy; Antonicelli, Frank; Al-Daccak, Reem; Bensussan, Armand; Giustiniani, Jerome

    2016-08-16

    Estrogen receptor-, progesterone receptor- and HER2-negative breast cancers, also known as triple-negative breast cancers (TNBCs), have poor prognoses and are refractory to current therapeutic agents, including epidermal growth factor receptor (EGFR) inhibitors. Resistance to anti-EGFR therapeutic agents is often associated with sustained kinase phosphorylation, which promotes EGFR activation and translocation to the nucleus and prevents these agents from acting on their targets. The mechanisms underlying this resistance have not been fully elucidated. In addition, the IL-17E receptor is overexpressed in TNBC tumors and is associated with a poor prognosis. We have previously reported that IL-17E promotes TNBC resistance to anti-mitotic therapies. Here, we investigated whether IL-17E promotes TNBC resistance to anti-EGFR therapeutic agents by exploring the link between the IL-17E/IL-17E receptor axis and EGF signaling. We found that IL-17E, similarly to EGF, activates the EGFR in TNBC cells that are resistant to EGFR inhibitors. It also activates the PYK-2, Src and STAT3 kinases, which are essential for EGFR activation and nuclear translocation. IL-17E binds its specific receptor, IL-17RA/IL17RB, on these TNBC cells and synergizes with the EGF signaling pathway, thereby inducing Src-dependent EGFR transactivation and pSTAT3 and pEGFR translocation to the nucleus. Collectively, our data indicate that the IL-17E/IL-17E receptor axis may underlie TNBC resistance to EGFR inhibitors and suggest that inhibiting IL-17E or its receptor in combination with EGFR inhibitor administration may improve TNBC management.

  2. Functional Promoter Polymorphisms of MMP-2 C-735T and MMP-9 C-1562T and Their Synergism with MMP-7 A-181G in Multiple Sclerosis.

    PubMed

    Rahimi, Zohreh; Abdan, Zahra; Rahimi, Ziba; Razazian, Nazanin; Shiri, Hadis; Vaisi-Raygani, Asad; Shakiba, Ebrahim; Vessal, Mahmood; Moradi, Mohammad-Taher

    2016-08-01

    Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. Matrix metalloproteinases (MMPs) play an important role in breakdown of blood-brain barrier, transmigration, and invasion of immune cells and formation of MS lesions. The aim of present study was to investigate the influence of MMP-2 C-735T and MMP-9 C-1562T variants and their synergism with MMP-7 A-181G on susceptibility to MS. In a case-control study 125 MS patients and 235 healthy individuals from Western Iran were investigated. The various genotypes of MMP-2, MMP-9, and MMP-7 were detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In females the presence of MMP-2 C allele was associated with an increased risk of MS (OR = 1.69, p = 0.041). No significant difference was detected between the frequency of MMP-9 T allele in MS patients (8.2%) and controls (12.8%, p = 0.068). The concomitant presence of both MMP-2 C and MMP-7 G alleles was associated with 1.82-fold increased risk of MS (p = 0.002). Also, a synergism was detected between MMP-9 C and MMP-7 G alleles that elevated the risk of MS by 1.5-times (p = 0.035). The presence of haplotype MMP-9 T, MMP-7 G, and MMP-2 C (TGC) compared to haplotype CAG increased the risk of MS by 3.13-fold (p = 0.16). The present study suggests that gene-gene interactions and variants of more genes instead of single gene might play a role in susceptibility to MS. We indicated that synergism between variants of MMP-2, MMP-7, and MMP-9 genes might increase the risk of MS.

  3. Skeletal consequences of RANKL-blocking antibody (IK22-5) injections during growth: mouse strain disparities and synergic effect with zoledronic acid.

    PubMed

    Lézot, Frédéric; Chesneau, Julie; Navet, Benjamin; Gobin, Bérengère; Amiaud, Jérome; Choi, YongWon; Yagita, Hideo; Castaneda, Beatriz; Berdal, Ariane; Mueller, Christopher G; Rédini, Françoise; Heymann, Dominique

    2015-04-01

    High doses of bone resorption inhibitors are currently under evaluation in pediatric oncology. Previous works have evidenced transient arrest in long bone and skull bone growth and tooth eruption blockage when mice were treated with zoledronic acid (ZOL). The question of potential similar effects with a RANKL-blocking antibody (IK22.5) was raised. Sensitivity disparities in these inhibitors between mouse strains and synergic effects of zoledronic acid and a RANKL-blocking antibody were subsidiary questions. In order to answer these questions, newborn C57BL/6J and CD1 mice were injected every two or three days (4 injections in total so 7 or 10 days of treatment length) with high doses of a RANKL-blocking antibody. The consequences on the tibia, craniofacial bones and teeth were analyzed by μCT and histology at the end of the treatment and one, two and three months later. The results obtained showed that RANKL-blocking antibody injections induced a transient arrest of tibia and skull bone growth and an irreversible blockage of tooth eruption in C57BL/6J mice. In CD1 mice, tooth eruption defects were also present but only at much higher doses. Similar mouse strain differences were obtained with zoledronic acid. Finally, a synergic effect of the two inhibitors was evidenced. In conclusion as previously observed for bisphosphonates (ZOL), a RANKL-blocking antibody induced a transient arrest in long bone and skull bone growth and a blockage of tooth eruption with however disparities between mouse strains with regard to this last effect. A synergic effect of both bone resorption inhibitors was also demonstrated. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Western spruce budworm outbreaks did not increase fire risk over the last three centuries: a dendrochronological analysis of inter-disturbance synergism.

    PubMed

    Flower, Aquila; Gavin, Daniel G; Heyerdahl, Emily K; Parsons, Russell A; Cohn, Gregory M

    2014-01-01

    Insect outbreaks are often assumed to increase the severity or probability of fire occurrence through increased fuel availability, while fires may in turn alter susceptibility of forests to subsequent insect outbreaks through changes in the spatial distribution of suitable host trees. However, little is actually known about the potential synergisms between these natural disturbances. Assessing inter-disturbance synergism is challenging due to the short length of historical records and the confounding influences of land use and climate changes on natural disturbance dynamics. We used dendrochronological methods to reconstruct defoliator outbreaks and fire occurrence at ten sites along a longitudinal transect running from central Oregon to western Montana. We assessed synergism between disturbance types, analyzed long-term changes in disturbance dynamics, and compared these disturbance histories with dendroclimatological moisture availability records to quantify the influence of moisture availability on disturbances. After approximately 1890, fires were largely absent and defoliator outbreaks became longer-lasting, more frequent, and more synchronous at our sites. Fires were more likely to occur during warm-dry years, while outbreaks were most likely to begin near the end of warm-dry periods. Our results show no discernible impact of defoliation events on subsequent fire risk. Any effect from the addition of fuels during defoliation events appears to be too small to detect given the overriding influence of climatic variability. We therefore propose that if there is any relationship between the two disturbances, it is a subtle synergistic relationship wherein climate determines the probability of occurrence of each disturbance type, and each disturbance type damps the severity, but does not alter the probability of occurrence, of the other disturbance type over long time scales. Although both disturbance types may increase in frequency or extent in response to future

  5. Western Spruce Budworm Outbreaks Did Not Increase Fire Risk over the Last Three Centuries: A Dendrochronological Analysis of Inter-Disturbance Synergism

    PubMed Central

    Flower, Aquila; G. Gavin, Daniel; Heyerdahl, Emily K.; Parsons, Russell A.; Cohn, Gregory M.

    2014-01-01

    Insect outbreaks are often assumed to increase the severity or probability of fire occurrence through increased fuel availability, while fires may in turn alter susceptibility of forests to subsequent insect outbreaks through changes in the spatial distribution of suitable host trees. However, little is actually known about the potential synergisms between these natural disturbances. Assessing inter-disturbance synergism is challenging due to the short length of historical records and the confounding influences of land use and climate changes on natural disturbance dynamics. We used dendrochronological methods to reconstruct defoliator outbreaks and fire occurrence at ten sites along a longitudinal transect running from central Oregon to western Montana. We assessed synergism between disturbance types, analyzed long-term changes in disturbance dynamics, and compared these disturbance histories with dendroclimatological moisture availability records to quantify the influence of moisture availability on disturbances. After approximately 1890, fires were largely absent and defoliator outbreaks became longer-lasting, more frequent, and more synchronous at our sites. Fires were more likely to occur during warm-dry years, while outbreaks were most likely to begin near the end of warm-dry periods. Our results show no discernible impact of defoliation events on subsequent fire risk. Any effect from the addition of fuels during defoliation events appears to be too small to detect given the overriding influence of climatic variability. We therefore propose that if there is any relationship between the two disturbances, it is a subtle synergistic relationship wherein climate determines the probability of occurrence of each disturbance type, and each disturbance type damps the severity, but does not alter the probability of occurrence, of the other disturbance type over long time scales. Although both disturbance types may increase in frequency or extent in response to future

  6. Synergic effects between ocellatin-F1 and bufotenine on the inhibition of BHK-21 cellular infection by the rabies virus.

    PubMed

    Cunha Neto, Rene Dos Santos; Vigerelli, Hugo; Jared, Carlos; Antoniazzi, Marta Maria; Chaves, Luciana Botelho; da Silva, Andréa de Cássia Rodrigues; Melo, Robson Lopes de; Sciani, Juliana Mozer; Pimenta, Daniel C

    2015-01-01

    Rabies is an incurable neglected zoonosis with worldwide distribution characterized as a lethal progressive acute encephalitis caused by a lyssavirus. Animal venoms and secretions have long been studied as new bioactive molecular sources, presenting a wide spectrum of biological effects, including new antiviral agents. Bufotenine, for instance, is an alkaloid isolated from the skin secretion of the anuran Rhinella jimi that inhibits cellular penetration by the rabies virus. Antimicrobial peptides, such as ocellatin-P1 and ocellatin-F1, are present in the skin secretion of anurans from the genus Leptodactylus and provide chemical defense against predators and microorganisms. Skin secretion from captive Leptodactylus labyrinthicus was collected by mechanical stimulation, analyzed by liquid chromatography and mass spectrometry, and assayed for antiviral and cytotoxic activities. Synthetic peptides were obtained using solid phase peptide synthesis, purified by liquid chromatography and structurally characterized by mass spectrometry, and assayed in the same models. Cytotoxicity assays based on changes in cellular morphology were performed using baby hamster kidney (BHK-21) cells. Fixed Rabies virus (Pasteur Virus - PV) strain was used for virological assays based on rapid fluorescent focus inhibition test. Herein, we describe a synergic effect between ocellatin-F1 and bufotenine. This synergism was observed when screening the L. labyrinthicus skin secretion for antiviral activities. The active fraction major component was the antimicrobial peptide ocellatin-F1. Nevertheless, when the pure synthetic peptide was assayed, little antiviral activity was detectable. In-depth analyses of the active fraction revealed the presence of residual alkaloids together with ocellatin-F1. By adding sub-effective doses (e.g. < IC50) of pure bufotenine to synthetic ocellatin-F1, the antiviral effect was regained. Moreover, a tetrapetide derived from ocellatin-F1, based on alignment with

  7. Synergic effects in the extraction of paracetamol from aqueous NaCl solution by the binary mixtures of diethyl ether and low molecular weight primary alcohols

    NASA Astrophysics Data System (ADS)

    Nikolić, G. M.; Živković, J. V.; Atanasković, D. S.; Nikolić, M. G.

    2013-12-01

    Liquid-liquid extraction of paracetamol from aqueous NaCl solutions was performed with diethyl ether, 1-propanol, 1-butanol, isobutanol, 1-pentanol, and binary mixtures diethyl ether/1-propanol, diethyl ether/1-butanol, and diethyl ether/isobutanol. Among the pure solvents investigated in this study best extraction efficacy was obtained with 1-butanol. Synergic effects in the extraction with binary mixtures was investigated and compared with some other systems used for the extraction of poorly extractable compounds. Results obtained in this study may be of both fundamental and practical importance.

  8. Synergism of activated carbon and undoped and nitrogen-doped TiO2 in the photocatalytic degradation of the chemical warfare agents soman, VX, and yperite.

    PubMed

    Cojocaru, Bogdan; Neaţu, Stefan; Pârvulescu, Vasile I; Somoghi, Vasile; Petrea, Nicoleta; Epure, Gabriel; Alvaro, Mercedes; Garcia, Hermenegildo

    2009-01-01

    Efficient photocatalytic decomposition of chemical warfare agents is a process that may find application in emergency situations or for the controlled destruction of chemical warfare stockpiles. A series of heterogeneous photocatalysts comprising TiO2-activated carbon or N-TiO2-activated carbon composites exhibit excellent photocatalytic activity to effect the complete decomposition of yperite, soman, and VX in high concentrations. The remarkable photocatalytic activity arises from the synergism between adsorption on active carbon and photoactivity by titania. Nitridation makes the composite also active under visible-light irradiation.

  9. The antitumor agent doxorubicin binds to Fanconi anemia group F protein.

    PubMed

    Kusayanagi, Tomoe; Tsukuda, Senko; Shimura, Satomi; Manita, Daisuke; Iwakiri, Kanako; Kamisuki, Shinji; Takakusagi, Yoichi; Takeuchi, Toshifumi; Kuramochi, Kouji; Nakazaki, Atsuo; Sakaguchi, Kengo; Kobayashi, Susumu; Sugawara, Fumio

    2012-11-01

    Doxorubicin, a commonly used cancer chemotherapy agent, elicits several potent biological effects, including synergistic-antitumor activity in combination with cisplatin. However, the mechanism of this synergism remains obscure. Here, we employed an improved T7 phage display screening method to identify Fanconi anemia group F protein (FANCF) as a doxorubicin-binding protein. The FANCF-doxorubicin interaction was confirmed by pull-down assay and SPR analysis. FANCF is a component of the Fanconi anemia complex, which monoubiquitinates D2 protein of Fanconi anemia group as a cellular response against DNA cross-linkers such as cisplatin. We observed that the monoubiquitination was inhibited by doxorubicin treatment.

  10. Interactive effect of light colours and temporal synergism of circadian neural oscillations in reproductive regulation of Japanese quail.

    PubMed

    Yadav, Suneeta; Chaturvedi, Chandra Mohini

    2016-09-01

    Avian literature reports the modulation of 'photoperiodic gonadal responses' by the temporal phase relation of serotonergic and dopaminergic oscillations in Japanese quail. But, the modulation of 'light colour responses' by the temporal synergism of neural oscillations is not yet known. Hence the present study was designed to investigate the interaction of the light colour (blue, red) and the phase relation of neural oscillations in the reproductive regulation of Japanese quail. Three week old male Japanese quail were divided into two groups and maintained under a long day length condition (16L:8D) and were exposed to a 30 lux intensity of blue LED (light emitting diode) (B LED) and a red LED light (R LED). At the age of 15.5weeks, quail of one subgroup of B LED were injected with serotonin precursor (5-HTP) and dopamine precursor (l-DOPA) 12hrs apart (B LED+12-hr) and those of the R LED group were injected with the same drugs (5mg/100g body weight over a period of thirteen days) but 8hrs apart (R LED+8-hr). The remaining subgroups of both the light colour groups (B LED & R LED) received normal saline twice daily and served as controls. Cloacal gland volume was recorded weekly until 35.5weeks of age when the study was terminated and reproductive parameters (testicular volume, GSI, seminiferous tubule diameter and plasma testosterone) were assessed. Results indicate that the 8-hr temporal phase relation of neural oscillations suppresses reproductive activity even during the photosensitive phase of the red light exposed quail (R LED+8-hr) compare to the R LED controls. On the other hand, the 12-hr temporal phase relation stimulates the gonadal development of the B LED+12-hr quail compared to the B LED controls which after completing one cycle entered into a regressive phase and remained sexually quiescent. These experiments suggest that the temporal phase relations of circadian neural oscillations, in addition to modulating the classical photoperiodic responses, may

  11. Characterization of the mixed axial ligand complex (4-cyanopyridine)(imidazole)(tetramesitylporphinato)iron(iii) perchlorate. Stabilization by synergic bonding

    PubMed Central

    Serth-Guzzo, Judith A.; Turowska-Tyrk, Ilona; Safo, Martin K.; Walker, F. Ann; Debrunner, Peter G.; Scheidt, W. Robert

    2016-01-01

    The reaction of [Fe(TMP)(OClO3)], where TMP is the dianion of tetramesitylporphyrin, with a combination of a strong π-acceptor ligand and a π-donating imidazole can lead to the preparation of mixed-ligand complexes [Fe(Porph)(4-CNPy)(L)]+ where L is imidazole itself or 1-acetylimidazole and 4-cyanopyridine is the strong π acceptor ligand. The stability of the new mixed-ligand pair is the presumed result of synergic bonding between the two axial ligands. The molecular structure and other characterization of the new mixed axial ligand complex, [Fe(TMP)(4-CNPy)(HIm)]ClO4 is described. The axial ligands have a relative perpendicular arrangement with Fe–N(imidazole) = 1.945 Å and Fe–N(pyridine) = 2.021 Å The average equatorial Fe–Np distance is 1.963 Å, which is consistent with the S4-ruffled TMP core. Despite the relative perpendicular arrangement of axial ligands, the EPR spectrum of the complex is a rhombic signal and not a large gmax signal. The EPR g-values are g1 = 3.05, g2 = 2.07, and g3 = 1.22. A quadrupole doublet was seen in the Mössbauer spectrum with an isomer shift of 0.197 mm/s and quadrupole splitting of 1.935 mm/s. Two crystalline forms of [Fe(TMP)(4-CNPy)(HIm)]ClO4 have been characterized; the two forms differ only in the solvent content of the lattice. Crystal data for form A: a = 15.432 (12) Å, b = 20.696 (2) Å, c = 19.970 (5) Å, and β = 99.256 (14)°, monoclinic, space group P21/n, V = 6295 (2) Å3, Z = 4, formula FeCl3O4N8C69H69, 8397 observed data, R1 = 0.086, wR2 = 0.210, refinement on F 2. Crystal data for form B: a = 15.267 (3) Å, b = 20.377 (6) Å, c = 19.670 (4) Å, and β = 98.14 (1)°, monoclinic, space group P21/n, V = 6058 (4) Å3, Z = 4, formula C65.25H60.5Cl1.5FeN8O4, 5464 observed data, R1 = 0.096, wR2 = 0.112, refinement on F. PMID:27574390

  12. Behavioral Effects of A1- and A2-Selective Adenosine Agonists and Antagonists: Evidence for Synergism and Antagonism

    PubMed Central

    NIKODIJEVIĆ, OLGA; SARGES, REINHARD; DALY, JOHN W.; JACOBSON, KENNETH A.

    2012-01-01

    The locomotor effects in mice of selective A1 and A2 adenosine agonists, antagonists and combinations of agonists were investigated using a computerized activity monitor. The A2-selective agonist 2-[(2-aminoethylamino)carbonylethylphenylethylamino]-5'-N-ethylcarboxamidoadenosine (APEC), an amine derivative of 2-(carboxyethylphenylethylamino)adenosine-5'-carboxamide, was a more potent locomotor depressant than its amide conjugates. The rank order of potency after i.p. injection for adenosine agonists was 5'-N-ethylcarboxamidoadenosine (NECA) (ED50, 5.8 nmol/kg) > APEC (ED50, 25 nmol/kg) > N6-cyclohexyladenosine (CHA) (ED50, 270 nmol/kg). An A1-selective, centrally acting, adenosine antagonist, 8-cyclopentyltheophylline (10 mg/kg), completely reversed the locomotor depressant effects of CHA (A1-selective) and NECA (nonselective) at doses of agonists as high as twice the ED50, and shifted the dose-response curves to the right, suggesting a primary involvement of A1 receptors. 8-cyclopentyltheophylline did not affect the depressant effects of APEC at the ED50, consistent with the A2-selectivity of APEC. The locomotor effects of APEC and CHA were completely reversed by theophylline, but not by the peripherally active 8-p-sulfophenyltheophylline, indicating central action of the adenosine agonists. The depressant effects of APEC, but not of NECA or CHA, were reversed significantly by an A2-selective adenosine receptor antagonist, 4-amino-8-chloro-1-phenyl-[1,2,4]triazol[4,3-a]quinoxaline. Low or subthreshold doses of CHA potentiated the depressant effects of APEC. A subthreshold dose of CHA did not alter the depressant effect of NECA, whereas a subthreshold dose of APEC increased the depressant effects of low doses of NECA. Thus, it appears that A1- and A2-selective adenosine agonists have separate central depressant effects, which can be potentiative. The relatively high potency of NECA in vivo could be due to a synergism between central A1 and A2receptor activation by

  13. P2Y12 receptor blockade synergizes strongly with nitric oxide and prostacyclin to inhibit platelet activation

    PubMed Central

    Chan, Melissa V.; Knowles, Rebecca B. M.; Lundberg, Martina H.; Tucker, Arthur T.; Mohamed, Nura A.; Kirkby, Nicholas S.; Armstrong, Paul C. J.; Mitchell, Jane A.

    2016-01-01

    Aims In vivo platelet function is a product of intrinsic platelet reactivity, modifiable by dual antiplatelet therapy (DAPT), and the extrinsic inhibitory endothelial mediators, nitric oxide (NO) and prostacyclin (PGI2), that are powerfully potentiated by P2Y12 receptor blockade. This implies that for individual patients endothelial mediator production is an important determinant of DAPT effectiveness. Here, we have investigated this idea using platelets taken from healthy volunteers treated with anti‐platelet drugs. Methods Three groups of male volunteers (n = 8) received either prasugrel (10 mg), aspirin (75 mg) or DAPT (prasugrel + aspirin) once daily for 7 days. Platelet reactivity in the presence of diethylammonium (Z)‐1‐(N,N‐diethylamino)diazen‐1‐ium‐1,2‐diolate (DEA/NONOate) and PGI2 was studied before and following treatment. Results Ex vivo, PGI2 and/or DEA/NONOate had little inhibitory effect on TRAP‐6‐induced platelet reactivity in control conditions. However, in the presence of DAPT, combination of DEA/NONOate + PGI2 reduced platelet aggregation (74 ± 3% to 19 ± 6%, P < 0.05). In vitro studies showed even partial (25%) P2Y12 receptor blockade produced a significant (67 ± 2% to 39 ± 10%, P < 0.05) inhibition when DEA/NONOate + PGI2 was present. Conclusions We have demonstrated that PGI2 and NO synergize with P2Y12 receptor antagonists to produce powerful platelet inhibition. Furthermore, even with submaximal P2Y12 blockade the presence of PGI2 and NO greatly enhances platelet inhibition. Our findings highlight the importance of endothelial mediator in vivo modulation of P2Y12 inhibition and introduces the concept of refining ex vivo platelet function testing by incorporating an assessment of endothelial function to predict thrombotic outcomes better and adjust therapy to prevent adverse outcomes in individual patients. PMID:26561399

  14. Anti-Invasive and Anti-Proliferative Synergism between Docetaxel and a Polynuclear Pd-Spermine Agent

    PubMed Central

    Batista de Carvalho, Ana L. M.; Medeiros, Paula S. C.; Costa, Francisco M.; Ribeiro, Vanessa P.; Sousa, Joana B.; Marques, Maria P. M.

    2016-01-01

    The present work is aimed at evaluating the antitumour properties of a Pd(II) dinuclear complex with the biogenic polyamine spermine, by investigating: i) the anti-angiogenic and anti-migration properties of a Pd(II) dinuclear complex with spermine (Pd2Spm); ii) the anti-proliferative activity of Pd2Spm against a triple negative human breast carcinoma (MDA-MB-231); and finally iii) the putative interaction mediated by combination of Pd2Spm with Docetaxel. Anti-invasive (anti-angiogenic and anti-migratory) as well as anti-proliferative capacities were assessed, for different combination schemes and drug exposure times, using the CAM assay and VEGFR2 activity measurement, the MatrigelTM method and the SRB proliferation test. The results thus obtained evidence the ability of Pd2Spm to restrict angiogenesis and cell migration: Pd2Spm induced a marked inhibition of migration (43.8±12.2%), and a higher inhibition of angiogenesis (81.8±4.4% for total length values, at 4 μM) as compared to DTX at the clinical dosage 4x10-2 μM (26.4±14.4%; n = 4 to 11). Combination of Pd2Spm/DTX was more effective as anti-invasive and anti-proliferative than DTX or Pd2Spm in sole administration, which is compatible with the occurrence of synergism: for the anti-angiogenic effect, IC50(Pd2Spm/DTX) = 0.5/0.5x10-2 μM vs IC50(DTX) = 1.7x10-2 μM and IC50(Pd2Spm) = 1.6 μM. In conclusion, the reported effects of Pd2Spm on angiogenesis, migration and proliferation showed that this compound is a promising therapeutic agent against this type of breast cancer. Moreover, combined administration of Pd2Spm and DTX was found to trigger a substantial synergetic effect regarding angiogenesis inhibition as well as anti-migratory and anti-proliferative activities reinforcing the putative use of Pd(II) complexes in chemotherapeutic regimens. This is a significant outcome, aiming at the application of these combined strategies towards metastatic breast cancer (or other type of resistant cancers

  15. Synergism between ivermectin and the tyrosine kinase/P-glycoprotein inhibitor crizotinib against Haemonchus contortus larvae in vitro.

    PubMed

    Raza, Ali; Kopp, Steven R; Kotze, Andrew C

    2016-08-30

    Anthelmintic resistance is a major problem in parasitic nematodes of livestock worldwide. One means to counter resistance is to use synergists that specifically inhibit resistance mechanisms in order to restore the toxicity, and hence preserve the usefulness, of currently available anthelmintics. P-glycoproteins (P-gps) eliminate a wide variety of structurally unrelated xenobiotics from cells, and have been implicated in anthelmintic resistance. Crizotinib is a tyrosine kinase inhibitor under development as a cancer therapeutic. The compound also inhibits P-gps, and has been shown to reverse multidrug resistance in cancer cells. We were therefore interested in determining if the compound was able to increase the sensitivity of Haemonchus contortus larvae to ivermectin, as measured by in vitro larval development and migration assays with a drug-resistant and a -susceptible isolate. In migration assays, co-administration of crizotinib increased the toxicity of ivermectin to resistant larvae (up to 5.7-fold decrease in ivermectin IC50), and rendered the resistant larvae equally or more sensitive to ivermectin than the susceptible isolate. On the other hand, co-administration of crizotinib had no effect on ivermectin sensitivity in the susceptible isolate. In development assays, significant increases in the sensitivity of both the resistant (up to 1.9-fold) and susceptible (up to 1.6-fold) larvae to ivermectin were observed, although the magnitude of the observed synergism was less than seen in migration assays, and the resistant larvae retained significant levels of ivermectin resistance. By highlighting the ability of the P-gp inhibitor crizotinib to increase the sensitivity of H. contortus larvae to ivermectin, this study provides further evidence that P-gp inhibitors are potential tools for modulating the efficacy of anthelmintics. In addition, the differences in the outcomes of the two assays, with 'resistance-breaking' effects being much more marked in migration

  16. Additive Synergism between Asbestos and Smoking in Lung Cancer Risk: A Systematic Review and Meta-Analysis.

    PubMed

    Ngamwong, Yuwadee; Tangamornsuksan, Wimonchat; Lohitnavy, Ornrat; Chaiyakunapruk, Nathorn; Scholfield, C Norman; Reisfeld, Brad; Lohitnavy, Manupat

    2015-01-01

    Smoking and asbestos exposure are important risks for lung cancer. Several epidemiological studies have linked asbestos exposure and smoking to lung cancer. To reconcile and unify these results, we conducted a systematic review and meta-analysis to provide a quantitative estimate of the increased risk of lung cancer associated with asbestos exposure and cigarette smoking and to classify their interaction. Five electronic databases were searched from inception to May, 2015 for observational studies on lung cancer. All case-control (N = 10) and cohort (N = 7) studies were included in the analysis. We calculated pooled odds ratios (ORs), relative risks (RRs) and 95% confidence intervals (CIs) using a random-effects model for the association of asbestos exposure and smoking with lung cancer. Lung cancer patients who were not exposed to asbestos and non-smoking (A-S-) were compared with; (i) asbestos-exposed and non-smoking (A+S-), (ii) non-exposure to asbestos and smoking (A-S+), and (iii) asbestos-exposed and smoking (A+S+). Our meta-analysis showed a significant difference in risk of developing lung cancer among asbestos exposed and/or smoking workers compared to controls (A-S-), odds ratios for the disease (95% CI) were (i) 1.70 (A+S-, 1.31-2.21), (ii) 5.65; (A-S+, 3.38-9.42), (iii) 8.70 (A+S+, 5.8-13.10). The additive interaction index of synergy was 1.44 (95% CI = 1.26-1.77) and the multiplicative index = 0.91 (95% CI = 0.63-1.30). Corresponding values for cohort studies were 1.11 (95% CI = 1.00-1.28) and 0.51 (95% CI = 0.31-0.85). Our results point to an additive synergism for lung cancer with co-exposure of asbestos and cigarette smoking. Assessments of industrial health risks should take smoking and other airborne health risks when setting occupational asbestos exposure limits.

  17. Additive Synergism between Asbestos and Smoking in Lung Cancer Risk: A Systematic Review and Meta-Analysis

    PubMed Central

    Ngamwong, Yuwadee; Tangamornsuksan, Wimonchat; Lohitnavy, Ornrat; Chaiyakunapruk, Nathorn; Scholfield, C. Norman; Reisfeld, Brad; Lohitnavy, Manupat

    2015-01-01

    Smoking and asbestos exposure are important risks for lung cancer. Several epidemiological studies have linked asbestos exposure and smoking to lung cancer. To reconcile and unify these results, we conducted a systematic review and meta-analysis to provide a quantitative estimate of the increased risk of lung cancer associated with asbestos exposure and cigarette smoking and to classify their interaction. Five electronic databases were searched from inception to May, 2015 for observational studies on lung cancer. All case-control (N = 10) and cohort (N = 7) studies were included in the analysis. We calculated pooled odds ratios (ORs), relative risks (RRs) and 95% confidence intervals (CIs) using a random-effects model for the association of asbestos exposure and smoking with lung cancer. Lung cancer patients who were not exposed to asbestos and non-smoking (A-S-) were compared with; (i) asbestos-exposed and non-smoking (A+S-), (ii) non-exposure to asbestos and smoking (A-S+), and (iii) asbestos-exposed and smoking (A+S+). Our meta-analysis showed a significant difference in risk of developing lung cancer among asbestos exposed and/or smoking workers compared to controls (A-S-), odds ratios for the disease (95% CI) were (i) 1.70 (A+S-, 1.31–2.21), (ii) 5.65; (A-S+, 3.38–9.42), (iii) 8.70 (A+S+, 5.8–13.10). The additive interaction index of synergy was 1.44 (95% CI = 1.26–1.77) and the multiplicative index = 0.91 (95% CI = 0.63–1.30). Corresponding values for cohort studies were 1.11 (95% CI = 1.00–1.28) and 0.51 (95% CI = 0.31–0.85). Our results point to an additive synergism for lung cancer with co-exposure of asbestos and cigarette smoking. Assessments of industrial health risks should take smoking and other airborne health risks when setting occupational asbestos exposure limits. PMID:26274395

  18. Leukotriene D4 and prostaglandin E2 signals synergize and potentiate vascular inflammation in a mast cell-dependent manner through cysteinyl leukotriene receptor 1 and E-prostanoid receptor 3.

    PubMed

    Kondeti, Vinay; Al-Azzam, Nosayba; Duah, Ernest; Thodeti, Charles K; Boyce, Joshua A; Paruchuri, Sailaja

    2016-01-01

    Although arachidonic acid metabolites, cysteinyl leukotrienes (cys-LTs; leukotriene [LT] C4, LTD4, and LTE4), and prostaglandin (PG) E2 are generated at the site of inflammation, it is not known whether crosstalk exists between these 2 classes of inflammatory mediators. We sought to determine the role of LTD4-PGE2 crosstalk in inducing vascular inflammation in vivo, identify effector cells, and ascertain specific receptors and pathways involved in vitro. Vascular (ear) inflammation was assessed by injecting agonists into mouse ears, followed by measuring ear thickness and histology, calcium influx with Fura-2, phosphorylation and expression of signaling molecules by means of immunoblotting, PGD2 and macrophage inflammatory protein 1β generation by using ELISA, and expression of transcripts by using RT-PCR. Candidate receptors and signaling molecules were identified by using antagonists and inhibitors and confirmed by using small interfering RNA. LTD4 plus PGE2 potentiated vascular permeability and edema, gearing the system toward proinflammation in wild-type mice but not in Kit(W-sh) mice. Furthermore, LTD4 plus PGE2, through cysteinyl leukotriene receptor 1 (CysLT1R) and E-prostanoid receptor (EP) 3, enhanced extracellular signal-regulated kinase (Erk) and c-fos phosphorylation, inflammatory gene expression, macrophage inflammatory protein 1β secretion, COX-2 upregulation, and PGD2 generation in mast cells. Additionally, we uncovered that this synergism is mediated through Gi, protein kinase G, and Erk signaling. LTD4 plus PGE2-potentiated effects are partially sensitive to CysLT1R or EP3 antagonists but completely abolished by simultaneous treatment both in vitro and in vivo. Our results unravel a unique LTD4-PGE2 interaction affecting mast cells through CysLT1R and EP3 involving Gi, protein kinase G, and Erk and contributing to vascular inflammation in vivo. Furthermore, current results also suggest an advantage of targeting both CysLT1R and EP3 in

  19. Synergic effect of atomic oxygen and outgassing phenomena on Carbon/SiC composites for space applications

    NASA Astrophysics Data System (ADS)

    Albano, Marta

    so that sublimation and ablation easily can take place. The key role played by carbon composites in re-entry environment is due to their high stability at high temperature, preserving their mechanical properties. However, most of these applications involve extended time periods in oxidizing environments where carbon reacts rapidly with oxygen at temperatures as low as 770K and the composites are subjected to oxidation degradation. For these reasons coated C/C and C/SiC composites are the most promising materials for the exposed surface of a thermal protection system. The modern approaches to a design of such materials assume broad application of mathematical and physical simulation methods. But mathematical simulation is impossible if there is no true information available on the characteristics (properties) of objects analyzed. In the majority of cases in practice the direct measurement of materials thermo physical properties, especially of complex composition, is impossible. There is only one way which permits to overcome these complexities - the indirect measurement. Mathematically, such an approach is usually formulated as a solution of the inverse problem: through direct measurements of system's state (temperature, component concentration, etc.) define the properties of a system analyzed, for example, the materials thermophysical characteristics. Violation of cause-and-effect relations in the statement of these problems results in their correctness in mathematical sense (i.e., the absence of existence and/or uniqueness and/or stability of the solution). Hence to solve such problems special methods are developed usually called regularized. In order to guarantee the success of a space structure there is the necessity to study the synergic effects of all the challenges that the harsh space environment place to the structure. For this reason here is presented a joint experimental study on synergic effects on C/SiC composites. Outgassing and atomic oxygen corrosion

  20. Systems modeling of anti-apoptotic pathways in prostate cancer: psychological stress triggers a synergism pattern switch in drug combination therapy.

    PubMed

    Sun, Xiaoqiang; Bao, Jiguang; Nelson, Kyle C; Li, King Chuen; Kulik, George; Zhou, Xiaobo

    2013-01-01

    Prostate cancer patients often have increased levels of psychological stress or anxiety, but the molecular mechanisms underlying the interaction between psychological stress and prostate cancer as well as therapy resistance have been rarely studied and remain poorly understood. Recent reports show that stress inhibits apoptosis in prostate cancer cells via epinephrine/beta2 adrenergic receptor/PKA/BAD pathway. In this study, we used experimental data on the signaling pathways that control BAD phosphorylation to build a dynamic network model of apoptosis regulation in prostate cancer cells. We then compared the predictive power of two different models with or without the role of Mcl-1, which justified the role of Mcl-1 stabilization in anti-apoptotic effects of emotional stress. Based on the selected model, we examined and quantitatively evaluated the induction of apoptosis by drug combination therapies. We predicted that the combination of PI3K inhibitor LY294002 and inhibition of BAD phosphorylation at S112 would produce the best synergistic effect among 8 interventions examined. Experimental validation confirmed the effectiveness of our predictive model. Moreover, we found that epinephrine signaling changes the synergism pattern and decreases efficacy of combination therapy. The molecular mechanisms responsible for therapeutic resistance and the switch in synergism were explored by analyzing a network model of signaling pathways affected by psychological stress. These results provide insights into the mechanisms of psychological stress signaling in therapy-resistant cancer, and indicate the potential benefit of reducing psychological stress in designing more effective therapies for prostate cancer patients.

  1. Investigating synergism during sequential inactivation of MS-2 phage and Bacillus subtilis spores with UV/H2O2 followed by free chlorine.

    PubMed

    Cho, Min; Gandhi, Varun; Hwang, Tae-Mun; Lee, Sangho; Kim, Jae-Hong

    2011-01-01

    A sequential application of UV as a primary disinfectant with and without H(2)O(2) addition followed by free chlorine as secondary, residual disinfectant was performed to evaluate the synergistic inactivation of selected indicator microorganisms, MS-2 bacteriophage and Bacillus subtilis spores. No synergism was observed when the UV irradiation treatment was followed by free chlorine, i.e., the overall level of inactivation was the same as the sum of the inactivation levels achieved by each disinfection step. With the addition of H(2)O(2) in the primary UV disinfection step, however, enhanced microbial inactivation was observed. The synergism was observed in two folds manners: (1) additional inactivation achieved by hydroxyl radicals generated from the photolysis of H(2)O(2) in the primary UV disinfection step, and (2) damage to microorganisms in the primary step which facilitated the subsequent chlorine inactivation. Addition of H(2)O(2) in the primary disinfection step was also found to be beneficial for the degradation of selected model organic pollutants including bisphenol-A (endocrine disruptor), geosmin (taste and odor causing compound) and 2,4-D (herbicide). The results suggest that the efficiency of UV/free chlorine sequential disinfection processes, which are widely employed in drinking water treatment, could be significantly enhanced by adding H(2)O(2) in the primary step and hence converting the UV process to an advanced oxidation process.

  2. Native and genetically inactivated pertussis toxins induce human dendritic cell maturation and synergize with lipopolysaccharide in promoting T helper type 1 responses.

    PubMed

    Ausiello, Clara M; Fedele, Giorgio; Urbani, Francesca; Lande, Roberto; Di Carlo, Beatrice; Cassone, Antonio

    2002-08-01

    The capacity of pertussis toxin (PT) to induce maturation and functional activities of human monocyte-derived dendritic cells (DCs) was investigated. Both native PT (nPT) and genetically detoxified PT (dPT) efficiently promoted expression on DCs of CD80, CD86, human leukocyte antigen-DR, and CD83 markers, alloreactive antigen presentation, and cytokine production, primarily interferon (IFN)-gamma. Although they did not affect interleukin (IL)-10 production by lipopolysaccharide (LPS)-stimulated DCs, both nPT and dPT strongly synergized with LPS for IL-12 production. PTs plus LPS-stimulated DCs secreted soluble factors fostering IFN-gamma but not IL-4 and IL-5 production by naive T cells. T helper type 1 (Th1) polarization was, as alloreactive antigen presentation, inhibited by anti-IL-12 monoclonal antibody. These findings support the notion that nPT, in addition to inducing specific immune response, is a potent Th1 adjuvant and that dPT fully preserves this adjuvanticity. The synergic interaction between PT and LPS in IL-12 production might be relevant for the mechanisms of vaccine-induced protection.

  3. Development and validation of a general approach to predict and quantify the synergism of anti-cancer drugs using experimental design and artificial neural networks.

    PubMed

    Pivetta, Tiziana; Isaia, Francesco; Trudu, Federica; Pani, Alessandra; Manca, Matteo; Perra, Daniela; Amato, Filippo; Havel, Josef

    2013-10-15

    The combination of two or more drugs using multidrug mixtures is a trend in the treatment of cancer. The goal is to search for a synergistic effect and thereby reduce the required dose and inhibit the development of resistance. An advanced model-free approach for data exploration and analysis, based on artificial neural networks (ANN) and experimental design is proposed to predict and quantify the synergism of drugs. The proposed method non-linearly correlates the concentrations of drugs with the cytotoxicity of the mixture, providing the possibility of choosing the optimal drug combination that gives the maximum synergism. The use of ANN allows for the prediction of the cytotoxicity of each combination of drugs in the chosen concentration interval. The method was validated by preparing and experimentally testing the combinations with the predicted highest synergistic effect. In all cases, the data predicted by the network were experimentally confirmed. The method was applied to several binary mixtures of cisplatin and [Cu(1,10-orthophenanthroline)2(H2O)](ClO4)2, Cu(1,10-orthophenanthroline)(H2O)2(ClO4)2 or [Cu(1,10-orthophenanthroline)2(imidazolidine-2-thione)](ClO4)2. The cytotoxicity of the two drugs, alone and in combination, was determined against human acute T-lymphoblastic leukemia cells (CCRF-CEM). For all systems, a synergistic effect was found for selected combinations.

  4. Synthesis, characterization, microbiological evaluation, genotoxicity and synergism tests of new nano silver complexes with sulfamoxole: X-ray diffraction of [Ag2(SMX)2]·DMSO.

    PubMed

    Velluti, Francesca; Mosconi, Natalia; Acevedo, Ana; Borthagaray, Graciela; Castiglioni, Jorge; Faccio, Ricardo; Back, Davi Fernando; Moyna, Guillermo; Rizzotto, Marcela; Torre, María H

    2014-12-01

    The synthesis and microbiological evaluation of two new Ag(I) complexes with sulfamoxole (SMX), [Ag2(SMX)2]·H2O and [Ag4(SCN)3(SMX)]·H2O are described. Both were characterized by elemental analysis, thermogravimetry, powder and single crystal X-ray diffraction, NMR, Raman and experimental and theoretical IR spectroscopies. Their antibacterial and antifungal properties were evaluated by agar and broth dilution assays, respectively. In addition, synergism tests for Pseudomonas aeruginosa were performed, and genotoxicity studies were carried out employing the Allium cepa test. Both complexes displayed good activity against Escherichia coli, Staphylococcus aureus, P. aeruginosa, and 10 fungi strains, with lower minimum inhibitory concentrations (MICs) than that of free SMX in all cases. The nanometrical crystallite particle size determined from XRPD, DLS and TEM might explain the good microbiological activity in spite of the low solubility of both complexes. The fractional inhibitory concentration (FIC) calculated from the P. aeruginosa test data indicated that the activity of the complexes is not due to synergism of the free components in the concentration ratios studied. Moreover, none of the complexes displayed cytotoxic effects on onions in the concentration range tested, and chromosome aberrations were not observed.

  5. Use of bacterial surrogates as a tool to explore antimalarial drug interaction: Synergism between inhibitors of malarial dihydrofolate reductase and dihydropteroate synthase.

    PubMed

    Talawanich, Yuwadee; Kamchonwongpaisan, Sumalee; Sirawaraporn, Worachart; Yu