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Sample records for acidic microenvironment synergistically

  1. Acidic tumor microenvironment and pH-sensing G protein-coupled receptors.

    Science.gov (United States)

    Justus, Calvin R; Dong, Lixue; Yang, Li V

    2013-12-05

    The tumor microenvironment is acidic due to glycolytic cancer cell metabolism, hypoxia, and deficient blood perfusion. It is proposed that acidosis in the tumor microenvironment is an important stress factor and selection force for cancer cell somatic evolution. Acidic pH has pleiotropic effects on the proliferation, migration, invasion, metastasis, and therapeutic response of cancer cells and the function of immune cells, vascular cells, and other stromal cells. However, the molecular mechanisms by which cancer cells and stromal cells sense and respond to acidic pH in the tumor microenvironment are poorly understood. In this article the role of a family of pH-sensing G protein-coupled receptors (GPCRs) in tumor biology is reviewed. Recent studies show that the pH-sensing GPCRs, including GPR4, GPR65 (TDAG8), GPR68 (OGR1), and GPR132 (G2A), regulate cancer cell metastasis and proliferation, immune cell function, inflammation, and blood vessel formation. Activation of the proton-sensing GPCRs by acidosis transduces multiple downstream G protein signaling pathways. Since GPCRs are major drug targets, small molecule modulators of the pH-sensing GPCRs are being actively developed and evaluated. Research on the pH-sensing GPCRs will continue to provide important insights into the molecular interaction between tumor and its acidic microenvironment and may identify new targets for cancer therapy and chemoprevention.

  2. Synergistic tumor microenvironment targeting and blood-brain barrier penetration via a pH-responsive dual-ligand strategy for enhanced breast cancer and brain metastasis therapy.

    Science.gov (United States)

    Li, Man; Shi, Kairong; Tang, Xian; Wei, Jiaojie; Cun, Xingli; Long, Yang; Zhang, Zhirong; He, Qin

    2018-05-22

    Cancer associated fibroblasts (CAFs) which shape the tumor microenvironment (TME) and the presence of blood brain barrier (BBB) remain great challenges in targeting breast cancer and its brain metastasis. Herein, we reported a strategy using PTX-loaded liposome co-modified with acid-cleavable folic acid (FA) and BBB transmigrating cell penetrating peptide dNP2 peptide (cFd-Lip/PTX) for enhanced delivery to orthotopic breast cancer and its brain metastasis. Compared with single ligand or non-cleavable Fd modified liposomes, cFd-Lip exhibited synergistic TME targeting and BBB transmigration. Moreover, upon arrival at the TME, the acid-cleavable cFd-Lip/PTX showed sensitive cleavage of FA, which reduced the hindrance effect and maximized the function of both FA and dNP2 peptide. Consequently, efficient targeting of folate receptor (FR)-positive tumor cells and FR-negative CAFs was achieved, leading to enhanced anti-tumor activity. This strategy provides a feasible approach to the cascade targeting of TME and BBB transmigration in orthotopic and metastatic cancer treatment. Copyright © 2018. Published by Elsevier Inc.

  3. Fate of the synergistic antioxidant system ascorbic acid, lecithin, and tocopherol in mayonnaise: Partion of ascorbic acid

    DEFF Research Database (Denmark)

    Meyer, Anne Merete Boye; Jacobsen, Charlotte Munch

    1996-01-01

    Meyer, A. S. & C. Jacobsen, 1996. Fate of the synergistic antioxidant system ascorbic acid, lecithin, and tocopherol in mayonnaise: Partion of ascorbic acid, J. Food Lipids, 3, 139-147.......Meyer, A. S. & C. Jacobsen, 1996. Fate of the synergistic antioxidant system ascorbic acid, lecithin, and tocopherol in mayonnaise: Partion of ascorbic acid, J. Food Lipids, 3, 139-147....

  4. Lactic acid in tumor microenvironments causes dysfunction of NKT cells by interfering with mTOR signaling.

    Science.gov (United States)

    Xie, Di; Zhu, Shasha; Bai, Li

    2016-12-01

    Cellular metabolism has been shown to regulate differentiation and function of immune cells. Tumor associated immune cells undergo phenotypic and functional alterations due to the change of cellular metabolism in tumor microenvironments. NKT cells are good candidates for immunotherapies against tumors and have been used in several clinical trials. However, the influences of tumor microenvironments on NKT cell functions remain unclear. In our studies, lactic acid in tumor microenvironments inhibited IFNγ and IL4 productions from NKT cells, and more profound influence on IFNγ was observed. By adjusting the pH of culture medium we further showed that, dysfunction of NKT cells could simply be induced by low extracellular pH. Moreover, low extracellular pH inhibited NKT cell functions by inhibiting mammalian target of rapamycin (mTOR) signaling and nuclear translocation of promyelocytic leukemia zinc-finger (PLZF). Together, our results suggest that tumor acidic microenvironments could interfere with NKT cell functions through metabolic controls.

  5. Fate of the synergistic antioxidant system ascorbic acid, lecithin, and tocopherol in mayonnaise : Partition of ascorbic acid

    DEFF Research Database (Denmark)

    Meyer, A.S.; Jacobsen, Charlotte Munch

    1996-01-01

    The distribution of ascorbic acid between the lipid and aqueous phase was investigated in mayonnaises enriched with fish oil containing a synergistic antioxidant mixture of ascorbic acid, lecithin and gamma-tocopherol, i.e., the A/L/T system (Loliger and Saucy 1989). The ascorbic acid was found...... to be located in the aqueous phase indicating that the A/L/T system broke down in mayonnaises. Based on the hypothesis that synergistic antioxidant action between ascorbic acid, lecithin and tocopherol requires that the three components are in close assembly, the results offer an explanation as to why the A...

  6. Targeting Pancreatic Ductal Adenocarcinoma Acidic Microenvironment

    Science.gov (United States)

    Cruz-Monserrate, Zobeida; Roland, Christina L.; Deng, Defeng; Arumugam, Thiruvengadam; Moshnikova, Anna; Andreev, Oleg A.; Reshetnyak, Yana K.; Logsdon, Craig D.

    2014-03-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA, accounting for ~40,000 deaths annually. The dismal prognosis for PDAC is largely due to its late diagnosis. Currently, the most sensitive diagnosis of PDAC requires invasive procedures, such as endoscopic ultrasonography, which has inherent risks and accuracy that is highly operator dependent. Here we took advantage of a general characteristic of solid tumors, the acidic microenvironment that is generated as a by-product of metabolism, to develop a novel approach of using pH (Low) Insertion Peptides (pHLIPs) for imaging of PDAC. We show that fluorescently labeled pHLIPs can localize and specifically detect PDAC in human xenografts as well as PDAC and PanIN lesions in genetically engineered mouse models. This novel approach may improve detection, differential diagnosis and staging of PDAC.

  7. Acidic microenvironments induce lymphangiogenesis and IL-8 production via TRPV1 activation in human lymphatic endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Nakanishi, Masako, E-mail: n-masako@wakayama-med.ac.jp [Department of Pathology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509 (Japan); Morita, Yoshihiro [Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871 (Japan); Department of Oral and Maxillofacial Surgery, Seichokai Hannan Municipal Hospital, Hannan, Osaka 599-0202 (Japan); Hata, Kenji [Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871 (Japan); Muragaki, Yasuteru, E-mail: ymuragak@wakayama-med.ac.jp [Department of Pathology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509 (Japan)

    2016-07-15

    Local acidosis is one of the characteristic features of the cancer microenvironment. Many reports indicate that acidosis accelerates the proliferation and invasiveness of cancer cells. However, whether acidic conditions affect lymphatic metastasis is currently unknown. In the present study, we focused on the effects of acidosis on lymphatic endothelial cells (LECs) to assess the relationship between acidic microenvironments and lymph node metastasis. We demonstrated that normal human LECs express various acid receptors by immunohistochemistry and reverse transcriptase-polymerase chain reaction (PCR). Acidic stimulation with low pH medium induced morphological changes in LECs to a spindle shape, and significantly promoted cellular growth and tube formation. Moreover, real-time PCR revealed that acidic conditions increased the mRNA expression of interleukin (IL)-8. Acidic stimulation increased IL-8 production in LECs, whereas a selective transient receptor potential vanilloid subtype 1 (TRPV1) antagonist, 5′-iodoresiniferatoxin, decreased IL-8 production. IL-8 accelerated the proliferation of LECs, and inhibition of IL-8 diminished tube formation and cell migration. In addition, phosphorylation of nuclear factor (NF)-κB was induced by acidic conditions, and inhibition of NF-κB activation reduced acid-induced IL-8 expression. These results suggest that acidic microenvironments in tumors induce lymphangiogenesis via TRPV1 activation in LECs, which in turn may promote lymphatic metastasis. - Highlights: • Acidity accelerates the growth, migration, and tube formation of LECs. • Acidic condition induces IL-8 expression in LECs. • IL-8 is critical for the changes of LECs. • IL-8 expression is induced via TRPV1 activation.

  8. Acidity generated by the tumor microenvironment drives local invasion.

    Science.gov (United States)

    Estrella, Veronica; Chen, Tingan; Lloyd, Mark; Wojtkowiak, Jonathan; Cornnell, Heather H; Ibrahim-Hashim, Arig; Bailey, Kate; Balagurunathan, Yoganand; Rothberg, Jennifer M; Sloane, Bonnie F; Johnson, Joseph; Gatenby, Robert A; Gillies, Robert J

    2013-03-01

    The pH of solid tumors is acidic due to increased fermentative metabolism and poor perfusion. It has been hypothesized that acid pH promotes local invasive growth and metastasis. The hypothesis that acid mediates invasion proposes that H(+) diffuses from the proximal tumor microenvironment into adjacent normal tissues where it causes tissue remodeling that permits local invasion. In the current work, tumor invasion and peritumoral pH were monitored over time using intravital microscopy. In every case, the peritumoral pH was acidic and heterogeneous and the regions of highest tumor invasion corresponded to areas of lowest pH. Tumor invasion did not occur into regions with normal or near-normal extracellular pH. Immunohistochemical analyses revealed that cells in the invasive edges expressed the glucose transporter-1 and the sodium-hydrogen exchanger-1, both of which were associated with peritumoral acidosis. In support of the functional importance of our findings, oral administration of sodium bicarbonate was sufficient to increase peritumoral pH and inhibit tumor growth and local invasion in a preclinical model, supporting the acid-mediated invasion hypothesis. Cancer Res; 73(5); 1524-35. ©2012 AACR. ©2012 AACR.

  9. Kinetic model of water disinfection using peracetic acid including synergistic effects.

    Science.gov (United States)

    Flores, Marina J; Brandi, Rodolfo J; Cassano, Alberto E; Labas, Marisol D

    2016-01-01

    The disinfection efficiencies of a commercial mixture of peracetic acid against Escherichia coli were studied in laboratory scale experiments. The joint and separate action of two disinfectant agents, hydrogen peroxide and peracetic acid, were evaluated in order to observe synergistic effects. A kinetic model for each component of the mixture and for the commercial mixture was proposed. Through simple mathematical equations, the model describes different stages of attack by disinfectants during the inactivation process. Based on the experiments and the kinetic parameters obtained, it could be established that the efficiency of hydrogen peroxide was much lower than that of peracetic acid alone. However, the contribution of hydrogen peroxide was very important in the commercial mixture. It should be noted that this improvement occurred only after peracetic acid had initiated the attack on the cell. This synergistic effect was successfully explained by the proposed scheme and was verified by experimental results. Besides providing a clearer mechanistic understanding of water disinfection, such models may improve our ability to design reactors.

  10. Microenvironment acidity as a major determinant of tumor chemoresistance: Proton pump inhibitors (PPIs) as a novel therapeutic approach.

    Science.gov (United States)

    Taylor, Sophie; Spugnini, Enrico Pierluigi; Assaraf, Yehuda G; Azzarito, Tommaso; Rauch, Cyril; Fais, Stefano

    2015-11-01

    Despite the major progresses in biomedical research and the development of novel therapeutics and treatment strategies, cancer is still among the dominant causes of death worldwide. One of the crucial challenges in the clinical management of cancer is primary (intrinsic) and secondary (acquired) resistance to both conventional and targeted chemotherapeutics. Multiple mechanisms have been identifiedthat underlie intrinsic and acquired chemoresistance: these include impaired drug uptake, increased drug efflux, deletion of receptors, altered drug metabolism, quantitative and qualitative alterations in drug targets, increased DNA damage repair and various mechanisms of anti-apoptosis. The fast efflux of anticancer drugs mediated by multidrug efflux pumps and the partial or complete reversibility of chemoresistance combined with the absence of genetic mutations suggests a multifactorial process. However, a growing body of recent evidence suggests that chemoresistance is often triggered by the highly acidic microenvironment of tumors. The vast majority of drugs, including conventional chemotherapeutics and more recent biological agents, are weak bases that are quickly protonated and neutralized in acidic environments, such as the extracellular microenvironment and the acidic organelles of tumor cells. It is therefore essential to develop new strategies to overcome the entrapment and neutralization of weak base drugs. One such strategy is the use of proton pump inhibitors which can enhance tumor chemosensitivity by increasing the pH of the tumor microenvironment. Recent clinical trials in animals with spontaneous tumors have indicated that patient alkalization is capable of reversing acquired chemoresistance in a large percentage of tumors that are refractory to chemotherapy. Of particular interest was the benefit of alkalization for patients undergoing metronomic regimens which are becoming more widely used in veterinary medicine. Overall, these results provide

  11. Synergistic anti-proliferative effects of gambogic acid with docetaxel in gastrointestinal cancer cell lines

    Directory of Open Access Journals (Sweden)

    Zou Zhengyun

    2012-04-01

    Full Text Available Summary Background Gambogic acid has a marked anti-tumor effect for gastric and colorectal cancers in vitro and in vivo. However, recent investigations on gambogic acid have focused mainly on mono-drug therapy, and its potential role in cancer therapy has not been comprehensively illustrated. This study aimed to assess the interaction between gambogic acid and docetaxel on human gastrointestinal cancer cells and to investigate the mechanism of gambogic acid plus docetaxel treatment-induced apoptotic cell death. Methods MTT assay was used to determine IC50 values in BGC-823, MKN-28, LOVO and SW-116 cells after gambogic acid and docetaxel administration. Median effect analysis was applied for determination of synergism and antagonism. Synergistic interaction between gambogic acid and docetaxel was evaluated using the combination index (CI method. Furthermore, cellular apoptosis was analyzed by Annexin-V and propidium iodide (PI double staining. Additionally, mRNA expression of drug-associated genes, i.e., β-tublin III and tau, and the apoptosis-related gene survivin, were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR. Results Gambogic acid provided a synergistic effect on the cytotoxicity induced by docetaxel in all four cell lines. The combined application of gambogic acid and docetaxel enhanced apoptosis in gastrointestinal cancer cells. Moreover, gambogic acid markedly decreased the mRNA expression of docetaxel-related genes, including β-tubulin III, tau and survivin, in BGC-823 cells. Conclusions Gambogic acid plus docetaxel produced a synergistic anti-tumor effect in gastrointestinal cancer cells, suggesting that the drug combination may offer a novel treatment option for patients with gastric and colorectal cancers.

  12. Gd-labeled glycol chitosan as a pH-responsive magnetic resonance imaging agent for detecting acidic tumor microenvironments.

    Science.gov (United States)

    Nwe, Kido; Huang, Ching-Hui; Tsourkas, Andrew

    2013-10-24

    Neoplastic lesions can create a hostile tumor microenvironment with low extracellular pH. It is commonly believed that these conditions can contribute to tumor progression as well as resistance to therapy. We report the development and characterization of a pH-responsive magnetic resonance imaging contrast agent for imaging the acidic tumor microenvironment. The preparation included the conjugation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid 1-(2,5-dioxo-1-pyrrolidinyl) ester (DOTA-NHS) to the surface of a water-soluble glycol chitosan (GC) polymer, which contains pH-titrable primary amines, followed by gadolinium complexation (GC-NH2-GdDOTA). GC-NH2-GdDOTA had a chelate-to-polymer ratio of approximately1:24 and a molar relaxivity of 9.1 mM(-1) s(-1). GC-NH2-GdDOTA demonstrated pH-dependent cellular association in vitro compared to the control. It also generated a 2.4-fold enhancement in signal in tumor-bearing mice 2 h postinjection. These findings suggest that glycol chitosan coupled with contrast agents can provide important diagnostic information about the tumor microenvironment.

  13. Synergistic action of fatty acids, sulphides and stilbene against acaricide-resistant Rhipicephalus microplus ticks.

    Science.gov (United States)

    Arceo-Medina, G N; Rosado-Aguilar, J A; Rodríguez-Vivas, R I; Borges-Argaez, R

    2016-09-15

    Six compounds in a methanolic extract of Petiveria alliacea stem (cis-stilbene; benzyl disulphide; benzyl trisulphide; and methyl esters of hexadecanoic acid, octadecadienoic acid and octadecenoic acid) are known to exercise acaricide activity against cattle tick Rhipicephalus microplus larvae and adults. The synergistic effect of 57 combinations of these six compounds on acaricide activity against R. microplus was evaluated. Larvae immersion tests produced the lethal concentrations needed to kill 50% (LC 50 ) and 99% (LC 99 ) of the population. Adult immersion tests produced rates (%) for mortality, oviposition inhibition and eclosion inhibition. Individually, none of the compounds (1% concentration) exhibited acaricide activity (mortality ≤2.3%). When combined, however, nine mixtures exhibited a synergistic increase in activity, with high mortality rates (≥92%) in larvae. Values for LC 50 ranged from 0.07 to 0.51% and those for LC 99 from 0.66 to 5.16%. Thirty six compound mixtures had no significant activity (mortality ≤30%) against larvae. Two mixtures exhibited synergism against adults, with high rates (≥92%) of oviposition inhibition. The mixtures based on the benzyl disulphide+benzyl trisulphide pairing produced a synergistic effect against acaricide-resistant R. microplus larva and adults, and are therefore the most promising combination for controlling this ubiquitous ectoparasite. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Mechanotransduction and Growth Factor Signalling to Engineer Cellular Microenvironments.

    Science.gov (United States)

    Cipitria, Amaia; Salmeron-Sanchez, Manuel

    2017-08-01

    Engineering cellular microenvironments involves biochemical factors, the extracellular matrix (ECM) and the interaction with neighbouring cells. This progress report provides a critical overview of key studies that incorporate growth factor (GF) signalling and mechanotransduction into the design of advanced microenvironments. Materials systems have been developed for surface-bound presentation of GFs, either covalently tethered or sequestered through physico-chemical affinity to the matrix, as an alternative to soluble GFs. Furthermore, some materials contain both GF and integrin binding regions and thereby enable synergistic signalling between the two. Mechanotransduction refers to the ability of the cells to sense physical properties of the ECM and to transduce them into biochemical signals. Various aspects of the physics of the ECM, i.e. stiffness, geometry and ligand spacing, as well as time-dependent properties, such as matrix stiffening, degradability, viscoelasticity, surface mobility as well as spatial patterns and gradients of physical cues are discussed. To conclude, various examples illustrate the potential for cooperative signalling of growth factors and the physical properties of the microenvironment for potential applications in regenerative medicine, cancer research and drug testing. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. The amino acid sequences and activities of synergistic hemolysins from Staphylococcus cohnii.

    Science.gov (United States)

    Mak, Pawel; Maszewska, Agnieszka; Rozalska, Malgorzata

    2008-10-01

    Staphylococcus cohnii ssp. cohnii and S. cohnii ssp. urealyticus are a coagulase-negative staphylococci considered for a long time as unable to cause infections. This situation changed recently and pathogenic strains of these bacteria were isolated from hospital environments, patients and medical staff. Most of the isolated strains were resistant to many antibiotics. The present work describes isolation and characterization of several synergistic peptide hemolysins produced by these bacteria and acting as virulence factors responsible for hemolytic and cytotoxic activities. Amino acid sequences of respective hemolysins from S. cohnii ssp. cohnii (named as H1C, H2C and H3C) and S. cohnii ssp. urealyticus (H1U, H2U and H3U) were identical. Peptides H1 and H3 possessed significant amino acid homology to three synergistic hemolysins secreted by Staphylococcus lugdunensis and to putative antibacterial peptide produced by Staphylococcus saprophyticus ssp. saprophyticus. On the other hand, hemolysin H2 had a unique sequence. All isolated peptides lysed red cells from different mammalian species and exerted a cytotoxic effect on human fibroblasts.

  16. Role of tumor microenvironment in triple-negative breast cancer and its prognostic significance

    Institute of Scientific and Technical Information of China (English)

    Tianjian Yu; Genhong Di

    2017-01-01

    Breast cancer has been shown to live in the tumor microenvironment,which consists of not only breast cancer cells themselves but also a significant amount of pathophysiologically altered surrounding stroma and cells.Diverse components of the breast cancer microenvironment,such as suppressive immune cells,re-programmed fibroblast cells,altered extracellular matrix (ECM) and certain soluble factors,synergistically impede an effective anti-tumor response and promote breast cancer progression and metastasis.Among these components,stromal cells in the breast cancer microenvironment are characterized by molecular alterations and aberrant signaling pathways,whereas the ECM features biochemical and biomechanical changes.However,triple-negative breast cancer (TNBC),the most aggressive subtype of this disease that lacks effective therapies available for other subtypes,is considered to feature a unique microenvironment distinct from that of other subtypes,especially compared to Luminal A subtype.Because these changes are now considered to significantly impact breast cancer development and progression,these unique alterations may serve as promising prognostic factors of clinical outcome or potential therapeutic targets for the treatment of TNBC.In this review,we focus on the composition of the TNBC microenvironment,concomitant distinct biological alteration,specific interplay between various cell types and TNBC cells,and the prognostic implications of these findings.

  17. Acidic tumor microenvironment abrogates the efficacy of mTORC1 inhibitors.

    Science.gov (United States)

    Faes, Seraina; Duval, Adrian P; Planche, Anne; Uldry, Emilie; Santoro, Tania; Pythoud, Catherine; Stehle, Jean-Christophe; Horlbeck, Janine; Letovanec, Igor; Riggi, Nicolo; Demartines, Nicolas; Dormond, Olivier

    2016-12-05

    Blocking the mechanistic target of rapamycin complex-1 (mTORC1) with chemical inhibitors such as rapamycin has shown limited clinical efficacy in cancer. The tumor microenvironment is characterized by an acidic pH which interferes with cancer therapies. The consequences of acidity on the anti-cancer efficacy of mTORC1 inhibitors have not been characterized and are thus the focus of our study. Cancer cell lines were treated with rapamycin in acidic or physiological conditions and cell proliferation was investigated. The effect of acidity on mTORC1 activity was determined by Western blot. The anticancer efficacy of rapamycin in combination with sodium bicarbonate to increase the intratumoral pH was tested in two different mouse models and compared to rapamycin treatment alone. Histological analysis was performed on tumor samples to evaluate proliferation, apoptosis and necrosis. Exposing cancer cells to acidic pH in vitro significantly reduced the anti-proliferative effect of rapamycin. At the molecular level, acidity significantly decreased mTORC1 activity, suggesting that cancer cell proliferation is independent of mTORC1 in acidic conditions. In contrast, the activation of mitogen-activated protein kinase (MAPK) or AKT were not affected by acidity, and blocking MAPK or AKT with a chemical inhibitor maintained an anti-proliferative effect at low pH. In tumor mouse models, the use of sodium bicarbonate increased mTORC1 activity in cancer cells and potentiated the anti-cancer efficacy of rapamycin. Combining sodium bicarbonate with rapamycin resulted in increased tumor necrosis, increased cancer cell apoptosis and decreased cancer cell proliferation as compared to single treatment. Taken together, these results emphasize the inefficacy of mTORC1 inhibitors in acidic conditions. They further highlight the potential of combining sodium bicarbonate with mTORC1 inhibitors to improve their anti-tumoral efficacy.

  18. Intramolecular synergistic effect of glutamic acid, cysteine and glycine against copper corrosion in hydrochloric acid solution

    International Nuclear Information System (INIS)

    Zhang Daquan; Xie Bin; Gao Lixin; Cai Qirui; Joo, Hyung Goun; Lee, Kang Yong

    2011-01-01

    The corrosion protection of copper by glutamic acid, cysteine, glycine and their derivative (glutathione) in 0.5 M hydrochloric acid solution has been studied by the electrochemical impedance spectroscopy and cyclic voltammetry. The inhibition efficiency of the organic inhibitors on copper corrosion increases in the order: glutathione > cysteine > cysteine + glutamic acid + glycine > glutamic acid > glycine. Maximum inhibition efficiency for cysteine reaches about 92.9% at 15 mM concentration level. The glutathione can give 96.4% inhibition efficiency at a concentration of 10 mM. The molecular structure parameters were obtained by PM3 (Parametric Method 3) semi-empirical calculation. The intramolecular synergistic effect of glutamic acid, cysteine and glycine moieties in glutathione is attributed to the lower energy of the lowest unoccupied molecular orbital (E LUMO ) level and to the excess hetero-atom adsorption centers and the bigger coverage on the copper surface.

  19. Tunable pH and redox-responsive drug release from curcumin conjugated γ-polyglutamic acid nanoparticles in cancer microenvironment.

    Science.gov (United States)

    Pillarisetti, Shameer; Maya, S; Sathianarayanan, S; Jayakumar, R

    2017-11-01

    Tunable pH and redox responsive polymer was prepared using γ-polyglutamic acid (γ-PGA) with linker 3-mercaptopropionic acid (3-MPA) (γ-PGA_SH) via oxidation to obtain redox responsive disulfide (γ-PGA_SS) backbone and adipic acid dihydrazide (ADH) (γ-PGA_SS_ADH) with hydrazide functional group for pH responsiveness. Further curcumin (Cur) was conjugated through hydrazone bond of the γ-PGA_SS_ADH via Schiff base reaction to obtain (γ-PGA_SS_ADH_Cur). The prepared systems were characterized by Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, Electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-Qq-TOF-MS/MS) and Solid state nuclear magnetic resonance (SS NMR) techniques. γ-PGA_SS_ADH_Cur formed self-assembled core shell nanoparticles (NPs) in existence of stabilized aqueous medium. γ-PGA_SS_ADH_Cur NPs maintained its stability in physiological condition. NPs tunable Cur release and cytotoxicity were observed for γ-PGA_SS_ADH_Cur NPs in both acidic and redox conditions mimicking the cancer microenvironment. γ-PGA_SS_ADH_Cur NPs uptake study showed via endocytosis mechanism resulted in the lysosomal entrapment of these NPs within the cell. γ-PGA_SS_ADH_Cur NPs exhibited a dual stimuli responsive drug delivery and can be used as a smart and potential drug delivery system in cancer microenvironment. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Design, synthesis, and evaluation of caffeic acid amides as synergists to sensitize fluconazole-resistant Candida albicans to fluconazole.

    Science.gov (United States)

    Dai, Li; Zang, Chengxu; Tian, Shujuan; Liu, Wei; Tan, Shanlun; Cai, Zhan; Ni, Tingjunhong; An, Maomao; Li, Ran; Gao, Yue; Zhang, Dazhi; Jiang, Yuanying

    2015-01-01

    A series of caffeic acid amides were designed, synthesized, and their synergistic activity with fluconazole against fluconazole-resistant Candida albicans was evaluated in vitro. The title caffeic acid amides 3-30 except 26 exhibited potent activity, and the subsequent SAR study was conducted. Compound 3, 5, 21, and 34c, at a concentration of 1.0 μg/ml, decreased the MIC₈₀ of fluconazole from 128.0 μg/ml to 1.0-0.5 μg/ml against the fluconazole-resistant C. albicans. This result suggests that the caffeic acid amides, as synergists, can sensitize drug-resistant fungi to fluconazole. The SAR study indicated that the dihydroxyl groups and the amido groups linking to phenyl or heterocyclic rings are the important pharmacophores of the caffeic acid amides.

  1. Mechanism of Sporicidal Activity for the Synergistic Combination of Peracetic Acid and Hydrogen Peroxide.

    Science.gov (United States)

    Leggett, Mark J; Schwarz, J Spencer; Burke, Peter A; McDonnell, Gerald; Denyer, Stephen P; Maillard, Jean-Yves

    2016-02-15

    There is still great interest in controlling bacterial endospores. The use of chemical disinfectants and, notably, oxidizing agents to sterilize medical devices is increasing. With this in mind, hydrogen peroxide (H2O2) and peracetic acid (PAA) have been used in combination, but until now there has been no explanation for the observed increase in sporicidal activity. This study provides information on the mechanism of synergistic interaction of PAA and H2O2 against bacterial spores. We performed investigations of the efficacies of different combinations, including pretreatments with the two oxidizers, against wild-type spores and a range of spore mutants deficient in the spore coat or small acid-soluble spore proteins. The concentrations of the two biocides were also measured in the reaction vessels, enabling the assessment of any shift from H2O2 to PAA formation. This study confirmed the synergistic activity of the combination of H2O2 and PAA. However, we observed that the sporicidal activity of the combination is largely due to PAA and not H2O2. Furthermore, we observed that the synergistic combination was based on H2O2 compromising the spore coat, which was the main spore resistance factor, likely allowing better penetration of PAA and resulting in the increased sporicidal activity. Copyright © 2016 Leggett et al.

  2. Synergistic Extraction of Lactic Acid with Tri-n-Octylamine and Try-n-Butylphosphate

    Energy Technology Data Exchange (ETDEWEB)

    Matsumoto, Michiaki.; Yuba, Seiji.; Kondo, Kazuo. (Doshisha University, Department of Chemical Engineering and Materials Science (Japan))

    1998-12-01

    Synergistic extraction system of lactic acid is examined to develop to in situ extractive fermentation process. The addition of try-n-butyl phosphate(TBP) to the extraction system of lactic acid(HA) with tri-n-actylamine(TOA) diluted by hexane causes a large synergism. Extraction reaction with the mixed extractant is interpreted quite well based on the formation of mixed complex, HA[center dot]TOA[center dot]2TBP. Though the addition of hexane solution containing TBP and TOA to the culture of Lactobacillus rhamnosus results in low lactate production, some lactate is produced. (author)

  3. Synergistic Extraction of Lactic Acid with Tri-n-Octylamine and Try-n-Butylphosphate

    Energy Technology Data Exchange (ETDEWEB)

    Matsumoto, Michiaki.; Yuba, Seiji.; Kondo, Kazuo. [Doshisha University, Department of Chemical Engineering and Materials Science (Japan)

    1998-12-01

    Synergistic extraction system of lactic acid is examined to develop to in situ extractive fermentation process. The addition of try-n-butyl phosphate(TBP) to the extraction system of lactic acid(HA) with tri-n-actylamine(TOA) diluted by hexane causes a large synergism. Extraction reaction with the mixed extractant is interpreted quite well based on the formation of mixed complex, HA{center_dot}TOA{center_dot}2TBP. Though the addition of hexane solution containing TBP and TOA to the culture of Lactobacillus rhamnosus results in low lactate production, some lactate is produced. (author)

  4. In vitro synergistic efficacy of conjugated linoleic acid, oleic acid, safflower oil and taxol cytotoxicity on PC3 cells.

    Science.gov (United States)

    Kızılşahin, Sadi; Nalbantsoy, Ayşe; Yavaşoğlu, N Ülkü Karabay

    2015-01-01

    The aim of this study was to determine in vitro synergistic efficacy of conjugated linoleic acid (CLA), oleic acid (OLA), safflower oil and taxol (Tax) cytotoxicity on human prostate cancer (PC3) cell line. To determine synergistic efficacy of oil combinations, PC3 treated with different doses of compounds alone and combined with 10 μg/mL Tax. The MTT results indicated that OLA-Tax combinations exhibited cytotoxicity against PC3 at doses of 30 nM+10 μg-Tax, 15 nM+5 μg-Tax and 7.5 nM+2.5 μg-Tax. The treatment of OLA or Tax did not show significant inhibition on PC3, while OLA-Tax combinations showed effective cytotoxicity at treated doses. CLA-Tax combinations demonstrated the same effect on PC3 as combined form with 45.72% versus the alone form as 74.51% viability. Cytotoxic synergy between Tax, OLA and CLA shows enhanced cytotoxicity on PC3 which might be used in the therapy of prostate cancer.

  5. Acid-base synergistic flame retardant wood pulp paper with high thermal stability.

    Science.gov (United States)

    Wang, Ning; Liu, Yuansen; Xu, Changan; Liu, Yuan; Wang, Qi

    2017-12-15

    Acid-catalytic degradation caused by acid source flame retardants is the main reason for a decline in thermal stability of flame-retarded lignocellulosic materials. In the present research, a guanidine phosphate (GP)/borax (BX) flame retardant system based on acid-base synergistic interaction was designed and used in wood pulp paper (WPP) to solve this problem. Results showed that the treated WPP obtained good flame retardancy with a limiting oxygen index (LOI) value of 35.7%. As a basic flame retardant, borax could chemically combine with the acids released by guanidine phosphate, thus decreasing the acidity of the system in the initial heating stage. In this way, acid-catalytic degradation is greatly retarded on the lignocelluloses to improve thermal stability (the temperature of maximum degradation peak from 286°C to 314°C). Meanwhile, borax was also advantageous to form a denser and firmer condensed phase through reinforcement of the acid-base reaction product, borophosphates, allowing it to provide a protective barrier with higher quality. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Acidic Microenvironments in Waste Rock Characterized by Neutral Drainage: Bacteria–Mineral Interactions at Sulfide Surfaces

    Directory of Open Access Journals (Sweden)

    John W. Dockrey

    2014-03-01

    Full Text Available Microbial populations and microbe-mineral interactions were examined in waste rock characterized by neutral rock drainage (NRD. Samples of three primary sulfide-bearing waste rock types (i.e., marble-hornfels, intrusive, exoskarn were collected from field-scale experiments at the Antamina Cu–Zn–Mo mine, Peru. Microbial communities within all samples were dominated by neutrophilic thiosulfate oxidizing bacteria. However, acidophilic iron and sulfur oxidizers were present within intrusive waste rock characterized by bulk circumneutral pH drainage. The extensive development of microbially colonized porous Fe(III (oxyhydroxide and Fe(III (oxyhydroxysulfate precipitates was observed at sulfide-mineral surfaces during examination by field emission-scanning electron microscopy-energy dispersive X-ray spectroscopy (FE-SEM-EDS. Linear combination fitting of bulk extended X-ray absorption fine structure (EXAFS spectra for these precipitates indicated they were composed of schwertmannite [Fe8O8(OH6–4.5(SO41–1.75], lepidocrocite [γ-FeO(OH] and K-jarosite [KFe3(OH6(SO42]. The presence of schwertmannite and K-jarosite is indicative of the development of localized acidic microenvironments at sulfide-mineral surfaces. Extensive bacterial colonization of this porous layer and pitting of underlying sulfide-mineral surfaces suggests that acidic microenvironments can play an important role in sulfide-mineral oxidation under bulk circumneutral pH conditions. These findings have important implications for water quality management in NRD settings.

  7. Aerobic glycolysis and high level of lactate in cancer metabolism and microenvironment

    Directory of Open Access Journals (Sweden)

    Bo Jiang

    2017-03-01

    Full Text Available Metabolic abnormalities is a hallmark of cancer. About 100 years ago, Nobel laureate Otto Heinrich Warburg first described high rate of glycolysis in cancer cells. Recently more and more novel opinions about cancer metabolism supplement to this hypothesis, consist of glucose uptake, lactic acid generation and secretion, acidification of the microenvironment and cancer immune evasion. Here we briefly review metabolic pathways generating lactate, and discuss the function of higher lactic acid in cancer microenvironments.

  8. The effect of enteral supplementation of specific neutral and acidic oligosaccharides on the faecal microbiota and intestinal microenvironment in preterm infants

    NARCIS (Netherlands)

    Westerbeek, E. A. M.; Slump, R. A.; Lafeber, H. N.; Knol, J.; Georgi, G.; Fetter, W. P. F.; van Elburg, R. M.

    2013-01-01

    We aimed to determine the effects of enteral supplementation of a prebiotic mixture of neutral and acidic oligosaccharides (scGOS/lcFOS/pAOS) on the faecal microbiota and microenvironment in preterm infants. Furthermore, we determined the influence of perinatal factors on the development of the

  9. Synergistic inhibition of cancer cell proliferation with a combination of δ-tocotrienol and ferulic acid

    International Nuclear Information System (INIS)

    Eitsuka, Takahiro; Tatewaki, Naoto; Nishida, Hiroshi; Kurata, Tadao; Nakagawa, Kiyotaka; Miyazawa, Teruo

    2014-01-01

    Highlights: • δ-Tocotrienol (δ-T3) and ferulic acid (FA) synergistically inhibit cancer cell growth. • The combination of δ-T3 and FA induces G1 arrest by up-regulating p21. • The synergy is attributed to an increase in the cellular concentration of δ-T3 by FA. - Abstract: Rice bran consists of many functional compounds and thus much attention has been focused on the health benefits of its components. Here, we investigated the synergistic inhibitory effects of its components, particularly δ-tocotrienol (δ-T3) and ferulic acid (FA), against the proliferation of an array of cancer cells, including DU-145 (prostate cancer), MCF-7 (breast cancer), and PANC-1 (pancreatic cancer) cells. The combination of δ-T3 and FA markedly reduced cell proliferation relative to δ-T3 alone, and FA had no effect when used alone. Although δ-T3 induced G1 arrest by up-regulating p21 in PANC-1 cells, more cells accumulated in G1 phase with the combination of δ-T3 and FA. This synergistic effect was attributed to an increase in the cellular concentration of δ-T3 by FA. Our results suggest that the combination of δ-T3 and FA may present a new strategy for cancer prevention and therapy

  10. Synergistic inhibition of cancer cell proliferation with a combination of δ-tocotrienol and ferulic acid

    Energy Technology Data Exchange (ETDEWEB)

    Eitsuka, Takahiro, E-mail: eitsuka@nupals.ac.jp [Faculty of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603 (Japan); Tatewaki, Naoto; Nishida, Hiroshi; Kurata, Tadao [Faculty of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603 (Japan); Nakagawa, Kiyotaka; Miyazawa, Teruo [Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555 (Japan)

    2014-10-24

    Highlights: • δ-Tocotrienol (δ-T3) and ferulic acid (FA) synergistically inhibit cancer cell growth. • The combination of δ-T3 and FA induces G1 arrest by up-regulating p21. • The synergy is attributed to an increase in the cellular concentration of δ-T3 by FA. - Abstract: Rice bran consists of many functional compounds and thus much attention has been focused on the health benefits of its components. Here, we investigated the synergistic inhibitory effects of its components, particularly δ-tocotrienol (δ-T3) and ferulic acid (FA), against the proliferation of an array of cancer cells, including DU-145 (prostate cancer), MCF-7 (breast cancer), and PANC-1 (pancreatic cancer) cells. The combination of δ-T3 and FA markedly reduced cell proliferation relative to δ-T3 alone, and FA had no effect when used alone. Although δ-T3 induced G1 arrest by up-regulating p21 in PANC-1 cells, more cells accumulated in G1 phase with the combination of δ-T3 and FA. This synergistic effect was attributed to an increase in the cellular concentration of δ-T3 by FA. Our results suggest that the combination of δ-T3 and FA may present a new strategy for cancer prevention and therapy.

  11. Antifungal activity of secondary plant metabolites from potatoes (Solanum tuberosum L.): Glycoalkaloids and phenolic acids show synergistic effects.

    Science.gov (United States)

    Sánchez-Maldonado, A F; Schieber, A; Gänzle, M G

    2016-04-01

    To study the antifungal effects of the potato secondary metabolites α-solanine, α-chaconine, solanidine and caffeic acid, alone or combined. Resistance to glycoalkaloids varied among the fungal species tested, as derived from minimum inhibitory concentrations assays. Synergistic antifungal activity between glycoalkaloids and phenolic compounds was found. Changes in the fluidity of fungal membranes caused by potato secondary plant metabolites were determined by calculation of the generalized polarization values. The results partially explained the synergistic effect between caffeic acid and α-chaconine and supported findings on membrane disruption mechanisms from previous studies on artificial membranes. LC/MS analysis was used to determine variability and relative amounts of sterols in the different fungal species. Results suggested that the sterol pattern of fungi is related to their resistance to potato glycoalkaloids and to their taxonomy. Fungal resistance to α-chaconine and possibly other glycoalkaloids is species dependent. α-Chaconine and caffeic acid show synergistic antifungal activity. The taxonomic classification and the sterol pattern play a role in fungal resistance to glycoalkaloids. Results improve the understanding of the antifungal mode of action of potato secondary metabolites, which is essential for their potential utilization as antifungal agents in nonfood systems. © 2016 The Society for Applied Microbiology.

  12. High Throughput Screening of Valganciclovir in Acidic Microenvironments of Polyester Thin Films

    Directory of Open Access Journals (Sweden)

    Teilo Schaller

    2015-04-01

    Full Text Available Ganciclovir and valganciclor are antiviral agents used for the treatment of cytomegalovirus retinitis. The conventional method for administering ganciclovir in cytomegalovirus retinitis patients is repeated intravitreal injections. In order to obviate the possible detrimental effects of repeated intraocular injections, to improve compliance and to eliminate systemic side-effects, we investigated the tuning of the ganciclovir pro-drug valganciclovir and the release from thin films of poly(lactic-co-glycolic acid (PLGA, polycaprolactone (PCL, or mixtures of both, as a step towards prototyping periocular valganciclovir implants. To investigate the drug release, we established and evaluated a high throughput fluorescence-based quantification screening assay for the detection of valganciclovir. Our protocol allows quantifying as little as 20 ng of valganciclovir in 96-well polypropylene plates and a 50× faster analysis compared to traditional HPLC measurements. This improvement can hence be extrapolated to other polyester matrix thin film formulations using a high-throughput approach. The acidic microenvironment within the polyester matrix was found to protect valganciclovir from degradation with resultant increases in the half-life of the drug in the periocular implant to 100 days. Linear release profiles were obtained using the pure polyester polymers for 10 days and 60 days formulations; however, gross phase separations of PCL and acid-terminated PLGA prevented tuning within these timeframes due to the phase separation of the polymer, valganciclovir, or both.

  13. Synergistic Effects of Zinc Oxide Nanoparticles and Fatty Acids on Toxicity to Caco-2 Cells

    DEFF Research Database (Denmark)

    Cao, Yi; Roursgaard, Martin; Kermanizadeh, Ali

    2015-01-01

    epithelial (Caco-2) cells. The ZnO NPs exposure concentration dependently induced cytotoxicity to Caco-2 cells showing as reduced proliferation and activity measured by 3 different assays. PA exposure induced cytotoxicity, and coexposure to ZnO NPs and PA showed the largest cytotoxic effects. The presence......Fatty acids exposure may increase sensitivity of intestinal epithelial cells to cytotoxic effects of zinc oxide (ZnO) nanoparticles (NPs). This study evaluated the synergistic effects of ZnO NPs and palmitic acid (PA) or free fatty acids (FFAs) mixture (oleic/PA 2:1) on toxicity to human colon...

  14. Synergistic effects of retinoic acid and tamoxifen on human breast cancer cells: Proteomic characterization

    International Nuclear Information System (INIS)

    Wang Ying; He Qingyu; Chen Hongming; Chiu Jenfu

    2007-01-01

    The anti-estrogen tamoxifen and vitamin A-related compound, all-trans retinoic acid (RA), in combination act synergistically to inhibit the growth of MCF-7 human breast cancer cells. In the present study, we applied two-dimensional gel electrophoresis based proteomic approach to globally analyze this synergistic effect of RA and tamoxifen. Proteomic study revealed that multiple clusters of proteins were involved in RA and tamoxifen-induced apoptosis in MCF-7 breast cancer cells, including post-transcriptional and splicing factors, proteins related to cellular proliferation or differentiation, and proteins related to energy production and internal degradation systems. The negative growth factor-transforming growth factor β (TGFβ) was secreted by RA and/or tamoxifen treatment and was studies as a potential mediator of the synergistic effects of RA and tamoxifen in apoptosis. By comparing protein alterations in treatments of RA and tamoxifen alone or in combination to those of TGFβ treatment, or co-treatment with TGFβ inhibitor SB 431542, proteomic results showed that a number of proteins were involved in TGFβ signaling pathway. These results provide valuable insights into the mechanisms of RA and tamoxifen-induced TGFβ signaling pathway in breast cancer cells

  15. Acidic sweep gas with carbonic anhydrase coated hollow fiber membranes synergistically accelerates CO2 removal from blood.

    Science.gov (United States)

    Arazawa, D T; Kimmel, J D; Finn, M C; Federspiel, W J

    2015-10-01

    The use of extracorporeal carbon dioxide removal (ECCO2R) is well established as a therapy for patients suffering from acute respiratory failure. Development of next generation low blood flow (carbonic anhydrase (CA) immobilized bioactive hollow fiber membrane (HFM) which significantly accelerates CO2 removal from blood in model gas exchange devices by converting bicarbonate to CO2 directly at the HFM surface. This present study tested the hypothesis that dilute sulfur dioxide (SO2) in oxygen sweep gas could further increase CO2 removal by creating an acidic microenvironment within the diffusional boundary layer adjacent to the HFM surface, facilitating dehydration of bicarbonate to CO2. CA was covalently immobilized onto poly (methyl pentene) (PMP) HFMs through glutaraldehyde activated chitosan spacers, potted in model gas exchange devices (0.0151 m(2)) and tested for CO2 removal rate with oxygen (O2) sweep gas and a 2.2% SO2 in oxygen sweep gas mixture. Using pure O2 sweep gas, CA-PMP increased CO2 removal by 31% (258 mL/min/m(2)) compared to PMP (197 mL/min/m(2)) (Premoval by 17% (230 mL/min/m(2)) compared to pure oxygen sweep gas control (Premoval increased by 109% (411 mL/min/m(2)) (Premoval, and when used in combination with bioactive CA-HFMs has a synergistic effect to more than double CO2 removal while maintaining physiologic pH. Through these technologies the next generation of intravascular and paracorporeal respiratory assist devices can remove more CO2 with smaller blood contacting surface areas. A clinical need exists for more efficient respiratory assist devices which utilize low blood flow rates (removal efficiency by shifting equilibrium from bicarbonate to gaseous CO2, through either a bioactive carbonic anhydrase enzyme coating or bulk blood acidification with lactic acid. In this study we demonstrate a novel approach to local blood acidification using an acidified sweep gas in combination with a bioactive coating to more than double CO2 removal

  16. Synergistic effect of defined artificial extracellular matrices and pulsed electric fields on osteogenic differentiation of human MSCs.

    Science.gov (United States)

    Hess, Ricarda; Jaeschke, Anna; Neubert, Holger; Hintze, Vera; Moeller, Stephanie; Schnabelrauch, Matthias; Wiesmann, Hans-Peter; Hart, David A; Scharnweber, Dieter

    2012-12-01

    In vivo, bone formation is a complex, tightly regulated process, influenced by multiple biochemical and physical factors. To develop a vital bone tissue engineering construct, all of these individual components have to be considered and integrated to gain an in vivo-like stimulation of target cells. The purpose of the present studies was to investigate the synergistic role of defined biochemical and physical microenvironments with respect to osteogenic differentiation of human mesenchymal stem cells (MSCs). Biochemical microenvironments have been designed using artificial extracellular matrices (aECMs), containing collagen I (coll) and glycosaminoglycans (GAGs) like chondroitin sulfate (CS), or a high-sulfated hyaluronan derivative (sHya), formulated as coatings on three-dimensional poly(caprolactone-co-lactide) (PCL) scaffolds. As part of the physical microenvironment, cells were exposed to pulsed electric fields via transformer-like coupling (TC). Results showed that aECM containing sHya enhanced osteogenic differentiation represented by increases in ALP activity and gene-expression (RT-qPCR) of several bone-related proteins (RUNX-2, ALP, OPN). Electric field stimulation alone did not influence cell proliferation, but osteogenic differentiation was enhanced if osteogenic supplements were provided, showing synergistic effects by the combination of sHya and electric fields. These results will improve the understanding of bone regeneration processes and support the development of effective tissue engineered bone constructs. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors

    Science.gov (United States)

    Bellone, Matteo; Calcinotto, Arianna; Filipazzi, Paola; De Milito, Angelo; Fais, Stefano; Rivoltini, Licia

    2013-01-01

    We have recently reported that lowering the pH to values that are frequently detected in tumors causes reversible anergy in both human and mouse CD8+ T lymphocytes in vitro. The same occurs in vivo, in the tumor microenvironment and the administration of proton pump inhibitors, which buffer tumor acidity, can revert T-cell anergy and increase the efficacy of immunotherapy. PMID:23483769

  18. Investigation of maltodextrin-based synergistic system with amino acid chiral ionic liquid as additive for enantioseparation in capillary electrophoresis.

    Science.gov (United States)

    Chen, Jiaquan; Du, Yingxiang; Sun, Xiaodong

    2017-12-01

    The combined use of chiral ionic liquids (ILs) and chiral selectors in capillary electrophoresis (CE) to establish a synergistic system has proven to be an effective approach for enantioseparation. In this article, tetramethylammonium-L-arginine, a kind of amino acid chiral IL, was applied to investigate its potential synergistic effect with maltodextrin in CE enantioseparation. The established maltodextrin-based synergistic system showed markedly improved enantioseparations compared with the single maltodextrin system. Parameters such as the chiral IL concentration, maltodextrin concentration, buffer pH, applied voltage, and capillary temperature were optimized. Satisfactory enantioseparation of the five studied drugs, including nefopam, duloxetine, ketoconazole, cetirizine, and citalopram was achieved in 50 mM Tris-H 3 PO 4 buffer solution (pH 3.0) containing 7.0% (m/v) maltodextrin and 60 mM tetramethylammonium-L-arginine. In addition, the chiral configuration of tetramethylammonium-L-arginine was also investigated to demonstrate the existence of a synergistic effect between chiral ILs and maltodextrin. © 2017 Wiley Periodicals, Inc.

  19. Investigating the synergistic antioxidant effects of some flavonoid and phenolic compounds

    Directory of Open Access Journals (Sweden)

    H. Hajimehdipoor

    2014-04-01

    Full Text Available Phenolic and flavonoid compounds are secondary metabolites of plants which possess various activities such as anti-inflammatory, analgesic, anti-diabetes and anticancer effects. It has been established that these compounds can scavenge free radicals produced in the body. Because of this ability, not only the plants containing phenolic and flavonoid compounds but also, the pure compounds are used in medicinal products for prevention and treatment of many disorders. Considering that the golden aim of the pharmaceutical industries is using the most effective compounds with lower concentrations, determination of the best combination of the compounds with synergistic effects is important. In the present study, synergistic antioxidant effects of four phenolic compounds including caffeic acid, gallic acid, rosmarinic acid, chlorogenic acid and two flavonoids,  rutin and quercetin, have been investigated by FRAP (Ferric Reducing Antioxidant Power method. The synergistic effect was assessed by comparing the experimental antioxidant activity of the mixtures with calculated theoretical values and the interactions of the compounds were determined. The results showed that combination of gallic acid and caffeic acid demonstrated considerable synergistic effects (137.8% while other combinations were less potent. Among examined substances, rutin was the only one which had no effect on the other compounds. The results of ternary combinations of compounds demonstrated antagonistic effects in some cases. This was more considerable in mixture of rutin, caffeic acid, rosmarinic acid (-21.8%, chlorogenic acid, caffeic acid, rosmarinic acid (-20%, rutin, rosmarinic acid, gallic acid (-18.5% and rutin, chlorogenic acid, caffeic acid (-15.8%, while, combination of quercetin, gallic acid, caffeic acid (59.4% and quercetin, gallic acid, rutin (55.2% showed the most synergistic effects. It was concluded that binary and ternary combination of quercetin, rutin, caffeic acid

  20. Combating against methicillin-resistant Staphylococcus aureus - two fatty acids from Purslane (Portulaca oleracea L.) exhibit synergistic effects with erythromycin.

    Science.gov (United States)

    Chan, Ben C L; Han, X Q; Lui, Sau Lai; Wong, C W; Wang, Tina B Y; Cheung, David W S; Cheng, Sau Wan; Ip, Margaret; Han, Simon Q B; Yang, Xiao-Sheng; Jolivalt, Claude; Lau, Clara B S; Leung, Ping Chung; Fung, Kwok Pui

    2015-01-01

    The aims of this study were to identify the active ingredients from Portulaca oleracea L. (PO) that could provide synergism with antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) and their possible mechanisms of resistance inhibition. High-speed counter-current chromatography (HSCCC) coupled with gas chromatography-mass spectrometry and a panel of laboratory MRSA strains were used for checkerboard and efflux inhibitory assays. Linoleic and oleic acids were identified from HSCCC fraction 18 of PO with synergistic antibacterial activity when combined with erythromycin against RN4220/pUL5054. Ethidium bromide efflux inhibitory studies revealed that linoleic and oleic acids may interfere the activity of MsrA pump. By comparing among a panel of linoleic and oleic acids analogues, unsaturated fatty acids in salt form with cis configuration and an increase in number of double bonds were found to further increase the antibacterial activity when used alone or in combination with antibiotics. This study reported for the first time that two active ingredients, namely linoleic and oleic acids, were identified from PO with synergistic antibacterial activity when combined with erythromycin against MRSA RN4220/pUL5054 and possibly act by inhibiting the efflux pumps of the bacteria cells. © 2014 Royal Pharmaceutical Society.

  1. The altered glucose metabolism in tumor and a tumor acidic microenvironment associated with extracellular matrix metalloproteinase inducer and monocarboxylate transporters

    Science.gov (United States)

    Li, Xiaofeng; Yu, Xiaozhou; Dai, Dong; Song, Xiuyu; Xu, Wengui

    2016-01-01

    Extracellular matrix metalloproteinase inducer, also knowns as cluster of differentiation 147 (CD147) or basigin, is a widely distributed cell surface glycoprotein that is involved in numerous physiological and pathological functions, especially in tumor invasion and metastasis. Monocarboxylate transporters (MCTs) catalyze the proton-linked transport of monocarboxylates such as L-lactate across the plasma membrane to preserve the intracellular pH and maintain cell homeostasis. As a chaperone to some MCT isoforms, CD147 overexpression significantly contributes to the metabolic transformation of tumor. This overexpression is characterized by accelerated aerobic glycolysis and lactate efflux, and it eventually provides the tumor cells with a metabolic advantage and an invasive phenotype in the acidic tumor microenvironment. This review highlights the roles of CD147 and MCTs in tumor cell metabolism and the associated molecular mechanisms. The regulation of CD147 and MCTs may prove to be with a therapeutic potential for tumors through the metabolic modification of the tumor microenvironment. PMID:27009812

  2. Chemotherapeutic Impact Of Natural Antioxidant Flavonoids Gallic Acid Rutin Quercetin And Mannitol On Pathogenic Microbes And Their Synergistic Effect

    Directory of Open Access Journals (Sweden)

    Ganesh Ghosh

    2015-08-01

    Full Text Available Several studies suggest that natural flavonoids with antioxidants and can influence the response to chemotherapy as well as the development of adverse side effects that results from treatment with antineoplastic agents and Its prevalence over Multi drug resistant bacterial strain revived interest on Flavonoids. Synergistic effect is defined as passive interaction arises when two agents combine and together they exert an inhibitory effect that is greater than the sum of individual effect The new Synergistic therapy so that antioxidant are more effective in combination on multi drug resistant bacterial strain. Interaction between natural antioxidants and topoisomerase enzyme can be seen through Quercetin as a potent antimicrobial compound alone and in combination with other natural antioxidant like rutin. MICMBC result show antibacterial activity of the flavonoids were enhanced when used in combination against Staphylococcus aureus Bacillus cereus Bacillus subtilis Klebsiella pneumonae Escherichia coli as the test bacteria. The combination of rutin and quercetin rutin and gallic acid mannitol and gallic acid were much more effective than either flavonoid alone. Furthermore Its gave a good relation between these antioxidant compound and antimicrobial activity. Flavonoids as a chemotherapeutic agent and its Synergistic effect can be solution for various microbial disease conditions.

  3. Influence of microenvironment pH, humidity, and temperature on the stability of polymorphic and amorphous forms of clopidogrel bisulfate

    DEFF Research Database (Denmark)

    Raijada, Dhara K; Singh, Saranjit; Bansal, Arvind K

    2010-01-01

    The effect of microenvironment pH, humidity, and temperature was evaluated on the stability of polymorphic and amorphous forms of clopidogrel bisulfate, when present alone or in combinations. Oxalic acid and sodium carbonate were used as solid stressors to create acidic and alkaline p...... more degradation than the individual forms above critical relative humidity (85% RH). Similar higher degradation was observed between 75% RH and 85% RH in case of acid-stressed samples. In alkaline microenvironment, all the samples showed identical decomposition attributed to conversion of bisulfate...

  4. Acid azo dye remediation in anoxic-aerobic-anoxic microenvironment under periodic discontinuous batch operation: bio-electro kinetics and microbial inventory.

    Science.gov (United States)

    Venkata Mohan, S; Suresh Babu, P; Naresh, K; Velvizhi, G; Madamwar, Datta

    2012-09-01

    Functional behavior of anoxic-aerobic-anoxic microenvironment on azo dye (C.I. Acid black 10B) degradation was evaluated in a periodic discontinuous batch mode operation for 26 cycles. Dye removal efficiency and azo-reductase activity (30.50 ± 1 U) increased with each feeding event until 13th cycle and further stabilized. Dehydrogenase activity also increased gradually and stabilized (2.0 ± 0.2 μg/ml) indicating the stable proton shuttling between metabolic intermediates providing higher number of reducing equivalents towards dye degradation. Voltammetric profiles showed drop in redox catalytic currents during stabilized phase also supports the consumption of reducing equivalents towards dye removal. Change in Tafel slopes, polarization resistance and other bioprocess parameters correlated well with the observed dye removal and biocatalyst behavior. Microbial community analysis documented the involvement of specific organism pertaining to aerobic and facultative functions with heterotrophic and autotrophic metabolism. Integrating anoxic microenvironment with aerobic operation might have facilitated effective dye mineralization due to the possibility of combining redox functions. Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. Lack of a synergistic effect of arginine-glutamic acid on the physical stability of spray-dried bovine serum albumin.

    Science.gov (United States)

    Reslan, Mouhamad; Demir, Yusuf K; Trout, Bernhardt L; Chan, Hak-Kim; Kayser, Veysel

    2017-09-01

    Improving the physical stability of spray-dried proteins is essential for enabling pulmonary delivery of biotherapeutics as a noninvasive alternative to injections. Recently, a novel combination of two amino acids - l-arginine (l-Arg) and l-glutamic acid (l-Glu), has been reported to have synergistic protein-stabilizing effects on various protein solutions. Using spray-dried bovine serum albumin (BSA) reconstituted in solution as a model protein, we investigated the synergistic effect of these amino acids on the physical stability of proteins. Five BSA solutions were prepared: (1) BSA with no amino acids (control); (2) with 50 mM l-Arg; (3) with 200 mM l-Arg, (4) with 50 mM l-Glu and (5) with 25:25 mM of Arg:Glu. All solutions were spray-dried and accelerated studies at high temperatures were performed. Following accelerated studies, monomer BSA loss was measured using SE-HPLC. We found that l-Arg significantly improved the physical stability of spray-dried BSA even at low concentrations, however, when combined with l-Glu, was ineffective at reducing monomer BSA loss. Our findings demonstrate the limitations in using Arg-Glu for the stabilization of spray-dried BSA. Furthermore, we found that a low concentration of l-Glu enhanced monomer BSA loss. These findings may have significant implications on the design of future biotherapeutic formulations.

  6. Dysregulated pH in Tumor Microenvironment Checkmates Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Jaleh Barar

    2013-12-01

    Full Text Available Introduction: The dysregulation of pH by cancerous cells of solid tumors is able to create a unique milieu that is in favor of progression, invasion and metastasis as well as chemo-/immuno-resistance traits of solid tumors. Bioelements involved in pH dysregulation provide new set of oncotargets, inhibition of which may result in better clinical outcome. Methods: To study the impacts of pH dysregulation, we investigated the tumor development and progression in relation with Warburg effect, glycolysis and formation of aberrant tumor microenvironment. Results: The upregulation of glucose transporter GLUT-1 and several enzymes involve in glycolysis exacerbates this phenomenon. The accumulation of lactic acids in cancer cells provokes upregulation of several transport machineries (MCT-1, NHE-1, CA IX and H+ pump V-ATPase resulting in reinforced efflux of proton into extracellular fluid. This deviant event makes pH to be settled at 7.4 and 6.6 respectively in cancer cells cytoplasm and extracellular fluid within the tumor microenvironment, which in return triggers secretion of lysosomal components (various enzymes in acidic milieu with pH 5 into cytoplasm. All these anomalous phenomena make tumor microenvironment (TME to be exposed to cocktail of various enzymes with acidic pH, upon which extracellular matrix (ECM can be remodeled and even deformed, resulting in emergence of a complex viscose TME with high interstitial fluid pressure. Conclusion: It seems that pH dysregulation is able to remodel various physiologic functions and make solid tumors to become much more invasive and metastatic. It also can cause undesired resistance to chemotherapy and immunotherapy. Hence, cancer therapy needs to be reinforced using specific inhibitors of bioelements involved in pH dysregulation of TME in solid tumors.

  7. Synergistic effect of amino acids modified on dendrimer surface in gene delivery.

    Science.gov (United States)

    Wang, Fei; Wang, Yitong; Wang, Hui; Shao, Naimin; Chen, Yuanyuan; Cheng, Yiyun

    2014-11-01

    Design of an efficient gene vector based on dendrimer remains a great challenge due to the presence of multiple barriers in gene delivery. Single-functionalization on dendrimer cannot overcome all the barriers. In this study, we synthesized a list of single-, dual- and triple-functionalized dendrimers with arginine, phenylalanine and histidine for gene delivery using a one-pot approach. The three amino acids play different roles in gene delivery: arginine is essential in formation of stable complexes, phenylalanine improves cellular uptake efficacy, and histidine increases pH-buffering capacity and minimizes cytotoxicity of the cationic dendrimer. A combination of these amino acids on dendrimer generates a synergistic effect in gene delivery. The dual- and triple-functionalized dendrimers show minimal cytotoxicity on the transfected NIH 3T3 cells. Using this combination strategy, we can obtain triple-functionalized dendrimers with comparable transfection efficacy to several commercial transfection reagents. Such a combination strategy should be applicable to the design of efficient and biocompatible gene vectors for gene delivery. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Elevated CO2 benefits the soil microenvironment in the rhizosphere of Robinia pseudoacacia L. seedlings in Cd- and Pb-contaminated soils.

    Science.gov (United States)

    Huang, Shuping; Jia, Xia; Zhao, Yonghua; Bai, Bo; Chang, Yafei

    2017-02-01

    Soil contamination by heavy metals in combination with elevated atmospheric CO 2 has important effects on the rhizosphere microenvironment by influencing plant growth. Here, we investigated the response of the R. pseudoacacia rhizosphere microenvironment to elevated CO 2 in combination with cadmium (Cd)- and lead (Pb)-contamination. Organic compounds (total soluble sugars, soluble phenolic acids, free amino acids, and organic acids), microbial abundance and activity, and enzyme activity (urease, dehydrogenase, invertase, and β-glucosidase) in rhizosphere soils increased significantly (p soil microbial community in the rhizosphere. Heavy metals alone resulted in an increase in total soluble sugars, free amino acids, and organic acids, a decrease in phenolic acids, microbial populations and biomass, and enzyme activity, and a change in microbial community in rhizosphere soils. Elevated CO 2 led to an increase in organic compounds, microbial populations, biomass, and activity, and enzyme activity (except for l-asparaginase), and changes in microbial community under Cd, Pb, or Cd + Pb treatments relative to ambient CO 2 . In addition, elevated CO 2 significantly (p soils. Overall, elevated CO 2 benefited the rhizosphere microenvironment of R. pseudoacacia seedlings under heavy metal stress, which suggests that increased atmospheric CO 2 concentrations could have positive effects on soil fertility and rhizosphere microenvironment under heavy metals. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Tumor microenvironment: Sanctuary of the devil.

    Science.gov (United States)

    Hui, Lanlan; Chen, Ye

    2015-11-01

    Tumor cells constantly interact with the surrounding microenvironment. Increasing evidence indicates that targeting the tumor microenvironment could complement traditional treatment and improve therapeutic outcomes for these malignancies. In this paper, we review new insights into the tumor microenvironment, and summarize selected examples of the cross-talk between tumor cells and their microenvironment, which have enhanced our understanding of pathophysiology of the microenvironment. We believe that this rapidly moving field promises many more to come, and they will guide the rational design of combinational therapies for success in cancer eradication. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. Synergistic extraction and separation of yttrium from heavy rare earths using mixture of sec-octylphenoxy acetic acid and bis(2,4,4-trimethylpentyl)phosphinic acid

    International Nuclear Information System (INIS)

    Sun Xiaobo; Zhao Junmei; Meng Shulan; Li Deqian

    2005-01-01

    Synergistic extraction and separation of yttrium (Y) from heavy rare earths (HRE) in chloride medium using mixture of sec-octylphenoxy acetic acid (CA-12, HA) and bis(2,4,4-trimethylpentyl)phosphinic acid (Cyanex272, HL) in n-heptane has been investigated. The synergistic enhancement coefficients, R max , were obtained for Ho 3+ (5.12), Y 3+ (5.34), Er 3+ (7.04), Tm 3+ (7.50), Yb 3+ (13.12) and Lu 3+ (17.58). The separation factors (SF) between Y 3+ and HRE were obtained, and it was found that Er 3+ would form the new complex as ErH 6 A 4 L 5 in the mixture system. A cation exchange mechanism was proposed. The equilibrium constant, formation constant and thermodynamic parameters such as ΔG = -18.48 kJ/mol, ΔH = -1.36 kJ/mol and ΔS = 0.058 kJ/mol were determined. The CA-12 and Cyanex272 mixture system showed higher extraction efficiency, larger separation factors as well as excellent stripping behaviors. The application potential of the mixture system to separate Y from HRE has been discussed

  11. Synergistic Effects of High Hydrostatic Pressure, Mild Heating, and Amino Acids on Germination and Inactivation of Clostridium sporogenes Spores

    Science.gov (United States)

    Ishimori, Takateru; Takahashi, Katsutoshi; Goto, Masato; Nakagawa, Suguru; Kasai, Yoshiaki; Konagaya, Yukifumi; Batori, Hiroshi; Kobayashi, Atsushi

    2012-01-01

    The synergistic effects of high hydrostatic pressure (HHP), mild heating, and amino acids on the germination of Clostridium sporogenes spores were examined by determining the number of surviving spores that returned to vegetative growth after pasteurization following these treatments. Pressurization at 200 MPa at a temperature higher than 40°C and treatment with some of the 19 l-amino acids at 10 mM or higher synergistically facilitated germination. When one of these factors was omitted, the level of germination was insignificant. Pressures of 100 and 400 MPa were less effective than 200 MPa. The spores were effectively inactivated by between 1.8 and 4.8 logs by pasteurization at 80°C after pressurization at 200 MPa at 45°C for 120 min with one of the amino acids with moderate hydrophobicity, such as Leu, Phe, Cys Met, Ala, Gly, or Ser. However, other amino acids showed poor inactivation effects of less than 0.9 logs. Spores in solutions containing 80 mM of either Leu, Phe, Cys, Met, Ala, Gly, or Ser were successfully inactivated by pasteurization by more than 5.4 logs after pressurization at 200 MPa at 70°C for 15 to 120 min. Ala and Met reduced the spore viability by 2.8 and 1.8 logs, respectively, by pasteurization at a concentration of 1 mM under 200 MPa at 70°C. These results indicate that germination of the spores is facilitated by a combination of high hydrostatic pressure, mild heating, and amino acids. PMID:22983975

  12. Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xiaofei; Zhu, Yanshuang [Department of Infectious Diseases, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China); He, Huabin [Department of Orthopedics, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China); Lou, Lianqing; Ye, Weiwei; Chen, Yongxin [Department of Infectious Diseases, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China); Wang, Jinghe, E-mail: Xiaofeili2000@163.com [Department of Infectious Diseases, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China)

    2013-06-28

    Highlights: •Novel combination therapy using aspirin and valproic acid (VPA). •Combination of aspirin and VPA elicits synergistic cytotoxic effects. •Combination of aspirin and VPA significantly reduces the drug dosage required alone. •Combination of aspirin and VPA significantly inhibit tumor growth. •Lower dose of aspirin in combination therapy will minimize side effects of aspirin. -- Abstract: Aspirin and valproic acid (VPA) have been extensively studied for inducing various malignancies growth inhibition respectively, despite their severe side effects. Here, we developed a novel combination by aspirin and VPA on hepatocellular cancer cells (HCCs). The viability of HCC lines were analyzed by MTT assay, apoptotic analysis of HepG2 and SMMC-7721 cell was performed. Real time-PCR and Western blotting were performed to determine the expression of apoptosis related genes and proteins such as Survivin, Bcl-2/Bax, Cyclin D1 and p15. Moreover, orthotopic xenograft tumors were challenged in nude mice to establish murine model, and then therapeutic effect was analyzed after drug combination therapy. The viability of HCC lines’ significantly decreased after drug combination treatment, and cancer cell apoptosis in combination group increasingly induced compared with single drug use. Therapeutic effect was significantly enhanced by combination therapy in tumor volume and tumor weight decrease. From the data shown here, aspirin and VPA combination have a synergistic killing effect on hepatocellular cancers cells proliferation and apoptosis.

  13. Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells

    International Nuclear Information System (INIS)

    Li, Xiaofei; Zhu, Yanshuang; He, Huabin; Lou, Lianqing; Ye, Weiwei; Chen, Yongxin; Wang, Jinghe

    2013-01-01

    Highlights: •Novel combination therapy using aspirin and valproic acid (VPA). •Combination of aspirin and VPA elicits synergistic cytotoxic effects. •Combination of aspirin and VPA significantly reduces the drug dosage required alone. •Combination of aspirin and VPA significantly inhibit tumor growth. •Lower dose of aspirin in combination therapy will minimize side effects of aspirin. -- Abstract: Aspirin and valproic acid (VPA) have been extensively studied for inducing various malignancies growth inhibition respectively, despite their severe side effects. Here, we developed a novel combination by aspirin and VPA on hepatocellular cancer cells (HCCs). The viability of HCC lines were analyzed by MTT assay, apoptotic analysis of HepG2 and SMMC-7721 cell was performed. Real time-PCR and Western blotting were performed to determine the expression of apoptosis related genes and proteins such as Survivin, Bcl-2/Bax, Cyclin D1 and p15. Moreover, orthotopic xenograft tumors were challenged in nude mice to establish murine model, and then therapeutic effect was analyzed after drug combination therapy. The viability of HCC lines’ significantly decreased after drug combination treatment, and cancer cell apoptosis in combination group increasingly induced compared with single drug use. Therapeutic effect was significantly enhanced by combination therapy in tumor volume and tumor weight decrease. From the data shown here, aspirin and VPA combination have a synergistic killing effect on hepatocellular cancers cells proliferation and apoptosis

  14. Liquid-liquid extraction of uranium from Egyptian phosphoric acid using a synergistic D2EHPA-DBBP mixture

    International Nuclear Information System (INIS)

    Abdel-Khalek, A.A.

    2011-01-01

    Extraction of uranium from Egyptian phosphoric acid with synergistic mixture of di-2-ethylhexylphosphoric acid (D2EHPA) and di-butyl butyl phosphonate (DBBP) is reported in this paper. The influence of various factors such as D2EHPA concentration, DBBP concentration, phosphoric acid concentration, contact time, aqueous: organic phase's ratio (aq:org) and temperature on the degree of extraction has been established. The data on the effect of temperature on the extraction showed that the enthalpy change is -23.12 kJ/mol. Uranium extracted by D2EHPA- DBBP is further subjected to a second cycle of extraction and scrubbing impurities. The uranium is finally converted to a high purity UO 3 product using precipitation with hydrogen peroxide and heat treatment at 375 deg C. (author)

  15. Synergistic effects on enantioselectivity of zwitterionic chiral stationary phases for separations of chiral acids, bases, and amino acids by HPLC.

    Science.gov (United States)

    Hoffmann, Christian V; Pell, Reinhard; Lämmerhofer, Michael; Lindner, Wolfgang

    2008-11-15

    In an attempt to overcome the limited applicability scope of earlier proposed Cinchona alkaloid-based chiral weak anion exchangers (WAX) and recently reported aminosulfonic acid-based chiral strong cation exchangers (SCX), which are conceptionally restricted to oppositely charged solutes, their individual chiral selector (SO) subunits have been fused in a combinatorial synthesis approach into single, now zwitterionic, chiral SO motifs. The corresponding zwitterionic ion-exchange-type chiral stationary phases (CSPs) in fact combined the applicability spectra of the parent chiral ion exchangers allowing for enantioseparations of chiral acids and amine-type solutes in liquid chromatography using polar organic mode with largely rivaling separation factors as compared to the parent WAX and SCX CSPs. Furthermore, the application spectrum could be remarkably expanded to various zwitterionic analytes such as alpha- and beta-amino acids and peptides. A set of structurally related yet different CSPs consisting of either a quinine or quinidine alkaloid moiety as anion-exchange subunit and various chiral or achiral amino acids as cation-exchange subunits enabled us to derive structure-enantioselectivity relationships, which clearly provided strong unequivocal evidence for synergistic effects of the two oppositely charged ion-exchange subunits being involved in molecular recognition of zwitterionic analytes by zwitterionic SOs driven by double ionic coordination.

  16. Rational Design of Zirconium-doped Titania Photocatalysts with Synergistic Brønsted Acidity and Photoactivity.

    Science.gov (United States)

    Ma, Runyuan; Wang, Liang; Zhang, Bingsen; Yi, Xianfeng; Zheng, Anmin; Deng, Feng; Yan, Xuhua; Pan, Shuxiang; Wei, Xiao; Wang, Kai-Xue; Su, Dang Sheng; Xiao, Feng-Shou

    2016-10-06

    The preparation of photocatalysts with high activities under visible-light illumination is challenging. We report the rational design and construction of a zirconium-doped anatase catalyst (S-Zr-TiO 2 ) with Brønsted acidity and photoactivity as an efficient catalyst for the degradation of phenol under visible light. Electron microscopy images demonstrate that the zirconium sites are uniformly distributed on the sub-10 nm anatase crystals. UV-visible spectrometry indicates that the S-Zr-TiO 2 is a visible-light-responsive catalyst with narrower band gap than conventional anatase. Pyridine-adsorption infrared and acetone-adsorption 13 C NMR spectra confirm the presence of Brønsted acidic sites on the S-Zr-TiO 2 sample. Interestingly, the S-Zr-TiO 2 catalyst exhibits high catalytic activity in the degradation of phenol under visible-light illumination, owing to a synergistic effect of the Brønsted acidity and photoactivity. Importantly, the S-Zr-TiO 2 shows good recyclability. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Characterization of synergistic anti-cancer effects of docosahexaenoic acid and curcumin on DMBA-induced mammary tumorigenesis in mice

    International Nuclear Information System (INIS)

    Siddiqui, Rafat A; Harvey, Kevin A; Walker, Candace; Altenburg, Jeffrey; Xu, Zhidong; Terry, Colin; Camarillo, Ignacio; Jones-Hall, Yava; Mariash, Cary

    2013-01-01

    The major obstacles to the successful use of individual nutritional compounds as preventive or therapeutic agents are their efficacy and bioavailability. One approach to overcoming this problem is to use combinations of nutrients to induce synergistic effects. The objective of this research was to investigate the synergistic effects of two dietary components: docosahexaenoic acid (DHA), an omega-3 fatty acid present in cold-water fish, and curcumin (CCM), an herbal nutrient present in turmeric, in an in vivo model of DMBA-induced mammary tumorigenesis in mice. We used the carcinogen DMBA to induce breast tumors in SENCAR mice on control, CCM, DHA, or DHA + CCM diets. Appearance and tumor progression were monitored daily. The tumors were harvested 15 days following their first appearance for morphological and immunohistological analysis. Western analysis was performed to determine expression of maspin and survivin in the tumor tissues. Characterization of tumor growth was analyzed using appropriate statistical methods. Otherwise all other results are reported as mean ± SD and analyzed with one-way ANOVA and Tukey’s post hoc procedure. Analysis of gene microarray data indicates that combined treatment with DHA + CCM altered the profile of “PAM50” genes in the SK-BR-3 cell line from an ER - /Her-2 + to that resembling a “normal-like” phenotype. The in vivo studies demonstrated that DHA + CCM treatment reduced the incidence of breast tumors, delayed tumor initiation, and reduced progression of tumor growth. Dietary treatment had no effect on breast size development, but tumors from mice on a control diet (untreated) were less differentiated than tumors from mice fed CCM or DHA + CCM diets. The synergistic effects also led to increased expression of the pro-apoptotic protein, maspin, but reduced expression of the anti-apoptotic protein, survivin. The SK-BR-3 cells and DMBA-induced tumors, both with an ER - and Her-2 + phenotype, were affected by the

  18. Regulation of the muscle fiber microenvironment by activated satellite cells during hypertrophy

    Science.gov (United States)

    Fry, Christopher S.; Lee, Jonah D.; Jackson, Janna R.; Kirby, Tyler J.; Stasko, Shawn A.; Liu, Honglu; Dupont-Versteegden, Esther E.; McCarthy, John J.; Peterson, Charlotte A.

    2014-01-01

    Our aim in the current study was to determine the necessity of satellite cells for long-term muscle growth and maintenance. We utilized a transgenic Pax7-DTA mouse model, allowing for the conditional depletion of > 90% of satellite cells with tamoxifen treatment. Synergist ablation surgery, where removal of synergist muscles places functional overload on the plantaris, was used to stimulate robust hypertrophy. Following 8 wk of overload, satellite cell-depleted muscle demonstrated an accumulation of extracellular matrix (ECM) and fibroblast expansion that resulted in reduced specific force of the plantaris. Although the early growth response was normal, an attenuation of hypertrophy measured by both muscle wet weight and fiber cross-sectional area occurred in satellite cell-depleted muscle. Isolated primary myogenic progenitor cells (MPCs) negatively regulated fibroblast ECM mRNA expression in vitro, suggesting a novel role for activated satellite cells/MPCs in muscle adaptation. These results provide evidence that satellite cells regulate the muscle environment during growth.—Fry, C. S., Lee, J. D., Jackson, J. R., Kirby, T. J., Stasko, S. A., Liu, H., Dupont-Versteegden, E. E., McCarthy, J. J., Peterson, C. A. Regulation of the muscle fiber microenvironment by activated satellite cells during hypertrophy. PMID:24376025

  19. Synergistic anti-Campylobacter jejuni activity of fluoroquinolone and macrolide antibiotics with phenolic compounds

    Science.gov (United States)

    Oh, Euna; Jeon, Byeonghwa

    2015-01-01

    The increasing resistance of Campylobacter to clinically important antibiotics, such as fluoroquinolones and macrolides, is a serious public health problem. The objective of this study is to investigate synergistic anti-Campylobacter jejuni activity of fluoroquinolones and macrolides in combination with phenolic compounds. Synergistic antimicrobial activity was measured by performing a checkerboard assay with ciprofloxacin and erythromycin in the presence of 21 phenolic compounds. Membrane permeability changes in C. jejuni by phenolic compounds were determined by measuring the level of intracellular uptake of 1-N-phenylnaphthylamine (NPN). Antibiotic accumulation assays were performed to evaluate the level of ciprofloxacin accumulation in C. jejuni. Six phenolic compounds, including p-coumaric acid, sinapic acid, caffeic acid, vanillic acid, gallic acid, and taxifolin, significantly increased the susceptibility to ciprofloxacin and erythromycin in several human and poultry isolates. The synergistic antimicrobial effect was also observed in ciprofloxacin- and erythromycin-resistant C. jejuni strains. The phenolic compounds also substantially increased membrane permeability and antibiotic accumulation in C. jejuni. Interestingly, some phenolic compounds, such as gallic acid and taxifolin, significantly reduced the expression of the CmeABC multidrug efflux pump. Phenolic compounds increased the NPN accumulation in the cmeB mutant, indicating phenolic compounds may affect the membrane permeability. In this study, we successfully demonstrated that combinational treatment of C. jejuni with antibiotics and phenolic compounds synergistically inhibits C. jejuni by impacting both antimicrobial influx and efflux. PMID:26528273

  20. Ferulic acid with ascorbic acid synergistically extenuates the mitochondrial dysfunction during beta-adrenergic catecholamine induced cardiotoxicity in rats.

    Science.gov (United States)

    Yogeeta, Surinder Kumar; Raghavendran, Hanumantha Rao Balaji; Gnanapragasam, Arunachalam; Subhashini, Rajakannu; Devaki, Thiruvengadam

    2006-10-27

    Disruption of mitochondria and free radical mediated tissue injury have been reported during cardiotoxicity induced by isoproterenol (ISO), a beta-adrenergic catecholamine. The present study was designed to investigate the effect of the combination of ferulic acid (FA) and ascorbic acid (AA) on the mitochondrial damage in ISO induced cardiotoxicity. Induction of rats with ISO (150 mg/kg b.wt., i.p.) for 2 days resulted in a significant decrease in the activities of respiratory chain enzymes (NADH dehydrogenase and cytochrome c-oxidase), tricarboxylic acid cycle enzymes (isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, alpha-ketoglutarate dehydrogenase), mitochondrial antioxidants (GPx, GST, SOD, CAT, GSH), cytochromes (b, c, c1, aa3) and in the level of mitochondrial phospholipids. A marked elevation in mitochondrial lipid peroxidation, mitochondrial levels of cholesterol, triglycerides and free fatty acids were also observed in ISO intoxicated rats. Pre-co-treatment with the combination of FA (20 mg/kg b.wt.) and AA (80 mg/kg b.wt.) orally for 6 days significantly enhanced the attenuation of these functional abnormalities and restored normal mitochondrial function when compared to individual drug treated groups. Mitigation of ISO induced biochemical and morphological changes in mitochondria were more pronounced with a combination of FA and AA rather than the individual drug treated groups. Transmission electron microscopic observations also correlated with these biochemical parameters. Hence, these findings demonstrate the synergistic ameliorative potential of FA and AA on mitochondrial function during beta-adrenergic catecholamine induced cardiotoxicity and associated oxidative stress in rats.

  1. The external microenvironment of healing skin wounds

    DEFF Research Database (Denmark)

    Kruse, Carla R; Nuutila, Kristo; Lee, Cameron Cy

    2015-01-01

    The skin wound microenvironment can be divided into two main components that influence healing: the external wound microenvironment, which is outside the wound surface; and the internal wound microenvironment, underneath the surface, to which the cells within the wound are exposed. Treatment...

  2. Cyclosporine A and palmitic acid treatment synergistically induce cytotoxicity in HepG2 cells

    Energy Technology Data Exchange (ETDEWEB)

    Luo, Yi, E-mail: yi.luo@pfizer.com; Rana, Payal; Will, Yvonne

    2012-06-01

    Immunosuppressant cyclosporine A (CsA) treatment can cause severe side effects. Patients taking immunosuppressant after organ transplantation often display hyperlipidemia and obesity. Elevated levels of free fatty acids have been linked to the etiology of metabolic syndromes, nonalcoholic fatty liver and steatohepatitis. The contribution of free fatty acids to CsA-induced toxicity is not known. In this study we explored the effect of palmitic acid on CsA-induced toxicity in HepG2 cells. CsA by itself at therapeutic exposure levels did not induce detectible cytotoxicity in HepG2 cells. Co-treatment of palmitic acid and CsA resulted in a dose dependent increase in cytotoxicity, suggesting that fatty acid could sensitize cells to CsA-induced cytotoxicity at the therapeutic doses of CsA. A synergized induction of caspase-3/7 activity was also observed, indicating that apoptosis may contribute to the cytotoxicity. We demonstrated that CsA reduced cellular oxygen consumption which was further exacerbated by palmitic acid, implicating that impaired mitochondrial respiration might be an underlying mechanism for the enhanced toxicity. Inhibition of c-Jun N-terminal kinase (JNK) attenuated palmitic acid and CsA induced toxicity, suggesting that JNK activation plays an important role in mediating the enhanced palmitic acid/CsA-induced toxicity. Our data suggest that elevated FFA levels, especially saturated FFA such as palmitic acid, may be predisposing factors for CsA toxicity, and patients with underlying diseases that would elevate free fatty acids may be susceptible to CsA-induced toxicity. Furthermore, hyperlipidemia/obesity resulting from immunosuppressive therapy may aggravate CsA-induced toxicity and worsen the outcome in transplant patients. -- Highlights: ► Palmitic acid and cyclosporine (CsA) synergistically increased cytotoxicity. ► The impairment of mitochondrial functions may contribute to the enhanced toxicity. ► Inhibition of JNK activity attenuated

  3. Synergistic effect of Brønsted acid and platinum on purification of automobile exhaust gases.

    Science.gov (United States)

    Fu, Wei; Li, Xin-Hao; Bao, Hong-Liang; Wang, Kai-Xue; Wei, Xiao; Cai, Yi-Yu; Chen, Jie-Sheng

    2013-01-01

    The catalytic purification of automobile exhaust gases (CO, NOx and hydrocarbons) is one of the most practiced conversion processes used to lower the emissions and to reduce the air pollution. Nevertheless, the good performance of exhaust gas purification catalysts often requires the high consumption of noble metals such as platinum. Here we report that the Brønsted acid sites on the external surface of a microporous silicoaluminophosphate (SAPO) act as a promoter for exhaust gas purification, effectively cutting the loading amount of platinum in the catalyst without sacrifice of performance. It is revealed that in the Pt-loaded SAPO-CHA catalyst, there exists a remarkable synergistic effect between the Brønsted acid sites and the Pt nanoparticles, the former helping to adsorb and activate the hydrocarbon molecules for NO reduction during the catalytic process. The thermal stability of SAPO-CHA also makes the composite catalyst stable and reusable without activity decay.

  4. Synergistic effect of Brønsted acid and platinum on purification of automobile exhaust gases

    Science.gov (United States)

    Fu, Wei; Li, Xin-Hao; Bao, Hong-Liang; Wang, Kai-Xue; Wei, Xiao; Cai, Yi-Yu; Chen, Jie-Sheng

    2013-01-01

    The catalytic purification of automobile exhaust gases (CO, NOx and hydrocarbons) is one of the most practiced conversion processes used to lower the emissions and to reduce the air pollution. Nevertheless, the good performance of exhaust gas purification catalysts often requires the high consumption of noble metals such as platinum. Here we report that the Brønsted acid sites on the external surface of a microporous silicoaluminophosphate (SAPO) act as a promoter for exhaust gas purification, effectively cutting the loading amount of platinum in the catalyst without sacrifice of performance. It is revealed that in the Pt-loaded SAPO-CHA catalyst, there exists a remarkable synergistic effect between the Brønsted acid sites and the Pt nanoparticles, the former helping to adsorb and activate the hydrocarbon molecules for NO reduction during the catalytic process. The thermal stability of SAPO-CHA also makes the composite catalyst stable and reusable without activity decay. PMID:23907148

  5. A novel dipicolinamide-dicarbollide synergistic solvent system for actinide extraction

    Energy Technology Data Exchange (ETDEWEB)

    Patil, Ajay Bhagwan [Bhabha Atomic Research Centre, Mumbai (India). Radiochemistry Div.; Pune Univ. (India). Garware Research Centre; Pathak, Priyanath; Mohapatra, Prasanta Kumar [Bhabha Atomic Research Centre, Mumbai (India). Radiochemistry Div.; Shinde, Vaishali Sanjay [Pune Univ. (India). Garware Research Centre; Alyapyshev, M.Yu.; Babain, Vasiliy A. [Federal Agency for Atomic Energy, St. Petersburg (Russian Federation). V.G. Khlopin Radium Institute

    2014-09-01

    Solvent extraction studies of several actinide ions such as Am(III), U(VI), Np(IV), Np(VI), Pu(IV) were carried out from nitric acid medium using a synergistic mixture of N,N'-diethyl-N,N'-di(para)fluorophenyl-2,6-dipicolinamide, (DEtD(p)FPhDPA, DPA), and hydrogen dicarbollylcobaltate (H{sup +}CCD{sup -}) dissolved in phenyltrifluoromethylsulphone (PTMS). The effects of different parameters such as aqueous phase acidity (0.01-3 M HNO{sub 3}), oxidation states of metal ions, ligand concentration, nature of diluent and temperature on the extraction behavior of metal ions were studied. The extracted Am(III) species was determined as H{sup +}[Am(DPA){sub 2}(CCD){sub 4}]{sup -} With increasing aqueous phase acidities, the extractability of both Am(III) and Eu(III) was found to decrease. The synergistic mixture showed better extraction in mM concentrations as compared to previously studied dipicolinamides. The thermodynamic studies were performed to calculate heat of extraction reaction and the extraction constants. The proposed synergistic mixture showed good extraction for all the metal ions, though lanthanide actinide separation results are not encouraging. (orig.)

  6. Synergistic Effects of Nucleating Agents and Plasticizers on the Crystallization Behavior of Poly(lactic acid

    Directory of Open Access Journals (Sweden)

    Xuetao Shi

    2015-01-01

    Full Text Available The synergistic effect of nucleating agents and plasticizers on the thermal and mechanical performance of PLA nanocomposites was investigated with the objective of increasing the crystallinity and balancing the stiffness and toughness of PLA mechanical properties. Calcium carbonate, halloysite nanotubes, talc and LAK (sulfates were compared with each other as heterogeneous nucleating agents. Both the DSC isothermal and non-isothermal studies indicated that talc and LAK were the more effective nucleating agents among the selected fillers. Poly(D-lactic acid (PDLA acted also as a nucleating agent due to the formation of the PLA stereocomplex. The half crystallization time was reduced by the addition of talc to about 2 min from 37.5 min of pure PLA by the isothermal crystallization study. The dynamic mechanical thermal study (DMTA indicated that nanofillers acted as both reinforcement fillers and nucleating agents in relation to the higher storage modulus. The plasticized PLA studied by DMTA indicated a decreasing glass transition temperature with the increasing of the PEG content. The addition of nanofiller increased the Young’s modulus. PEG had the plasticization effect of increasing the break deformation, while sharply decreasing the stiffness and strength of PLA. The synergistic effect of nanofillers and plasticizer achieved the balance between stiffness and toughness with well-controlled crystallization.

  7. Synergistic retention strategy of RGD active targeting and radiofrequency-enhanced permeability for intensified RF & chemotherapy synergistic tumor treatment.

    Science.gov (United States)

    Zhang, Kun; Li, Pei; He, Yaping; Bo, Xiaowan; Li, Xiaolong; Li, Dandan; Chen, Hangrong; Xu, Huixiong

    2016-08-01

    Despite gaining increasing attention, chelation of multiple active targeting ligands greatly increase the formation probability of protein corona, disabling active targeting. To overcome it, a synergistic retention strategy of RGD-mediated active targeting and radiofrequency (RF) electromagnetic field-enhanced permeability has been proposed here. It is validated that such a special synergistic retention strategy can promote more poly lactic-co-glycolic acid (PLGA)-based capsules encapsulating camptothecin (CPT) and solid DL-menthol (DLM) to enter and retain in tumor in vitro and in vivo upon exposure to RF irradiation, receiving an above 8 fold enhancement in HeLa retention. Moreover, the PLGA-based capsules can respond RF field to trigger the entrapped DLM to generate solid-liquid-gas (SLG) tri-phase transformation for enhancing RF ablation and CPT release. Therefore, depending on the enhanced RF ablation and released CPT and the validated synergistic retention effect, the inhibitory outcome for tumor growth has gained an over 10-fold improvement, realizing RF ablation & chemotherapy synergistic treatment against HeLa solid tumor, which indicates a significant promise in clinical RF ablation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Poly(acrylic acid) conjugated hollow mesoporous carbon as a dual-stimuli triggered drug delivery system for chemo-photothermal synergistic therapy

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xian; Liu, Chang; Wang, Shengyu; Jiao, Jian; Di, Donghua; Jiang, Tongying; Zhao, Qinfu, E-mail: zqf021110505@163.com; Wang, Siling, E-mail: silingwang@syphu.edu.cn

    2017-02-01

    In this work, we described the development of the redox and pH dual stimuli-responsive drug delivery system and combination of the chemotherapy and photothermal therapy for cancer treatment. The poly(acrylic acid) (PAA) was conjugated on the outlets of hollow mesoporous carbon (HMC) via disulfide bonds. PAA was used as a capping to block drug within the mesopores of HMC for its lots of favorable advantages, such as good biocompatibility, appropriate molecular weight to block the mesopores of HMC, extension of the blood circulation, and the improvement of the dispersity of the nano-carriers in physiological environment. The DOX loaded DOX/HMC-SS-PAA had a high drug loading amount up to 51.9%. The in vitro drug release results illustrated that DOX/HMC-SS-PAA showed redox and pH dual-responsive drug release, and the release rate could be further improved by the near infrared (NIR) irradiation. Cell viability experiment indicated that DOX/HMC-SS-PAA had a synergistic therapeutic effect by combination of chemotherapy and photothermal therapy. This work suggested that HMC-SS-PAA exhibited dual-responsive drug release property and could be used as a NIR-adsorbing drug delivery system for chemo-photothermal synergistic therapy. - Highlights: • Poly(acrylic acid) was grafted on hollow mesoporous carbon (HMC) via disulfide bonds. • The grafted PAA could increase the biocompatibility and stability of HMC. • The DOX-loaded DOX/HMC-SS-PAA had a high drug loading efficiency up to 51.9%. • DOX/HMC-SS-PAA showed redox/pH dual-responsive and NIR-triggered drug release. • DOX/HMC-SS-PAA showed a chemo/photothermal synergistic therapy effect.

  9. Poly(acrylic acid) conjugated hollow mesoporous carbon as a dual-stimuli triggered drug delivery system for chemo-photothermal synergistic therapy

    International Nuclear Information System (INIS)

    Li, Xian; Liu, Chang; Wang, Shengyu; Jiao, Jian; Di, Donghua; Jiang, Tongying; Zhao, Qinfu; Wang, Siling

    2017-01-01

    In this work, we described the development of the redox and pH dual stimuli-responsive drug delivery system and combination of the chemotherapy and photothermal therapy for cancer treatment. The poly(acrylic acid) (PAA) was conjugated on the outlets of hollow mesoporous carbon (HMC) via disulfide bonds. PAA was used as a capping to block drug within the mesopores of HMC for its lots of favorable advantages, such as good biocompatibility, appropriate molecular weight to block the mesopores of HMC, extension of the blood circulation, and the improvement of the dispersity of the nano-carriers in physiological environment. The DOX loaded DOX/HMC-SS-PAA had a high drug loading amount up to 51.9%. The in vitro drug release results illustrated that DOX/HMC-SS-PAA showed redox and pH dual-responsive drug release, and the release rate could be further improved by the near infrared (NIR) irradiation. Cell viability experiment indicated that DOX/HMC-SS-PAA had a synergistic therapeutic effect by combination of chemotherapy and photothermal therapy. This work suggested that HMC-SS-PAA exhibited dual-responsive drug release property and could be used as a NIR-adsorbing drug delivery system for chemo-photothermal synergistic therapy. - Highlights: • Poly(acrylic acid) was grafted on hollow mesoporous carbon (HMC) via disulfide bonds. • The grafted PAA could increase the biocompatibility and stability of HMC. • The DOX-loaded DOX/HMC-SS-PAA had a high drug loading efficiency up to 51.9%. • DOX/HMC-SS-PAA showed redox/pH dual-responsive and NIR-triggered drug release. • DOX/HMC-SS-PAA showed a chemo/photothermal synergistic therapy effect.

  10. The intestinal microenvironment in sepsis.

    Science.gov (United States)

    Fay, Katherine T; Ford, Mandy L; Coopersmith, Craig M

    2017-10-01

    The gastrointestinal tract has long been hypothesized to function as "the motor" of multiple organ dysfunction syndrome. The gastrointestinal microenvironment is comprised of a single cell layer epithelia, a local immune system, and the microbiome. These three components of the intestine together play a crucial role in maintaining homeostasis during times of health. However, the gastrointestinal microenvironment is perturbed during sepsis, resulting in pathologic changes that drive both local and distant injury. In this review, we seek to characterize the relationship between the epithelium, gastrointestinal lymphocytes, and commensal bacteria during basal and pathologic conditions and how the intestinal microenvironment may be targeted for therapeutic gain in septic patients. Published by Elsevier B.V.

  11. Silica ecosystem for synergistic biotransformation

    Science.gov (United States)

    Mutlu, Baris R.; Sakkos, Jonathan K.; Yeom, Sujin; Wackett, Lawrence P.; Aksan, Alptekin

    2016-06-01

    Synergistical bacterial species can perform more varied and complex transformations of chemical substances than either species alone, but this is rarely used commercially because of technical difficulties in maintaining mixed cultures. Typical problems with mixed cultures on scale are unrestrained growth of one bacterium, which leads to suboptimal population ratios, and lack of control over bacterial spatial distribution, which leads to inefficient substrate transport. To address these issues, we designed and produced a synthetic ecosystem by co-encapsulation in a silica gel matrix, which enabled precise control of the microbial populations and their microenvironment. As a case study, two greatly different microorganisms: Pseudomonas sp. NCIB 9816 and Synechococcus elongatus PCC 7942 were encapsulated. NCIB 9816 can aerobically biotransform over 100 aromatic hydrocarbons, a feat useful for synthesis of higher value commodity chemicals or environmental remediation. In our system, NCIB 9816 was used for biotransformation of naphthalene (a model substrate) into CO2 and the cyanobacterium PCC 7942 was used to provide the necessary oxygen for the biotransformation reactions via photosynthesis. A mathematical model was constructed to determine the critical cell density parameter to maximize oxygen production, and was then used to maximize the biotransformation rate of the system.

  12. Investigation of the synergistic effect of alcoholic compounds on the extraction of H3PO4 from Syrian wet phosphoric acid by TBP

    International Nuclear Information System (INIS)

    Abdulbaki, M. K.; Shino, O.; Wahoud, A.

    2006-01-01

    This paper studies the synergistic effects of alcoholic compounds such as isoamyl alcohol. Pentanol, hexanol and heptanol on the extraction of H 3 PO 4 from Syrian phosphoric acid by (TBP). The possibility to use these alcoholic compounds as a diluent instead of kerosene was also studied. The results show that the alcoholic compounds has bigger extraction yield than (TBP) diluted in kerosene. The alcoholic compounds has an important synergistic effect, when it was used as a diluent instead of kerosene, on the extraction of H 3 PO 4 by (TBP) and they have a bigger extraction yield and the quicker phase separation comparing with kerosene. Extraction of uranium, fluoride, sulfate and heavy metals is relatively small. (Authors)

  13. Synergistic inhibition between o-phenanthroline and chloride ion for steel corrosion in sulphuric acid

    International Nuclear Information System (INIS)

    Li Xueming; Tang Libin; Li Lin; Mu Guannan; Liu Guangheng

    2006-01-01

    The corrosion inhibition of cold rolled steel in 0.5 M sulphuric acid in the presence of o-phenanthroline and sodium chloride (NaCl) has been investigated by using weight loss and electrochemical techniques. The experimental data suggest that the inhibition efficiency increases with increasing NaCl concentration in the presence of 0.0002 M o-phenanthroline, but decreases with increasing temperature. A synergistic effect is observed when o-phenanthroline and chloride ions are used together to prevent cold rolled steel corrosion in 0.5 M sulphuric acid. The polarization curves showed that the complex of o-phenanthroline and NaCl acts as a mixed type inhibitor. The experimental results suggested that the presence of chloride ions in the solution stabilized the adsorption of o-phenanthroline molecules on the metal surface and improved the inhibition efficiency of o-phenanthroline. The adsorption of the complex accords with the Langmuir adsorption isotherm. Some thermodynamic parameters such as adsorption heat, adsorption entropy and adsorption free energy have been calculated by employing thermodynamic equations. Kinetic parameters such as apparent activation energy and pre-exponential factor have been calculated and discussed

  14. Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment

    Science.gov (United States)

    Finkernagel, Florian; Lieber, Sonja; Schnitzer, Evelyn; Legrand, Nathalie; Schober, Yvonne; Nockher, W. Andreas; Toth, Philipp M.; Diederich, Wibke E.; Nist, Andrea; Stiewe, Thorsten; Wagner, Uwe; Reinartz, Silke; Müller-Brüsselbach, Sabine; Müller, Rolf

    2015-01-01

    The nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a lipid ligand-inducible transcription factor associated with macrophage polarization. However, its function in tumor-associated macrophages (TAMs) has not been investigated to date. Here, we report the PPARβ/δ-regulated transcriptome and cistrome for TAMs from ovarian carcinoma patients. Comparison with monocyte-derived macrophages shows that the vast majority of direct PPARβ/δ target genes are upregulated in TAMs and largely refractory to synthetic agonists, but repressible by inverse agonists. Besides genes with metabolic functions, these include cell type-selective genes associated with immune regulation and tumor progression, e.g., LRP5, CD300A, MAP3K8 and ANGPTL4. This deregulation is not due to increased expression of PPARβ/δ or its enhanced recruitment to target genes. Instead, lipidomic analysis of malignancy-associated ascites revealed high concentrations of polyunsaturated fatty acids, in particular linoleic acid, acting as potent PPARβ/δ agonists in macrophages. These fatty acid ligands accumulate in lipid droplets in TAMs, thereby providing a reservoir of PPARβ/δ ligands. These observations suggest that the deregulation of PPARβ/δ target genes by ligands of the tumor microenvironment contributes to the pro-tumorigenic polarization of ovarian carcinoma TAMs. This conclusion is supported by the association of high ANGPTL4 expression with a shorter relapse-free survival in serous ovarian carcinoma. PMID:25968567

  15. Investigation of antioxidant interactions between Radix Astragali and Cimicifuga foetida and identification of synergistic antioxidant compounds.

    Directory of Open Access Journals (Sweden)

    Fei Wang

    Full Text Available The medicinal plants of Huang-qi (Radix Astragali and Sheng-ma (Cimicifuga foetida demonstrate significantly better antioxidant effects when used in combination than when used alone. However, the bioactive components and interactional mechanism underlying this synergistic action are still not well understood. In the present study, 2,2-diphenyl-1-picrylhydrazyl (DPPH radical scavenging assay was employed to investigate the antioxidant capacity of single herbs and their combination with the purpose of screening synergistic antioxidant compounds from them. Chromatographic isolation was performed on silica gel, Sephadex LH-20 columns and HPLC, and consequently to yield formononetin, calycosin, ferulic acid and isoferulic acid, which were identified by their retention time, UV λmax, MS and MS/MS data. The combination of isoferulic acid and calycosin at a dose ratio of 1∶1 resulted in significant synergy in scavenging DPPH radicals and ferric reducing antioxidant power (FRAP assay. Furthermore, the protective effects of these four potential synergistic compounds were examined using H2O2-induced HepG2 Cells bioassay. Results revealed that the similar synergy was observed in the combination of isoferulic acid and calycosin. These findings might provide some theoretical basis for the purported synergistic efficiency of Huang-qi and Sheng-ma as functional foods, dietary supplements and medicinal drugs.

  16. Ascorbic acid and a cytostatic inhibitor of glycolysis synergistically induce apoptosis in non-small cell lung cancer cells.

    Directory of Open Access Journals (Sweden)

    Saleha B Vuyyuri

    Full Text Available Ascorbic acid (AA exhibits significant anticancer activity at pharmacologic doses achievable by parenteral administration that have minimal effects on normal cells. Thus, AA has potential uses as a chemotherapeutic agent alone or in combination with other therapeutics that specifically target cancer-cell metabolism. We compared the effects of AA and combinations of AA with the glycolysis inhibitor 3-(3-pyridinyl-1-(4-pyridinyl-2-propen-1-one (3-PO on the viability of three non-small cell lung cancer (NSCLC cell lines to the effects on an immortalized lung epithelial cell line. AA concentrations of 0.5 to 5 mM caused a complete loss of viability in all NSCLC lines compared to a <10% loss of viability in the lung epithelial cell line. Combinations of AA and 3-PO synergistically enhanced cell death in all NSCLC cell lines at concentrations well below the IC50 concentrations for each compound alone. A synergistic interaction was not observed in combination treatments of lung epithelial cells and combination treatments that caused a complete loss of viability in NSCLC cells had modest effects on normal lung cell viability and reactive oxygen species (ROS levels. Combination treatments induced dramatically higher ROS levels compared to treatment with AA and 3-PO alone in NSCLC cells and combination-induced cell death was inhibited by addition of catalase to the medium. Analyses of DNA fragmentation, poly (ADP-ribose polymerase cleavage, annexin V-binding, and caspase activity demonstrated that AA-induced cell death is caused via the activation of apoptosis and that the combination treatments caused a synergistic induction of apoptosis. These results demonstrate the effectiveness of AA against NSCLC cells and that combinations of AA with 3-PO synergistically induce apoptosis via a ROS-dependent mechanism. These results support further evaluation of pharmacologic concentrations of AA as an adjuvant treatment for NSCLC and that combination of AA with

  17. Inhibitive and Synergistic Properties of Ethanolic Extract of ...

    African Journals Online (AJOL)

    It was also noted that only KCl was synergistic to the ethanol extract of Anogeissus leiocarpus, while other halides tested were antagonistic. All the data acquired reveal that the ethanolic extract of Anogeissus leiocarpus act as an inhibitor in the acid environment due to the phytochemicals: saponin, tannins, flavonoid, ...

  18. Influence of three-dimensional hyaluronic acid microenvironments on mesenchymal stem cell chondrogenesis.

    Science.gov (United States)

    Chung, Cindy; Burdick, Jason A

    2009-02-01

    Mesenchymal stem cells (MSCs) are multipotent progenitor cells whose plasticity and self-renewal capacity have generated significant interest for applications in tissue engineering. The objective of this study was to investigate MSC chondrogenesis in photo-cross-linked hyaluronic acid (HA) hydrogels. Because HA is a native component of cartilage, and MSCs may interact with HA via cell surface receptors, these hydrogels could influence stem cell differentiation. In vitro and in vivo cultures of MSC-laden HA hydrogels permitted chondrogenesis, measured by the early gene expression and production of cartilage-specific matrix proteins. For in vivo culture, MSCs were encapsulated with and without transforming growth factor beta-3 (TGF-beta3) or pre-cultured for 2 weeks in chondrogenic medium before implantation. Up-regulation of type II collagen, aggrecan, and sox 9 was observed for all groups over MSCs at the time of encapsulation, and the addition of TGF-beta3 further enhanced the expression of these genes. To assess the influence of scaffold chemistry on chondrogenesis, HA hydrogels were compared with relatively inert poly(ethylene glycol) (PEG) hydrogels and showed enhanced expression of cartilage-specific markers. Differences between HA and PEG hydrogels in vivo were most noticeable for MSCs and polymer alone, indicating that hydrogel chemistry influences the commitment of MSCs to undergo chondrogenesis (e.g., approximately 43-fold up-regulation of type II collagen of MSCs in HA over PEG hydrogels). Although this study investigated only early markers of tissue regeneration, these results emphasize the importance of material cues in MSC differentiation microenvironments, potentially through interactions between scaffold materials and cell surface receptors.

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

    Science.gov (United States)

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

    2015-01-01

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

  20. New Yellow Synergist for Stable Pigment Dispersion of Inkjet Ink.

    Science.gov (United States)

    Song, Gihyun; Lee, Hayoon; Jung, Hyocheol; Kang, Seokwoo; Park, Jongwook

    2018-02-01

    Minimizing ink droplet and self-dispersed pigment mixture are becoming hot issues for high resolution of inkjet printing. New synergist including sulfonic acid group of PY-74 was suggested and synthesized. Pigment itself did not show water solubility but new synergist, SY-11 exhibited good solubility in water and organic solvents such as DMSO and DMF. When aqueous pigment ink was prepared with SY-11, storage stability of the ink has been remained for 7 days under periodically repeated heating and cooling conditions. Particle size of formulated ink was around 150 nm.

  1. Synergistic effect of the combination of gallic acid and famotidine in protection of rat gastric mucosa.

    Science.gov (United States)

    Asokkumar, K; Sen, Saikat; Umamaheswari, M; Sivashanmugam, A T; Subhadradevi, V

    2014-08-01

    Antioxidant supplements with existing drugs may confer better therapeutic efficacy in oxidative stress related diseases. The purpose of the present work was to characterize the interaction and investigate the protective effect of H2 blocker famotidine and gallic acid in combination against experimentally induced peptic ulcer. Preventive effect of gallic acid and famotidine in different combinations was investigated against aspirin plus pyloric ligation induced ulcer in rat. Ulcer index, gastric juice volume, pH, other biochemical parameters of gastric juice and antioxidant activity using stomach tissue were estimated. Pretreatment with gallic acid and famotidine in combinations for 7 days, protected the gastric mucosa significantly (pacidity, total protein, pepsin and DNA content, and increase in pH, carbohydrates concentration in gastric juice. Combination treatment increases levels of superoxide dismutase, catalase, reduced glutathione, glutathione reductase and glucose-6-phosphate dehydrogenase, and decreases lipid peroxidation, myloperoxidase in stomach tissue. Along with higher dose combination, lower dose combinations like gallic acid (50mg/kg) plus famotidine (10mg/kg) also offered better antiulcer activity than their individual effect. Histopathological studies confirmed their antiulcer activity. Combination treatments confer synergistic protective effect against peptic ulcer in rats, which was related to the gastroprotective, antisecratory and antioxidant activity of combination treatment. Results proved that use of gallic acid with existing antiulcer drug will be more useful in the prevention/management of peptic ulcer. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  2. Alkaline biodegradable implants for osteoporotic bone defects--importance of microenvironment pH.

    Science.gov (United States)

    Liu, W; Wang, T; Yang, C; Darvell, B W; Wu, J; Lin, K; Chang, J; Pan, H; Lu, W W

    2016-01-01

    Change of microenvironment pH by biodegradable implants may ameliorate unbalanced osteoporotic bone remodeling. The present work demonstrated that a weak alkaline condition stimulated osteoblasts differentiation while suppressed osteoclast generation. In vivo, implants with an alkaline microenvironment pH (monitored by a pH microelectrode) exhibited a promising healing effect for the repair of osteoporotic bone defects. Under osteoporotic conditions, the response of the bone microenvironment to an endosseous implant is significantly impaired, and this substantially increases the risk of fracture, non-union and aseptic implant loosening. Acid-base equilibrium is an important factor influencing bone cell behaviour. The present purpose was to study the effect of a series of alkaline biodegradable implant materials on regeneration of osteoporotic bone defect, monitoring the microenvironment pH (μe-pH) over time. The proliferation and differentiation potential of osteoporotic rat bone marrow stromal cells and RAW 264.7 cells were examined under various pH conditions. Ovariectomized rat bone defects were filled with specific biodegradable materials, and μe-pH was measured by pH microelectrode. New osteoid and tartrate-resistant acid phosphatase-positive osteoclast-like cells were examined by Goldner's trichrome and TRAP staining, respectively. The intermediate layer between implants and new bone were studied using energy-dispersive X-ray spectroscopy (EDX) linear scanning. In vitro, weak alkaline conditions stimulated osteoporotic rat bone marrow stromal cells (oBMSC) differentiation, while inhibiting the formation of osteoclasts. In vivo, μe-pH differs from that of the homogeneous peripheral blood and exhibits variations over time particular to each material. Higher initial μe-pH was associated with more new bone formation, late response of TRAP-positive osteoclast-like cells and the development of an intermediate 'apatitic' layer in vivo. EDX suggested that

  3. Dynamic microenvironments: the fourth dimension.

    Science.gov (United States)

    Tibbitt, Mark W; Anseth, Kristi S

    2012-11-14

    The extracellular space, or cell microenvironment, choreographs cell behavior through myriad controlled signals, and aberrant cues can result in dysfunction and disease. For functional studies of human cell biology or expansion and delivery of cells for therapeutic purposes, scientists must decipher this intricate map of microenvironment biology and develop ways to mimic these functions in vitro. In this Perspective, we describe technologies for four-dimensional (4D) biology: cell-laden matrices engineered to recapitulate tissue and organ function in 3D space and over time.

  4. Commensal bacteria modulate the tumor microenvironment.

    Science.gov (United States)

    Poutahidis, Theofilos; Erdman, Susan E

    2016-09-28

    It has been recently shown that gut microbes modulate whole host immune and hormonal factors impacting the fate of distant preneoplastic lesions toward malignancy or regression. This raises the possibility that the tumor microenvironment interacts with broader systemic microbial-immune networks. These accumulated findings suggest novel therapeutic opportunities for holobiont engineering in emerging tumor microenvironments. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. Optical microassembly platform for constructing reconfigurable microenvironment for biomedical studies

    DEFF Research Database (Denmark)

    Rodrigo, Peter John; Kelemen, Lóránd; Palima, Darwin

    2009-01-01

    Cellular development is highly influenced by the surrounding microenvironment. We propose user-reconfigurable microenvironments and bio-compatible scaffolds as an approach for understanding cellular development processes. We demonstrate a model platform for constructing versatile microenvironment...

  6. Enduring epigenetic landmarks define the cancer microenvironment

    Science.gov (United States)

    Pidsley, Ruth; Lawrence, Mitchell G.; Zotenko, Elena; Niranjan, Birunthi; Statham, Aaron; Song, Jenny; Chabanon, Roman M.; Qu, Wenjia; Wang, Hong; Richards, Michelle; Nair, Shalima S.; Armstrong, Nicola J.; Nim, Hieu T.; Papargiris, Melissa; Balanathan, Preetika; French, Hugh; Peters, Timothy; Norden, Sam; Ryan, Andrew; Pedersen, John; Kench, James; Daly, Roger J.; Horvath, Lisa G.; Stricker, Phillip; Frydenberg, Mark; Taylor, Renea A.; Stirzaker, Clare; Risbridger, Gail P.; Clark, Susan J.

    2018-01-01

    The growth and progression of solid tumors involves dynamic cross-talk between cancer epithelium and the surrounding microenvironment. To date, molecular profiling has largely been restricted to the epithelial component of tumors; therefore, features underpinning the persistent protumorigenic phenotype of the tumor microenvironment are unknown. Using whole-genome bisulfite sequencing, we show for the first time that cancer-associated fibroblasts (CAFs) from localized prostate cancer display remarkably distinct and enduring genome-wide changes in DNA methylation, significantly at enhancers and promoters, compared to nonmalignant prostate fibroblasts (NPFs). Differentially methylated regions associated with changes in gene expression have cancer-related functions and accurately distinguish CAFs from NPFs. Remarkably, a subset of changes is shared with prostate cancer epithelial cells, revealing the new concept of tumor-specific epigenome modifications in the tumor and its microenvironment. The distinct methylome of CAFs provides a novel epigenetic hallmark of the cancer microenvironment and promises new biomarkers to improve interpretation of diagnostic samples. PMID:29650553

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

    Science.gov (United States)

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

    2016-04-01

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

  8. Synergistic efficacy of salicylic acid with a penetration enhancer on human skin monitored by OCT and diffuse reflectance spectroscopy

    Science.gov (United States)

    Zhao, Qingliang; Dai, Cuixia; Fan, Shanhui; Lv, Jing; Nie, Liming

    2016-10-01

    Salicylic acid (SA) has been frequently used as a facial chemical peeling agent (FCPA) in various cosmetics for facial rejuvenation and dermatological treatments in the clinic. However, there is a tradeoff between therapeutic effectiveness and possible adverse effects caused by this agent for cosmetologists. To optimize the cosmetic efficacy with minimal concentration, we proposed a chemical permeation enhancer (CPE) azone to synergistically work with SA on human skin in vivo. The optical properties of human skin after being treated with SA alone and SA combined with azone (SA@azone) were successively investigated by diffuse reflectance spectroscopy (DRS) and optical coherence tomography (OCT). Our results revealed that as the SA concentration increased, the light reflectance decreased and the absorption increased. We also found that SA@azone exhibited a synergistic effect on enhancing light penetration and OCT imaging depth. We demonstrated that the combination of DRS and OCT techniques could be used as a noninvasive, rapid and accurate measurement method to monitor the subtle changes of skin tissue after treatment with FCPA and CPE. The approach will greatly benefit the development of clinical cosmetic surgery, dermatosis diagnosis and therapeutic effect inspection in related biomedical studies.

  9. Composition dependence of the synergistic effect of nucleating agent and plasticizer in poly(lactic acid: A Mixture Design study

    Directory of Open Access Journals (Sweden)

    M. K. Fehri

    2016-04-01

    Full Text Available Blends consisting of commercial poly(lactic acid (PLA, poly(lactic acid oligomer (OLA8 as plasticizer and a sulfonic salt of a phthalic ester and poly(D-lactic acid as nucleating agents were prepared by melt extrusion, following a Mixture Design approach, in order to systematically study mechanical and thermal properties as a function of composition. The full investigation was carried out by differential scanning calorimetry (DSC, dynamic mechanical thermal analysis (DMTA and tensile tests. The crystallization half-time was also studied at 105 °C as a function of the blends composition. A range of compositions in which the plasticizer and the nucleation agent minimized the crystallization half-time in a synergistic way was clearly identified thanks to the application of the Mixture Design approach. The results allowed also the identification of a composition range to maximize the crystallinity developed during the rapid cooling below glass transition temperature in injection moulding, thus allowing an easier processing of PLA based materials. Moreover the mechanical properties were discussed by correlating them to the chemical structural features and thermal behaviour of blends.

  10. Immunological Dysregulation in Multiple Myeloma Microenvironment

    OpenAIRE

    Romano, Alessandra; Conticello, Concetta; Cavalli, Maide; Vetro, Calogero; La Fauci, Alessia; Parrinello, Nunziatina Laura; Di Raimondo, Francesco

    2014-01-01

    Multiple Myeloma (MM) is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC) in bone marrow (BM). Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extr...

  11. Multiparametric classification links tumor microenvironments with tumor cell phenotype.

    Directory of Open Access Journals (Sweden)

    Bojana Gligorijevic

    2014-11-01

    Full Text Available While it has been established that a number of microenvironment components can affect the likelihood of metastasis, the link between microenvironment and tumor cell phenotypes is poorly understood. Here we have examined microenvironment control over two different tumor cell motility phenotypes required for metastasis. By high-resolution multiphoton microscopy of mammary carcinoma in mice, we detected two phenotypes of motile tumor cells, different in locomotion speed. Only slower tumor cells exhibited protrusions with molecular, morphological, and functional characteristics associated with invadopodia. Each region in the primary tumor exhibited either fast- or slow-locomotion. To understand how the tumor microenvironment controls invadopodium formation and tumor cell locomotion, we systematically analyzed components of the microenvironment previously associated with cell invasion and migration. No single microenvironmental property was able to predict the locations of tumor cell phenotypes in the tumor if used in isolation or combined linearly. To solve this, we utilized the support vector machine (SVM algorithm to classify phenotypes in a nonlinear fashion. This approach identified conditions that promoted either motility phenotype. We then demonstrated that varying one of the conditions may change tumor cell behavior only in a context-dependent manner. In addition, to establish the link between phenotypes and cell fates, we photoconverted and monitored the fate of tumor cells in different microenvironments, finding that only tumor cells in the invadopodium-rich microenvironments degraded extracellular matrix (ECM and disseminated. The number of invadopodia positively correlated with degradation, while the inhibiting metalloproteases eliminated degradation and lung metastasis, consistent with a direct link among invadopodia, ECM degradation, and metastasis. We have detected and characterized two phenotypes of motile tumor cells in vivo, which

  12. [Prostate cancer microenvironment: Its structure, functions and therapeutic applications].

    Science.gov (United States)

    Lorion, R; Bladou, F; Spatz, A; van Kempen, L; Irani, J

    2016-06-01

    In the field of prostate cancer there is a growing tendency for more and more studies to emphasise the predominant role of the zone situated between the tumour and the host: the tumour microenvironment. The aim of this article is to describe the structure and the functions of the prostate cancer microenvironment as well as the principal treatments that are being applied to it. PubMed and ScienceDirect databases have been interrogated using the association of keywords "tumour microenvironment" and "neoplasm therapy" along with "microenvironnement tumoral" and "traitements". Of the 593 articles initially found, 50 were finally included. The tumour microenvironment principally includes host elements that are diverted from their primary functions and encourage the development of the tumour. In it we find immunity cells, support tissue as well as vascular and lymphatic neovascularization. Highlighting the major role played by this microenvironment has led to the development of specific treatments, notably antiangiogenic therapy and immunotherapy. The tumour microenvironment, the tumour and the host influence themselves mutually and create a variable situation over time. Improvement of the knowledge of the prostate cancer microenvironment gradually enables us to pass from an approach centred on the tumour to a broader approach to the whole tumoral ecosystem. This enabled the emergence of new treatments whose place in the therapeutic arsenal still need to be found. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  13. The synergistic effects of ω-3 fatty acids and nano-curcumin supplementation on tumor necrosis factor (TNF)-α gene expression and serum level in migraine patients.

    Science.gov (United States)

    Abdolahi, Mina; Tafakhori, Abbas; Togha, Mansoureh; Okhovat, Ali Asghar; Siassi, Feridoun; Eshraghian, Mohammad Reza; Sedighiyan, Mohsen; Djalali, Mona; Mohammadzadeh Honarvar, Niyaz; Djalali, Mahmoud

    2017-06-01

    Migraine is a destabilizing neuroinflammatory disorder characterized by recurrent headache attacks. Evidences show tumor necrosis factor (TNF)-α play a role in neuroimmunity pathogenesis of migraine. TNF-α increase prostanoid production, hyperexcitability of neurons, and nociceptor activation resulted in neuroinflammation and neurogenic pain. ω-3 fatty acids and curcumin exert neuroprotective and anti-inflammatory effects via several mechanisms including suppression of TNF-α gene expression and its serum levels. The aim of this study is an evaluation of synergistic effects of ω-3 fatty acids and nano-curcumin on TNF-α gene expression and serum levels in migraine patients. The present study performed as a clinical trial over a 2 month period included 74 episodic migraine patients in 4 groups and received ω-3 fatty acids, nano-curcumin, and combination of them or placebo. At the start and the end of the study, the gene expression of TNF-α and TNF-α serum levels was measured by real-time PCR and ELISA method, respectively. Our results showed that the combination of ω-3 fatty acids and nano-curcumin downregulated TNF-α messenger RNA (mRNA) significantly in a synergistic manner (P curcumin alone did not show significant reduction either in mRNA or serum levels of TNF-α. In addition, a much greater reduction in attack frequency was found in the combination group (P curcumin supplementation can be considered as a new promising approach in migraine management.

  14. Microenvironment-Centred Dynamics in Aggressive B-Cell Lymphomas

    Directory of Open Access Journals (Sweden)

    Matilde Cacciatore

    2012-01-01

    Full Text Available Aggressive B-cell lymphomas share high proliferative and invasive attitudes and dismal prognosis despite heterogeneous biological features. In the interchained sequence of events leading to cancer progression, neoplastic clone-intrinsic molecular events play a major role. Nevertheless, microenvironment-related cues have progressively come into focus as true determinants for this process. The cancer-associated microenvironment is a complex network of nonneoplastic immune and stromal cells embedded in extracellular components, giving rise to a multifarious crosstalk with neoplastic cells towards the induction of a supportive milieu. The immunological and stromal microenvironments have been classically regarded as essential partners of indolent lymphomas, while considered mainly negligible in the setting of aggressive B-cell lymphomas that, by their nature, are less reliant on external stimuli. By this paper we try to delineate the cardinal microenvironment-centred dynamics exerting an influence over lymphoid clone progression in aggressive B-cell lymphomas.

  15. Tumor microenvironment indoctrination: an emerging hallmark of cancer.

    Science.gov (United States)

    Goetz, Jacky G

    2012-01-01

    Nastiness of cancer does not only reside in the corruption of cancer cells by genetic aberrations that drive their sustained proliferative power--the roots of malignancy--but also in its aptitude to reciprocally sculpt its surrounding environment and cellular stromal ecosystem, in such a way that the corrupted tumor microenvironment becomes a full pro-tumorigenic entity. Such a contribution had been appreciated three decades ago already, with the discovery of tumor angiogenesis and extracellular matrix remodeling. Nevertheless, the recent emergence of the tumor microenvironment as the critical determinant in cancer biology is paralleled by the promising therapeutic potential it carries, opening alternate routes to fight cancer. The study of the tumor microenvironment recruited numerous lead-scientists over the years, with distinct perspectives, and some of them have kindly accepted to contribute to the elaboration of this special issue entitled Tumor microenvironment indoctrination: An emerging hallmark of cancer.

  16. Extractants for uranium recovery from wet phosphoric acid

    International Nuclear Information System (INIS)

    Musikas, C.; Benjelloun, N.; Lours, S.

    1982-01-01

    Synergistic mixtures containing phosphine oxide plus one of the acidic extractants: dialkyldithiophosphoric acid, dialkylthiophosphoric acid and dialkylphosphoric acid have been compared with respect to U(VI) and Fe(III) extraction from wet phosphoric acid. Distribution curves slope analysis showed that U(VI) extraction mechanisms are totally different. It has been found that U(VI) is extracted as: UO 2 (H 2 PO 4 )(DEHDTP)(TOPO) ; UO 2 (H 2 PO 4 )(DBTP)(POX) 2 and UO 2 (DEHP)(HDEHP) 2 TOPO in dodecane solutions containing di 2 ethylhexyldithiophosphoric acid (HDEHDTP) or dibutylthiophosphoric acid (HDBTP) or di-2-ethylhexylphosphoric acid (HDEHP) plus a phosphine oxide (TOPO or dihexylmethoxyoctylphosphine oxide (POX 11)). The synergistic mixtures containing HDEHDTP gave the highest U(VI) distribution coefficients. Back extraction with oxalic solutions can be achieved only with the synergistic mixtures containing the acidic thiophosphoric donors

  17. Engineering Breast Cancer Microenvironments and 3D Bioprinting

    Directory of Open Access Journals (Sweden)

    Jorge A. Belgodere

    2018-05-01

    Full Text Available The extracellular matrix (ECM is a critical cue to direct tumorigenesis and metastasis. Although two-dimensional (2D culture models have been widely employed to understand breast cancer microenvironments over the past several decades, the 2D models still exhibit limited success. Overwhelming evidence supports that three dimensional (3D, physiologically relevant culture models are required to better understand cancer progression and develop more effective treatment. Such platforms should include cancer-specific architectures, relevant physicochemical signals, stromal–cancer cell interactions, immune components, vascular components, and cell-ECM interactions found in patient tumors. This review briefly summarizes how cancer microenvironments (stromal component, cell-ECM interactions, and molecular modulators are defined and what emerging technologies (perfusable scaffold, tumor stiffness, supporting cells within tumors and complex patterning can be utilized to better mimic native-like breast cancer microenvironments. Furthermore, this review emphasizes biophysical properties that differ between primary tumor ECM and tissue sites of metastatic lesions with a focus on matrix modulation of cancer stem cells, providing a rationale for investigation of underexplored ECM proteins that could alter patient prognosis. To engineer breast cancer microenvironments, we categorized technologies into two groups: (1 biochemical factors modulating breast cancer cell-ECM interactions and (2 3D bioprinting methods and its applications to model breast cancer microenvironments. Biochemical factors include matrix-associated proteins, soluble factors, ECMs, and synthetic biomaterials. For the application of 3D bioprinting, we discuss the transition of 2D patterning to 3D scaffolding with various bioprinting technologies to implement biophysical cues to model breast cancer microenvironments.

  18. Making microenvironments: A look into incorporating macromolecular crowding into in vitro experiments, to generate biomimetic microenvironments which are capable of directing cell function for tissue engineering applications.

    Science.gov (United States)

    Benny, Paula; Raghunath, Michael

    2017-01-01

    Biomimetic microenvironments are key components to successful cell culture and tissue engineering in vitro. One of the most accurate biomimetic microenvironments is that made by the cells themselves. Cell-made microenvironments are most similar to the in vivo state as they are cell-specific and produced by the actual cells which reside in that specific microenvironment. However, cell-made microenvironments have been challenging to re-create in vitro due to the lack of extracellular matrix composition, volume and complexity which are required. By applying macromolecular crowding to current cell culture protocols, cell-made microenvironments, or cell-derived matrices, can be generated at significant rates in vitro. In this review, we will examine the causes and effects of macromolecular crowding and how it has been applied in several in vitro systems including tissue engineering.

  19. Dry Eye Management: Targeting the Ocular Surface Microenvironment

    Science.gov (United States)

    Zhang, Xiaobo; Jeyalatha M, Vimalin; Qu, Yangluowa; He, Xin; Ou, Shangkun; Bu, Jinghua; Jia, Changkai; Wang, Junqi; Wu, Han; Liu, Zuguo

    2017-01-01

    Dry eye can damage the ocular surface and result in mild corneal epithelial defect to blinding corneal pannus formation and squamous metaplasia. Significant progress in the treatment of dry eye has been made in the last two decades; progressing from lubricating and hydrating the ocular surface with artificial tear to stimulating tear secretion; anti-inflammation and immune regulation. With the increase in knowledge regarding the pathophysiology of dry eye, we propose in this review the concept of ocular surface microenvironment. Various components of the microenvironment contribute to the homeostasis of ocular surface. Compromise in one or more components can result in homeostasis disruption of ocular surface leading to dry eye disease. Complete evaluation of the microenvironment component changes in dry eye patients will not only lead to appropriate diagnosis, but also guide in timely and effective clinical management. Successful treatment of dry eye should be aimed to restore the homeostasis of the ocular surface microenvironment. PMID:28661456

  20. Dry Eye Management: Targeting the Ocular Surface Microenvironment.

    Science.gov (United States)

    Zhang, Xiaobo; M, Vimalin Jeyalatha; Qu, Yangluowa; He, Xin; Ou, Shangkun; Bu, Jinghua; Jia, Changkai; Wang, Junqi; Wu, Han; Liu, Zuguo; Li, Wei

    2017-06-29

    Dry eye can damage the ocular surface and result in mild corneal epithelial defect to blinding corneal pannus formation and squamous metaplasia. Significant progress in the treatment of dry eye has been made in the last two decades; progressing from lubricating and hydrating the ocular surface with artificial tear to stimulating tear secretion; anti-inflammation and immune regulation. With the increase in knowledge regarding the pathophysiology of dry eye, we propose in this review the concept of ocular surface microenvironment. Various components of the microenvironment contribute to the homeostasis of ocular surface. Compromise in one or more components can result in homeostasis disruption of ocular surface leading to dry eye disease. Complete evaluation of the microenvironment component changes in dry eye patients will not only lead to appropriate diagnosis, but also guide in timely and effective clinical management. Successful treatment of dry eye should be aimed to restore the homeostasis of the ocular surface microenvironment.

  1. Age-related inflammatory bone marrow microenvironment induces ineffective erythropoiesis mimicking del(5q) MDS.

    Science.gov (United States)

    Mei, Y; Zhao, B; Basiorka, A A; Yang, J; Cao, L; Zhang, J; List, A; Ji, P

    2018-04-01

    Anemia is characteristic of myelodysplastic syndromes (MDS). The mechanisms of anemia in MDS are unclear. Using a mouse genetic approach, here we show that dual deficiency of mDia1 and miR-146a, encoded on chromosome 5q and commonly deleted in MDS (del(5q) MDS), causes an age-related anemia and ineffective erythropoiesis mimicking human MDS. We demonstrate that the ageing bone marrow microenvironment is important for the development of ineffective erythropoiesis in these mice. Damage-associated molecular pattern molecules (DAMPs), whose levels increase in ageing bone marrow, induced TNFα and IL-6 upregulation in myeloid-derived suppressor cells (MDSCs) in mDia1/miR-146a double knockout mice. Mechanistically, we reveal that pathologic levels of TNFα and IL-6 inhibit erythroid colony formation and differentially affect terminal erythropoiesis through reactive oxygen species-induced caspase-3 activation and apoptosis. Treatment of the mDia1/miR-146a double knockout mice with all-trans retinoic acid, which promoted the differentiation of MDSCs and ameliorated the inflammatory bone marrow microenvironment, significantly rescued anemia and ineffective erythropoiesis. Our study underscores the dual roles of the ageing microenvironment and genetic abnormalities in the pathogenesis of ineffective erythropoiesis in del(5q) MDS.

  2. Bioengineering Embryonic Stem Cell Microenvironments for the Study of Breast Cancer

    Directory of Open Access Journals (Sweden)

    Yubing Xie

    2011-11-01

    Full Text Available Breast cancer is the most prevalent disease amongst women worldwide and metastasis is the main cause of death due to breast cancer. Metastatic breast cancer cells and embryonic stem (ES cells display similar characteristics. However, unlike metastatic breast cancer cells, ES cells are nonmalignant. Furthermore, embryonic microenvironments have the potential to convert metastatic breast cancer cells into a less invasive phenotype. The creation of in vitro embryonic microenvironments will enable better understanding of ES cell-breast cancer cell interactions, help elucidate tumorigenesis, and lead to the restriction of breast cancer metastasis. In this article, we will present the characteristics of breast cancer cells and ES cells as well as their microenvironments, importance of embryonic microenvironments in inhibiting tumorigenesis, convergence of tumorigenic and embryonic signaling pathways, and state of the art in bioengineering embryonic microenvironments for breast cancer research. Additionally, the potential application of bioengineered embryonic microenvironments for the prevention and treatment of invasive breast cancer will be discussed.

  3. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism.

    Science.gov (United States)

    Zhao, Hongyun; Yang, Lifeng; Baddour, Joelle; Achreja, Abhinav; Bernard, Vincent; Moss, Tyler; Marini, Juan C; Tudawe, Thavisha; Seviour, Elena G; San Lucas, F Anthony; Alvarez, Hector; Gupta, Sonal; Maiti, Sourindra N; Cooper, Laurence; Peehl, Donna; Ram, Prahlad T; Maitra, Anirban; Nagrath, Deepak

    2016-02-27

    Cancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers. Altered cellular metabolism is a hallmark of cancer, and much of the published literature has focused on neoplastic cell-autonomous processes for these adaptations. We demonstrate that exosomes secreted by patient-derived CAFs can strikingly reprogram the metabolic machinery following their uptake by cancer cells. We find that CAF-derived exosomes (CDEs) inhibit mitochondrial oxidative phosphorylation, thereby increasing glycolysis and glutamine-dependent reductive carboxylation in cancer cells. Through 13C-labeled isotope labeling experiments we elucidate that exosomes supply amino acids to nutrient-deprived cancer cells in a mechanism similar to macropinocytosis, albeit without the previously described dependence on oncogenic-Kras signaling. Using intra-exosomal metabolomics, we provide compelling evidence that CDEs contain intact metabolites, including amino acids, lipids, and TCA-cycle intermediates that are avidly utilized by cancer cells for central carbon metabolism and promoting tumor growth under nutrient deprivation or nutrient stressed conditions.

  4. Fatty acid, carotenoid and tocopherol compositions of 20 Canadian lentil cultivars and synergistic contribution to antioxidant activities.

    Science.gov (United States)

    Zhang, Bing; Deng, Zeyuan; Tang, Yao; Chen, Peter; Liu, Ronghua; Ramdath, D Dan; Liu, Qiang; Hernandez, Marta; Tsao, Rong

    2014-10-15

    Understanding the profile of lipophilic phytochemicals in lentils is necessary to better understand the health benefits of lentils. The fatty acid, carotenoid and tocopherol compositions and antioxidant activities of the lipophilic extracts of 20 lentil cultivars (10 red and 10 green) were therefore examined. Lentils contained 1.52-2.95% lipids, of which 77.5-81.7% were unsaturated essential fatty acids. Total tocopherols ranged from 37 to 64μg/g DW, predominantly γ-tocopherol (96-98% of the tocopherol content), followed by δ- and α-tocopherol. trans-Lutein was the primary and major carotenoid (64-78%) followed by trans-zeaxanthin (5-13%). Carotenoids and tocopherols showed weak correlation with 2,2-diphenyl-1-picrylhydrazyl (DPPH) activity (r=0.4893 and 0.3259, respectively), but good correlation when combined (r=0.6688), suggesting they may act synergistically. Carotenoids were found to contribute the most to the strong antioxidant activity measured by photochemiluminescence (PCL) assay. Results from this study contribute to the development of lentil cultivars and related functional foods with increased health benefits. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

  5. Extra-pancreatic invasion induces lipolytic and fibrotic changes in the adipose microenvironment, with released fatty acids enhancing the invasiveness of pancreatic cancer cells

    Science.gov (United States)

    Okumura, Takashi; Ohuchida, Kenoki; Sada, Masafumi; Abe, Toshiya; Endo, Sho; Koikawa, Kazuhiro; Iwamoto, Chika; Miura, Daisuke; Mizuuchi, Yusuke; Moriyama, Taiki; Nakata, Kohei; Miyasaka, Yoshihiro; Manabe, Tatsuya; Ohtsuka, Takao; Nagai, Eishi; Mizumoto, Kazuhiro; Oda, Yoshinao; Hashizume, Makoto; Nakamura, Masafumi

    2017-01-01

    Pancreatic cancer progression involves components of the tumor microenvironment, including stellate cells, immune cells, endothelial cells, and the extracellular matrix. Although peripancreatic fat is the main stromal component involved in extra-pancreatic invasion, its roles in local invasion and metastasis of pancreatic cancer remain unclear. This study investigated the role of adipose tissue in pancreatic cancer progression using genetically engineered mice (Pdx1-Cre; LSL-KrasG12D; Trp53R172H/+) and an in vitro model of organotypic fat invasion. Mice fed a high fat diet had significantly larger primary pancreatic tumors and a significantly higher rate of distant organ metastasis than mice fed a standard diet. In the organotypic fat invasion model, pancreatic cancer cell clusters were smaller and more elongated in shape and showed increased fibrosis. Adipose tissue-derived conditioned medium enhanced pancreatic cancer cell invasiveness and gemcitabine resistance, as well as inducing morphologic changes in cancer cells and increasing the numbers of lipid droplets in their cytoplasm. The concentrations of oleic, palmitoleic, and linoleic acids were higher in adipose tissue-derived conditioned medium than in normal medium, with these fatty acids significantly enhancing the migration of cancer cells. Mature adipocytes were smaller and the concentration of fatty acids in the medium higher when these cells were co-cultured with cancer cells. These findings indicate that lipolytic and fibrotic changes in peripancreatic adipose tissue enhance local invasiveness and metastasis via adipocyte-released fatty acids. Inhibition of fatty acid uptake by cancer cells may be a novel therapy targeting interactions between cancer and stromal cells. PMID:28407685

  6. Synergistic Diazo-OH Insertion/Conia-Ene Cascade Catalysis for the Stereoselective Synthesis of γ-Butyrolactones and Tetrahydrofurans.

    Science.gov (United States)

    Hunter, Arianne C; Schlitzer, Steven C; Sharma, Indrajeet

    2016-11-02

    A novel and highly efficient diazo-OH insertion/Conia-ene cascade reaction of readily available homopropargylic acids and alcohols with diazo carbonyl compounds is described. The cascade reaction involves a synergistic Rh/Ag/Au catalyst cocktail and proceeds instantly with a variety of substituted diazo compounds and acids/alcohols to provide functionalized γ-butyrolactones and tetrahydrofurans with complete regio- and stereoselectivity. The unprecedented rate-enhancement, complete stereoselectivity, and the enabling of new Conia-ene cyclizations suggest a concerted [4+1]-cycloaddition reaction pathway under synergistic (Rh/Ag/Au)-catalysis conditions. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Metabolomics of the tumor microenvironment in pediatric acute lymphoblastic leukemia.

    Directory of Open Access Journals (Sweden)

    Stefano Tiziani

    Full Text Available The tumor microenvironment is emerging as an important therapeutic target. Most studies, however, are focused on the protein components, and relatively little is known of how the microenvironmental metabolome might influence tumor survival. In this study, we examined the metabolic profiles of paired bone marrow (BM and peripheral blood (PB samples from 10 children with acute lymphoblastic leukemia (ALL. BM and PB samples from the same patient were collected at the time of diagnosis and after 29 days of induction therapy, at which point all patients were in remission. We employed two analytical platforms, high-resolution magnetic resonance spectroscopy and gas chromatography-mass spectrometry, to identify and quantify 102 metabolites in the BM and PB. Standard ALL therapy, which includes l-asparaginase, completely removed circulating asparagine, but not glutamine. Statistical analyses of metabolite correlations and network reconstructions showed that the untreated BM microenvironment was characterized by a significant network-level signature: a cluster of highly correlated lipids and metabolites involved in lipid metabolism (p<0.006. In contrast, the strongest correlations in the BM upon remission were observed among amino acid metabolites and derivatives (p<9.2 × 10(-10. This study provides evidence that metabolic characterization of the cancer niche could generate new hypotheses for the development of cancer therapies.

  8. Synergistic apoptotic response between valproic acid and fludarabine in chronic lymphocytic leukaemia (CLL) cells involves the lysosomal protease cathepsin B

    International Nuclear Information System (INIS)

    Yoon, J-Y; Szwajcer, D; Ishdorj, G; Benjaminson, P; Xiao, W; Kumar, R; Johnston, J B; Gibson, S B

    2013-01-01

    Fludarabine, a nucleoside analogue, is commonly used in combination with other agents for the treatment of chronic lymphocytic leukaemia (CLL). In previous studies, valproic acid (VPA), an inhibitor of histone deacetylases, combined with fludarabine to synergistically increase apoptotic cell death in CLL cells. In the present study, we found that the combination of fludarabine and VPA decreases the level of the anti-apoptotic proteins Mcl-1 and XIAP in primary CLL cells. Treatment with fludarabine alone, or in combination with VPA, led to the loss of lysosome integrity, and chemical inhibition of the lysosomal protease cathepsin B, using CA074-Me, was sufficient to reduce apoptosis. VPA treatment increased cathepsin B levels and activities in primary CLL cells, thereby priming CLL cells for lysosome-mediated cell death. Six previously treated patients with relapsed CLL were treated with VPA, followed by VPA/fludarabine combination. The combined therapy resulted in reduced lymphocyte count in five out of six and reduced lymph node sizes in four out of six patients. In vivo VPA treatment increased histone-3 acetylation and cathepsin B expression levels. Thus, the synergistic apoptotic response with VPA and fludarabine in CLL is mediated by cathepsin B activation leading to a decrease in the anti-apoptotic proteins

  9. Synergism between hydrogen peroxide and seventeen acids against six bacterial strains.

    Science.gov (United States)

    Martin, H; Maris, P

    2012-09-01

    The objective of this study was to evaluate the bactericidal 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 were reference strains and strains representative of contaminating bacteria in the food industry. Each synergistic hydrogen peroxide/acid combination found after 5-min contact time at 20°C in distilled water was then tested in conditions simulating four different use conditions. Thirty-two combinations were synergistic in distilled water; twenty-five of these remained synergistic with one or more of the four mineral and organic interfering substances selected. Hydrogen peroxide/formic acid combination was synergistic for all six bacterial strains in distilled water and remained synergistic with interfering substances. Six other combinations maintained their synergistic effect in the presence of an organic load but only for one or two bacterial strains. Synergistic combinations of disinfectants were revealed, among them the promising hydrogen peroxide/formic acid combination. A rapid screening method was proposed and used to reveal the synergistic potential of disinfectant and/or sanitizer combinations. © 2012 ANSES Fougères Laboratory Journal of Applied Microbiology © 2012 The Society for Applied Microbiology.

  10. Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Jaehong Kim

    2016-01-01

    Full Text Available Distinct tumor microenvironment forms in each progression step of cancer and has diverse capacities to induce both adverse and beneficial consequences for tumorigenesis. It is now known that immune cells can be activated to favor tumor growth and progression, most probably influenced by the tumor microenvironment. Tumor-associated macrophages and tumor-associated neutrophils can exert protumoral functions, enhancing tumor cell invasion and metastasis, angiogenesis, and extracellular matrix remodeling, while inhibiting the antitumoral immune surveillance. Considering that neutrophils in inflammatory environments recruit macrophages and that recruited macrophages affect neutrophil functions, there may be various degrees of interaction between tumor-associated macrophages and tumor-associated neutrophils. Platelets also play an important role in the recruitment and regulation of monocytic and granulocytic cells in the tumor tissues, suggesting that platelet function may be essential for generation of tumor-associated macrophages and tumor-associated neutrophils. In this review, we will explore the biology of tumor-associated macrophages and tumor-associated neutrophils and their possible interactions in the tumor microenvironment. Special attention will be given to the recruitment and activation of these tumor-associated cells and to the roles they play in maintenance of the tumor microenvironment and progression of tumors.

  11. Tumor Biology and Microenvironment Research

    Science.gov (United States)

    Part of NCI's Division of Cancer Biology's research portfolio, research in this area seeks to understand the role of tumor cells and the tumor microenvironment (TME) in driving cancer initiation, progression, maintenance and recurrence.

  12. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism

    Science.gov (United States)

    Zhao, Hongyun; Yang, Lifeng; Baddour, Joelle; Achreja, Abhinav; Bernard, Vincent; Moss, Tyler; Marini, Juan C; Tudawe, Thavisha; Seviour, Elena G; San Lucas, F Anthony; Alvarez, Hector; Gupta, Sonal; Maiti, Sourindra N; Cooper, Laurence; Peehl, Donna; Ram, Prahlad T; Maitra, Anirban; Nagrath, Deepak

    2016-01-01

    Cancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers. Altered cellular metabolism is a hallmark of cancer, and much of the published literature has focused on neoplastic cell-autonomous processes for these adaptations. We demonstrate that exosomes secreted by patient-derived CAFs can strikingly reprogram the metabolic machinery following their uptake by cancer cells. We find that CAF-derived exosomes (CDEs) inhibit mitochondrial oxidative phosphorylation, thereby increasing glycolysis and glutamine-dependent reductive carboxylation in cancer cells. Through 13C-labeled isotope labeling experiments we elucidate that exosomes supply amino acids to nutrient-deprived cancer cells in a mechanism similar to macropinocytosis, albeit without the previously described dependence on oncogenic-Kras signaling. Using intra-exosomal metabolomics, we provide compelling evidence that CDEs contain intact metabolites, including amino acids, lipids, and TCA-cycle intermediates that are avidly utilized by cancer cells for central carbon metabolism and promoting tumor growth under nutrient deprivation or nutrient stressed conditions. DOI: http://dx.doi.org/10.7554/eLife.10250.001 PMID:26920219

  13. Development and characterization of a microfluidic model of the tumour microenvironment.

    Science.gov (United States)

    Ayuso, Jose M; Virumbrales-Muñoz, María; Lacueva, Alodia; Lanuza, Pilar M; Checa-Chavarria, Elisa; Botella, Pablo; Fernández, Eduardo; Doblare, Manuel; Allison, Simon J; Phillips, Roger M; Pardo, Julián; Fernandez, Luis J; Ochoa, Ignacio

    2016-10-31

    The physical microenvironment of tumours is characterized by heterotypic cell interactions and physiological gradients of nutrients, waste products and oxygen. This tumour microenvironment has a major impact on the biology of cancer cells and their response to chemotherapeutic agents. Despite this, most in vitro cancer research still relies primarily on cells grown in 2D and in isolation in nutrient- and oxygen-rich conditions. Here, a microfluidic device is presented that is easy to use and enables modelling and study of the tumour microenvironment in real-time. The versatility of this microfluidic platform allows for different aspects of the microenvironment to be monitored and dissected. This is exemplified here by real-time profiling of oxygen and glucose concentrations inside the device as well as effects on cell proliferation and growth, ROS generation and apoptosis. Heterotypic cell interactions were also studied. The device provides a live 'window' into the microenvironment and could be used to study cancer cells for which it is difficult to generate tumour spheroids. Another major application of the device is the study of effects of the microenvironment on cellular drug responses. Some data is presented for this indicating the device's potential to enable more physiological in vitro drug screening.

  14. Tumor Acidity as Evolutionary Spite

    International Nuclear Information System (INIS)

    Alfarouk, Khalid O.; Muddathir, Abdel Khalig; Shayoub, Mohammed E. A.

    2011-01-01

    Most cancer cells shift their metabolic pathway from a metabolism reflecting the Pasteur-effect into one reflecting the Warburg-effect. This shift creates an acidic microenvironment around the tumor and becomes the driving force for a positive carcinogenesis feedback loop. As a consequence of tumor acidity, the tumor microenvironment encourages a selection of certain cell phenotypes that are able to survive in this caustic environment to the detriment of other cell types. This selection can be described by a process which can be modeled upon spite: the tumor cells reduce their own fitness by making an acidic environment, but this reduces the fitness of their competitors to an even greater extent. Moreover, the environment is an important dimension that further drives this spite process. Thus, diminishing the selective environment most probably interferes with the spite process. Such interference has been recently utilized in cancer treatment

  15. Impact of the ovarian microenvironment on serous cancer

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-14-1-0182 TITLE: Impact of the ovarian microenvironment on serous cancer PRINCIPAL INVESTIGATOR: Joanna E. Burdette...Impact of the ovarian microenvironment on serous cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0182 5c. PROGRAM ELEMENT NUMBER 6...for intervention that would block serous cancer while still confined to the fallopian tubes. Using a series of normal, modified, and tumorigenic tubal

  16. Synergistic extraction of gold from sulfuric acid solution containing thiourea. Ryusan sansei chio nyoso yoeki kara no kin no kyodo chushutsu

    Energy Technology Data Exchange (ETDEWEB)

    Niinae, M.; Nakahiro, Y.; Wakamatsu, T. (Kyoto Univ., Kyoto (Japan). Faculty of Engineering); Oboso, A. (Kyoto Univ., Kyoto (Japan). Graduate School); Takenaka, Y. (Kyoto Univ., Kyoto (Japan))

    1991-08-20

    Solvent extraction was investigated as a method of recovering Au from sulfuric acid solution containing thiourea. With the objective of improving Au extraction by die-(2-ethylhexyl) phosphoric acid (D2EHPA) and tri-n-octylamine (TOA), effects of D2EHPA, TOA, TBP (tri-n-butyl phosphate), and trioctyl phosphine oxide (TOPO) as extractants were investigated. When mixed extractant of D2EHPA with TBP or TOPO, or mixture of TOA with TBP or TOPO was used, synergistic effect was observed for the extraction of AU, and they were proved to be effective for the improvement of Au extraction. When D2EHPA/TBP and D2EHPA/TOPO mixtures were used, the extraction of Fe was suppressed on the contrary, and they were found to be effective for the separation of Au and Fe. Benzene used as diluent seemed to be favorable to both the extraction of Au and the separation of Au and Fe. The selection of sulfuric acid concentration seemed to be an important factor for the extraction efficiency of Au and the separation efficiency of Au and Fe, while little effect was observed with the concentration of thiourea. 4 refs., 8 figs., 4 tabs.

  17. Synergistic enhancement of ethylene production and germination with kinetin and 1-aminocyclopropane-1-carboxylic Acid in lettuce seeds exposed to salinity stress.

    Science.gov (United States)

    Khan, A A; Huang, X L

    1988-08-01

    Relief of salt (0.1 molar NaCl) stress on germination of lettuce (Lactuca sativa L., cv Mesa 659) seeds occurred with applications of 0.05 millimolar kinetin (KIN) and 1 to 10 millimolar 1-aminocyclopropane 1-carboxylic acid (ACC). Treatment with KIN enhanced the pregermination ethylene production under saline condition. A synergistic or an additive enhancement of pregermination ethylene production and germination occurred under saline condition in the presence of KIN and a saturating dose (10 millimolar) of ACC. No KIN-ACC synergism was noted in ethylene production or germination under nonsaline condition. Addition of 1 millimolar aminoethoxyvinylglycine (AVG) inhibited the KIN-enhanced pregermination ethylene production (85 to 89%) and germination (58%) under saline condition but not the synergistic effect of KIN + ACC on ethylene production. Under nonsaline condition, AVG had no effect on germination even though ethylene production was strongly inhibited. Alleviation of salt stress by KIN was inhibited in a competitive manner by 2,5-norbornadiene (NBD) (0.02-0.2 milliliter per liter), and the addition of ACC and/or ethylene reduced this inhibition. An increase in the pregermination ethylene production and germination occurred also by cotylenin E (CN) under saline condition. However, neither AVG (1 millimolar) nor NBD (0.02 to 0.2 milliliter per liter) prevented the relief of salt stress by CN. Thus, KIN may alleviate salt stress on germination by promoting both ACC production and its conversion to ethylene. Rapid utilization of ACC may be the basis for the synergistic or the additive effect of KIN plus ACC. The need for ethylene production and action for the relief of salt stress is circumvented by a treatment with CN.

  18. Synergistic protective role of mirazid (Commiphora molmol) and ascorbic acid against tilmicosin-induced cardiotoxicity in mice.

    Science.gov (United States)

    Abdel-Daim, Mohamed M; Ghazy, Emad W; Fayez, Mostafa

    2015-01-01

    Tilmicosin (TIL) is a long-acting macrolide antibiotic approved for the treatment of cattle with Bovine Respiratory Disease. However, overdose of TIL has been reported to induce cardiotoxicity. The purpose of our experiment was to evaluate the protective effects of Commiphora molmol (mirazid (MRZ); myrrh) and (or) ascorbic acid (AA) against TIL-induced cardiotoxicity in mice. MRZ and AA were orally administered using stomach gavage, either alone or in combination for 5 consecutive days, followed with a single TIL overdose. TIL overdose induced a significant increase in serum levels of cardiac damage biomarkers (AST, LDH, CK, CK-MB, and cTnT), as well as cardiac lipid peroxidation, but cardiac levels of antioxidant biomarkers (GSH, SOD, CAT, and TAC) were decreased. Both MRZ and AA tended to normalize the elevated serum levels of cardiac injury biomarkers. Furthermore, MRZ and AA reduced TIL-induced lipid peroxidation and oxidative stress parameters. MRZ and AA combined produced a synergistic cardioprotective effect. We conclude that myrrh and (or) vitamin C administration minimizes the toxic effects of TIL through their free-radical-scavenging and potent antioxidant activities.

  19. Schinus terebinthifolius Raddi extract and linoleic acid from Passiflora edulis synergistically decrease melanin synthesis in B16 cells and reconstituted epidermis.

    Science.gov (United States)

    Jorge, A T S; Arroteia, K F; Santos, I A; Andres, E; Medina, S P H; Ferrari, C R; Lourenço, C B; Biaggio, R M T T; Moreira, P L

    2012-10-01

    Several treatments for skin whitening are available today, but few of them are completely adequate, especially owing to the carcinogenic potential attributed to classical drugs like hydroquinone, arbutin and kojic acid. To provide an alternative and safer technology for whitening, we developed two botanical compounds originated from Brazilian biodiversity, an extract of Schinus terebinthifolius Raddi and a linoleic acid fraction isolated from Passiflora edulis oil. The whitening effect of these compounds was assessed using biochemical assays and in vitro models including cellular assays and equivalent skin. The results showed that S. terebinthifolius Raddi extract is able to reduce the tyrosinase activity in vitro, and the combination of this extract with linoleic acid is able to decrease the level of melanin produced by B16 cells cultured with melanocyte-stimulating hormone. Furthermore, melanin was also reduced in human reconstituted epidermis (containing melanocytes) treated with the compounds. The combination of the compounds may provide a synergistic positive whitening effect rather than their isolated use. Finally, we demonstrated that the performance of these mixed compounds is comparable to classical molecules used for skin whitening, as kojic acid. This new natural mixture could be considered an alternative therapeutic agent for treating hyperpigmentation and an effective component in whitening cosmetics. © 2012 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

  20. Synergistic effects of intravenous and intra-articular tranexamic acid on reducing hemoglobin loss in revision total knee arthroplasty: a prospective, randomized, controlled study.

    Science.gov (United States)

    Yuan, Xiangwei; Wang, Jiaxing; Wang, Qiaojie; Zhang, Xianlong

    2018-04-01

    Tranexamic acid decreases blood loss in primary total knee arthroplasty, and no related prospective randomized clinical trials have been conducted to evaluate the effectiveness and safety of tranexamic acid in revision total knee arthroplasty. Thus, we conducted this work to evaluate the synergistic effects of intravenous plus intra-articular tranexamic acid on reducing hemoglobin loss compared with intra-articular tranexamic acid alone in revision total knee arthroplasty. This prospective, controlled study randomized 96 patients undergoing revision total knee arthroplasty into two groups: an intravenous plus intra-articular tranexamic acid group (48 patients who received 20 mg/kg intravenous tranexamic acid and 3.0 g intra-articular tranexamic acid); and an intra-articular tranexamic acid alone group (48 patients who received the same intravenous volume of normal saline and 3.0 g intra-articular tranexamic acid). The primary outcome was hemoglobin loss. Secondary outcomes included the volume of drain output, the percentage of patients who received transfusions, the number of units transfused, and thromboembolic events. The baseline data, preoperative hemoglobin, and tourniquet time were similar in both groups. There was significantly less hemoglobin loss in the intravenous plus intra-articular tranexamic acid group compared with the intra-articular tranexamic acid alone group (2.7 ± 0.6 g/dL and 3.7 ± 0.7 g/dL; p tranexamic acid alone group, the intravenous plus intra-articular tranexamic acid group also had significantly less drain output, fewer patients who received transfusions, and fewer units transfused (all p tranexamic acid alone, combined intravenous plus intra-articular tranexamic acid significantly reduced hemoglobin loss and the need for transfusion without an apparent increase in thromboembolic events in patients who underwent revision total knee arthroplasty. © 2018 AABB.

  1. Cellular immobilization within microfluidic microenvironments: dielectrophoresis with polyelectrolyte multilayers.

    Science.gov (United States)

    Forry, Samuel P; Reyes, Darwin R; Gaitan, Michael; Locascio, Laurie E

    2006-10-25

    The development of biomimetic microenvironments will improve cell culture techniques by enabling in vitro cell cultures that mimic in vivo behavior; however, experimental control over attachment, cellular position, or intercellular distances within such microenvironments remains challenging. We report here the rapid and controllable immobilization of suspended mammalian cells within microfabricated environments using a combination of electronic (dielectrophoresis, DEP) and chemical (polyelectrolyte multilayers, PEMS) forces. While cellular position within the microsystem is rapidly patterned via intermittent DEP trapping, persistent adhesion after removal of electronic forces is enabled by surface treatment with PEMS that are amenable to cellular attachment. In contrast to DEP trapping alone, persistent adhesion enables the soluble microenvironment to be systematically varied, facilitating the use of soluble probes of cell state and enabling cellular characterization in response to various soluble stimuli.

  2. The PCa Tumor Microenvironment.

    Science.gov (United States)

    Sottnik, Joseph L; Zhang, Jian; Macoska, Jill A; Keller, Evan T

    2011-12-01

    The tumor microenvironment (TME) is a very complex niche that consists of multiple cell types, supportive matrix and soluble factors. Cells in the TME consist of both host cells that are present at tumor site at the onset of tumor growth and cells that are recruited in either response to tumor- or host-derived factors. PCa (PCa) thrives on crosstalk between tumor cells and the TME. Crosstalk results in an orchestrated evolution of both the tumor and microenvironment as the tumor progresses. The TME reacts to PCa-produced soluble factors as well as direct interaction with PCa cells. In return, the TME produces soluble factors, structural support and direct contact interactions that influence the establishment and progression of PCa. In this review, we focus on the host side of the equation to provide a foundation for understanding how different aspects of the TME contribute to PCa progression. We discuss immune effector cells, specialized niches, such as the vascular and bone marrow, and several key protein factors that mediate host effects on PCa. This discussion highlights the concept that the TME offers a potentially very fertile target for PCa therapy.

  3. Ascorbic Acid-Induced Cardiac Differentiation of Murine Pluripotent Stem Cells: Transcriptional Profiling and Effect of a Small Molecule Synergist of Wnt/β-Catenin Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Dina Ivanyuk

    2015-05-01

    Full Text Available Background: Reproducible and efficient differentiation of pluripotent stem cells (PSCs to cardiomyocytes (CMs is essential for their use in regenerative medicine, drug testing and disease modeling. The aim of this study was to evaluate the effect of some previously reported cardiogenic substances on cardiac differentiation of mouse PSCs. Methods: Differentiation was performed by embryoid body (EB-based method using three different murine PSC lines. The differentiation efficiency was monitored by RT-qPCR, immunocytochemistry and flow cytometry, and the effect mechanistically evaluated by transcriptome analysis of treated EBs. Results: Among the five tested compounds (ascorbic acid, dorsomorphin, cyclic adenosine 3',5'-monophosphate, cardiogenol C, cyclosporin A only ascorbic acid (AA exerted a strong and reproducible cardiogenic effect in CGR8 cells which was less consistent in other two PSC lines. AA induced only minor changes in transcriptome of CGR8 cells after administration during the initial two days of differentiation. Cardiospecific genes and transcripts involved in angiogenesis, erythropoiesis and hematopoiesis were up-regulated on day 5 but not on days 2 or 3 of differentiation. The cardiac differentiation efficiency was improved when QS11, a small-molecule synergist of Wnt/β-catenin signaling pathway, was added to cultures after AA-treatment. Conclusion: This study demonstrates that only minor transcriptional changes are sufficient for enhancement of cardiogenesis of murine PSCs by AA and that AA and QS11 exhibit synergistic effects and enhance the efficiency of CM differentiation of murine PSCs.

  4. Review of microfluidic cell culture devices for the control of gaseous microenvironments in vitro

    Science.gov (United States)

    Wu, H.-M.; Lee, T.-A.; Ko, P.-L.; Chiang, H.-J.; Peng, C.-C.; Tung, Y.-C.

    2018-04-01

    Gaseous microenvironments play important roles in various biological activities in vivo. However, it is challenging to precisely control gaseous microenvironments in vitro for cell culture due to the high diffusivity nature of gases. In recent years, microfluidics has paved the way for the development of new types of cell culture devices capable of manipulating cellular microenvironments, and provides a powerful tool for in vitro cell studies. This paper reviews recent developments of microfluidic cell culture devices for the control of gaseous microenvironments, and discusses the advantages and limitations of current devices. We conclude with suggestions for the future development of microfluidic cell culture devices for the control of gaseous microenvironments.

  5. Bioinspired Hydrogels to Engineer Cancer Microenvironments.

    Science.gov (United States)

    Park, Kyung Min; Lewis, Daniel; Gerecht, Sharon

    2017-06-21

    Recent research has demonstrated that tumor microenvironments play pivotal roles in tumor development and metastasis through various physical, chemical, and biological factors, including extracellular matrix (ECM) composition, matrix remodeling, oxygen tension, pH, cytokines, and matrix stiffness. An emerging trend in cancer research involves the creation of engineered three-dimensional tumor models using bioinspired hydrogels that accurately recapitulate the native tumor microenvironment. With recent advances in materials engineering, many researchers are developing engineered tumor models, which are promising platforms for the study of cancer biology and for screening of therapeutic agents for better clinical outcomes. In this review, we discuss the development and use of polymeric hydrogel materials to engineer native tumor ECMs for cancer research, focusing on emerging technologies in cancer engineering that aim to accelerate clinical outcomes.

  6. Towards an interpretation of the mechanism of the actinides(III)/lanthanides(III) separation by synergistic solvent extraction with nitrogen-containing polydendate ligands

    International Nuclear Information System (INIS)

    Francois, N.

    2000-01-01

    In the field of the separation of long-lived radionuclides from the wastes produced by nuclear fuel reprocessing, aromatic nitrogen-containing polydendate ligands are potential candidates for the selective extraction, alone or in synergistic mixture with acidic extractants, of trivalent actinides from trivalent lanthanides. The first part of this work deals with the complexation of trivalent f cations with various nitrogen-containing ligands (poly-pyridine analogues). Time-resolved laser-induced fluorimetry (TRLIF) and UV-visible spectrophotometry were used to determine the nature and evaluate the stability of each complex. Among the ligands studied, the least basic Me-Btp proved to be highly selective towards americium(III) in acidic solution. In the second part, two synergistic systems (nitrogen-containing polydendate ligand and lipophilic carboxylic acid) are studied and compared in regard to the extraction and separation of lanthanides(III) and actinides(III). TRLIF and gamma spectrometry allowed the nature of the extracted complexes and the optimal conditions of efficiency of both systems to be determined. Comparison between these different studies showed that the selectivity of complexation of trivalent f cations by a given nitrogen-containing polydendate ligand could not always be linked to the Am(III)Eu(III) selectivity reached in synergistic extraction. The latter depends on the 'balance' between the acid-basic properties on the one hand, and on the hard-soft characteristics on the other hand, of both components of synergistic system. (author)

  7. Proteomic analysis of Taenia hydatigena cyst fluid reveals unique internal microenvironment.

    Science.gov (United States)

    Zheng, Yadong

    2017-12-01

    Taenia hydatigena is a parasitic flatworm that is widely distributed around the world. Using MS/MS, the proteome of T. hydatigena cyst fluid (CF) was profiled and a total of 520 proteins were identified, 430 of which were of sheep origin. T. hydatigena shared 37 parasite-origin and 109 host-origin CF proteins with Echinococcus granulosus. Compared with E. granulosus, T. hydatigena had much more CF proteins associated with amino acid synthesis and complement cascades. In addition, glutamate metabolism and anti-oxidative reactions were identified as relatively more important events. These results suggest that T. hydatigena metacestodes have internal microenvironment with special immune and oxidative conditions. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Microenvironments and microscale productivity of cyanobacterial desert crusts

    Science.gov (United States)

    Garcia-Pichel, F.; Belnap, Jayne

    1996-01-01

    We used microsensors to characterize physicochemical microenvironments and photosynthesis occurring immediately after water saturation in two desert soil crusts from southeastern Utah, which were formed by the cyanobacteria Microcoleus vaginatus Gomont, Nostoc spp., and Scytonema sp. The light fields within the crusts presented steep vertical gradients in magnitude and spectral composition. Near-surface light-trapping zones were formed due to the scattering nature of the sand particles, but strong light attenuation resulted in euphotic zones only ca. 1 mm deep, which were progressively enriched in longer wavelengths with depth. Rates of gross photosynthesis (3.4a??9.4 mmol O2A?ma??2A?ha??1) and dark respiration (0.81a??3.1 mmol Oa??2A?ma??2A?ha??1) occurring within 1 to several mm from the surface were high enough to drive the formation of marked oxygen microenvironments that ranged from oxygen supersaturation to anoxia. The photosynthetic activity also resulted in localized pH values in excess of 10, 2a??3 units above the soil pH. Differences in metabolic parameters and community structure between two types of crusts were consistent with a successional pattern, which could be partially explained on the basis of the microenvironments. We discuss the significance of high metabolic rates and the formation of microenvironments for the ecology of desert crusts, as well as the advantages and limitations of microsensor-based methods for crust investigation.

  9. Synergism between hydrogen peroxide and seventeen acids against five agri-food-borne fungi and one yeast strain.

    Science.gov (United States)

    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.

  10. Nutrient sensing via mTOR in T cells maintains a tolerogenic microenvironment

    Directory of Open Access Journals (Sweden)

    Duncan eHowie

    2014-08-01

    Full Text Available We have proposed that tolerance can be maintained by the induction, by Treg cells, of a tolerogenic microenvironment within tolerated tissues that inhibits effector cell activity but which supports the generation of further Treg cells by infectious tolerance. Two important components of this tolerogenic microenvironment depend on metabolism and nutrient sensing. The first is due to the up-regulation of multiple enzymes that consume essential amino acids (EAAs, which are sensed in naive T cells primarily via inhibition of the mTOR pathway, which in turn encourages their further differentiation into foxp3+ Treg cells. The second mechanism is the metabolism of extracellular ATP to adenosine by the ectoenzymes CD39 and CD73. These two enzymes are constitutively co-expressed on Treg cells, but can also be induced on a wide variety of cell types by TGFbeta and the adenosine generated can be shown to be a potent inhibitor of T cell proliferation. This review will focus on mechanisms of nutrient sensing in T cells, how these are integrated with TCR and cytokine signals via the mnTOR pathway, and what impact this has on intracellular metabolism and subsequently the control of differentiation into different effector or regulatory T cell subsets.

  11. Synergistic effect of cellulase and xylanase during hydrolysis of natural lignocellulosic substrates.

    Science.gov (United States)

    Song, Hui-Ting; Gao, Yuan; Yang, Yi-Min; Xiao, Wen-Jing; Liu, Shi-Hui; Xia, Wu-Cheng; Liu, Zi-Lu; Yi, Li; Jiang, Zheng-Bing

    2016-11-01

    Synergistic combination of cellulase and xylanase has been performed on pre-treated substrates in many previous studies, while few on natural substrates. In this study, three unpretreated lignocellulosic substrates were studied, including corncob, corn stover, and rice straw. The results indicated that when the mixed cellulase and xylanase were applied, reducing sugar concentrations were calculated as 19.53, 15.56, and 17.35mg/ml, respectively, based on the 3,5 dinitrosalicylic acid (DNS) method. Compared to the treatment with only cellulose, the hydrolysis yields caused by mixed cellulase and xylanase were improved by 133%, 164%, and 545%, respectively. In addition, the conversion yield of corncob, corn stover, and rice straw by cellulase-xylanase co-treatment reached 43.9%, 48.5%, and 40.2%, respectively, based on HPLC analysis, which confirmed the synergistic effect of cellulase-xylanase that was much higher than either of the single enzyme treatment. The substrate morphology was also evaluated to explore the synergistic mechanism of cellulase-xylanase. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Short-Chain Fatty Acids from Periodontal Pathogens Suppress Histone Deacetylases, EZH2, and SUV39H1 To Promote Kaposi's Sarcoma-Associated Herpesvirus Replication

    Science.gov (United States)

    Yu, Xiaolan; Shahir, Abdel-Malek; Sha, Jingfeng; Feng, Zhimin; Eapen, Betty; Nithianantham, Stanley; Das, Biswajit; Karn, Jonathan; Weinberg, Aaron; Bissada, Nabil F.

    2014-01-01

    ABSTRACT Periodontal pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum produce five different short-chain fatty acids (SCFAs) as metabolic by-products. We detect significantly higher levels of SCFAs in the saliva of patients with severe periodontal disease. The different SCFAs stimulate lytic gene expression of Kaposi's sarcoma-associated herpesvirus (KSHV) dose dependently and synergistically. SCFAs inhibit class-1/2 histone deacetylases (HDACs) and downregulate expression of silent information regulator-1 (SIRT1). SCFAs also downregulate expression of enhancer of zeste homolog2 (EZH2) and suppressor of variegation 3-9 homolog1 (SUV39H1), which are two histone N-lysine methyltransferases (HLMTs). By suppressing the different components of host epigenetic regulatory machinery, SCFAs increase histone acetylation and decrease repressive histone trimethylations to transactivate the viral chromatin. These new findings provide mechanistic support that SCFAs from periodontal pathogens stimulate KSHV replication and infection in the oral cavity and are potential risk factors for development of oral Kaposi's sarcoma (KS). IMPORTANCE About 20% of KS patients develop KS lesions first in the oral cavity, while other patients never develop oral KS. It is not known if the oral microenvironment plays a role in oral KS tumor development. In this work, we demonstrate that a group of metabolic by-products, namely, short-chain fatty acids, from bacteria that cause periodontal disease promote lytic replication of KSHV, the etiological agent associated with KS. These new findings provide mechanistic support that periodontal pathogens create a unique microenvironment in the oral cavity that contributes to KSHV replication and development of oral KS. PMID:24501407

  13. Royal Society Scientific Meeting: Extracellular vesicles in the tumour microenvironment.

    Science.gov (United States)

    Pink, Ryan Charles; Elmusrati, Areeg A; Lambert, Daniel; Carter, David Raul Francisco

    2018-01-05

    Cancer cells do not grow as an isolated homogeneous mass; tumours are, in fact, complex and heterogeneous collections of cancer and surrounding stromal cells, collectively termed the tumour microenvironment. The interaction between cancer cells and stromal cells in the tumour microenvironment has emerged as a key concept in the regulation of cancer progression. Understanding the intercellular dialogue in the tumour microenvironment is therefore an important goal. One aspect of this dialogue that has not been appreciated until recently is the role of extracellular vesicles (EVs). EVs are small vesicles released by cells under both normal and pathological conditions; they can transfer biological molecules between cells leading to changes in phenotype. EVs have emerged as important regulators of biological processes and can be dysregulated in diseases such as cancer; rapidly growing interest in their biology and therapeutic potential led to the Royal Society hosting a Scientific Meeting to explore the roles of EVs in the tumour microenvironment. This cross-disciplinary meeting explored examples of how aberrant crosstalk between tumour and stromal cells can promote cancer progression, and how such signalling can be targeted for diagnostic, prognostic and therapeutic benefit. In this review, and the special edition of Philosophical Transactions of the Royal Society B that follows, we will provide an overview of the content and outcomes of this exciting meeting.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'. © 2017 The Author(s).

  14. Multimodal imaging of lung cancer and its microenvironment (Conference Presentation)

    Science.gov (United States)

    Hariri, Lida P.; Niederst, Matthew J.; Mulvey, Hillary; Adams, David C.; Hu, Haichuan; Chico Calero, Isabel; Szabari, Margit V.; Vakoc, Benjamin J.; Hasan, Tayyaba; Bouma, Brett E.; Engelman, Jeffrey A.; Suter, Melissa J.

    2016-03-01

    Despite significant advances in targeted therapies for lung cancer, nearly all patients develop drug resistance within 6-12 months and prognosis remains poor. Developing drug resistance is a progressive process that involves tumor cells and their microenvironment. We hypothesize that microenvironment factors alter tumor growth and response to targeted therapy. We conducted in vitro studies in human EGFR-mutant lung carcinoma cells, and demonstrated that factors secreted from lung fibroblasts results in increased tumor cell survival during targeted therapy with EGFR inhibitor, gefitinib. We also demonstrated that increased environment stiffness results in increased tumor survival during gefitinib therapy. In order to test our hypothesis in vivo, we developed a multimodal optical imaging protocol for preclinical intravital imaging in mouse models to assess tumor and its microenvironment over time. We have successfully conducted multimodal imaging of dorsal skinfold chamber (DSC) window mice implanted with GFP-labeled human EGFR mutant lung carcinoma cells and visualized changes in tumor development and microenvironment facets over time. Multimodal imaging included structural OCT to assess tumor viability and necrosis, polarization-sensitive OCT to measure tissue birefringence for collagen/fibroblast detection, and Doppler OCT to assess tumor vasculature. Confocal imaging was also performed for high-resolution visualization of EGFR-mutant lung cancer cells labeled with GFP, and was coregistered with OCT. Our results demonstrated that stromal support and vascular growth are essential to tumor progression. Multimodal imaging is a useful tool to assess tumor and its microenvironment over time.

  15. Microenvironment of Breast Tissue: Lithocholic Acid and Other Intestinal Steroids

    National Research Council Canada - National Science Library

    Javitt, Norman

    1997-01-01

    Although it is known that bile acids including lithocholic acid are present in breast cyst fluid, analysis by gas-liquid chromatography-mass spectrometry requires the preparation of volatile derivatives...

  16. Immunological dysregulation in multiple myeloma microenvironment.

    Science.gov (United States)

    Romano, Alessandra; Conticello, Concetta; Cavalli, Maide; Vetro, Calogero; La Fauci, Alessia; Parrinello, Nunziatina Laura; Di Raimondo, Francesco

    2014-01-01

    Multiple Myeloma (MM) is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC) in bone marrow (BM). Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extracellular matrix proteins, adhesion molecules, cytokines, and growth factors produced by both stromal cells and PC themselves. All these components are able to protect PC from cytotoxic effect of chemo- and radiotherapy. This review is focused on the role of immunome to sustain MM progression, the emerging role of myeloid derived suppressor cells, and their potential clinical implications as novel therapeutic target.

  17. Immunological Dysregulation in Multiple Myeloma Microenvironment

    Directory of Open Access Journals (Sweden)

    Alessandra Romano

    2014-01-01

    Full Text Available Multiple Myeloma (MM is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC in bone marrow (BM. Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extracellular matrix proteins, adhesion molecules, cytokines, and growth factors produced by both stromal cells and PC themselves. All these components are able to protect PC from cytotoxic effect of chemo- and radiotherapy. This review is focused on the role of immunome to sustain MM progression, the emerging role of myeloid derived suppressor cells, and their potential clinical implications as novel therapeutic target.

  18. Lysyl Oxidase and the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Tong-Hong Wang

    2016-12-01

    Full Text Available The lysyl oxidase (LOX family of oxidases contains a group of extracellular copper-dependent enzymes that catalyze the cross-linking of collagen and elastin by oxidation, thus maintaining the rigidity and structural stability of the extracellular matrix (ECM. Aberrant expression or activation of LOX alters the cellular microenvironment, leading to many diseases, including atherosclerosis, tissue fibrosis, and cancer. Recently, a number of studies have shown that LOX is overexpressed in most cancers and that it is involved in the regulation of tumor progression and metastasis. In contrast, a few reports have also indicated the tumor-suppressing role of LOX. In this short review, we discuss recent research on the correlations between LOX and cancer. Further, the role of LOX in tumor microenvironment remodeling, tumorigenesis, and metastasis and the underlying mechanisms have also been elucidated.

  19. Pd-Pt alloys nanowires as support-less electrocatalyst with high synergistic enhancement in efficiency for methanol oxidation in acidic medium.

    Science.gov (United States)

    Rana, Moumita; Patil, Pramod K; Chhetri, Manjeet; Dileep, K; Datta, Ranjan; Gautam, Ujjal K

    2016-02-01

    In a facile approach, Pd73Pt27 alloy nanowires (NWs) with large aspect ratios were synthesized in high yield by using sacrificial templates. Unlike majority of processes, our synthesis was carried out in aqueous solution with no intermittent separating stages for the products, while maintaining the NW morphology up to ∼30% of Pt. Upon evaporation of their dispersion, the NWs transform into a stable porous membrane due to self-entanglement and can be directly lifted and employed for electrocatalytic applications without external catalyst supports. We show that the NW membranes exhibit efficient electrocatalytic performance for methanol oxidation reaction (MOR) with 10 times higher mass activity and 4.4 times higher specific activity in acidic media as compared to commercial Pt catalysts. The membrane electrocatalysts is robust and exhibited very good stability with retention of ∼70% mass-activity after 4000 potential cycles. Since Pd was found to be inert towards MOR in acidic medium, our investigation provides a direct estimate of synergistic enhancement of efficiency. Over 10 times increment of mass activity appears to be significantly higher than previous investigations in various other reaction media. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Activation of Retinoid X Receptors by Phytanic Acid and Docohexaenoic Acid: Role in the Prevention and Therapy of Prostate Cancer

    National Research Council Canada - National Science Library

    Tang, Xiao-Han

    2005-01-01

    .... Meanwhile, both phytanic acid and DHA inhibited the growth of Pc-3 and LNCaP cells. Phytanic acid and retinoic acid synergistically inhibited the growth of both of these prostate cancer cell lines...

  1. Synergistic Interaction within Bifunctional Ruthenium Nanoparticle/SILP Catalysts for the Selective Hydrodeoxygenation of Phenols.

    Science.gov (United States)

    Luska, Kylie L; Migowski, Pedro; El Sayed, Sami; Leitner, Walter

    2015-12-21

    Ruthenium nanoparticles immobilized on acid-functionalized supported ionic liquid phases (Ru NPs@SILPs) act as efficient bifunctional catalysts in the hydrodeoxygenation of phenolic substrates under batch and continuous flow conditions. A synergistic interaction between the metal sites and acid groups within the bifunctional catalyst leads to enhanced catalytic activities for the overall transformation as compared to the individual steps catalyzed by the separate catalytic functionalities. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Proto-oncogene FBI-1 (Pokemon) and SREBP-1 Synergistically Activate Transcription of Fatty-acid Synthase Gene (FASN)*S⃞

    Science.gov (United States)

    Choi, Won-Il; Jeon, Bu-Nam; Park, Hyejin; Yoo, Jung-Yoon; Kim, Yeon-Sook; Koh, Dong-In; Kim, Myung-Hwa; Kim, Yu-Ri; Lee, Choong-Eun; Kim, Kyung-Sup; Osborne, Timothy F.; Hur, Man-Wook

    2008-01-01

    FBI-1 (Pokemon/ZBTB7A) is a proto-oncogenic transcription factor of the BTB/POZ (bric-à-brac, tramtrack, and broad complex and pox virus zinc finger) domain family. Recent evidence suggested that FBI-1 might be involved in adipogenic gene expression. Coincidentally, expression of FBI-1 and fatty-acid synthase (FASN) genes are often increased in cancer and immortalized cells. Both FBI-1 and FASN are important in cancer cell proliferation. SREBP-1 is a major regulator of many adipogenic genes, and FBI-1 and SREBP-1 (sterol-responsive element (SRE)-binding protein 1) interact with each other directly via their DNA binding domains. FBI-1 enhanced the transcriptional activation of SREBP-1 on responsive promoters, pGL2-6x(SRE)-Luc and FASN gene. FBI-1 and SREBP-1 synergistically activate transcription of the FASN gene by acting on the proximal GC-box and SRE/E-box. FBI-1, Sp1, and SREBP-1 can bind to all three SRE, GC-box, and SRE/E-box. Binding competition among the three transcription factors on the GC-box and SRE/E-box appears important in the transcription regulation. FBI-1 is apparently changing the binding pattern of Sp1 and SREBP-1 on the two elements in the presence of induced SREBP-1 and drives more Sp1 binding to the proximal promoter with less of an effect on SREBP-1 binding. The changes induced by FBI-1 appear critical in the synergistic transcription activation. The molecular mechanism revealed provides insight into how proto-oncogene FBI-1 may attack the cellular regulatory mechanism of FASN gene expression to provide more phospholipid membrane components needed for rapid cancer cell proliferation. PMID:18682402

  3. Antisense oligonucleotides and all-trans retinoic acid have a synergistic anti-tumor effect on oral squamous cell carcinoma

    International Nuclear Information System (INIS)

    Xu, Qin; Zhang, Zhiyuan; Zhang, Ping; Chen, Wantao

    2008-01-01

    Antisense oligonucleotides against hTR (As-ODN-hTR) have shown promising results as treatment strategies for various human malignancies. All-trans retinoic acid (ATRA) is a signalling molecule with important roles in differentiation and apoptosis. Biological responses to ATRA are currently used therapeutically in various human cancers. The aim of this study was to evaluate the anti-tumor effects of As-ODN-hTR combined with ATRA in vivo. In situ human oral squamous cell carcinoma (OSCC) models were established by subcutaneous injection of Tca8113 cells. Mice were treated with sense oligonucleotides against hTR(S-ODN-hTR) alone, As-ODN-hTR alone, ATRA alone, As-ODN-hTR plus ATRA, or S-ODN-hTR plus ATRA. Tumor size and weight were assessed in the mice. Telomerase activity was detected by a TRAP assay, apoptotic cells were evaluated with a Tunel assay, the expression of apoptosis-related proteins (Bcl-2 and Bax) was evaluated by immunohistochemistry and ultrastructural morphological changes in the tumor specimen were examined. Both As-ODN-hTR and ATRA can significantly inhibit tumor growth in this OSCC xenograft solid-tumor model, and the combination of the two agents had a synergistic anti-tumorogenic effect. We also demonstrated that this anti-tumor effect correlated with inhibition of telomerase activity. Furthermore, significant increases in the number of apoptotic cells, typical apoptotic morphology and a downregulation of the anti-apoptotic protein, bcl-2 were observed in the treated tissues. The combination of As-ODN-hTR and ATRA has a synergistic anti-tumor effect. This anti-tumor effect can be mainly attributed to apoptosis induced by a decrease in telomerase activity. Bcl-2 plays an important role in this process. Therefore, combining As-ODN-hTR and ATRA may be an approach for the treatment of human oral squamous cell carcinoma

  4. Synergistic effects of squalene and polyunsaturated fatty acid ...

    African Journals Online (AJOL)

    GREGO

    2007-04-16

    Apr 16, 2007 ... (EPA, C20:5n-3) and docosahexaenoic acid (DHA,. C22:6n-3) present in ... is secreted in human serum, where it protects the skin from ultraviolet radiation ..... Omega-3 fatty acids from fish oils and cardiovascular disease. Mol.

  5. Optimization of the tumor microenvironment and nanomedicine properties simultaneously to improve tumor therapy.

    Science.gov (United States)

    Zhang, Bo; Shi, Wei; Jiang, Ting; Wang, Lanting; Mei, Heng; Lu, Heng; Hu, Yu; Pang, Zhiqing

    2016-09-20

    Effective delivery of nanomedicines to tumor tissues depends on both the tumor microenvironment and nanomedicine properties. Accordingly, tumor microenvironment modification or advanced design of nanomedicine was emerging to improve nanomedicine delivery to tumors. However, few studies have emphasized the necessity to optimize the tumor microenvironment and nanomedicine properties simultaneously to improve tumor treatment. In the present study, imatinib mesylate (IMA) was used to normalize the tumor microenvironment including platelet-derived growth factor receptor-β expression inhibition, tumor vessel normalization, and tumor perfusion improvement as demonstrated by immunofluorescence staining. In addition, the effect of tumor microenvironment normalization on tumor delivery of nanomedicines with different sizes was carefully investigated. It was shown that IMA treatment significantly reduced the accumulation of nanoparticles (NPs) around 110 nm but enhanced the accumulation of micelles around 23 nm by in vivo fluorescence imaging experiment. Furthermore, IMA treatment limited the distribution of NPs inside tumors but increased that of micelles with a more homogeneous pattern. Finally, the anti-tumor efficacy study displayed that IMA pretreatment could significantly increase the therapeutic effects of paclitaxel-loaded micelles. All-together, a new strategy to improve nanomedicine delivery to tumor was provided by optimizing both nanomedicine size and the tumor microenvironment simultaneously, and it will have great potential in clinics for tumor treatment.

  6. Chlorophyll a and chlorophyllide a inside liposomes made of saturated and unsaturated lipids: A possible impact of the lipids microenvironment

    Directory of Open Access Journals (Sweden)

    Petrović Sanja M.

    2014-01-01

    Full Text Available The aim of this work was to examine a possible impact of liposomes lipids microenvironment, dictated by a chemical composition of the fatty acid branches, on incorporation and spectral behaviour of chlorophyll a, and its derivative, chlorophyllide a inside small liposomes. The liposomes with the incorporated chlorophylls were made of dimirystoyl phosphatidylcholine (DMPC, and unsaturated phosphatidylcholine (PC, containing significant fractions of unsaturated fatty acid moieties. In order to achieve the goal, both absorption and fluorescence polarization spectroscopy were applied, and the obtained data for the two incorporated pigments, which play a role of molecular sensors, were compared. In addition, quercetin, a well-known antioxidant, was used as the (chlorophylls emission quencher, in order to estimate the type of environment sensed by the two pigments for the two liposomes that differ in chemical composition. The results, based primarily on fluorescence polarization data have shown that the emissions as well as the emission quenching were notably affected by a change in the lipids’ chemical composition. That is an indirect proof of the impact of the liposomes microenvironment on the incorporated pigments’ spectral behaviour.[ Projekat Ministarstva nauke Republike Srbije, br. TR-34012 i br. OI-172044

  7. Roles of stromal microenvironment in colon cancer progression.

    Science.gov (United States)

    Taketo, Makoto Mark

    2012-05-01

    Although our understanding of epithelial cancer cells has advanced significantly, our understanding of the cancer microenvironment is still fragmentary. In contrast to our intuitive impression that our body always suppresses cancer growth, recent pieces of evidence show that cancer often exploits our body reactions to expand, invade local tissues and metastasize to distant organs. Accordingly, investigations of such body reactions in the tumour microenvironment should help us to design novel therapeutic strategies that can be combined with the traditional therapeutics targeted at the cancer cells themselves. In this article, I am going to review our recent efforts in search of novel therapeutic strategies against colon cancer using mouse models.

  8. KEY FEATURES OF THE INTRAGRAFT MICROENVIRONMENT THAT DETERMINE LONG-TERM SURVIVAL FOLLOWING TRANSPLANTATION

    Directory of Open Access Journals (Sweden)

    Sarah eBruneau

    2012-04-01

    Full Text Available In this review, we discuss how changes in the intragraft microenvironment serve to promote or sustain the development of chronic allograft rejection. We propose two key elements within the microenvironment that contribute to the rejection process. The first is endothelial cell proliferation and angiogenesis that serve to create abnormal microvascular blood flow patterns as well as local tissue hypoxia, and precedes endothelial-to-mesenchymal transition (EndMT. The second is the overexpression of local cytokines and growth factors that serve to sustain inflammation and, in turn, function to promote a leukocyte-induced angiogenesis reaction. Central to both events is overexpression of vascular endothelial growth factor (VEGF, which is both pro-inflammatory and pro-angiogenic, and thus drives progression of the chronic rejection microenvironment. In our discussion, we focus on how inflammation results in angiogenesis and how leukocyte-induced angiogenesis is pathological. We also discuss how VEGF is a master control factor that fosters the development of the chronic rejection microenvironment. Overall, this review provides insight into the intragraft microenvironment as an important paradigm for future direction in the field.

  9. Key Features of the Intragraft Microenvironment that Determine Long-Term Survival Following Transplantation

    Science.gov (United States)

    Bruneau, Sarah; Woda, Craig Bryan; Daly, Kevin Patrick; Boneschansker, Leonard; Jain, Namrata Gargee; Kochupurakkal, Nora; Contreras, Alan Gabriel; Seto, Tatsuichiro; Briscoe, David Michael

    2012-01-01

    In this review, we discuss how changes in the intragraft microenvironment serve to promote or sustain the development of chronic allograft rejection. We propose two key elements within the microenvironment that contribute to the rejection process. The first is endothelial cell proliferation and angiogenesis that serve to create abnormal microvascular blood flow patterns as well as local tissue hypoxia, and precedes endothelial-to-mesenchymal transition. The second is the overexpression of local cytokines and growth factors that serve to sustain inflammation and, in turn, function to promote a leukocyte-induced angiogenesis reaction. Central to both events is overexpression of vascular endothelial growth factor (VEGF), which is both pro-inflammatory and pro-angiogenic, and thus drives progression of the chronic rejection microenvironment. In our discussion, we focus on how inflammation results in angiogenesis and how leukocyte-induced angiogenesis is pathological. We also discuss how VEGF is a master control factor that fosters the development of the chronic rejection microenvironment. Overall, this review provides insight into the intragraft microenvironment as an important paradigm for future direction in the field. PMID:22566935

  10. Influence of the Tumor Microenvironment on Cancer Cells Metabolic Reprogramming

    Directory of Open Access Journals (Sweden)

    Victoire Gouirand

    2018-04-01

    Full Text Available As with castles, tumor cells are fortified by surrounding non-malignant cells, such as cancer-associated fibroblasts, immune cells, but also nerve fibers and extracellular matrix. In most cancers, this fortification creates a considerable solid pressure which limits oxygen and nutrient delivery to the tumor cells and causes a hypoxic and nutritional stress. Consequently, tumor cells have to adapt their metabolism to survive and proliferate in this harsh microenvironment. To satisfy their need in energy and biomass, tumor cells develop new capacities to benefit from metabolites of the microenvironment, either by their uptake through the macropinocytosis process or through metabolite transporters, or by a cross-talk with stromal cells and capture of extracellular vesicles that are released by the neighboring cells. However, the microenvironments of primary tumor and metastatic niches differ tremendously in their cellular/acellular components and available nutrients. Therefore, cancer cells must develop a metabolic flexibility conferring on them the ability to satisfy their biomass and energetic demands at both primary and metastasis sites. In this review, we propose a brief overview of how proliferating cancer cells take advantage of their surrounding microenvironment to satisfy their high metabolic demand at both primary and metastasis sites.

  11. Comparative synergistic (technetium-actinide) extraction chemistry by tributylphosphate and some amide extractants

    International Nuclear Information System (INIS)

    Condamines, N.; Musikas, C.

    1993-01-01

    In nuclear fuel reprocessing, technetium (TcO 4 - ) leads to bad interferences in the extractions, being synergistically co-extracted with different actinide cations as Uranium (VI), Plutonium (IV) and Zirconium (IV). It destroys the hydrazine in the reductive partition of U and Pu, it decreases the decontamination of U and Pu from fission products. Thus, its extraction behaviour with new extractants as N,N-diakylamides is useful to be known. TcO 4 - extraction in nitric acid media is compared for TBP and different amides. The influence of nitric acidity is related to the amides formula

  12. Determining lower threshold concentrations for synergistic effects

    DEFF Research Database (Denmark)

    Bjergager, Maj-Britt Andersen; Dalhoff, Kristoffer; Kretschmann, Andreas

    2017-01-01

    which proven synergists cease to act as synergists towards the aquatic crustacean Daphnia magna. To do this, we compared several approaches and test-setups to evaluate which approach gives the most conservative estimate for the lower threshold for synergy for three known azole synergists. We focus...... on synergistic interactions between the pyrethroid insecticide, alpha-cypermethrin, and one of the three azole fungicides prochloraz, propiconazole or epoxiconazole measured on Daphnia magna immobilization. Three different experimental setups were applied: A standard 48h acute toxicity test, an adapted 48h test...... of immobile organisms increased more than two-fold above what was predicted by independent action (vertical assessment). All three tests confirmed the hypothesis of the existence of a lower azole threshold concentration below which no synergistic interaction was observed. The lower threshold concentration...

  13. Dynamic Reciprocity in the Wound Microenvironment

    Science.gov (United States)

    Schultz, Gregory S.; Davidson, Jeffrey M.; Kirsner, Robert S.; Bornstein, Paul; Herman, Ira M.

    2011-01-01

    Here, we define dynamic reciprocity (DR) as an ongoing, bidirectional interaction amongst cells and their surrounding microenvironment. In the review, we posit that DR is especially meaningful during wound healing as the DR-driven biochemical, biophysical and cellular responses to injury play pivotal roles in regulating tissue regenerative responses. Such cell-extracellular matrix interactions not only guide and regulate cellular morphology, but cellular differentiation, migration, proliferation, and survival during tissue development, including e.g. embryogenesis, angiogenesis, as well as during pathologic processes including cancer diabetes, hypertension and chronic wound healing. Herein, we examine DR within the wound microenvironment while considering specific examples across acute and chronic wound healing. This review also considers how a number of hypotheses that attempt to explain chronic wound pathophysiology, which may be understood within the DR framework. The implications of applying the principles of dynamic reciprocity to optimize wound care practice and future development of innovative wound healing therapeutics are also briefly considered. PMID:21362080

  14. The Microenvironment in Gliomas: Phenotypic Expressions

    Directory of Open Access Journals (Sweden)

    Davide Schiffer

    2015-12-01

    Full Text Available The microenvironment of malignant gliomas is described according to its definition in the literature. Beside tumor cells, a series of stromal cells (microglia/macrophages, pericytes, fibroblasts, endothelial cells, normal and reactive astrocytes represents the cell component, whereas a complex network of molecular signaling represents the functional component. Its most evident expressions are perivascular and perinecrotic niches that are believed to be the site of tumor stem cells or progenitors in the tumor. Phenotypically, both niches are not easily recognizable; here, they are described together with a critical revision of their concept. As for perinecrotic niches, an alternative interpretation is given about their origin that regards the tumor stem cells as the residue of those that populated hyperproliferating areas in which necroses develop. This is based on the concept that the stem-like is a status and not a cell type, depending on the microenvironment that regulates a conversion of tumor non-stem cells and tumor stem cells through a cell reprogramming.

  15. Biological stoichiometry in tumor micro-environments.

    Directory of Open Access Journals (Sweden)

    Irina Kareva

    Full Text Available Tumors can be viewed as evolving ecological systems, in which heterogeneous populations of cancer cells compete with each other and somatic cells for space and nutrients within the ecosystem of the human body. According to the growth rate hypothesis (GRH, increased phosphorus availability in an ecosystem, such as the tumor micro-environment, may promote selection within the tumor for a more proliferative and thus potentially more malignant phenotype. The applicability of the GRH to tumor growth is evaluated using a mathematical model, which suggests that limiting phosphorus availability might promote intercellular competition within a tumor, and thereby delay disease progression. It is also shown that a tumor can respond differently to changes in its micro-environment depending on the initial distribution of clones within the tumor, regardless of its initial size. This suggests that composition of the tumor as a whole needs to be evaluated in order to maximize the efficacy of therapy.

  16. Biomimetic strategies for the glioblastoma microenvironment

    Science.gov (United States)

    Cha, Junghwa; Kim, Pilnam

    2017-12-01

    Glioblastoma multiforme (GBM) is a devastating type of tumor with high mortality, caused by extensive infiltration into adjacent tissue and rapid recurrence. Most therapies for GBM have focused on the cytotoxicity, and have not targeted GBM spread. However, there have been numerous attempts to improve therapy by addressing GBM invasion, through understanding and mimicking its behavior using three-dimensional (3D) experimental models. Compared with two-dimensional models and in vivo animal models, 3D GBM models can capture the invasive motility of glioma cells within a 3D environment comprising many cellular and non-cellular components. Based on tissue engineering techniques, GBM invasion has been investigated within a biologically relevant environment, from biophysical and biochemical perspectives, to clarify the pro-invasive factors of GBM. This review discusses the recent progress in techniques for modeling the microenvironments of GBM tissue and suggests future directions with respect to recreating the GBM microenvironment and preclinical applications.

  17. Porcine spermatogonial stem cells self-renew effectively in a three dimensional culture microenvironment.

    Science.gov (United States)

    Park, Ji Eun; Park, Min Hee; Kim, Min Seong; Park, Yeo Reum; Yun, Jung Im; Cheong, Hee Tae; Kim, Minseok; Choi, Jung Hoon; Lee, Eunsong; Lee, Seung Tae

    2017-12-01

    Generally, self-renewal of spermatogonial stem cells (SSCs) is maintained in vivo in a three-dimensional (3D) microenvironment consisting of the seminiferous tubule basement membrane, indicating the importance of the 3D microenvironment for in vitro culture of SSCs. Here, we report a 3D culture microenvironment that effectively maintains porcine SSC self-renewal during culture. Porcine SSCs were cultured in an agarose-based 3D hydrogel and in 2D culture plates either with or without feeder cells. Subsequently, the effects of 3D culture on the maintenance of undifferentiated SSCs were identified by analyzing cell colony formation and morphology, AP activity, and transcriptional and translational regulation of self-renewal-related genes and the effects on proliferation by analyzing cell viability and single cell-derived colony number. The 3D culture microenvironment constructed using a 0.2% (w/v) agarose-based 3D hydrogel showed the strongest maintenance of porcine SSC self-renewal and induced significant improvements in proliferation compared with 2D culture microenvironments. These results demonstrate that self-renewal of porcine SSCs can be maintained more effectively in a 3D than in a 2D culture microenvironment. Moreover, this will play a significant role in developing novel culture systems for SSCs derived from diverse species in the future, which will contribute to SSC-related research. © 2017 International Federation for Cell Biology.

  18. Am and Eu extraction from acidic media by synergistic mixtures of substituted bis-tetrazolyl pyridines with chlorinated cobalt dicarbollide

    International Nuclear Information System (INIS)

    Smirnov, I.V.; Chirkov, A.V.; Babain, V.A.; Pokrovskaya, E.Yu.; Artamonova, T.A.

    2009-01-01

    Americium (Am) and europium (Eu) extraction from HNO 3 and HClO 4 media by a synergistic mixture of 2.6-bis(1-aryl-1H-tetrazol-5-yl)pyridines (ATP) with chlorinated cobalt dicarbollide (CCD) was studied by using m-nitrobenzotrifluoride, phenyltrifluoromethyl sulfone, and 1,2-dichloroethane as diluents. We examined the effects of diluents, of the aqueous phase composition and the nature of substituents in the ATP aryl ring on Am/Eu extraction efficiency and selectivity. The Am/Eu separation factor was found to be close to 100 at the optimal ratio of ATPs: CCD ∝ 1:1. We also studied the extraction of 85 Sr, 137 Cs and 133 Ba; a PhATP-CCD mixture provided the separation of the Sr/Ba pair with a factor of 35. A high resistance of 2,6-bis-aryltetrazolyl pyridines to 6 M nitric and perchloric acids at 95 C was demonstrated. (orig.)

  19. Microenvironments and Signaling Pathways Regulating Early Dissemination, Dormancy, and Metastasis

    Science.gov (United States)

    2016-09-01

    regulators of branching morphogenesis during mammary gland development 17,18, arguing that normal mammary epithelial cells cooperate with these innate ...CD45+CD11b+F4/80+ cells lacking lymphoid and granulocytic markers (Supplementary Fig.3B). viSNE plots 30 of myelo- monocytic cells (Fig.5A) showed that...cancer cells and how the microenvironment in these primary sites named P-TMEM (Primary Tumor Microenvironment of Metastases) contribute to early

  20. Synergistic Antibacterial Effects of Chitosan-Caffeic Acid Conjugate against Antibiotic-Resistant Acne-Related Bacteria.

    Science.gov (United States)

    Kim, Ji-Hoon; Yu, Daeung; Eom, Sung-Hwan; Kim, Song-Hee; Oh, Junghwan; Jung, Won-Kyo; Kim, Young-Mog

    2017-06-08

    The object of this study was to discover an alternative therapeutic agent with fewer side effects against acne vulgaris, one of the most common skin diseases. Acne vulgaris is often associated with acne-related bacteria such as Propionibacterium acnes , Staphylococcus epidermidis , Staphylococcus aureus , and Pseudomonas aeruginosa . Some of these bacteria exhibit a resistance against commercial antibiotics that have been used in the treatment of acne vulgaris (tetracycline, erythromycin, and lincomycin). In the current study, we tested in vitro antibacterial effect of chitosan-phytochemical conjugates on acne-related bacteria. Three chitosan-phytochemical conjugates used in this study exhibited stronger antibacterial activity than that of chitosan (unmodified control). Chitosan-caffeic acid conjugate (CCA) showed the highest antibacterial effect on acne-related bacteria along with minimum inhibitory concentration (MIC; 8 to 256 μg/mL). Additionally, the MIC values of antibiotics against antibiotic-resistant P. acnes and P. aeruginosa strains were dramatically reduced in combination with CCA, suggesting that CCA would restore the antibacterial activity of the antibiotics. The analysis of fractional inhibitory concentration (FIC) indices clearly revealed a synergistic antibacterial effect of CCA with antibiotics. Thus, the median sum of FIC (∑FIC) values against the antibiotic-resistant bacterial strains ranged from 0.375 to 0.533 in the combination mode of CCA and antibiotics. The results of the present study suggested a potential possibility of chitosan-phytochemical conjugates in the control of infections related to acne vulgaris.

  1. Direct and indirect inactivation of tumor cell protective catalase by salicylic acid and anthocyanidins reactivates intercellular ROS signaling and allows for synergistic effects.

    Science.gov (United States)

    Scheit, Katrin; Bauer, Georg

    2015-03-01

    Salicylic acid and anthocyanidins are known as plant-derived antioxidants, but also can provoke paradoxically seeming prooxidant effects in vitro. These prooxidant effects are connected to the potential of salicylic acid and anthocyanidins to induce apoptosis selectively in tumor cells in vitro and to inhibit tumor growth in animal models. Several epidemiological studies have shown that salicylic acid and its prodrug acetylsalicylic acid are tumor-preventive for humans. The mechanism of salicylic acid- and anthocyanidin-dependent antitumor effects has remained enigmatic so far. Extracellular apoptosis-inducing reactive oxygen species signaling through the NO/peroxynitrite and the HOCl signaling pathway specifically induces apoptosis in transformed cells. Tumor cells have acquired resistance against intercellular reactive oxygen species signaling through expression of membrane-associated catalase. Here, we show that salicylic acid and anthocyanidins inactivate tumor cell protective catalase and thus reactive apoptosis-inducing intercellular reactive oxygen species signaling of tumor cells and the mitochondrial pathway of apoptosis Salicylic acid inhibits catalase directly through its potential to transform compound I of catalase into the inactive compound II. In contrast, anthocyanidins provoke a complex mechanism for catalase inactivation that is initiated by anthocyanidin-mediated inhibition of NO dioxygenase. This allows the formation of extracellular singlet oxygen through the reaction between H(2)O(2) and peroxynitrite, amplification through a caspase8-dependent step and subsequent singlet oxygen-mediated inactivation of catalase. The combination of salicylic acid and anthocyanidins allows for a remarkable synergistic effect in apoptosis induction. This effect may be potentially useful to elaborate novel therapeutic approaches and crucial for the interpretation of epidemiological results related to the antitumor effects of secondary plant compounds. © The

  2. Protein-mediated efficient synergistic "antenna effect" in a ternary system in D₂O medium.

    Science.gov (United States)

    Ghorai, Shyamal Kr; Samanta, Swarna Kamal; Mukherjee, Manini; Ghosh, Sanjib

    2012-08-16

    A ternary system consisting of a protein, catechin (either + or - epimer), and Tb(III) in suitable aqueous buffer medium at physiological pH (= 6.8) has been shown to exhibit highly efficient "antenna effect". Steady state and time-resolved emission studies of each component in the binary complexes (protein with Tb(III) and (+)- or (-)-catechin with Tb(III)) and the ternary systems along with the molecular docking studies reveal that the efficient sensitization could be ascribed to the effective shielding of microenvironment of Tb(III) from O-H oscillator and increased Tb-C (+/-) interaction in the ternary systems in aqueous medium. The ternary system exhibits protein-mediated efficient antenna effect in D(2)O medium due to synergistic ET from both the lowest ππ* triplet state of Trp residue in protein and that of catechin apart from protection of the Tb(III) environment from matrix vibration. The simple system consisting of (+)- or (-)-catechin and Tb(III) in D(2)O buffer at pH 6.8 has been prescribed to be a useful biosensor.

  3. "Smart" gold nanoparticles for photoacoustic imaging: an imaging contrast agent responsive to the cancer microenvironment and signal amplification via pH-induced aggregation.

    Science.gov (United States)

    Song, Jaejung; Kim, Jeesu; Hwang, Sekyu; Jeon, Mansik; Jeong, Sanghwa; Kim, Chulhong; Kim, Sungjee

    2016-07-07

    'Smart' gold nanoparticles can respond to mild acidic environments, rapidly form aggregates, and shift the absorption to red and near-infrared. They were used as a photoacoustic imaging agent responsive to the cancer microenvironment, and have demonstrated the cancer-specific accumulation at the cellular level and an amplified signal which is twice higher than the control in vivo.

  4. Probing the tumor microenvironment: collection and induction

    Science.gov (United States)

    Williams, James K.; Padgen, Michael R.; Wang, Yarong; Entenberg, David; Gertler, Frank; Condeelis, John S.; Castracane, James

    2012-03-01

    The Nano Intravital Device, or NANIVID, is under development as an optically transparent, implantable tool to study the tumor microenvironment. Two etched glass substrates are sealed using a thin polymer membrane to create a reservoir with a single outlet. This reservoir is loaded with a hydrogel blend that contains growth factors or other chemicals to be delivered to the tumor microenvironment. When the device is implanted in the tumor, the hydrogel will swell and release these entrapped molecules, forming a gradient. Validation of the device has been performed in vitro using epidermal growth factor (EGF) and MenaINV, a highly invasive, rat mammary adenocarcinoma cell line. In both 2-D and 3-D environments, cells migrated toward the gradient of EGF released from the device. The chorioallantoic membrane (CAM) of White Leghorn chicken eggs is being utilized to grow xenograft tumors that will be used for ex vivo cell collection. Device optimization is being performed for in vivo use as a tool to collect the invasive cell population. Preliminary cell collection experiments in vivo were performed using a mouse model of breast cancer. As a second application, the device is being explored as a delivery vehicle for chemicals that induce controlled changes in the tumor microenvironment. H2O2 was loaded in the device and generated intracellular reactive oxygen species (ROS) in cells near the device outlet. In the future, other induction targets will be explored, including hypoglycemia and the manipulation of extracellular matrix stiffness.

  5. Cell microenvironment engineering and monitoring for tissue engineering and regenerative medicine: the recent advances.

    Science.gov (United States)

    Barthes, Julien; Özçelik, Hayriye; Hindié, Mathilde; Ndreu-Halili, Albana; Hasan, Anwarul; Vrana, Nihal Engin

    2014-01-01

    In tissue engineering and regenerative medicine, the conditions in the immediate vicinity of the cells have a direct effect on cells' behaviour and subsequently on clinical outcomes. Physical, chemical, and biological control of cell microenvironment are of crucial importance for the ability to direct and control cell behaviour in 3-dimensional tissue engineering scaffolds spatially and temporally. In this review, we will focus on the different aspects of cell microenvironment such as surface micro-, nanotopography, extracellular matrix composition and distribution, controlled release of soluble factors, and mechanical stress/strain conditions and how these aspects and their interactions can be used to achieve a higher degree of control over cellular activities. The effect of these parameters on the cellular behaviour within tissue engineering context is discussed and how these parameters are used to develop engineered tissues is elaborated. Also, recent techniques developed for the monitoring of the cell microenvironment in vitro and in vivo are reviewed, together with recent tissue engineering applications where the control of cell microenvironment has been exploited. Cell microenvironment engineering and monitoring are crucial parts of tissue engineering efforts and systems which utilize different components of the cell microenvironment simultaneously can provide more functional engineered tissues in the near future.

  6. Cell Microenvironment Engineering and Monitoring for Tissue Engineering and Regenerative Medicine: The Recent Advances

    Directory of Open Access Journals (Sweden)

    Julien Barthes

    2014-01-01

    Full Text Available In tissue engineering and regenerative medicine, the conditions in the immediate vicinity of the cells have a direct effect on cells’ behaviour and subsequently on clinical outcomes. Physical, chemical, and biological control of cell microenvironment are of crucial importance for the ability to direct and control cell behaviour in 3-dimensional tissue engineering scaffolds spatially and temporally. In this review, we will focus on the different aspects of cell microenvironment such as surface micro-, nanotopography, extracellular matrix composition and distribution, controlled release of soluble factors, and mechanical stress/strain conditions and how these aspects and their interactions can be used to achieve a higher degree of control over cellular activities. The effect of these parameters on the cellular behaviour within tissue engineering context is discussed and how these parameters are used to develop engineered tissues is elaborated. Also, recent techniques developed for the monitoring of the cell microenvironment in vitro and in vivo are reviewed, together with recent tissue engineering applications where the control of cell microenvironment has been exploited. Cell microenvironment engineering and monitoring are crucial parts of tissue engineering efforts and systems which utilize different components of the cell microenvironment simultaneously can provide more functional engineered tissues in the near future.

  7. Synergistic interaction of fatty acids and oxysterols impairs mitochondrial function and limits liver adaptation during nafld progression

    Directory of Open Access Journals (Sweden)

    Francesco Bellanti

    2018-05-01

    Full Text Available The complete mechanism accounting for the progression from simple steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD has not been elucidated. Lipotoxicity refers to cellular injury caused by hepatic free fatty acids (FFAs and cholesterol accumulation. Excess cholesterol autoxidizes to oxysterols during oxidative stress conditions. We hypothesize that interaction of FAs and cholesterol derivatives may primarily impair mitochondrial function and affect biogenesis adaptation during NAFLD progression. We demonstrated that the accumulation of specific non-enzymatic oxysterols in the liver of animals fed high-fat+high-cholesterol diet induces mitochondrial damage and depletion of proteins of the respiratory chain complexes. When tested in vitro, 5α-cholestane-3β,5,6β-triol (triol combined to FFAs was able to reduce respiration in isolated liver mitochondria, induced apoptosis in primary hepatocytes, and down-regulated transcription factors involved in mitochondrial biogenesis. Finally, a lower protein content in the mitochondrial respiratory chain complexes was observed in human non-alcoholic steatohepatitis. In conclusion, hepatic accumulation of FFAs and non-enzymatic oxysterols synergistically facilitates development and progression of NAFLD by impairing mitochondrial function, energy balance and biogenesis adaptation to chronic injury.

  8. Remodeling the Vascular Microenvironment of Glioblastoma with α-Particles.

    Science.gov (United States)

    Behling, Katja; Maguire, William F; Di Gialleonardo, Valentina; Heeb, Lukas E M; Hassan, Iman F; Veach, Darren R; Keshari, Kayvan R; Gutin, Philip H; Scheinberg, David A; McDevitt, Michael R

    2016-11-01

    Tumors escape antiangiogenic therapy by activation of proangiogenic signaling pathways. Bevacizumab is approved for the treatment of recurrent glioblastoma, but patients inevitably develop resistance to this angiogenic inhibitor. We previously investigated targeted α-particle therapy with 225 Ac-E4G10 as an antivascular approach and showed increased survival and tumor control in a high-grade transgenic orthotopic glioblastoma model. Here, we investigated changes in tumor vascular morphology and functionality caused by 225 Ac-E4G10. We investigated remodeling of the tumor microenvironment in transgenic Ntva glioblastoma mice using a therapeutic 7.4-kBq dose of 225 Ac-E4G10. Immunofluorescence and immunohistochemical analyses imaged morphologic changes in the tumor blood-brain barrier microenvironment. Multicolor flow cytometry quantified the endothelial progenitor cell population in the bone marrow. Diffusion-weighted MR imaged functional changes in the tumor vascular network. The mechanism of drug action is a combination of remodeling of the glioblastoma vascular microenvironment, relief of edema, and depletion of regulatory T and endothelial progenitor cells. The primary remodeling event is the reduction of both endothelial and perivascular cell populations. Tumor-associated edema and necrosis were lessened, resulting in increased perfusion and reduced diffusion. Pharmacologic uptake of dasatinib into tumor was enhanced after α-particle therapy. Targeted antivascular α-particle radiation remodels the glioblastoma vascular microenvironment via a multimodal mechanism of action and provides insight into the vascular architecture of platelet-derived growth factor-driven glioblastoma. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  9. Synergistic extraction behaviour of americium from simulated acidic waste solutions

    International Nuclear Information System (INIS)

    Pathak, P.N.; Veeraraghavan, R.; Mohapatra, P.K.; Manchanda, V.K.

    1998-01-01

    The extraction behaviour of americium has been investigated with mixtures of 3-phenyl-4-benzoyl-5-isoxazolone (PBI) and oxodonors viz. tri-n-butyl phosphate (TBP), tri-n-octyl phosphine oxide (TOPO) and di-n-butyl octanamide (DBOA) using dodecane as the diluent from 1-6 M HNO 3 media. It is observed that D Am remains unaltered with PBI concentration (in the range 0.06-0.1 M) at 1.47 M TBP in the entire range of HNO 3 concentration. PBI and TBP in combination appears more promising compared to other synergistic systems. The possibility of using this mixture for americium removal from high level liquid waste solution has been explored. Extraction studies indicated that prior removal of uranium by 20% TBP in dodecane is helpful in the quantitative recovery of americium in three contacts. Effect of lanthanides on D Am is found to be marginal. (orig.)

  10. A study for radiation-related tumor microenvironment

    International Nuclear Information System (INIS)

    Son, Young Sook; Hong, Seok Il; Kim, Young Soon; Jin Yong Jae; Lee, Tae Hee; Chung, Eun Kyung; Yi, Jae Yeun; Park, Myung Jin; Kim, Yun Young; Kang, Sin Keun

    1999-04-01

    In this study, we attempted to elucidate the mechanism involved in radiation-induced modification and changes of biological factors and physicochemical factors of tumor microenvironment and develop techniques and agents for the modification of tumor microenvironment which is favorable for efficient radio-cancer therapy based on our basic study. We established in vitro tumor invasion and angiogenesis model, elucidated the importance of MMPs activation and the MMPs/TIMPs complex in the invasive transition of tumor. Furthermore we showed the signaling pathway for MMPs induction through EGF receptor and TGF beta 1 stimulated E-M transition. We also established primary culture of human endothelial cells and tubule forming condition which is utilized for the detection of novel angiogenic factors. We also identified hypoxia induced signaling pathway and showed that GBE improved blood perfusion which may increase the effectiveness of radio-cancer therapy

  11. A study for radiation-related tumor microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Son, Young Sook; Hong, Seok Il; Kim, Young Soon; Jin Yong Jae; Lee, Tae Hee; Chung, Eun Kyung; Yi, Jae Yeun; Park, Myung Jin; Kim, Yun Young; Kang, Sin Keun

    1999-04-01

    In this study, we attempted to elucidate the mechanism involved in radiation-induced modification and changes of biological factors and physicochemical factors of tumor microenvironment and develop techniques and agents for the modification of tumor microenvironment which is favorable for efficient radio-cancer therapy based on our basic study. We established in vitro tumor invasion and angiogenesis model, elucidated the importance of MMPs activation and the MMPs/TIMPs complex in the invasive transition of tumor. Furthermore we showed the signaling pathway for MMPs induction through EGF receptor and TGF beta 1 stimulated E-M transition. We also established primary culture of human endothelial cells and tubule forming condition which is utilized for the detection of novel angiogenic factors. We also identified hypoxia induced signaling pathway and showed that GBE improved blood perfusion which may increase the effectiveness of radio-cancer therapy.

  12. Cutaneous mast cell maturation does not depend on an intact bone marrow microenvironment

    International Nuclear Information System (INIS)

    Charley, M.R.; Mikhael, A.; Sontheimer, R.D.; Gilliam, J.N.; Bennett, M.

    1984-01-01

    A study was made to determine whether the maturation of murine cutaneous mast cells from stem cells depends on an intact bone marrow microenvironment. Normal bone marrow cells (+/+) were infused into 2 groups of mast cell-deficient mice: WBB6F1-W/Wv mice and 89 Sr-pretreated W/Wv mice. 89 Sr is a long-lived bone-seeking radioisotope which provides continuous irradiation of the marrow and thereby ablates the marrow microenvironment. Skin biopsies revealed that the 89 Sr-pretreated mice and the controls had repopulated their skin with mast cells equally well. Natural killer cell function was significantly depressed in the 89 Sr-treated mice, confirming that the marrow microenvironment had been functionally altered. It appears that, although the precursors for cutaneous mast cells are marrow derived, they do not need an intact marrow microenvironment for maturation

  13. Navy and black bean supplementation primes the colonic mucosal microenvironment to improve gut health.

    Science.gov (United States)

    Monk, Jennifer M; Lepp, Dion; Wu, Wenqing; Pauls, K Peter; Robinson, Lindsay E; Power, Krista A

    2017-11-01

    Common beans (Phaseolus vulgaris L.) are enriched in non-digestible fermentable carbohydrates and phenolic compounds that can modulate the colonic microenvironment (microbiota and host epithelial barrier) to improve gut health. In a comprehensive assessment of the impact of two commonly consumed bean varieties (differing in levels and types of phenolic compounds) within the colonic microenvironment, C57Bl/6 mice were fed diets supplemented with 20% cooked navy bean (NB) or black bean (BB) flours or an isocaloric basal diet control (BD) for 3 weeks. NB and BB similarly altered the fecal microbiota community structure (16S rRNA sequencing) notably by increasing the abundance of carbohydrate fermenting bacteria such as Prevotella, S24-7 and Ruminococcus flavefaciens, which coincided with enhanced short chain fatty acid (SCFA) production (microbial-derived carbohydrate fermentation products) and colonic expression of the SCFA receptors GPR-41/-43/-109a. Both NB and BB enhanced multiple aspects of mucus and epithelial barrier integrity vs. BD including: (i) goblet cell number, crypt mucus content and mucin mRNA expression, (ii) anti-microbial defenses (Reg3γ), (iii) crypt length and epithelial cell proliferation, (iv) apical junctional complex components (occludin, JAM-A, ZO-1 and E-cadherin) mRNA expression and (v) reduced serum endotoxin concentrations. Interestingly, biomarkers of colon barrier integrity (crypt height, mucus content, cell proliferation and goblet cell number) were enhanced in BB vs. NB-fed mice, suggesting added benefits attributable to unique BB components (e.g., phenolics). Overall, NB and BB improved baseline colonic microenvironment function by altering the microbial community structure and activity and promoting colon barrier integrity and function; effects which may prove beneficial in attenuating gut-associated diseases. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  14. Tumor Microenvironment Gene Signature as a Prognostic Classifier and Therapeutic Target

    Science.gov (United States)

    2016-06-01

    AWARD NUMBER: W81XWH-14-1-0107 TITLE: Tumor Microenvironment Gene Signature as a Prognostic Classifier and Therapeutic Target PRINCIPAL...AND SUBTITLE Tumor Microenvironment Gene Signature as a 5a. CONTRACT NUMBER W81XWH-14-1-0107 Prognostic Classifier and Therapeutic Target 5b...gene signature that correlates with poor survival in ovarian cancer patients. We are refining this gene signature to develop biomarkers for the

  15. Interaction of tumor cells with the microenvironment

    Directory of Open Access Journals (Sweden)

    Lehnert Hendrik

    2011-09-01

    Full Text Available Abstract Recent advances in tumor biology have revealed that a detailed analysis of the complex interactions of tumor cells with their adjacent microenvironment (tumor stroma is mandatory in order to understand the various mechanisms involved in tumor growth and the development of metastasis. The mutual interactions between tumor cells and cellular and non-cellular components (extracellular matrix = ECM of the tumor microenvironment will eventually lead to a loss of tissue homeostasis and promote tumor development and progression. Thus, interactions of genetically altered tumor cells and the ECM on the one hand and reactive non-neoplastic cells on the other hand essentially control most aspects of tumorigenesis such as epithelial-mesenchymal-transition (EMT, migration, invasion (i.e. migration through connective tissue, metastasis formation, neovascularisation, apoptosis and chemotherapeutic drug resistance. In this mini-review we will focus on these issues that were recently raised by two review articles in CCS.

  16. Synergy of boric acid and added salts in the catalytic dehydration of hexoses to 5-hydroxymethylfurfural in water

    DEFF Research Database (Denmark)

    Hansen, Thomas Steen; Mielby, Jerrik Jørgen; Riisager, Anders

    2011-01-01

    Boric acid and salts showed a synergistic effect on the dehydration of concentrated aqueous sugar solutions to yield 5-hydroxymethylfurfural.......Boric acid and salts showed a synergistic effect on the dehydration of concentrated aqueous sugar solutions to yield 5-hydroxymethylfurfural....

  17. Chemical and physical microenvironments at the Viking landing sites

    Science.gov (United States)

    Clark, B. C.

    1979-01-01

    Physical and chemical considerations permit the division of the near-surface regolith on Mars into at least six zones of distinct microenvironments. The zones are euphotic, duricrust/peds, tempofrost, permafrost, endolithic, and interfacial/transitional. Microenvironments vary significantly in temperature extremes, mean temperature, salt content, relative pressure of water vapor, UV and visible light irradiance, and exposure to ionizing radiation events (100 Mrad) and oxidative molecular species. From what is known of the chemistry of the atmosphere and regolith fines (soil), limits upon the aqueous chemistry of soil pastes may be estimated. Heat of wetting could reach 45 cal/g dry soil; initial pH is indeterminate between 1 and 10; ionic strength and salinity are predicted to be extremely high; freezing point depression is inadequate to provide quantities of liquid water except in special cases. The prospects for biotic survival are grim by terrestrial standards, but the extremes of biological resiliency are inaccessible to evaluation. Second-generation in situ experiments which will better define Martian microenvironments are clearly possible. Antarctic dry valleys are approximations to Martian conditions, but deviate significantly by at least half-a-dozen criteria.

  18. Intraportal islet transplantation: the impact of the liver microenvironment.

    Science.gov (United States)

    Delaune, Vaihere; Berney, Thierry; Lacotte, Stéphanie; Toso, Christian

    2017-03-01

    The portal vein remains the preferred site for pancreatic islet transplantation due to its easy access and low morbidity. However, despite great progress in isolation and transplantation protocols over the past few years, it is still associated with the early loss of some 50-70% of transplanted islets. The complex liver microenvironment itself presumably plays an important role in this loss. The present review focuses on the specifics of the liver microenvironment, notably the localized hepatic ischemia/reperfusion injury following transplantation, the low oxygenation of the portal vein, the instant blood-mediated inflammatory reaction, the endogenous liver immune system, and the gut-liver axis, and how they can each have an impact on the transplanted islets. It identifies the potential, or already applied, clinical interventions for improving intraportal islet survival, and pinpoints those promising areas still lacking preclinical research. Future interventions on clinical intraportal islet transplantation need to take into account the global context of the liver microenvironment, with multi-point interventions being most likely to improve early islet survival and engraftment. © 2017 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.

  19. Modulating the Tumor Microenvironment to Enhance Tumor Nanomedicine Delivery

    Directory of Open Access Journals (Sweden)

    Bo Zhang

    2017-12-01

    Full Text Available Nanomedicines including liposomes, micelles, and nanoparticles based on the enhanced permeability and retention (EPR effect have become the mainstream for tumor treatment owing to their superiority over conventional anticancer agents. Advanced design of nanomedicine including active targeting nanomedicine, tumor-responsive nanomedicine, and optimization of physicochemical properties to enable highly effective delivery of nanomedicine to tumors has further improved their therapeutic benefits. However, these strategies still could not conquer the delivery barriers of a tumor microenvironment such as heterogeneous blood flow, dense extracellular matrix, abundant stroma cells, and high interstitial fluid pressure, which severely impaired vascular transport of nanomedicines, hindered their effective extravasation, and impeded their interstitial transport to realize uniform distribution inside tumors. Therefore, modulation of tumor microenvironment has now emerged as an important strategy to improve nanomedicine delivery to tumors. Here, we review the existing strategies and approaches for tumor microenvironment modulation to improve tumor perfusion for helping more nanomedicines to reach the tumor site, to facilitate nanomedicine extravasation for enhancing transvascular transport, and to improve interstitial transport for optimizing the distribution of nanomedicines. These strategies may provide an avenue for the development of new combination chemotherapeutic regimens and reassessment of previously suboptimal agents.

  20. Modulating the Tumor Microenvironment to Enhance Tumor Nanomedicine Delivery

    Science.gov (United States)

    Zhang, Bo; Hu, Yu; Pang, Zhiqing

    2017-01-01

    Nanomedicines including liposomes, micelles, and nanoparticles based on the enhanced permeability and retention (EPR) effect have become the mainstream for tumor treatment owing to their superiority over conventional anticancer agents. Advanced design of nanomedicine including active targeting nanomedicine, tumor-responsive nanomedicine, and optimization of physicochemical properties to enable highly effective delivery of nanomedicine to tumors has further improved their therapeutic benefits. However, these strategies still could not conquer the delivery barriers of a tumor microenvironment such as heterogeneous blood flow, dense extracellular matrix, abundant stroma cells, and high interstitial fluid pressure, which severely impaired vascular transport of nanomedicines, hindered their effective extravasation, and impeded their interstitial transport to realize uniform distribution inside tumors. Therefore, modulation of tumor microenvironment has now emerged as an important strategy to improve nanomedicine delivery to tumors. Here, we review the existing strategies and approaches for tumor microenvironment modulation to improve tumor perfusion for helping more nanomedicines to reach the tumor site, to facilitate nanomedicine extravasation for enhancing transvascular transport, and to improve interstitial transport for optimizing the distribution of nanomedicines. These strategies may provide an avenue for the development of new combination chemotherapeutic regimens and reassessment of previously suboptimal agents. PMID:29311946

  1. Herbicidal Activities of Some Allelochemicals and Their Synergistic Behaviors toward Amaranthus tricolor L.

    Directory of Open Access Journals (Sweden)

    Nawasit Chotsaeng

    2017-10-01

    Full Text Available Seven allelochemicals, namely R-(+-limonene (A, vanillin (B, xanthoxyline (C, vanillic acid (D, linoleic acid (E, methyl linoleate (F, and (±-odorine (G, were investigated for their herbicidal activities on Chinese amaranth (Amaranthus tricolor L.. At 400 μM, xanthoxyline (C showed the greatest inhibitory activity on seed germination and seedling growth of the tested plant. Both vanillic acid (D and (±-odorine (G inhibited shoot growth, however, apart from xanthoxyline (C, only vanillic acid (D could inhibit root growth. Interestingly, R-(+-limonene (A lightly promoted root length. Other substances had no allelopathic effect on seed germination and seedling growth of the tested plant. To better understand and optimize the inhibitory effects of these natural herbicides, 21 samples of binary mixtures of these seven compounds were tested at 400 μM using 0.25% (v/v Tween® 80 as a control treatment. The results showed that binary mixtures of R-(+-limonene:xanthoxyline (A:C, vanillin:xanthoxyline (B:C, and xanthoxyline:linoleic acid (C:E exhibited strong allelopathic activities on germination and seedling growth of the tested plant, and the level of inhibition was close to the effect of xanthoxyline (C at 400 µM and was better than the effect of xanthoxyline (C at 200 µM. The inhibition was hypothesized to be from a synergistic interaction of each pair of alleochemicals. Mole ratios of each pair of allelochemicals ((A:C, (B:C, and (C:E were then evaluated, and the best ratios of the binary mixtures A:C, B:C and C:E were found to be 2:8, 2:8, and 4:6 respectively. These binary mixtures significantly inhibited germination and shoot and root growth of Chinese amaranth at low concentrations. The results reported here highlight a synergistic behavior of some allelochemicals which could be applied in the development of potential herbicides.

  2. Phenotypic characterization of prostate cancer LNCaP cells cultured within a bioengineered microenvironment.

    Directory of Open Access Journals (Sweden)

    Shirly Sieh

    Full Text Available Biophysical and biochemical properties of the microenvironment regulate cellular responses such as growth, differentiation, morphogenesis and migration in normal and cancer cells. Since two-dimensional (2D cultures lack the essential characteristics of the native cellular microenvironment, three-dimensional (3D cultures have been developed to better mimic the natural extracellular matrix. To date, 3D culture systems have relied mostly on collagen and Matrigel™ hydrogels, allowing only limited control over matrix stiffness, proteolytic degradability, and ligand density. In contrast, bioengineered hydrogels allow us to independently tune and systematically investigate the influence of these parameters on cell growth and differentiation. In this study, polyethylene glycol (PEG hydrogels, functionalized with the Arginine-glycine-aspartic acid (RGD motifs, common cell-binding motifs in extracellular matrix proteins, and matrix metalloproteinase (MMP cleavage sites, were characterized regarding their stiffness, diffusive properties, and ability to support growth of androgen-dependent LNCaP prostate cancer cells. We found that the mechanical properties modulated the growth kinetics of LNCaP cells in the PEG hydrogel. At culture periods of 28 days, LNCaP cells underwent morphogenic changes, forming tumor-like structures in 3D culture, with hypoxic and apoptotic cores. We further compared protein and gene expression levels between 3D and 2D cultures upon stimulation with the synthetic androgen R1881. Interestingly, the kinetics of R1881 stimulated androgen receptor (AR nuclear translocation differed between 2D and 3D cultures when observed by immunofluorescent staining. Furthermore, microarray studies revealed that changes in expression levels of androgen responsive genes upon R1881 treatment differed greatly between 2D and 3D cultures. Taken together, culturing LNCaP cells in the tunable PEG hydrogels reveals differences in the cellular responses to

  3. Osteoblasts generate an osteogenic microenvironment when grown on surfaces with rough microtopographies

    Directory of Open Access Journals (Sweden)

    Boyan B. D.

    2003-10-01

    Full Text Available Osteoblasts respond to microarchitectural features of their substrate. On smooth surfaces (tissue culture plastic, tissue culture glass, and titanium, the cells attach and proliferate but they exhibit relatively low expression of differentiation markers in monolayer cultures, even when confluent. When grown on microrough Ti surfaces with an average roughness (Ra of 4-7 µm, proliferation is reduced but differentiation is enhanced and in some cases, is synergistic with the effects of surface microtopography. In addition, cells on microrough Ti substrates form hydroxyapatite in a manner that is more typical of bone than do cells cultured on smooth surfaces. Osteoblasts also respond to growth factors and cytokines in a surface-dependent manner. On rougher surfaces, the effects of regulatory factors like 1alpha,25(OH2D3 or 17beta-estradiol are enhanced. The response to the surface is mediated by integrins, which signal to the cell through many of the same mechanisms used by growth factors and hormones. Studies using PEG-modified surfaces indicate that increased differentiation may be related to altered attachment to the surface. When osteoblasts are grown on surfaces with chemistries or microarchitectures that reduce cell attachment and proliferation, and enhance differentiation, the cells tend to increase production of factors like TGF-beta1 that promote osteogenesis while decreasing osteoclastic activity. Thus, on microrough Ti surface, osteoblasts create a microenvironment conducive to new bone formation.

  4. Global niche of marine anaerobic metabolisms expanded by particle microenvironments

    Science.gov (United States)

    Bianchi, Daniele; Weber, Thomas S.; Kiko, Rainer; Deutsch, Curtis

    2018-04-01

    In ocean waters, anaerobic microbial respiration should be confined to the anoxic waters found in coastal regions and tropical oxygen minimum zones, where it is energetically favourable. However, recent molecular and geochemical evidence has pointed to a much broader distribution of denitrifying and sulfate-reducing microbes. Anaerobic metabolisms are thought to thrive in microenvironments that develop inside sinking organic aggregates, but the global distribution and geochemical significance of these microenvironments is poorly understood. Here, we develop a new size-resolved particle model to predict anaerobic respiration from aggregate properties and seawater chemistry. Constrained by observations of the size spectrum of sinking particles, the model predicts that denitrification and sulfate reduction can be sustained throughout vast, hypoxic expanses of the ocean, and could explain the trace metal enrichment observed in particles due to sulfide precipitation. Globally, the expansion of the anaerobic niche due to particle microenvironments doubles the rate of water column denitrification compared with estimates based on anoxic zones alone, and changes the sensitivity of the marine nitrogen cycle to deoxygenation in a warming climate.

  5. Role of the Microenvironment in Ovarian Cancer Stem Cell Maintenance

    Directory of Open Access Journals (Sweden)

    Jennifer Pasquier

    2013-01-01

    Full Text Available Despite recent progresses in cancer therapy and increased knowledge in cancer biology, ovarian cancer remains a challenging condition. Among the latest concepts developed in cancer biology, cancer stem cells and the role of microenvironment in tumor progression seem to be related. Indeed, cancer stem cells have been described in several solid tumors including ovarian cancers. These particular cells have the ability to self-renew and reconstitute a heterogeneous tumor. They are characterized by specific surface markers and display resistance to therapeutic regimens. During development, specific molecular cues from the tumor microenvironment can play a role in maintaining and expanding stemness of cancer cells. The tumor stroma contains several compartments: cellular component, cytokine network, and extracellular matrix. These different compartments interact to form a permissive niche for the cancer stem cells. Understanding the molecular cues underlying this crosstalk will allow the design of new therapeutic regimens targeting the niche. In this paper, we will discuss the mechanisms implicated in the interaction between ovarian cancer stem cells and their microenvironment.

  6. Synergistic solvent extraction of Eu(III) and Tb(III) with mixtures of various organophosphorus extractants

    International Nuclear Information System (INIS)

    Reddy, B.V.; Reddy, L.K.; Reddy, A.S.

    1994-01-01

    Synergistic solvent extraction of Eu(III) and Tb(III) from thiocyanate solutions with mixtures of 2-ethylhexylphosphonic acid mono-2-ethylhexyl ester (EHPNA) and di-2-ethylhexylphosphoric acid (DEHPA) or tributyl phosphate (TBP) or trioctylphosphine oxide (TOPO) or triphenylphosphine oxide (TPhPO) in benzene has been studied. The mechanism of extraction can be explained by a simple chemically based model. The equilibrium constants of the mixed-ligand species of the various neutral donors have been determined by non-linear regression analysis. (author) 13 refs.; 9 figs.; 2 tabs

  7. Molecular imaging of the tumor microenvironment for precision medicine and theranostics.

    Science.gov (United States)

    Penet, Marie-France; Krishnamachary, Balaji; Chen, Zhihang; Jin, Jiefu; Bhujwalla, Zaver M

    2014-01-01

    Morbidity and mortality from cancer and their associated conditions and treatments continue to extract a heavy social and economic global burden despite the transformative advances in science and technology in the twenty-first century. In fact, cancer incidence and mortality are expected to reach pandemic proportions by 2025, and costs of managing cancer will escalate to trillions of dollars. The inability to establish effective cancer treatments arises from the complexity of conditions that exist within tumors, the plasticity and adaptability of cancer cells coupled with their ability to escape immune surveillance, and the co-opted stromal cells and microenvironment that assist cancer cells in survival. Stromal cells, although destroyed together with cancer cells, have an ever-replenishing source that can assist in resurrecting tumors from any residual cancer cells that may survive treatment. The tumor microenvironment landscape is a continually changing landscape, with spatial and temporal heterogeneities that impact and influence cancer treatment outcome. Importantly, the changing landscape of the tumor microenvironment can be exploited for precision medicine and theranostics. Molecular and functional imaging can play important roles in shaping and selecting treatments to match this landscape. Our purpose in this review is to examine the roles of molecular and functional imaging, within the context of the tumor microenvironment, and the feasibility of their applications for precision medicine and theranostics in humans. © 2014 Elsevier Inc. All rights reserved.

  8. Engineering mechanical microenvironment of macrophage and its biomedical applications.

    Science.gov (United States)

    Li, Jing; Li, Yuhui; Gao, Bin; Qin, Chuanguang; He, Yining; Xu, Feng; Yang, Hui; Lin, Min

    2018-03-01

    Macrophages are the most plastic cells in the hematopoietic system and can be widely found in almost all tissues. Recently studies have shown that mechanical cues (e.g., matrix stiffness and stress/strain) can significantly affect macrophage behaviors. Although existing reviews on the physical and mechanical cues that regulate the macrophage's phenotype are available, engineering mechanical microenvironment of macrophages in vitro as well as a comprehensive overview and prospects for their biomedical applications (e.g., tissue engineering and immunotherapy) has yet to be summarized. Thus, this review provides an overview on the existing methods for engineering mechanical microenvironment of macrophages in vitro and then a section on their biomedical applications and further perspectives are presented.

  9. Direct laser writing by two-photon polymerization as a tool for developing microenvironments for evaluation of bacterial growth

    Energy Technology Data Exchange (ETDEWEB)

    Otuka, A.J.G. [Instituto de Física de São Carlos, Universidade de São Paulo, CP.369, 13560-970 São Carlos, SP (Brazil); Corrêa, D.S. [Laboratório Nacional de Nanotecnologia para o Agronegócio (LNNA), Embrapa Instrumentação, Rua XV de Novembro, 1452, CP.741, 13560-970 São Carlos, SP (Brazil); Fontana, C.R. [Department of Clinical Analysis, School of Pharmaceutical Sciences, University of São Paulo State (UNESP), 1621 Expedicionarios do Brasil Street, Araraquara, Sao Paulo 14801-960 (Brazil); Mendonça, C.R., E-mail: crmendon@ifsc.usp.br [Instituto de Física de São Carlos, Universidade de São Paulo, CP.369, 13560-970 São Carlos, SP (Brazil)

    2014-02-01

    Monitoring bacteria growth and motion in environments is fundamental to understand, for instance, how they proliferate and contaminate organism. Therefore, techniques to fabricate microenvironments for in situ and in vivo studies are interesting for that purpose. In this work we used two-photon polymerization to fabricate microenvironments and, as a proof of principle, we demonstrated the development of the bacteria ATCC 25922 Escherichia coli (E. coli) into the microstructure surroundings. Two varieties of polymeric microenvironments are presented: (i) a microenvironment doped at specific site with ciprofloxacin, an antibiotic typically used in the treatment of diseases caused by E. coli and (ii) micro-fences, which serve as traps for bacteria. These microenvironments, fabricated by two-photon polymerization, may be a potential platform for drug delivery system, by promoting or inhibiting the growth of bacteria in specific biological or synthetic sites. - Highlights: • Microenvironments were fabricated by two-photon polymerization. • We demonstrated the development of Escherichia coli into the microstructure surroundings. • Microenvironment doped with the antibiotic ciprofloxacin was fabricated. • Micro-fences, which serve as traps for bacteria, were also produced.

  10. Direct laser writing by two-photon polymerization as a tool for developing microenvironments for evaluation of bacterial growth

    International Nuclear Information System (INIS)

    Otuka, A.J.G.; Corrêa, D.S.; Fontana, C.R.; Mendonça, C.R.

    2014-01-01

    Monitoring bacteria growth and motion in environments is fundamental to understand, for instance, how they proliferate and contaminate organism. Therefore, techniques to fabricate microenvironments for in situ and in vivo studies are interesting for that purpose. In this work we used two-photon polymerization to fabricate microenvironments and, as a proof of principle, we demonstrated the development of the bacteria ATCC 25922 Escherichia coli (E. coli) into the microstructure surroundings. Two varieties of polymeric microenvironments are presented: (i) a microenvironment doped at specific site with ciprofloxacin, an antibiotic typically used in the treatment of diseases caused by E. coli and (ii) micro-fences, which serve as traps for bacteria. These microenvironments, fabricated by two-photon polymerization, may be a potential platform for drug delivery system, by promoting or inhibiting the growth of bacteria in specific biological or synthetic sites. - Highlights: • Microenvironments were fabricated by two-photon polymerization. • We demonstrated the development of Escherichia coli into the microstructure surroundings. • Microenvironment doped with the antibiotic ciprofloxacin was fabricated. • Micro-fences, which serve as traps for bacteria, were also produced

  11. Engineering three-dimensional cell mechanical microenvironment with hydrogels.

    Science.gov (United States)

    Huang, Guoyou; Wang, Lin; Wang, Shuqi; Han, Yulong; Wu, Jinhui; Zhang, Qiancheng; Xu, Feng; Lu, Tian Jian

    2012-12-01

    Cell mechanical microenvironment (CMM) significantly affects cell behaviors such as spreading, migration, proliferation and differentiation. However, most studies on cell response to mechanical stimulation are based on two-dimensional (2D) planar substrates, which cannot mimic native three-dimensional (3D) CMM. Accumulating evidence has shown that there is a significant difference in cell behavior in 2D and 3D microenvironments. Among the materials used for engineering 3D CMM, hydrogels have gained increasing attention due to their tunable properties (e.g. chemical and mechanical properties). In this paper, we provide an overview of recent advances in engineering hydrogel-based 3D CMM. Effects of mechanical cues (e.g. hydrogel stiffness and externally induced stress/strain in hydrogels) on cell behaviors are described. A variety of approaches to load mechanical stimuli in 3D hydrogel-based constructs are also discussed.

  12. Engineering three-dimensional cell mechanical microenvironment with hydrogels

    International Nuclear Information System (INIS)

    Huang Guoyou; Wang Lin; Han Yulong; Zhang Qiancheng; Xu Feng; Lu Tianjian; Wang Shuqi; Wu Jinhui

    2012-01-01

    Cell mechanical microenvironment (CMM) significantly affects cell behaviors such as spreading, migration, proliferation and differentiation. However, most studies on cell response to mechanical stimulation are based on two-dimensional (2D) planar substrates, which cannot mimic native three-dimensional (3D) CMM. Accumulating evidence has shown that there is a significant difference in cell behavior in 2D and 3D microenvironments. Among the materials used for engineering 3D CMM, hydrogels have gained increasing attention due to their tunable properties (e.g. chemical and mechanical properties). In this paper, we provide an overview of recent advances in engineering hydrogel-based 3D CMM. Effects of mechanical cues (e.g. hydrogel stiffness and externally induced stress/strain in hydrogels) on cell behaviors are described. A variety of approaches to load mechanical stimuli in 3D hydrogel-based constructs are also discussed. (topical review)

  13. Changes in Cytokines of the Bone Microenvironment during Breast Cancer Metastasis

    International Nuclear Information System (INIS)

    Sosnoski, D.M.; Krishnan, V.; Mastro, A.M.; Kraemer, W.J.; Dunn-Lewis, C.

    2012-01-01

    It is commonly accepted that cancer cells interact with host cells to create a microenvironment favoring malignant colonization. The complex bone microenvironment produces an ever changing array of cytokines and growth factors. In this study, we examined levels of MCP-1, IL-6, KC, MIP-2, VEGF, MIG, and eotaxin in femurs of athymic nude mice inoculated via intracardiac injection with MDA-MB-231GFP human metastatic breast cancer cells, MDA-MB-231 BRMS1GFP, a metastasis suppressed variant, or PBS. Animals were euthanized (day 3, 11, 19, 27 after injection) to examine femoral cytokine levels at various stages of cancer cell colonization. The epiphysis contained significantly more cytokines than the diaphysis except for MIG which was similar throughout the bone. Variation among femurs was evident within all groups. By day 27, MCP-1, MIG, VEGF and eotaxin levels were significantly greater in femurs of cancer cell-inoculated mice. These pro-osteoclastic and angiogenic cytokines may manipulate the bone microenvironment to enhance cancer cell colonization

  14. Assembly of hydrogel units for 3D microenvironment in a poly(dimethylsiloxane) channel

    Science.gov (United States)

    Cho, Chang Hyun; Kwon, Seyong; Park, Je-Kyun

    2017-12-01

    Construction of three-dimensional (3D) microenvironment become an important issue in recent biological studies due to their biological relevance compared to conventional two-dimensional (2D) microenvironment. Various fabrication techniques have been employed to construct a 3D microenvironment, however, it is difficult to fully satisfy the biological and mechanical properties required for the 3D cell culture system, such as heterogeneous tissue structures generated from the functional differences or diseases. We propose here an assembly method for facile construction of 3D microenvironment in a poly(dimethylsiloxane) (PDMS) channel using hydrogel units. The high-aspect-ratio of hydrogel units was achieved by fabricating these units using a 2D mold. With this approach, 3D heterogeneous hydrogel units were produced and assembled in a PDMS channel by structural hookup. In vivo-like 3D heterogeneous microenvironment in a precisely controllable fluidic system was also demonstrated using a controlled assembly of different types of hydrogel units, which was difficult to obtain from previous methods. By regulating the flow condition, the mechanical stability of the assembled hydrogel units was verified by the flow-induced deformation of hydrogel units. In addition, in vivo-like cell culture environment was demonstrated using an assembly of cell-coated hydrogel units in the fluidic channel. Based on these features, our method expects to provide a beneficial tool for the 3D cell culture module and biomimetic engineering.

  15. Synergistic Manganese(I) C-H Activation Catalysis in Continuous Flow: Chemoselective Hydroarylation.

    Science.gov (United States)

    Wang, Hui; Pesciaioli, Fabio; Oliveira, João C A; Warratz, Svenja; Ackermann, Lutz

    2017-11-20

    Chemoselective hydroarylations were accomplished by a novel synergistic Brønsted acid/manganese(I)-catalyzed C-H activation manifold. Thus, alkynes bearing O-leaving groups could, for the first time, be employed for C-H alkenylations without concurrent β-O elimination, thereby setting the stage for versatile late-stage diversifications. Also described is the first manganese-catalyzed C-H activation in continuous flow, thus enabling efficient hydroarylations within only 20 minutes. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Targeting the tumor microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Kenny, P.A.; Lee, G.Y.; Bissell, M.J.

    2006-11-07

    Despite some notable successes cancer remains, for the most part, a seemingly intractable problem. There is, however, a growing appreciation that targeting the tumor epithelium in isolation is not sufficient as there is an intricate mutually sustaining synergy between the tumor epithelial cells and their surrounding stroma. As the details of this dialogue emerge, new therapeutic targets have been proposed. The FDA has already approved drugs targeting microenvironmental components such as VEGF and aromatase and many more agents are in the pipeline. In this article, we describe some of the 'druggable' targets and processes within the tumor microenvironment and review the approaches being taken to disrupt these interactions.

  17. Controlled synthesis of ordered mesoporous TiO{sub 2}-supported on activated carbon and pore-pore synergistic photocatalytic performance

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Chen; Li, Youji, E-mail: bcclyj@163.com; Xu, Peng; Li, Ming; Zeng, Mengxiong

    2015-01-15

    Ordered mesoporous titania/activated carbon (OMTAC) were prepared by the template technique with the aid of an ultrasonic method. To explore the relationship between the structure and properties of OMTAC, the ultrasonic-sol-gel technique was applied to synthesize titania dioxide/activated carbon (USTAC). The obtained material structure was characterized by X-ray diffraction (XRD), nitrogen adsorption – desorption, transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), UV diffuse reflectance (DRS) and Photoluminescence (PL) emission spectra. OMTAC photocatalytic performance was evaluated by means of acid red B (ARB) degradation. The pore-pore synergistic amplification mechanism of photocatalysis was proposed and the effects of catalytic conditions on synergistic amplification were explored. The results show that compared to OMT, OMTAC has a small particle size, low electron-hole recombination rate and high surface areas, due to the hindering effect of activated carbon on crystalline grain growth and an ordered mesoporous structure of titania. OMTAC has higher catalytic activity than USTAC, OMT and P25, due to pore-pore synergistic amplification effect of photocatalysis. The OMT content is strongly affected OMTAC photocatalytic activity, and OMTAC-3 (loading 3 times of OMT on AC) has the highest photocatalytic activity due to high hydroxyl concentration, surface area and low electron-hole recombination rate. When ARB is degraded by OMTAC-3, the optimum catalytic conditions are a catalyst concentration of 1 g/L, an ARB concentration of 15 mg/L and a pH of 5. - Graphical abstract: We investigate the influence of mesoporous titania content upon the photocatalytic performance of OMTAC in acid red B degradation. - Highlights: • OMTAC were fabricated by a template technique with the aid of an ultrasonic method. • OMTAC show high photoactivity for acid red B (ARB) degradation. • OMTAC also show pore-pore synergistic photocatalytic

  18. Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2017-12-01

    AWARD NUMBER: W81XWH-13-1-0163 TITLE: Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-resistant Prostate Cancer ...Prostate Cancer 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Feng Yang, Ph.D. 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: fyang@bcm.edu...W81XWH-13-1-0163 " Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-resistant Prostate Cancer " Introduction AR signaling

  19. Tumor-Associated Macrophages as Major Players in the Tumor Microenvironment

    International Nuclear Information System (INIS)

    Chanmee, Theerawut; Ontong, Pawared; Konno, Kenjiro; Itano, Naoki

    2014-01-01

    During tumor progression, circulating monocytes and macrophages are actively recruited into tumors where they alter the tumor microenvironment to accelerate tumor progression. Macrophages shift their functional phenotypes in response to various microenvironmental signals generated from tumor and stromal cells. Based on their function, macrophages are divided broadly into two categories: classical M1 and alternative M2 macrophages. The M1 macrophage is involved in the inflammatory response, pathogen clearance, and antitumor immunity. In contrast, the M2 macrophage influences an anti-inflammatory response, wound healing, and pro-tumorigenic properties. Tumor-associated macrophages (TAMs) closely resemble the M2-polarized macrophages and are critical modulators of the tumor microenvironment. Clinicopathological studies have suggested that TAM accumulation in tumors correlates with a poor clinical outcome. Consistent with that evidence, experimental and animal studies have supported the notion that TAMs can provide a favorable microenvironment to promote tumor development and progression. In this review article, we present an overview of mechanisms responsible for TAM recruitment and highlight the roles of TAMs in the regulation of tumor angiogenesis, invasion, metastasis, immunosuppression, and chemotherapeutic resistance. Finally, we discuss TAM-targeting therapy as a promising novel strategy for an indirect cancer therapy

  20. Tumor-Associated Macrophages as Major Players in the Tumor Microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Chanmee, Theerawut [Institute of Advanced Technology, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555 (Japan); Ontong, Pawared [Division of Engineering (Biotechnology), Graduate School of Engineering, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555 (Japan); Konno, Kenjiro [Department of Animal Medical Sciences, Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555 (Japan); Itano, Naoki, E-mail: itanon@cc.kyoto-su.ac.jp [Institute of Advanced Technology, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555 (Japan); Division of Engineering (Biotechnology), Graduate School of Engineering, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555 (Japan); Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555 (Japan)

    2014-08-13

    During tumor progression, circulating monocytes and macrophages are actively recruited into tumors where they alter the tumor microenvironment to accelerate tumor progression. Macrophages shift their functional phenotypes in response to various microenvironmental signals generated from tumor and stromal cells. Based on their function, macrophages are divided broadly into two categories: classical M1 and alternative M2 macrophages. The M1 macrophage is involved in the inflammatory response, pathogen clearance, and antitumor immunity. In contrast, the M2 macrophage influences an anti-inflammatory response, wound healing, and pro-tumorigenic properties. Tumor-associated macrophages (TAMs) closely resemble the M2-polarized macrophages and are critical modulators of the tumor microenvironment. Clinicopathological studies have suggested that TAM accumulation in tumors correlates with a poor clinical outcome. Consistent with that evidence, experimental and animal studies have supported the notion that TAMs can provide a favorable microenvironment to promote tumor development and progression. In this review article, we present an overview of mechanisms responsible for TAM recruitment and highlight the roles of TAMs in the regulation of tumor angiogenesis, invasion, metastasis, immunosuppression, and chemotherapeutic resistance. Finally, we discuss TAM-targeting therapy as a promising novel strategy for an indirect cancer therapy.

  1. Synergistic antioxidant activity of green tea with some herbs

    Directory of Open Access Journals (Sweden)

    Dheeraj P Jain

    2011-01-01

    Full Text Available Cardiovascular diseases, cancer, arthritis, etc. are caused by free radicals that are byproducts of metabolic pathways. Selected plants namely Vitis vinifera, Phyllanthus emblica L., Punica granatum, Cinnamomum cassia, Ginkgo biloba L., and Camellia sinensis Linn. are reported to produce antioxidant property. This study is undertaken to support the hypothesis that formulation of a polyherbal combination of these plants shows a synergistic effect with green tea. The extracts of each drug were characterized by phytochemical studies and tests for phenolics and flavonoids. In vitro antioxidant activity for individual drug and its combination was determined by 1,1-diphenyl-2-picrylhydrazyl (DPPH, superoxide, and nitric oxide free radical scavenging methods. Our results suggest that a combination of all these herbs with green tea can synergistically enhance antioxidant activity and thus lower doses of each herb with green tea may be used. Antioxidant potential of polyherbal combination was also comparable to that of standard ascorbic acid. Studies showed that selected individual plants contained abundant quantity of phenolics and flavonoids and their polyherbal combination with green tea was found to produce best antioxidant activity among all individual extracts. This will help in avoiding undesirable side effects due to higher doses of single herb.

  2. Synergistic association of changes in serum uric acid and triglycerides with changes in insulin resistance after walking exercise in community-dwelling older women.

    Science.gov (United States)

    Kawamoto, Ryuichi; Katoh, Takeaki; Ninomiya, Daisuke; Kumagi, Teru; Abe, Masanori; Kohara, Katsuhiko

    2016-05-01

    Serum uric acid (SUA) and triglyceride (TG) levels are strongly correlated with insulin resistance; however, the association after a walking exercise program in community-dwelling older women has not been investigated. The present study included 100 postmenopausal women (mean ± standard deviation, 68 ± 7 years) from a rural village in Japan. The Nordic walking program of 120 min per week was performed for 12 weeks. Before and after the intervention, SUA, TG, various relevant factors and homeostasis model assessment of insulin resistance (HOMA-IR) were measured. Multivariate linear regression analysis showed that baseline TG and γ-glutamyltransferase (GGT) were significantly associated with baseline HOMA-IR. After the 12-week training program, changes in TG, SUA and GGT were significantly associated with changes in HOMA-IR. In addition to their direct associations, we observed a synergistic association between changes in TG and SUA and changes in HOMA-IR. Participants were divided into three groups (tertiles) according to changes in TG and SUA. The tertiles of changes in SUA correlated significantly with changes in HOMA-IR in participants in the tertile with the greatest decrease in TG (r = 0.525, p = 0.001), but not in the other two tertiles of change in TG (r = 0.049, p = 0.699). There was a significant interaction between SUA and TG for changes in HOMA-IR (β = 0.281, p = 0.005). These results suggest that changes in TG and SUA are synergistic factors associated with changes in insulin resistance after a 12-week walking exercise program in community-dwelling older women.

  3. Statistical metamodeling for revealing synergistic antimicrobial interactions.

    Directory of Open Access Journals (Sweden)

    Hsiang Chia Chen

    2010-11-01

    Full Text Available Many bacterial pathogens are becoming drug resistant faster than we can develop new antimicrobials. To address this threat in public health, a metamodel antimicrobial cocktail optimization (MACO scheme is demonstrated for rapid screening of potent antibiotic cocktails using uropathogenic clinical isolates as model systems. With the MACO scheme, only 18 parallel trials were required to determine a potent antimicrobial cocktail out of hundreds of possible combinations. In particular, trimethoprim and gentamicin were identified to work synergistically for inhibiting the bacterial growth. Sensitivity analysis indicated gentamicin functions as a synergist for trimethoprim, and reduces its minimum inhibitory concentration for 40-fold. Validation study also confirmed that the trimethoprim-gentamicin synergistic cocktail effectively inhibited the growths of multiple strains of uropathogenic clinical isolates. With its effectiveness and simplicity, the MACO scheme possesses the potential to serve as a generic platform for identifying synergistic antimicrobial cocktails toward management of bacterial infection in the future.

  4. Immune Microenvironment in Colorectal Cancer: A New Hallmark to Change Old Paradigms

    OpenAIRE

    de la Cruz-Merino, Luis; Henao Carrasco, Fernando; Vicente Baz, David; Nogales Fernández, Esteban; Reina Zoilo, Juan José; Codes Manuel de Villena, Manuel; Pulido, Enrique Grande

    2011-01-01

    Impact of immune microenvironment in prognosis of solid tumors has been extensively studied in the last few years. Specifically in colorectal carcinoma, increased knowledge of the immune events around these tumors and their relation with clinical outcomes have led to consider immune microenvironment as one of the most important prognostic factors in this disease. In this review we will summarize and update the current knowledge with respect to this intriguing and complex new hallmark of cance...

  5. Synergistic Enhancement of Microwave Absorption Using Hybridized Polyaniline@helical CNTs with Dual Chirality.

    Science.gov (United States)

    Tian, Xin; Meng, Fanbin; Meng, Fanchen; Chen, Xiangnan; Guo, Yifan; Wang, Ying; Zhu, Wenjun; Zhou, Zuowan

    2017-05-10

    In this study, we designed a dual-chirality hierarchical structure to achieve a synergistically enhanced effect in microwave absorption via the hybridization of nanomaterials. Herein, polyaniline (PANi) nanorods with tunable chirality are grown on helical carbon nanotubes (HCNTs), a typical nanoscale chiral structure, through in situ polymerization. The experimental results show that the hierarchical hybrids (PANi@HCNTs) exhibit distinctly dual chirality and a significant enhancement in electromagnetic (EM) losses compared to those of either pure PANi or HCNTs. The maximum reflection loss of the as-prepared hybrids can reach -32.5 dB at 8.9 GHz. Further analysis demonstrates that combinations of chiral acid-doped PANi and coiled HCNTs with molecular and nanoscale chirality lead to synergistic effects resulting from the dual chirality. The so-called cross-polarization may result in additional interactions with induced EM waves in addition to multiscaled relaxations from functional groups and interfacial polarizations, which can benefit EM absorption.

  6. Changes in Cytokines of the Bone Microenvironment during Breast Cancer Metastasis

    Directory of Open Access Journals (Sweden)

    Donna M. Sosnoski

    2012-01-01

    Full Text Available It is commonly accepted that cancer cells interact with host cells to create a microenvironment favoring malignant colonization. The complex bone microenvironment produces an ever changing array of cytokines and growth factors. In this study, we examined levels of MCP-1, IL-6, KC, MIP-2, VEGF, MIG, and eotaxin in femurs of athymic nude mice inoculated via intracardiac injection with MDA-MB-231GFP human metastatic breast cancer cells, MDA-MB-231BRMS1GFP, a metastasis suppressed variant, or PBS. Animals were euthanized (day 3, 11, 19, 27 after injection to examine femoral cytokine levels at various stages of cancer cell colonization. The epiphysis contained significantly more cytokines than the diaphysis except for MIG which was similar throughout the bone. Variation among femurs was evident within all groups. By day 27, MCP-1, MIG, VEGF and eotaxin levels were significantly greater in femurs of cancer cell-inoculated mice. These pro-osteoclastic and angiogenic cytokines may manipulate the bone microenvironment to enhance cancer cell colonization.

  7. White piedra: further evidence of a synergistic infection.

    Science.gov (United States)

    Youker, Summer R; Andreozzi, Robert J; Appelbaum, Peter C; Credito, Kim; Miller, Jeffrey J

    2003-10-01

    White piedra is a fungal infection of the hair shaft caused by Trichosporon beigelii. A synergistic coryneform bacterial infection is often present with T beigelii. White piedra, although not commonly reported to infect scalp hair in North America, is an important consideration in the differential diagnosis of scalp hair concretions. We report a case of white piedra of scalp hair with synergistic coryneform bacterial infection in two sisters, both US natives. Culture and light and electronmicroscopic evidence of the synergistic infection are presented.

  8. Synergistic effects of irradiation of waste water

    International Nuclear Information System (INIS)

    Woodbridge, D.D.; Cooper, P.C.; Vandenburg, A.J.; Musselman, H.D.; Lowe, H.N.; Florida Inst. of Tech., Melbourne; Army Facilities Engineering Support Agency, Fort Belvoir, Va.

    1975-01-01

    Theoretical considerations of the use of high level radiation in the treatment of waste water have failed to consider the effects of the hydrated electron and the potential of possible synergistic effects of combining chlorine, oxygen, and irradiation. An extensive testing program at the University Center for Pollution Research of Florida Institute of Technology over the past four years has shown that irradiation of waste water samples immersed in an aqueous environment provide bacterial kill and reduction in organic pollution far greater than that obtained from theoretical considerations of G values and earlier experiments where the waste samples were not immersed in an aqueous environment. These testing programs have investigated the synergistic effects of combining oxygen and irradiation. Each of these combined treatments resulted in an increased bacterial kill factor. Tests on Staphylococcus aureus bacteria and fecal streptococcus bacteria indicate that the synergistic effects observed for fecal coliform bacteria also apply to the pathogenic bacteria. A statistical analysis of the data obtained shows the interrelationships between the various effects on the bacteria. A definite shielding factor due to the turbidity of the waste water has been shown to exist. Synergistic effects have been shown to significantly offset the shielding effects. Optimization of these synergistic effects can greatly increase the effectiveness of irradiation in the treatment of waste water. (orig.) [de

  9. Breast cancer by proxy: Can the microenvironment be both the cause and consequence?

    Energy Technology Data Exchange (ETDEWEB)

    Ronnov-Jessen, Lone; Bissell, Mina J

    2008-11-16

    Breast cancer is one of the most clear-cut examples of a solid tumor in which systemic cues play a decisive part in its development. The breast tissue is constantly subjected to changes in hormone levels and modifications in the microenvironment. This scenario is even more striking during tumor development because of the dramatic loss or aberration of basement membrane (BM) and myoepithelial cells and the gain of peritumoral myofibroblasts. We suggest that the microenvironment, defined here as all components of the mammary gland other than luminal and/or tumor epithelial cells, might be instrumental in maintaining organ integrity and in promoting, and at times even initiating, breast cancer development. As such, the tumor microenvironment and its constituents, alone or in combination, might serve as promising targets for therapy.

  10. Nature of strontium extraction by synergistic mixtures of chlorinated cobalt dicarbollide and polyethers

    International Nuclear Information System (INIS)

    Smirnov, I.V.; Stoyanov, E.S.; Vorob'eva, T.P.

    2003-01-01

    Extraction of strontium by synergistic mixtures of chlorinated cobalt dicarbollide (DCC) with different polyethers was studied. In the acidic media the distribution coefficients (D(Sr)) decreases in the order 15-crown-5 > PEG-400 > 18-crown-6 and does not correspond to the row of constants stability of the strontium complexes with these polyethers. When passing to the salt media (Li and Na nitrates) the row of D(Sr) is changed: PEG-400 > 18 crown 6 > 15 crown 5. IR-spectroscopy study has shown that in synergistic mixtures the proton forms [H 5O2 + .PEG], [H 5O2 + .(15-crown-5)2] and [H 3 O + .(18 crown 6)] cations, which are exchange on Sr 2+ resulting to formation [Sr 2+ .PEG], [Sr 2+ .(15-crown-5)2] and [Sr 2+ .(18-crown-6)(H 2 O)n] cations correspondingly. The PEG-400 is the best among polyethylene glycols, since its all six COC groups and two even more active OH groups complete the first co-ordination sphere of Sr 2+ . Extremely low extractability of Sr 2+ from acidic media in the presence of 18-crown-6 as compared with 15-crown-5 is mainly caused by the high stability of the [H 3 O + .(18-crown-6)] cation that is responsible for less extractable hydrated Sr complex formation. (author)

  11. Targets in the microenvironment of rectal cancer : A focus on angiogenic growth factors and chemokines

    NARCIS (Netherlands)

    Tamas, Karin Rita

    2015-01-01

    Cancer cells interact with each other, and with cells of the tumor microenvironment. This coincides with the production of numerous soluble factors which can stimulate cancer cell growth and migration. In addition the tumor microenvironment can facilitate cancer cells to escape the effect of

  12. Designing the stem cell microenvironment for guided connective tissue regeneration.

    Science.gov (United States)

    Bogdanowicz, Danielle R; Lu, Helen H

    2017-12-01

    Adult mesenchymal stem cells (MSCs) are an attractive cell source for regenerative medicine because of their ability to self-renew and their capacity for multilineage differentiation and tissue regeneration. For connective tissues, such as ligaments or tendons, MSCs are vital to the modulation of the inflammatory response following acute injury while also interacting with resident fibroblasts to promote cell proliferation and matrix synthesis. To date, MSC injection for connective tissue repair has yielded mixed results in vivo, likely due to a lack of appropriate environmental cues to effectively control MSC response and promote tissue healing instead of scar formation. In healthy tissues, stem cells reside within a complex microenvironment comprising cellular, structural, and signaling cues that collectively maintain stemness and modulate tissue homeostasis. Changes to the microenvironment following injury regulate stem cell differentiation, trophic signaling, and tissue healing. Here, we focus on models of the stem cell microenvironment that are used to elucidate the mechanisms of stem cell regulation and inspire functional approaches to tissue regeneration. Recent studies in this frontier area are highlighted, focusing on how microenvironmental cues modulate MSC response following connective tissue injury and, more importantly, how this unique cell environment can be programmed for stem cell-guided tissue regeneration. © 2017 New York Academy of Sciences.

  13. Effects of ground insulation and greenhouse microenvironment on ...

    African Journals Online (AJOL)

    A study was conducted at Egerton University, Njoro, Kenya to establish the potential of plastic digester to produce biogas under natural and greenhouse microenvironment. The specific objectives were to evaluate the effects of greenhouse and ground insulation on the rate and quality of biogas generation. A greenhouse ...

  14. Remodeling the blood–brain barrier microenvironment by natural products for brain tumor therapy

    Institute of Scientific and Technical Information of China (English)

    Xiao Zhao; Rujing Chen; Mei Liu; Jianfang Feng; Jun Chen; Kaili Hu

    2017-01-01

    Brain tumor incidence shows an upward trend in recent years; brain tumors account for 5% of adult tumors, while in children, this figure has increased to 70%. Moreover, 20%–30% of malignant tumors will eventually metastasize into the brain. Both benign and malignant tumors can cause an increase in intracranial pressure and brain tissue compression, leading to central nervous system(CNS) damage which endangers the patients’ lives. Despite the many approaches to treating brain tumors and the progress that has been made, only modest gains in survival time of brain tumor patients have been achieved. At present, chemotherapy is the treatment of choice for many cancers, but the special structure of the blood–brain barrier(BBB) limits most chemotherapeutic agents from passing through the BBB and penetrating into tumors in the brain. The BBB microenvironment contains numerous cell types, including endothelial cells, astrocytes, peripheral cells and microglia, and extracellular matrix(ECM). Many chemical components of natural products are reported to regulate the BBB microenvironment near brain tumors and assist in their treatment. This review focuses on the composition and function of the BBB microenvironment under both physiological and pathological conditions, and the current research progress in regulating the BBB microenvironment by natural products to promote the treatment of brain tumors.

  15. Self-Delivery Nanoparticles of Amphiphilic Methotrexate-Gemcitabine Prodrug for Synergistic Combination Chemotherapy via Effect of Deoxyribonucleotide Pools.

    Science.gov (United States)

    Wang, Yao; Huang, Ping; Hu, Minxi; Huang, Wei; Zhu, Xinyuan; Yan, Deyue

    2016-11-16

    The distinct and complementary biochemical mechanisms of folic acid analog methotrexate (MTX) and cytidine analog gemcitabine (GEM) make their synergistic combination effective. Unfortunately, such a combination faces severe pharmacokinetic problems and several transportation barriers. To overcome these problems, a new strategy of amphiphilic small molecule prodrug (ASMP) is developed to improve their synergistic combination effect. The ASMP was prepared by the amidation of the hydrophilic GEM with the hydrophobic MTX at a fixed ratio. Owing to its inherent amphiphilicity, the MTX-GEM ASMP self-assembled into stable nanoparticles (ASMP-NPs) with high drug loading capacity (100%), in which the MTX and GEM could self-deliver without any carriers and release synchronously in cancer cells. In vitro studies showed that the MTX-GEM ASMP-NPs could greatly improve the synergistic combination effects by the reason of arresting more S phase of the cell cycle and reducing levels of deoxythymidine triphosphate (dTTP), deoxyadenosine triphosphate (dATP), and deoxycytidine triphosphate (dCTP). The stronger synergistic effects caused the higher cell cytotoxicity and apoptotic ratio, and circumvented the multidrug resistance (MDR) of tumor cells. Additionally, MTX-GEM ASMP-NPs could achieve the same anticancer effect with the greatly reduced dosage compared with the free drugs according to the dose-reduction index (DRI) values of MTX and GEM in MTX-GEM ASMP-NPs, which may be beneficial for reducing the side effects.

  16. Graft polymerization of acrylic acid and methacrylic acid onto poly(vinylidene fluoride) powder in presence of metallic salt and sulfuric acid

    Science.gov (United States)

    Deng, Bo; Yu, Yang; Zhang, Bowu; Yang, Xuanxuan; Li, Linfan; Yu, Ming; Li, Jingye

    2011-02-01

    Poly(vinylidene fluoride) (PVDF) powder was grafted with acrylic acid (AAc) or methacrylic acid (MAA) by the pre-irradiation induced graft polymerization technique. The presence of graft chains was proven by FT-IR spectroscopy. The degree of grafting (DG) was calculated by the acid-base back titration method. The synergistic effect of acid and Mohr's salt on the grafting kinetics was examined. The results indicated that adding sulfuric acid and Mohr's salt simultaneously in AAc or MAA solutions led to a strong enhancement in the degree of grafting. The grafted PVDF powder was cast into microfiltration (MF) membranes using the phase inversion method and some properties of the obtained MF membranes were characterized.

  17. Graft polymerization of acrylic acid and methacrylic acid onto poly(vinylidene fluoride) powder in presence of metallic salt and sulfuric acid

    Energy Technology Data Exchange (ETDEWEB)

    Deng Bo [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, No. 2019, Jialuo Road, Jiading Dist., 201800 Shanghai (China); Yu Yang; Zhang Bowu; Yang Xuanxuan [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, No. 2019, Jialuo Road, Jiading Dist., 201800 Shanghai (China); Graduate University of Chinese Academy of Sciences, No. 19, Yuquan Road, Shijingshan Dist., 100049 Beijing (China); Li Linfan; Yu Ming [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, No. 2019, Jialuo Road, Jiading Dist., 201800 Shanghai (China); Li Jingye, E-mail: jingyeli@sinap.ac.c [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, No. 2019, Jialuo Road, Jiading Dist., 201800 Shanghai (China)

    2011-02-15

    Poly(vinylidene fluoride) (PVDF) powder was grafted with acrylic acid (AAc) or methacrylic acid (MAA) by the pre-irradiation induced graft polymerization technique. The presence of graft chains was proven by FT-IR spectroscopy. The degree of grafting (DG) was calculated by the acid-base back titration method. The synergistic effect of acid and Mohr's salt on the grafting kinetics was examined. The results indicated that adding sulfuric acid and Mohr's salt simultaneously in AAc or MAA solutions led to a strong enhancement in the degree of grafting. The grafted PVDF powder was cast into microfiltration (MF) membranes using the phase inversion method and some properties of the obtained MF membranes were characterized.

  18. Graft polymerization of acrylic acid and methacrylic acid onto poly(vinylidene fluoride) powder in presence of metallic salt and sulfuric acid

    International Nuclear Information System (INIS)

    Deng Bo; Yu Yang; Zhang Bowu; Yang Xuanxuan; Li Linfan; Yu Ming; Li Jingye

    2011-01-01

    Poly(vinylidene fluoride) (PVDF) powder was grafted with acrylic acid (AAc) or methacrylic acid (MAA) by the pre-irradiation induced graft polymerization technique. The presence of graft chains was proven by FT-IR spectroscopy. The degree of grafting (DG) was calculated by the acid-base back titration method. The synergistic effect of acid and Mohr's salt on the grafting kinetics was examined. The results indicated that adding sulfuric acid and Mohr's salt simultaneously in AAc or MAA solutions led to a strong enhancement in the degree of grafting. The grafted PVDF powder was cast into microfiltration (MF) membranes using the phase inversion method and some properties of the obtained MF membranes were characterized.

  19. Associations of erythrocyte fatty acid patterns with insulin resistance

    Science.gov (United States)

    Background: Synergistic and/or additive effects on cardiometabolic risk may be missed by examining individual fatty acids (FA). A pattern analysis may be a more useful approach. As well, it remains unclear whether erythrocyte fatty acid composition relates to insulin resistance among Hispanic/Latino...

  20. Glioblastoma cancer stem cell lines express functional acid sensing ion channels ASIC1a and ASIC3

    DEFF Research Database (Denmark)

    Tian, Yuemin; Bresenitz, Pia; Reska, Anna

    2017-01-01

    Acidic microenvironment is commonly observed in tumour tissues, including glioblastoma (GBM), the most aggressive and lethal brain tumour in adults. Acid sensing ion channels (ASICs) are neuronal voltage-insensitive sodium channels, which are sensors of extracellular protons. Here we studied...

  1. Synergistic effect of eugenol with Colistin against clinical isolated Colistin-resistant Escherichia coli strains

    Directory of Open Access Journals (Sweden)

    Yi-ming Wang

    2018-01-01

    Full Text Available Abstract Background Bacterial infections have become more challenging to treat due to the emergence of multidrug-resistant pathogenic bacteria. Combined antibiotics prove to be a relatively effective method to control such resistant strains. This study aim to investigate synergistic activity of eugenol combined with colistin against a collection of clinical isolated Escherichia coli (E.coli strains, and to evaluate potential interaction. Methods Antimicrobial susceptibility, minimum inhibitory concentration (MIC and fractional inhibitory concentration index (FICI of the bacteria were determined by disk diffusion assay, broth microdilution method and checkerboard assay, respectively. The mcr-1 mRNA expression was measured by Real-time PCR. To predict possible interactions between eugenol and MCR-1, molecular docking assay was taken. Results For total fourteen strains including eight colistin-resistant strains, eugenol was determined with MIC values of 4 to 8 μg/mL. Checkerboard dilution test suggested that eugenol exhibited synergistic activity when combined with colistin (FICI ranging from 0.375 to 0.625. Comparison analysis of Real-time PCR showed that synergy could significantly down-regulate expression of mcr-1 gene. A metal ion coordination bond with catalytic zinc atom and a hydrogen bond with crucial amino acid residue Ser284 of MCR-1 were observed after molecular docking, indicating antibacterial activity and direct molecular interactions of eugenol with MCR-1 protein. Conclusions Our results demonstrated that eugenol exhibited synergistic effect with colistin and enhanced its antimicrobial activity. This might further contribute to the antibacterial actions against colistin-resistant E.coli strains. Graphical abstract Synergistic effect of eugenol with colistin against colistin-resistant Escherichia coli isolates.

  2. Zebrafish seizure model identifies p,p -DDE as the dominant contaminant of fetal California sea lions that accounts for synergistic activity with domoic acid.

    Science.gov (United States)

    Tiedeken, Jessica A; Ramsdell, John S

    2010-04-01

    Fetal poisoning of California sea lions (CSLs; Zalophus californianus) has been associated with exposure to the algal toxin domoic acid. These same sea lions accumulate a mixture of persistent environmental contaminants including pesticides and industrial products such as polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). Developmental exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) and its stable metabolite 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene (p,p -DDE) has been shown to enhance domoic acid-induced seizures in zebrafish; however, the contribution of other co-occurring contaminants is unknown. We formulated a mixture of contaminants to include PCBs, PBDEs, hexachlorocyclohexane (HCH), and chlordane at levels matching those reported for fetal CSL blubber to determine the impact of co-occurring persistent contaminants with p,p -DDE on chemically induced seizures in zebrafish as a model for the CSLs. Embryos were exposed (6-30 hr postfertilization) to p,p -DDE in the presence or absence of a defined contaminant mixture prior to neurodevelopment via either bath exposure or embryo yolk sac microinjection. After brain maturation (7 days postfertilization), fish were exposed to a chemical convulsant, either pentylenetetrazole or domoic acid; resulting seizure behavior was then monitored and analyzed for changes, using cameras and behavioral tracking software. Induced seizure behavior did not differ significantly between subjects with embryonic exposure to a contaminant mixture and those exposed to p,p -DDE only. These studies demonstrate that p,p -DDE--in the absence of PCBs, HCH, chlordane, and PBDEs that co-occur in fetal sea lions--accounts for the synergistic activity that leads to greater sensitivity to domoic acid seizures.

  3. Critical assessment of day time traffic noise level at curbside open-air microenvironment of Kolkata City, India.

    Science.gov (United States)

    Kundu Chowdhury, Anirban; Debsarkar, Anupam; Chakrabarty, Shibnath

    2015-01-01

    The objective of the research work is to assess day time traffic noise level at curbside open-air microenvironment of Kolkata city, India under heterogeneous environmental conditions. Prevailing traffic noise level in terms of A-weighted equivalent noise level (Leq) at the microenvironment was in excess of 12.6 ± 2.1 dB(A) from the day time standard of 65 dB(A) for commercial area recommended by the Central Pollution Control Board (CPCB) of India. Noise Climate and Traffic Noise Index of the microenvironment were accounted for 13 ± 1.8 dB(A) and 88.8 ± 6.1 dB(A) respectively. A correlation analysis explored that prevailing traffic noise level of the microenvironment had weak negative (-0.21; p air temperature and relative humidity. A Varimax rotated principal component analysis explored that motorized traffic volume had moderate positive loading with background noise component (L90, L95, L99) and prevailing traffic noise level had very strong positive loading with peak noise component (L1, L5, L10). Background and peak noise component cumulatively explained 80.98 % of variance in the data set. Traffic noise level at curbside open-air microenvironment of Kolkata City was higher than the standard recommended by CPCB of India. It was highly annoying also. Air temperature and relative humidity had little influence and the peak noise component had the most significant influence on the prevailing traffic noise level at curbside open-air microenvironment. Therefore, traffic noise level at the microenvironment of the city can be reduced with careful honking and driving.

  4. Synergistic combination of valproic acid and oncolytic parvovirus H-1PV as a potential therapy against cervical and pancreatic carcinomas.

    Science.gov (United States)

    Li, Junwei; Bonifati, Serena; Hristov, Georgi; Marttila, Tiina; Valmary-Degano, Séverine; Stanzel, Sven; Schnölzer, Martina; Mougin, Christiane; Aprahamian, Marc; Grekova, Svitlana P; Raykov, Zahari; Rommelaere, Jean; Marchini, Antonio

    2013-10-01

    The rat parvovirus H-1PV has oncolytic and tumour-suppressive properties potentially exploitable in cancer therapy. This possibility is being explored and results are encouraging, but it is necessary to improve the oncotoxicity of the virus. Here we show that this can be achieved by co-treating cancer cells with H-1PV and histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA). We demonstrate that these agents act synergistically to kill a range of human cervical carcinoma and pancreatic carcinoma cell lines by inducing oxidative stress, DNA damage and apoptosis. Strikingly, in rat and mouse xenograft models, H-1PV/VPA co-treatment strongly inhibits tumour growth promoting complete tumour remission in all co-treated animals. At the molecular level, we found acetylation of the parvovirus nonstructural protein NS1 at residues K85 and K257 to modulate NS1-mediated transcription and cytotoxicity, both of which are enhanced by VPA treatment. These results warrant clinical evaluation of H-1PV/VPA co-treatment against cervical and pancreatic ductal carcinomas. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

  5. Impact of Microenvironment and Stem-Like Plasticity in Cholangiocarcinoma

    DEFF Research Database (Denmark)

    Raggi, Chiara; Invernizzi, Pietro; Andersen, Jesper Bøje

    2014-01-01

    or tumor microenvironment (TME) likely promotes initiation and progression of this malignancy contributing to its heterogeneity. This review will emphasize the dynamic interplay between stem-like intrinsic and TME-extrinsic pathways, which may represent novel options for multi-targeted therapies in CCA....

  6. Comparison of radiofrequency electromagnetic field exposure levels in different everyday microenvironments in an international context.

    Science.gov (United States)

    Sagar, Sanjay; Adem, Seid M; Struchen, Benjamin; Loughran, Sarah P; Brunjes, Michael E; Arangua, Lisa; Dalvie, Mohamed Aqiel; Croft, Rodney J; Jerrett, Michael; Moskowitz, Joel M; Kuo, Tony; Röösli, Martin

    2018-05-01

    The aim of this study was to quantify RF-EMF exposure applying a tested protocol of RF-EMF exposure measurements using portable devices with a high sampling rate in different microenvironments of Switzerland, Ethiopia, Nepal, South Africa, Australia and the United States of America. We used portable measurement devices for assessing RF-EMF exposure in 94 outdoor microenvironments and 18 public transport vehicles. The measurements were taken either by walking with a backpack with the devices at the height of the head and a distance of 20-30 cm from the body, or driving a car with the devices mounted on its roof, which was 170-180 cm above the ground. The measurements were taken for about 30 min while walking and about 15-20 min while driving in each microenvironment, with a sampling rate of once every 4 s (ExpoM-RF) and 5 s (EME Spy 201). Mean total RF-EMF exposure in various outdoor microenvironments varied between 0.23 V/m (non-central residential area in Switzerland) and 1.85 V/m (university area in Australia), and across modes of public transport between 0.32 V/m (bus in rural area in Switzerland) and 0.86 V/m (Auto rickshaw in urban area in Nepal). For most outdoor areas the major exposure contribution was from mobile phone base stations. Otherwise broadcasting was dominant. Uplink from mobile phone handsets was generally very small, except in Swiss trains and some Swiss buses. This study demonstrates high RF-EMF variability between the 94 selected microenvironments from all over the world. Exposure levels tended to increase with increasing urbanity. In most microenvironments downlink from mobile phone base stations is the most relevant contributor. Copyright © 2018 Elsevier Ltd. All rights reserved.

  7. [Design of an anesthesia and micro-environment information management system in mobile operating room].

    Science.gov (United States)

    Wang, Xianwen; Liu, Zhiguo; Zhang, Wenchang; Wu, Qingfu; Tan, Shulin

    2013-08-01

    We have designed a mobile operating room information management system. The system is composed of a client and a server. A client, consisting of a PC, medical equipments, PLC and sensors, provides the acquisition and processing of anesthesia and micro-environment data. A server is a powerful computer that stores the data of the system. The client gathers the medical device data by using the C/S mode, and analyzes the obtained HL7 messages through the class library call. The client collects the micro-environment information with PLC, and finishes the data reading with the OPC technology. Experiment results showed that the designed system could manage the patient anesthesia and micro-environment information well, and improve the efficiency of the doctors' works and the digital level of the mobile operating room.

  8. 3D bioprinting: improving in vitro models of metastasis with heterogeneous tumor microenvironments

    Directory of Open Access Journals (Sweden)

    Jacob L. Albritton

    2017-01-01

    Full Text Available Even with many advances in treatment over the past decades, cancer still remains a leading cause of death worldwide. Despite the recognized relationship between metastasis and increased mortality rate, surprisingly little is known about the exact mechanism of metastatic progression. Currently available in vitro models cannot replicate the three-dimensionality and heterogeneity of the tumor microenvironment sufficiently to recapitulate many of the known characteristics of tumors in vivo. Our understanding of metastatic progression would thus be boosted by the development of in vitro models that could more completely capture the salient features of cancer biology. Bioengineering groups have been working for over two decades to create in vitro microenvironments for application in regenerative medicine and tissue engineering. Over this time, advances in 3D printing technology and biomaterials research have jointly led to the creation of 3D bioprinting, which has improved our ability to develop in vitro models with complexity approaching that of the in vivo tumor microenvironment. In this Review, we give an overview of 3D bioprinting methods developed for tissue engineering, which can be directly applied to constructing in vitro models of heterogeneous tumor microenvironments. We discuss considerations and limitations associated with 3D printing and highlight how these advances could be harnessed to better model metastasis and potentially guide the development of anti-cancer strategies.

  9. 3D bioprinting: improving in vitro models of metastasis with heterogeneous tumor microenvironments.

    Science.gov (United States)

    Albritton, Jacob L; Miller, Jordan S

    2017-01-01

    Even with many advances in treatment over the past decades, cancer still remains a leading cause of death worldwide. Despite the recognized relationship between metastasis and increased mortality rate, surprisingly little is known about the exact mechanism of metastatic progression. Currently available in vitro models cannot replicate the three-dimensionality and heterogeneity of the tumor microenvironment sufficiently to recapitulate many of the known characteristics of tumors in vivo Our understanding of metastatic progression would thus be boosted by the development of in vitro models that could more completely capture the salient features of cancer biology. Bioengineering groups have been working for over two decades to create in vitro microenvironments for application in regenerative medicine and tissue engineering. Over this time, advances in 3D printing technology and biomaterials research have jointly led to the creation of 3D bioprinting, which has improved our ability to develop in vitro models with complexity approaching that of the in vivo tumor microenvironment. In this Review, we give an overview of 3D bioprinting methods developed for tissue engineering, which can be directly applied to constructing in vitro models of heterogeneous tumor microenvironments. We discuss considerations and limitations associated with 3D printing and highlight how these advances could be harnessed to better model metastasis and potentially guide the development of anti-cancer strategies. © 2017. Published by The Company of Biologists Ltd.

  10. St8sia2 deficiency plus juvenile cannabis exposure in mice synergistically affect higher cognition in adulthood.

    Science.gov (United States)

    Tantra, Martesa; Kröcher, Tim; Papiol, Sergi; Winkler, Daniela; Röckle, Iris; Jatho, Jasmin; Burkhardt, Hannelore; Ronnenberg, Anja; Gerardy-Schahn, Rita; Ehrenreich, Hannelore; Hildebrandt, Herbert

    2014-12-15

    The neural cell adhesion molecule (NCAM) and its functionally linked polysialyltransferases, ST8SIA2 and ST8SIA4, are crucial for synaptic plasticity. Variations in encoding genes have been associated with mental illness. Since cannabinoids can alter NCAM polysialylation, we hypothesized that delta-9-tetrahydrocannabinol (Δ9-THC) might act as environmental 'second hit' regarding cognition of St8sia2(-/-) mice. These mice show per se minor behavioral abnormalities, consisting of reduced anxiety and mild cognitive deficits. Chronic Δ9-THC treatment of juvenile male wildtype mice (St8sia2(+/+)) (7mg/kg every other day over 3 weeks) did not appreciably affect cognition. St8sia2(-/-) mice, however, displayed a synergistic negative consequence of Δ9-THC on learning/memory, accompanied by polysialic acid-free NCAM-180 reduction in hippocampus and polysialic acid increase in dentate outer molecular layer. These synergistic effects became obvious only months after the last Δ9-THC. We conclude that juvenile cannabis exposure may cause delayed but lasting damage on cognition in subjects genetically predisposed to altered NCAM polysialylation. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Effect of Interleukin 1b on rat thymus microenvironment

    Directory of Open Access Journals (Sweden)

    M Artico

    2009-12-01

    Full Text Available The effect of interleukin 1b on the thymus of control and chemically sympathectomized adult and aged rats was studied with the aim of assessing the importance of adrenergic nerve fibres (ANF in the regulation of some immunological functions.The whole thymus was removed from normal, sympathectomized (with the neurotoxin 6-OH-dopamine and treated (interleukin 1b rats. Thymic slices were stained with eosin orange (for the recognition of microanatomical details of the thymic microenvironment and with Bodian’s method for staining of nerve fibres. Histofluorescence microscopy was employed for staining ANF and immunofluorescence was used for detecting NPY-like immunoreactivity. All images were submitted to quantitative morphometrical analysis and statistical analysis of data. Moreover, the amount of proteins and noradrenaline was measured on thymic homogenates. The results indicate that in normal conditions the formation of the thymic nerve plexi in the rat is complex: the majority of ANF are destroyed after chemical sympathectomy with 6-OH-dopamine and do not change after treatment with interleukin 1b; on the contrary, treatment with interleukin 1b induces substantial changes in the fresh weight of the thymus, the thymic microenvironment, thymic nerve fibers, ANF, NPY-like positive nerve fibres, and on the total amount of proteins and noradrenaline in rat thymic tissue homogenates.Immunostimulation with interleukin 1b induces substantial changes in the whole thymus, in its microenvironment and in ANF and NPY-like nerve fibres. After chemical sympathectomy, no significant immune response was evoked by interleukin 1b, since the majority of ANF was destroyed by chemical sympathectomy.

  12. Brief Communication: Tissue-engineered Microenvironment Systems for Modeling Human Vasculature

    Science.gov (United States)

    Tourovskaia, Anna; Fauver, Mark; Kramer, Gregory; Simonson, Sara; Neumann, Thomas

    2015-01-01

    The high attrition rate of drug candidates late in the development process has led to an increasing demand for test assays that predict clinical outcome better than conventional 2D cell culture systems and animal models. Government agencies, the military, and the pharmaceutical industry have started initiatives for the development of novel in-vitro systems that recapitulate functional units of human tissues and organs. There is growing evidence that 3D cell arrangement, co-culture of different cell types, and physico-chemical cues lead to improved predictive power. A key element of all tissue microenvironments is the vasculature. Beyond transporting blood the microvasculature assumes important organ-specific functions. It is also involved in pathologic conditions, such as inflammation, tumor growth, metastasis, and degenerative diseases. To provide a tool for modeling this important feature of human tissue microenvironments, we developed a microfluidic chip for creating tissue-engineered microenvironment systems (TEMS) composed of tubular cell structures. Our chip design encompasses a small chamber that is filled with an extracellular matrix (ECM) surrounding one or more tubular channels. Endothelial cells seeded into the channels adhere to the ECM walls and grow into perfusable tubular tissue structures that are fluidically connected to upstream and downstream fluid channels in the chip. Using these chips we created models of angiogenesis, the blood-brain-barrier (BBB), and tumor-cell extravasation. Our angiogenesis model recapitulates true angiogenesis, in which sprouting occurs from a “parent” vessel in response to a gradient of growth factors. Our BBB model is composed of a microvessel generated from brain-specific endothelial cells (ECs) within an ECM populated with astrocytes and pericytes. Our tumor-cell extravasation model can be utilized to visualize and measure tumor-cell migration through vessel walls into the surrounding matrix. The described

  13. pH-Responsive Magnetic Mesoporous Silica-Based Nanoplatform for Synergistic Photodynamic Therapy/Chemotherapy.

    Science.gov (United States)

    Tang, Xiang-Long; Jing, Feng; Lin, Ben-Lan; Cui, Sheng; Yu, Ru-Tong; Shen, Xiao-Dong; Wang, Ting-Wei

    2018-05-02

    By overcoming drug resistance and subsequently enhancing the treatment, the combination therapy of photodynamic therapy (PDT) and chemotherapy has promising potential for cancer treatment. However, the major challenge is how to establish an advanced nanoplatform that can be efficiently guided to tumor sites and can then stably release both chemotherapy drugs and a photosensitizer simultaneously and precisely. In this study, which considered the possibility and targeting efficiency of a magnetic targeting strategy, a novel Fe 3 O 4 @mSiO 2 (DOX)@HSA(Ce6) nanoplatform was successfully built; this platform could be employed as an efficient synergistic antitumor nanoplatform with magnetic guidance for highly specific targeting and retention. Doxorubicin (DOX) molecules were loaded into mesoporous silica with high loading capability, and the mesoporous channels were blocked by a polydopamine coating. Human serum albumin (HSA) was conjugated to the outer surface to increase the biocompatibility and blood circulation time, as well as to provide a vehicle for loading photosensitizer chlorin e6 (Ce6). The sustained release of DOX under acidic conditions and the PDT induced by red light exerted a synergistic inhibitory effect on glioma cells. Our experiments demonstrated that the pH-responsive Fe 3 O 4 @mSiO 2 (DOX)@HSA(Ce6) nanoplatform was guided to the tumor region by magnetic targeting and that the nanoplatform suppressed glioma tumor growth efficiently, implying that the system is a highly promising photodynamic therapy/chemotherapy combination nanoplatform with synergistic effects for cancer treatment.

  14. Breast cancer by proxy: can the microenvironment be both the cause and consequence?

    DEFF Research Database (Denmark)

    Rønnov-Jessen, Lone; Bissell, Mina J

    2009-01-01

    development because of the dramatic loss or aberration of basement membrane (BM) and myoepithelial cells and the gain of peritumoral myofibroblasts. We suggest that the microenvironment, defined here as all components of the mammary gland other than luminal and/or tumor epithelial cells, might be instrumental...... in maintaining organ integrity and in promoting, and at times even initiating, breast cancer development. As such, the tumor microenvironment and its constituents, alone or in combination, might serve as promising targets for therapy....

  15. T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments.

    Science.gov (United States)

    Hawkins, Edwin D; Duarte, Delfim; Akinduro, Olufolake; Khorshed, Reema A; Passaro, Diana; Nowicka, Malgorzata; Straszkowski, Lenny; Scott, Mark K; Rothery, Steve; Ruivo, Nicola; Foster, Katie; Waibel, Michaela; Johnstone, Ricky W; Harrison, Simon J; Westerman, David A; Quach, Hang; Gribben, John; Robinson, Mark D; Purton, Louise E; Bonnet, Dominique; Lo Celso, Cristina

    2016-10-27

    It is widely accepted that complex interactions between cancer cells and their surrounding microenvironment contribute to disease development, chemo-resistance and disease relapse. In light of this observed interdependency, novel therapeutic interventions that target specific cancer stroma cell lineages and their interactions are being sought. Here we studied a mouse model of human T-cell acute lymphoblastic leukaemia (T-ALL) and used intravital microscopy to monitor the progression of disease within the bone marrow at both the tissue-wide and single-cell level over time, from bone marrow seeding to development/selection of chemo-resistance. We observed highly dynamic cellular interactions and promiscuous distribution of leukaemia cells that migrated across the bone marrow, without showing any preferential association with bone marrow sub-compartments. Unexpectedly, this behaviour was maintained throughout disease development, from the earliest bone marrow seeding to response and resistance to chemotherapy. Our results reveal that T-ALL cells do not depend on specific bone marrow microenvironments for propagation of disease, nor for the selection of chemo-resistant clones, suggesting that a stochastic mechanism underlies these processes. Yet, although T-ALL infiltration and progression are independent of the stroma, accumulated disease burden leads to rapid, selective remodelling of the endosteal space, resulting in a complete loss of mature osteoblastic cells while perivascular cells are maintained. This outcome leads to a shift in the balance of endogenous bone marrow stroma, towards a composition associated with less efficient haematopoietic stem cell function. This novel, dynamic analysis of T-ALL interactions with the bone marrow microenvironment in vivo, supported by evidence from human T-ALL samples, highlights that future therapeutic interventions should target the migration and promiscuous interactions of cancer cells with the surrounding microenvironment

  16. Persistent injury-associated anemia: the role of the bone marrow microenvironment.

    Science.gov (United States)

    Millar, Jessica K; Kannan, Kolenkode B; Loftus, Tyler J; Alamo, Ines G; Plazas, Jessica; Efron, Philip A; Mohr, Alicia M

    2017-06-15

    The regulation of erythropoiesis involves hematopoietic progenitor cells, bone marrow stroma, and the microenvironment. Following severe injury, a hypercatecholamine state develops that is associated with increased mobilization of hematopoietic progenitor cells to peripheral blood and decreased growth of bone marrow erythroid progenitor cells that manifests clinically as a persistent injury-associated anemia. Changes within the bone marrow microenvironment influence the development of erythroid progenitor cells. Therefore, we sought to determine the effects of lung contusion, hemorrhagic shock, and chronic stress on the hematopoietic cytokine response. Bone marrow was obtained from male Sprague-Dawley rats (n = 6/group) killed 7 d after lung contusion followed by hemorrhagic shock (LCHS) or LCHS followed by daily chronic restraint stress (LCHS/CS). End point polymerase chain reaction was performed for interleukin-1β, interleukin-10, stem cell factor, transforming growth factor-β, high-mobility group box-1 (HMGB-1), and B-cell lymphoma-extra large. Seven days following LCHS and LCHS/CS, bone marrow expression of prohematopoietic cytokines (interleukin-1β, interleukin-10, stem cell factor, and transforming growth factor-β) was significantly decreased, and bone marrow expression of HMGB-1 was significantly increased. B-cell lymphoma-extra large bone marrow expression was not affected by LCHS or LCHS/CS (naïve: 44 ± 12, LCHS: 44 ± 12, LCHS/CS: 37 ± 1, all P > 0.05). The bone marrow microenvironment was significantly altered following severe trauma in a rodent model. Prohematopoietic cytokines were downregulated, and the proinflammatory cytokine HMGB-1 had increased bone marrow expression. Modulation of the bone marrow microenvironment may represent a therapeutic strategy following severe trauma to alleviate persistent injury-associated anemia. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Interaction of Benzimidazoles and Benzotriazole: Its Corrosion Protection Properties on Mild Steel in Hydrochloric Acid

    Science.gov (United States)

    Ramya, K.; Mohan, Revathi; Joseph, Abraham

    2014-11-01

    Synergistic hydrogen-bonded interaction of alkyl benzimidazoles and 1,2,3-benzotrizole and its corrosion protection properties on mild steel in hydrochloric acid at different temperatures have been studied using polarization, EIS, adsorption, surface studies, and computational methods. The extent of synergistic interaction increases with temperature. Quantum chemical approach is used to calculate some electronic properties of the molecules and to ascertain the synergistic interaction, inhibitive effect, and molecular structures. The corrosion inhibition efficiencies and the global chemical reactivity relate to some parameters, such as total energy, E HOMO, E LUMO, and gap energy (Δ E). 1,2,3-Benzotrizole interacts with benzimidazoles derivatives up to a bond length of approximately 1.99 Å. This interaction represents the formation of a hydrogen bond between the 1,2,3-benzotrizole and benzimidazoles. This synergistic interaction of 1,2,3-benzotrizole and benzimidazole derivatives offers extended inhibition efficiency toward mild steel in hydrochloric acid.

  18. Multiple Myeloma Macrophages: Pivotal Players in the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Simona Berardi

    2013-01-01

    Full Text Available Tumor microenvironment is essential for multiple myeloma (MM growth, progression, and drug resistance through provision of survival signals and secretion of growth and proangiogenic factors. This paper examines the importance of macrophages within MM bone marrow (BM microenvironment, referred to as MM-associated macrophages, as a potential niche component that supports tumor plasma cells. These macrophages are derived from peripheral blood monocytes recruited into the tumor. Upon activation by MM plasma cells and mesenchymal stromal cells, macrophages can release growth factors, proteolytic enzymes, cytokines, and inflammatory mediators that promote plasma cell growth and survival. Macrophages promote tumor progression through several mechanisms including angiogenesis, growth, and drug resistance. Indeed, these macrophages are essential for the induction of an angiogenic response through vasculogenic mimicry, and this ability proceeds in step with progression of the plasma cell tumors. Data suggest that macrophages play an important role in the biology and survival of patients with MM, and they may be a target for the MM antivascular management.

  19. Intravenous microemulsion of docetaxel containing an anti-tumor synergistic ingredient (Brucea javanica oil: formulation and pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Ma S

    2013-10-01

    Full Text Available Shilin Ma,1 Fen Chen,1 Xiaohui Ye,2 Yingjie Dong,2 Yingna Xue,1 Heming Xu,1 Wenji Zhang,1 Shuangshuang Song,1 Li Ai,2 Naixian Zhang,2 Weisan Pan1 1School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 2Liaoning Institute of Pharmaceutical Industry, Liaoning, The People's Republic of China Abstract: The purpose of this study was to develop a docetaxel microemulsion containing an anti-tumor synergistic ingredient (Brucea javanica oil and to investigate the characteristics of the microemulsion. Brucea javanica oil contains oleic acid and linoleic acids that have been shown by animal and human studies to inhibit tumor formation. The microemulsion containing Brucea javanica oil, medium-chain triglyceride, soybean lecithin, Solutol®HS 15, PEG 400, and water was developed for docetaxel intravenous administration. A formulation with higher drug content, lower viscosity, and smaller particle size was developed. The droplet size distribution of the dispersed phase of the optimized microemulsion was 13.5 nm, determined using a dynamic light scattering technique. The small droplet size enabled the microemulsion droplets to escape from uptake and phagocytosis by the reticuloendothelial system and increased the circulation time of the drug. The zeta potential was -41.3 mV. The optimized microemulsion was pale yellow, transparent, and non-opalescent in appearance. The value of the combination index was 0.58, showing that there was a synergistic effect when docetaxel was combined with Brucea javanica oil. After a single intravenous infusion dose (10 mg/kg in male Sprague Dawley rats, the area under the curve of the microemulsion was higher and the half-time was longer compared with that of docetaxel solution alone, and showed superior pharmacokinetic characteristics. These results indicate that this preparation of docetaxel in emulsion is likely to provide an excellent prospect for clinical tumor treatment. Keywords: microemulsion, docetaxel

  20. Local iron homeostasis in the breast ductal carcinoma microenvironment

    International Nuclear Information System (INIS)

    Marques, Oriana; Porto, Graça; Rêma, Alexandra; Faria, Fátima; Cruz Paula, Arnaud; Gomez-Lazaro, Maria; Silva, Paula; Martins da Silva, Berta; Lopes, Carlos

    2016-01-01

    While the deregulation of iron homeostasis in breast epithelial cells is acknowledged, iron-related alterations in stromal inflammatory cells from the tumor microenvironment have not been explored. Immunohistochemistry for hepcidin, ferroportin 1 (FPN1), transferrin receptor 1 (TFR1) and ferritin (FT) was performed in primary breast tissues and axillary lymph nodes in order to dissect the iron-profiles of epithelial cells, lymphocytes and macrophages. Furthermore, breast carcinoma core biopsies frozen in optimum cutting temperature (OCT) compound were subjected to imaging flow cytometry to confirm FPN1 expression in the cell types previously evaluated and determine its cellular localization. We confirm previous results by showing that breast cancer epithelial cells present an ‘iron-utilization phenotype’ with an increased expression of hepcidin and TFR1, and decreased expression of FT. On the other hand, lymphocytes and macrophages infiltrating primary tumors and from metastized lymph nodes display an ‘iron-donor’ phenotype, with increased expression of FPN1 and FT, concomitant with an activation profile reflected by a higher expression of TFR1 and hepcidin. A higher percentage of breast carcinomas, compared to control mastectomy samples, present iron accumulation in stromal inflammatory cells, suggesting that these cells may constitute an effective tissue iron reservoir. Additionally, not only the deregulated expression of iron-related proteins in epithelial cells, but also on lymphocytes and macrophages, are associated with clinicopathological markers of breast cancer poor prognosis, such as negative hormone receptor status and tumor size. The present results reinforce the importance of analyzing the tumor microenvironment in breast cancer, extending the contribution of immune cells to local iron homeostasis in the tumor microenvironment context

  1. Tumor microenvironment in invasive lobular carcinoma: possible therapeutic targets.

    Science.gov (United States)

    Nakagawa, Saki; Miki, Yasuhiro; Miyashita, Minoru; Hata, Shuko; Takahashi, Yayoi; Rai, Yoshiaki; Sagara, Yasuaki; Ohi, Yasuyo; Hirakawa, Hisashi; Tamaki, Kentaro; Ishida, Takanori; Watanabe, Mika; Suzuki, Takashi; Ohuchi, Noriaki; Sasano, Hironobu

    2016-01-01

    Invasive ductal and lobular carcinomas (IDC and ILC) are the two most common histological types of breast cancer, and have been considered to develop from terminal duct lobular unit but their molecular, pathological, and clinical features are markedly different between them. These differences could be due to different mechanisms of carcinogenesis and tumor microenvironment, especially cancer-associated fibroblasts (CAFs) but little has been explored in this aspect. Therefore, in this study, we evaluated the status of angiogenesis, maturation of intratumoral microvessels, and proliferation of CAFs using immunohistochemistry and PCR array analysis to explore the differences of tumor microenvironment between ILC and IDC. We studied grade- and age-matched, luminal-like ILC and IDC. We immunolocalized CD34 and αSMA for an evaluation of CAFs and CD31, Vasohibin-1, a specific marker of proliferative endothelial cells and nestin, a marker of pericytes for studying the status of proliferation and maturation of intratumoral microvessel. We also performed PCR array analysis to evaluate angiogenic factors in tumor stromal components. The number of CAFs, microvessel density, and vasohibin-1/CD31 positive ratio were all significantly higher in ILC than IDC but nestin immunoreactivity in intratumoral microvessel was significantly lower in ILC. These results did indicate that proliferation of CAFs and endothelial cells was more pronounced in ILC than IDC but newly formed microvessels were less mature than those in IDC. PCR array analysis also revealed that IGF-1 expression was higher in ILC than IDC. This is the first study to demonstrate the differences of tumor microenvironment including CAFs and proliferation and maturation of intratumoral vessels between ILC and IDC.

  2. Overview of synergistic aging effects

    International Nuclear Information System (INIS)

    Steigelmann, W.; Farber, M.

    1982-01-01

    Proper, technically defensible qualification of materials and equipment for nuclear power facilities requires that the effects of combined environment exposures be addressed. The full significance of synergistic effects resulting from combined stresses still remains largely an unknown to be provided for by use of conservatisms, allowing a sizeable margin in test programs and analyses to account for possible combined effects. However, these margins, when applied to sequential aging tests, may under- or over-estimate the qualified life of the material or equipment. Experimentation with radiation dose-rate effects, simultaneous vs. sequential ordered exposures, and other combined environment testing are highlighted in this paper to provide an overview of the current state-of-knowledge concerning synergistic effects and their significance to qualification programs

  3. Photocatalytic degradation of clofibric acid, carbamazepine and iomeprol using conglomerated TiO2 and activated carbon in aqueous suspension.

    Science.gov (United States)

    Ziegmann, Markus; Frimmel, Fritz H

    2010-01-01

    The combination of powdered activated carbon (PAC) and TiO(2) has been tested for synergistic/antagonistic effects in the photocatalytic degradation of carbamazepine, clofibric acid and iomeprol. Synergistic effects are thought to be caused by rapid adsorption on the PAC surface followed by diffusion to the TiO(2) surface and photocatalytic degradation. The Freundlich constant K(F) was used for comparing the sorption properties of the three substances and it was found that K(F) for clofibric acid was 3 times lower than for carbamazepine and iomeprol, regardless of the kind of PAC used. A PAC with a distinct tendency to form conglomerates was selected so that a high percentage of the PAC surface was in direct proximity to the TiO(2) surface. The photocatalytic degradation of the pharmaceutically active compounds studied followed pseudo-first order kinetics. Synergistic effects only occurred for clofibric acid (factor 1.5) and an inverse relationship between adsorption affinity and synergistic effects was found. High affinity of the target substances to the PAC surface seemed to be counterproductive for the photocatalytic degradation.

  4. [Study on sweat gland regeneration induced by microenvironment of three-dimensional bioprinting].

    Science.gov (United States)

    Yao, B; Xie, J F; Huang, S; Fu, X B

    2017-01-20

    Sweat glands are abundant in the body surface and essential for thermoregulation. Sweat glands fail to conduct self-repair in patients with large area of burn and trauma, and the body temperature of patients increases in hot climate, which may cause shock or even death. Now, co-culture system, reprogramming, and tissue engineering have made progresses in inducing sweat gland regeneration, but the inductive efficiency and duration need to be improved. Cellular microenvironment can regulate cell biological behavior, including cell migration and cell differentiation. This article reviews the studies of establishment of microenvironment in vitro by three-dimensional bioprinting technology to induce sweat gland regeneration.

  5. Synergistic effects of irradiation of waste-water

    International Nuclear Information System (INIS)

    Woodbridge, D.D.

    1975-01-01

    Water is an absolute necessity for all forms of animal and plant life. As man's requirements for water increase, the need for better methods of purification also increase. Technology has been slow to develop new methods of water treatment for the direct utilization of waste-water. Many new construction projects are at a standstill because waste-water treatment methods have not been developed to handle adequately the ever-increasing flow of sewage. Theoretical considerations of the use of high-level radiation in the treatment of waste-water have failed to consider the effects of the hydrated electron, and the potential of the possible synergistic effects of combining chlorine, oxygen and irradiation. An extensive testing programme at the University Center for Pollution Research of the Florida Institute of Technology over the past four years has shown that irradiation of waste-water samples immersed in an aqueous environment provide bacterial kill and reduction in organic pollution far greater than that obtained from theoretical considerations of G values and earlier experiments where the waste samples were not immersed in an aqueous environment. These testing programmes have investigated the synergistic effects of combining oxygen and irradiation. Each of these combined treatments resulted in an increased bacterial kill factor. Tests on Staphylococcus aureus bacteria and faecal streptococcus bacteria indicate that the synergistic effects observed for faecal coliform bacteria also apply to the pathogenic bacteria. A statistical analysis of the data obtained shows the relationships between the various effects on the bacteria. A definite shielding factor from the turbidity of the waste-water has been shown to exist. Synergistic effects have been shown to offset significantly the shielding effects. Optimization of these synergistic effects can greatly increase the effectiveness of irradiation in the treatment of waste-water. (author)

  6. Ionic Liquids: The Synergistic Catalytic Effect in the Synthesis of Cyclic Carbonates

    Directory of Open Access Journals (Sweden)

    Flora T.T. Ng

    2013-10-01

    Full Text Available This review presents the synergistic effect in the catalytic system of ionic liquids (ILs for the synthesis of cyclic carbonate from carbon dioxide and epoxide. The emphasis of this review is on three aspects: the catalytic system of metal-based ionic liquids, the catalytic system of hydrogen bond-promoted ionic liquids and supported ionic liquids. Metal and ionic liquids show a synergistic effect on the cycloaddition reactions of epoxides. The cations and anions of ionic liquids show a synergistic effect on the cycloaddition reactions. The functional groups in cations or supports combined with the anions have a synergistic effect on the cycloaddition reactions. Synergistic catalytic effects of ILs play an important role of promoting the cycloaddition reactions of epoxides. The design of catalytic system of ionic liquids will be possible if the synergistic effect on a molecular level is understood.

  7. Functional live cell imaging of the pulmonary neuroepithelial body microenvironment

    NARCIS (Netherlands)

    De Proost, Ian; Pintelon, Isabel; Brouns, Inge; Kroese, A; Riccardi, Daniela; Kemp, Paul J.; Timmermans, Jean-Pierre; Adriaensen, Dirk

    Pulmonary neuroepithelial bodies (NEBs) are densely innervated groups of neuroendocrine cells invariably accompanied by Clara-like cells. Together with NEBs, Clara-like cells form the so-called "NEB microenvironment," which recently has been assigned a potential pulmonary stem cell niche. Conclusive

  8. High-fat-diet-induced obesity causes an inflammatory and tumor-promoting microenvironment in the rat kidney

    Directory of Open Access Journals (Sweden)

    Kerstin Stemmer

    2012-09-01

    Obesity and concomitant comorbidities have emerged as public health problems of the first order. For instance, obese individuals have an increased risk for kidney cancer. However, direct mechanisms linking obesity with kidney cancer remain elusive. We hypothesized that diet-induced obesity (DIO promotes renal carcinogenesis by inducing an inflammatory and tumor-promoting microenvironment. We compared chow-fed lean Wistar rats with those that were sensitive (DIOsens or partially resistant (DIOres to DIO to investigate the impact of body adiposity versus dietary nutrient overload in the development of renal preneoplasia and activation of tumor-promoting signaling pathways. Our data clearly show a correlation between body adiposity, the severity of nephropathy, and the total number and incidence of preneoplastic renal lesions. However, similar plasma triglyceride, plasma free fatty acid and renal triglyceride levels were found in chow-fed, DIOres and DIOsens rats, suggesting that lipotoxicity is not a critical contributor to the renal pathology. Obesity-related nephropathy was further associated with regenerative cell proliferation, monocyte infiltration and higher renal expression of monocyte chemotactic protein-1 (MCP-1, interleukin (IL-6, IL-6 receptor and leptin receptor. Accordingly, we observed increased signal transducer and activator of transcription 3 (STAT3 and mammalian target of rapamycin (mTOR phosphorylation in tubules with preneoplastic phenotypes. In summary, our results demonstrate that high body adiposity induces an inflammatory and proliferative microenvironment in rat kidneys that promotes the development of preneoplastic lesions, potentially via activation of the STAT3 and mTOR signaling pathways.

  9. Theranostic 2D ultrathin MnO2 nanosheets with fast responsibility to endogenous tumor microenvironment and exogenous NIR irradiation.

    Science.gov (United States)

    Liu, Zhuang; Zhang, Shengjian; Lin, Han; Zhao, Menglong; Yao, Heliang; Zhang, Linlin; Peng, Weijun; Chen, Yu

    2018-02-01

    The fabrication of functional nanoparticles with unique ultra-sensitivity to endogenous tumor microenvironment (TME) is of great significance for their improved theranostic performance and easy excretion out of the body, which has not been realized among diverse nano-sized photothermal agents for photothermal therapy (PTT) of tumor. In this work, we report on the synthesis of 2D ultrathin MnO 2 nanosheets for highly efficient PTT against tumor with ultra-sensitivity to endogenous TME. These ultrathin 2D MnO 2 nanosheets show the intriguing characteristic of disintegration and releasing of Mn 2+ in response to the mild acidic condition and elevated reducing microenvironment of TME, which has successfully realized the pH- and reducing-responsive T 1 -weighted magnetic resonance imaging of tumor. Importantly, the high PTT efficiency of 2D MnO 2 nanosheets responsive to exogenous NIR irradiation has been systematically demonstrated both in vitro and in vivo for suppressing the tumor growth. This first report on the exploring of TME-sensitive photothermal agents with concurrent diagnostic and therapeutic (theranostic) functions significantly broadens the biomedical application of 2D functional biomaterials, which also promotes the further potential clinical translations of nano-sized photothermal agents. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Immunotherapeutic Potential of Oncolytic H-1 Parvovirus: Hints of Glioblastoma Microenvironment Conversion towards Immunogenicity.

    Science.gov (United States)

    Angelova, Assia L; Barf, Milena; Geletneky, Karsten; Unterberg, Andreas; Rommelaere, Jean

    2017-12-15

    Glioblastoma, one of the most aggressive primary brain tumors, is characterized by highly immunosuppressive microenvironment. This contributes to glioblastoma resistance to standard treatment modalities and allows tumor growth and recurrence. Several immune-targeted approaches have been recently developed and are currently under preclinical and clinical investigation. Oncolytic viruses, including the autonomous protoparvovirus H-1 (H-1PV), show great promise as novel immunotherapeutic tools. In a first phase I/IIa clinical trial (ParvOryx01), H-1PV was safe and well tolerated when locally or systemically administered to recurrent glioblastoma patients. The virus was able to cross the blood-brain (tumor) barrier after intravenous infusion. Importantly, H-1PV treatment of glioblastoma patients was associated with immunogenic changes in the tumor microenvironment. Tumor infiltration with activated cytotoxic T cells, induction of cathepsin B and inducible nitric oxide (NO) synthase (iNOS) expression in tumor-associated microglia/macrophages (TAM), and accumulation of activated TAM in cluster of differentiation (CD) 40 ligand (CD40L)-positive glioblastoma regions was detected. These are the first-in-human observations of H-1PV capacity to switch the immunosuppressed tumor microenvironment towards immunogenicity. Based on this pilot study, we present a tentative model of H-1PV-mediated modulation of glioblastoma microenvironment and propose a combinatorial therapeutic approach taking advantage of H-1PV-induced microglia/macrophage activation for further (pre)clinical testing.

  11. The effects of electric fields on charged molecules and particles in individual microenvironments

    Science.gov (United States)

    Jamieson, K. S.; ApSimon, H. M.; Jamieson, S. S.; Bell, J. N. B.; Yost, M. G.

    Measurements of small air ion concentrations, electrostatic potential and AC electric field strengths were taken in an office setting to investigate the link between electric fields and charged molecule and particle concentrations in individual microenvironments. The results obtained indicate that the electromagnetic environments individuals can be exposed to whilst indoors can often bear little resemblance to those experienced outdoors in nature, and that many individuals may spend large periods of their time in "Faraday cage"-like conditions exposed to inappropriate levels and types of electric fields that can reduce localised concentrations of biologically essential and microbiocidal small air ions. Such conditions may escalate their risk of infection from airborne contaminants, including microbes, whilst increasing localised surface contamination. The degree of "electro-pollution" that individuals are exposed to was shown to be influenced by the type of microenvironment they occupy, with it being possible for very different types of microenvironment to exist within the same room. It is suggested that adopting suitable electromagnetic hygiene/productivity guidelines that seek to replicate the beneficial effects created by natural environments may greatly mitigate such problems.

  12. Construction of extracellular microenvironment to improve surface endothelialization of NiTi alloy substrate

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Peng, E-mail: liupeng79@cqu.edu.cn [Key Laboratory of Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044 (China); State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai 200433 (China); Zhao, Yongchun; Yan, Ying; Hu, Yan; Yang, Weihu [Key Laboratory of Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044 (China); Cai, Kaiyong, E-mail: kaiyong_cai@cqu.edu.cn [Key Laboratory of Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044 (China)

    2015-10-01

    To mimic extracellular microenvironment of endothelial cell, a bioactive multilayered structure of gelatin/chitosan pair, embedding with vascular endothelial growth factor (VEGF), was constructed onto NiTi alloy substrate surface via a layer-by-layer assembly technique. The successful fabrication of the multilayered structure was demonstrated by scanning electron microscopy, atomic force microscopy, contact angle measurement, attenuated total reflection-fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy, respectively. The growth behaviors of endothelial cells on various NiTi alloy substrates were investigated in vitro. Cytoskeleton observation, MTT assay, and wound healing assay proved that the VEGF-embedded multilayer structure positively stimulated adhesion, proliferation and motogenic responses of endothelial cells. More importantly, the present system promoted the nitric oxide production of endothelial cells. The approach affords an alternative to construct extracellular microenvironment for improving surface endothelialization of a cardiovascular implant. - Highlights: • Biofunctional multilayer films mimicking extracellular microenvironment were successfully fabricated. • Multilayered structure stimulated the biological responses of endothelial cells. • The approach affords an efficient approach for surface endothelialization of stent implant.

  13. Reprograming the Metastatic Microenvironment to Combat Disease Recurrence

    Science.gov (United States)

    2017-10-01

    0704-0188 Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing...truly eliminate “residual disease” and prevent metastatic recurrence. We believe we have found a way to accomplish this by inhibiting colony- stimulating ...the bone microenvironment lead to pathological bone loss, which can stimulate tumor cell outgrowth. In addition to contributing to morbidity, this

  14. Natural product derivative BIO promotes recovery after myocardial infarction via unique modulation of the cardiac microenvironment

    Science.gov (United States)

    Kim, Yong Sook; Jeong, Hye-yun; Kim, Ah Ra; Kim, Woong-Hee; Cho, Haaglim; Um, JungIn; Seo, Youngha; Kang, Wan Seok; Jin, Suk-Won; Kim, Min Chul; Kim, Yong-Chul; Jung, Da-Woon; Williams, Darren R.; Ahn, Youngkeun

    2016-01-01

    The cardiac microenvironment includes cardiomyocytes, fibroblasts and macrophages, which regulate remodeling after myocardial infarction (MI). Targeting this microenvironment is a novel therapeutic approach for MI. We found that the natural compound derivative, BIO ((2′Z,3′E)-6-Bromoindirubin-3′-oxime) modulated the cardiac microenvironment to exert a therapeutic effect on MI. Using a series of co-culture studies, BIO induced proliferation in cardiomyocytes and inhibited proliferation in cardiac fibroblasts. BIO produced multiple anti-fibrotic effects in cardiac fibroblasts. In macrophages, BIO inhibited the expression of pro-inflammatory factors. Significantly, BIO modulated the molecular crosstalk between cardiac fibroblasts and differentiating macrophages to induce polarization to the anti-inflammatory M2 phenotype. In the optically transparent zebrafish-based heart failure model, BIO induced cardiomyocyte proliferation and completely recovered survival rate. BIO is a known glycogen synthase kinase-3β inhibitor, but these effects could not be recapitulated using the classical inhibitor, lithium chloride; indicating novel therapeutic effects of BIO. We identified the mechanism of BIO as differential modulation of p27 protein expression and potent induction of anti-inflammatory interleukin-10. In a rat MI model, BIO reduced fibrosis and improved cardiac performance. Histological analysis revealed modulation of the cardiac microenvironment by BIO, with increased presence of anti-inflammatory M2 macrophages. Our results demonstrate that BIO produces unique effects in the cardiac microenvironment to promote recovery post-MI. PMID:27510556

  15. On effect of diluent nature on synergistic extraction

    International Nuclear Information System (INIS)

    Shmidt, V.S.; Rybakov, K.A.; Rubisov, V.N.

    1982-01-01

    Published experimental mass data on the effect of diluent nature on the extraction of metals by mixtures of acidic (HA) and neutral (B) extractants are analysed using correlations based on the linearity of ratios of free energies. It is determined that the logarithm of equilibrium constant of MAsub(n)Bsub(m) adduct formation in the organic phase causing synergism decreases linearity as diluent tabular BP * parameters increase according to lgKsub(s)=lgKsub(os)-aBP * formula while the sensitivity coefficient a grows roughly proportionally to the augmentation of solvation number m and lgKsub(os) increases as extraction ability B grows. Values of logarithms of metal extraction constants by mixtures of extractants (Ksub(ex)) also decrease linearly as diluent BP * increases, the sensitivity coefficcient of this dependence being connected with the value of HA physical distribution constant and its hydrophobic nature. The found regularities permit to forecast using BP * scale, the effect of diluent nature on synergistic extraction of metal cations by mixtures of acidic extractants of different hydrophobic nature with neutral extractants and to describe quantitatively in a brief form mass data of extraction constants for series of such systems within the limits of which only the nature of the diluent changes

  16. CXCR7 maintains osteosarcoma invasion after CXCR4 suppression in bone marrow microenvironment.

    Science.gov (United States)

    Han, Yan; Wu, Chunlei; Wang, Jing; Liu, Na

    2017-05-01

    The major cause of death in osteosarcoma is the invasion and metastasis. Better understanding of the molecular mechanism of osteosarcoma invasion is essential in developing effective tumor-suppressive therapies. Interaction between chemokine receptors plays a crucial role in regulating osteosarcoma invasion. Here, we investigated the relationship between CXCR7 and CXCR4 in osteosarcoma invasion induced by bone marrow microenvironment. Human bone marrow mesenchymal stem cells were co-cultured with osteosarcoma cells to mimic actual bone marrow microenvironment. Osteosarcoma cell invasion and CXCL12/CXCR4 activation were observed within this co-culture model. Interestingly, in this co-culture model, osteosarcoma cell invasion was not inhibited by suppressing CXCR4 expression with neutralizing antibody or specific inhibitor AMD3100. Downstream signaling extracellular signal-regulated kinase and signal transducer and activator of transcription 3 were not significantly affected by CXCR4 inhibition. However, suppressing CXCR4 led to CXCR7 upregulation. Constitutive expression of CXCR7 could maintain osteosarcoma cell invasion when CXCR4 was suppressed. Simultaneously, inhibiting CXCR4 and CXCR7 compromised osteosarcoma invasion in co-culture system and suppressed extracellular signal-regulated kinase and signal transducer and activator of transcription 3 signals. Moreover, bone marrow microenvironment, not CXCL12 alone, is required for CXCR7 activation after CXCR4 suppression. Taken together, suppressing CXCR4 is not enough to impede osteosarcoma invasion in bone marrow microenvironment since CXCR7 is activated to sustain invasion. Therefore, inhibiting both CXCR4 and CXCR7 could be a promising strategy in controlling osteosarcoma invasion.

  17. Galectin-1 as a potent target for cancer therapy: role in the tumor microenvironment.

    Science.gov (United States)

    Ito, Koichi; Stannard, Kimberley; Gabutero, Elwyn; Clark, Amanda M; Neo, Shi-Yong; Onturk, Selda; Blanchard, Helen; Ralph, Stephen J

    2012-12-01

    The microenvironment of a tumor is a highly complex milieu, primarily characterized by immunosuppression, abnormal angiogenesis, and hypoxic regions. These features promote tumor progression and metastasis, resulting in poor prognosis and greater resistance to existing cancer therapies. Galectin-1 is a β-galactoside binding protein that is abundantly secreted by almost all types of malignant tumor cells. The expression of galectin-1 is regulated by hypoxia-inducible factor-1 (HIF-1) and it plays vital pro-tumorigenic roles within the tumor microenvironment. In particular, galectin-1 suppresses T cell-mediated cytotoxic immune responses and promotes tumor angiogenesis. However, since galectin-1 displays many different activities by binding to a number of diverse N- or O-glycan modified target proteins, it has been difficult to fully understand how galectin-1 supports tumor growth and metastasis. This review explores the importance of galectin-1 and glycan expression patterns in the tumor microenvironment and the potential effects of inhibiting galectin-1 as a therapeutic target for cancer treatment.

  18. Differential immune microenvironments and response to immune checkpoint blockade amongst molecular subtypes of murine medulloblastoma

    Science.gov (United States)

    Pham, Christina D.; Flores, Catherine; Yang, Changlin; Pinheiro, Elaine M.; Yearley, Jennifer H.; Sayour, Elias J.; Pei, Yanxin; Moore, Colin; McLendon, Roger E.; Huang, Jianping; Sampson, John H.; Wechsler-Reya, Robert; Mitchell, Duane A.

    2016-01-01

    PURPOSE Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma (MB), the role of the immune system and its interplay with the tumor microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and Group 3 MB for preclinical evaluation in immunocompetent C57BL/6 mice. METHODS AND RESULTS Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid derived suppressor cells and tumor-associated macrophages in murine SHH model tumors compared with Group 3 tumors. However, murine Group 3 tumors had higher percentages of CD8+ PD-1+ T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial Group 3 tumors compared to SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1+ peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3+ T cells within the tumor microenvironment. CONCLUSIONS This is the first immunologic characterization of preclinical models of molecular subtypes of MB and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment. PMID:26405194

  19. Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma.

    Science.gov (United States)

    Pham, Christina D; Flores, Catherine; Yang, Changlin; Pinheiro, Elaine M; Yearley, Jennifer H; Sayour, Elias J; Pei, Yanxin; Moore, Colin; McLendon, Roger E; Huang, Jianping; Sampson, John H; Wechsler-Reya, Robert; Mitchell, Duane A

    2016-02-01

    Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma, the role of the immune system and its interplay with the tumor microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and group 3 medulloblastoma for preclinical evaluation in immunocompetent C57BL/6 mice. Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid-derived suppressor cells, and tumor-associated macrophages in murine SHH model tumors compared with group 3 tumors. However, murine group 3 tumors had higher percentages of CD8(+) PD-1(+) T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial group 3 tumors compared with SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1(+) peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3(+) T cells within the tumor microenvironment. This is the first immunologic characterization of preclinical models of molecular subtypes of medulloblastoma and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment. ©2015 American Association for Cancer Research.

  20. Effects of the thymic microenvironment on autoantibody production in (NZB X NZW)F1 mice

    International Nuclear Information System (INIS)

    Huston, D.P.; Smathers, P.A.; Reeves, J.P.; Steinberg, A.D.

    1983-01-01

    The effects of the thymic microenvironment on autoantibody production in (NZB X NZW)F1 mice were studied. Neonatally thymectomized male and female F1 mice reconstituted with a parental or F1-irradiated thymic lobe were compared to nonreconstituted and sham-thymectomized controls. While maleness retarded the spontaneous production of ss- and ds-DNA antibodies, thymic grafts did not suppress antibodies to ss-DNA in either sex, but did suppress the production of antibodies to ds-DNA in female mice. A unique property of NZB thymic grafts was the inability to suppress anti-RBC antibodies in male mice. Thus, (i) the gender of the F1 recipient was the most important determinant of production of antibodies to ss-DNA, (ii) either maleness or the thymic microenvironment could retard production of anti-ds-DNA antibodies, and (iii) both gender and the thymic microenvironment were important in the regulation of anti-RBC antibody production. Since the administration of thymosin did not suppress autoantibody production, the effects of the thymic grafts was not solely via thymic hormone production. These studies suggest that sex hormones and/or the thymic microenvironment can exert a suppressive effect on autoantibody production and that autoantibodies differ in their susceptibility to such suppression

  1. The effect of allometric scaling in coral thermal microenvironments.

    Directory of Open Access Journals (Sweden)

    Robert H Ong

    Full Text Available A long-standing interest in marine science is in the degree to which environmental conditions of flow and irradiance, combined with optical, thermal and morphological characteristics of individual coral colonies, affects their sensitivity of thermal microenvironments and susceptibility to stress-induced bleaching within and/or among colonies. The physiological processes in Scleractinian corals tend to scale allometrically as a result of physical and geometric constraints on body size and shape. There is a direct relationship between scaling to thermal stress, thus, the relationship between allometric scaling and rates of heating and cooling in coral microenvironments is a subject of great interest. The primary aim of this study was to develop an approximation that predicts coral thermal microenvironments as a function of colony morphology (shape and size, light or irradiance, and flow velocity or regime. To do so, we provided intuitive interpretation of their energy budgets for both massive and branching colonies, and then quantified the heat-size exponent (b* and allometric constant (m using logarithmic linear regression. The data demonstrated a positive relationship between thermal rates and changes in irradiance, A/V ratio, and flow, with an interaction where turbulent regime had less influence on overall stress which may serve to ameliorate the effects of temperature rise compared to the laminar regime. These findings indicated that smaller corals have disproportionately higher stress, however they can reach thermal equilibrium quicker. Moreover, excellent agreements between the predicted and simulated microscale temperature values with no significant bias were observed for both the massive and branching colonies, indicating that the numerical approximation should be within the accuracy with which they could be measured. This study may assist in estimating the coral microscale temperature under known conditions of water flow and irradiance

  2. Poly(ethylene glycol) (PEG)-lactic acid nanocarrier-based degradable hydrogels for restoring the vaginal microenvironment

    Science.gov (United States)

    Rajan, Sujata Sundara; Turovskiy, Yevgeniy; Singh, Yashveer; Chikindas, Michael L.; Sinko, Patrick J.

    2014-01-01

    Women with bacterial vaginosis (BV) display reduced vaginal acidity, which make them susceptible to associated infections such as HIV. In the current study, poly(ethylene glycol) (PEG) nanocarrier-based degradable hydrogels were developed for the controlled release of lactic acid in the vagina of BV-infected women. PEG-lactic acid (PEG-LA) nanocarriers were prepared by covalently attaching lactic acid to 8-arm PEG-SH via cleavable thioester bonds. PEG-LA nanocarriers with 4 copies of lactic acid per molecule provided controlled release of lactic acid with a maximum release of 23% and 47% bound lactic acid in phosphate buffered saline (PBS, pH 7.4) and acetate buffer (AB, pH 4.3), respectively. The PEG nanocarrier-based hydrogels were formed by cross-linking the PEG-LA nanocarriers with 4-arm PEG-NHS via degradable thioester bonds. The nanocarrier-based hydrogels formed within 20 min under ambient conditions and exhibited an elastic modulus that was 100-fold higher than the viscous modulus. The nanocarrier-based degradable hydrogels provided controlled release of lactic acid for several hours; however, a maximum release of only 10%–14% bound lactic acid was observed possibly due to steric hindrance of the polymer chains in the cross-linked hydrogel. In contrast, hydrogels with passively entrapped lactic acid showed burst release with complete release within 30 min. Lactic acid showed antimicrobial activity against the primary BV pathogen Gardnerella vaginalis with a minimum inhibitory concentration (MIC) of 3.6 mg/ml. In addition, the hydrogels with passively entrapped lactic acid showed retained antimicrobial activity with complete inhibition G. vaginalis growth within 48 h. The results of the current study collectively demonstrate the potential of PEG nanocarrier-based hydrogels for vaginal administration of lactic acid for preventing and treating BV. PMID:25223229

  3. Hypoxia alters the physical properties of the tumor microenvironment

    Science.gov (United States)

    Gilkes, Daniele

    Of all the deaths attributed to cancer, 90% are due to metastasis, or the spread of cancer cells from a primary tumor to distant organs, and treatments that prevent or cure metastasis remain elusive. Emerging data indicate that low oxygen states within a tumor, termed hypoxia, can alter the chemical and physical parameters of the extracellular matrix (ECM), or scaffold of the tumor tissue. These changes generate a microenvironment that may be more conducive for promoting metastasis. During tumor evolution, changes in the composition and the overall content of the ECM reflect both its biophysical and biological properties and these strongly influence the cells properties, such as cellular proliferation and cell motility. The talk will cover how hypoxia arises within normal tissue and also in tumors. We will cover the role of hypoxia in collagen biogenesis which influences compositional changes to the tumor microenvironment and discuss how these changes lead to a stiffer tumor stroma. The challenges in determining the influence of chemical versus physical cues on cancer progression will also be considered.

  4. Tumor Microenvironment and Immune Effects of Antineoplastic Therapy in Lymphoproliferative Syndromes

    Science.gov (United States)

    Álvaro, Tomás; de la Cruz-Merino, Luis; Henao-Carrasco, Fernando; Villar Rodríguez, José Luis; Vicente Baz, David; Codes Manuel de Villena, Manuel; Provencio, Mariano

    2010-01-01

    Lymphomas represent a wide group of heterogenic diseases with different biological and clinical behavior. The underlying microenvironment-specific composition seems to play an essential role in this scenario, harboring the ability to develop successful immune responses or, on the contrary, leading to immune evasion and even promotion of tumor growth. Depending on surrounding lymphoid infiltrates, lymphomas may have different prognosis. Moreover, recent evidences have emerged that confer a significant impact of main lymphoma's treatment over microenvironment, with clinical consequences. In this review, we summarize these concepts from a pathological and clinical perspective. Also, the state of the art of lymphoma's anti-idiotype vaccine development is revised, highlighting the situations where this strategy has proven to be successful and eventual clues to obtain better results in the future. PMID:20814546

  5. Synergistic Effect of L-Methionine and KI on Copper Corrosion Inhibition in HNO3 (1M

    Directory of Open Access Journals (Sweden)

    Amel SEDIK

    2014-05-01

    Full Text Available L-Methionine (L-Met efficiency as a non-toxic corrosion inhibitor for copper in 1M HNO3 has been studied by using electrochemical impedance spectroscopy (EIS and potentiodynamic polarization. Copper corrosion rate significant decrease was observed in the presence of L-Met at 10-4M. The Obtained Results from potentiodynamic polarization and impedance measurements are in good agreement. L-Methionine adsorption on copper surface follows Langmuir isotherm. L-Met free energy adsorption on copper (-30 KJ mol-1 reveals an inhibition strong physical adsorption on copper surface. In order to evaluate the L-Met effect, L-Met and iodide ion’synergistic effect was used to prevent copper corrosion in nitric acid. It was found that inhibitor efficiency (IE reached 98.27 % in 1M solution containing 10-4M L-Met and 10- 3 M KI. The synergistic effect was attributed to iodide ions adsorption on copper surface, which facilitated the L-Met adsorption and an inhibitive film formation.

  6. Enhancing cytotoxic and apoptotic effect in OVCAR-3 and MDAH-2774 cells with all-trans retinoic acid and zoledronic acid: a paradigm of synergistic molecular targeting treatment for ovarian cancer

    Directory of Open Access Journals (Sweden)

    Kısım Aslı

    2010-07-01

    Full Text Available Abstract Background Ovarian cancer is the most fatal gynecologic malignancies in the world. Although, platinum based treatments are widely used, the disease becomes treatment refractory within two years, and novel treatment options should be searched. All- trans retinoic acid (ATRA induces growth arrest, differentiation and cell death in some types of cancer cells and its combination with various anticancer agents results in enhanced cytotoxicity. Zoledronic acid is a common bisphosphonate known for its anticancer effects beyond its current use in the treatment of cancer-induced bone disease. We aimed to investigate the possible additive/synergistic effect of both agents in OVCAR-3 and MDAH-2774 ovarian cancer cell lines, since both agents show superiority to conventional cytotoxics in terms of adverse events. Methods XTT cell proliferation assay was used for showing cytotoxicity. For verifying apoptosis, both DNA Fragmentation by ELISA assay and caspase 3/7 activity measurement were used. OligoGeArray® which consists of 112 apoptosis related genes was used to elucidate the genetic changes within cancer cells. To validate our oligoarray results, quantitative real-time PCR was performed on four selected genes that were maximally effected by the combination treatment: lymphotoxin beta receptor (LTBR, myeloid cell leukemia-1 (MCL-1, tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A, TNFRSF1A-associated death domain protein (TRADD. Results We demonstrated that a novel combination of ATRA and zoledronic acid is a strong inducer of apoptotic related cell death in both ovarian cancer cells. While the combination therapy significantly induced proapoptotic genes such as tumor necrosis factor receptor superfamily (TNFRSF, TRADD and caspase 4, some of the antiapoptotic genes such as members of MCL-1, LTBR, BAG3 and Bcl-2 family members were inhibited. Conclusions These are the preliminary molecular results of a novel combination treatment of

  7. The senescent microenvironment promotes the emergence of heterogeneous cancer stem-like cells.

    Science.gov (United States)

    Castro-Vega, Luis Jaime; Jouravleva, Karina; Ortiz-Montero, Paola; Liu, Win-Yan; Galeano, Jorge Luis; Romero, Martha; Popova, Tatiana; Bacchetti, Silvia; Vernot, Jean Paul; Londoño-Vallejo, Arturo

    2015-10-01

    There is a well-established association between aging and the onset of metastasis. Although the mechanisms through which age impinges upon the malignant phenotype remain uncharacterized, the role of a senescent microenvironment has been emphasized. We reported previously that human epithelial cells that undergo telomere-driven chromosome instability (T-CIN) display global microRNA (miR) deregulation and develop migration and invasion capacities. Here, we show that post-crisis cells are not able to form tumors unless a senescent microenvironment is provided. The characterization of cell lines established from such tumors revealed that these cells have acquired cell autonomous tumorigenicity, giving rise to heterogeneous tumors. Further experiments demonstrate that explanted cells, while displaying differences in cell differentiation markers, are all endowed of enhanced stem cell properties including self-renewal and multilineage differentiation capacity. Treatments of T-CIN+ cells with senescence-conditioned media induce sphere formation exclusively in cells with senescence-associated tumorigenicity, a capacity that depends on miR-145 repression. These results indicate that the senescent microenvironment, while promoting further transdifferentiations in cells with genome instability, is able to propel the progression of premalignant cells towards a malignant, cell stem-like state. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. Synergistic effect of fluoride and laser irradiation for the inhibition of the demineralization of dental enamel

    Science.gov (United States)

    Lee, Raymond; Chan, Kenneth H.; Jew, Jamison; Simon, Jacob C.; Fried, Daniel

    2017-02-01

    Both laser irradiation and fluoride treatment alone are known to provide increased resistance to acid dissolution. CO2 lasers tuned to a wavelength of 9.3 μm can be used to efficiently convert the carbonated hydroxyapatite of enamel to a much more acid resistant purer phase hydroxyapatite (HAP). Further studies have shown that fluoride application to HAP yields fluoroapatite (FAP) which is even more resistant against acid dissolution. Previous studies show that CO2 lasers and fluoride treatments interact synergistically to provide significantly higher protection than either method alone, but the mechanism of interaction has not been elucidated. We recently observed the formation of microcracks or a "crazed" zone in the irradiated region that is resistant to demineralization using high-resolution microscopy. The microcracks are formed due to the slight contraction of enamel due to transformation of carbonated hydroxyapatite to the more acid resistant pure phase hydroxyapatite (HAP) that has a smaller lattice. In this study, we test the hypothesis that these small cracks will provide greater adhesion for topical fluoride for greater protection against acid demineralization.

  9. Human body micro-environment: The benefits of controlling airflow interaction

    DEFF Research Database (Denmark)

    Melikov, Arsen Krikor

    2015-01-01

    This paper focuses on the micro-environment around a human body, and especially on its interaction with the surrounding environment. Research on the free convection flow generated by a human body (including the convective boundary layer around the body and the thermal plume above the body), its...

  10. Video-rate resonant scanning multiphoton microscopy: An emerging technique for intravital imaging of the tumor microenvironment

    OpenAIRE

    Kirkpatrick, Nathaniel D.; Chung, Euiheon; Cook, Daniel C.; Han, Xiaoxing; Gruionu, Gabriel; Liao, Shan; Munn, Lance L.; Padera, Timothy P.; Fukumura, Dai; Jain, Rakesh K.

    2012-01-01

    The abnormal tumor microenvironment fuels tumor progression, metastasis, immune suppression, and treatment resistance. Over last several decades, developments in and applications of intravital microscopy have provided unprecedented insights into the dynamics of the tumor microenvironment. In particular, intravital multiphoton microscopy has revealed the abnormal structure and function of tumor-associated blood and lymphatic vessels, the role of aberrant tumor matrix in drug delivery, invasion...

  11. The local microenvironment surrounding dansyl molecules attached to controlled pore glass in pure and alcohol-modified supercritical carbon dioxide.

    Science.gov (United States)

    Page, Phillip M; McCarty, Taylor A; Munson, Chase A; Bright, Frank V

    2008-06-01

    We report on the local microenvironment surrounding a free dansyl probe, dansyl attached to controlled pore glass (D-CPG), and dansyl molecules attached to trimethylsilyl-capped CPG (capped D-CPG) in pure and alcohol-modified supercritical CO2. These systems were selected to provide insights into the local microenvironment surrounding a reactive agent immobilized at a silica surface in contact with pure and cosolvent-modified supercritical CO2. Local surface-bound dansyl molecule solvation on the CPG surface depends on the dansyl molecule surface loading, the surface chemistry (uncapped versus capped), the bulk fluid density, and the alcohol gas phase absolute acidity. At high dansyl loadings, the surface-bound dansyl molecules are largely "solvated" by other dansyl molecules and these molecules are not affected significantly by the fluid phase. When the dansyl surface loading decreases, dansyl molecules can be accessed/solvated/wetted by the fluid phase. However, at the lowest dansyl loadings studied, the dansyl molecules are in a fluid inaccessible/restrictive environment and do not sense the fluid phase to any significant degree. In uncapped D-CPG, one can poise the system such that the local concentration of an environmentally less responsible cosolvent (alcohol) in the immediate vicinity of surface-immobilized dansyl molecules can approach 100% even though the bulk solution contains orders of magnitude less of this less environmentally responsible cosolvent. In capped C-CPG, the surface excess is attenuated in comparison to that of uncapped D-CPG. The extent of this cosolvent surface excess is discussed in terms of the dansyl surface loading, the local density fluctuations, the cosolvent and surface silanol gas phase acidities, and the silica surface chemistry. These results also have implications for cleanings, extractions, heterogeneous reactions, separations, and nanomaterial fabrication using supercritical fluids.

  12. Activity pattern and personal exposure to nitrogen dioxide in indoor and outdoor microenvironments.

    Science.gov (United States)

    Kornartit, C; Sokhi, R S; Burton, M A; Ravindra, Khaiwal

    2010-01-01

    People are exposed to air pollution from a range of indoor and outdoor sources. Concentrations of nitrogen dioxide (NO(2)), which is hazardous to health, can be significant in both types of environments. This paper reports on the measurement and analysis of indoor and outdoor NO(2) concentrations and their comparison with measured personal exposure in various microenvironments during winter and summer seasons. Furthermore, the relationship between NO(2) personal exposure in various microenvironments and including activities patterns were also studied. Personal, indoor microenvironments and outdoor measurements of NO(2) levels were conducted using Palmes tubes for 60 subjects. The results showed significant differences in indoor and outdoor NO(2) concentrations in winter but not for summer. In winter, indoor NO(2) concentrations were found to be strongly correlated with personal exposure levels. NO(2) concentration in houses using a gas cooker was higher in all rooms than those with an electric cooker during the winter campaign, whereas there was no significant difference noticed in summer. The average NO(2) levels in kitchens with a gas cooker were twice as high as those with an electric cooker, with no significant difference in the summer period. A time-weighted average personal exposure was calculated and compared with measured personal exposures in various indoor microenvironments (e.g. front doors, bedroom, living room and kitchen); including non-smokers, passive smokers and smoker. The estimated results were closely correlated, but showed some underestimation of the measured personal exposures to NO(2) concentrations. Interestingly, for our particular study higher NO(2) personal exposure levels were found during summer (14.0+/-1.5) than winter (9.5+/-2.4).

  13. Cocktails of ramsons and acidic berries kill E. coli in a piglet gastrointestinal model: an alternative to antibiotics?

    DEFF Research Database (Denmark)

    Højberg, Ole; Canibe, Nuria; Grevsen, Kai

    2017-01-01

    Mixing ramsons and acidic berries enhances, in a synergistic manner, the antimicrobial activity observed for the plants separately, and make the plant cocktails of interest as a feed additives as an alternative to antibiotics in both organic and conventional pig production.......Mixing ramsons and acidic berries enhances, in a synergistic manner, the antimicrobial activity observed for the plants separately, and make the plant cocktails of interest as a feed additives as an alternative to antibiotics in both organic and conventional pig production....

  14. Investigation of cerium salt/sulfuric acid anodizing technology for 1420 aluminum alloy

    Energy Technology Data Exchange (ETDEWEB)

    Di Li; Yue Peng Deng; Bao Lan Guo; Guo Qiang Li [Beijing Univ. of Aeronautics and Astronautics (China). Dept. of Mater. Sci. and Eng.

    2000-07-01

    In this paper, the effect of cerium addition agent on the property of anodized coating of 1420 Al alloy has been studied by corrosion experiment (immersion test and neutral salt spray test), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and measurement of polarization curves. The result show that only pitting could be observed in all corrosion tests while intergranular corrosion and exfoliation corrosion did not appear on 1420 Al-Li alloys. When organic carboxylic acid S or the cerium (IV) salt was added into sulfuric acid anodizing electrolyte separately, there was no significant improvement in corrosion resistance of anodized film. However, in the case of adding them into sulfuric acid anodizing electrolyte together, the corrosion resistance of anodized film increased greatly owing to synergistic effect. The synergistic effect may relate to the formation of cerium-organic carboxylic acid S complex compound and its effects on film growth and film structure. (orig.)

  15. Acid-induced autophagy protects human lung cancer cells from apoptosis by activating ER stress.

    Science.gov (United States)

    Xie, Wen-Yue; Zhou, Xiang-Dong; Li, Qi; Chen, Ling-Xiu; Ran, Dan-Hua

    2015-12-10

    An acidic tumor microenvironment exists widely in solid tumors. However, the detailed mechanism of cell survival under acidic stress remains unclear. The aim of this study is to clarify whether acid-induced autophagy exists and to determine the function and mechanism of autophagy in lung cancer cells. We have found that acute low pH stimulated autophagy by increasing LC3-positive punctate vesicles, increasing LC3 II expression levels and reducing p62 protein levels. Additionally, autophagy was inhibited by the addition of Baf or knockdown of Beclin 1, and cell apoptosis was increased markedly. In mouse tumors, the expression of cleaved caspase3 and p62 was enhanced by oral treatment with sodium bicarbonate, which can raise the intratumoral pH. Furthermore, the protein levels of ER stress markers, including p-PERK, p-eIF2α, CHOP, XBP-1s and GRP78, were also increased in response to acidic pH. The antioxidant NAC, which reduces ROS accumulation, alleviated acid-mediated ER stress and autophagy, and knocking down GRP78 reduced autophagy activation under acidic conditions, which suggests that autophagy was induced by acidic pH through ER stress. Taken together, these results indicate that the acidic microenvironment in non-small cell lung cancer cells promotes autophagy by increasing ROS-ER stress, which serves as a survival adaption in this setting. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. A Review of Hyaluronic Acid and Hyaluronic Acid-based Hydrogels for Vocal Fold Tissue Engineering.

    Science.gov (United States)

    Walimbe, Tanaya; Panitch, Alyssa; Sivasankar, Preeti M

    2017-07-01

    Vocal fold scarring is a common cause of dysphonia. Current treatments involving vocal fold augmentation do not yield satisfactory outcomes in the long term. Tissue engineering and regenerative medicine offer an attractive treatment option for vocal fold scarring, with the aim to restore the native extracellular matrix microenvironment and biomechanical properties of the vocal folds by inhibiting progression of scarring and thus leading to restoration of normal vocal function. Hyaluronic acid is a bioactive glycosaminoglycan responsible for maintaining optimum viscoelastic properties of the vocal folds and hence is widely targeted in tissue engineering applications. This review covers advances in hyaluronic acid-based vocal fold tissue engineering and regeneration strategies. Copyright © 2017. Published by Elsevier Inc.

  17. Bone marker gene expression in calvarial bones: different bone microenvironments.

    Science.gov (United States)

    Al-Amer, Osama

    2017-12-01

    In calvarial mice, mesenchymal stem cells (MSCs) differentiate into osteoprogenitor cells and then differentiate into osteoblasts that differentiate into osteocytes, which become embedded within the bone matrix. In this case, the cells participating in bone formation include MSCs, osteoprogenitor cells, osteoblasts and osteocytes. The calvariae of C57BL/KaLwRijHsD mice consist of the following five bones: two frontal bones, two parietal bones and one interparietal bone. This study aimed to analyse some bone marker genes and bone related genes to determine whether these calvarial bones have different bone microenvironments. C57BL/KaLwRijHsD calvariae were carefully excised from five male mice that were 4-6 weeks of age. Frontal, parietal, and interparietal bones were dissected to determine the bone microenvironment in calvariae. Haematoxylin and eosin staining was used to determine the morphology of different calvarial bones under microscopy. TaqMan was used to analyse the relative expression of Runx2, OC, OSX, RANK, RANKL, OPG, N-cadherin, E-cadherin, FGF2 and FGFR1 genes in different parts of the calvariae. Histological analysis demonstrated different bone marrow (BM) areas between the different parts of the calvariae. The data show that parietal bones have the smallest BM area compared to frontal and interparietal bones. TaqMan data show a significant increase in the expression level of Runx2, OC, OSX, RANKL, OPG, FGF2 and FGFR1 genes in the parietal bones compared with the frontal and interparietal bones of calvariae. This study provides evidence that different calvarial bones, frontal, parietal and interparietal, contain different bone microenvironments.

  18. Immune microenvironment in colorectal cancer: a new hallmark to change old paradigms.

    Science.gov (United States)

    de la Cruz-Merino, Luis; Henao Carrasco, Fernando; Vicente Baz, David; Nogales Fernández, Esteban; Reina Zoilo, Juan José; Codes Manuel de Villena, Manuel; Pulido, Enrique Grande

    2011-01-01

    Impact of immune microenvironment in prognosis of solid tumors has been extensively studied in the last few years. Specifically in colorectal carcinoma, increased knowledge of the immune events around these tumors and their relation with clinical outcomes have led to consider immune microenvironment as one of the most important prognostic factors in this disease. In this review we will summarize and update the current knowledge with respect to this intriguing and complex new hallmark of cancer, paying special attention to infiltration by T-infiltrating lymphocytes and their subtypes in colorectal cancer, as well as its eventual clinical translation in terms of long-term prognosis. Finally, we suggest some possible investigational approaches based on combinatorial strategies to trigger and boost immune reaction against tumor cells.

  19. Mathematical description of synergistic interaction between radon and smoking

    International Nuclear Information System (INIS)

    Jin Kyu Kim; Petin, V.G.; Belkina, S.V.

    2007-01-01

    Complete text of publication follows. Background: A certain level of background exposure to ionizing radiation and natural or man-made chemicals is always present in the environment. Radon and its short-lived decay products are considered as important sources of public exposure to the natural radioactivity. It is well known from epidemiological and toxicological studies that synergistic interaction between smoking and radon occurs, which is especially important for high natural background areas. Objective: This study has been done to suggest a mathematical model to describe the synergistic interaction of radon with tobacco smoking, and to demonstrate the ability of the model to describe carcinogenic effects of the combined action. Methods: A simple mathematical model was formulated to describe and predict the synergistic interaction of radon with smoking. The model postulates that the occurrence of synergism is to be expected as a result of additional carcinogenic damage arisen from the interaction of sublesions induced by the two factors under consideration. Results: The predictions of the model were verified by comparison with experimental data published by other researchers. The model appears to be appropriate and the predictions are valid. Conclusions: : The suggested mathematical model predicts the greatest level of synergistic effect and condition under which the maximum synergy is attained. The synergistic effect appeared to decline with any deviation from the optimal value of the ratio of carcinogenic effective damages produced by each agent alone.

  20. Co-delivery of chemotherapeutics and proteins for synergistic therapy.

    Science.gov (United States)

    He, Chaoliang; Tang, Zhaohui; Tian, Huayu; Chen, Xuesi

    2016-03-01

    Combination therapy with chemotherapeutics and protein therapeutics, typically cytokines and antibodies, has been a type of crucial approaches for synergistic cancer treatment. However, conventional approaches by simultaneous administration of free chemotherapeutic drugs and proteins lead to limitations for further optimizing the synergistic effects, due to the distinct in vivo pharmacokinetics and distribution of small drugs and proteins, insufficient tumor selectivity and tumor accumulation, unpredictable drug/protein ratios at tumor sites, short half-lives, and serious systemic adverse effects. Consequently, to obtain optimal synergistic anti-tumor efficacy, considerable efforts have been devoted to develop the co-delivery systems for co-incorporating chemotherapeutics and proteins into a single carrier system and subsequently releasing the dual or multiple payloads at desired target sites in a more controllable manner. The co-delivery systems result in markedly enhanced blood stability and in vivo half-lives of the small drugs and proteins, elevated tumor accumulation, as well as the capability of delivering the multiple agents to the same target sites with rational drug/protein ratios, which may facilitate maximizing the synergistic effects and therefore lead to optimal antitumor efficacy. This review emphasizes the recent advances in the co-delivery systems for chemotherapeutics and proteins, typically cytokines and antibodies, for systemic or localized synergistic cancer treatment. Moreover, the proposed mechanisms responsible for the synergy of chemotherapeutic drugs and proteins are discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Dose-dependent folic acid and memantine treatments promote synergistic or additive protection against Aβ(25-35) peptide-induced apoptosis in SH-SY5Y cells mediated by mitochondria stress-associated death signals.

    Science.gov (United States)

    Chen, Ta-Fu; Tang, Ming-Chi; Chou, Chia-Hui; Chiu, Ming-Jang; Huang, R-F S

    2013-12-01

    Increased dietary folic acid (FA) is associated with reduced risks of Alzheimer's disease (AD). The AD drug memantine (Mn) has had limited therapeutic effects for the treatment of patients with moderate to severe AD. This study investigated whether and the underlying mechanisms by which the combination of Mn and FA may have synergistic or additive effects in protecting against amyloid-β(25-35) peptide (Aβ)-induced neurocytotoxicity. Aβ treatment of human neuroblastoma SH-SY5Y cells significantly induced a 6-fold increase of apoptotic cells compared with the Aβ-untreated group. Preincubation of Aβ-exposed cells with FA (500 μM) or Mn (20 μM) caused a 22% and 10% reduction of apoptotic cells, respectively, whereas the combo-treatments at such doses synergistically alleviated Aβ-induced apoptosis by 60% (P<0.05). The apoptotic protection by the combo-treatments coincided with attenuating Aβ-elicited mitochondrial (mt) membrane depolarization and abolishing Aβ-induced mt cytochrome c release to the cytosol. Increased levels of FA at 1000 μM in combination with 20 μM Mn exerted an additive protection against Aβ(25-35)-induced-apoptosis as compared to the isolate Mn group (P<0.05). The combo-treatments reversed Aβ-elicited mt membrane depolarization, attenuated Aβ-elicited mt cytochrome c release to the cytosol, and diminished Aβ-promoted superoxide generation. The apoptotic-protection by such combo-treatments was partially abolished by carbonyl cyanide 3-chlorophenylhydrazone (mt membrane potential uncoupler) and sodium azide (mt cytochrome c oxidase inhibitor). Taken together, the data demonstrated that dose-dependent FA and Mn synergistically or additively protected SH-SY5Y cells against Aβ-induced apoptosis, which was partially, if not completely, mediated by mt stress-associated death signals. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. 3D is not enough: Building up a cell instructive microenvironment for tumoral stroma microtissues.

    Science.gov (United States)

    Brancato, Virginia; Garziano, Alessandro; Gioiella, Filomena; Urciuolo, Francesco; Imparato, Giorgia; Panzetta, Valeria; Fusco, Sabato; Netti, Paolo A

    2017-01-01

    We fabricated three-dimensional microtissues with the aim to replicate in vitro the composition and the functionalities of the tumor microenvironment. By arranging either normal fibroblasts (NF) or cancer-activated fibroblasts (CAF) in two different three dimensional (3D) configurations, two kinds of micromodules were produced: spheroids and microtissues. Spheroids were obtained by means of the traditional cell aggregation technique resulting in a 3D model characterized by high cell density and low amount of extracellular proteins. The microtissues were obtained by culturing cells into porous gelatin microscaffolds. In this latter configuration, cells assembled an intricate network of collagen, fibronectin and hyaluronic acid. We investigated the biophysical properties of both 3D models in terms of cell growth, metabolic activity, texture and composition of the extracellular matrix (via histological analysis and multiphoton imaging) and cell mechanical properties (via Particle Tracking Microrheology). In the spheroid models such biophysical properties remained unchanged regardless to the cell type used. In contrast, normal-microtissues and cancer-activated-microtissues displayed marked differences. CAF-microtissues possessed higher proliferation rate, superior contraction capability, different micro-rheological properties and an extracellular matrix richer in collagen fibronectin and hyaluronic acid. At last, multiphoton investigation revealed differences in the collagen network architecture. Taken together, these results suggested that despite to cell spheroids, microtissues better recapitulate the important differences existing in vivo between normal and cancer-activated stroma representing a more suitable system to mimic in vitro the stromal element of the tumor tissues. This work concerns the engineering of tumor tissue in vitro. Tumor models serve as biological equivalent to study pathologic progression and to screen or validate the drugs efficacy. Tumor

  3. Aluminium tolerance in rice is antagonistic with nitrate preference and synergistic with ammonium preference.

    Science.gov (United States)

    Zhao, Xue Qiang; Guo, Shi Wei; Shinmachi, Fumie; Sunairi, Michio; Noguchi, Akira; Hasegawa, Isao; Shen, Ren Fang

    2013-01-01

    Acidic soils are dominated chemically by more ammonium and more available, so more potentially toxic, aluminium compared with neutral to calcareous soils, which are characterized by more nitrate and less available, so less toxic, aluminium. However, it is not known whether aluminium tolerance and nitrogen source preference are linked in plants. This question was investigated by comparing the responses of 30 rice (Oryza sativa) varieties (15 subsp. japonica cultivars and 15 subsp. indica cultivars) to aluminium, various ammonium/nitrate ratios and their combinations under acidic solution conditions. indica rice plants were generally found to be aluminium-sensitive and nitrate-preferring, while japonica cultivars were aluminium-tolerant and relatively ammonium-preferring. Aluminium tolerance of different rice varieties was significantly negatively correlated with their nitrate preference. Furthermore, aluminium enhanced ammonium-fed rice growth but inhibited nitrate-fed rice growth. The results suggest that aluminium tolerance in rice is antagonistic with nitrate preference and synergistic with ammonium preference under acidic solution conditions. A schematic diagram summarizing the interactions of aluminium and nitrogen in soil-plant ecosystems is presented and provides a new basis for the integrated management of acidic soils.

  4. Paired single cell co-culture microenvironments isolated by two-phase flow with continuous nutrient renewal.

    Science.gov (United States)

    Chen, Yu-Chih; Cheng, Yu-Heng; Kim, Hong Sun; Ingram, Patrick N; Nor, Jacques E; Yoon, Euisik

    2014-08-21

    Cancer-stromal cell interactions are a critical process in tumorigenesis. Conventional dish-based assays, which simply mix two cell types, have limitations in three aspects: 1) limited control of the cell microenvironment; 2) inability to study cell behavior in a single-cell manner; and 3) have difficulties in characterizing single cell behavior within a highly heterogeneous cell population (e.g. tumor). An innovative use of microfluidic technology is for improving the spatial resolution for single cell assays. However, it is challenging to isolate the paired interacting cells while maintaining nutrient renewal. In this work, two-phase flow was used as a simple isolation method, separating the microenvironment of each individual chamber. As nutrients in an isolated chamber are consumed by cells, media exchange is required. To connect the cell culture chamber to the media exchange layer, we demonstrated a 3D microsystem integration technique using vertical connections fabricated by deep reactive-ion etching (DRIE). Compared to previous approaches, the presented process allows area reduction of vertical connections by an order of magnitude, enabling compact 3D integration. A semi-permeable membrane was sandwiched between the cell culture layer and the media exchange layer. The selectivity of the semi-permeable membrane results in the retention of the signaling proteins within the chamber while allowing free diffusion of nutrients (e.g., glucose and amino acids). Thus, paracrine signals are accumulated inside the chamber without cross-talk between cells in other chambers. Utilizing these innovations, we co-cultured UM-SCC-1 (head and neck squamous cell carcinoma) cells and endothelial cells to simulate tumor proliferation enhancement in the vascular endothelial niche.

  5. Individual and population intake fractions of diesel particulate matter (DPM) in bus stop microenvironments

    International Nuclear Information System (INIS)

    Xu, Jia; Jin, Taosheng; Miao, Yaning; Han, Bin; Gao, Jiajia; Bai, Zhipeng; Xu, Xiaohong

    2015-01-01

    Diesel particulate matter (DPM) is associated with adverse human health effects. This study aims to investigate the relationship between DPM exposure and emissions by estimating the individual intake fraction (iF_i) and population intake fraction (iF_p) of DPM. Daily average concentrations of particulate matter at two bus stops during rush hours were measured, and then they were apportioned to DPM due to heavy-duty diesel bus emissions using Chemical Mass Balance Model. The DPM emissions of diesel buses for different driving conditions (idling, creeping and traveling) were estimated on the basis of field observations and published emission factors. The median iF_i of DPM was 0.67 and 1.39 per million for commuters standing at the bus stop and pedestrians/cyclists passing through the bus stop during rush hours, respectively. The median iF_p of DPM was 94 per million. Estimations of iF_i and iF_p of DPM are potentially significant for exposure assessment and risk management. - Highlights: • Methods to estimate the individual and population intake fraction in bus stop microenvironments were established. • Source apportionment was performed to estimate the DPM due to diesel bus emissions in bus stop microenvironments. • The DPM emission in bus stop microenvironments rather than in the entire urban area was considered. • The movement of people and their exposure duration were introduced in the estimation of population intake fraction. - This work established a method to estimate the individual and population intake fraction in transportation microenvironments on the basis of PM source apportionment.

  6. Interleukin-8 promotes canine hemangiosarcoma growth by regulating the tumor microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jong-Hyuk, E-mail: jhkim@umn.edu [Department of Veterinary Clinical Science, College of Veterinary Medicine, University of Minnesota, St. Paul, MN (United States); Masonic Cancer Center, University of Minnesota, Minneapolis, MN (United States); Frantz, Aric M.; Anderson, Katie L.; Graef, Ashley J.; Scott, Milcah C. [Department of Veterinary Clinical Science, College of Veterinary Medicine, University of Minnesota, St. Paul, MN (United States); Robinson, Sally [Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN (United States); Sharkey, Leslie C. [Department of Veterinary Clinical Science, College of Veterinary Medicine, University of Minnesota, St. Paul, MN (United States); Masonic Cancer Center, University of Minnesota, Minneapolis, MN (United States); O' Brien, Timothy D. [Department of Veterinary Clinical Science, College of Veterinary Medicine, University of Minnesota, St. Paul, MN (United States); Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN (United States); Dickerson, Erin B. [Department of Veterinary Clinical Science, College of Veterinary Medicine, University of Minnesota, St. Paul, MN (United States); Masonic Cancer Center, University of Minnesota, Minneapolis, MN (United States); Modiano, Jaime F., E-mail: modiano@umn.edu [Department of Veterinary Clinical Science, College of Veterinary Medicine, University of Minnesota, St. Paul, MN (United States); Masonic Cancer Center, University of Minnesota, Minneapolis, MN (United States)

    2014-04-15

    Interleukin-8 (IL-8) gene expression is highly up-regulated in canine hemangiosarcoma (HSA); however, its role in the pathogenesis of this disease is unknown. We investigated the expression of IL-8 in canine HSA tissues and cell lines, as well and the effects of IL-8 on canine HSA in vitro, and in vivo using a mouse xenograft model for the latter. Constitutive expression of IL-8 mRNA, IL-8 protein, and IL-8 receptor were variable among different tumor samples and cell lines, but they showed stable steady states in each cell line. Upon the addition of IL-8, HSA cells showed transient intracellular calcium fluxes, suggesting that their IL-8 receptors are functional and that IL-8 binding activates relevant signaling pathways. Yet, neither addition of exogenous IL-8 nor blockade of endogenous IL-8 by neutralizing anti-IL-8 antibody (α-IL-8 Ab) affected HSA cell proliferation or survival in vitro. To assess potential effects of IL-8 in other tumor constituents, we stratified HSA cell lines and whole tumor samples into “IL-8 high” and “IL-8 low” groups. Genome-wide gene expression profiling showed that samples in the “IL-8 high” tumor group were enriched for genes associated with a “reactive microenvironment,” including activation of coagulation, inflammation, and fibrosis networks. Based on these findings, we hypothesized that the effects of IL-8 on these tumors were mostly indirect, regulating interactions with the microenvironment. This hypothesis was supported by in vivo xenograft experiments where survival and engraftment of tumor cells was inhibited by administration of neutralizing α-IL-8 Ab. Together, our results suggest that IL-8 contributes to establishing a permissive microenvironment during the early stages of tumorigenesis in HSA. - Highlights: • IL-8 is expressed in canine hemangiosarcoma tumor samples and cell lines. • IL-8 transduces a relevant biological signal in canine hemangiosarcoma cells. • IL-8 gene signature is associated

  7. Interleukin-8 promotes canine hemangiosarcoma growth by regulating the tumor microenvironment

    International Nuclear Information System (INIS)

    Kim, Jong-Hyuk; Frantz, Aric M.; Anderson, Katie L.; Graef, Ashley J.; Scott, Milcah C.; Robinson, Sally; Sharkey, Leslie C.; O'Brien, Timothy D.; Dickerson, Erin B.; Modiano, Jaime F.

    2014-01-01

    Interleukin-8 (IL-8) gene expression is highly up-regulated in canine hemangiosarcoma (HSA); however, its role in the pathogenesis of this disease is unknown. We investigated the expression of IL-8 in canine HSA tissues and cell lines, as well and the effects of IL-8 on canine HSA in vitro, and in vivo using a mouse xenograft model for the latter. Constitutive expression of IL-8 mRNA, IL-8 protein, and IL-8 receptor were variable among different tumor samples and cell lines, but they showed stable steady states in each cell line. Upon the addition of IL-8, HSA cells showed transient intracellular calcium fluxes, suggesting that their IL-8 receptors are functional and that IL-8 binding activates relevant signaling pathways. Yet, neither addition of exogenous IL-8 nor blockade of endogenous IL-8 by neutralizing anti-IL-8 antibody (α-IL-8 Ab) affected HSA cell proliferation or survival in vitro. To assess potential effects of IL-8 in other tumor constituents, we stratified HSA cell lines and whole tumor samples into “IL-8 high” and “IL-8 low” groups. Genome-wide gene expression profiling showed that samples in the “IL-8 high” tumor group were enriched for genes associated with a “reactive microenvironment,” including activation of coagulation, inflammation, and fibrosis networks. Based on these findings, we hypothesized that the effects of IL-8 on these tumors were mostly indirect, regulating interactions with the microenvironment. This hypothesis was supported by in vivo xenograft experiments where survival and engraftment of tumor cells was inhibited by administration of neutralizing α-IL-8 Ab. Together, our results suggest that IL-8 contributes to establishing a permissive microenvironment during the early stages of tumorigenesis in HSA. - Highlights: • IL-8 is expressed in canine hemangiosarcoma tumor samples and cell lines. • IL-8 transduces a relevant biological signal in canine hemangiosarcoma cells. • IL-8 gene signature is associated

  8. Towards an interpretation of the mechanism of the actinides(III)/lanthanides(III) separation by synergistic solvent extraction with nitrogen-containing polydendate ligands; Vers une interpretation des mecanismes de la separation actinides(III)/lanthanides(III) par extraction liquide-liquide synergique impliquant des ligands polyazotes

    Energy Technology Data Exchange (ETDEWEB)

    Francois, N [CEA/VALRHO - site de Marcoule, Dept. de Recherche en Retraitement et en Vitrification, (DRRV), 30 - Marcoule (France); Universite Henri Poincare, 54 - Vandoeuvre-les-Nancy (France)

    2000-07-01

    In the field of the separation of long-lived radionuclides from the wastes produced by nuclear fuel reprocessing, aromatic nitrogen-containing polydendate ligands are potential candidates for the selective extraction, alone or in synergistic mixture with acidic extractants, of trivalent actinides from trivalent lanthanides. The first part of this work deals with the complexation of trivalent f cations with various nitrogen-containing ligands (poly-pyridine analogues). Time-resolved laser-induced fluorimetry (TRLIF) and UV-visible spectrophotometry were used to determine the nature and evaluate the stability of each complex. Among the ligands studied, the least basic Me-Btp proved to be highly selective towards americium(III) in acidic solution. In the second part, two synergistic systems (nitrogen-containing polydendate ligand and lipophilic carboxylic acid) are studied and compared in regard to the extraction and separation of lanthanides(III) and actinides(III). TRLIF and gamma spectrometry allowed the nature of the extracted complexes and the optimal conditions of efficiency of both systems to be determined. Comparison between these different studies showed that the selectivity of complexation of trivalent f cations by a given nitrogen-containing polydendate ligand could not always be linked to the Am(III)Eu(III) selectivity reached in synergistic extraction. The latter depends on the 'balance' between the acid-basic properties on the one hand, and on the hard-soft characteristics on the other hand, of both components of synergistic system. (author)

  9. Towards an interpretation of the mechanism of the actinides(III)/lanthanides(III) separation by synergistic solvent extraction with nitrogen-containing polydendate ligands; Vers une interpretation des mecanismes de la separation actinides(III)/lanthanides(III) par extraction liquide-liquide synergique impliquant des ligands polyazotes

    Energy Technology Data Exchange (ETDEWEB)

    Francois, N. [CEA/VALRHO - site de Marcoule, Dept. de Recherche en Retraitement et en Vitrification, (DRRV), 30 - Marcoule (France); Universite Henri Poincare, 54 - Vandoeuvre-les-Nancy (France)

    2000-07-01

    In the field of the separation of long-lived radionuclides from the wastes produced by nuclear fuel reprocessing, aromatic nitrogen-containing polydendate ligands are potential candidates for the selective extraction, alone or in synergistic mixture with acidic extractants, of trivalent actinides from trivalent lanthanides. The first part of this work deals with the complexation of trivalent f cations with various nitrogen-containing ligands (poly-pyridine analogues). Time-resolved laser-induced fluorimetry (TRLIF) and UV-visible spectrophotometry were used to determine the nature and evaluate the stability of each complex. Among the ligands studied, the least basic Me-Btp proved to be highly selective towards americium(III) in acidic solution. In the second part, two synergistic systems (nitrogen-containing polydendate ligand and lipophilic carboxylic acid) are studied and compared in regard to the extraction and separation of lanthanides(III) and actinides(III). TRLIF and gamma spectrometry allowed the nature of the extracted complexes and the optimal conditions of efficiency of both systems to be determined. Comparison between these different studies showed that the selectivity of complexation of trivalent f cations by a given nitrogen-containing polydendate ligand could not always be linked to the Am(III)Eu(III) selectivity reached in synergistic extraction. The latter depends on the 'balance' between the acid-basic properties on the one hand, and on the hard-soft characteristics on the other hand, of both components of synergistic system. (author)

  10. Halfway between 2D and Animal Models: Are 3D Cultures the Ideal Tool to Study Cancer-Microenvironment Interactions?

    Directory of Open Access Journals (Sweden)

    Jessica Hoarau-Véchot

    2018-01-01

    Full Text Available An area that has come to be of tremendous interest in tumor research in the last decade is the role of the microenvironment in the biology of neoplastic diseases. The tumor microenvironment (TME comprises various cells that are collectively important for normal tissue homeostasis as well as tumor progression or regression. Seminal studies have demonstrated the role of the dialogue between cancer cells (at many sites and the cellular component of the microenvironment in tumor progression, metastasis, and resistance to treatment. Using an appropriate system of microenvironment and tumor culture is the first step towards a better understanding of the complex interaction between cancer cells and their surroundings. Three-dimensional (3D models have been widely described recently. However, while it is claimed that they can bridge the gap between in vitro and in vivo, it is sometimes hard to decipher their advantage or limitation compared to classical two-dimensional (2D cultures, especially given the broad number of techniques used. We present here a comprehensive review of the different 3D methods developed recently, and, secondly, we discuss the pros and cons of 3D culture compared to 2D when studying interactions between cancer cells and their microenvironment.

  11. Halfway between 2D and Animal Models: Are 3D Cultures the Ideal Tool to Study Cancer-Microenvironment Interactions?

    Science.gov (United States)

    Hoarau-Véchot, Jessica; Rafii, Arash; Touboul, Cyril; Pasquier, Jennifer

    2018-01-18

    An area that has come to be of tremendous interest in tumor research in the last decade is the role of the microenvironment in the biology of neoplastic diseases. The tumor microenvironment (TME) comprises various cells that are collectively important for normal tissue homeostasis as well as tumor progression or regression. Seminal studies have demonstrated the role of the dialogue between cancer cells (at many sites) and the cellular component of the microenvironment in tumor progression, metastasis, and resistance to treatment. Using an appropriate system of microenvironment and tumor culture is the first step towards a better understanding of the complex interaction between cancer cells and their surroundings. Three-dimensional (3D) models have been widely described recently. However, while it is claimed that they can bridge the gap between in vitro and in vivo, it is sometimes hard to decipher their advantage or limitation compared to classical two-dimensional (2D) cultures, especially given the broad number of techniques used. We present here a comprehensive review of the different 3D methods developed recently, and, secondly, we discuss the pros and cons of 3D culture compared to 2D when studying interactions between cancer cells and their microenvironment.

  12. Ultrastrong Bioinspired Graphene-Based Fibers via Synergistic Toughening.

    Science.gov (United States)

    Zhang, Yuanyuan; Li, Yuchen; Ming, Peng; Zhang, Qi; Liu, Tianxi; Jiang, Lei; Cheng, Qunfeng

    2016-04-13

    Ultrastrong bioinspired graphene-based fibers are designed and prepared via synergistic toughening of ionic and covalent bonding. The tensile strength reaches up to 842.6 MPa and is superior to all other reported graphene-based fibers. In addition, its electrical conductivity is as high as 292.4 S cm(-1). This bioinspired synergistic toughening strategy supplies new insight toward the construction of integrated high-performance graphene-based fibers in the near future. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Combination cancer treatment through photothermally controlled release of selenous acid from gold nanocages.

    Science.gov (United States)

    Cheng, Haoyan; Huo, Da; Zhu, Chunlei; Shen, Song; Wang, Wenxia; Li, Haoxuan; Zhu, Zhihong; Xia, Younan

    2018-04-03

    Selenite, one of the inorganic forms of selenium, is emerging as an attractive chemotherapeutic agent owing to its selectivity in eradicating cancer cells. Here we demonstrate a new formulation of nanomedicine based on selenous acid, which is mixed with lauric acid (a phase-change material with a melting point around 43 °C) and then loaded into the cavities of Au nanocages. The Au nanocages can serve as a carrier during cell endocytosis and then as a photothermal agent to melt the lauric acid upon the irradiation with a near-infrared laser, triggering the swift release of selenous acid. The photothermal and chemo therapies can also work synergistically, leading to enhanced destruction of cancer cells relative to normal cells. Our systematic study suggests that the impaired mitochondrial function arising from the ROS generated through combination treatment is responsible for the cell death. This study offers an appealing candidate that holds great promise for synergistic cancer treatment. Published by Elsevier Ltd.

  14. Cancer stem cells and the tumor microenvironment: interplay in tumor heterogeneity.

    Science.gov (United States)

    Albini, Adriana; Bruno, Antonino; Gallo, Cristina; Pajardi, Giorgio; Noonan, Douglas M; Dallaglio, Katiuscia

    2015-01-01

    Tumor cells able to recapitulate tumor heterogeneity have been tracked, isolated and characterized in different tumor types, and are commonly named Cancer Stem Cells or Cancer Initiating Cells (CSC/CIC). CSC/CIC are disseminated in the tumor mass and are resistant to anti-cancer therapies and adverse conditions. They are able to divide into another stem cell and a "proliferating" cancer cell. They appear to be responsible for disease recurrence and metastatic dissemination even after apparent eradication of the primary tumor. The modulation of CSC/CIC activities by the tumor microenvironment (TUMIC) is still poorly known. CSC/CIC may mutually interact with the TUMIC in a special and unique manner depending on the TUMIC cells or proteins encountered. The TUMIC consists of extracellular matrix components as well as cellular players among which endothelial, stromal and immune cells, providing and responding to signals to/from the CSC/CIC. This interplay can contribute to the mechanisms through which CSC/CIC may reside in a dormant state in a tissue for years, later giving rise to tumor recurrence or metastasis in patients. Different TUMIC components, including the connective tissue, can differentially activate CIC/CSC in different areas of a tumor and contribute to the generation of cancer heterogeneity. Here, we review possible networking activities between the different components of the tumor microenvironment and CSC/CIC, with a focus on its role in tumor heterogeneity and progression. We also summarize novel therapeutic options that could target both CSC/CIC and the microenvironment to elude resistance mechanisms activated by CSC/CIC, responsible for disease recurrence and metastases.

  15. Biomimetic and enzyme-responsive dynamic hydrogels for studying cell-matrix interactions in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Liu, Hung-Yi; Korc, Murray; Lin, Chien-Chi

    2018-04-01

    The tumor microenvironment (TME) governs all aspects of cancer progression and in vitro 3D cell culture platforms are increasingly developed to emulate the interactions between components of the stromal tissues and cancer cells. However, conventional cell culture platforms are inadequate in recapitulating the TME, which has complex compositions and dynamically changing matrix mechanics. In this study, we developed a dynamic gelatin-hyaluronic acid hybrid hydrogel system through integrating modular thiol-norbornene photopolymerization and enzyme-triggered on-demand matrix stiffening. In particular, gelatin was dually modified with norbornene and 4-hydroxyphenylacetic acid to render this bioactive protein photo-crosslinkable (through thiol-norbornene gelation) and responsive to tyrosinase-triggered on-demand stiffening (through HPA dimerization). In addition to the modified gelatin that provides basic cell adhesive motifs and protease cleavable sequences, hyaluronic acid (HA), an essential tumor matrix, was modularly and covalently incorporated into the cell-laden gel network. We systematically characterized macromer modification, gel crosslinking, as well as enzyme-triggered stiffening and degradation. We also evaluated the influence of matrix composition and dynamic stiffening on pancreatic ductal adenocarcinoma (PDAC) cell fate in 3D. We found that either HA-containing matrix or a dynamically stiffened microenvironment inhibited PDAC cell growth. Interestingly, these two factors synergistically induced cell phenotypic changes that resembled cell migration and/or invasion in 3D. Additional mRNA expression array analyses revealed changes unique to the presence of HA, to a stiffened microenvironment, or to the combination of both. Finally, we presented immunostaining and mRNA expression data to demonstrate that these irregular PDAC cell phenotypes were a result of matrix-induced epithelial-mesenchymal transition (EMT). Copyright © 2018 Elsevier Ltd. All rights

  16. Phenomenological theory of synergistic effects in plasma-wall interaction

    International Nuclear Information System (INIS)

    Itoh, N.; Hasebe, Y.

    1986-01-01

    A phenomenological theory for synergistic effects under multi-species particle bombardement has been developed. The theory is based on a model in which two free-energy minima are assumed to be overcome under actions of radiation for a process to be completed. The synergistic factor, the ratio of the yield of the process under irradiation with two species of particles to the summation of the yields of the process under irradiation with each of two component species, is obtained as a function of the beam flux for several parameters relevant to thermodynamic and radiation-enhanced processes. The criterion for the synergistic effect is obtained. The theory has been shown to be able to explain the yield-flux relation obtained by Haasz et al. for hydrogen-induced methane formation from graphite. (orig.)

  17. Targeting Gas6/TAM in cancer cells and tumor microenvironment.

    Science.gov (United States)

    Wu, Guiling; Ma, Zhiqiang; Cheng, Yicheng; Hu, Wei; Deng, Chao; Jiang, Shuai; Li, Tian; Chen, Fulin; Yang, Yang

    2018-01-31

    Growth arrest-specific 6, also known as Gas6, is a human gene encoding the Gas6 protein, which was originally found to be upregulated in growth-arrested fibroblasts. Gas6 is a member of the vitamin K-dependent family of proteins expressed in many human tissues and regulates several biological processes in cells, including proliferation, survival and migration, by binding to its receptors Tyro3, Axl and Mer (TAM). In recent years, the roles of Gas6/TAM signalling in cancer cells and the tumour microenvironment have been studied, and some progress has made in targeted therapy, providing new potential directions for future investigations of cancer treatment. In this review, we introduce the Gas6 and TAM receptors and describe their involvement in different cancers and discuss the roles of Gas6 in cancer cells, the tumour microenvironment and metastasis. Finally, we introduce recent studies on Gas6/TAM targeting in cancer therapy, which will assist in the experimental design of future analyses and increase the potential use of Gas6 as a therapeutic target for cancer.

  18. Urban air pollution in school-related microenvironments in Bogota, Colombia

    Directory of Open Access Journals (Sweden)

    Juan Felipe Franco

    2013-05-01

    Full Text Available Particle-related pollution (PM10, PM2.5 and soot was measured in both indoor and outdoor microenvironments at four public elementary schools in Bogota, Colombia. Three of these schools were located alongside major urban roads in which different types of public transit systems are used (bus rapid transit system and conventional transit buses. The fourth school was located on a non-congested road (background school. Pollutant levels at schools situated on major-roads were higher than those found at the low-congestion-road school. Outdoor black carbon daily mean concentrations at the schools located near major roads were up to six times higher than those recorded at the background school. Mean particulate matter concentrations at schools near major roads were above international standards, suggesting that school-age children in Bogota are exposed to pollution levels that are considered to be harmful by environmental and public health authorities. Elevated indoor and outdoor pollutant concentrations documented in this study suggested that traffic has a direct impact on air quality regarding the schools’ characterised microenvironments.

  19. Intravenous microemulsion of docetaxel containing an anti-tumor synergistic ingredient (Brucea javanica oil): formulation and pharmacokinetics.

    Science.gov (United States)

    Ma, Shilin; Chen, Fen; Ye, Xiaohui; Dong, Yingjie; Xue, Yingna; Xu, Heming; Zhang, Wenji; Song, Shuangshuang; Ai, Li; Zhang, Naixian; Pan, Weisan

    2013-01-01

    The purpose of this study was to develop a docetaxel microemulsion containing an anti-tumor synergistic ingredient (Brucea javanica oil) and to investigate the characteristics of the microemulsion. Brucea javanica oil contains oleic acid and linoleic acids that have been shown by animal and human studies to inhibit tumor formation. The microemulsion containing Brucea javanica oil, medium-chain triglyceride, soybean lecithin, Solutol®HS 15, PEG 400, and water was developed for docetaxel intravenous administration. A formulation with higher drug content, lower viscosity, and smaller particle size was developed. The droplet size distribution of the dispersed phase of the optimized microemulsion was 13.5 nm, determined using a dynamic light scattering technique. The small droplet size enabled the microemulsion droplets to escape from uptake and phagocytosis by the reticuloendothelial system and increased the circulation time of the drug. The zeta potential was -41.3 mV. The optimized microemulsion was pale yellow, transparent, and non-opalescent in appearance. The value of the combination index was 0.58, showing that there was a synergistic effect when docetaxel was combined with Brucea javanica oil. After a single intravenous infusion dose (10 mg/kg) in male Sprague Dawley rats, the area under the curve of the microemulsion was higher and the half-time was longer compared with that of docetaxel solution alone, and showed superior pharmacokinetic characteristics. These results indicate that this preparation of docetaxel in emulsion is likely to provide an excellent prospect for clinical tumor treatment.

  20. Probing the electrostatics of active site microenvironments along the catalytic cycle for Escherichia coli dihydrofolate reductase.

    Science.gov (United States)

    Liu, C Tony; Layfield, Joshua P; Stewart, Robert J; French, Jarrod B; Hanoian, Philip; Asbury, John B; Hammes-Schiffer, Sharon; Benkovic, Stephen J

    2014-07-23

    Electrostatic interactions play an important role in enzyme catalysis by guiding ligand binding and facilitating chemical reactions. These electrostatic interactions are modulated by conformational changes occurring over the catalytic cycle. Herein, the changes in active site electrostatic microenvironments are examined for all enzyme complexes along the catalytic cycle of Escherichia coli dihydrofolate reductase (ecDHFR) by incorporation of thiocyanate probes at two site-specific locations in the active site. The electrostatics and degree of hydration of the microenvironments surrounding the probes are investigated with spectroscopic techniques and mixed quantum mechanical/molecular mechanical (QM/MM) calculations. Changes in the electrostatic microenvironments along the catalytic environment lead to different nitrile (CN) vibrational stretching frequencies and (13)C NMR chemical shifts. These environmental changes arise from protein conformational rearrangements during catalysis. The QM/MM calculations reproduce the experimentally measured vibrational frequency shifts of the thiocyanate probes across the catalyzed hydride transfer step, which spans the closed and occluded conformations of the enzyme. Analysis of the molecular dynamics trajectories provides insight into the conformational changes occurring between these two states and the resulting changes in classical electrostatics and specific hydrogen-bonding interactions. The electric fields along the CN axes of the probes are decomposed into contributions from specific residues, ligands, and solvent molecules that make up the microenvironments around the probes. Moreover, calculation of the electric field along the hydride donor-acceptor axis, along with decomposition of this field into specific contributions, indicates that the cofactor and substrate, as well as the enzyme, impose a substantial electric field that facilitates hydride transfer. Overall, experimental and theoretical data provide evidence for

  1. Detection of different microenvironments and Lactobacillus sakei biotypes in Ventricina, a traditional fermented sausage from central Italy.

    Science.gov (United States)

    Tremonte, Patrizio; Sorrentino, Elena; Pannella, Gianfranco; Tipaldi, Luca; Sturchio, Marina; Masucci, Armando; Maiuro, Lucia; Coppola, Raffaele; Succi, Mariantonietta

    2017-02-02

    The present study evaluated the physico-chemical and microbiological features of Ventricina, considering for the first time the presence of different compartments deriving from the technology of production. In fact meat pieces (pork muscle and fat cut into cubes of about 10-20cm 3 ), mixed with other ingredients and then stuffed into pig bladder, are still distinguishable at the end of the ripening. They appear delimited on the outside by the casing and inside by thin layers consisting of spices (mainly red pepper powder), salt and meat juices. Our results showed that the exterior (portion of the product in contact with the casing), the interstice (area between the different cubes of meat or fat) and the heart (the inner portion of meat cubes) had distinctive values of pH and a w , and a typical microbial progression, so that they can be considered as different ecological niches, here called microenvironments. The study of lactic acid bacteria population, performed with PCR-DGGE and sequence analysis targeting the V1-V3 region of the 16S rRNA gene (rDNA), highlighted the presence of a few species, including Lactobacillus sakei, Lb. plantarum, Weissella hellenica and Leuconostoc mesenteroides. The RAPD-PCR analysis performed on Lb. sakei, recognised as the predominant species, allowed the differentiation into three biotypes, with that characterised by the highest acidifying and proteolytic activities and the highest ability to grow in the presence of sodium chloride prevailing. This leading biotype, detectable in the interstice during the entire ripening period, was isolated in the microenvironments exterior and heart starting from the 30th d of ripening, and it was the sole biotype present at the end of the ripening. The analysis of microenvironments through the scanning electron microscopy (SEM) evidenced the presence of micro-channels, which could favour the microbial flow from the interstice to the exterior and the heart. Moreover, the SEM analysis allowed the

  2. Magnetocaloric Effect and Thermoelectric Cooling - A Synergistic Cooling Technology

    Science.gov (United States)

    2018-01-16

    Thermoelectric Cooling - A Synergistic Cooling Technology Sb. GRANT NUMBER N00173-14-1-G016 Sc. PROGRAM ELEMENT NUMBER 82-2020-17 6. AUTHOR(S) 5d...Magnetocaloric Effect and Thermoelectric Cooling - A Synergistic Cooling Technology NRL Grant N00173-14-l-G016 CODE 8200: Spacecraft Engineering Department...82-11-0 1: Space and Space Systems Technology General Engineering & Research, L.L.C. Technical & Administrative point of contact: Dr. Robin

  3. Inorganic Arsenic?Related Changes in the Stromal Tumor Microenvironment in a Prostate Cancer Cell?Conditioned Media Model

    OpenAIRE

    Shearer, Joseph J.; Wold, Eric A.; Umbaugh, Charles S.; Lichti, Cheryl F.; Nilsson, Carol L.; Figueiredo, Marxa L.

    2015-01-01

    Background: The tumor microenvironment plays an important role in the progression of cancer by mediating stromal?epithelial paracrine signaling, which can aberrantly modulate cellular proliferation and tumorigenesis. Exposure to environmental toxicants, such as inorganic arsenic (iAs), has also been implicated in the progression of prostate cancer. Objective: The role of iAs exposure in stromal signaling in the tumor microenvironment has been largely unexplored. Our objective was to elucidate...

  4. Bed Microenvironment in Hospital Patient Rooms with Natural or Mechanical Ventilation

    DEFF Research Database (Denmark)

    Melikov, Arsen Krikor; Li, Yuguo; Georgiev, Emanuil

    2012-01-01

    We studied how to provide patients in bed with thermally comfortable microenvironment in both naturally and mechanically ventilated hospital rooms for both winter and summer seasons. A climate chamber was used to resemble a hospital room and thermal manikin to simulate a patient lying in a bed...

  5. Synergistic extraction of actinides : Part I. Hexa-and pentavalent actinides

    International Nuclear Information System (INIS)

    Patil, S.K.; Ramakrishna, V.V.

    1980-01-01

    A detailed discussion on the reported literature on the synergistic extraction of hexa- and pentavalent actinide ions, by different combinations of extractants and from different aqueous media, is presented. Structural aspects of the various complexes involved in synergism also are reviewed. A short account of the applications based on synergistic extraction is also given. (author)

  6. Synergistic induction of astrocytic differentiation by factors secreted from meninges in the mouse developing brain.

    Science.gov (United States)

    Kawamura, Yoichiro; Katada, Sayako; Noguchi, Hirofumi; Yamamoto, Hiroyuki; Sanosaka, Tsukasa; Iihara, Koji; Nakashima, Kinichi

    2017-11-01

    Astrocytes, which support diverse neuronal functions, are generated from multipotent neural stem/precursor cells (NS/PCs) during brain development. Although many astrocyte-inducing factors have been identified and studied in vitro, the regions and/or cells that produce these factors in the developing brain remain elusive. Here, we show that meninges-produced factors induce astrocytic differentiation of NS/PCs. Consistent with the timing when astrocytic differentiation of NS/PCs increases, expression of astrocyte-inducing factors is upregulated. Meningeal secretion-mimicking combinatorial treatment of NS/PCs with bone morphogenetic protein 4, retinoic acid and leukemia inhibitory factor synergistically activate the promoter of a typical astrocytic marker, glial fibrillary acidic protein. Taken together, our data suggest that meninges play an important role in astrocytic differentiation of NS/PCs in the developing brain. © 2017 Federation of European Biochemical Societies.

  7. PAR-1 and thrombin: the ties that bind the microenvironment to melanoma metastasis.

    Science.gov (United States)

    Zigler, Maya; Kamiya, Takafumi; Brantley, Emily C; Villares, Gabriel J; Bar-Eli, Menashe

    2011-11-01

    Progression of melanoma is dependent on cross-talk between tumor cells and the adjacent microenvironment. The thrombin receptor, protease-activated receptor-1 (PAR-1), plays a key role in exerting this function during melanoma progression. PAR-1 and its activating factors, which are expressed on tumor cells and the surrounding stroma, induce not only coagulation but also cell signaling, which promotes the metastatic phenotype. Several adhesion molecules, cytokines, growth factors, and proteases have recently been identified as downstream targets of PAR-1 and have been shown to modulate interactions between tumor cells and the microenvironment in the process of melanoma growth and metastasis. Inhibiting such interactions by targeting PAR-1 could potentially be a useful therapeutic modality for melanoma patients. ©2011 AACR.

  8. Hypoxia Pathway Proteins As Central Mediators of Metabolism in the Tumor Cells and Their Microenvironment

    Directory of Open Access Journals (Sweden)

    Sundary Sormendi

    2018-01-01

    Full Text Available Low oxygen tension or hypoxia is a determining factor in the course of many different processes in animals, including when tissue expansion and cellular metabolism result in high oxygen demands that exceed its supply. This is mainly happening when cells actively proliferate and the proliferating mass becomes distant from the blood vessels, such as in growing tumors. Metabolic alterations in response to hypoxia can be triggered in a direct manner, such as the switch from oxidative phosphorylation to glycolysis or inhibition of fatty acid desaturation. However, as the modulated action of hypoxia-inducible factors or the oxygen sensors (prolyl hydroxylase domain-containing enzymes can also lead to changes in enzyme expression, these metabolic changes can also be indirect. With this review, we want to summarize our current knowledge of the hypoxia-induced changes in metabolism during cancer development, how they are affected in the tumor cells and in the cells of the microenvironment, most prominently in immune cells.

  9. Effect of the Premalignant and Tumor Microenvironment on Immune Cell Cytokine Production in Head and Neck Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, Sara D. [Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425 (United States); De Costa, Anna-Maria A. [Department of Otolaryngology, Head and Neck Surgery, Medical University of South Carolina, 135 Rutledge Avenue, Charleston, SC 29425 (United States); Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425 (United States); Young, M. Rita I., E-mail: rita.young@va.gov [Department of Otolaryngology, Head and Neck Surgery, Medical University of South Carolina, 135 Rutledge Avenue, Charleston, SC 29425 (United States); Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425 (United States); Medical Research Service (151), Ralph H. Johnson Veterans Affairs Medical Center, 109 Bee Street, Charleston, SC 29401 (United States)

    2014-04-02

    Head and neck squamous cell carcinoma (HNSCC) is marked by immunosuppression, a state in which the established tumor escapes immune attack. However, the impact of the premalignant and tumor microenvironments on immune reactivity has yet to be elucidated. The purpose of this study was to determine how soluble mediators from cells established from carcinogen-induced oral premalignant lesions and HNSCC modulate immune cell cytokine production. It was found that premalignant cells secrete significantly increased levels of G-CSF, RANTES, MCP-1, and PGE{sub 2} compared to HNSCC cells. Splenocytes incubated with premalignant supernatant secreted significantly increased levels of Th1-, Th2-, and Th17-associated cytokines compared to splenocytes incubated with HNSCC supernatant. These studies demonstrate that whereas the premalignant microenvironment elicits proinflammatory cytokine production, the tumor microenvironment is significantly less immune stimulatory and may contribute to immunosuppression in established HNSCC.

  10. Synergistic Man: Outcome Model for Counselors

    Science.gov (United States)

    Rousseve, Ronald J.

    1973-01-01

    Drawing on the insights of Ruth Benedict and Abraham Maslow in their search for an ethical gauge by which to rate personal-social health, this article proposes synergistic man'' as the desired outcome model for counselors. (Author)

  11. Pulmonary emphysema and tumor microenvironment in primary lung cancer.

    Science.gov (United States)

    Murakami, Junichi; Ueda, Kazuhiro; Sano, Fumiho; Hayashi, Masataro; Nishimoto, Arata; Hamano, Kimikazu

    2016-02-01

    To clarify the relationship between the presence of pulmonary emphysema and tumor microenvironment and their significance for the clinicopathologic aggressiveness of non-small cell lung cancer. The subjects included 48 patients with completely resected and pathologically confirmed stage I non-small cell lung cancer. Quantitative computed tomography was used to diagnose pulmonary emphysema, and immunohistochemical staining was performed to evaluate the matrix metalloproteinase (MMP) expression status in the intratumoral stromal cells as well as the microvessel density (MVD). Positive MMP-9 staining in the intratumoral stromal cells was confirmed in 17 (35%) of the 48 tumors. These 17 tumors were associated with a high MVD, frequent lymphovascular invasion, a high proliferative activity, and high postoperative recurrence rate (all, P pulmonary emphysema (P = 0.02). Lung cancers arising from pulmonary emphysema were also associated with a high MVD, proliferative activity, and postoperative recurrence rate (all, P < 0.05). The MMP-9 expression in intratumoral stromal cells is associated with the clinicopathologic aggressiveness of lung cancer and is predominantly identified in tumors arising in emphysematous lungs. Further studies regarding the biological links between the intratumoral and extratumoral microenvironment will help to explain why lung cancers originating in emphysematous lung tissues are associated with a poor prognosis. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Synergistic Removal of Humic Acid in Water by Coupling Adsorption and Photocatalytic Degradation Using TiO2/Coconut Shell Powder Composite

    Directory of Open Access Journals (Sweden)

    Jong Kyu Kim

    2016-01-01

    Full Text Available The feasibility of applying nanoscale TiO2/coconut shell powder (TCNSP composite to remove HA in aqueous solution was evaluated, and the optimization of the photocatalytic systems using newly developed TCNSP composite was performed. The developed TCNSP composite has high specific surface area (i.e., 454 m2/g and great porosity (i.e., 66.9% with pore size of less than 5 μm. High removal efficiencies (≥95% of HA were observed due to the significant synergistic effects by coupling adsorption and photocatalytic reaction of TCNSP composite. As the initial concentration of HA increased, the degradation rate (Kapp decreased due to HA sorption saturation to the surface of TCNSP composite and the photon interception by HA molecules in aqueous solution. Since the increased loading amount of TCNSP composite enhanced the number of active sites, Kapp values increased until the optimum loading amount of TCNSP composite. As pH values increased, HA removal efficiency decreased due to increasing electrostatic repulsion between HA and TCNSP composite. Based on the response surface methodology, higher HA removal efficiencies were obtained with acidic condition, longer reaction time, and appropriated loading amount of TCNSP. Further pilot-scale study is in progress using TCNSP composite combined with UVC to remove HA from large amounts of surface water (i.e., 200 m3/d.

  13. Aqueous citric acid as a promising cleaning agent of whey evaporators

    DEFF Research Database (Denmark)

    Hedegaard, Martina Vavrusova; P. Johansen, Nikolaj; Garcia, André Castilho

    2017-01-01

    concentration of citric acid was the most effective for all the investigated volumes. From the citric acid solutions, spontaneously supersaturated in calcium citrate tetrahydrate during scale dissolution in the smaller volumes for all citric acid concentrations, calcium citrate tetrahydrate slowly precipitated...... in acceptable purity for technical use. Dissolution efficiency of aqueous solutions of 0.200 mol L−1 nitric acid combined with 0.100, 0.500, and 1.00 mol L−1 citric acid with final volumes of 100, 50, and 25 mL showed synergistic effect especially for the higher concentrations and lower volumes of two acids...

  14. Quantifying the mechanical micro-environment during three-dimensional cell expansion on microbeads by means of individual cell-based modelling.

    Science.gov (United States)

    Smeets, Bart; Odenthal, Tim; Tijskens, Engelbert; Ramon, Herman; Van Oosterwyck, Hans

    2013-10-01

    Controlled in vitro three-dimensional cell expansion requires culture conditions that optimise the biophysical micro-environment of the cells during proliferation. In this study, we propose an individual cell-based modelling platform for simulating the mechanics of cell expansion on microcarriers. The lattice-free, particle-based method considers cells as individual interacting particles that deform and move over time. The model quantifies how the mechanical micro-environment of individual cells changes during the time of confluency. A sensitivity analysis is performed, which shows that changes in the cell-specific properties of cell-cell adhesion and cell stiffness cause the strongest change in the mechanical micro-environment of the cells. Furthermore, the influence of the mechanical properties of cells and microbead is characterised. The mechanical micro-environment is strongly influenced by the adhesive properties and the size of the microbead. Simulations show that even in the absence of strong biological heterogeneity, a large heterogeneity in mechanical stresses can be expected purely due to geometric properties of the culture system.

  15. Glycyrrhetic acid synergistically enhances β₂-adrenergic receptor-Gs signaling by changing the location of Gαs in lipid rafts.

    Directory of Open Access Journals (Sweden)

    Qian Shi

    Full Text Available Glycyrrhetic acid (GA exerts synergistic anti-asthmatic effects via a β₂-adrenergic receptor (β₂AR-mediated pathway. Cholesterol is an important component of the structure and function of lipid rafts, which play critical roles in the β₂AR-Gs-adenylate cyclase (AC-mediated signaling pathway. Owing to the structural similarities between GA and cholesterol, we investigated the possibility that GA enhances β₂AR signaling by altering cholesterol distribution. Azide-terminal GA (ATGA was synthesized and applied to human embryonic kidney 293 (HEK293 cells expressing fusion β₂AR, and the electron spin resonance (ESR technique was utilized. GA was determined to be localized predominantly on membrane and decreased their cholesterol contents. Thus, the fluidity of the hydrophobic region increased but not the polar surface of the cell membrane. The conformations of membrane proteins were also changed. GA further changed the localization of Gαs from lipid rafts to non-raft regions, resulting the binding of β₂AR and Gαs, as well as in reduced β₂AR internalization. Co-localization of β₂AR, Gαs, and AC increased isoproterenol-induced cAMP production and cholesterol reloading attenuated this effect. A speculation wherein GA enhances beta-adrenergic activity by increasing the functional linkage between the subcomponents of the membrane β₂AR-protein kinase A (PKA signaling pathway was proposed. The enhanced efficacy of β₂AR agonists by this novel mechanism could prevent tachyphylaxis.

  16. Synergistic interactions promote behavior spreading and alter phase transitions on multiplex networks

    Science.gov (United States)

    Liu, Quan-Hui; Wang, Wei; Cai, Shi-Min; Tang, Ming; Lai, Ying-Cheng

    2018-02-01

    Synergistic interactions are ubiquitous in the real world. Recent studies have revealed that, for a single-layer network, synergy can enhance spreading and even induce an explosive contagion. There is at the present a growing interest in behavior spreading dynamics on multiplex networks. What is the role of synergistic interactions in behavior spreading in such networked systems? To address this question, we articulate a synergistic behavior spreading model on a double layer network, where the key manifestation of the synergistic interactions is that the adoption of one behavior by a node in one layer enhances its probability of adopting the behavior in the other layer. A general result is that synergistic interactions can greatly enhance the spreading of the behaviors in both layers. A remarkable phenomenon is that the interactions can alter the nature of the phase transition associated with behavior adoption or spreading dynamics. In particular, depending on the transmission rate of one behavior in a network layer, synergistic interactions can lead to a discontinuous (first-order) or a continuous (second-order) transition in the adoption scope of the other behavior with respect to its transmission rate. A surprising two-stage spreading process can arise: due to synergy, nodes having adopted one behavior in one layer adopt the other behavior in the other layer and then prompt the remaining nodes in this layer to quickly adopt the behavior. Analytically, we develop an edge-based compartmental theory and perform a bifurcation analysis to fully understand, in the weak synergistic interaction regime where the dynamical correlation between the network layers is negligible, the role of the interactions in promoting the social behavioral spreading dynamics in the whole system.

  17. Carbonic anhydrase IX (CA IX) mediates tumor cell interactions with microenvironment

    Czech Academy of Sciences Publication Activity Database

    Závadová, Zuzana; Závada, Jan

    2005-01-01

    Roč. 13, č. 5 (2005), s. 977-982 ISSN 1021-335X R&D Projects: GA ČR(CZ) GA203/02/0405 Institutional research plan: CEZ:AV0Z50520514 Keywords : carbonic anhydrase IX * cell adhesion * microenvironment Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.572, year: 2005

  18. Interactive Effects of Jasmonic Acid, Salicylic Acid, and Gibberellin on Induction of Trichomes in Arabidopsis1

    Science.gov (United States)

    Traw, M. Brian; Bergelson, Joy

    2003-01-01

    Leaf trichomes protect plants from attack by insect herbivores and are often induced following damage. Hormonal regulation of this plant induction response has not been previously studied. In a series of experiments, we addressed the effects of artificial damage, jasmonic acid, salicylic acid, and gibberellin on induction of trichomes in Arabidopsis. Artificial damage and jasmonic acid caused significant increases in trichome production of leaves. The jar1-1 mutant exhibited normal trichome induction following treatment with jasmonic acid, suggesting that adenylation of jasmonic acid is not necessary. Salicylic acid had a negative effect on trichome production and consistently reduced the effect of jasmonic acid, suggesting negative cross-talk between the jasmonate and salicylate-dependent defense pathways. Interestingly, the effect of salicylic acid persisted in the nim1-1 mutant, suggesting that the Npr1/Nim1 gene is not downstream of salicylic acid in the negative regulation of trichome production. Last, we found that gibberellin and jasmonic acid had a synergistic effect on the induction of trichomes, suggesting important interactions between these two compounds. PMID:14551332

  19. Antimicrobial and enhancement of the antibiotic activity by phenolic compounds: Gallic acid, caffeic acid and pyrogallol.

    Science.gov (United States)

    Lima, Valéria N; Oliveira-Tintino, Cícera D M; Santos, Enaide S; Morais, Luís P; Tintino, Saulo R; Freitas, Thiago S; Geraldo, Yuri S; Pereira, Raimundo L S; Cruz, Rafael P; Menezes, Irwin R A; Coutinho, Henrique D M

    2016-10-01

    The indiscriminate use of antimicrobial drugs has increased the spectrum of exposure of these organisms. In our studies, these phenolic compounds were evaluated: gallic acid, caffeic acid and pyrogallol. The antibacterial, antifungal and modulatory of antibiotic activities of these compounds were assayed using microdilution method of Minimum Inhibitory Concentration (MIC) to bacteria and Minimum Fungicide Concentration (MFC) to fungi. The modulation was made by comparisons of the MIC and MFC of the compounds alone and combined with drugs against bacteria and fungi respectively, using a sub-inhibitory concentration of 128 μg/mL of substances (MIC/8). All substances not demonstrated clinically relevant antibacterial activity with a MIC above ≥1024 μg/mL. As a result, we observed that the caffeic acid presented a potentiating antibacterial effect over the 3 groups of bacteria studied. Pyrogallol showed a synergistic effect with two of the antibiotics tested, but only against Staphylococcus aureus. In general, caffeic acid was the substance that presented with the greatest number of antibiotics and with the greatest number of bacteria. In relation to the antifungal activity of all the compounds, the verified results were ≥1024 μg/mL, not demonstrating significant activity. Regarding potentiation of the effect of fluconazole, was observed synergistic effect only when assayed against Candida tropicalis, with all substances. Therefore, as can be seen, the compounds presented as substances that can be promising potentiating agents of antimicrobial drugs, even though they do not have direct antibacterial and antifungal action. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Evaluation of daily time spent in transportation and traffic-influenced microenvironments by urban Canadians.

    Science.gov (United States)

    Matz, Carlyn J; Stieb, David M; Egyed, Marika; Brion, Orly; Johnson, Markey

    2018-01-01

    Exposure to traffic and traffic-related air pollution is associated with a wide array of health effects. Time spent in a vehicle, in active transportation, along roadsides, and in close proximity to traffic can substantially contribute to daily exposure to air pollutants. For this study, we evaluated daily time spent in transportation and traffic-influenced microenvironments by urban Canadians using the Canadian Human Activity Pattern Survey (CHAPS) 2 results. Approximately 4-7% of daily time was spent in on- or near-road locations, mainly associated with being in a vehicle and smaller contributions from active transportation. Indoor microenvironments can be impacted by traffic emissions, especially when located near major roadways. Over 60% of the target population reported living within one block of a roadway with moderate to heavy traffic, which was variable with income level and city, and confirmed based on elevated NO 2 exposure estimated using land use regression. Furthermore, over 55% of the target population ≤ 18 years reported attending a school or daycare in close proximity to moderate to heavy traffic, and little variation was observed based on income or city. The results underline the importance of traffic emissions as a major source of exposure in Canadian urban centers, given the time spent in traffic-influenced microenvironments.

  1. Catalog of gene expression in adult neural stem cells and their in vivo microenvironment

    International Nuclear Information System (INIS)

    Williams, Cecilia; Wirta, Valtteri; Meletis, Konstantinos; Wikstroem, Lilian; Carlsson, Leif; Frisen, Jonas; Lundeberg, Joakim

    2006-01-01

    Stem cells generally reside in a stem cell microenvironment, where cues for self-renewal and differentiation are present. However, the genetic program underlying stem cell proliferation and multipotency is poorly understood. Transcriptome analysis of stem cells and their in vivo microenvironment is one way of uncovering the unique stemness properties and provides a framework for the elucidation of stem cell function. Here, we characterize the gene expression profile of the in vivo neural stem cell microenvironment in the lateral ventricle wall of adult mouse brain and of in vitro proliferating neural stem cells. We have also analyzed an Lhx2-expressing hematopoietic-stem-cell-like cell line in order to define the transcriptome of a well-characterized and pure cell population with stem cell characteristics. We report the generation, assembly and annotation of 50,792 high-quality 5'-end expressed sequence tag sequences. We further describe a shared expression of 1065 transcripts by all three stem cell libraries and a large overlap with previously published gene expression signatures for neural stem/progenitor cells and other multipotent stem cells. The sequences and cDNA clones obtained within this framework provide a comprehensive resource for the analysis of genes in adult stem cells that can accelerate future stem cell research

  2. L-Amino Acids Elicit Diverse Response Patterns in Taste Sensory Cells: A Role for Multiple Receptors

    Science.gov (United States)

    Pal Choudhuri, Shreoshi; Delay, Rona J.; Delay, Eugene R.

    2015-01-01

    Umami, the fifth basic taste, is elicited by the L-amino acid, glutamate. A unique characteristic of umami taste is the response potentiation by 5’ ribonucleotide monophosphates, which are also capable of eliciting an umami taste. Initial reports using human embryonic kidney (HEK) cells suggested that there is one broadly tuned receptor heterodimer, T1r1+T1r3, which detects L-glutamate and all other L-amino acids. However, there is growing evidence that multiple receptors detect glutamate in the oral cavity. While much is understood about glutamate transduction, the mechanisms for detecting the tastes of other L-amino acids are less well understood. We used calcium imaging of isolated taste sensory cells and taste cell clusters from the circumvallate and foliate papillae of C57BL/6J and T1r3 knockout mice to determine if other receptors might also be involved in detection of L-amino acids. Ratiometric imaging with Fura-2 was used to study calcium responses to monopotassium L-glutamate, L-serine, L-arginine, and L-glutamine, with and without inosine 5’ monophosphate (IMP). The results of these experiments showed that the response patterns elicited by L-amino acids varied significantly across taste sensory cells. L-amino acids other than glutamate also elicited synergistic responses in a subset of taste sensory cells. Along with its role in synergism, IMP alone elicited a response in a large number of taste sensory cells. Our data indicate that synergistic and non-synergistic responses to L-amino acids and IMP are mediated by multiple receptors or possibly a receptor complex. PMID:26110622

  3. Intravenous microemulsion of docetaxel containing an anti-tumor synergistic ingredient (Brucea javanica oil): formulation and pharmacokinetics

    Science.gov (United States)

    Ma, Shilin; Chen, Fen; Ye, Xiaohui; Dong, Yingjie; Xue, Yingna; Xu, Heming; Zhang, Wenji; Song, Shuangshuang; Ai, Li; Zhang, Naixian; Pan, Weisan

    2013-01-01

    The purpose of this study was to develop a docetaxel microemulsion containing an anti-tumor synergistic ingredient (Brucea javanica oil) and to investigate the characteristics of the microemulsion. Brucea javanica oil contains oleic acid and linoleic acids that have been shown by animal and human studies to inhibit tumor formation. The microemulsion containing Brucea javanica oil, medium-chain triglyceride, soybean lecithin, Solutol®HS 15, PEG 400, and water was developed for docetaxel intravenous administration. A formulation with higher drug content, lower viscosity, and smaller particle size was developed. The droplet size distribution of the dispersed phase of the optimized microemulsion was 13.5 nm, determined using a dynamic light scattering technique. The small droplet size enabled the microemulsion droplets to escape from uptake and phagocytosis by the reticuloendothelial system and increased the circulation time of the drug. The zeta potential was −41.3 mV. The optimized microemulsion was pale yellow, transparent, and non-opalescent in appearance. The value of the combination index was 0.58, showing that there was a synergistic effect when docetaxel was combined with Brucea javanica oil. After a single intravenous infusion dose (10 mg/kg) in male Sprague Dawley rats, the area under the curve of the microemulsion was higher and the half-time was longer compared with that of docetaxel solution alone, and showed superior pharmacokinetic characteristics. These results indicate that this preparation of docetaxel in emulsion is likely to provide an excellent prospect for clinical tumor treatment. PMID:24179332

  4. Synergistic effects in mixed Escherichia coli biofilms

    DEFF Research Database (Denmark)

    Reisner, A.; Holler, B.M.; Molin, Søren

    2006-01-01

    Bacterial biofilms, often composed of multiple species and genetically distinct strains, develop under complex influences of cell-cell interactions. Although detailed knowledge about the mechanisms underlying formation of single-species laboratory biofilms has emerged, little is known about...... the pathways governing development of more complex heterogeneous communities. In this study, we established a laboratory model where biofilm-stimulating effects due to interactions between genetically diverse strains of Escherichia coli were monitored. Synergistic induction of biofilm formation resulting from...... the cocultivation of 403 undomesticated E. coli strains with a characterized E. coli K-12 strain was detected at a significant frequency. The survey suggests that different mechanisms underlie the observed stimulation, yet synergistic development of biofilm within the subset of E. coli isolates (n = 56) exhibiting...

  5. Flame retardant finishing of cotton fabric based on synergistic compounds containing boron and nitrogen.

    Science.gov (United States)

    Xie, Kongliang; Gao, Aiqin; Zhang, Yongsheng

    2013-10-15

    Boric acid and compound containing nitrogen, 2,4,6-tri[(2-hydroxy-3-trimethyl-ammonium)propyl]-1,3,5-triazine chloride (Tri-HTAC) were used to finish cotton fabric. The flame retardant properties of the finished cotton fabrics and the synergetic effects of boron and nitrogen elements were investigated and evaluated by limited oxygen index (LOI) method. The mechanism of cross-linking reaction among cotton fiber, Tri-HTAC, and boric acid was discussed by FTIR and element analysis. The thermal stability and surface morphology of the finished cotton fabrics were investigated by thermogravimetric analysis (TGA) and scanning electron microscope (SEM), respectively. The finishing system of the mixture containing boron and nitrogen showed excellent synergistic flame retardancy for cotton fabric. The cotton fabric finished with mixture system had excellent flame retardancy. The LOI value of the treated cotton fabric increased over 27.5. Tri-HTAC could form covalent bonds with cellulose fiber and boric acid. The flame retardant cotton fabric showed a slight decrease in tensile strength and whiteness. The surface morphology of flame retardant cotton fiber was smooth. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. ATP/P2X7 axis modulates myeloid-derived suppressor cell functions in neuroblastoma microenvironment.

    Science.gov (United States)

    Bianchi, G; Vuerich, M; Pellegatti, P; Marimpietri, D; Emionite, L; Marigo, I; Bronte, V; Di Virgilio, F; Pistoia, V; Raffaghello, L

    2014-03-20

    Tumor microenvironment of solid tumors is characterized by a strikingly high concentration of adenosine and ATP. Physiological significance of this biochemical feature is unknown, but it has been suggested that it may affect infiltrating immune cell responses and tumor progression. There is increasing awareness that many of the effects of extracellular ATP on tumor and inflammatory cells are mediated by the P2X7 receptor (P2X7R). Aim of this study was to investigate whether: (i) extracellular ATP is a component of neuroblastoma (NB) microenvironment, (ii) myeloid-derived suppressor cells (MDSCs) express functional P2X7R and (iii) the ATP/P2X7R axis modulates MDSC functions. Our results show that extracellular ATP was detected in NB microenvironment in amounts that increased in parallel with tumor progression. The percentage of CD11b(+)/Gr-1(+) cells was higher in NB-bearing mice compared with healthy animals. Within the CD11b/Gr-1(+) population, monocytic MDSCs (M-MDSCs) produced higher levels of reactive oxygen species (ROS), arginase-1 (ARG-1), transforming growth factor-β1 (TGF-β1) and stimulated more potently in vivo tumor growth, as compared with granulocytic MDSCs (G-MDSCs). P2X7R of M-MDSCs was localized at the plasma membrane, coupled to increased functionality, upregulation of ARG-1, TGF-β1 and ROS. Quite surprisingly, the P2X7R in primary MDSCs as well as in the MSC-1 and MSC-2 lines was uncoupled from cytotoxicity. This study describes a novel scenario in which MDSC immunosuppressive functions are modulated by the ATP-enriched tumor microenvironment.

  7. Dietary flaxseed modulates the colonic microenvironment in healthy C57Bl/6 male mice which may alter susceptibility to gut-associated diseases.

    Science.gov (United States)

    Power, Krista A; Lepp, Dion; Zarepoor, Leila; Monk, Jennifer M; Wu, Wenqing; Tsao, Rong; Liu, Ronghua

    2016-02-01

    Understanding how dietary components alter the healthy baseline colonic microenvironment is important in determining their roles in influencing gut health and gut-associated diseases. Dietary flaxseed (FS) has demonstrated anti-colon cancer effects in numerous rodent models, however, exacerbated acute colonic mucosal injury and inflammation in a colitis model. This study investigates whether FS alters critical aspects of gut health in healthy unchallenged mice, which may help explain some of the divergent effects observed following different gut-associated disease challenges. Four-week-old C57Bl/6 male mice were fed an AIN-93G basal diet (BD) or an isocaloric BD+10% ground FS diet for 3 weeks. FS enhanced colon goblet cell density, mucus production, MUC2 mRNA expression, and cecal short chain fatty acid levels, indicative of beneficial intestinal barrier integrity responses. Additionally, FS enhanced colonic regenerating islet-derived protein 3 gamma (RegIIIγ) and reduced MUC1 and resistin-like molecule beta (RELMβ) mRNA expression which may indicate altered responses in regulating microbial defense and injury repair responses. FS diet altered the fecal microbial community structure (16S rRNA gene profiling), including a 20-fold increase in Prevotella spp. and a 30-fold reduction in Akkermansia muciniphila abundance. A 10-fold reduction in A. muciniphila abundance by FS was also demonstrated in the colon tissue-associated microbiota (quantitative PCR). Furthermore, fecal branched chain fatty acids were increased by FS, indicative of increased microbial-derived putrefactive compounds. In conclusion, consumption of a FS-supplemented diet alters the baseline colonic microenvironment of healthy mice which may modify subsequent mucosal microbial defense and injury-repair responses leading to altered susceptibility to different gut-associated diseases. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

  8. Synergistic Synthetic Biology: Units in Concert

    Science.gov (United States)

    Trosset, Jean-Yves; Carbonell, Pablo

    2013-01-01

    Synthetic biology aims at translating the methods and strategies from engineering into biology in order to streamline the design and construction of biological devices through standardized parts. Modular synthetic biology devices are designed by means of an adequate elimination of cross-talk that makes circuits orthogonal and specific. To that end, synthetic constructs need to be adequately optimized through in silico modeling by choosing the right complement of genetic parts and by experimental tuning through directed evolution and craftsmanship. In this review, we consider an additional and complementary tool available to the synthetic biologist for innovative design and successful construction of desired circuit functionalities: biological synergies. Synergy is a prevalent emergent property in biological systems that arises from the concerted action of multiple factors producing an amplification or cancelation effect compared with individual actions alone. Synergies appear in domains as diverse as those involved in chemical and protein activity, polypharmacology, and metabolic pathway complementarity. In conventional synthetic biology designs, synergistic cross-talk between parts and modules is generally attenuated in order to verify their orthogonality. Synergistic interactions, however, can induce emergent behavior that might prove useful for synthetic biology applications, like in functional circuit design, multi-drug treatment, or in sensing and delivery devices. Synergistic design principles are therefore complementary to those coming from orthogonal design and may provide added value to synthetic biology applications. The appropriate modeling, characterization, and design of synergies between biological parts and units will allow the discovery of yet unforeseeable, novel synthetic biology applications. PMID:25022769

  9. Synergistic Synthetic Biology: Units in Concert

    International Nuclear Information System (INIS)

    Trosset, Jean-Yves; Carbonell, Pablo

    2013-01-01

    Synthetic biology aims at translating the methods and strategies from engineering into biology in order to streamline the design and construction of biological devices through standardized parts. Modular synthetic biology devices are designed by means of an adequate elimination of cross-talk that makes circuits orthogonal and specific. To that end, synthetic constructs need to be adequately optimized through in silico modeling by choosing the right complement of genetic parts and by experimental tuning through directed evolution and craftsmanship. In this review, we consider an additional and complementary tool available to the synthetic biologist for innovative design and successful construction of desired circuit functionalities: biological synergies. Synergy is a prevalent emergent property in biological systems that arises from the concerted action of multiple factors producing an amplification or cancelation effect compared with individual actions alone. Synergies appear in domains as diverse as those involved in chemical and protein activity, polypharmacology, and metabolic pathway complementarity. In conventional synthetic biology designs, synergistic cross-talk between parts and modules is generally attenuated in order to verify their orthogonality. Synergistic interactions, however, can induce emergent behavior that might prove useful for synthetic biology applications, like in functional circuit design, multi-drug treatment, or in sensing and delivery devices. Synergistic design principles are therefore complementary to those coming from orthogonal design and may provide added value to synthetic biology applications. The appropriate modeling, characterization, and design of synergies between biological parts and units will allow the discovery of yet unforeseeable, novel synthetic biology applications.

  10. SYNERGISTIC ANTIBACTERIAL EFFECT OF STEM BARK ...

    African Journals Online (AJOL)

    userpc

    ABSTRACT. The study was aimed at screening the stem bark extracts of Faidherbia albida and Psidium guajava for synergistic antibacterial effect against methicillin resistant Staphylococcus aureus (MRSA). The powdered plant materials were extracted with methanol using cold maceration technique and the extracts were ...

  11. Ascorbic acid effects on in vitro maturation of mouse oocyte with or ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-10-19

    Oct 19, 2009 ... in origin, that function interactively and synergistically to neutralize free radicals. ... antioxidant properties of ascorbic acid enable it to protect tissues from reactive oxygen ..... Effect of cyclic AMP on the isolated oocytecumulus ...

  12. Personal exposure monitoring of PM2.5 in indoor and outdoor microenvironments

    DEFF Research Database (Denmark)

    Steinle, Susanne; Reis, Stefan; Sabel, Clive E

    2015-01-01

    to define six microenvironments (MEs) to assess everyday exposure of individuals to short-term PM2.5 concentrations. The Dylos was combined with a GPS receiver to track movement and exposure of individuals across the MEs. Seventeen volunteers collected 35 profiles. Profiles may have a different overall...

  13. Molecular characterization and geological microenvironment of a microbial community inhabiting weathered receding shale cliffs.

    Science.gov (United States)

    Cockell, Charles S; Pybus, David; Olsson-Francis, Karen; Kelly, Laura; Petley, David; Rosser, Nick; Howard, Kieren; Mosselmans, Fred

    2011-01-01

    Shales play an important role in many earth system processes including coastal erosion, and they form the foundations of many engineering structures. The geobiology of the interior of pyrite-containing receding shale cliffs on the coast of northeast England was examined. The surface of the weathered shales was characterised by a thin layer of disordered authigenic iron oxyhydroxides and localised acicular, platy and aggregated gypsum, which was characterised by Raman spectroscopy, XAS and SEM. These chemical changes are likely to play an important role in causing rock weakening along fractures at the micron scale, which ultimately lead to coastal retreat at the larger scale. The surface of the shale hosts a novel, low-diversity microbial community. The bacterial community was dominated by Proteobacteria, with phylotypes closely associating with Methylocella and other members of the γ-subdivision. The second largest phylogenetic group corresponded to Nitrospira. The archaeal 16S rRNA phylotypes were dominated by a single group of sequences that matched phylotypes reported from South African gold mines and possessed ammonia monooxygenase (amoA) genes. Both the phylogenetic and the mineral data show that acidic microenvironments play an important role in shale weathering, but the shale has a higher microbial diversity than previously described pyritic acid mine drainage sites. The presence of a potentially biogeochemically active microbial population on the rock surface suggests that microorganisms may contribute to early events of shale degradation and coastal erosion.

  14. Co-delivery of cisplatin and CJM-126 via photothermal conversion nanoparticles for enhanced synergistic antitumor efficacy

    Science.gov (United States)

    You, Chaoqun; Wu, Hongshuai; Wang, Mingxin; Gao, Zhiguo; Zhang, Xiangyang; Sun, Baiwang

    2018-01-01

    Polymeric biomaterials that can be smartly disassembled through the cleavage of the covalent bonds in a controllable way upon an environmental stimulus such as pH change, redox, special enzymes, temperature, or ultrasound, as well as light irradiation, but are otherwise stable under normal physiological conditions have attracted great attention in recent decades. The 2-(4-aminophenyl) benzothiazole molecule (CJM-126), as one of the benzothiazole derivatives, has exhibited a synergistic effect with cisplatin (CDDP) and restrains the bioactivities of a series of human breast cancer cell lines. In our study, novel NIR-responsive targeted binary-drug-loaded nanoparticles encapsulating indocyanine green (ICG) dye were prepared as a new co-delivery and combined therapeutic vehicle. The prepared drug-loaded polymeric nanoparticles (TNPs/CDDP-ICG) are stable under normal physiological conditions, while burst drugs release upon NIR laser irradiation in a mild acidic environment. The results further confirmed that the designed co-delivery platform showed higher cytotoxicity than the single free CDDP due to the synergistic treatment of CJM-126 and CDDP in vitro. Taken together, the work might provide a promising approach for effective site-specific antitumor therapy.

  15. Trabectedin and Plitidepsin: Drugs from the Sea that Strike the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Carlos M. Galmarini

    2014-01-01

    Full Text Available The prevailing paradigm states that cancer cells acquire multiple genetic mutations in oncogenes or tumor suppressor genes whose respective activation/up-regulation or loss of function serve to impart aberrant properties, such as hyperproliferation or inhibition of cell death. However, a tumor is now considered as an organ-like structure, a complex system composed of multiple cell types (e.g., tumor cells, inflammatory cells, endothelial cells, fibroblasts, etc. all embedded in an inflammatory stroma. All these components influence each other in a complex and dynamic cross-talk, leading to tumor cell survival and progression. As the microenvironment has such a crucial role in tumor pathophysiology, it represents an attractive target for cancer therapy. In this review, we describe the mechanism of action of trabectedin and plitidepsin as an example of how these specific drugs of marine origin elicit their antitumor activity not only by targeting tumor cells but also the tumor microenvironment.

  16. Nocardia brasiliensis induces an immunosuppressive microenvironment that favors chronic infection in BALB/c mice.

    Science.gov (United States)

    Rosas-Taraco, Adrian G; Perez-Liñan, Amira R; Bocanegra-Ibarias, Paola; Perez-Rivera, Luz I; Salinas-Carmona, Mario C

    2012-07-01

    Nocardia brasiliensis is an intracellular microorganism and the most common etiologic agent of actinomycetoma in the Americas. Several intracellular pathogens induce an immunosuppressive microenvironment through increases in CD4+ Foxp3+ regulatory T cells (Treg), thus downregulating other T-cell subpopulations and assuring survival in the host. In this study, we determined whether N. brasiliensis modulates T-lymphocyte responses and their related cytokine profiles in a murine experimental model. We also examined the relationship between N. brasiliensis immunomodulation and pathogenesis and bacterial survival. In early infection, Th17/Tc17 cells were increased at day 3 (P 1 log) was also observed (P brasiliensis modulates the immune system to induce an immunosuppressive microenvironment that benefits its survival during the chronic stage of infection.

  17. Using synergistic exogenous phytohormones to enhance somatic ...

    African Journals Online (AJOL)

    Southern Forests: a Journal of Forest Science ... Eucalyptus spp. has been limited to germinated seeds, flowers, lignotubers or zygotic embryos. ... explants could be enhanced through pairing of synergistic exogenous plant growth regulators, ...

  18. Purification of di-nonyl phenyl phosphoric acid (DNPPA) for synergistic extraction of uranium from strong phosphoric acid

    International Nuclear Information System (INIS)

    Singh, D.K.; Vijayalakshmi, R.; Singh, H.; Sharma, J.N.; Ruhela, R.

    2009-01-01

    Di-nonyl phenyl phosphoric acid (DNPPA) obtained from various synthesis methods is always associated with impurities such as mono-nonyl phenyl phosphoric acid and nonyl phenol which need to be separated for its effective use in the extraction of uranium from strong phosphoric acid. Two methods of purification namely liquid-solid separation method using neodymium salt and liquid-liquid separation method using methylene glycol have been described. In the liquid solid separation method the purity of DNPPA obtained was about 95% with less than 1.0% monoester, however it heavily suffers in the recovery aspect which is of the order of 50-60%. The methylene glycol treatment method, results in high purity and recovery of the product. Purity obtained was about 95.0% diester and less than 0.5% monoester and recovery was more than 90%. Analysis of DNPPA was done by potentiometric titration method using autotitrator. (author)

  19. Decontamination effectiveness of mixtures of citric acid, oxalic acid and EDTA

    International Nuclear Information System (INIS)

    Speranzini, R.A.

    1990-01-01

    An experimental study of the decontamination effectiveness of citric acid, oxalic acid and EDTA mixtures was conducted to assess whether oxalic acid could be removed from decontamination solutions to minimize corrosion. In loop experiments, radioactive specimens from two boiling water reactors and one pressurized water reactor were suspended in solutions of single acids or in mixtures of reagents at total reagent concentrations of less than 0.1 wt% under conditions similar to those used to decontaminate reactor systems. Rate constants for dissolution of oxides and decontamination factors were measured. Based on the results, it was concluded that under certain conditions, oxalic acid was the most effective reagent for the dissolution of oxides. It was also found, however, that conditions under which effective dissolution occurred in solutions of oxalic acid and/or citric acid were difficult to define and control. EDTA was found to be an effective reagent for dissolution of oxides such that rates of dissolution in EDTA containing solutions at 117 degrees Celsius were comparable to rates in oxalic acid containing solutions. At 90 degrees Celsius, EDTA acted synergistically with oxalic acid such that the rate of dissolution of oxides in citric-acid/oxalic-acid/EDTA solutions was higher than in citric-acid/EDTA solutions. The rates of dissolution of oxides were significantly reduced when 60 mg/kg of ferric ion was added to the citric-acid/oxalic-acid, citric-acid/EDTA and citric-acid/oxalic-acid/EDTA solutions. It was concluded that effective decontaminations of BWR and PWR systems could be achieved with mixtures of citric acid and EDTA

  20. Effect of O-methylated and glucuronosylated flavonoids from Tamarix gallica on α-glucosidase inhibitory activity: structure-activity relationship and synergistic potential.

    Science.gov (United States)

    Ben Hmidene, Asma; Smaoui, Abderrazak; Abdelly, Chedly; Isoda, Hiroko; Shigemori, Hideyuki

    2017-03-01

    O-Methylated and glucuronosylated flavonoids were isolated from Tamarix gallica as α-glucosidase inhibitors. Structure-activity relationship of these flavonoids suggests that catechol moiety and glucuronic acid at C-3 are factors in the increase in α-glucosidase inhibitory activity. Furthermore, rhamnetin, tamarixetin, rhamnazin, KGlcA, KGlcA-Me, QGlcA, and QGlcA-Me exhibit synergistic potential when applied with a very low concentration of acarbose to α-glucosidase from rat intestine.

  1. Importance of medium chain fatty acids in animal nutrition

    Science.gov (United States)

    Baltić, B.; Starčević, M.; Đorđević, J.; Mrdović, B.; Marković, R.

    2017-09-01

    Fats in animal and human nutrition are a common subject of research. These studies most often pay attention to particular fat groups (saturated, unsaturated, polyunsaturated fats or fats grouped by the length of their fatty acid chains into short, medium or long chain fatty acids). Medium chain fatty acids (MCFAs) have two main sources: milk and coconut oil. To date, research has shown these acids have positive effects on health, production, feed digestibility and lower body and muscle fats in broilers and swine. MCFAs possess antibacterial, anticoccidial and antiviral effects. Also, it has been proven that these acids act synergistically if they are used together with organic acids, essential oils, or probiotics. Nowadays, commercial MCFA products are available for use in animal nutrition as feed additives.

  2. Sensitivity of Dendritic Cells to Microenvironment Signals

    Directory of Open Access Journals (Sweden)

    Juliana Maria Motta

    2016-01-01

    Full Text Available Dendritic cells are antigen-presenting cells capable of either activating the immune response or inducing and maintaining immune tolerance. They do this by integrating stimuli from the environment and changing their functional status as a result of plasticity. The modifications suffered by these cells have consequences in the way the organism may respond. In the present work two opposing situations known to affect dendritic cells are analyzed: tumor growth, leading to a microenvironment that favors the induction of a tolerogenic profile, and organ transplantation, which leads to a proinflammatory profile. Lessons learned from these situations may help to understand the mechanisms of modulation resulting not only from the above circumstances, but also from other pathologies.

  3. Synergistic effects of arsenic trioxide combined with ascorbic acid in human osteosarcoma MG-63 cells: a systems biology analysis.

    Science.gov (United States)

    Huang, X C; Maimaiti, X Y M; Huang, C W; Zhang, L; Li, Z B; Chen, Z G; Gao, X; Chen, T Y

    2014-01-01

    To further understand the synergistic mechanism of As2O3 and asscorbic acid (AA) in human osteosarcoma MG-63 cells by systems biology analysis. Human osteosarcoma MG-63 cells were treated by As2O3 (1 µmol/L), AA (62.5 µmol/L) and combined drugs (1 µmol/L As2O3 plus 62.5 µmol/L AA). Dynamic morphological characteristics were recorded by Cell-IQ system, and growth rate was calculated. Illumina beadchip assay was used to analyze the differential expression genes in different groups. Synergic effects on differential expression genes (DEGs) were analyzed by mixture linear model and singular value decomposition model. KEGG pathway annotations and GO enrichment analysis were performed to figure out the pathways involved in the synergic effects. We captured 1987 differential expression genes in combined therapy MG-63 cells. FAT1 gene was significantly upregulated in all three groups, which is a promising drug target as an important tumor suppressor analogue; meanwhile, HIST1H2BD gene was markedly downregulated in the As2O3 monotherapy group and the combined therapy group, which was found to be upregulated in prostatic cancer. These two genes might play critical roles in synergetic effects of AA and As2O3, although the exact mechanism needs further investigation. KEGG pathway analysis showed many DEGs were related with tight junction, and GO analysis also indicated that DEGs in the combined therapy cells gathered in occluding junction, apical junction complex, cell junction, and tight junction. AA potentiates the efficacy of As2O3 in MG-63 cells. Systems biology analysis showed the synergic effect on the DEGs.

  4. Synergistic intrafibrillar/extrafibrillar mineralization of collagen scaffolds based on a biomimetic strategy to promote the regeneration of bone defects

    Directory of Open Access Journals (Sweden)

    Wang Y

    2016-05-01

    Full Text Available Yao Wang,1 Ngo Van Manh,1,2 Haorong Wang,1 Xue Zhong,1 Xu Zhang,1 Changyi Li1 1School of Dentistry, Hospital of Stomatology, Tianjin Medical University, Tianjin, People’s Republic of China; 2Thaibinh University of Medicine and Pharmacy, Thaibinh, Vietnam Abstract: The mineralization of collagen scaffolds can improve their mechanical properties and biocompatibility, thereby providing an appropriate microenvironment for bone regeneration. The primary purpose of the present study is to fabricate a synergistically intra- and extrafibrillar mineralized collagen scaffold, which has many advantages in terms of biocompatibility, biomechanical properties, and further osteogenic potential. In this study, mineralized collagen scaffolds were fabricated using a traditional mineralization method (ie, immersed in simulated body fluid as a control group and using a biomimetic method based on the polymer-induced liquid precursor process as an experimental group. In the polymer-induced liquid precursor process, a negatively charged polymer, carboxymethyl chitosan (CMC, was used to stabilize amorphous calcium phosphate (ACP to form nanocomplexes of CMC/ACP. Collagen scaffolds mineralized based on the polymer-induced liquid precursor process were in gel form such that nanocomplexes of CMC/ACP can easily be drawn into the interstices of the collagen fibrils. Scanning electron microscopy and transmission electron microscopy were used to examine the porous micromorphology and synergistic mineralization pattern of the collagen scaffolds. Compared with simulated body fluid, nanocomplexes of CMC/ACP significantly increased the modulus of the collagen scaffolds. The results of in vitro experiments showed that the cell count and differentiated degrees in the experimental group were higher than those in the control group. Histological staining and micro-computed tomography showed that the amount of new bone regenerated in the experimental group was larger than that in the

  5. Visceral Congestion in Heart Failure: Right Ventricular Dysfunction, Splanchnic Hemodynamics, and the Intestinal Microenvironment.

    Science.gov (United States)

    Polsinelli, Vincenzo B; Sinha, Arjun; Shah, Sanjiv J

    2017-12-01

    Visceral venous congestion of the gut may play a key role in the pathogenesis of right-sided heart failure (HF) and cardiorenal syndromes. Here, we review the role of right ventricular (RV) dysfunction, visceral congestion, splanchnic hemodynamics, and the intestinal microenvironment in the setting of right-sided HF. We review recent literature on this topic, outline possible mechanisms of disease pathogenesis, and discuss potential therapeutics. There are several mechanisms linking RV-gut interactions via visceral venous congestion which could result in (1) hypoxia and acidosis in enterocytes, which may lead to enhanced sodium-hydrogen exchanger 3 (NHE3) expression with increased sodium and fluid retention; (2) decreased luminal pH in the intestines, which could lead to alteration of the gut microbiome which could increase gut permeability and inflammation; (3) alteration of renal hemodynamics with triggering of the cardiorenal syndrome; and (4) altered phosphate metabolism resulting in increased pulmonary artery stiffening, thereby increasing RV afterload. A wide variety of therapeutic interventions that act on the RV, pulmonary vasculature, intestinal microenvironment, and the kidney could alter these pathways and should be tested in patients with right-sided HF. The RV-gut axis is an important aspect of HF pathogenesis that deserves more attention. Modulation of the pathways interconnecting the right heart, visceral congestion, and the intestinal microenvironment could be a novel avenue of intervention for right-sided HF.

  6. Evaluation of cage micro-environment of mice housed on various types of bedding materials.

    Science.gov (United States)

    Smith, Ellen; Stockwell, Jason D; Schweitzer, Isabelle; Langley, Stephen H; Smith, Abigail L

    2004-07-01

    A variety of environmental factors can affect the outcomes of studies using laboratory rodents. One such factor is bedding. Several new bedding materials and processing methods have been introduced to the market in recent years, but there are few reports of their performance. In the studies reported here, we have assessed the cage micro-environment (in-cage ammonia levels, temperature, and humidity) of mice housed on various kinds of bedding and their combinations. We also compared results for bedding supplied as Nestpaks versus loose bedding. We studied C57BL/6J mice (commonly used) and NOD/LtJ mice (heavy soilers) that were maintained, except in one study, in static duplex cages. In general, we observed little effect of bedding type on in-cage temperature or humidity; however, there was considerable variation in ammonia concentrations. The lowest ammonia concentrations occurred in cages housing mice on hardwood bedding or a mixture of corncob and alpha cellulose. In one experiment comparing the micro-environments of NOD/LtJ male mice housed on woodpulp fiber bedding in static versus ventilated caging, we showed a statistically significant decrease in ammonia concentrations in ventilated cages. Therefore, our data show that bedding type affects the micro-environment in static cages and that effects may differ for ventilated cages, which are being used in vivaria with increasing frequency. Copyright 2004 American Association for Laboratory Animal Science

  7. Nanomedicine-based combination anticancer therapy between nucleic acids and small-molecular drugs.

    Science.gov (United States)

    Huang, Wei; Chen, Liqing; Kang, Lin; Jin, Mingji; Sun, Ping; Xin, Xin; Gao, Zhonggao; Bae, You Han

    2017-06-01

    Anticancer therapy has always been a vital challenge for the development of nanomedicine. Repeated single therapeutic agent may lead to undesirable and severe side effects, unbearable toxicity and multidrug resistance due to complex nature of tumor. Nanomedicine-based combination anticancer therapy can synergistically improve antitumor outcomes through multiple-target therapy, decreasing the dose of each therapeutic agent and reducing side effects. There are versatile combinational anticancer strategies such as chemotherapeutic combination, nucleic acid-based co-delivery, intrinsic sensitive and extrinsic stimulus combinational patterns. Based on these combination strategies, various nanocarriers and drug delivery systems were engineered to carry out the efficient co-delivery of combined therapeutic agents for combination anticancer therapy. This review focused on illustrating nanomedicine-based combination anticancer therapy between nucleic acids and small-molecular drugs for synergistically improving anticancer efficacy. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Uranium(VI) and ruthenium extraction by dialkyldithio-phosphoric acids

    International Nuclear Information System (INIS)

    Fitoussi, R.; Musikas, C.

    1980-01-01

    Oxygen donors like dialkylphosphoric acids are good extractants for actinide ions, but little is known about their sulfur homologs. Investigations of U(VI) and Ru extraction from various aqueous media are reported. This includes extraction of U(VI) from nitric, perchloric, and phosphoric acids by solutions of dialkyldithiophosphoric acids in dodecane or benzene. Extraction of U(VI) by synergistic mixtures, of which at least one of the components is a sulfur donor, has been investigated. The extracted species have been identified, and a comparison with the complexes obtained by extraction with the homologous oxygen donors is made. The sulfur-actinide bond is weaker than the oxygen-actinide one, but in some synergistic extractions the dialkyldithiophosphonates are more efficient than the oxygen donors. In addition to size effects, this behavior could be attributed to the weakness of the hydrogen bonds of the SH groups, which allows a greater variety of the ligands to enter the coordination sphere of the metal. Ruthenium, like the d-transition elements, gives strong bonds with the sulfur donors. However, its extraction from nitric acid is slow. We investigated the influence of several parameters on the distribution coefficients and found that the presence of a reagent which destroys nitrous ions is necessary to achieve quantitative extraction. The role of RuNO groups is also discussed

  9. Of Microenvironments and Mammary Stem Cells

    Energy Technology Data Exchange (ETDEWEB)

    LaBarge, Mark A; Petersen, Ole W; Bissell, Mina J

    2007-06-01

    In most adult tissues there reside pools of stem and progenitor cells inside specialized microenvironments referred to as niches. The niche protects the stem cells from inappropriate expansion and directs their critical functions. Thus guided, stem cells are able to maintain tissue homeostasis throughout the ebb and flow of metabolic and physical demands encountered over a lifetime. Indeed, a pool of stem cells maintains mammary gland structure throughout development, and responds to the physiological demands associated with pregnancy. This review discusses how stem cells were identified in both human and mouse mammary glands; each requiring different techniques that were determined by differing biological needs and ethical constraints. These studies together create a robust portrait of mammary gland biology and identify the location of the stem cell niche, elucidate a developmental hierarchy, and suggest how the niche might be manipulated for therapeutic benefit.

  10. Real-time monitoring of thermodynamic microenvironment in a pan coater.

    Science.gov (United States)

    Pandey, Preetanshu; Bindra, Dilbir S

    2013-02-01

    The current study demonstrates the use of tablet-size data logging devices (PyroButtons) to quantify the microenvironment experienced by tablets during pan coating process. PyroButtons were fixed at the inlet and exhaust plenums, and were also placed to freely move with the tablets. The effects of process parameters (spray rate and inlet-air humidity) on the thermodynamic conditions inside the pan coater were studied. It was shown that the same exhaust temperature (a parameter most commonly monitored and controlled during film coating) can be attained with very different tablet-bed conditions. The tablet-bed conditions were found to be more sensitive to the changes in spray rate as compared with the inlet-air humidity. Both spray rate and inlet-air humidity were shown to have an effect on the number of tablet defects (loss of logo definition), and a good correlation between number of tablet defects and tablet-bed humidity was observed. The ability to quantify the thermodynamic microenvironment experienced by the tablets during coating and be able to correlate that to macroscopic tablet defects can be an invaluable tool that can help to establish a process design space during product development. Copyright © 2012 Wiley Periodicals, Inc.

  11. Targeting Autophagy in the Tumor Microenvironment: New Challenges and Opportunities for Regulating Tumor Immunity

    Directory of Open Access Journals (Sweden)

    Bassam Janji

    2018-04-01

    Full Text Available Cancer cells evolve in the tumor microenvironment, which is now well established as an integral part of the tumor and a determinant player in cancer cell adaptation and resistance to anti-cancer therapies. Despite the remarkable and fairly rapid progress over the past two decades regarding our understanding of the role of the tumor microenvironment in cancer development, its precise contribution to cancer resistance is still fragmented. This is mainly related to the complexity of the “tumor ecosystem” and the diversity of the stromal cell types that constitute the tumor microenvironment. Emerging data indicate that several factors, such as hypoxic stress, activate a plethora of resistance mechanisms, including autophagy, in tumor cells. Hypoxia-induced autophagy in the tumor microenvironment also activates several tumor escape mechanisms, which effectively counteract anti-tumor immune responses mediated by natural killer and cytotoxic T lymphocytes. Therefore, strategies aiming at targeting autophagy in cancer cells in combination with other therapeutic strategies have inspired significant interest to overcome immunological tolerance and promote tumor regression. However, a number of obstacles still hamper the application of autophagy inhibitors in clinics. First, the lack of selectivity of the current pharmacological inhibitors of autophagy makes difficult to draw a clear statement about its effective contribution in cancer. Second, autophagy has been also described as an important mechanism in tumor cells involved in presentation of antigens to T cells. Third, there is a circumstantial evidence that autophagy activation in some innate immune cells may support the maturation of these cells, and it is required for their anti-tumor activity. In this review, we will address these aspects and discuss our current knowledge on the benefits and the drawbacks of targeting autophagy in the context of anti-tumor immunity. We believe that it is

  12. Impact of hypoxia and the metabolic microenvironment on radiotherapy of solid tumors. Introduction of a multiinstitutional research project

    International Nuclear Information System (INIS)

    Zips, D.; Petersen, C.; Adam, M.; Molls, M.; Philbrook, C.; Flentje, M.; Haase, A.; Schmitt, P.; Mueller-Klieser, W.; Thews, O.; Walenta, S.; Baumann, M.

    2004-01-01

    Background: recent developments in imaging technology and tumor biology have led to new techniques to detect hypoxia and related alterations of the metabolic microenvironment in tumors. However, whether these new methods can predict radiobiological hypoxia and outcome after fractionated radiotherapy still awaits experimental evaluation. Material and methods: the present article will introduce a multiinstitutional research project addressing the impact of hypoxia and the metabolic microenvironment on radiotherapy of solid tumors. The four laboratories involved are situated at the universities of Dresden, Mainz, Munich and Wuerzburg, Germany. Results: the joint scientific project started to collect data obtained on a set of ten different human tumor xenografts growing in nude mice by applying various imaging techniques to detect tumor hypoxia and related parameters of the metabolic microenvironment. These techniques include magnetic resonance imaging and spectroscopy, metabolic mapping with quantitative bioluminescence and single-photon imaging, histological multiparameter analysis of biochemical hypoxia, perfusion and vasculature, and immunohistochemistry of factors related to angiogenesis, invasion and metastasis. To evaluate the different methods, baseline functional radiobiological data including radiobiological hypoxic fraction and outcome after fractionated irradiation will be determined. Conclusion: besides increasing our understanding of tumor biology, the project will focus on new, clinically applicable strategies for microenvironment profiling and will help to identify those patients that might benefit from targeted interventions to improve tumor oxygenation. (orig.)

  13. Disruption of in vivo chronic lymphocytic leukemia tumor-microenvironment interactions by ibrutinib - findings from an investigator initiated phase 2 study

    DEFF Research Database (Denmark)

    Niemann, Carsten U; Herman, Sarah E M; Maric, Irina

    2016-01-01

    PURPOSE: Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental interactions for proliferation and survival that are at least partially mediated through B cell receptor (BCR) signaling. Ibrutinib, a Bruton's tyrosine kinase inhibitor, disrupts BCR signaling and leads to the egress...... of tumor cells from the microenvironment. While the on-target effects on CLL cells are well defined, the impact on the microenvironment is less well studied. We therefore sought to characterize the in vivo effects of ibrutinib on the tumor microenvironment. EXPERIMENTAL DESIGN: Patients received single...... agent ibrutinib on an investigator-initiated phase 2 trial. Serial blood and tissue samples were collected pre-treatment and during treatment. Changes in cytokine levels, cellular subsets and microenvironmental interactions were assessed. RESULTS: Serum levels of key chemokines and inflammatory...

  14. A synergistic antiproliferation effect of curcumin and docosahexaenoic acid in SK-BR-3 breast cancer cells: unique signaling not explained by the effects of either compound alone

    International Nuclear Information System (INIS)

    Altenburg, Jeffrey D; Bieberich, Andrew A; Terry, Colin; Harvey, Kevin A; VanHorn, Justin F; Xu, Zhidong; Jo Davisson, V; Siddiqui, Rafat A

    2011-01-01

    Breast cancer is a collection of diseases in which molecular phenotypes can act as both indicators and mediators of therapeutic strategy. Therefore, candidate therapeutics must be assessed in the context of multiple cell lines with known molecular phenotypes. Docosahexaenoic acid (DHA) and curcumin (CCM) are dietary compounds known to antagonize breast cancer cell proliferation. We report that these compounds in combination exert a variable antiproliferative effect across multiple breast cell lines, which is synergistic in SK-BR-3 cells and triggers cell signaling events not predicted by the activity of either compound alone. Dose response curves for CCM and DHA were generated for five breast cell lines. Effects of the DHA+ CCM combination on cell proliferation were evaluated using varying concentrations, at a fixed ratio, of CCM and DHA based on their individual ED 50 . Detection of synergy was performed using nonlinear regression of a sigmoid dose response model and Combination Index approaches. Cell molecular network responses were investigated through whole genome microarray analysis of transcript level changes. Gene expression results were validated by RT-PCR, and western blot analysis was performed for potential signaling mediators. Cellular curcumin uptake, with and without DHA, was analyzed via flow cytometry and HPLC. CCM+DHA had an antiproliferative effect in SK-BR-3, MDA-MB-231, MDA-MB-361, MCF7 and MCF10AT cells. The effect was synergistic for SK-BR-3 (ER - PR - Her2 + ) relative to the two compounds individually. A whole genome microarray approach was used to investigate changes in gene expression for the synergistic effects of CCM+DHA in SK-BR-3 cells lines. CCM+DHA triggered transcript-level responses, in disease-relevant functional categories, that were largely non-overlapping with changes caused by CCM or DHA individually. Genes involved in cell cycle arrest, apoptosis, inhibition of metastasis, and cell adhesion were upregulated, whereas genes

  15. The inflammatory milieu within the pancreatic cancer microenvironment correlates with clinicopathologic parameters, chemoresistance and survival

    International Nuclear Information System (INIS)

    Delitto, Daniel; Black, Brian S.; Sorenson, Heather L.; Knowlton, Andrea E.; Thomas, Ryan M.; Sarosi, George A.; Moldawer, Lyle L.; Behrns, Kevin E.; Liu, Chen; George, Thomas J.; Trevino, Jose G.; Wallet, Shannon M.; Hughes, Steven J.

    2015-01-01

    The tumor microenvironment impacts pancreatic cancer (PC) development, progression and metastasis. How intratumoral inflammatory mediators modulate this biology remains poorly understood. We hypothesized that the inflammatory milieu within the PC microenvironment would correlate with clinicopathologic findings and survival. Pancreatic specimens from normal pancreas (n = 6), chronic pancreatitis (n = 9) and pancreatic adenocarcinoma (n = 36) were homogenized immediately upon resection. Homogenates were subjected to multiplex analysis of 41 inflammatory mediators. Twenty-three mediators were significantly elevated in adenocarcinoma specimens compared to nonmalignant controls. Increased intratumoral IL-8 concentrations associated with larger tumors (P = .045) and poor differentiation (P = .038); the administration of neoadjuvant chemotherapy associated with reduced IL-8 concentrations (P = .003). Neoadjuvant therapy was also associated with elevated concentrations of Flt-3 L (P = .005). Elevated levels of pro-inflammatory cytokines IL-1β (P = .017) and TNFα (P = .033) were associated with a poor histopathologic response to neoadjuvant therapy. Elevated concentrations of G-CSF (P = .016) and PDGF-AA (P = .012) correlated with reduced overall survival. Conversely, elevated concentrations of FGF-2 (P = .038), TNFα (P = .031) and MIP-1α (P = .036) were associated with prolonged survival. The pancreatic cancer microenvironment harbors a unique inflammatory milieu with potential diagnostic and prognostic value

  16. Metastasis in context : modeling the tumor microenvironment with cancer-on-a-chip approaches

    NARCIS (Netherlands)

    Sleeboom, Jelle J.F.; Amirabadi, Hossein Eslami; Nair, Poornima; Sahlgren, Cecilia M.; Den Toonder, Jaap M.J.

    2018-01-01

    Most cancer deaths are not caused by the primary tumor, but by secondary tumors formed through metastasis, a complex and poorly understood process. Cues from the tumor microenvironment, such as the biochemical composition, cellular population, extracellular matrix, and tissue (fluid) mechanics, have

  17. Melanoma cell-derived exosomes promote epithelial-mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment

    Science.gov (United States)

    Xiao, Deyi; Barry, Samantha; Kmetz, Daniel; Egger, Michael; Pan, Jianmin; Rai, Shesh N; Qu, Jifu; McMasters, Kelly M.; Hao, Hongying

    2016-01-01

    The tumor microenvironment is abundant with exosomes that are secreted by the cancer cells themselves. Exosomes are nanosized, organelle-like membranous structures that are increasingly being recognized as major contributors in the progression of malignant neoplasms. A critical element in melanoma progression is its propensity to metastasize, but little is known about how melanoma cell-derived exosomes modulate the microenvironment to optimize conditions for tumor progression and metastasis. Here, we provide evidence that melanoma cell-derived exosomes promote phenotype switching in primary melanocytes through paracrine/autocrine signaling. We found that the mitogen-activated protein kinase (MAPK) signaling pathway was activated during the exosome-mediated epithelial-to-mesenchymal transition (EMT)-resembling process, which promotes metastasis. Let-7i, an miRNA modulator of EMT, was also involved in this process. We further defined two other miRNA modulators of EMT (miR-191 and let-7a) in serum exosomes for differentiating stage I melanoma patients from non-melanoma subjects. These results provide the first strong molecular evidence that melanoma cell-derived exosomes promote the EMT-resembling process in the tumor microenvironment. Thus, novel strategies targeting EMT and modulating the tumor microenvironment may emerge as important approaches for the treatment of metastatic melanoma. PMID:27063098

  18. Effect of Microenvironment on Differentiation of Human Umbilical Cord Mesenchymal Stem Cells into Hepatocytes In Vitro and In Vivo

    Directory of Open Access Journals (Sweden)

    Gai Xue

    2016-01-01

    Full Text Available Human umbilical cord-derived mesenchymal stem cells (hUCMSCs are considered to be an ideal cell source for cell therapy of many diseases. The aim of this study was to investigate the contribution of the microenvironment to the hepatic differentiation potential of hUCMSCs in vitro and in vivo and to explore their therapeutic use in acute liver injury in rats. We established a new model to simulate the liver tissue microenvironment in vivo using liver homogenate supernatant (LHS in vitro. This induced environment could drive hUCMSCs to differentiate into hepatocyte-like cells within 7 days. The differentiated cells expressed hepatocyte-specific markers and demonstrated hepatocellular functions. We also injected hUCMSCs into rats with CCl4-induced acute hepatic injury. The hUCMSCs were detected in the livers of recipient rats and expressed the human hepatocyte-specific markers, suggesting that hUCMSCs could differentiate into hepatocyte-like cells in vivo in the liver tissue microenvironment. Levels of biochemistry markers improved significantly after transplantation of hUCMSCs compared with the nontransplantation group (P<0.05. In conclusion, this study demonstrated that the liver tissue microenvironment may contribute to the differentiation of hUCMSCs into hepatocytes both in vitro and in vivo.

  19. Effect of Microenvironment on Differentiation of Human Umbilical Cord Mesenchymal Stem Cells into Hepatocytes In Vitro and In Vivo

    Science.gov (United States)

    Xue, Gai; Han, Xiaolei; Ma, Xin; Wu, Honghai; Qin, Yabin; Liu, Jianfang; Hu, Yuqin; Hong, Yang; Hou, Yanning

    2016-01-01

    Human umbilical cord-derived mesenchymal stem cells (hUCMSCs) are considered to be an ideal cell source for cell therapy of many diseases. The aim of this study was to investigate the contribution of the microenvironment to the hepatic differentiation potential of hUCMSCs in vitro and in vivo and to explore their therapeutic use in acute liver injury in rats. We established a new model to simulate the liver tissue microenvironment in vivo using liver homogenate supernatant (LHS) in vitro. This induced environment could drive hUCMSCs to differentiate into hepatocyte-like cells within 7 days. The differentiated cells expressed hepatocyte-specific markers and demonstrated hepatocellular functions. We also injected hUCMSCs into rats with CCl4-induced acute hepatic injury. The hUCMSCs were detected in the livers of recipient rats and expressed the human hepatocyte-specific markers, suggesting that hUCMSCs could differentiate into hepatocyte-like cells in vivo in the liver tissue microenvironment. Levels of biochemistry markers improved significantly after transplantation of hUCMSCs compared with the nontransplantation group (P < 0.05). In conclusion, this study demonstrated that the liver tissue microenvironment may contribute to the differentiation of hUCMSCs into hepatocytes both in vitro and in vivo. PMID:27088093

  20. The Immunomodulatory Effects of Mesenchymal Stem Cell Polarization within the Tumor Microenvironment Niche

    Directory of Open Access Journals (Sweden)

    Cosette M. Rivera-Cruz

    2017-01-01

    Full Text Available Mesenchymal stem cells (MSCs represent a promising tool for cell therapy, particularly for their antitumor effects. This cell population can be isolated from multiple tissue sources and also display an innate ability to home to areas of inflammation, such as tumors. Upon entry into the tumor microenvironment niche, MSCs promote or inhibit tumor progression by various mechanisms, largely through the release of soluble factors. These factors can be immunomodulatory by activating or inhibiting both the adaptive and innate immune responses. The mechanisms by which MSCs modulate the immune response are not well understood. Because of this, the relationship between MSCs and immune cells within the tumor microenvironment niche continues to be an active area of research in order to help explain the apparent contradictory findings currently available in the literature. The ongoing research aims to enhance the potential of MSCs in future therapeutic applications.

  1. Synergistic effects in threshold models on networks

    Science.gov (United States)

    Juul, Jonas S.; Porter, Mason A.

    2018-01-01

    Network structure can have a significant impact on the propagation of diseases, memes, and information on social networks. Different types of spreading processes (and other dynamical processes) are affected by network architecture in different ways, and it is important to develop tractable models of spreading processes on networks to explore such issues. In this paper, we incorporate the idea of synergy into a two-state ("active" or "passive") threshold model of social influence on networks. Our model's update rule is deterministic, and the influence of each meme-carrying (i.e., active) neighbor can—depending on a parameter—either be enhanced or inhibited by an amount that depends on the number of active neighbors of a node. Such a synergistic system models social behavior in which the willingness to adopt either accelerates or saturates in a way that depends on the number of neighbors who have adopted that behavior. We illustrate that our model's synergy parameter has a crucial effect on system dynamics, as it determines whether degree-k nodes are possible or impossible to activate. We simulate synergistic meme spreading on both random-graph models and networks constructed from empirical data. Using a heterogeneous mean-field approximation, which we derive under the assumption that a network is locally tree-like, we are able to determine which synergy-parameter values allow degree-k nodes to be activated for many networks and for a broad family of synergistic models.

  2. Dansyl-labeled cholic acid as a tool to build speciation diagrams for the aggregation of bile acids.

    Science.gov (United States)

    Gomez-Mendoza, Miguel; Marin, M Luisa; Miranda, Miguel A

    2012-12-27

    Bile acids (BAs) are a family of natural steroids biosynthesized from cholesterol in the liver that tend to form aggregates in solution. A fluorescent derivative of cholic acid, namely 3α-Dns-ChA, was employed as a reporter to establish the speciation diagrams of the most abundant BAs that can be found mainly in three microenvironments, solution, and primary and secondary aggregates. The developed methodology is based on the analysis of the combined steady-state and time-resolved experiments performed on 3α-Dns-ChA whose emission behavior was found to be strongly medium dependent. In particular, speciation diagrams of sodium glycocholate (NaGCh), sodium taurocholate (NaTCh), sodium chenodeoxycholate (NaCDCh), sodium glycochenodeoxycholate (NaGCDCh), sodium deoxycholate (NaDCh), and sodium ursodeoxycholate (NaUDCh) were successfully built up.

  3. Oxygen microenvironment affects the uptake of nanoparticles in head and neck tumor cells

    Science.gov (United States)

    Chen, Eunice Y.; Hodge, Sasson; Tai, Katherine; Hou, Huagang; Khan, Nadeem; Hoopes, P. Jack; Samkoe, Kimberley S.

    2013-02-01

    Survival of head and neck cancer patients has not improved in several decades despite advances in diagnostic and therapeutic techniques. Tumor hypoxia in head and neck cancers is a critical factor that leads to poor prognosis, resistance to radiation and chemotherapies, and increased metastatic potential. Magnetic nanoparticle hyperthermia (mNPHT) is a promising therapy for hypoxic tumors because nanoparticles (NP) can be directly injected into, or targeted to, hypoxic tumor cells and exposed to alternating magnetic fields (AMF) to induce hyperthermia. Magnetic NPHT can improve therapeutic effectiveness by two modes of action: 1) direct killing of hypoxic tumor cells; and 2) increase in tumor oxygenation, which has the potential to make the tumor more susceptible to adjuvant therapies such as radiation and chemotherapy. Prior studies in breast cancer cells demonstrated that a hypoxic microenvironment diminished NP uptake in vitro; however, mNPHT with intratumoral NP injection in hypoxic tumors increased tumor oxygenation and delayed tumor growth. In this study, head and neck squamous cell carcinoma (HNSCC) cell lines were incubated in normoxic, hypoxic, and hyperoxic conditions with iron oxide NP for 4-72 hours. After incubation, the cells were analyzed for iron uptake by mass spectrometry, Prussian blue staining, and electron microscopy. In contrast to breast cancer cells, uptake of NPs was increased in hypoxic microenvironments as compared to normoxic conditions in HNSCC cells. In future studies, we will confirm the effect of the oxygen microenvironment on NP uptake and efficacy of mNPHT both in vitro and in vivo.

  4. Inflammatory models drastically alter tumor growth and the immune microenvironment in hepatocellular carcinoma.

    Science.gov (United States)

    Markowitz, Geoffrey J; Michelotti, Gregory A; Diehl, Anna Mae; Wang, Xiao-Fan

    2015-04-01

    Initiation and progression of hepatocellular carcinoma (HCC) is intimately associated with a chronically diseased liver tissue. This diseased liver tissue background is a drastically different microenvironment from the healthy liver, especially with regard to immune cell prevalence and presence of mediators of immune function. To better understand the consequences of liver disease on tumor growth and the interplay with its microenvironment, we utilized two standard methods of fibrosis induction and orthotopic implantation of tumors into the inflamed and fibrotic liver to mimic the liver condition in human HCC patients. Compared to non-diseased controls, tumor growth was significantly enhanced under fibrotic conditions. The immune cells that infiltrated the tumors were also drastically different, with decreased numbers of natural killer cells but greatly increased numbers of immune-suppressive CD11b + Gr1 hi myeloid cells in both models of fibrosis. In addition, there were model-specific differences: Increased numbers of CD11b + myeloid cells and CD4 + CD25 + T cells were found in tumors in the bile duct ligation model but not in the carbon tetrachloride model. Induction of fibrosis altered the cytokine production of implanted tumor cells, which could have farreaching consequences on the immune infiltrate and its functionality. Taken together, this work demonstrates that the combination of fibrosis induction with orthotopic tumor implantation results in a markedly different tumor microenvironment and tumor growth kinetics, emphasizing the necessity for more accurate modeling of HCC progression in mice, which takes into account the drastic changes in the tissue caused by chronic liver disease.

  5. Carbon dioxide and nisin act synergistically on Listeria monocytogenes

    DEFF Research Database (Denmark)

    Nilsson, Lilian; Chen, Y.H.; Chikindas, M.L.

    2000-01-01

    This paper examines the synergistic action of carbon dioxide and nisin on Listeria monocytogenes Scott A wild-type and nisin-resistant (Nis(r)) cells grown in broth at 4 degrees C. Carbon dioxide extended the lag phase and decreased the specific growth rate of both strains, but to a greater degree...... for cultures in CO2. This synergism between nisin and CO2 was examined mechanistically by following the leakage of carboxyfluorescein (CF) from listerial liposomes. Carbon dioxide enhanced nisin-induced CF leakage, indicating that the synergistic action of CO2 and nisin occurs at the cytoplasmic membrane...

  6. VOC source identification from personal and residential indoor, outdoor and workplace microenvironment samples in EXPOLIS-Helsinki, Finland

    Energy Technology Data Exchange (ETDEWEB)

    Edwards, Rufus D. [KTL-Finnish National Inst. of Public Health, Dept. of Environmental Hygiene, Kuopio (Finland); California Univ., School of Public Health, Berkeley, CA (United States); Jurvelin, J. [KTL-Finnish National Inst. of Public Health, Dept. of Environmental Hygiene, Kuopio (Finland); Jyvaeskylae Polytechnic, School of Engineering and Technology, Jyvaeskylae (Finland); Koistinen, K. [KTL-Finnish National Inst. of Public Health, Dept. of Environmental Hygiene, Kuopio (Finland); Saarela, K. [VTT, Chemical Technology, Espoo (Finland); Jantunen, M. [EC JRC, Inst. of the Environment, Ispra (Italy)

    2001-07-01

    Principal component analyses (varimax rotation) were used to identify common sources of 30 target volatile organic compounds (VOCs) in residential outdoor, residential indoor and workplace microenvironment and personal 48-h exposure samples, as a component of the EXPOLIS-Helsinki study. Variability in VOC concentrations in residential outdoor microenvironments was dominated by compounds associated with long-range transport of pollutants, followed by traffic emissions, emissions from trees and product emissions. Variability in VOC concentrations in environmental tobacco smoke (ETS) free residential indoor environments was dominated by compounds associated with indoor cleaning products, followed by compounds associated with traffic emissions, long-range transport of pollutants and product emissions. Median indoor/outdoor ratios for compounds typically associated with traffic emissions and long-range transport of pollutants exceeded 1, in some cases quite considerably, indicating substantial indoor source contributions. Changes in the median indoor/outdoor ratios during different seasons reflected different seasonal ventilation patterns as increased ventilation led to dilution of those VOC compounds in the indoor environment that had indoor sources. Variability in workplace VOC concentrations was dominated by compounds associated with traffic emissions followed by product emissions, long-range transport and air fresheners. Variability in VOC concentrations in ETS free personal exposure samples was dominated by compounds associated with traffic emissions, followed by long-range transport, cleaning products and product emissions. VOC sources in personal exposure samples reflected the times spent in different microenvironments, and personal exposure samples were not adequately represented by any one microenvironment, demonstrating the need for personal exposure sampling. (Author)

  7. Microenvironment alters epigenetic and gene expression profiles in Swarm rat chondrosarcoma tumors

    International Nuclear Information System (INIS)

    Hamm, Christopher A; Wang, Deli; Malchenko, Sergey; Fatima Bonaldo, Maria de; Casavant, Thomas L; Hendrix, Mary JC; Soares, Marcelo B; Stevens, Jeff W; Xie, Hehuang; Vanin, Elio F; Morcuende, Jose A; Abdulkawy, Hakeem; Seftor, Elisabeth A; Sredni, Simone T; Bischof, Jared M

    2010-01-01

    Chondrosarcomas are malignant cartilage tumors that do not respond to traditional chemotherapy or radiation. The 5-year survival rate of histologic grade III chondrosarcoma is less than 30%. An animal model of chondrosarcoma has been established - namely, the Swarm Rat Chondrosarcoma (SRC) - and shown to resemble the human disease. Previous studies with this model revealed that tumor microenvironment could significantly influence chondrosarcoma malignancy. To examine the effect of the microenvironment, SRC tumors were initiated at different transplantation sites. Pyrosequencing assays were utilized to assess the DNA methylation of the tumors, and SAGE libraries were constructed and sequenced to determine the gene expression profiles of the tumors. Based on the gene expression analysis, subsequent functional assays were designed to determine the relevancy of the specific genes in the development and progression of the SRC. The site of transplantation had a significant impact on the epigenetic and gene expression profiles of SRC tumors. Our analyses revealed that SRC tumors were hypomethylated compared to control tissue, and that tumors at each transplantation site had a unique expression profile. Subsequent functional analysis of differentially expressed genes, albeit preliminary, provided some insight into the role that thymosin-β4, c-fos, and CTGF may play in chondrosarcoma development and progression. This report describes the first global molecular characterization of the SRC model, and it demonstrates that the tumor microenvironment can induce epigenetic alterations and changes in gene expression in the SRC tumors. We documented changes in gene expression that accompany changes in tumor phenotype, and these gene expression changes provide insight into the pathways that may play a role in the development and progression of chondrosarcoma. Furthermore, specific functional analysis indicates that thymosin-β4 may have a role in chondrosarcoma metastasis

  8. Microenvironment alters epigenetic and gene expression profiles in Swarm rat chondrosarcoma tumors

    Directory of Open Access Journals (Sweden)

    Hamm Christopher A

    2010-09-01

    Full Text Available Abstract Background Chondrosarcomas are malignant cartilage tumors that do not respond to traditional chemotherapy or radiation. The 5-year survival rate of histologic grade III chondrosarcoma is less than 30%. An animal model of chondrosarcoma has been established - namely, the Swarm Rat Chondrosarcoma (SRC - and shown to resemble the human disease. Previous studies with this model revealed that tumor microenvironment could significantly influence chondrosarcoma malignancy. Methods To examine the effect of the microenvironment, SRC tumors were initiated at different transplantation sites. Pyrosequencing assays were utilized to assess the DNA methylation of the tumors, and SAGE libraries were constructed and sequenced to determine the gene expression profiles of the tumors. Based on the gene expression analysis, subsequent functional assays were designed to determine the relevancy of the specific genes in the development and progression of the SRC. Results The site of transplantation had a significant impact on the epigenetic and gene expression profiles of SRC tumors. Our analyses revealed that SRC tumors were hypomethylated compared to control tissue, and that tumors at each transplantation site had a unique expression profile. Subsequent functional analysis of differentially expressed genes, albeit preliminary, provided some insight into the role that thymosin-β4, c-fos, and CTGF may play in chondrosarcoma development and progression. Conclusion This report describes the first global molecular characterization of the SRC model, and it demonstrates that the tumor microenvironment can induce epigenetic alterations and changes in gene expression in the SRC tumors. We documented changes in gene expression that accompany changes in tumor phenotype, and these gene expression changes provide insight into the pathways that may play a role in the development and progression of chondrosarcoma. Furthermore, specific functional analysis indicates that

  9. Synergistic interactions between HDAC and sirtuin inhibitors in human leukemia cells.

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    Michele Cea

    Full Text Available Aberrant histone deacetylase (HDAC activity is frequent in human leukemias. However, while classical, NAD(+-independent HDACs are an established therapeutic target, the relevance of NAD(+-dependent HDACs (sirtuins in leukemia treatment remains unclear. Here, we assessed the antileukemic activity of sirtuin inhibitors and of the NAD(+-lowering drug FK866, alone and in combination with traditional HDAC inhibitors. Primary leukemia cells, leukemia cell lines, healthy leukocytes and hematopoietic progenitors were treated with sirtuin inhibitors (sirtinol, cambinol, EX527 and with FK866, with or without addition of the HDAC inhibitors valproic acid, sodium butyrate, and vorinostat. Cell death was quantified by propidium iodide cell staining and subsequent flow-cytometry. Apoptosis induction was monitored by cell staining with FITC-Annexin-V/propidium iodide or with TMRE followed by flow-cytometric analysis, and by measuring caspase3/7 activity. Intracellular Bax was detected by flow-cytometry and western blotting. Cellular NAD(+ levels were measured by enzymatic cycling assays. Bax was overexpressed by retroviral transduction. Bax and SIRT1 were silenced by RNA-interference. Sirtuin inhibitors and FK866 synergistically enhanced HDAC inhibitor activity in leukemia cells, but not in healthy leukocytes and hematopoietic progenitors. In leukemia cells, HDAC inhibitors were found to induce upregulation of Bax, a pro-apoptotic Bcl2 family-member whose translocation to mitochondria is normally prevented by SIRT1. As a result, leukemia cells become sensitized to sirtuin inhibitor-induced apoptosis. In conclusion, NAD(+-independent HDACs and sirtuins cooperate in leukemia cells to avoid apoptosis. Combining sirtuin with HDAC inhibitors results in synergistic antileukemic activity that could be therapeutically exploited.

  10. Evaluation of synergistic antimicrobial effect of vitamins (A, B1, B2, B6, B12, C, D, E and K) with antibiotics against resistant bacterial strains.

    Science.gov (United States)

    Shahzad, Shakeel; Ashraf, M Adnan; Sajid, M; Shahzad, Aqeel; Rafique, Azhar; Mahmood, M Shahid

    2018-02-02

    Multiple drug resistant super bugs of Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus (MRSA) are becoming challenge for healthcare professionals. In this study, vitamins were evaluated for synergistic activity with the antibiotics. Synergistic effect between antibiotic and stock solutions of vitamins is evaluated by using Kirby-Bauer disc diffusion assay. Distilled water and propylene glycol were used as solvent for water soluble vitamins and fat-soluble vitamins respectively. The final concentration of 10mg/ml of each water-soluble vitamin B1 (Thiamine), B2 (Riboflavin), B6 (Pyridoxine) B12 (Methylcobalamin), C (Ascorbic acid) and 0.1mg/ml of each fat soluble vitamin A (retinol), D (cholecalciferol) E (αTocopherol) K (Menadione) were used with the antibiotics. The results depicted that vitamin K and E have better synergistic activity with piperacillin-tazobactam, imipenem and doripenem antibiotics against A. baumannii. While vitamin B1, B2 and B12 showed remarkable synergistic activity with linezolid against MRSA. Vitamin B1 was further tested to have better synergism with antibiotics oxacillin, tetracycline, rifampicin and linezolid against MRSA. The fat-soluble vitamins E and K were good in synergism against Gram negative A. baumannii while water soluble vitamins as B1, B2 and B12 were effective against MRSA but not against A. baumannii. This synergistic action of vitamins with the antibiotics can be used as a tool to treat multiple drug resistant super bugs with further evaluation at molecular level. Copyright © 2018 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

  11. An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia.

    Science.gov (United States)

    Zhou, Yuan; He, Yongzheng; Xing, Wen; Zhang, Peng; Shi, Hui; Chen, Shi; Shi, Jun; Bai, Jie; Rhodes, Steven D; Zhang, Fengqui; Yuan, Jin; Yang, Xianlin; Zhu, Xiaofan; Li, Yan; Hanenberg, Helmut; Xu, Mingjiang; Robertson, Kent A; Yuan, Weiping; Nalepa, Grzegorz; Cheng, Tao; Clapp, D Wade; Yang, Feng-Chun

    2017-06-01

    Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation. Copyright© Ferrata Storti Foundation.

  12. Heterogeneity of passenger exposure to air pollutants in public transport microenvironments

    Science.gov (United States)

    Yang, Fenhuan; Kaul, Daya; Wong, Ka Chun; Westerdahl, Dane; Sun, Li; Ho, Kin-fai; Tian, Linwei; Brimblecombe, Peter; Ning, Zhi

    2015-05-01

    Epidemiologic studies have linked human exposure to pollutants with adverse health effects. Passenger exposure in public transport systems contributes an important fraction of daily burden of air pollutants. While there is extensive literature reporting the concentrations of pollutants in public transport systems in different cities, there are few studies systematically addressing the heterogeneity of passenger exposure in different transit microenvironments, in cabins of different transit vehicles and in areas with different characteristics. The present study investigated PM2.5 (particulate matter with aerodynamic diameters smaller than 2.5 μm), black carbon (BC), ultrafine particles (UFP) and carbon monoxide (CO) pollutant concentrations in various public road transport systems in highly urbanized city of Hong Kong. Using a trolley case housing numerous portable air monitors, we conducted a total of 119 trips during the campaign. Transit microenvironments, classified as 1). busy and secondary roadside bus stops; 2). open and enclosed termini; 3). above- and under-ground Motor Rail Transport (MTR) platforms, were investigated and compared to identify the factors that may affect passenger exposures. The pollutants inside bus and MTR cabins were also investigated together with a comparison of time integrated exposure between the transit modes. Busy roadside and enclosed termini demonstrated the highest average particle concentrations while the lowest was found on the MTR platforms. Traffic-related pollutants BC, UFP and CO showed larger variations than PM2.5 across different microenvironments and areas confirming their heterogeneity in urban environments. In-cabin pollutant concentrations showed distinct patterns with BC and UFP high in diesel bus cabins and CO high in LPG bus cabins, suggesting possible self-pollution issues and/or penetration of on-road pollutants inside cabins during bus transit. The total passenger exposure along selected routes, showed bus

  13. Culture and neuroscience: additive or synergistic?

    Science.gov (United States)

    Dapretto, Mirella; Iacoboni, Marco

    2010-01-01

    The investigation of cultural phenomena using neuroscientific methods—cultural neuroscience (CN)—is receiving increasing attention. Yet it is unclear whether the integration of cultural study and neuroscience is merely additive, providing additional evidence of neural plasticity in the human brain, or truly synergistic, yielding discoveries that neither discipline could have achieved alone. We discuss how the parent fields to CN: cross-cultural psychology, psychological anthropology and cognitive neuroscience inform the investigation of the role of cultural experience in shaping the brain. Drawing on well-established methodologies from cross-cultural psychology and cognitive neuroscience, we outline a set of guidelines for CN, evaluate 17 CN studies in terms of these guidelines, and provide a summary table of our results. We conclude that the combination of culture and neuroscience is both additive and synergistic; while some CN methodologies and findings will represent the direct union of information from parent fields, CN studies employing the methodological rigor required by this logistically challenging new field have the potential to transform existing methodologies and produce unique findings. PMID:20083533

  14. Mathematical description and prognosis of Synergistic interaction of radon and tobacco smoking

    International Nuclear Information System (INIS)

    Kim, J. K.; Belkina, S. A.; Petin, V. G.

    2007-01-01

    : Radon and its short-lived decay products are considered as the important sources of public exposure to natural radioactivity. The synergistic interaction between tobacco smoking and radon is known to be an actual problem. This study has provided a mathematical description and prognosis of the carcinogenic effects after combined action of radon with smoking. Materials and Methods: A simple mathematical model was adjusted for the optimization and prognosis of the synergistic interaction of radon with smoking. The model postulates that the occurrence of synergism is to be expected as a result of additional carcinogenic damage arising from the interaction of sub lesions induced by the two agents under consideration. Results: The predictions of the model were verified by comparison with experimental data published by other researchers. The model appears to be appropriate and the predictions valid. Conclusion: The suggested mathematical model predicts the greatest level of synergistic effect and condition under which this level is reached. The synergistic effect appeared to decline with any deviation from the optimal value of the ratio of carcinogenic effective damages produced by each agent alone

  15. Gamma irradiation of the fetus damages the developing hemopoietic microenvironment rather than the hemopoietic progenitor cells

    International Nuclear Information System (INIS)

    Yang, F.T.; Lord, B.I.; Hendry, J.H.

    1995-01-01

    Hemopoiesis is the product of two components: the hemopoietic tissue and the regulatory stromal microenvironment in which it resides. Plutonium-239, incorporated during fetal development in mice, is known to cause deficient hemopoiesis. A predetermined equivalent γ-ray dose has now been used in combination with cross-transplantation experiments to separate these two components and define where the damage arises. It was confirmed that 1.8 Gy γ irradiation at midterm gestation caused a 40% reduction in the hemopoietic stem (spleen colony-forming) cell population of their offspring which persisted to at least 24 weeks of age. Spleen colony formation after sublethal doses of γ rays reflected this reduced complement of endogenous stem cells. The regulatory hemopoietic microenvironment, measured as fibroblastoid colony-forming cells, was similarly depleted. Normal growth of the CFU-S population after transplantation into standard recipients showed that the quality of the stem cell population in the offspring of irradiated mothers was not affected. By contrast, when used as recipients of a bone marrow transplant from either normal or irradiated offspring, the offspring of irradiated mothers were unable to support normal growth: there was a twofold difference in the number of CFU-S per femur for at least 100 days after transplantation. There were 70% fewer CFU-F in the femur 1 month after bone marrow transplantation when the offspring of irradiated mothers were used as transplant recipients compared to when normal offspring were used. This not only confirmed their reduced capacity to host normal stem cells but also indicated that CFU-F in the transplant were unable to compensate for the poor microenvironment in the irradiated offspring hosts. It is concluded that irradiation at midterm gestation damages the developing regulatory microenvironment but not the hemopoietic stem cell population that it hosts. 12 refs., 1 fig., 4 tabs

  16. Fatigue Resistant Bioinspired Composite from Synergistic Two-Dimensional Nanocomponents.

    Science.gov (United States)

    Wan, Sijie; Zhang, Qi; Zhou, Xiaohang; Li, Dechang; Ji, Baohua; Jiang, Lei; Cheng, Qunfeng

    2017-07-25

    Portable and wearable electronics require much more flexible graphene-based electrode with high fatigue life, which could repeatedly bend, fold, or stretch without sacrificing its mechanical properties and electrical conductivity. Herein, a kind of ultrahigh fatigue resistant graphene-based nanocomposite via tungsten disulfide (WS 2 ) nanosheets is synthesized by introducing a synergistic effect with covalently cross-linking inspired by the orderly layered structure and abundant interfacial interactions of nacre. The fatigue life of resultant graphene-based nanocomposites is more than one million times at the stress level of 270 MPa, and the electrical conductivity can be kept as high as 197.1 S/cm after 1.0 × 10 5 tensile testing cycles. These outstanding properties are attributed to the synergistic effect from lubrication of WS 2 nanosheets for deflecting crack propagation, and covalent bonding between adjacent GO nanosheets for bridging crack, which is verified by the molecular dynamics (MD) simulations. The WS 2 induced synergistic effect with covalent bonding offers a guidance for constructing graphene-based nanocomposites with high fatigue life, which have great potential for applications in flexible and wearable electronic devices, etc.

  17. Esterase inhibition by synergists in the western flower thrips Frankliniella occidentalis.

    Science.gov (United States)

    López-Soler, Neus; Cervera, Amelia; Quinto, Vicente; Abellán, Jaime; Bielza, Pablo; Martínez-Pardo, Rafael; Garcerá, Maria Dolores

    2011-12-01

    Western flower thrips (WFT), Frankliniella occidentalis (Pergande), is among the most important crop pests in the south-eastern region of Spain. Its increasing resistance to insecticides constitutes a serious problem, and understanding the mechanisms involved is therefore of great interest. Use of synergists to inhibit the enzymes involved in insecticide detoxification is widely used to determine their responsibility for insecticide resistance. However, they do not always act as intended or expected, and caution must be exercised when interpreting synergist results. Laboratory-selected strains of WFT were used to analyse the effects of the synergists piperonyl butoxide (PBO), S,S,S-tributyl phosphorotrithioate (DEF) and methiocarb on total esterase activity. Significant differences were found, indicating esterase activity inhibition by DEF, a lower effect for methiocarb and a small inhibition of the activity by PBO. Esterase isoenzyme inhibition by these compounds showed a similar result; this assay revealed an extreme sensitivity of Triplet A (resistance-associated esterases) to DEF. In an in vivo assay carried out with these compounds at different incubation times, only DEF caused posterior in vitro esterase activity inhibition, with a maximum effect 1 h after treatment. In this work, only DEF shows true synergistic inhibition of WFT esterases. Copyright © 2011 Society of Chemical Industry.

  18. Adipocytes and Macrophages Interplay in the Orchestration of Tumor Microenvironment: New Implications in Cancer Progression

    Directory of Open Access Journals (Sweden)

    Luís Henrique Corrêa

    2017-09-01

    Full Text Available Inflammation has been known as one of the main keys to the establishment and progression of cancers. Chronic low-grade inflammation is also a strategic condition that underlies the causes and development of metabolic syndrome and obesity. Moreover, obesity has been largely related to poor prognosis of tumors by modulating tumor microenvironment with secretion of several inflammatory mediators by tumor-associated adipocytes (TAAs, which can modulate and recruit tumor-associated macrophages. Thus, the understanding of cellular and molecular mechanisms that underlay and link inflammation, obesity, and cancer is crucial to identify potential targets that interfere with this important route. Knowledge about the exact role of each component of the tumor microenvironment is not yet fully understood, but the new insights in literature highlight the essential role of adipocytes and macrophages interplay as key factor to determine the fate of cancer progression. In this review article, we focus on the functions of adipocytes and macrophages orchestrating cellular and molecular mechanisms that lead to inflammatory modulation in tumor microenvironment, which will be crucial to cancer establishment. We also emphasized the mechanisms by which the tumor promotes itself by recruiting and polarizing macrophages, discussing the role of adipocytes in this process. In addition, we discuss here the newest possible anticancer therapeutic treatments aiming to retard the development of the tumor based on what is known about cancer, adipocyte, and macrophage polarization.

  19. Synergistic Enhancement of Cancer Therapy Using a Combination of Ceramide and Docetaxel

    Directory of Open Access Journals (Sweden)

    Li-Xia Feng

    2014-03-01

    Full Text Available Ceramide (CE-based combination therapy (CE combination as a novel therapeutic strategy has attracted great attention in the field of anti-cancer therapy. The principal purposes of this study were to investigate the synergistic effect of CE in combination with docetaxel (DTX (CE + DTX and to explore the synergy mechanisms of CE + DTX. The 3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT and combination index (CI assay showed that simultaneous administration of CE and DTX with a molar ratio of 0.5:1 could generate the optimal synergistic effect on murine malignant melanoma cell (B16, CI = 0.31 and human breast carcinoma cell (MCF-7, CI = 0.48. The apoptosis, cell cycle, and cytoskeleton destruction study demonstrated that CE could target and destruct the microfilament actin, subsequently activate Caspase-3 and induce apoptosis. Meanwhile, DTX could target and disrupt the microtubules cytoskeleton, leading to a high proportion of cancer cells in G2/M-phase arrest. Moreover, CE plus DTX could cause a synergistic destruction of cytoskeleton, which resulted in a significantly higher apoptosis and a significantly higher arrest in G2/M arrest comparing with either agent alone (p < 0.01. The in vivo antitumor study evaluated in B16 tumor-bearing mice also validated the synergistic effects. All these results suggested that CE could enhance the antitumor activity of DTX in a synergistic manner, which suggest promising application prospects of CE + DTX combination treatment.

  20. Disruption of in vivo Chronic Lymphocytic Leukemia Tumor-Microenvironment Interactions by Ibrutinib--Findings from an Investigator-Initiated Phase II Study.

    Science.gov (United States)

    Niemann, Carsten U; Herman, Sarah E M; Maric, Irina; Gomez-Rodriguez, Julio; Biancotto, Angelique; Chang, Betty Y; Martyr, Sabrina; Stetler-Stevenson, Maryalice; Yuan, Constance M; Calvo, Katherine R; Braylan, Raul C; Valdez, Janet; Lee, Yuh Shan; Wong, Deanna H; Jones, Jade; Sun, Clare; Marti, Gerald E; Farooqui, Mohammed Z H; Wiestner, Adrian

    2016-04-01

    Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental interactions for proliferation and survival that are at least partially mediated through B-cell receptor (BCR) signaling. Ibrutinib, a Bruton tyrosine kinase inhibitor, disrupts BCR signaling and leads to the egress of tumor cells from the microenvironment. Although the on-target effects on CLL cells are well defined, the impact on the microenvironment is less well studied. We therefore sought to characterize the in vivo effects of ibrutinib on the tumor microenvironment. Patients received single-agent ibrutinib on an investigator-initiated phase II trial. Serial blood and tissue samples were collected pretreatment and during treatment. Changes in cytokine levels, cellular subsets, and microenvironmental interactions were assessed. Serum levels of key chemokines and inflammatory cytokines decreased significantly in patients on ibrutinib. Furthermore, ibrutinib treatment decreased circulating tumor cells and overall T-cell numbers. Most notably, a reduced frequency of the Th17 subset of CD4(+)T cells was observed concurrent with reduced expression of activation markers and PD-1 on T cells. Consistent with direct inhibition of T cells, ibrutinib inhibited Th17 differentiation of murine CD4(+)T cells in vitro Finally, in the bone marrow microenvironment, we found that ibrutinib disaggregated the interactions of macrophages and CLL cells, inhibited secretion of CXCL13, and decreased the chemoattraction of CLL cells. In conjunction with inhibition of BCR signaling, these changes in the tumor microenvironment likely contribute to the antitumor activity of ibrutinib and may impact the efficacy of immunotherapeutic strategies in patients with CLL. See related commentary by Bachireddy and Wu, p. 1547. ©2015 American Association for Cancer Research.

  1. Synergistic acceleration of thyroid hormone degradation by phenobarbital and the PPARα agonist WY14643 in rat hepatocytes

    International Nuclear Information System (INIS)

    Wieneke, N.; Neuschaefer-Rube, F.; Bode, L.M.; Kuna, M.; Andres, J.; Carnevali, L.C.; Hirsch-Ernst, K.I.; Pueschel, G.P.

    2009-01-01

    Energy balance is maintained by controlling both energy intake and energy expenditure. Thyroid hormones play a crucial role in regulating energy expenditure. Their levels are adjusted by a tight feedback-controlled regulation of thyroid hormone production/incretion and by their hepatic metabolism. Thyroid hormone degradation has previously been shown to be enhanced by treatment with phenobarbital or other antiepileptic drugs due to a CAR-dependent induction of phase II enzymes of xenobiotic metabolism. We have recently shown, that PPARα agonists synergize with phenobarbital to induce another prototypical CAR target gene, CYP2B1. Therefore, it was tested whether a PPARα agonist could enhance the phenobarbital-dependent acceleration of thyroid hormone elimination. In primary cultures of rat hepatocytes the apparent half-life of T3 was reduced after induction with a combination of phenobarbital and the PPARα agonist WY14643 to a larger extent than after induction with either compound alone. The synergistic reduction of the half-life could be attributed to a synergistic induction of CAR and the CAR target genes that code for enzymes and transporters involved in the hepatic elimination of T3, such as OATP1A1, OATP1A3, UGT1A3 and UGT1A10. The PPARα-dependent CAR induction and the subsequent induction of T3-eliminating enzymes might be of physiological significance for the fasting-induced reduction in energy expenditure by fatty acids as natural PPARα ligands. The synergism of the PPARα agonist WY14643 and phenobarbital in inducing thyroid hormone breakdown might serve as a paradigm for the synergistic disruption of endocrine control by other combinations of xenobiotics.

  2. Interpolymer complexses of vinyl ether copolymer with polyacrylic and polymethacrylic acids

    Directory of Open Access Journals (Sweden)

    E. Shaikhutdinov

    2012-03-01

    Full Text Available The interactions between macromolecules of copolymers based on vinyl ethers (vinyl ether of monoethanolamine and vinyl buthyl ether and 2-acryloilamido-2-methylpropanesulphonic acid with polyacrylic and polymethacrylic acid and, as well as study the effect of interpolymer interactions in the adsorption of polymers at the aqueous solution-air interface were investigated. The observed synergistic increase in surface activity of macromolecules into polyelectrolyte mixtures explained by the formation of interpolymer complexes polyacid - copolymer.

  3. Household air pollution (HAP), microenvironment and child health: Strategies for mitigating HAP exposure in urban Rwanda

    Science.gov (United States)

    Das, Ipsita; Pedit, Joseph; Handa, Sudhanshu; Jagger, Pamela

    2018-04-01

    Exposure to household air pollution (HAP) from cooking and heating with solid fuels is a major risk factor for morbidity and mortality in sub-Saharan Africa. Children under five are particularly at risk for acute lower respiratory infection. We use baseline data from a randomized controlled trial evaluating a household energy intervention in Gisenyi, Rwanda to investigate the role of the microenvironment as a determinant of children’s HAP-related health symptoms. Our sample includes 529 households, with 694 children under five. We examine the association between likelihood of HAP-related health symptom prevalence and characteristics of the microenvironment including: dwelling and cooking area structure; distance to nearest road; and tree cover. We find that children residing in groups of enclosed dwellings, in households that cook indoors, and in households proximate to tree cover, are significantly more likely to experience symptoms of respiratory infection, illness with cough and difficulty breathing. On the other hand, children in households with cemented floors and ventilation holes in the cooking area, are significantly less likely to experience the same symptoms. Our findings suggest that in addition to promoting increased access to clean cooking technologies, there are important infrastructure and microenvironment-related interventions that mitigate HAP exposure.

  4. Disruption of in vivo chronic lymphocytic leukemia tumor-microenvironment interactions by ibrutinib – findings from an investigator initiated phase 2 study

    Science.gov (United States)

    Niemann, Carsten U.; Herman, Sarah E. M.; Maric, Irina; Gomez-Rodriguez, Julio; Biancotto, Angelique; Chang, Betty Y.; Martyr, Sabrina; Stetler-Stevenson, Maryalice; Yuan, Constance; Calvo, Katherine R.; Braylan, Raul C.; Valdez, Janet; Lee, Yuh Shan; Wong, Deanna H.; Jones, Jade; Sun, Clare C. L.; Marti, Gerald E.; Farooqui, Mohammed Z.; Wiestner, Adrian

    2016-01-01

    Purpose Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental interactions for proliferation and survival that are at least partially mediated through B cell receptor (BCR) signaling. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, disrupts BCR signaling and leads to the egress of tumor cells from the microenvironment. While the on-target effects on CLL cells are well defined, the impact on the microenvironment is less well studied. We therefore sought to characterize the in vivo effects of ibrutinib on the tumor microenvironment. Experimental Design Patients received single agent ibrutinib on an investigator-initiated phase 2 trial. Serial blood and tissue samples were collected pre-treatment and during treatment. Changes in cytokine levels, cellular subsets and microenvironmental interactions were assessed. Results Serum levels of key chemokines and inflammatory cytokines decreased significantly in patients on ibrutinib. Further, ibrutinib treatment decreased circulating tumor cells and overall T cell numbers. Most notably, a reduced frequency of the Th17 subset of CD4+ T cells was observed concurrent with reduced activation markers and expression of PD-1 on T cells. Consistent with direct inhibition of T cells, ibrutinib inhibited Th17 differentiation of murine CD4+ T cells in vitro. Lastly, in the bone marrow microenvironment, we found that ibrutinib disaggregated the interactions of macrophages and CLL cells, inhibited secretion of CXCL13 and decreased the chemoattraction of CLL cells. Conclusions In conjunction with inhibition of BCR signaling, these changes in the tumor microenvironment likely contribute to the anti-tumor activity of ibrutinib and may impact the efficacy of immunotherapeutic strategies in patients with CLL. PMID:26660519

  5. The Synergistic Priming Effect of Exogenous Salicylic Acid and H2O2 on Chilling Tolerance Enhancement during Maize (Zea mays L.) Seed Germination.

    Science.gov (United States)

    Li, Zhan; Xu, Jungui; Gao, Yue; Wang, Chun; Guo, Genyuan; Luo, Ying; Huang, Yutao; Hu, Weimin; Sheteiwy, Mohamed S; Guan, Yajing; Hu, Jin

    2017-01-01

    Chilling stress is an important constraint for maize seedling establishment in the field. To examine the role of salicylic acid (SA) and hydrogen peroxide (H 2 O 2 ) in response to chilling stress, we investigated the effects of seed priming with SA, H 2 O 2 , and SA+H 2 O 2 combination on maize resistance under chilling stress (13°C). Priming with SA, H 2 O 2 , and especially SA+H 2 O 2 shortened seed germination time and enhanced seed vigor and seedling growth as compared with hydropriming and non-priming treatments under low temperature. Meanwhile, SA+H 2 O 2 priming notably increased the endogenous H 2 O 2 and SA content, antioxidant enzymes activities and their corresponding genes ZmPAL, ZmSOD4, ZmAPX2, ZmCAT2 , and ZmGR expression levels. The α-amylase activity was enhanced to mobilize starch to supply metabolites such as soluble sugar and energy for seed germination under chilling stress. In addition, the SA+H 2 O 2 combination positively up-regulated expressions of gibberellic acid (GA) biosynthesis genes ZmGA20ox1 and ZmGA3ox2 , and down-regulated GA catabolism gene ZmGA2ox1 expression; while it promoted GA signaling transduction genes expressions of ZmGID1 and ZmGID2 and decreased the level of seed germination inhibitor gene ZmRGL2 . The abscisic acid (ABA) catabolism gene ZmCYP707A2 and the expressions of ZmCPK11 and ZmSnRK2.1 encoding response receptors in ABA signaling pathway were all up-regulated. These results strongly suggested that priming with SA and H 2 O 2 synergistically promoted hormones metabolism and signal transduction, and enhanced energy supply and antioxidant enzymes activities under chilling stress, which were closely relevant with chilling injury alleviation and chilling-tolerance improvement in maize seed. Highlights: Seed germination and seedling growth were significantly improved under chilling stress by priming with SA+H 2 O 2 combination, which was closely relevant with the change of reactive oxygen species, metabolites and

  6. Evaluation of bacterial expansin EXLX1 as a cellulase synergist for the saccharification of lignocellulosic Agro-industrial wastes.

    Directory of Open Access Journals (Sweden)

    Hui Lin

    Full Text Available Various types of lignocellulosic wastes extensively used in biofuel production were provided to assess the potential of EXLX1 as a cellulase synergist. Enzymatic hydrolysis of natural wheat straw showed that all the treatments using mixtures of cellulase and an optimized amount of EXLX1, released greater quantities of sugars than those using cellulase alone, regardless of cellulase dosage and incubation time. EXLX1 exhibited different synergism and binding characteristics for different wastes, but this can be related to their lignocellulosic components. The cellulose proportion could be one of the important factors. However, when the cellulose proportion of different biomass samples exhibited no remarkable differences, a higher synergism of EXLX1 is prone to occur on these materials, with a high proportion of hemicellulose and a low proportion of lignin. The information could be favorable to assess whether EXLX1 is effective as a cellulase synergist for the hydrolysis of the used materials. Binding assay experiments further suggested that EXLX1 bound preferentially to alkali pretreated materials, as opposed to acid pretreated materials under the assay condition and the binding preference would be affected by incubation temperature.

  7. Evaluation of Bacterial Expansin EXLX1 as a Cellulase Synergist for the Saccharification of Lignocellulosic Agro-Industrial Wastes

    Science.gov (United States)

    Lin, Hui; Shen, Qi; Zhan, Ju-Mei; Wang, Qun; Zhao, Yu-Hua

    2013-01-01

    Various types of lignocellulosic wastes extensively used in biofuel production were provided to assess the potential of EXLX1 as a cellulase synergist. Enzymatic hydrolysis of natural wheat straw showed that all the treatments using mixtures of cellulase and an optimized amount of EXLX1, released greater quantities of sugars than those using cellulase alone, regardless of cellulase dosage and incubation time. EXLX1 exhibited different synergism and binding characteristics for different wastes, but this can be related to their lignocellulosic components. The cellulose proportion could be one of the important factors. However, when the cellulose proportion of different biomass samples exhibited no remarkable differences, a higher synergism of EXLX1 is prone to occur on these materials, with a high proportion of hemicellulose and a low proportion of lignin. The information could be favorable to assess whether EXLX1 is effective as a cellulase synergist for the hydrolysis of the used materials. Binding assay experiments further suggested that EXLX1 bound preferentially to alkali pretreated materials, as opposed to acid pretreated materials under the assay condition and the binding preference would be affected by incubation temperature. PMID:24086425

  8. Synergistic effect of Glomus fasciculatum and Trichoderma ...

    African Journals Online (AJOL)

    The plants treated with both fungus and mycorrhizal (F+M) treatment showed the maximum uptake of metals and thus the synergistic effect of these fungi can be exploited in decontamination of metals from tannery sludge. Key words: Phytoextraction, tannery sludge, heavy metals, resistant rhizosphere fungi, Arbuscular ...

  9. Synergistic Antimicrobial Activities Of Phytoestrogens In Crude ...

    African Journals Online (AJOL)

    Ethanolic, methanolic and aqueous extracts of both leaves were studied for their in-vitro synergistic antimicrobial activity against both Gram positive and Gram negative micro-organisms, and Yeast using Agar diffusion method. The GC-MS phytochemical screening of methanolic extract showed that the major compounds in ...

  10. Neuro-immune modulation of the thymus microenvironment (review).

    Science.gov (United States)

    Mignini, Fiorenzo; Sabbatini, Maurizio; Mattioli, Laura; Cosenza, Monica; Artico, Marco; Cavallotti, Carlo

    2014-06-01

    The thymus is the primary site for T-cell lympho-poiesis. Its function includes the maturation and selection of antigen specific T cells and selective release of these cells to the periphery. These highly complex processes require precise parenchymal organization and compartmentation where a plethora of signalling pathways occur, performing strict control on the maturation and selection processes of T lymphocytes. In this review, the main morphological characteristics of the thymus microenvironment, with particular emphasis on nerve fibers and neuropeptides were assessed, as both are responsible for neuro-immune‑modulation functions. Among several neurotransmitters that affect thymus function, we highlight the dopaminergic system as only recently has its importance on thymus function and lymphocyte physiology come to light.

  11. Combined Effects of Pericytes in the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Aline Lopes Ribeiro

    2015-01-01

    Full Text Available Pericytes are multipotent perivascular cells whose involvement in vasculature development is well established. Evidences in the literature also suggest that pericytes display immune properties and that these cells may serve as an in vivo reservoir of stem cells, contributing to the regeneration of diverse tissues. Pericytes are also capable of tumor homing and are important cellular components of the tumor microenvironment (TME. In this review, we highlight the contribution of pericytes to some classical hallmarks of cancer, namely, tumor angiogenesis, growth, metastasis, and evasion of immune destruction, and discuss how collectively these hallmarks could be tackled by therapies targeting pericytes, providing a rationale for cancer drugs aiming at the TME.

  12. Emerging Roles for Eosinophils in the Tumor Microenvironment.

    Science.gov (United States)

    Reichman, Hadar; Karo-Atar, Danielle; Munitz, Ariel

    2016-11-01

    Eosinophils are evolutionary conserved cells largely studied in the context of allergy. Although eosinophils were first described in tumors more than 120 years ago, their roles in cancer are often overlooked. This is puzzling given their potent immune modulatory, cytotoxic, and/or tissue repair capabilities, and recent studies demonstrating key roles for eosinophils in contexts far beyond their 'classical' field (e.g., metabolism, thermogenesis, and tissue regeneration). Recent data suggest that this frequently ignored cell is emerging as a potent immune effector and immune modulator in the tumor microenvironment. This review discusses the relevance of eosinophils to tumorigenesis and the potential to harness their function in cancer therapies. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Rapid determination of the volatile components in tobacco by ultrasound-microwave synergistic extraction coupled to headspace solid-phase microextraction with gas chromatography-mass spectrometry.

    Science.gov (United States)

    Yang, Yanqin; Chu, Guohai; Zhou, Guojun; Jiang, Jian; Yuan, Kailong; Pan, Yuanjiang; Song, Zhiyu; Li, Zuguang; Xia, Qian; Lu, Xinbo; Xiao, Weiqiang

    2016-03-01

    An ultrasound-microwave synergistic extraction coupled to headspace solid-phase microextraction was first employed to determine the volatile components in tobacco samples. The method combined the advantages of ultrasound, microwave, and headspace solid-phase microextraction. The extraction, separation, and enrichment were performed in a single step, which could greatly simplify the operation and reduce the whole pretreatment time. In the developed method, several experimental parameters, such as fiber type, ultrasound power, and irradiation time, were optimized to improve sampling efficiency. Under the optimal conditions, there were 37, 36, 34, and 36 components identified in tobacco from Guizhou, Hunan, Yunnan, and Zimbabwe, respectively, including esters, heterocycles, alkanes, ketones, terpenoids, acids, phenols, and alcohols. The compound types were roughly the same while the contents were varied from different origins due to the disparity of their growing conditions, such as soil, water, and climate. In addition, the ultrasound-microwave synergistic extraction coupled to headspace solid-phase microextraction method was compared with the microwave-assisted extraction coupled to headspace solid-phase microextraction and headspace solid-phase microextraction methods. More types of volatile components were obtained by using the ultrasound-microwave synergistic extraction coupled to headspace solid-phase microextraction method, moreover, the contents were high. The results indicated that the ultrasound-microwave synergistic extraction coupled to headspace solid-phase microextraction technique was a simple, time-saving and highly efficient approach, which was especially suitable for analysis of the volatile components in tobacco. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Synergistic effects of iron powder on intumescent flame retardant polypropylene system

    Directory of Open Access Journals (Sweden)

    2009-06-01

    Full Text Available The effects of iron powder as a synergistic agent on the flame retardancy of intumescent flame retardant polypropylene composites (IFR-PP were studied. The thermogravimetric analysis (TGA and cone calorimeter (CONE were used to evaluate the synergistic effects of iron powder (Fe. The TGA data showed that Fe could enhance the thermal stability of the IFR-PP systems at high temperature and effectively increase the char residue formation. The CONE results revealed that Fe and IFR could clearly change the decomposition behavior of PP and form a char layer on the surface of the composites, consequently resulting in efficient reduction of the flammability parameters, such as heat release rate (HRR, mass loss (ML, Mass loss rate (MLR, total heat release (THR, carbon monoxide and so on. Thus, a suitable amount of Fe plays a synergistic effect in the flame retardancy of IFR composites.

  15. In vitro microfluidic models of tumor microenvironment to screen transport of drugs and nanoparticles.

    Science.gov (United States)

    Ozcelikkale, Altug; Moon, Hye-Ran; Linnes, Michael; Han, Bumsoo

    2017-09-01

    Advances in nanotechnology have enabled numerous types of nanoparticles (NPs) to improve drug delivery to tumors. While many NP systems have been proposed, their clinical translation has been less than anticipated primarily due to failure of current preclinical evaluation techniques to adequately model the complex interactions between the NP and physiological barriers of tumor microenvironment. This review focuses on microfluidic tumor models for characterization of delivery efficacy and toxicity of cancer nanomedicine. Microfluidics offer significant advantages over traditional macroscale cell cultures by enabling recapitulation of tumor microenvironment through precise control of physiological cues such as hydrostatic pressure, shear stress, oxygen, and nutrient gradients. Microfluidic systems have recently started to be adapted for screening of drugs and NPs under physiologically relevant settings. So far the two primary application areas of microfluidics in this area have been high-throughput screening using traditional culture settings such as single cells or multicellular tumor spheroids, and mimicry of tumor microenvironment for study of cancer-related cell-cell and cell-matrix interactions. These microfluidic technologies are also useful in modeling specific steps in NP delivery to tumor and characterize NP transport properties and outcomes by systematic variation of physiological conditions. Ultimately, it will be possible to design drug-screening platforms uniquely tailored for individual patient physiology using microfluidics. These in vitro models can contribute to development of precision medicine by enabling rapid and patient-specific evaluation of cancer nanomedicine. WIREs Nanomed Nanobiotechnol 2017, 9:e1460. doi: 10.1002/wnan.1460 For further resources related to this article, please visit the WIREs website. © 2017 Wiley Periodicals, Inc.

  16. Synergistic effect of Elephantopus scaber L and Sauropus ...

    African Journals Online (AJOL)

    Synergistic effect of Elephantopus scaber L and Sauropus androgynus L ... Hematopoietic cells were isolated from bone marrow at 12 days post-infection. Prolactin ... breast milk after birth [2]. .... hosts as a natural means of protection against.

  17. Antitussive arabinogalactan of Andrographis paniculata demonstrates synergistic effect with andrographolide.

    Science.gov (United States)

    Nosáľová, Gabriela; Majee, Sujay Kumar; Ghosh, Kanika; Raja, Washim; Chatterjee, Udipta Ranjan; Jureček, Ludovít; Ray, Bimalendu

    2014-08-01

    Traditional Indian medicines have been used in humans for thousands of years. While the link to a particular indication has been established in man, the active principle of the formulations often remains unknown. In this study, we aim to investigate the structural features and antitussive activity of fractions from Andrographis paniculata leaves. In vivo investigations of water extract (WE), and both ethanol-soluble (WES) and precipitated (WEP) fractions from WE on the citric-acid induced cough efforts and airways smooth muscle reactivity in guinea pigs were performed. Chemical, chromatographic and spectroscopic analysis revealed the existence of a highly branched pectic arabinogalactan (109kDa) in WEP and andrographolide in WES. WEP showed significant antitussive activity while the potencies of WE and WES are even higher. Neither WE nor WES significantly alter specific airway smooth muscle reactivity. Remarkably, the antitussive activity of arabinogalactan could be increased by synergistic action with andrographolide. Finally, traditional aqueous extraction method provides an arabinogalactan from A. paniculata, which stimulate biological response but without addiction. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Microenvironment Determinants of Brain Metastasis

    Directory of Open Access Journals (Sweden)

    Zhang Chenyu

    2011-02-01

    Full Text Available Abstract Metastasis accounts for 90% of cancer-related mortality. Brain metastases generally present during the late stages in the natural history of cancer progression. Recent advances in cancer treatment and management have resulted in better control of systemic disease metastatic to organs other than the brain and improved patient survival. However, patients who experience recurrent disease manifest an increasing number of brain metastases, which are usually refractory to therapies. To meet the new challenges of controlling brain metastasis, the research community has been tackling the problem with novel experimental models and research tools, which have led to an improved understanding of brain metastasis. The time-tested "seed-and-soil" hypothesis of metastasis indicates that successful outgrowth of deadly metastatic tumors depends on permissible interactions between the metastatic cancer cells and the site-specific microenvironment in the host organs. Consistently, recent studies indicate that the brain, the major component of the central nervous system, has unique physiological features that can determine the outcome of metastatic tumor growth. The current review summarizes recent discoveries on these tumor-brain interactions, and the potential clinical implications these novel findings could have for the better treatment of patients with brain metastasis.

  19. Glioblastoma-Initiating Cells: Relationship with Neural Stem Cells and the Micro-Environment

    Energy Technology Data Exchange (ETDEWEB)

    Goffart, Nicolas [Laboratory of Developmental Neurobiology, GIGA-Neurosciences Research Center, University of Liège, Liège 4000 (Belgium); Kroonen, Jérôme [Human Genetics, CHU and University of Liège, Liège 4000 (Belgium); The T& P Bohnenn Laboratory for Neuro-Oncology, Department of Neurology and Neurosurgery, UMC Utrecht, Utrecht 3556 (Netherlands); Rogister, Bernard, E-mail: Bernard.Register@ulg.ac.be [Laboratory of Developmental Neurobiology, GIGA-Neurosciences Research Center, University of Liège, Liège 4000 (Belgium); Department of Neurology, CHU and University of Liège, Liège 4000 (Belgium); GIGA-Development, Stem Cells and Regenerative Medicine, University of Liège, Liège 4000 (Belgium)

    2013-08-14

    Glioblastoma multiforme (GBM, WHO grade IV) is the most common and lethal subtype of primary brain tumor with a median overall survival of 15 months from the time of diagnosis. The presence in GBM of a cancer population displaying neural stem cell (NSC) properties as well as tumor-initiating abilities and resistance to current therapies suggests that these glioblastoma-initiating cells (GICs) play a central role in tumor development and are closely related to NSCs. However, it is nowadays still unclear whether GICs derive from NSCs, neural progenitor cells or differentiated cells such as astrocytes or oligodendrocytes. On the other hand, NSCs are located in specific regions of the adult brain called neurogenic niches that have been shown to control critical stem cell properties, to nourish NSCs and to support their self-renewal. This “seed-and-soil” relationship has also been adapted to cancer stem cell research as GICs also require a specific micro-environment to maintain their “stem cell” properties. In this review, we will discuss the controversies surrounding the origin and the identification of GBM stem cells and highlight the micro-environment impact on their biology.

  20. Glioblastoma-Initiating Cells: Relationship with Neural Stem Cells and the Micro-Environment

    International Nuclear Information System (INIS)

    Goffart, Nicolas; Kroonen, Jérôme; Rogister, Bernard

    2013-01-01

    Glioblastoma multiforme (GBM, WHO grade IV) is the most common and lethal subtype of primary brain tumor with a median overall survival of 15 months from the time of diagnosis. The presence in GBM of a cancer population displaying neural stem cell (NSC) properties as well as tumor-initiating abilities and resistance to current therapies suggests that these glioblastoma-initiating cells (GICs) play a central role in tumor development and are closely related to NSCs. However, it is nowadays still unclear whether GICs derive from NSCs, neural progenitor cells or differentiated cells such as astrocytes or oligodendrocytes. On the other hand, NSCs are located in specific regions of the adult brain called neurogenic niches that have been shown to control critical stem cell properties, to nourish NSCs and to support their self-renewal. This “seed-and-soil” relationship has also been adapted to cancer stem cell research as GICs also require a specific micro-environment to maintain their “stem cell” properties. In this review, we will discuss the controversies surrounding the origin and the identification of GBM stem cells and highlight the micro-environment impact on their biology

  1. Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Alessandro Poggi

    2016-11-01

    Full Text Available The tumor microenvironment is a good target for therapy in solid tumors and hematological malignancies. Indeed, solid tumor cells’ growth and expansion can influence neighboring cells’ behavior, leading to a modulation of mesenchymal stromal cell (MSC activities and remodeling of extracellular matrix components. This leads to an altered microenvironment, where reparative mechanisms, in the presence of sub-acute inflammation, are not able to reconstitute healthy tissue. Carcinoma cells can undergo epithelial mesenchymal transition (EMT, a key step to generate metastasis; these mesenchymal-like cells display the functional behavior of MSC. Furthermore, MSC can support the survival and growth of leukemic cells within bone marrow participating in the leukemic cell niche. Notably, MSC can inhibit the anti-tumor immune response through either carcinoma-associated fibroblasts or bone marrow stromal cells. Experimental data have indicated their relevance in regulating cytolytic effector lymphocytes of the innate and adaptive arms of the immune system. Herein, we will discuss some of the evidence in hematological malignancies and solid tumors. In particular, we will focus our attention on the means by which it is conceivable to inhibit MSC-mediated immune suppression and trigger anti-tumor innate immunity.

  2. Glioblastoma-Initiating Cells: Relationship with Neural Stem Cells and the Micro-Environment

    Directory of Open Access Journals (Sweden)

    Nicolas Goffart

    2013-08-01

    Full Text Available Glioblastoma multiforme (GBM, WHO grade IV is the most common and lethal subtype of primary brain tumor with a median overall survival of 15 months from the time of diagnosis. The presence in GBM of a cancer population displaying neural stem cell (NSC properties as well as tumor-initiating abilities and resistance to current therapies suggests that these glioblastoma-initiating cells (GICs play a central role in tumor development and are closely related to NSCs. However, it is nowadays still unclear whether GICs derive from NSCs, neural progenitor cells or differentiated cells such as astrocytes or oligodendrocytes. On the other hand, NSCs are located in specific regions of the adult brain called neurogenic niches that have been shown to control critical stem cell properties, to nourish NSCs and to support their self-renewal. This “seed-and-soil” relationship has also been adapted to cancer stem cell research as GICs also require a specific micro-environment to maintain their “stem cell” properties. In this review, we will discuss the controversies surrounding the origin and the identification of GBM stem cells and highlight the micro-environment impact on their biology.

  3. Synergistic effects of antimicrobial peptide DP7 combined with antibiotics against multidrug-resistant bacteria

    Directory of Open Access Journals (Sweden)

    Wu X

    2017-03-01

    Full Text Available Xiaozhe Wu,1 Zhan Li,1 Xiaolu Li,2,3 Yaomei Tian,1 Yingzi Fan,1 Chaoheng Yu,1 Bailing Zhou,1 Yi Liu,4 Rong Xiang,5 Li Yang1 1State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, 2International Center for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 3Department of Plastic and Burn Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, 4Department of Microbial Examination, Sichuan Center for Disease Control and Prevention, Chengdu, 5Nankai University School of Medicine, Tianjin, People’s Republic of China Abstract: Antibiotic-resistant bacteria present a great threat to public health. In this study, the synergistic effects of antimicrobial peptides (AMPs and antibiotics on several multidrug-resistant bacterial strains were studied, and their synergistic effects on azithromycin (AZT-resistance genes were analyzed to determine the relationships between antimicrobial resistance and these synergistic effects. A checkerboard method was used to evaluate the synergistic effects of AMPs (DP7 and CLS001 and several antibiotics (gentamicin, vancomycin [VAN], AZT, and amoxicillin on clinical bacterial strains (Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, and Escherichia coli. The AZT-resistance genes (ermA, ermB, ermC, mefA, and msrA were identified in the resistant strains using quantitative polymerase chain reaction. For all the clinical isolates tested that were resistant to different antibiotics, DP7 had high antimicrobial activity (≤32 mg/L. When DP7 was combined with VAN or AZT, the effect was most frequently synergistic. When we studied the resistance genes of the AZT-resistant isolates, the synergistic effect of DP7–AZT occurred most frequently in highly resistant strains or strains carrying more than two AZT-resistance genes. A transmission electron microscopic analysis of the S. aureus

  4. A multi-functional nanoplatform for tumor synergistic phototherapy

    Science.gov (United States)

    Zhang, Huijuan; Jiao, Xiaojing; Chen, Qianqian; Ji, Yandan; Zhang, Xiaoge; Zhu, Xing; Zhang, Zhenzhong

    2016-02-01

    Phototherapy, which mainly includes photothermal treatment (PTT) and photodynamic treatment (PDT), is a photo-initiated, noninvasive and effective approach for cancer treatment. The high accumulation of photosensitizers (PSs) in a targeted tumor is still a major challenge for efficient light conversion, to generate reactive oxygen species (ROS) and local hyperthermia. In this study, a simple and efficient hyaluronic acid (HA)-modified nanoplatform (HA-TiO2@MWCNTs) with high tumor-targeting ability, excellent phototherapy efficiency, low light-associated side effects and good water solubility was developed. It could be an effective carrier to load hematoporphyrin monomethyl ether (HMME), owing to the tubular conjugate structure. Apart from this, the as-prepared TiO2@MWCNTs nanocomposites could also be used as PSs for tumor PTT and PDT. Those results in vitro and in vivo showed that the anti-tumor effect of this system-mediated PTT/PDT were significantly better than those of single treatment manner. In addition, this drug delivery system could realize high ratio of drug loading, sustained drug release, prolonged circulation in vivo and active targeted accumulation in tumor. These results suggest that HA-TiO2@MWCNTs/HMME has high potential for tumor synergistic phototherapy as a smart theranostic nanoplatform.

  5. A multi-functional nanoplatform for tumor synergistic phototherapy

    International Nuclear Information System (INIS)

    Zhang, Huijuan; Jiao, Xiaojing; Chen, Qianqian; Ji, Yandan; Zhang, Xiaoge; Zhu, Xing; Zhang, Zhenzhong

    2016-01-01

    Phototherapy, which mainly includes photothermal treatment (PTT) and photodynamic treatment (PDT), is a photo-initiated, noninvasive and effective approach for cancer treatment. The high accumulation of photosensitizers (PSs) in a targeted tumor is still a major challenge for efficient light conversion, to generate reactive oxygen species (ROS) and local hyperthermia. In this study, a simple and efficient hyaluronic acid (HA)-modified nanoplatform (HA-TiO 2 @MWCNTs) with high tumor-targeting ability, excellent phototherapy efficiency, low light-associated side effects and good water solubility was developed. It could be an effective carrier to load hematoporphyrin monomethyl ether (HMME), owing to the tubular conjugate structure. Apart from this, the as-prepared TiO 2 @MWCNTs nanocomposites could also be used as PSs for tumor PTT and PDT. Those results in vitro and in vivo showed that the anti-tumor effect of this system-mediated PTT/PDT were significantly better than those of single treatment manner. In addition, this drug delivery system could realize high ratio of drug loading, sustained drug release, prolonged circulation in vivo and active targeted accumulation in tumor. These results suggest that HA-TiO 2 @MWCNTs/HMME has high potential for tumor synergistic phototherapy as a smart theranostic nanoplatform. (paper)

  6. Ocean warming and acidification synergistically increase coral mortality

    Science.gov (United States)

    Prada, F.; Caroselli, E.; Mengoli, S.; Brizi, L.; Fantazzini, P.; Capaccioni, B.; Pasquini, L.; Fabricius, K. E.; Dubinsky, Z.; Falini, G.; Goffredo, S.

    2017-01-01

    Organisms that accumulate calcium carbonate structures are particularly vulnerable to ocean warming (OW) and ocean acidification (OA), potentially reducing the socioeconomic benefits of ecosystems reliant on these taxa. Since rising atmospheric CO2 is responsible for global warming and increasing ocean acidity, to correctly predict how OW and OA will affect marine organisms, their possible interactive effects must be assessed. Here we investigate, in the field, the combined temperature (range: 16-26 °C) and acidification (range: pHTS 8.1-7.4) effects on mortality and growth of Mediterranean coral species transplanted, in different seasonal periods, along a natural pH gradient generated by a CO2 vent. We show a synergistic adverse effect on mortality rates (up to 60%), for solitary and colonial, symbiotic and asymbiotic corals, suggesting that high seawater temperatures may have increased their metabolic rates which, in conjunction with decreasing pH, could have led to rapid deterioration of cellular processes and performance. The net calcification rate of the symbiotic species was not affected by decreasing pH, regardless of temperature, while in the two asymbiotic species it was negatively affected by increasing acidification and temperature, suggesting that symbiotic corals may be more tolerant to increasing warming and acidifying conditions compared to asymbiotic ones.

  7. Synergistic energy conversion process using nuclear energy and fossil fuels

    International Nuclear Information System (INIS)

    Hori, Masao

    2007-01-01

    Because primary energies such as fossil fuels, nuclear energy and renewable energy are limited in quantity of supply, it is necessary to use available energies effectively for the increase of energy demand that is inevitable this century while keeping environment in good condition. For this purpose, an efficient synergistic energy conversion process using nuclear energy and fossil fuels together converted to energy carriers such are electricity, hydrogen, and synthetic fuels seems to be effective. Synergistic energy conversion processes containing nuclear energy were surveyed and effects of these processes on resource saving and the CO 2 emission reduction were discussed. (T.T.)

  8. In vitro effectiveness of triterpenoids and their synergistic effect with antibiotics against Staphylococcus aureus strains.

    Science.gov (United States)

    Hamza, Muhammad; Nadir, Maha; Mehmood, Nadir; Farooq, Adeel

    2016-01-01

    The aim of this study is to evaluate the effect of four triterpenoids such as oleanolic acid, ursolic acid, cycloastragenol, and beta-boswellic acid alone and in combination with antibiotics against Staphylococcus aureus strains. Sixteen clinical strains of S. aureus from infected wounds were isolated. Eight were methicillin-sensitive S. aureus (MSSA), and the other eight were methicillin-resistant S. aureus (MRSA). The activity was also seen in reference S. aureus American Type Culture Collection ™ strains. The activity of all the triterpenoids and antibiotics against S. aureus was evaluated by broth microdilution method. The effectiveness was judged by comparing the minimum inhibitory concentrations (MICs) of the compounds with antibiotics. The combination of antibiotics with compounds was evaluated by their fractional inhibitory concentrations (FIC). Against both clinical and reference MSSA strains, none of the compounds exhibited comparable activity to antibiotics vancomycin or cefradine except for ursolic acid (MIC 7.8 μg/ml). Against MRSA, all compounds (MIC 16-128 μg/ml) showed lesser activity than vancomycin (MIC 5.8 μg/ml). Among triterpenoid-antibiotic combinations, the most effective were ursolic acid and vancomycin against clinical strain MSSA (FIC S 0.17). However, overall, different combinations between triterpenoids and antibiotics showed 95%-46% ( P antibiotics compared to when antibiotics were used alone. Cefradine, a drug not suitable for treating MRSA (MIC = 45 μg/ml), showed a remarkable decrease in its MIC (87% Pantibiotics. However, when used in combination with antibiotics, they showed remarkable synergistic effect and thus can help in prolonging the viability of these antibiotics against S. aureus infections. Furthermore, reduction in MIC of cefradine with oleanolic acid indicates their potential use against MRSA.

  9. Response of maize to reduced urea application combined with compound nitrogen fertilizer synergists

    International Nuclear Information System (INIS)

    Tian Xiuying; WANG Zhengyin

    2006-01-01

    Pot and field experiments were conducted to study the response to application rate of urea labeled with 15 N combined with compound nitrogen fertilizer synergists in the growth, yield, uptake and utilization rate of urea of maize. In pot experiment, the standard urea application rate is 120 mg/perpot; in field experiment, the standard urea application rate is 157.5 kg/hm 2 . Maize with 15 N-urea. The results showed that the growth of maize seedling was obviously promoted with appropriate dosage of compound nitrogen fertilizer synergists (20%-60% of N). The treatments of urea application rate reduced by 5%-15% and added compound nitrogen fertilizer synergists, the growth and nitrogen content of maize were not significant changed, and the total 15 N uptake and nitrogen uptake by maize were the same as CK 2 or increased a little. Nitrogen use efficiency of other treatments increased by 5.6%-7.3% comparing with CK, except the treatment of urea application rate reduced by 30%. The apparent utilization rate of nitrogen was enhanced by 7.7%-17.0%. Under the field condition, maize yield, total uptake, net uptake, physiological rate and agronomic use efficiency of nitrogen were the same as CK or increased. The apparent utilization rate of nitrogen was enhanced by 14.8%-15.2% treated with urea reduced by 5%-15% (7.8-23.7 kg/hm 2 ) and added with compound nitrogen fertilizer synergists. It was not helpful for the growth and nitrogen utilization rate of maize when urea reduced by 30% and combined with compound nitrogen fertilizer synergists. As a result, treated with urea decreased by 15% and combined with appropriate dosage of compound nitrogen fertilizer synergists (20% of urea), the growth and yield of maize had litter effect and higher the uptake and utilization of nitrogen. (authors)

  10. Impacts of exhalation flow on the microenvironment around the human body under different room temperatures

    Science.gov (United States)

    Jafari, Mohammad Javad; Gharari, Noradin; Azari, Mansour Rezazade; Ashrafi, Khosro

    2018-04-01

    Exhalation flow and room temperature can have a considerable effect on the microenvironment in the vicinity of human body. In this study, impacts of exhalation flow and room temperature on the microenvironment around a human body were investigated using a numerical simulation. For this purpose, a computational fluid dynamic program was applied to study thermal plume around a sitting human body at different room temperatures of a calm indoor room by considering the exhalation flow. The simulation was supported by some experimental measurements. Six different room temperatures (18 to 28 °C) with two nose exhalation modes (exhalation and non-exhalation) were investigated. Overhead and breathing zone velocities and temperatures were simulated in different scenarios. This study finds out that the exhalation through the nose has a significant impact on both quantitative and qualitative features of the human microenvironment in different room temperatures. At a given temperature, the exhalation through the nose can change the location and size of maximum velocity at the top of the head. In the breathing zone, the effect of exhalation through the nose on velocity and temperature distribution was pronounced for the point close to mouth. Also, the exhalation through the nose strongly influences the thermal boundary layer on the breathing zone while it only minimally influences the convective boundary layer on the breathing zone. Overall results demonstrate that it is important to take the exhalation flow into consideration in all areas, especially at a quiescent flow condition with low temperature.

  11. Microenvironment is involved in cellular response to hydrostatic pressures during chondrogenesis of mesenchymal stem cells.

    Science.gov (United States)

    Ye, Rui; Hao, Jin; Song, Jinlin; Zhao, Zhihe; Fang, Shanbao; Wang, Yating; Li, Juan

    2014-06-01

    Chondrocytes integrate numerous microenvironmental cues to mount physiologically relevant differentiation responses, and the regulation of mechanical signaling in chondrogenic differentiation is now coming into intensive focus. To facilitate tissue-engineered chondrogenesis by mechanical strategy, a thorough understanding about the interactional roles of chemical factors under mechanical stimuli in regulating chondrogenesis is in great need. Therefore, this study attempts to investigate the interaction of rat MSCs with their microenvironment by imposing dynamic and static hydrostatic pressure through modulating gaseous tension above the culture medium. Under dynamic pressure, chemical parameters (pH, pO2, and pCO2) were kept in homeostasis. In contrast, pH was remarkably reduced due to increased pCO2 under static pressure. MSCs under the dynamically pressured microenvironment exhibited a strong accumulation of GAG within and outside the alginate beads, while cells under the statically pressured environment lost newly synthesized GAG into the medium with a speed higher than its production. In addition, the synergic influence on expression of chondrogenic genes was more persistent under dynamic pressure than that under static pressure. This temporal contrast was similar to that of activation of endogenous TGF-β1. Taken altogether, it indicates that a loading strategy which can keep a homeostatic chemical microenvironment is preferred, since it might sustain the stimulatory effects of mechanical stimuli on chondrogenesis via activation of endogenous TGF-β1. © 2013 Wiley Periodicals, Inc.

  12. The Bioelectric Code: Reprogramming Cancer and Aging From the Interface of Mechanical and Chemical Microenvironments

    Directory of Open Access Journals (Sweden)

    Brian B. Silver

    2018-03-01

    Full Text Available Cancer is a complex, heterogeneous group of diseases that can develop through many routes. Broad treatments such as chemotherapy destroy healthy cells in addition to cancerous ones, but more refined strategies that target specific pathways are usually only effective for a limited number of cancer types. This is largely due to the multitude of physiological variables that differ between cells and their surroundings. It is therefore important to understand how nature coordinates these variables into concerted regulation of growth at the tissue scale. The cellular microenvironment might then be manipulated to drive cells toward a desired outcome at the tissue level. One unexpected parameter, cellular membrane voltage (Vm, has been documented to exert control over cellular behavior both in culture and in vivo. Manipulating this fundamental cellular property influences a remarkable array of organism-wide patterning events, producing striking outcomes in both tumorigenesis as well as regeneration. These studies suggest that Vm is not only a key intrinsic cellular property, but also an integral part of the microenvironment that acts in both space and time to guide cellular behavior. As a result, there is considerable interest in manipulating Vm both to treat cancer as well as to regenerate organs damaged or deteriorated during aging. However, such manipulations have produced conflicting outcomes experimentally, which poses a substantial barrier to understanding the fundamentals of bioelectrical reprogramming. Here, we summarize these inconsistencies and discuss how the mechanical microenvironment may impact bioelectric regulation.

  13. Plasticity of the Muscle Stem Cell Microenvironment.

    Science.gov (United States)

    Dinulovic, Ivana; Furrer, Regula; Handschin, Christoph

    2017-01-01

    Satellite cells (SCs) are adult muscle stem cells capable of repairing damaged and creating new muscle tissue throughout life. Their functionality is tightly controlled by a microenvironment composed of a wide variety of factors, such as numerous secreted molecules and different cell types, including blood vessels, oxygen, hormones, motor neurons, immune cells, cytokines, fibroblasts, growth factors, myofibers, myofiber metabolism, the extracellular matrix and tissue stiffness. This complex niche controls SC biology-quiescence, activation, proliferation, differentiation or renewal and return to quiescence. In this review, we attempt to give a brief overview of the most important players in the niche and their mutual interaction with SCs. We address the importance of the niche to SC behavior under physiological and pathological conditions, and finally survey the significance of an artificial niche both for basic and translational research purposes.

  14. Synergistic effects of sodium hypochlorite and ultraviolet radiation in reducing the levels of selected foodborne pathogenic bacteria.

    Science.gov (United States)

    Ha, Ji-Hyoung; Ha, Sang-Do

    2011-05-01

    The purpose of this study was to determine whether combined treatment would produce synergistic effects to facilitate the sterilization of food products during production relative to single treatment. To assess this hypothesis, we investigated the bactericidal effects of ultraviolet (UV) irradiation and a commercial chemical disinfectant, sodium hypochlorite (NaClO), on Bacillus cereus F4810/72, Cronobacter sakazakii KCTC 2949, Staphylococcus aureus ATCC 35556, Escherichia coli ATCC 10536, and Salmonella Typhimurium novobiocin/nalidixic acid in vitro. Various concentrations of NaClO (20, 60, 100, and 200 ppm NaClO) were tested along with exposure to UV radiation at various doses (6, 96, 216, 360, and 504 mW s/cm(2)). The combined NaClO/UV treatments resulted in greater reductions in bacterial counts than either treatment alone. The synergy values against B. cereus, C. sakazakii, S. aureus, Salmonella Typhimurium, and E. coli were 0.25-1.17, 0.33-1.97, 0.42-1.72, 0.02-1.44, and 0.01-0.85 log(10) CFU/mL, respectively. The results of this study suggest that a significant synergistic benefit results from combined NaClO/UV processing against food-borne pathogenic bacteria in vitro.

  15. The synergistic effect between coal macerals during hydropyrolysis

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Q.; Li, W.; Chen, H.; Li, B. [CAS, Taiyuan (China)

    2007-01-15

    Using TGA technology, the volatile matter yields during hydropyrolysis of Chinese Shenmu coal and its derived high purity macerals under different heating rates and pressures were investigated. The {Delta}W, calculated by the difference between the volatile matter yield of parent coal and that of macerals, is used to evaluate the synergistic effect of macerals during hydropyrolysis. The results showed that with increasing pressure and decreasing heating rate, the Delta W increases. At temperature of 500{sup o}C and pressure of 3 MPa, the difference of volatile matter yield between parent coal and vitrinite reaches the maximum and the {Delta} W also occurs the highest value of 14.1%, suggesting the existence of the synergistic effect between macerals during hydropyrolysis. Based on the structural characteristics of macerals and the basic knowledge of hydropyrolysis, the possible explanation for the synergism are proposed.

  16. Absorbed dose in fibrotic microenvironment models employing Monte Carlo simulation

    International Nuclear Information System (INIS)

    Zambrano Ramírez, O.D.; Rojas Calderón, E.L.; Azorín Vega, E.P.; Ferro Flores, G.; Martínez Caballero, E.

    2015-01-01

    The presence or absence of fibrosis and yet more, the multimeric and multivalent nature of the radiopharmaceutical have recently been reported to have an effect on the radiation absorbed dose in tumor microenvironment models. Fibroblast and myofibroblast cells produce the extracellular matrix by the secretion of proteins which provide structural and biochemical support to cells. The reactive and reparative mechanisms triggered during the inflammatory process causes the production and deposition of extracellular matrix proteins, the abnormal excessive growth of the connective tissue leads to fibrosis. In this work, microenvironment (either not fibrotic or fibrotic) models composed of seven spheres representing cancer cells of 10 μm in diameter each with a 5 μm diameter inner sphere (cell nucleus) were created in two distinct radiation transport codes (PENELOPE and MCNP). The purpose of creating these models was to determine the radiation absorbed dose in the nucleus of cancer cells, based on previously reported radiopharmaceutical retain (by HeLa cells) percentages of the 177 Lu-Tyr 3 -octreotate (monomeric) and 177 Lu-Tyr 3 -octreotate-AuNP (multimeric) radiopharmaceuticals. A comparison in the results between the PENELOPE and MCNP was done. We found a good agreement in the results of the codes. The percent difference between the increase percentages of the absorbed dose in the not fibrotic model with respect to the fibrotic model of the codes PENELOPE and MCNP was found to be under 1% for both radiopharmaceuticals. (authors)

  17. 'Americium(III)/trivalent lanthanides' separation using organothiophosphinic acids

    International Nuclear Information System (INIS)

    Hill, C.; Madic, C.; Baron, P.; Ozawa, Masaki; Tanaka, Yasumasa.

    1997-01-01

    The present paper describes the extraction of neodymium and other lanthanides by saponified Cyanex 301 acid. The saponification of commercial Cyanex 301 acid favoured the extraction of macro concentrations of neodymium from sodium nitrate aqueous solutions (pH eq ∼ 4). The amount of lanthanide extracted in the organic phase always reached the third of the initial concentration of saponified Cyanex 301 acid, which assumed a cation exchange mechanism to occur during the extraction. No nitrate anion took part in the complex formation. This paper also compares the abilities of purified Cyanex 301, Cyanex 302 and Cyanex 272 acids to extract and separate 241 Am(III) from 152 Eu(III). Very high separation factors S.F. Am/Eu were observed in the case of purified Cyanex 301 acid. Finally some studies are presented herein using tri-n-butylphosphate (TBP) as a synergistic extractant with Cyanex 301 acid to separate actinides from trivalent lanthanide. (author)

  18. Theoretical Approach to Synergistic Interaction of Ionizing Radiation with Other Factors

    International Nuclear Information System (INIS)

    Kim, Jin Kyu; Petinb, Vladislav G.

    2005-01-01

    Living objects including men are never exposed to merely one harmful agent. Many physical, chemical, biological and social factors may simultaneously exert their deleterious influence to man and the environment. Risk assessment is generally performed with the simplest assumption that the factor under consideration acts largely independently of others. However, the combined exposure to two harmful agents could result in a higher effect than would be expected from the addition of the separate exposures to individual agents. Hence, there is a possibility that, at least at high exposures, the combined effect of ionizing radiation with other environmental factors can be resulted in a greater overall risk. The problem is not so clear for low intensity and there is no possibility of testing all conceivable combinations of agents. For further insight into the mode of synergistic interaction, discussed are a common feature of synergistic interaction display and a theoretical model to describe, optimize and predict the synergistic effects

  19. Fatty acid-based formulations for wood protection against mold and sapstain

    Science.gov (United States)

    Carol A. Clausen; Robert D. Coleman; Vina W. Yang

    2010-01-01

    Safer, highly effective biocides providing long-term protection of mold growth on wood-based materials is of interest to the wood protection industry. Moldicide formulations containing synergistic combinations of ingredients derived from natural sources are commonly recognized as a promising approach for the next generation of wood protectants. Although fatty acid (FA...

  20. Neuroblastoma arginase activity creates an immunosuppressive microenvironment that impairs autologous and engineered immunity

    Science.gov (United States)

    Mussai, Francis; Egan, Sharon; Hunter, Stuart; Webber, Hannah; Fisher, Jonathan; Wheat, Rachel; McConville, Carmel; Sbirkov, Yordan; Wheeler, Kate; Bendle, Gavin; Petrie, Kevin; Anderson, John; Chesler, Louis; De Santo, Carmela

    2015-01-01

    Neuroblastoma is the most common extra cranial solid tumour of childhood, and survival remains poor for patients with advanced disease. Novel immune therapies are currently in development, but clinical outcomes have not matched preclinical results. Here, we describe key mechanisms in which neuroblastoma inhibits the immune response. We show that murine and human neuroblastoma tumour cells suppress T cell proliferation, through increased arginase activity. Arginase II is the predominant isoform expressed and creates an arginine deplete local and systemic microenvironment. Neuroblastoma arginase activity results in inhibition of myeloid cell activation and suppression of bone marrow CD34+ progenitor proliferation. Finally we demonstrate that the arginase activity of neuroblastoma impairs NY-ESO-1 specific TCR and GD2-specific CAR engineered T cell proliferation and cytotoxicity. High arginase II expression correlates with poor survival for neuroblastoma patients. The results support the hypothesis that neuroblastoma creates an arginase-dependent immunosuppressive microenvironment in both the tumour and blood that leads to impaired immune surveillance and sub-optimal efficacy of immunotherapeutic approaches. PMID:26054597

  1. Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease

    Science.gov (United States)

    Cruz, Nelly M.; Song, Xuewen; Czerniecki, Stefan M.; Gulieva, Ramila E.; Churchill, Angela J.; Kim, Yong Kyun; Winston, Kosuke; Tran, Linh M.; Diaz, Marco A.; Fu, Hongxia; Finn, Laura S.; Pei, York; Himmelfarb, Jonathan; Freedman, Benjamin S.

    2017-11-01

    Polycystic kidney disease (PKD) is a life-threatening disorder, commonly caused by defects in polycystin-1 (PC1) or polycystin-2 (PC2), in which tubular epithelia form fluid-filled cysts. A major barrier to understanding PKD is the absence of human cellular models that accurately and efficiently recapitulate cystogenesis. Previously, we have generated a genetic model of PKD using human pluripotent stem cells and derived kidney organoids. Here we show that systematic substitution of physical components can dramatically increase or decrease cyst formation, unveiling a critical role for microenvironment in PKD. Removal of adherent cues increases cystogenesis 10-fold, producing cysts phenotypically resembling PKD that expand massively to 1-centimetre diameters. Removal of stroma enables outgrowth of PKD cell lines, which exhibit defects in PC1 expression and collagen compaction. Cyclic adenosine monophosphate (cAMP), when added, induces cysts in both PKD organoids and controls. These biomaterials establish a highly efficient model of PKD cystogenesis that directly implicates the microenvironment at the earliest stages of the disease.

  2. Laboratory Studies of Aedes aegypti Attraction to Ketones, Sulfides, and Primary Chloroalkanes Tested Alone and in Combination with L-Lactic Acid.

    Science.gov (United States)

    Bernier, Ulrich R; Kline, Daniel L; Allan, Sandra A; Barnard, Donald R

    2015-03-01

    The attraction of female Aedes aegypti to single compounds and binary compositions containing L-lactic acid and an additional saturated compound from a set of ketones, sulfides, and chloroalkanes was studied using a triple-cage dual-port olfactometer. These chemical classes were studied because of their structural relation to acetone, dimethyl disulfide, and dichloromethane, which have all been reported to synergize attraction to L-lactic acid. Human odors, carbon dioxide, and the binary mixture of L-lactic acid and CO₂served as controls for comparison of attraction responses produced by the binary mixtures. All tested mixtures that contained chloroalkanes attracted mosquitoes at synergistic levels, as did L-lactic acid and CO₂. Synergism was less frequent in mixtures of L-lactic acid with sulfides and ketones; in the case of ketones, synergistic attraction was observed only for L-lactic acid combined with acetone or butanone. Suppression or inhibition of attraction response was observed for combinations that contained ketones of C7-C12 molecular chain length (optimum in the C8-C10 range). This inhibition effect is similar to that observed previously for specific ranges of carboxylic acids, aldehydes, and alcohols.

  3. HematoPorphyrin Monomethyl Ether polymer contrast agent for ultrasound/photoacoustic dual-modality imaging-guided synergistic high intensity focused ultrasound (HIFU) therapy.

    Science.gov (United States)

    Yan, Sijing; Lu, Min; Ding, Xiaoya; Chen, Fei; He, Xuemei; Xu, Chunyan; Zhou, Hang; Wang, Qi; Hao, Lan; Zou, Jianzhong

    2016-08-18

    This study is to prepare a hematoporphyrin monomethyl ether (HMME)-loaded poly(lactic-co-glycolic acid) (PLGA) microcapsules (HMME/PLGA), which could not only function as efficient contrast agent for ultrasound (US)/photoacoustic (PA) imaging, but also as a synergistic agent for high intensity focused ultrasound (HIFU) ablation. Sonosensitizer HMME nanoparticles were integrated into PLGA microcapsules with the double emulsion evaporation method. After characterization, the cell-killing and cell proliferation-inhibiting effects of HMME/PLGA microcapsules on ovarian cancer SKOV3 cells were assessed. The US/PA imaging-enhancing effects and synergistic effects on HIFU were evaluated both in vitro and in vivo. HMME/PLGA microcapsules were highly dispersed with well-defined spherical morphology (357 ± 0.72 nm in diameter, PDI = 0.932). Encapsulation efficiency and drug-loading efficiency were 58.33 ± 0.95% and 4.73 ± 0.15%, respectively. The HMME/PLGA microcapsules remarkably killed the SKOV3 cells and inhibited the cell proliferation, significantly enhanced the US/PA imaging results and greatly enhanced the HIFU ablation effects on ovarian cancer in nude mice by the HMME-mediated sono-dynamic chemistry therapy (SDT). HMME/PLGA microcapsules represent a potential multifunctional contrast agent for HIFU diagnosis and treatment, which might provide a novel strategy for the highly efficient imaging-guided non-invasive HIFU synergistic therapy for cancers by SDT in clinic.

  4. The species origin of the cellular microenvironment influences markers of beta cell fate and function in EndoC-βH1 cells.

    Science.gov (United States)

    Jeffery, N; Richardson, S; Beall, C; Harries, L W

    2017-12-15

    Interaction between islet cell subtypes and the extracellular matrix influences beta-cell function in mammals. The tissue architecture of rodent islets is very different to that of human islets; cell-to-cell communication and interaction with the extracellular matrix may vary between species. In this work, we have compared the responses of the human EndoC-βH1 cell line to non-human and human-derived growth matrices in terms of growth morphology, gene expression and glucose-stimulated insulin secretion (GSIS). EndoC-βH1 cells demonstrated a greater tendency to form cell clusters when cultured in a human microenvironment and exhibited reduced alpha cell markers at the mRNA level; mean expression difference - 0.23 and - 0.51; p = 0.009 and 0.002 for the Aristaless-related homeobox (ARX) and Glucagon (GCG) genes respectively. No differences were noted in the protein expression of mature beta cell markers such as Pdx1 and NeuroD1 were noted in EndoC-βH1 cells grown in a human microenvironment but cells were however more sensitive to glucose (4.3-fold increase in insulin secretion following glucose challenge compared with a 1.9-fold increase in cells grown in a non-human microenvironment; p = 0.0003). Our data suggests that the tissue origin of the cellular microenvironment has effects on the function of EndoC-βH1 cells in vitro, and the use of a more human-like culture microenvironment may bring benefits in terms of increased physiological relevance. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Synergistic effects of Chinese herbal medicine: a comprehensive review of methodology and current research

    Directory of Open Access Journals (Sweden)

    Xian Zhou

    2016-07-01

    Full Text Available Traditional Chinese medicine is an important part of primary health care in Asian countries that has utilised complex herbal formulations (consisting 2 or more medicinal herbs for treating diseases over thousands of years. There seems to be a general assumption that the synergistic therapeutic effects of Chinese herbal medicine derive from the complex interactions between the multiple bioactive components within the herbs and/or herbal formulations. However, evidence to support these synergistic effects remains weak and controversial due to several reasons, including the very complex nature of Chinese herbal medicine, misconceptions about synergy, methodological challenges to study design. In this review, we clarify the definition of synergy, identify common errors in synergy research and describe current methodological approaches to test for synergistic interaction. We discuss the strengthen and weakness of these models in the context of Chinese herbal medicine and summarise the current status of synergy research in CHM. Despite the availability of some scientific data to support the synergistic effects of multi-herbal and/or herb-drug combinations, the level of evidence remains low and the clinical relevancy of most of these findings is undetermined. There remain significant challenges in the development of suitable methods for synergistic studies of complex herbal combinations.

  6. Inhibitors of Fatty Acid Synthesis Induce PPAR α -Regulated Fatty Acid β -Oxidative Genes: Synergistic Roles of L-FABP and Glucose.

    Science.gov (United States)

    Huang, Huan; McIntosh, Avery L; Martin, Gregory G; Petrescu, Anca D; Landrock, Kerstin K; Landrock, Danilo; Kier, Ann B; Schroeder, Friedhelm

    2013-01-01

    While TOFA (acetyl CoA carboxylase inhibitor) and C75 (fatty acid synthase inhibitor) prevent lipid accumulation by inhibiting fatty acid synthesis, the mechanism of action is not simply accounted for by inhibition of the enzymes alone. Liver fatty acid binding protein (L-FABP), a mediator of long chain fatty acid signaling to peroxisome proliferator-activated receptor- α (PPAR α ) in the nucleus, was found to bind TOFA and its activated CoA thioester, TOFyl-CoA, with high affinity while binding C75 and C75-CoA with lower affinity. Binding of TOFA and C75-CoA significantly altered L-FABP secondary structure. High (20 mM) but not physiological (6 mM) glucose conferred on both TOFA and C75 the ability to induce PPAR α transcription of the fatty acid β -oxidative enzymes CPT1A, CPT2, and ACOX1 in cultured primary hepatocytes from wild-type (WT) mice. However, L-FABP gene ablation abolished the effects of TOFA and C75 in the context of high glucose. These effects were not associated with an increased cellular level of unesterified fatty acids but rather by increased intracellular glucose. These findings suggested that L-FABP may function as an intracellular fatty acid synthesis inhibitor binding protein facilitating TOFA and C75-mediated induction of PPAR α in the context of high glucose at levels similar to those in uncontrolled diabetes.

  7. THE SYNERGISTIC SYLLABUS FOR TEACHING READING IN 32 TOURISM VOCATIONAL HIGH SCHOOL

    Directory of Open Access Journals (Sweden)

    Ahlis Qoidah Noor

    2017-12-01

    Full Text Available The new Syllabus at 2013 Curriculum for vocational high school created many problems to apply in the class. Based on the Need Analysis, the writer develops a Synergistic Syllabus for teaching Reading in vocational high school. It contains the syllabus combined from Task- Based Learning, Situational Syllabus, Program of International Student Assessment ( PISA item test and Character Building. It is a R and D research uses three phases of Observation, Developing and Try Out. It is in a True Experimental Research. The main findings are Reading Skill cannot be taught effectively for some reasons. There is no appropriate syllabus for teaching Reading; most teachers need some models in a syllabus. The results are the Synergistic Syllabus for teaching Reading, a set of Reading Material for Teaching Reading and a set of the lesson plan for one semester at Grade X of Tourism VHS. It is measured through mean, median and t- Test. To Sum up Synergistic Syllabus can develop many aspects, the systematic and meaningful activities in the class, motivation and good attitude. The standardized item of assignment, and a sense of competition in Reading activities and the Synergistic Syllabus assist teachers in teaching Reading using 2013 curriculum in the class effectively.

  8. Macrophages in Mildly Acid Microenvironment

    African Journals Online (AJOL)

    1College of Stomatology, Guiyang Medical University, 2Guiyang Stomatological Hospital, Guiyang, Guizhou 550004, PR China ... supernatants were collected after 24-h culture, and the content of VEGF and VEGF-C in each ... concentration at the same pH value, and reached a minimum at 50 ug/mL and pH 6.6. Conclusion ...

  9. Albumin nanoparticles with synergistic antitumor efficacy against metastatic lung cancers.

    Science.gov (United States)

    Kim, Bomi; Seo, Bohyung; Park, Sanghyun; Lee, Changkyu; Kim, Jong Oh; Oh, Kyung Taek; Lee, Eun Seong; Choi, Han-Gon; Youn, Yu Seok

    2017-10-01

    Albumin nanoparticles are well-known as effective drug carriers used to deliver hydrophobic chemotherapeutic agents. Albumin nanoparticles encapsulating curcumin and doxorubicin were fabricated using slightly modified nanoparticle albumin-bound (nab™) technology, and the synergistic effects of these two drugs were examined. Albumin nanoparticles encapsulating curcumin, doxorubicin, and both curcumin and doxorubicin were prepared using a high pressure homogenizer. The sizes of albumin nanoparticles were ∼130nm, which was considered to be suitable for the EPR (enhanced permeability and retention) effect. Albumin nanoparticles gradually released drugs over a period of 24h without burst effect. To confirm the synergistic effect of two drugs, in vitro cytotoxicity assay was performed using B16F10 melanoma cells. The cytotoxic effect on B16F10 melanoma cells was highest when co-treated with both curcumin and doxorubicin compared to single treatment of either curcumin and doxorubicin. The combined index calculated by medium-effect equation was 0.6069, indicating a synergistic effect. Results of confocal laser scanning microscopy and fluorescence-activated cell sorting corresponded to results from an in vitro cytotoxicity assay, indicating synergistic cytotoxicity induced by both drugs. A C57BL/6 mouse model induced by B16F10 lung metastasis was used to study in vivo therapeutic effects. When curcumin and doxorubicin were simultaneously treated, the metastatic melanoma mass in the lungs macroscopically decreased compared to curcumin or doxorubicin alone. Albumin nanoparticles encapsulating two anticancer drugs were shown to have an effective therapeutic result and would be an excellent way to treat resistant lung cancers. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Kinetin Enhanced 1-Aminocyclopropane-1-Carboxylic Acid Utilization during Alleviation of High Temperatures Stress in Lettuce Seeds.

    Science.gov (United States)

    Khan, A A; Prusinski, J

    1989-10-01

    The thermoinhibition at 35 and 32 degrees C of pregermination ethylene production and germination in lettuce (Lactuca sativa L. cv Mesa 659) seeds was synergistically or additively alleviated by 0.05 millimolar kinetin (KIN) and 10 millimolar 1-aminocyclopropane-1-carboxylic acid (ACC). The synergistic effect of KIN + ACC on ethylene production and germination at 35 degrees C was inhibited by Co(2+) (44-46%) but not by aminoethoxyvinyl glycine (AVG). The uptake of ACC by the seed was not influenced by KIN. Upon slitting of the seed coats (composed of pericarp, testa and endosperm), following the uptake of chemicals, ACC was readily converted into ethylene at all temperatures, and the synergistic effects of KIN + ACC at 35 degrees C were lost. At 35 degrees C, KIN acted synergistically with ACC or ethephon (ETH) in alleviating the osmotic restraint. At 25 degrees C, ETH was more active than KIN or KIN + ACC in overcoming the osmotic restraint. Thus, the integrity of the seed coats, the KIN-enhanced ACC utilization, and an interaction of KIN with the ethylene produced may be the basis for the synergistic or additive effects of KIN + ACC at high temperature.

  11. Synergistic Effect of Auto-Activation and Small RNA Regulation on Gene Expression

    Science.gov (United States)

    Xiong, Li-Ping; Ma, Yu-Qiang; Tang, Lei-Han

    2010-09-01

    Auto-activation and small ribonucleic acid (RNA)-mediated regulation are two important mechanisms in controlling gene expression. We study the synergistic effect of these two regulations on gene expression. It is found that under this combinatorial regulation, gene expression exhibits bistable behaviors at the transition regime, while each of these two regulations, if working solely, only leads to monostability. Within the stochastic framework, the base pairing strength between sRNA and mRNA plays an important role in controlling the transition time between on and off states. The noise strength of protein number in the off state approaches 1 and is smaller than that in the on state. The noise strength also depends on which parameters, the feedback strength or the synthesis rate of small RNA, are tuned in switching the gene expression on and off. Our findings may provide a new insight into gene-regulation mechanism and can be applied in synthetic biology.

  12. Synergistic Effect of Auto-Activation and Small RNA Regulation on Gene Expression

    International Nuclear Information System (INIS)

    Li-Ping, Xiong; Yu-Qiang, Ma; Lei-Han, Tang

    2010-01-01

    Auto-activation and small ribonucleic acid (RNA)-mediated regulation are two important mechanisms in controlling gene expression. We study the synergistic effect of these two regulations on gene expression. It is found that under this combinatorial regulation, gene expression exhibits bistable behaviors at the transition regime, while each of these two regulations, if working solely, only leads to monostability. Within the stochastic framework, the base pairing strength between sRNA and mRNA plays an important role in controlling the transition time between on and off states. The noise strength of protein number in the off state approaches 1 and is smaller than that in the on state. The noise strength also depends on which parameters, the feedback strength or the synthesis rate of small RNA, are tuned in switching the gene expression on and off. Our findings may provide a new insight into gene-regulation mechanism and can be applied in synthetic biology

  13. Bioprinting the Cancer Microenvironment.

    Science.gov (United States)

    Zhang, Yu Shrike; Duchamp, Margaux; Oklu, Rahmi; Ellisen, Leif W; Langer, Robert; Khademhosseini, Ali

    2016-10-10

    Cancer is intrinsically complex, comprising both heterogeneous cellular compositions and microenvironmental cues. During the various stages of cancer initiation, development, and metastasis, cell-cell interactions (involving vascular and immune cells besides cancerous cells) as well as cell-extracellular matrix (ECM) interactions (e.g., alteration in stiffness and composition of the surrounding matrix) play major roles. Conventional cancer models both two- and three-dimensional (2D and 3D) present numerous limitations as they lack good vascularization and cannot mimic the complexity of tumors, thereby restricting their use as biomimetic models for applications such as drug screening and fundamental cancer biology studies. Bioprinting as an emerging biofabrication platform enables the creation of high-resolution 3D structures and has been extensively used in the past decade to model multiple organs and diseases. More recently, this versatile technique has further found its application in studying cancer genesis, growth, metastasis, and drug responses through creation of accurate models that recreate the complexity of the cancer microenvironment. In this review we will focus first on cancer biology and limitations with current cancer models. We then detail the current bioprinting strategies including the selection of bioinks for capturing the properties of the tumor matrices, after which we discuss bioprinting of vascular structures that are critical toward construction of complex 3D cancer organoids. We finally conclude with current literature on bioprinted cancer models and propose future perspectives.

  14. Synergistic Effect of Quercetin and α-Lipoic Acid on Aluminium Chloride Induced Neurotoxicity in Rats

    Directory of Open Access Journals (Sweden)

    Sooad Saud Al-Otaibi

    2018-01-01

    Full Text Available Objectives. The present study was carried out to study the protective effects of quercetin and α-lipoic acid alone and in combination against aluminum chloride induced neurotoxicity in rats. Materials and Methods. The study consisted of eight groups, namely, Group 1: control rats, Group 2: rats receiving aluminium chloride 7 mg/kg body weight intraperitoneal route (i.p for two weeks, Group 3: rats receiving quercetin 50 mg/kg body weight i.p. for two weeks, Group 4: rats receiving quercetin 50 mg/kg body weight followed by aluminium chloride 7 mg/kg body weight i.p. for two weeks, Group 5: rats receiving α-lipoic acid 20 mg/kg body weight i.p. for two weeks, Group 6: rats receiving lipoic acid 20 mg/kg body weight followed by aluminium chloride 7 mg/kg body weight i.p. for two weeks, Group 7: rats receiving α-lipoic acid 20 mg/kg body weight and quercetin 50 mg/kg body weight i.p. for two weeks, and Group 8: rats receiving α-lipoic acid 20 mg/kg body weight and quercetin 50 mg/kg body weight followed by aluminium chloride 7 mg/kg body weight i.p. for two weeks. The animals were killed after 24 hours of the last dose by cervical dislocation. Results. Aluminium chloride treatment of rats resulted in significant increases in lipid peroxidation, protein carbonyl levels, and acetylcholine esterase activity in the brain. This was accompanied with significant decreases in reduced glutathione, activities of the glutathione reductase, and superoxide dismutase. Pretreatment of AlCl3 exposed rats to either quercetin or α-lipoic acid also restored altered lipid peroxidation and superoxide dismutase to near normal levels. Quercetin or α-lipoic acid pretreatment of AlCl3 exposed rats improved the protein carbonyl and reduced glutathione, glutathione reductase, and acetylcholine esterase activities in rat brains towards normal levels. Combined pretreatment of AlCl3 exposed rats with quercetin and α-lipoic acid resulted in a

  15. The role of the tissue microenvironment in the regulation of cancer cell motility and invasion

    Directory of Open Access Journals (Sweden)

    Brábek Jan

    2010-09-01

    Full Text Available Abstract During malignant neoplastic progression the cells undergo genetic and epigenetic cancer-specific alterations that finally lead to a loss of tissue homeostasis and restructuring of the microenvironment. The invasion of cancer cells through connective tissue is a crucial prerequisite for metastasis formation. Although cell invasion is foremost a mechanical process, cancer research has focused largely on gene regulation and signaling that underlie uncontrolled cell growth. More recently, the genes and signals involved in the invasion and transendothelial migration of cancer cells, such as the role of adhesion molecules and matrix degrading enzymes, have become the focus of research. In this review we discuss how the structural and biomechanical properties of extracellular matrix and surrounding cells such as endothelial cells influence cancer cell motility and invasion. We conclude that the microenvironment is a critical determinant of the migration strategy and the efficiency of cancer cell invasion.

  16. Synergistic permeability enhancing effect of lysophospholipids and fatty acids on lipid membranes

    DEFF Research Database (Denmark)

    Davidsen, Jesper; Mouritsen, O.G.; Jørgensen, K.

    2002-01-01

    The permeability-enhancing effects of the two surfactants, 1-paltnitoyl-2-lyso-sn-gycero-3-pllosplloclloline (lysoPPC) and palmitic acid (PA), on lipid membranes that at physiological temperatures are in the gel, fluid, and liquid-ordered phases were determined using the concentration-dependent s...

  17. Decreased decorin expression in the tumor microenvironment

    International Nuclear Information System (INIS)

    Bozoky, Benedek; Savchenko, Andrii; Guven, Hayrettin; Ponten, Fredrik; Klein, George; Szekely, Laszlo

    2014-01-01

    Decorin is a small leucine-rich proteoglycan, synthesized and deposited by fibroblasts in the stroma where it binds to collagen I. It sequesters several growth factors and antagonizes numerous members of the receptor tyrosine kinase family. In experimental murine systems, it acted as a potent tumor suppressor. Examining the Human Protein Atlas online database of immunostained tissue samples we have surveyed decorin expression in silico in several different tumor types, comparing them with corresponding normal tissues. We found that decorin is abundantly secreted and deposited in normal connective tissue but its expression is consistently decreased in the tumor microenvironment. We developed a software to quantitate the difference in expression. The presence of two closely related proteoglycans in the newly formed tumor stroma indicated that the decreased decorin expression was not caused by the delay in proteoglycan deposition in the newly formed connective tissue surrounding the tumor

  18. Method of dissolving metal oxides with di- or polyphosphonic acid and a redundant

    Science.gov (United States)

    Horwitz, Earl P.; Chiarizia, Renato

    1996-01-01

    A method of dissolving metal oxides using a mixture of a di- or polyphosphonic acid and a reductant wherein each is present in a sufficient amount to provide a synergistic effect with respect to the dissolution of metal oxides and optionally containing corrosion inhibitors and pH adjusting agents.

  19. Concomitant ingestion of lactic acid bacteria and black tea synergistically enhances flavonoid bioavailability and attenuates d-galactose-induced oxidative stress in mice via modulating glutathione antioxidant system.

    Science.gov (United States)

    Zhao, Danyue; Shah, Nagendra P

    2016-12-01

    Black tea (BT) has been positively linked to improved redox status, while its efficacy is limited due to the low bioavailability of BT flavonoids. In addition to the direct antioxidant activity, flavonoids regulate redox balance via inducing endogenous antioxidants, particularly glutathione (GSH) and GSH-dependent antioxidant enzymes. This work first examined the effect of lactic acid bacteria (LAB) and BT alone or in combination on flavonoid bioavailability and metabolism; next, the effect of LAB-fermented BT diet in attenuating oxidative stress in mice and the underlying mechanisms were studied. Phenolic profiles of plasma, urine and feces from healthy mice consuming plain yogurt, BT milk (BTM) or BT yogurt (BTY) were acquired using LC-MS/MS. Plasma antioxidant capacity, lipid peroxidation level, content of nonprotein thiols and expression of GSH-related antioxidant enzymes and Nrf2 were examined in d-galactose-treated mice. Total flavonoid content in plasma following a single dose of BTY attained 0.657 μmol/l, increased by 50% compared with the BTM group. Increased excretion of phenolic metabolite and hippuric acid in urine and feces indicated enhanced metabolism of flavonoids in BTY-fed mice. In the second study, 8-week concomitant LAB-BT treatment of oxidatively stressed mice effectively restored plasma antioxidant capacity and GSH levels, and mitigated lipid peroxidation, which were associated with significant induction of GSH-dependent antioxidant enzymes and nuclear accumulation of Nrf2. Our results demonstrated the effect of LAB fermentation in enhancing BT flavonoid bioavailability in vivo. The synergistic antioxidant efficacy of LAB-BT diet implied its therapeutic potential in enhancing antioxidant defenses and protecting organisms from oxidative damage. Copyright © 2016. Published by Elsevier Inc.

  20. Are a healthy diet and physical activity synergistically associated with cognitive functioning in older adults?

    NARCIS (Netherlands)

    Nijholt, W.; Jager-Wittenaar, H.; Visser, M.; Van der Schans, C. P.; Hobbelen, J. S. M.

    Previous research has demonstrated that being both physically active and adhering a healthy diet is associated with improved cognitive functioning; however, it remains unclear whether these factors act synergistically. We investigated the synergistic association of a healthy diet and being

  1. Are a Healthy Diet and Physical Activity Synergistically Associated with Cognitive Functioning in Older Adults?

    NARCIS (Netherlands)

    Nijholt, W; Jager-Wittenaar, H; Visser, M; van der Schans, C P; Hobbelen, J S M

    2016-01-01

    OBJECTIVES: Previous research has demonstrated that being both physically active and adhering a healthy diet is associated with improved cognitive functioning; however, it remains unclear whether these factors act synergistically. We investigated the synergistic association of a healthy diet and

  2. Are a healthy diet and physical activity synergistically associated with cognitive functioning in older adults?

    NARCIS (Netherlands)

    Nijholt, Willemke; Jager, Harriët; Visser, M.; van der Schans, Cees; Hobbelen, Hans

    2015-01-01

    Objectives: Previous research has demonstrated that being both physically active and adhering a healthy diet is associated with improved cognitive functioning; however, it remains unclear whether these factors act synergistically. We investigated the synergistic association of a healthy diet and

  3. The anti-tumor histone deacetylase inhibitor SAHA and the natural flavonoid curcumin exhibit synergistic neuroprotection against amyloid-beta toxicity.

    Directory of Open Access Journals (Sweden)

    Jia Meng

    Full Text Available With the trend of an increasing aged population worldwide, Alzheimer's disease (AD, an age-related neurodegenerative disorder, as one of the major causes of dementia in elderly people is of growing concern. Despite the many hard efforts attempted during the past several decades in trying to elucidate the pathological mechanisms underlying AD and putting forward potential therapeutic strategies, there is still a lack of effective treatments for AD. The efficacy of many potential therapeutic drugs for AD is of main concern in clinical practice. For example, large bodies of evidence show that the anti-tumor histone deacetylase (HDAC inhibitor, suberoylanilidehydroxamic acid (SAHA, may be of benefit for the treatment of AD; however, its extensive inhibition of HDACs makes it a poor therapeutic. Moreover, the natural flavonoid, curcumin, may also have a potential therapeutic benefit against AD; however, it is plagued by low bioavailability. Therefore, the integrative effects of SAHA and curcumin were investigated as a protection against amyloid-beta neurotoxicity in vitro. We hypothesized that at low doses their synergistic effect would improve therapeutic selectivity, based on experiments that showed that at low concentrations SAHA and curcumin could provide comprehensive protection against Aβ25-35-induced neuronal damage in PC12 cells, strongly implying potent synergism. Furthermore, network analysis suggested that the possible mechanism underlying their synergistic action might be derived from restoration of the damaged functional link between Akt and the CBP/p300 pathway, which plays a crucial role in the pathological development of AD. Thus, our findings provided a feasible avenue for the application of a synergistic drug combination, SAHA and curcumin, in the treatment of AD.

  4. Microtissues in Cardiovascular Medicine: Regenerative Potential Based on a 3D Microenvironment

    Directory of Open Access Journals (Sweden)

    Julia Günter

    2016-01-01

    Full Text Available More people die annually from cardiovascular diseases than from any other cause. In particular, patients who suffer from myocardial infarction may be affected by ongoing adverse remodeling processes of the heart that may ultimately lead to heart failure. The introduction of stem and progenitor cell-based applications has raised substantial hope for reversing these processes and inducing cardiac regeneration. However, current stem cell therapies using single-cell suspensions have failed to demonstrate long-lasting efficacy due to the overall low retention rate after cell delivery to the myocardium. To overcome this obstacle, the concept of 3D cell culture techniques has been proposed to enhance therapeutic efficacy and cell engraftment based on the simulation of an in vivo-like microenvironment. Of great interest is the use of so-called microtissues or spheroids, which have evolved from their traditional role as in vitro models to their novel role as therapeutic agents. This review will provide an overview of the therapeutic potential of microtissues by addressing primarily cardiovascular regeneration. It will accentuate their advantages compared to other regenerative approaches and summarize the methods for generating clinically applicable microtissues. In addition, this review will illustrate the unique properties of the microenvironment within microtissues that makes them a promising next-generation therapeutic approach.

  5. Tungsten Targets the Tumor Microenvironment to Enhance Breast Cancer Metastasis

    Science.gov (United States)

    Bolt, Alicia M.; Sabourin, Valérie; Molina, Manuel Flores; Police, Alice M.; Negro Silva, Luis Fernando; Plourde, Dany; Lemaire, Maryse; Ursini-Siegel, Josie; Mann, Koren K.

    2015-01-01

    The number of individuals exposed to high levels of tungsten is increasing, yet there is limited knowledge of the potential human health risks. Recently, a cohort of breast cancer patients was left with tungsten in their breasts following testing of a tungsten-based shield during intraoperative radiotherapy. While monitoring tungsten levels in the blood and urine of these patients, we utilized the 66Cl4 cell model, in vitro and in mice to study the effects of tungsten exposure on mammary tumor growth and metastasis. We still detect tungsten in the urine of patients’ years after surgery (mean urinary tungsten concentration at least 20 months post-surgery = 1.76 ng/ml), even in those who have opted for mastectomy, indicating that tungsten does not remain in the breast. In addition, standard chelation therapy was ineffective at mobilizing tungsten. In the mouse model, tungsten slightly delayed primary tumor growth, but significantly enhanced lung metastasis. In vitro, tungsten did not enhance 66Cl4 proliferation or invasion, suggesting that tungsten was not directly acting on 66Cl4 primary tumor cells to enhance invasion. In contrast, tungsten changed the tumor microenvironment, enhancing parameters known to be important for cell invasion and metastasis including activated fibroblasts, matrix metalloproteinases, and myeloid-derived suppressor cells. We show, for the first time, that tungsten enhances metastasis in an animal model of breast cancer by targeting the microenvironment. Importantly, all these tumor microenvironmental changes are associated with a poor prognosis in humans. PMID:25324207

  6. Synergistic Effect of Copper and Cobalt in Cu-Co-O Composite Nanocatalyst for Catalytic Ozonation

    International Nuclear Information System (INIS)

    Dong, Yuming; Wu, Lina; Wang, Guangli; Zhao, Hui; Jiang, Pingping; Feng, Cuiyun

    2013-01-01

    A novel Cu-Co-O composite nanocatalyst was designed and prepared for the ozonation of phenol. A synergistic effect of copper and cobalt was observed over the Cu-Co-O composite nanocatalyst, which showed higher activity than either copper or cobalt oxide alone. In addition, the Cu-Co-O composite revealed good activity in a wide initial pH range (4.11-8.05) of water. The fine dispersion of cobalt on the surface of copper oxide boosted the interaction between catalyst and ozone, and the surface Lewis acid sites on the Cu-Co-O composite were determined as the active sites. The Raman spectroscopy also proved that the Cu-Co-O composite was quite sensitive to the ozone. The trivalent cobalt in the Cu-Co-O composite was proposed as the valid state

  7. Tumour microenvironment and radiation response in sarcomas originating from tumourigenic human mesenchymal stem cells

    DEFF Research Database (Denmark)

    D'Andrea, Filippo Peder; Safwat, Akmal Ahmed; Burns, Jorge S.

    2012-01-01

    : Immune deficient female mice were implanted on the backs with cells from one of the clones. The subsequent tumours were subjected to either radiation treatment or had the tumour microenvironment assayed, when they reached 400mm3. Radiation was given as a single fraction of 0 to 15 Gy and the degree...

  8. Enhanced granulocyte growth on peritoneal cell-coated membranes following irradiation: a dual effect of humoral stimulation and repair of x ray-induced damage to the microenvironment

    International Nuclear Information System (INIS)

    Turner, A.R.; Pfrimmer, W.J.; Boggs, D.R.; Carpe, A.I.

    1978-01-01

    An experimental model of the hematopoietic microenvironment was created by allowing a peritoneal cell coating to form on a disk of cellulose acetate placed in the peritoneal cavity of mice. An effective microenvironment capable of supporting colony growth, primarily granulocytic, was established if the cellulose acetate disk was in the peritoneum for 3 to 5 days. Its effectiveness was hampered by transferring it to another mouse or by exposure to toxic agents such as a propylene glycol-ethanol mixture or irradiation. An exponential dose-related decrease in colony formation was seen with increasing doses or irradiation of the microenvironment before colonization. After a low dose of irradiation, recovery of colony support capacity occurred over a 6-day period. Enhancement of colony growth was seen when cell injection was delayed for 2 to 3 days after irradiation. The effects of irradiation on the cellular stroma were separated from the systemic changes in the host by transferring an established hematopoietic microenvironment to a secondary host. It was shown that there are two distinct effects of irradiation on granulocytic colony growth; one was a short-lived period, 2 to 3 days of stimulation, presumably humoral, and the other was dose-dependent reversible microenvironment damage

  9. Estimation of solubility of organo-phosphorus extractants by P determination using molybdovanadophosphoric acid method

    International Nuclear Information System (INIS)

    Gill, J.S.; Kotekar, M.K.; Singh, H.

    2005-01-01

    Solvent extraction processes have been found to be suitable for uranium recovery from phosphoric acid. Various extractants like di-2-ethyl hexylphosphoric acid (D2EHPA), di-nonylphenyl phosphoric acid (DNPPA) and synergistic agents like tri-butyl phosphate (TBP), tri-octyl phosphine oxide (TOPO) have been used in liquid-liquid extraction of uranium from phosphoric acid. Contents of these organo-phosphorus compounds in aqueous raffinates need estimation for process requirements. Solubility of Tri-butyl phosphate (TBP) and Di-2-ethylhexyl phosphoric acid (D2EHPA) extractants have been determined in different media of water, oxalic acid (0.6M) and sulphuric acid (3.75M) solutions. These compounds were estimated by determining their phosphorus (P) contents employing molybdovanadophosphoric acid method, after digesting and solubalizing them in nitric and perchloric acid. (author)

  10. Fatty acids profile and alteration of lemon seeds extract (Citrus limon) added to soybean oil under thermoxidation.

    Science.gov (United States)

    Luzia, Débora Maria Moreno; Jorge, Neuza

    2013-10-01

    This paper aimed at evaluating fatty acids profile and the total alteration of lemon seeds extract added to soybean oil under thermoxidation, verifying the isolated and synergistic effect of these antioxidants. Therefore, Control treatments, LSE (2,400 mg/kg Lemon Seeds Extract), TBHQ (mg/kg), Mixture 1 (LSE + 50 mg/kg TBHQ) and Mixture 2 (LSE + 25 mg/kg TBHQ) were subjected to 180°C for 20 h. Samples were taken at 0, 5, 10, 15 and 20 h intervals and analyzed as for fatty acid profile and total polar compounds. Results were subjected to variance analyses and Tukey tests at a 5% significance level. An increase in the percentage of saturated fatty acids and mono-unsaturated, and decrease in polyunsaturated fatty acids was observed, regardless of the treatments studied. For total polar compounds, it was verified that Mixtures 1 and 2 presented values lower than 25% with 20 h of heating, not surpassing the limits established in many countries for disposal of oils and fats under high temperatures, thus proving the synergistic effect of antioxidants.

  11. Some aspects of synergistic extraction of actinides and lanthanides from mixed aqueous-organic media

    International Nuclear Information System (INIS)

    Shukla, J.P.; Subramanian, M.S.

    1981-01-01

    Various aspects of the synergistic extraction and separation of actinides and lanthanides from mixed aqueous-organic solutions (polar media) have been reviewed. Notable recent developments as well as its current status in solvent extraction systems where the aqueous acidic phase contains an organic solvent which is completely miscible with water, are presented briefly. In general, extraction increases in the presence of an organic component. The less polar the additive, the higher is the tendency to form neutral metal complexes which ultimately brings about an increase in the extraction. In a polar media, synergism has mostly been observed, though antagonism is not uncommon. An attempt has been made to classify the factors that play an important role in polar phase extractions. Also, their influence particularly on the extractability of actinides and lanthanides is discussed. The discussion is limited to the factors affecting the extraction equilibria, effect of dielectric constant of the polar medium, solvation of the extracting agent and to the composition and stability of the metal complex in the organic phase. Hydroxyl (OHsup(-)) bearing organic additives, e.g. alcohols, and solvents not containing the hydroxyl group such as acetone, dimethylsulphoxide, tetrahydrofuran, amides and acetonitrile etc. are the two major classes of organic additives considered in these studies. Generally, synergistic effect in extraction of the ion-association (TBP, TOPO, sulphoxides etc.) or anion exchange (amines etc.) type is relatively more pronounced compared to other extractions. A tabular summary concerning extraction of actinides and lanthanides from polar media is appended for ready reference. (author)

  12. Synergistic Combination of Unquenching and Plasmonic Fluorescence Enhancement in Fluorogenic Nucleic Acid Hybridization Probes.

    Science.gov (United States)

    Vietz, Carolin; Lalkens, Birka; Acuna, Guillermo P; Tinnefeld, Philip

    2017-10-11

    Fluorogenic nucleic acid hybridization probes are widely used for detecting and quantifying nucleic acids. The achieved sensitivity strongly depends on the contrast between a quenched closed form and an unquenched opened form with liberated fluorescence. So far, this contrast was improved by improving the quenching efficiency of the closed form. In this study, we modularly combine these probes with optical antennas used for plasmonic fluorescence enhancement and study the effect of the nanophotonic structure on the fluorescence of the quenched and the opened form. As quenched fluorescent dyes are usually enhanced more by fluorescence enhancement, a detrimental reduction of the contrast between closed and opened form was anticipated. In contrast, we could achieve a surprising increase of the contrast with full additivity of quenching of the dark form and fluorescence enhancement of the bright form. Using single-molecule experiments, we demonstrate that the additivity of the two mechanisms depends on the perfect quenching in the quenched form, and we delineate the rules for new nucleic acid probes for enhanced contrast and absolute brightness. Fluorogenic hybridization probes optimized not only for quenching but also for the brightness of the open form might find application in nucleic acid assays with PCR avoiding detection schemes.

  13. Antioxidant, antimicrobial and synergistic activities of tea polyphenols

    African Journals Online (AJOL)

    Microbial resistance to antibiotics has become an increasing global problem and there is a need to find out novel potent antimicrobial agents with alternative modes of action as accessories to antibiotic therapy. This study investigated the antioxidant, antimicrobial and synergistic properties of tea polyphenols. The tea ...

  14. Diets that differ in their FODMAP content alter the colonic luminal microenvironment.

    Science.gov (United States)

    Halmos, Emma P; Christophersen, Claus T; Bird, Anthony R; Shepherd, Susan J; Gibson, Peter R; Muir, Jane G

    2015-01-01

    A low FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides And Polyols) diet reduces symptoms of IBS, but reduction of potential prebiotic and fermentative effects might adversely affect the colonic microenvironment. The effects of a low FODMAP diet with a typical Australian diet on biomarkers of colonic health were compared in a single-blinded, randomised, cross-over trial. Twenty-seven IBS and six healthy subjects were randomly allocated one of two 21-day provided diets, differing only in FODMAP content (mean (95% CI) low 3.05 (1.86 to 4.25) g/day vs Australian 23.7 (16.9 to 30.6) g/day), and then crossed over to the other diet with ≥21-day washout period. Faeces passed over a 5-day run-in on their habitual diet and from day 17 to day 21 of the interventional diets were pooled, and pH, short-chain fatty acid concentrations and bacterial abundance and diversity were assessed. Faecal indices were similar in IBS and healthy subjects during habitual diets. The low FODMAP diet was associated with higher faecal pH (7.37 (7.23 to 7.51) vs. 7.16 (7.02 to 7.30); p=0.001), similar short-chain fatty acid concentrations, greater microbial diversity and reduced total bacterial abundance (9.63 (9.53 to 9.73) vs. 9.83 (9.72 to 9.93) log10 copies/g; pdiet. To indicate direction of change, in comparison with the habitual diet the low FODMAP diet reduced total bacterial abundance and the typical Australian diet increased relative abundance for butyrate-producing Clostridium cluster XIVa (median ratio 6.62; pDiets differing in FODMAP content have marked effects on gut microbiota composition. The implications of long-term reduction of intake of FODMAPs require elucidation. ACTRN12612001185853. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  15. Video-rate resonant scanning multiphoton microscopy: An emerging technique for intravital imaging of the tumor microenvironment.

    Science.gov (United States)

    Kirkpatrick, Nathaniel D; Chung, Euiheon; Cook, Daniel C; Han, Xiaoxing; Gruionu, Gabriel; Liao, Shan; Munn, Lance L; Padera, Timothy P; Fukumura, Dai; Jain, Rakesh K

    2012-01-01

    The abnormal tumor microenvironment fuels tumor progression, metastasis, immune suppression, and treatment resistance. Over last several decades, developments in and applications of intravital microscopy have provided unprecedented insights into the dynamics of the tumor microenvironment. In particular, intravital multiphoton microscopy has revealed the abnormal structure and function of tumor-associated blood and lymphatic vessels, the role of aberrant tumor matrix in drug delivery, invasion and metastasis of tumor cells, the dynamics of immune cell trafficking to and within tumors, and gene expression in tumors. However, traditional multiphoton microscopy suffers from inherently slow imaging rates-only a few frames per second, thus unable to capture more rapid events such as blood flow, lymphatic flow, and cell movement within vessels. Here, we report the development and implementation of a video-rate multiphoton microscope (VR-MPLSM) based on resonant galvanometer mirror scanning that is capable of recording at 30 frames per second and acquiring intravital multispectral images. We show that the design of the system can be readily implemented and is adaptable to various experimental models. As examples, we demonstrate the utility of the system to directly measure flow within tumors, capture metastatic cancer cells moving within the brain vasculature and cells in lymphatic vessels, and image acute responses to changes in a vascular network. VR-MPLSM thus has the potential to further advance intravital imaging and provide new insight into the biology of the tumor microenvironment.

  16. Strong synergistic effects in PLA/PCL blends: Impact of PLA matrix viscosity.

    Science.gov (United States)

    Ostafinska, Aleksandra; Fortelný, Ivan; Hodan, Jiří; Krejčíková, Sabina; Nevoralová, Martina; Kredatusová, Jana; Kruliš, Zdeněk; Kotek, Jiří; Šlouf, Miroslav

    2017-05-01

    Blends of two biodegradable polymers, poly(lactic acid) (PLA) and poly(ϵ-caprolactone) (PCL), with strong synergistic improvement in mechanical performance were prepared by melt-mixing using the optimized composition (80/20) and the optimized preparation procedure (a melt-mixing followed by a compression molding) according to our previous study. Three different PLA polymers were employed, whose viscosity decreased in the following order: PLC ≈ PLA1 > PLA2 > PLA3. The blends with the highest viscosity matrix (PLA1/PCL) exhibited the smallest PCL particles (d∼0.6μm), an elastic-plastic stable fracture (as determined from instrumented impact testing) and the strongest synergistic improvement in toughness (>16× with respect to pure PLA, exceeding even the toughness of pure PCL). According to the available literature, this was the highest toughness improvement in non-compatiblized PLA/PCL blends ever achieved. The decrease in the matrix viscosity resulted in an increase in the average PCL particle size and a dramatic decrease in the overall toughness: the completely stable fracture (for PLA1/PCL) changed to the stable fracture followed by unstable crack propagation (for PLA2/PCL) and finally to the completely brittle fracture (for PLA3/PCL). The stiffness of all blends remained at well acceptable level, slightly above the theoretical predictions based on the equivalent box model. Despite several previous studies, the results confirmed that PLA and PCL could behave as compatible polymers, but the final PLA/PCL toughness is extremely sensitive to the PCL particle size distribution, which is influenced by both processing conditions and PLA viscosity. PLA/PCL blends with high stiffness (due to PLA) and toughness (due to PCL) are very promising materials for medical applications, namely for the bone tissue engineering. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Can toxicokinetic and toxicodynamic modeling be used to understand and predict synergistic interactions between chemicals?

    DEFF Research Database (Denmark)

    Cedergreen, Nina; Dalhoff, Kristoffer; Li, Dan

    2017-01-01

    including synergists. The aim of the present study is to develop a mechanistic toxicokinetic (TK) and toxicodynamic (TD) model for the synergistic mixture of the azole fungicide, propiconazole (the synergist), and the insecticide, α-cypermethrin, on the mortality of the crustacean Daphnia magna. The study...... by their effect on the biotransformation rate but that this effect could only partly be explained by the effect of the two azoles on cytochrome P450 activity, measured on D. magna in vivo. TKTD models of interacting mixtures seem to be a promising tool to test mechanisms of interactions between chemicals...

  18. Enhanced Suppressive Activity of Regulatory T Cells in the Microenvironment of Malignant Pleural Effusions

    Directory of Open Access Journals (Sweden)

    Joanna Budna

    2018-01-01

    Full Text Available Cancer metastatic spread to serous cavity causes malignant pleural effusions (MPEs, indicating dismal prognosis. Tumor microenvironment can implement suppressive activity on host immune responses. Thus, we investigated the prevalence of Tregs and the relationship between them and TGF-β and IL-10 concentrations and measured expression of FOXP3, CTLA-4, CD28, and GITR genes, as well as protein expression of selected genes in benign effusions and MPEs. The percentage of Tregs was determined by means of multicolor flow cytometry system. TGF-β and IL-10 concentrations were measured using human TGF-β1 and IL-10 ELISA kit. Relative mRNA expression of studied genes was analyzed by real-time PCR. The frequency of Tregs was significantly higher in MPEs compared to benign effusions; however, the level of TGF-β and IL-10 in analyzed groups was comparable, and no correlation between concentrations of TGF-β and IL-10 and percentage of Tregs was observed. Relative mRNA expression of all the genes was higher in CD4+CD25+ compared to CD4+CD25− cells. In CD4+CD25+ cells from MPEs, relative mRNA expression of FOXP3, CTLA-4, and CD28 genes was significantly higher than in benign effusions; however, the level of CD4+CD25+CTLA-4+ cells in analyzed groups showed no significant differences. We found numerous genes correlations in an entire CD4+CD25+ cell subset and CD4+CD25+ cells from MPEs. Enhanced suppressive activity of Tregs is observed in the microenvironment of MPEs. Understanding of relations between cellular and cytokine immunosuppressive factors in tumor microenvironment may determine success of anticancer response.

  19. Of plasticity and specificity: dialectics of the microenvironment and macroenvironment and the organ phenotype.

    Science.gov (United States)

    Bhat, Ramray; Bissell, Mina J

    2014-01-01

    The study of biological form and how it arises is the domain of the developmental biologists; but once the form is achieved, the organ poses a fascinating conundrum for all the life scientists: how are form and function maintained in adult organs throughout most of the life of the organism? That they do appears to contradict the inherently plastic nature of organogenesis during development. How do cells with the same genetic information arrive at, and maintain such different architectures and functions, and how do they keep remembering that they are different from each other? It is now clear that narratives based solely on genes and an irreversible regulatory dynamics cannot answer these questions satisfactorily, and the concept of microenvironmental signaling needs to be added to the equation. During development, cells rearrange and differentiate in response to diffusive morphogens, juxtacrine signals, and the extracellular matrix (ECM). These components, which constitute the modular microenvironment, are sensitive to cues from other tissues and organs of the developing embryo as well as from the external macroenvironment. On the other hand, once the organ is formed, these modular constituents integrate and constrain the organ architecture, which ensures structural and functional homeostasis and therefore, organ specificity. We argue here that a corollary of the above is that once the organ architecture is compromised in adults by mutations or by changes in the microenvironment such as aging or inflammation, that organ becomes subjected to the developmental and embryonic circuits in search of a new identity. But since the microenvironment is no longer embryonic, the confusion leads to cancer: hence as we have argued, tumors become new evolutionary organs perhaps in search of an elusive homeostasis. © 2013 Wiley Periodicals, Inc.

  20. Cellular Microenvironment Dictates Androgen Production by Murine Fetal Leydig Cells in Primary Culture1

    Science.gov (United States)

    Carney, Colleen M.; Muszynski, Jessica L.; Strotman, Lindsay N.; Lewis, Samantha R.; O'Connell, Rachel L.; Beebe, David J.; Theberge, Ashleigh B.; Jorgensen, Joan S.

    2014-01-01

    ABSTRACT Despite the fact that fetal Leydig cells are recognized as the primary source of androgens in male embryos, the mechanisms by which steroidogenesis occurs within the developing testis remain unclear. A genetic approach was used to visualize and isolate fetal Leydig cells from remaining cells within developing mouse testes. Cyp11a1-Cre mice were bred to mT/mG dual reporter mice to target membrane-tagged enhanced green fluorescent protein (GFP) within steroidogenic cells, whereas other cells expressed membrane-tagged tandem-dimer tomato red. Fetal Leydig cell identity was validated using double-labeled immunohistochemistry against GFP and the steroidogenic enzyme 3beta-HSD, and cells were successfully isolated as indicated by qPCR results from sorted cell populations. Because fetal Leydig cells must collaborate with neighboring cells to synthesize testosterone, we hypothesized that the fetal Leydig cell microenvironment defined their capacity for androgen production. Microfluidic culture devices were used to measure androstenedione and testosterone production of fetal Leydig cells that were cultured in cell-cell contact within a mixed population, were isolated but remained in medium contact via compartmentalized co-culture with other testicular cells, or were isolated and cultured alone. Results showed that fetal Leydig cells maintained their identity and steroidogenic activity for 3–5 days in primary culture. Microenvironment dictated proficiency of testosterone production. As expected, fetal Leydig cells produced androstenedione but not testosterone when cultured in isolation. More testosterone accumulated in medium from mixed cultures than from compartmentalized co-cultures initially; however, co-cultures maintained testosterone synthesis for a longer time. These data suggest that a combination of cell-cell contact and soluble factors constitute the ideal microenvironment for fetal Leydig cell activity in primary culture. PMID:25143354

  1. Targeting the Prometastatic Microenvironment of the Involuting Mammary Gland

    Science.gov (United States)

    2017-11-01

    Danvers, MA, USA), andro- gen receptor (1:500, Santa Cruz Biotechnologies, Santa Cruz, CA, USA) and guinea pig antibodies against Vimentin (1:1,000...Problems…………………………………………………….29 6. Products ………………………………………………………………..29-30 7. Participants/Collaborators……………………………………………30-31 8. Special Reporting...a prometastatic microenvironment. The production of the Ltbp1-TGF-beta complex by luminal cells has consequences for our understanding of the

  2. Modelling synergistic effects of appetite regulating hormones

    DEFF Research Database (Denmark)

    Schmidt, Julie Berg; Ritz, Christian

    2016-01-01

    We briefly reviewed one definition of dose addition, which is applicable within the framework of generalized linear models. We established how this definition of dose addition corresponds to effect addition in case only two doses per compound are considered for evaluating synergistic effects. The....... The link between definitions was exemplified for an appetite study where two appetite hormones were studied....

  3. Interleukin 33 in tumor microenvironment is crucial for the accumulation and function of myeloid-derived suppressor cells

    Science.gov (United States)

    Xiao, Peng; Wan, Xiaopeng; Cui, Bijun; Liu, Yang; Qiu, Chenyang; Rong, Jiabing; Zheng, Mingzhu; Song, Yinjing; Chen, Luoquan; He, Jia; Tan, Qinchun; Wang, Xiaojia; Shao, Xiying; Liu, Yuhua; Cao, Xuetao; Wang, Qingqing

    2016-01-01

    ABSTRACT Tumor-induced, myeloid-derived suppressor cells (MDSCs)-mediated immune dysfunction is an important mechanism that leads to tumor immune escape and the inefficacy of cancer immunotherapy. Importantly, tumor-infiltrating MDSCs have much stronger ability compared to MDSCs in the periphery. However, the mechanisms that tumor microenvironment induces the accumulation and function of MDSCs are poorly understood. Here, we report that Interleukin-33 (IL-33) – a cytokine which can be abundantly released in tumor tissues both in 4T1-bearing mice and breast cancer patients, is crucial for facilitating the expansion of MDSCs. IL-33 in tumor microenvironment reduces the apoptosis and sustains the survival of MDSCs through induction of autocrine secretion of GM-CSF, which forms a positive amplifying loop for MDSC accumulation. This is in conjunction with IL-33-driven induction of arginase-1 expression and activation of NF-κB and MAPK signaling in MDSCs which augments their immunosuppressive ability, and histone modifications were involved in IL-33 signaling in MDSCs. In ST2−/− mice, the defect of IL-33 signaling in MDSCs attenuates the immunosuppressive and pro-tumoral capacity of MDSCs. Our results identify IL-33 as a critical mediator that contributes to the abnormal expansion and enhanced immunosuppressive function of MDSCs within tumor microenvironment, which can be potentially targeted to reverse MDSC-mediated tumor immune evasion. PMID:26942079

  4. Synergistic anti-tumor effects of melatonin and PUFAs from walnuts in a murine mammary adenocarcinoma model.

    Science.gov (United States)

    Garcia, Carolina P; Lamarque, Alicia L; Comba, Andrea; Berra, María A; Silva, Renata A; Labuckas, Diana O; Das, Undurti N; Eynard, Aldo R; Pasqualini, Maria E

    2015-04-01

    The aim of this study was to determine the effects of some polyunsaturated fatty acids plus phytomelatonin from walnuts in the development of mammary gland adenocarcinoma. BALB/c mice were fed a semisynthetic diet supplemented with either 6% walnut oil and 8% walnut flour containing phytomelatonin (walnut diet: WD); or 6% corn oil plus commercial melatonin (melatonin diet: MD), or the control group (CD), which received only 6% of corn oil. Membrane fatty acids of tumor cells (TCs) were analyzed by gas liquid chromatography, cyclooxygenase (COX) and lipoxygenase (LOX) derivatives, and plasma melatonin by high-performance liquid chromatography; apoptosis and tumor-infiltrating lymphocytes by flow cytometry. TCs from the MD and WD mice showed significant decreases in linoleic acid compared with the CD group (P < 0.05). Significantly lower levels of LOX-[13(S)-HODE] were found in TCs from the MD and WD group than in CD (P < 0.0001). COX-[12(S)-HHT] was lower and 12 LOX-[12(S)-HETE] was higher in TCs from the MD group than form the WD and CD arms (P < 0.05). Plasma melatonin, apoptosis, tumor infiltration, and survival time were significantly lower in CD mice than in MD and WD mice (P < 0.05). This study shows that melatonin, along with polyunsaturated fatty acids, exerts a selective inhibition of some COX and LOX activities and has a synergistic anti-tumor effect on a mammary gland adenocarcinoma model. Published by Elsevier Inc.

  5. Inhibition of Siah2 Ubiquitin Ligase by Vitamin K3 Attenuates Chronic Myeloid Leukemia Chemo-Resistance in Hypoxic Microenvironment.

    Science.gov (United States)

    Huang, Jixian; Lu, Ziyuan; Xiao, Yajuan; He, Bolin; Pan, Chengyun; Zhou, Xuan; Xu, Na; Liu, Xiaoli

    2018-02-05

    BACKGROUND A hypoxic microenvironment is associated with resistance to tyrosine kinase inhibitors (TKIs) and a poor prognosis in chronic myeloid leukemia (CML). The E3 ubiquitin ligase Siah2 plays a vital role in the regulation of hypoxia response, as well as in leukemogenesis. However, the role of Siah2 in CML resistance is unclear, and it is unknown whether vitaminK3 (a Siah2 inhibitor) can improve the chemo-sensitivity of CML cells in a hypoxic microenvironment. MATERIAL AND METHODS The expression of Siah2 was detected in CML patients (CML-CP and CML-BC), K562 cells, and K562-imatinib-resistant cells (K562-R cells). We measured the expression of PHD3, HIF-1α, and VEGF in both cell lines under normoxia and hypoxic conditions, and the degree of leukemic sensitivity to imatinib and VitaminK3 were evaluated. RESULTS Siah2 was overexpressed in CML-BC patients (n=9) as compared to CML-CP patients (n=13). Similarly, K562-imatinib-resistant cells (K562-R cells) showed a significantly higher expression of Siah2 as compared to K562 cells in a hypoxic microenvironment. Compared to normoxia, under hypoxic conditions, both cell lines had lower PHD3, higher HIF-1α, and higher VEGF expression. Additionally, Vitamin K3 (an inhibitor of Siah2) reversed these changes and promoted a higher degree of leukemic sensitivity to imatinib. CONCLUSIONS Our findings indicate that the Siah2-PHD3- HIF-1α-VEGF axis is an important hypoxic signaling pathway in a leukemic microenvironment. An inhibitor of Siah2, combined with TKIs, might be a promising therapy for relapsing and refractory CML patients.

  6. Synergistic Antimicrobial Effect of Tribulus terrestris and Bitter Almond Extracts

    Directory of Open Access Journals (Sweden)

    Hamid Abtahi

    2014-12-01

    Full Text Available Background: The antimicrobial effects of the extracts of different kinds of plants have been demonstrated in several studies. However, no study has been conducted so far on the synergistic effects of two herbal extracts on their germicidal effects. In this study, in addition to antibacterial effects of the aqueous, methanol or ethanol extracts of Tribulus terrestris and bitter almond on some bacteria, the synergistic effects of the extracts of these two plants were also evaluated. Materials and Methods: In this experimental study, water, methanol and ethanol extracts of seeds were screened against some bacterial strains. Seeds were extracted by percolation method. Aliquots of the extracts at variable concentrations were then incubated with different bacterial strains, and the antimicrobial activities of the extracts from seeds were determined by MIC. Three antibiotics were used as reference compounds for antibacterial activities. Seeds extract inhibited significantly the growth of the tested bacterial strains. Results: The greatest synergistic effect of T. terrestris and bitter almond extracts is detected in methanol and aqueous extracts. Among the bacterial strains tested, Staphylococcus aureus was most susceptibility. Conclusion: The results showed the highest antibacterial effect in the combination of methanol extract of T. terrestris and the aqueous extract of the bitter almond.

  7. Tungstate as a synergist to phosphonate-based formulation for ...

    Indian Academy of Sciences (India)

    Administrator

    Synergistic inhibition of corrosion of carbon steel in low chloride aqueous .... 200 high resolution scanning electron microscope ..... mation of a thick and less permeable protective film ..... the surface of the metal due to its very low solubility.

  8. A rhizosphere-associated symbiont, Photobacterium spp. strain MELD1, and its targeted synergistic activity for phytoprotection against mercury.

    Directory of Open Access Journals (Sweden)

    Dony Chacko Mathew

    Full Text Available Though heavy metal such as mercury is toxic to plants and microorganisms, the synergistic activity between them may offer benefit for surviving. In this study, a mercury-reducing bacterium, Photobacterium spp. strain MELD1, with an MIC of 33 mg x kg(-1 mercury was isolated from a severely mercury and dioxin contaminated rhizosphere soil of reed (Phragmites australis. While the whole genome sequencing of MELD1 confirmed the presence of a mer operon, the mercury reductase MerA gene showed 99% sequence identity to Vibrio shilloni AK1 and implicates its route resulted from the event of horizontal gene transfer. The efficiency of MELD1 to vaporize mercury (25 mg x kg(-1, 24 h and its tolerance to toxic metals and xenobiotics such as lead, cadmium, pentachlorophenol, pentachloroethylene, 3-chlorobenzoic acid, 2,3,7,8-tetrachlorodibenzo-p-dioxin and 1,2,3,7,8,9-hexachlorodibenzo-p-dioxin is promising. Combination of a long yard bean (Vigna unguiculata ssp. Sesquipedalis and strain MELD1 proved beneficial in the phytoprotection of mercury in vivo. The effect of mercury (Hg on growth, distribution and tolerance was examined in root, shoot, leaves and pod of yard long bean with and without the inoculation of strain MELD1. The model plant inoculated with MELD1 had significant increases in biomass, root length, seed number, and increased mercury uptake limited to roots. Biolog plate assay were used to assess the sole-carbon source utilization pattern of the isolate and Indole-3-acetic acid (IAA productivity was analyzed to examine if the strain could contribute to plant growth. The results of this study suggest that, as a rhizosphere-associated symbiont, the synergistic activity between the plant and MELD1 can improve the efficiency for phytoprotection, phytostabilization and phytoremediation of mercury.

  9. A rhizosphere-associated symbiont, Photobacterium spp. strain MELD1, and its targeted synergistic activity for phytoprotection against mercury.

    Science.gov (United States)

    Mathew, Dony Chacko; Ho, Ying-Ning; Gicana, Ronnie Gicaraya; Mathew, Gincy Marina; Chien, Mei-Chieh; Huang, Chieh-Chen

    2015-01-01

    Though heavy metal such as mercury is toxic to plants and microorganisms, the synergistic activity between them may offer benefit for surviving. In this study, a mercury-reducing bacterium, Photobacterium spp. strain MELD1, with an MIC of 33 mg x kg(-1) mercury was isolated from a severely mercury and dioxin contaminated rhizosphere soil of reed (Phragmites australis). While the whole genome sequencing of MELD1 confirmed the presence of a mer operon, the mercury reductase MerA gene showed 99% sequence identity to Vibrio shilloni AK1 and implicates its route resulted from the event of horizontal gene transfer. The efficiency of MELD1 to vaporize mercury (25 mg x kg(-1), 24 h) and its tolerance to toxic metals and xenobiotics such as lead, cadmium, pentachlorophenol, pentachloroethylene, 3-chlorobenzoic acid, 2,3,7,8-tetrachlorodibenzo-p-dioxin and 1,2,3,7,8,9-hexachlorodibenzo-p-dioxin is promising. Combination of a long yard bean (Vigna unguiculata ssp. Sesquipedalis) and strain MELD1 proved beneficial in the phytoprotection of mercury in vivo. The effect of mercury (Hg) on growth, distribution and tolerance was examined in root, shoot, leaves and pod of yard long bean with and without the inoculation of strain MELD1. The model plant inoculated with MELD1 had significant increases in biomass, root length, seed number, and increased mercury uptake limited to roots. Biolog plate assay were used to assess the sole-carbon source utilization pattern of the isolate and Indole-3-acetic acid (IAA) productivity was analyzed to examine if the strain could contribute to plant growth. The results of this study suggest that, as a rhizosphere-associated symbiont, the synergistic activity between the plant and MELD1 can improve the efficiency for phytoprotection, phytostabilization and phytoremediation of mercury.

  10. A Rhizosphere-Associated Symbiont, Photobacterium spp. Strain MELD1, and Its Targeted Synergistic Activity for Phytoprotection against Mercury

    Science.gov (United States)

    Mathew, Dony Chacko; Ho, Ying-Ning; Gicana, Ronnie Gicaraya; Mathew, Gincy Marina; Chien, Mei-Chieh; Huang, Chieh-Chen

    2015-01-01

    Though heavy metal such as mercury is toxic to plants and microorganisms, the synergistic activity between them may offer benefit for surviving. In this study, a mercury-reducing bacterium, Photobacterium spp. strain MELD1, with an MIC of 33 mg . kg-1 mercury was isolated from a severely mercury and dioxin contaminated rhizosphere soil of reed (Phragmites australis). While the whole genome sequencing of MELD1 confirmed the presence of a mer operon, the mercury reductase MerA gene showed 99% sequence identity to Vibrio shilloni AK1 and implicates its route resulted from the event of horizontal gene transfer. The efficiency of MELD1 to vaporize mercury (25 mg . kg-1, 24 h) and its tolerance to toxic metals and xenobiotics such as lead, cadmium, pentachlorophenol, pentachloroethylene, 3-chlorobenzoic acid, 2,3,7,8-tetrachlorodibenzo-p-dioxin and 1,2,3,7,8,9-hexachlorodibenzo-p-dioxin is promising. Combination of a long yard bean (Vigna unguiculata ssp. Sesquipedalis) and strain MELD1 proved beneficial in the phytoprotection of mercury in vivo. The effect of mercury (Hg) on growth, distribution and tolerance was examined in root, shoot, leaves and pod of yard long bean with and without the inoculation of strain MELD1. The model plant inoculated with MELD1 had significant increases in biomass, root length, seed number, and increased mercury uptake limited to roots. Biolog plate assay were used to assess the sole-carbon source utilization pattern of the isolate and Indole-3-acetic acid (IAA) productivity was analyzed to examine if the strain could contribute to plant growth. The results of this study suggest that, as a rhizosphere-associated symbiont, the synergistic activity between the plant and MELD1 can improve the efficiency for phytoprotection, phytostabilization and phytoremediation of mercury. PMID:25816328

  11. Synergistic effects of mica and wollastonite fillers on thermal performance of intumescent fire retardant coating

    Energy Technology Data Exchange (ETDEWEB)

    Zia-ul-Mustafa, M., E-mail: engr.ziamustafa@gmail.com; Ahmad, Faiz; Megat-Yusoff, Puteri S. M.; Aziz, Hammad [Mechanical Engineering Department, Universiti Teknologi PETRONAS, Bandar Seri Iskandar, 31750 Tronoh, Perak (Malaysia)

    2015-07-22

    In this study, intumescent fire retardant coatings (IFRC) were developed to investigate the synergistic effects of reinforced mica and wollastonite fillers based IFRC towards heat shielding, char expansion, char composition and char morphology. Ammonium poly-phosphate (APP) was used as acid source, expandable graphite (EG) as carbon source, melamine as blowing agent, boric acid as additive and Hardener H-2310 polyamide amine in bisphenol A epoxy resin BE-188(BPA) was used as curing agent. Bunsen burner fire test was used for thermal performance according to UL-94 for 1 h. Field Emission Scanning Electron Microscopy (FESEM) was used to observe char microstructure. X-Ray Diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) were used to analyse char composition. The results showed that addition of clay filler in IFRC enhanced the fire protection performance of intumescent coating. X-Ray Diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) results showed the presence of boron phosphate, silicon phosphate oxide, aluminium borate in the char that improved the thermal performance of intumescent fire retardant coating (IFRC). Resultantly, the presence of these developed compounds enhanced the Integrity of structural steel upto 500°C.

  12. Towards enhancing photocatalytic hydrogen generation: Which is more important, alloy synergistic effect or plasmonic effect?

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Zhenhe; Kibria, Md Golam; AlOtaibi, Bandar; Duchesne, Paul N.; Besteiro, Lucas V.; Gao, Yu; Zhang, Qingzhe; Mi, Zetian; Zhang, Peng; Govorov, Alexander O.; Mai, Liqiang; Chaker, Mohamed; Ma, Dongling

    2018-02-01

    Synergistic effect in alloys and plasmonic effect have both been explored for increasing the efficiency of water splitting. In depth understanding and comparison of their respective contributions in certain promising systems is highly desired for catalyst development, yet rarely investigated so far. We report herein our thorough investigations on a series of highly interesting nanocomposites composed of Pt, Au and C3N4 nanocomponents, which are designed to benefit from both synergistic and plasmonic effects. Detailed analyses led to an important conclusion that the contribution from the synergistic effect was at least 3.5 times that from the plasmonic effect in the best performing sample, Pt50Au50 alloy decorated C3N4. It showed remarkable turnover frequency of >1.6 mmol h-1 g-1 at room temperature. Our work provides physical insights for catalyst development by rationally designing samples to compare long-known synergistic effect with recently emerging, attractive plasmonic effect and represents the first case study in the field.

  13. Tumour–stromal interactions in acid-mediated invasion: A mathematical model

    KAUST Repository

    Martin, Natasha K.

    2010-12-01

    It is well established that the tumour microenvironment can both promote and suppress tumour growth and invasion, however, most mathematical models of invasion view the normal tissue as inhibiting tumour progression via immune modulation or spatial constraint. In particular, the production of acid by tumour cells and the subsequent creation of a low extracellular pH environment has been explored in several \\'acid-mediated tumour invasion\\' models where the acidic environment facilitates normal cell death and permits tumour invasion. In this paper, we extend the acid-invasion model developed by Gatenby and Gawlinski (1996) to include both the competitive and cooperative interactions between tumour and normal cells, by incorporating the influence of extracellular matrix and protease production at the tumour-stroma interface. Our model predicts an optimal level of tumour acidity which produces both cell death and matrix degradation. Additionally, very aggressive tumours prevent protease production and matrix degradation by excessive normal cell destruction, leading to an acellular (but matrix filled) gap between the tumour and normal tissue, a feature seen in encapsulated tumours. These results suggest, counterintuitively, that increasing tumour acidity may, in some cases, prevent tumour invasion.

  14. Preclinical demonstration of synergistic Active Nutrients/Drug (AND combination as a potential treatment for malignant pleural mesothelioma.

    Directory of Open Access Journals (Sweden)

    Viviana Volta

    Full Text Available Malignant pleural mesothelioma (MPM is a poor prognosis disease lacking adequate therapy. We have previously shown that ascorbic acid administration is toxic to MPM cells. Here we evaluated a new combined therapy consisting of ascorbate/epigallocatechin-3-gallate/gemcitabine mixture (called AND, for Active Nutrients/Drug. In vitro effects of AND therapy on various MPM cell lines revealed a synergistic cytotoxic mechanism. In vivo experiments on a xenograft mouse model for MPM, obtained by REN cells injection in immunocompromised mice, showed that AND strongly reduced the size of primary tumor as well as the number and size of metastases, and prevented abdominal hemorrhage. Kaplan Meier curves and the log-rank test indicated a marked increase in the survival of AND-treated animals. Histochemical analysis of dissected tumors showed that AND induced a shift from cell proliferation to apoptosis in cancer cells. Lysates of tumors from AND-treated mice, analyzed with an antibody array, revealed decreased TIMP-1 and -2 expressions and no effects on angiogenesis regulating factors. Multiplex analysis for signaling protein phosphorylation exhibited inactivation of cell proliferation pathways. The complex of data showed that the AND treatment is synergistic in vitro on MPM cells, and blocks in vivo tumor progression and metastasization in REN-based xenografts. Hence, the AND combination is proposed as a new treatment for MPM.

  15. Inorganic Arsenic–Related Changes in the Stromal Tumor Microenvironment in a Prostate Cancer Cell–Conditioned Media Model

    Science.gov (United States)

    Shearer, Joseph J.; Wold, Eric A.; Umbaugh, Charles S.; Lichti, Cheryl F.; Nilsson, Carol L.; Figueiredo, Marxa L.

    2015-01-01

    Background: The tumor microenvironment plays an important role in the progression of cancer by mediating stromal–epithelial paracrine signaling, which can aberrantly modulate cellular proliferation and tumorigenesis. Exposure to environmental toxicants, such as inorganic arsenic (iAs), has also been implicated in the progression of prostate cancer. Objective: The role of iAs exposure in stromal signaling in the tumor microenvironment has been largely unexplored. Our objective was to elucidate molecular mechanisms of iAs-induced changes to stromal signaling by an enriched prostate tumor microenvironment cell population, adipose-derived mesenchymal stem/stromal cells (ASCs). Results: ASC-conditioned media (CM) collected after 1 week of iAs exposure increased prostate cancer cell viability, whereas CM from ASCs that received no iAs exposure decreased cell viability. Cytokine array analysis suggested changes to cytokine signaling associated with iAs exposure. Subsequent proteomic analysis suggested a concentration-dependent alteration to the HMOX1/THBS1/TGFβ signaling pathway by iAs. These results were validated by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) and Western blotting, confirming a concentration-dependent increase in HMOX1 and a decrease in THBS1 expression in ASC following iAs exposure. Subsequently, we used a TGFβ pathway reporter construct to confirm a decrease in stromal TGFβ signaling in ASC following iAs exposure. Conclusions: Our results suggest a concentration-dependent alteration of stromal signaling: specifically, attenuation of stromal-mediated TGFβ signaling following exposure to iAs. Our results indicate iAs may enhance prostate cancer cell viability through a previously unreported stromal-based mechanism. These findings indicate that the stroma may mediate the effects of iAs in tumor progression, which may have future therapeutic implications. Citation: Shearer JJ, Wold EA, Umbaugh CS, Lichti CF, Nilsson CL

  16. Human Breast Cancer Cells Are Redirected to Mammary Epithelial Cells upon Interaction with the Regenerating Mammary Gland Microenvironment In-Vivo

    Science.gov (United States)

    Bussard, Karen M.; Smith, Gilbert H.

    2012-01-01

    Breast cancer is the second leading cause of cancer deaths in the United States. At present, the etiology of breast cancer is unknown; however the possibility of a distinct cell of origin, i.e. a cancer stem cell, is a heavily investigated area of research. Influencing signals from the tissue niche are known to affect stem cells. Literature has shown that cancer cells lose their tumorigenic potential and display ‘normal’ behavior when placed into ‘normal’ ontogenic environments. Therefore, it may be the case that the tissue microenvironment is able to generate signals to redirect cancer cell fate. Previously, we showed that pluripotent human embryonal carcinoma cells could be redirected by the regenerating mammary gland microenvironment to contribute epithelial progeny for ‘normal’ gland development in-vivo. Here, we show that that human metastatic, non-metastatic, and metastasis-suppressed breast cancer cells proliferate and contribute to normal mammary gland development in-vivo without tumor formation. Immunochemistry for human-specific mitochondria, keratin 8 and 14, as well as human-specific milk proteins (alpha-lactalbumin, impregnated transplant hosts) confirmed the presence of human cell progeny. Features consistent with normal mammary gland development as seen in intact hosts (duct, lumen formation, development of secretory acini) were recapitulated in both primary and secondary outgrowths from chimeric implants. These results suggest the dominance of the tissue microenvironment over cancer cell fate. This work demonstrates that cultured human breast cancer cells (metastatic and non-metastatic) respond developmentally to signals generated by the mouse mammary gland microenvironment during gland regeneration in-vivo. PMID:23155468

  17. Human breast cancer cells are redirected to mammary epithelial cells upon interaction with the regenerating mammary gland microenvironment in-vivo.

    Directory of Open Access Journals (Sweden)

    Karen M Bussard

    Full Text Available Breast cancer is the second leading cause of cancer deaths in the United States. At present, the etiology of breast cancer is unknown; however the possibility of a distinct cell of origin, i.e. a cancer stem cell, is a heavily investigated area of research. Influencing signals from the tissue niche are known to affect stem cells. Literature has shown that cancer cells lose their tumorigenic potential and display 'normal' behavior when placed into 'normal' ontogenic environments. Therefore, it may be the case that the tissue microenvironment is able to generate signals to redirect cancer cell fate. Previously, we showed that pluripotent human embryonal carcinoma cells could be redirected by the regenerating mammary gland microenvironment to contribute epithelial progeny for 'normal' gland development in-vivo. Here, we show that that human metastatic, non-metastatic, and metastasis-suppressed breast cancer cells proliferate and contribute to normal mammary gland development in-vivo without tumor formation. Immunochemistry for human-specific mitochondria, keratin 8 and 14, as well as human-specific milk proteins (alpha-lactalbumin, impregnated transplant hosts confirmed the presence of human cell progeny. Features consistent with normal mammary gland development as seen in intact hosts (duct, lumen formation, development of secretory acini were recapitulated in both primary and secondary outgrowths from chimeric implants. These results suggest the dominance of the tissue microenvironment over cancer cell fate. This work demonstrates that cultured human breast cancer cells (metastatic and non-metastatic respond developmentally to signals generated by the mouse mammary gland microenvironment during gland regeneration in-vivo.

  18. Engineering Enriched Microenvironments with Gradients of Platelet Lysate in Hydrogel Fibers.

    Science.gov (United States)

    Santo, Vítor E; Babo, Pedro; Amador, Miguel; Correia, Cláudia; Cunha, Bárbara; Coutinho, Daniela F; Neves, Nuno M; Mano, João F; Reis, Rui L; Gomes, Manuela E

    2016-06-13

    Gradients of physical and chemical cues are characteristic of specific tissue microenvironments and contribute toward morphogenesis and tissue regeneration upon injury. Recent advances on microfluidics and hydrogel manipulation raised the possibility of generating biomimetic biomaterials enriched with bioactive factors and encapsulating cells following designs specifically tailored for a target application. The novelty of this work relies on the combination of methacrylated gellan gum (MeGG) with platelet lysate (PL), aiming to generate novel advanced 3D PL-enriched photo-cross-linkable hydrogels and overcoming the lack of adhesion sites provided by the native MeGG hydrogels. This combination takes advantage of the availability, enriched growth factor composition, and potential autologous application of PL while simultaneously preserving the ability provided by MeGG to tailor mechanical properties, protein release kinetics, and shape of the construct according to the desired goal. Incorporation of PL in the hydrogels significantly improved cellular adhesion and viability in the constructs. The use of microfluidic tools allowed the design of a fiber-like hydrogel incorporating a gradient of PL along the length of the fiber. These spatial protein gradients led to the viability and cell number gradients caused by maintenance of human umbilical vein endothelial cells (HUVECs) survival in the fibers toward the PL-enriched sections in comparison with the nonloaded MeGG sections of the fibers. Altogether, we propose a proof of concept strategy to design a PL gradient biomaterial with potential in tissue engineering approaches and analysis of cell-microenvironment interactions.

  19. Choline-Deficient-Diet-Induced Fatty Liver Is a Metastasis-Resistant Microenvironment.

    Science.gov (United States)

    Nakamura, Miki; Suetsugu, Atsushi; Hasegawa, Kosuke; Matsumoto, Takuro; Aoki, Hitomi; Kunisada, Takahiro; Shimizu, Masahito; Saji, Shigetoyo; Moriwaki, Hisataka; Hoffman, Robert M

    2017-07-01

    Fatty liver disease is increasing in the developed and developing world. Liver metastasis from malignant lymphoma in the fatty liver is poorly understood. In a previous report, we developed color-coded imaging of the tumor microenvironment (TME) of the murine EL4-RFP malignant lymphoma during metastasis, including the lung. In the present report, we investigated the potential and microenvironment of the fatty liver induced by a choline-deficient diet as a metastatic site in this mouse lymphoma model. C57BL/6-GFP transgenic mice were fed with a choline-deficient diet in order to establish a fatty liver model. EL4-RFP cells were injected in the spleen of normal mice and fatty-liver mice. Metastases in mice with fatty liver or normal liver were imaged with the Olympus SZX7 microscope and the Olympus FV1000 confocal microscope. Metastases of EL4-RFP were observed in the liver, ascites and bone marrow. Primary tumors were imaged in the spleen at the injection site. The fewest metastases were observed in the fatty liver. In addition, the fewest cancer-associated fibroblasts (CAFs) were observed in the fatty liver. The relative metastatic resistance of the fatty liver may be due to the reduced number of CAFs in the fatty livers. The mechanism of the effect of the choline-deficient diet is discussed. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  20. Abdominal and internal intercostal motoneurones are strong synergists for expiration but are not synergists for Group I monosynaptic afferent inputs