WorldWideScience

Sample records for synergistic antitumor effect

  1. Synergistic Antitumor Effect of Doxorubicin and Tacrolimus (FK506 on Hepatocellular Carcinoma Cell Lines

    Francesca Capone

    2014-01-01

    Full Text Available Hepatocellular carcinoma is the fifth most common cancer worldwide and shows a complex clinical course, poor response to pharmacological treatment, and a severe prognosis. Thus, the aim of this study was to investigate whether tacrolimus (FK506 has synergistic antitumor effects with doxorubicin on two human hepatocellular carcinoma cell lines, Huh7 and HepG2. Cell viability was analyzed by Sulforhodamine B assay and synergic effect was evaluated by the software CalcuSyn. Cell apoptosis was evaluated using Annexin V and Dead Cell assay. Apoptosis-related protein PARP-1 cleaved and autophagy-related protein expressions (Beclin-1 and LC3B were measured by western blotting analysis. Cytokines concentration in cellular supernatants after treatments was studied by Bio-Plex assay. Interestingly the formulation with doxorubicin and tacrolimus induced higher cytotoxicity level on tumor cells than single treatment. Moreover, our results showed that the mechanisms involved were (i a strong cell apoptosis induction, (ii contemporaneous decrease of autophagy activation, understood as prosurvival process, and (iii downregulation of proinflammatory cytokines. In conclusion, future studies could relate to the doxorubicin/tacrolimus combination effects in mice models bearing HCC in order to see if this formulation could be useful in HCC treatment.

  2. Novel synergistic antitumor effects of rapamycin with bortezomib on hepatocellular carcinoma cells and orthotopic tumor model

    Wang Cun

    2012-05-01

    Full Text Available Abstract Background Despite recent advances in the treatment of hepatocellular carcinoma (HCC, the chemotherapy efficacy against HCC is still unsatisfactory. The mammalian target of rapamycin (mTOR has been emerged as an important cancer therapeutic target. However, HCC cells often resistant to rapamycin because of the paradoxical activation of Akt by rapamycin. In this study, we investigated whether bortezomib could enhance the antitumor effects of rapamycin. Methods The effects of rapamycin and bortezomib on HCC proliferation, apoptosis, migration, and invasiveness in vitro were assessed by CCK-8 analysis, flow cytometry, Hoechst 33342 staining and transwell assays, respectively. Total and phosphorylated protein levels of Akt were detected by Western blotting. The effects of rapamycin and/or bortezomib on the mRNA expression levels of p53, p27, p21 and Bcl-2 family in HCCLM3 cells were evaluated by RT-PCR. The roles of rapamycin and bortezomib on HCC growth and metastasis in xenograft models were evaluated by tumor volumes and fluorescent signals. The effects of rapamycin and bortezomib on cell proliferation and apoptosis in vivo were test by PCNA and TUNEL staining. Results Bortezomib synergized with rapamycin to reduce cell growth, induce apoptosis, and inhibit cell mobility in vitro. Further mechanistic studies showed that bortezomib inhibited rapamycin-induced phosphorylated Akt, which in turn enhanced apoptosis of HCC cell lines. The alteration of the mRNA expression of cell cycle inhibitors p53, p27, p21 and apoptosis associated genes Bcl-2, Bax were also involved in the synergistic antitumor effects of rapamycin and bortezomib. P53 inhibitor PFT-α significantly attenuate the effect of rapamycin and bortezomib on cell apoptosis, which indicated that the pro-apoptotic effect of rapamycin and bortezomib may be p53-dependent. Treatment of HCCLM3-R bearing nude mice with rapamycin and bortezomib significantly enhanced tumor growth

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

    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 anti-tumor effects of melatonin and PUFAs from walnuts in a murine mammary adenocarcinoma model.

    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. Synergistic effect of intervention of glypican-3 gene transcription combined with antitumor drugs in inhibiting hepatoma cell proliferation

    YANG Jie

    2016-12-01

    .20 μmol/L, 7.85±2.00 nmol/L, and 18.36±0.56 μmol/L, respectively, and their combination with shRNA1 had an HepG2 cell inhibition rate of 95.11%. ConclusionIntervention of GPC3 gene transcription with specific shRNA can inhibit hepatoma cell proliferation, migration and movement, and invasion ability, induce hepatoma cell apoptosis, and inhibit hepatoma cell proliferation when combined with antitumor drugs in a synergistic manner. This suggests that GPC3 may be an effective therapeutic target for liver cancer and that combined targeted therapy can provide better strategies for the treatment of liver cancer.

  6. Combined SEP and anti-PD-L1 antibody produces a synergistic antitumor effect in B16-F10 melanoma-bearing mice.

    Hu, Zhengping; Ye, Liang; Xing, Yingying; Hu, Jinhang; Xi, Tao

    2018-01-09

    The increased PD-L1 induces poorer prognosis in melanoma. The treatment with PD-1/PD-L1 antibodies have a low response rate. The combination immunotherapies are the encouraging drug development strategy to receive maximal therapeutic benefit. In this study, we investigated the enhanced antitumor and immunomodulatory activity of combined SEP and αPD-L1 in B16-F10 melanoma-bearing mice. The results shown that combined SEP and αPD-L1 presented significant synergistic antitumor effects, increased the frequency of CD8 + and CD4 + T cells in spleen and tumor, cytotoxic activity of CTL in spleen, and IL-2 and IFN-γ levels in splenocytes and tumor. The combination treatment also produced synergistic increase in P-ERK1/2 level in spleen. Immunohistochemistry shown that SEP induced the PD-L1 expression in melanoma tissue possibly by promoting IFN-γ excretion, which led to the synergistic anti-tumor effects of aPD-L1 and SEP. Furthermore, in the purified T lymphocyte from the naive mice, the combination of SEP and αPD-L1 had more potent than SEP or αPD-L1 in promoting T lymphocyte proliferation and cytokines secretion including IL-2 and IFN-γ, at least partially by activating MEK/ERK pathway. Our study provides the scientific basis for a clinical trial that would involve combination of anti-PD-L1 mAb and SEP for sustained melanoma control.

  7. Synergistic antitumor effect of 3-bromopyruvate and 5-fluorouracil against human colorectal cancer through cell cycle arrest and induction of apoptosis.

    Chong, Dianlong; Ma, Linyan; Liu, Fang; Zhang, Zhirui; Zhao, Surong; Huo, Qiang; Zhang, Pei; Zheng, Hailun; Liu, Hao

    2017-09-01

    3-Bromopyruvic acid (3-BP) is a well-known inhibitor of energy metabolism. It has been proposed as an anticancer agent as well as a chemosensitizer for use in combination with anticancer drugs. 5-Fluorouracil (5-FU) is the first-line chemotherapeutic agent for colorectal cancer; however, most patients develop resistance to 5-FU through various mechanisms. The aim of this study was to investigate whether 3-BP has a synergistic antitumor effect with 5-FU on human colorectal cancer cells. In our study, combined 3-BP and 5-FU treatment upregulated p53 and p21, whereas cyclin-dependent kinase CDK4 and CDK2 were downregulated, which led to G0/G1 phase arrest. Furthermore, there was an increase in reactive oxygen species levels and a decrease in adenosine triphosphate levels. It was also observed that Bax expression increased, whereas Bcl-2 expression reduced, which were indicative of mitochondria-dependent apoptosis. In addition, the combination of 3-BP and 5-FU significantly suppressed tumor growth in the BALB/c mice in vivo. Therefore, 3-BP inhibits tumor proliferation and induces S and G2/M phase arrest. It also exerts a synergistic antitumor effect with 5-FU on SW480 cells.

  8. Spin-labeled 1-alkyl-1-nitrosourea synergists of antitumor antibiotics.

    Gadjeva, V; Koldamova, R

    2001-01-01

    A new method for synthesis of four spin-labeled structural analogues of the antitumor drug 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), using ethyl nitrite for nitrosation of the intermediate spin-labeled ureas has been described. In vitro synergistic effects of 1-ethyl-3-[4-(2,2,6,6-tetramethylpiperidine-1-oxyl)]-1-nitrosourea (3b) on the cytotoxicity of bleomycin and farmorubicin were found in human lymphoid leukemia tumor cells. We measured the tissue distribution of 3b in organ homogenates of C57BL mice by an electron paramagnetic resonance method. The spin-labeled nitrosourea was mainly localized in the lungs. Our results strongly support the development and validation of a new approach for synthesis of less toxic nitrosourea derivatives as potential synergists of antitumor drugs.

  9. Albumin nanoparticles with synergistic antitumor efficacy against metastatic lung cancers.

    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. Dual Inhibition of PI3K/AKT and MEK/ERK Pathways Induces Synergistic Antitumor Effects in Diffuse Intrinsic Pontine Glioma Cells

    Y. Linda Wu

    2017-04-01

    Full Text Available Diffuse intrinsic pontine glioma (DIPG is a devastating disease with an extremely poor prognosis. Recent studies have shown that platelet-derived growth factor receptor (PDGFR and its downstream effector pathway, PI3K/AKT/mTOR, are frequently amplified in DIPG, and potential therapies targeting this pathway have emerged. However, the addition of targeted single agents has not been found to improve clinical outcomes in DIPG, and targeting this pathway alone has produced insufficient clinical responses in multiple malignancies investigated, including lung, endometrial, and bladder cancers. Acquired resistance also seems inevitable. Activation of the Ras/Raf/MEK/ERK pathway, which shares many nodes of cross talk with the PI3K/AKT pathway, has been implicated in the development of resistance. In the present study, perifosine, a PI3K/AKT pathway inhibitor, and trametinib, a MEK inhibitor, were combined, and their therapeutic efficacy on DIPG cells was assessed. Growth delay assays were performed with each drug individually or in combination. Here, we show that dual inhibition of PI3K/AKT and MEK/ERK pathways synergistically reduced cell viability. We also reveal that trametinib induced AKT phosphorylation in DIPG cells that could not be effectively attenuated by the addition of perifosine, likely due to the activation of other compensatory mechanisms. The synergistic reduction in cell viability was through the pronounced induction of apoptosis, with some effect from cell cycle arrest. We conclude that the concurrent inhibition of the PI3K/AKT and MEK/ERK pathways may be a potential therapeutic strategy for DIPG.

  11. HDAC inhibitor L-carnitine and proteasome inhibitor bortezomib synergistically exert anti-tumor activity in vitro and in vivo.

    Hongbiao Huang

    Full Text Available Combinations of proteasome inhibitors and histone deacetylases (HDAC inhibitors appear to be the most potent to produce synergistic cytotoxicity in preclinical trials. We have recently confirmed that L-carnitine (LC is an endogenous HDAC inhibitor. In the current study, the anti-tumor effect of LC plus proteasome inhibitor bortezomib (velcade, Vel was investigated both in cultured hepatoma cancer cells and in Balb/c mice bearing HepG2 tumor. Cell death and cell viability were assayed by flow cytometry and MTS, respectively. Gene, mRNA expression and protein levels were detected by gene microarray, quantitative real-time PCR and Western blot, respectively. The effect of Vel on the acetylation of histone H3 associated with the p21(cip1 gene promoter was examined by using ChIP assay and proteasome peptidase activity was detected by cell-based chymotrypsin-like (CT-like activity assay. Here we report that (i the combination of LC and Vel synergistically induces cytotoxicity in vitro; (ii the combination also synergistically inhibits tumor growth in vivo; (iii two major pathways are involved in the synergistical effects of the combinational treatment: increased p21(cip1 expression and histone acetylation in vitro and in vivo and enhanced Vel-induced proteasome inhibition by LC. The synergistic effect of LC and Vel in cancer therapy should have great potential in the future clinical trials.

  12. The antitumor natural product tanshinone IIA inhibits protein kinase C and acts synergistically with 17-AAG.

    Lv, Chao; Zeng, Hua-Wu; Wang, Jin-Xin; Yuan, Xing; Zhang, Chuang; Fang, Ting; Yang, Pei-Ming; Wu, Tong; Zhou, Yu-Dong; Nagle, Dale G; Zhang, Wei-Dong

    2018-02-07

    Tanshinone IIA (Tan IIA), the primary bioactive compound derived from the traditional Chinese medicine (TCM) Salvia miltiorrhiza Bunge, has been reported to possess antitumor activity. However, its antitumor mechanisms are not fully understood. To resolve the potential antitumor mechanism(s) of Tan IIA, its gene expression profiles from our database was analyzed by connectivity map (CMAP) and the CMAP-based mechanistic predictions were confirmed/validated in further studies. Specifically, Tan IIA inhibited total protein kinase C (PKC) activity and selectively suppressed the expression of cytosolic and plasma membrane PKC isoforms ζ and ε. The Ras/MAPK pathway that is closely regulated by the PKC signaling is also inhibited by Tan IIA. While Tan IIA did not inhibit heat shock protein 90 (Hsp90), it synergistically enhanced the antitumor efficacy of the Hsp90 inhibitors 17-AAG and ganetespib in human breast cancer MCF-7 cells. In addition, Tan IIA significantly inhibited PI3K/Akt/mTOR signaling, and induced both cell cycle arrest and autophagy. Collectively, these studies provide new insights into the molecular mechanisms responsible for antitumor activity of Tan IIA.

  13. Combined Inhibition of CDK4/6 and PI3K/AKT/mTOR Pathways Induces a Synergistic Anti-Tumor Effect in Malignant Pleural Mesothelioma Cells

    Mara A. Bonelli

    2017-08-01

    Full Text Available Malignant pleural mesothelioma (MPM is a progressive malignancy associated to the exposure of asbestos fibers. The most frequently inactivated tumor suppressor gene in MPM is CDKN2A/ARF, encoding for the cell cycle inhibitors p16INK4a and p14ARF, deleted in about 70% of MPM cases. Considering the high frequency of alterations of this gene, we tested in MPM cells the efficacy of palbociclib (PD-0332991, a highly selective inhibitor of cyclin-dependent kinase (CDK 4/6. The analyses were performed on a panel of MPM cell lines and on two primary culture cells from pleural effusion of patients with MPM. All the MPM cell lines, as well as the primary cultures, were sensitive to palbociclib with a significant blockade in G0/G1 phase of the cell cycle and with the acquisition of a senescent phenotype. Palbociclib reduced the phosphorylation levels of CDK6 and Rb, the expression of myc with a concomitant increased phosphorylation of AKT. Based on these results, we tested the efficacy of the combination of palbociclib with the PI3K inhibitors NVP-BEZ235 or NVP-BYL719. After palbociclib treatment, the sequential association with PI3K inhibitors synergistically hampered cell proliferation and strongly increased the percentage of senescent cells. In addition, AKT activation was repressed while p53 and p21 were up-regulated. Interestingly, two cycles of sequential drug administration produced irreversible growth arrest and senescent phenotype that were maintained even after drug withdrawal. These findings suggest that the sequential association of palbociclib with PI3K inhibitors may represent a valuable therapeutic option for the treatment of MPM.

  14. Synthesis and antitumor evaluation of some new N4 substituted sulfa pyridine derivatives with studying the synergistic effect of γ-irradiation

    Elsaid Agha, H.M.S.

    2011-01-01

    The aim of the present investigation is to synthesize a new class of N 4 substituted sulfa pyridine derivatives with anticipated cytotoxic activity. All the newly synthesized compounds were screened for their in-vitro cytotoxic activity against breast cancer cell line (MCF-7) compared to the reference drug Doxorubicin. Also the synergism of the most potent synthesized compounds with γ- radiation was studied. Moreover, a molecular docking study was carried out by docking the most active synthesized compounds in the active site of Cyclin Dependent Kinase 2 receptor to assess their inhibitory effect upon this enzyme as this may have a role in their anticancer activity.

  15. Synergistic antitumor activity of histamine plus melphalan in isolated limb perfusion: preclinical studies.

    Brunstein, Flavia; Hoving, Saske; Seynhaeve, Ann L B; van Tiel, Sandra T; Guetens, Gunther; de Bruijn, Ernst A; Eggermont, Alexander M M; ten Hagen, Timo L M

    2004-11-03

    We have previously shown how tumor response of isolated limb perfusion (ILP) with melphalan was improved when tumor necrosis factor alpha (TNF-alpha) was added. Taking into account that other vasoactive drugs could also improve tumor response to ILP, we evaluated histamine (Hi) as an alternative to TNF-alpha. We used a rat ILP model to assess the combined effects of Hi and melphalan (n = 6) on tumor regression, melphalan uptake (n = 6), and tissue histology (n = 2) compared with Hi or melphalan alone. We also evaluated the growth of BN-175 tumor cells as well as apoptosis, necrosis, cell morphology, and paracellular permeability of human umbilical vein endothelial cells (HUVECs) after Hi treatment alone and in combination with melphalan. The antitumor effect of the combination of Hi and melphalan in vivo was synergistic, and Hi-dependent reduction in tumor volume was blocked by H1 and H2 receptor inhibitors. Tumor regression was observed in 66% of the animals treated with Hi and melphalan, compared with 17% after treatment with Hi or melphalan alone. Tumor melphalan uptake increased and vascular integrity in the surrounding tissue was reduced after ILP treatment with Hi and melphalan compared with melphalan alone. In vitro results paralleled in vivo results. BN-175 tumor cells were more sensitive to the cytotoxicity of combined treatment than HUVECs, and Hi treatment increased the permeability of HUVECs. Hi in combination with melphalan in ILP improved response to that of melphalan alone through direct and indirect mechanisms. These results warrant further evaluation in the clinical ILP setting and, importantly, in organ perfusion.

  16. OSU-2S/sorafenib synergistic antitumor combination against hepatocellular carcinoma: The role of PKCδ/p53

    Hany A Omar

    2016-11-01

    Full Text Available Background: Sorafenib (Nexavar® is an FDA-approved systemic therapy for advanced hepatocellular carcinoma (HCC. However, the low efficacy and adverse effects at high doses limit the clinical application of sorafenib and strongly recommend its combination with other agents aiming at ameliorating its drawbacks. OSU-2S, a PKCδ activator, was selected as a potential candidate anticancer agent to be combined with sorafenib to promote the anti-cancer activity through synergistic interaction. Methods: The antitumor effects of sorafenib, OSU-2S and their combination were assessed by MTT assay, caspase activation, Western blotting, migration/invasion assays in four different HCC cell lines. The synergistic interactions were determined by Calcusyn analysis. PKCδ knockdown was used to elucidate the role of PKCδ activation as a mechanism for the synergy. The knockdown/over-expression of p53 was used to explain the differential sensitivity of HCC cell lines to sorafenib and/or OSU-2S. Results: OSU-2S synergistically enhanced the anti-proliferative effects of sorafenib in the four used HCC cell lines with combination indices < 1. This effect was accompanied by parallel increases in caspase 3/7 activity, PARP cleavage, PKCδ activation and HCC cell migration/invasion. In addition, PKCδ knockdown abolished the synergy between sorafenib and OSU-2S. Furthermore, p53 restoration in Hep3B cells through the over-expression rendered them more sensitive to both agents while p53 knockdown from HepG2 cells increased their resistance to both agents. Conclusions: OSU-2S augments the anti-proliferative effect of sorafenib in HCC cell lines, in part, through the activation of PKCδ. The p53 status in HCC cells predicts their sensitivity towards both sorafenib and OSU-2S. The proposed combination represents a therapeutically relevant approach that can lead to a new HCC therapeutic protocol.

  17. Co-delivery of cisplatin and CJM-126 via photothermal conversion nanoparticles for enhanced synergistic antitumor efficacy

    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.

  18. Overview of synergistic aging effects

    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

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

    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. Effects of Androgen Ablation on Anti-Tumor Immunity

    Kast, Martin

    2004-01-01

    .... This AA induced autoimmune-like response exerts limited anti-tumor activity in a murine prostate cancer model, but could be synergistic with CTLA-4 blockade that promotes the development of autoreactive T cell...

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

    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

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

    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

  3. Radiation protection and antitumor effects in Hatakeshimeji (Lyophyllum decastes sing)

    Ukawa, Yuuichi; Gu, Yeunhwa; Suzuki, Ikukatsu; Park, Sangrae; Hasegawa, Takeo; Tsukada, Sekihito; Terai, Kaoru; Tawaraya, Hitoshi

    2002-01-01

    The effect on an anti-tumor is admitted in the lyophyllum decastes sing extraction thing, and it has the action mechanism cleared to depend on the immunity action. The existence of the synergistic effect in effect on an anti-tumor radiation irradiation, an individual with the medication of lyophyllum decastes sing and effect on combination and the effect on protection of the leukocyte decrease by the radiation was examined by this research. After about 2x10 6 inoculated sarcoma 180 on the ICR mice, a lyophyllum decastes sing extraction thing gave 100mg/kg for 2 weeks in endoceliac at the every other day. After that, the radiation irradiation of 2 Gy was done three times, and it went to the sutra time target the number of the leukocytes, the lymph node ball some prizes of measurement. And, weight and tumor size were measured after the cancer cell inoculation two weeks. The decrease of the clear tumor size was recognized by the group that only a cancer cell was inoculated by the radiation independent irradiation group, lyophyllum decastes sing and the radiation combination group though tumor size increased as it passed. It faced by the group that only a cancer cell was inoculated after the irradiation 15 days though it died the precedent, and a half existed by lyophyllum decastes sing and the radiation combination group. And, the numbers of the leukocytes, the number of the lymphocyte were on the increase regardless of the existence of the radiation irradiation by the medication of lyophyllum decastes sing. It thinks with the thing that the effect is shown for the effect on immunity recovery in the radiotherapy and the prevention of a side effect of the radiation from this result. Showing the effect for not only effect on prevention of the cancer and effect on healing but also the effect on immunity recovery in the radiotherapy, the prevention of a side effect by taking lyophyllum decastes sing is considered

  4. Combination of Gold Nanoparticle-Conjugated Tumor Necrosis Factor-α and Radiation Therapy Results in a Synergistic Antitumor Response in Murine Carcinoma Models.

    Koonce, Nathan A; Quick, Charles M; Hardee, Matthew E; Jamshidi-Parsian, Azemat; Dent, Judith A; Paciotti, Giulio F; Nedosekin, Dmitry; Dings, Ruud P M; Griffin, Robert J

    2015-11-01

    Although remarkable preclinical antitumor effects have been shown for tumor necrosis factor-α (TNF) alone and combined with radiation, its clinical use has been hindered by systemic dose-limiting toxicities. We investigated the physiological and antitumor effects of radiation therapy combined with the novel nanomedicine CYT-6091, a 27-nm average-diameter polyethylene glycol-TNF-coated gold nanoparticle, which recently passed through phase 1 trials. The physiologic and antitumor effects of single and fractionated radiation combined with CYT-6091 were studied in the murine 4T1 breast carcinoma and SCCVII head and neck tumor squamous cell carcinoma models. In the 4T1 murine breast tumor model, we observed a significant reduction in the tumor interstitial fluid pressure (IFP) 24 hours after CYT-6091 alone and combined with a radiation dose of 12 Gy (P.05 vs control) despite extensive vascular damage observed. The IFP reduction in the 4T1 model was also associated with marked vascular damage and extravasation of red blood cells into the tumor interstitium. A sustained reduction in tumor cell density was observed in the combined therapy group compared with all other groups (P<.05). Finally, we observed a more than twofold delay in tumor growth when CYT-6091 was combined with a single 20-Gy radiation dose-notably, irrespective of the treatment sequence. Moreover, when hypofractionated radiation (12 Gy × 3) was applied with CYT-6091 treatment, a more than five-fold growth delay was observed in the combined treatment group of both tumor models and determined to be synergistic. Our results have demonstrated that TNF-labeled gold nanoparticles combined with single or fractionated high-dose radiation therapy is effective in reducing IFP and tumor growth and shows promise for clinical translation. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Synergistic effects of irradiation of waste water

    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

  6. Synergistic combination therapy of antitumor agents, membrane modification agents and irradiation

    Watarai, Jiro; Itagaki, Takatomo; Akutsu, Thoru; Yamaguchi, Kouichi; Kato, Isao

    1983-01-01

    Larygeal cancer were treated with synergistic combination therapy of Futraful in suppository, vitamin A, cepharanthin and irradiation from April 1981 to June 1982. This combination therapy resulted in high percentage of the tumor regression in the case of the invading laryngeal cancer and negligible complication. (author)

  7. The anti-tumor histone deacetylase inhibitor SAHA and the natural flavonoid curcumin exhibit synergistic neuroprotection against amyloid-beta toxicity.

    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.

  8. Modelling synergistic effects of appetite regulating hormones

    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....

  9. Synergistic Effects of PPARγ Ligands and Retinoids in Cancer Treatment

    Masahito Shimizu

    2008-01-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are members of the nuclear receptor superfamily. The activation of PPARs by their specific ligands is regarded as one of the promising strategies to inhibit cancer cell growth. However, recent clinical trials targeting several common cancers showed no beneficial effect when PPAR ligands are used as a monotherapy. Retinoid X receptors (RXRs, which play a critical role in normal cell proliferation as a master regulator for nuclear receptors, preferentially form heterodimers with PPARs. A malfunction of RXRα due to phosphorylation by the Ras/MAPK signaling pathway is associated with the development of certain types of human malignancies. The activation of PPARγ/RXR heterodimer by their respective ligands synergistically inhibits cell growth, while inducing apoptosis in human colon cancer cells when the phosphorylation of RXRα was inhibited. We herein review the synergistic antitumor effects produced by the combination of the PPAR, especially PPARγ, ligands plus other agents, especially retinoids, in a variety of human cancers. We also focus on the phosphorylation of RXRα because the inhibition of RXRα phosphorylation and the restoration of its physiological function may activate PPAR/RXR heterodimer and, therefore, be a potentially effective and critical strategy for the inhibition of cancer cell growth.

  10. Anti-tumor effect of polysaccharides from rhizome of Curculigo ...

    The anti-tumor effect of PDC on cervical cancer was investigated in vivo in mice injected with Hela cells. The parameters measured were tumor volume and weight. In vitro anti-tumor effects of PDC were assessed by measuring expressions of caspase-3, caspase-9 and P53 proteins in Hela cells via ELISA assay. Thymus ...

  11. SYNERGISTIC ANTIBACTERIAL EFFECT OF STEM BARK ...

    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 ...

  12. Synergistic effect of Glomus fasciculatum and Trichoderma ...

    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 ...

  13. Combination of Gold Nanoparticle-Conjugated Tumor Necrosis Factor-α and Radiation Therapy Results in a Synergistic Antitumor Response in Murine Carcinoma Models

    Koonce, Nathan A. [Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Quick, Charles M. [Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Hardee, Matthew E.; Jamshidi-Parsian, Azemat; Dent, Judith A. [Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Paciotti, Giulio F. [CytImmune Sciences, Rockville, Maryland (United States); Nedosekin, Dmitry [Department of Otolaryngology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Dings, Ruud P.M. [Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Griffin, Robert J., E-mail: RJGriffin@uams.edu [Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States)

    2015-11-01

    Purpose: Although remarkable preclinical antitumor effects have been shown for tumor necrosis factor-α (TNF) alone and combined with radiation, its clinical use has been hindered by systemic dose-limiting toxicities. We investigated the physiological and antitumor effects of radiation therapy combined with the novel nanomedicine CYT-6091, a 27-nm average-diameter polyethylene glycol-TNF-coated gold nanoparticle, which recently passed through phase 1 trials. Methods and Materials: The physiologic and antitumor effects of single and fractionated radiation combined with CYT-6091 were studied in the murine 4T1 breast carcinoma and SCCVII head and neck tumor squamous cell carcinoma models. Results: In the 4T1 murine breast tumor model, we observed a significant reduction in the tumor interstitial fluid pressure (IFP) 24 hours after CYT-6091 alone and combined with a radiation dose of 12 Gy (P<.05 vs control). In contrast, radiation alone (12 Gy) had a negligible effect on the IFP. In the SCCVII head and neck tumor model, the baseline IFP was not markedly elevated, and little additional change occurred in the IFP after single-dose radiation or combined therapy (P>.05 vs control) despite extensive vascular damage observed. The IFP reduction in the 4T1 model was also associated with marked vascular damage and extravasation of red blood cells into the tumor interstitium. A sustained reduction in tumor cell density was observed in the combined therapy group compared with all other groups (P<.05). Finally, we observed a more than twofold delay in tumor growth when CYT-6091 was combined with a single 20-Gy radiation dose—notably, irrespective of the treatment sequence. Moreover, when hypofractionated radiation (12 Gy × 3) was applied with CYT-6091 treatment, a more than five-fold growth delay was observed in the combined treatment group of both tumor models and determined to be synergistic. Conclusions: Our results have demonstrated that TNF-labeled gold

  14. Antitumor effects and mechanisms of Ganoderma extracts and spores oil

    Chen, Chun; Li, Peng; Li, Ye; Yao, Guan; Xu, Jian-Hua

    2016-01-01

    Ganoderma lucidum is a popular herbal medicine used in China to promote health. Modern studies have disclosed that the active ingredients of Ganoderma can exhibit several effects, including antitumor effects and immunomodulation. The present study evaluated the antitumor effects of self-prepared Ganoderma extracts and spores oil, and investigated the possible underlying mechanisms by observing the effects of the extracts and oil on topoisomerases and the cell cycle. The results showed that Ga...

  15. Synergistic effects in mixed Escherichia coli biofilms

    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...

  16. Antitumor Effect of Burchellin Derivatives Against Neuroblastoma.

    Kurita, Masahiro; Takada, Tomomi; Wakabayashi, Noriko; Asami, Satoru; Ono, Shinichi; Uchiyama, Taketo; Suzuki, Takashi

    2018-02-01

    Neuroblastoma is one of the most commonly encountered malignant solid tumors in the pediatric age group. We examined the antitumor effects of five burchellin derivatives against human neuroblastoma cell lines. We evaluated cytotoxicity by the MTT assay for four human neuroblastoma and two normal cell lines. We also performed analysis of the apoptotic induction effect by flow cytometry, and examined the expression levels of apoptosis- and cell growth-related proteins by western blot analysis. We found that one of the burchellin derivatives (compound 4 ) exerted cytotoxicity against the neuroblastoma cell lines. Compound 4 induced caspase-dependent apoptosis via a mitochondrial pathway. The apoptosis mechanisms induced by compound 4 involved caspase-3, -7 and -9 activation and poly (ADP-ribose) polymerase cleavage. In addition, compound 4 induced cell death through inhibition of the cell growth pathway (via extracellular signal-regulated kinase 1 and 2, AKT8 virus oncogene cellular homolog, and signal transducer and activator of transcription 3). Compound 4 exerted cellular cytotoxicity against neuroblastoma cells via induction of caspase-dependent apoptosis, and may offer promise for further development as a useful drug for the treatment of advanced neuroblastoma. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  17. Synergistic effects in threshold models on networks

    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.

  18. The anti-tumor effect of ACNU and x-irradiation on mouse glioma

    Nakagawa, Hidemitsu; Hori, Masaharu; Hasegawa, Hiroshi; Mogami, Heitaro; Hayakawa, Toru.

    1979-01-01

    Anti-tumor activities of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and x-irradiation on methylcholanthrene induced glioma in C 57 BL mice were studied in vitro and in vivo. In vitro experiments using cultured glioma cells (MGB cells), the synchronization of cell cycle was done by excess addition of thymidine, and the anti-tumor cell effect were investigated by mean of determinations of DNA synthesis, mitotic index and the number of the living cells following the treatments. As the results, it appeared obvious that ACNU was most effective on MGB cells in S phase and x-irradiation in M phase. As to the combined therapy of ACNU and x-irradiation, the anti-tumor effect was most remarkable when the cells were treated by x-irradiation in the G 2 , M phase, which were hervested by addition of ACNU 44 hours before irradiation. However simultaneous treatment of ACNU and x-irradiation on the cells in G 1 phase was not so remarkable. In vivo experiments the anti-tumor effect of ACNU and x-irradiation on subcutaneously or intracranially transplanted glioma in mice was investigated. Either ACNU 10 mg/kg or local x-irradiation 1240 rads showed inhibitory effect on the tumor growth and prolonged the survival time of the tumor bearing mice. The combination therapy was more effective than ACNU or x-irradiation alone, particularly combination therapy of ACNU and repeated small doses irradiation of x-ray was remarkably effective. Evidence obtained indicated that the combination therapy of ACNU and x-irradiation have synergistic anti-tumor effect on experimental mouse glioma. (author)

  19. Andrographolide enhanced 5-fluorouracil-induced antitumor effect in colorectal cancer via inhibition of c-MET pathway

    Su M

    2017-11-01

    Full Text Available Meng Su,1 Baoli Qin,1 Fang Liu,2 Yuze Chen,2 Rui Zhang2 1Department of Internal Medicine, 2Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Liaoning, China Abstract: Colorectal cancer (CRC is the third most common malignant neoplasm worldwide. 5-Fluorouracil (5-Fu is the most important chemotherapeutic drug used for the treatment of CRC. However, resistance to 5-Fu therapies is a growing concern in CRC clinical practice recently. Andrographolide (Andro is a main bioactive constituent of the herb Andrographis paniculata, which has various biological effects including anti-inflammation and antitumor activities. In the present study, we investigated the effects of combined Andro with 5-Fu against CRC HCT-116 cells. In vitro studies showed that Andro synergistically enhanced the anti-proliferation effect of 5-Fu on HCT-116 cells due to increased apoptotic cells. Meanwhile, results of the enzyme linked immunosorbent assay indicated that the level of phosphorylated cellular-mesenchymal to epithelial transition factor (p-MET was decreased by the combination treatment. Further study suggested that Andro promoted the antitumor effect of 5-Fu by downregulating the level of p-MET. In conclusion, these results confirmed the synergistic antitumor activity of Andro on CRC and provide evidence for possible clinical application of Andro for enhancing the antitumor effect of 5-Fu in CRC treatment. Keywords: Andro, 5-Fu, HCT-116 cells, apoptosis, p-MET

  20. Modification of carcinogenic and antitumor radiation effects (biomedical aspects)

    Vilenchik, M.M.

    1985-01-01

    In the book the data on modification of carcinogenic radiation effects by physiologicaly active compounds (caffeine, hormones, promoters and others) as well as on potentiation of antitumor radiation effects by means of hyperthermia are systematized. It is shown that as a basis of synergetic (superadditive) carcinogenic or antitumor radiation effects combined with other factor can be the inhibiting effects of the latter on the reparation process of radiation-induced DNA injuries. The results of experimental investigations and the data on quantitative analysis can be used as a theoretical basis for improvement of the ways and means of the prophylaxis of tumor diseases as well as for increasing the efficiency of radiotherapy

  1. Determining lower threshold concentrations for synergistic effects

    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...

  2. Anti-tumor effect of polysaccharides isolated from Taraxacum ...

    The effects of extraction temperature, liquid-solid ratio and extraction time on the yield of PTM were investigated using a Box-Behnken design (BBD). The in vitro anti-tumor effect of PTM on MCF-7 cells was investigated by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay, while the mechanism of PTM-induced ...

  3. Anti-tumor effect of cisplatin in human oral squamous cell carcinoma was enhanced by andrographolide via upregulation of phospho-p53 in vitro and in vivo.

    Chen, Songjie; Hu, Hui; Miao, Shushu; Zheng, Jiayong; Xie, Zhijian; Zhao, Hui

    2017-05-01

    Oral squamous cell carcinoma is one of the most common neoplasm in the world. Despite the improvements in diagnosis and treatment, the outcome is still poor now. Thus, the development of novel therapeuticapproaches is needed. The aim of this study is to assess the synergistic anti-tumor effect of andrographolide with cisplatin (DDP) in oral squamous cell carcinoma CAL-27 cells in vitro and in vivo. We performed Cell Counting Kit-8 proliferation assay, apoptosis assay, and western blotting on CAL-27 cells treated with andrographolide, DDP or the combination in vitro. In vivo, we also treated CAL-27 xenografts with andrographolide or the combination, and performed terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay and immunohistochemical analysis of Ki-67. The results showed the combination of andrographolide and DDP synergistically inhibited CAL-27 cell proliferation in vitro and caused tumor regression in vivo in the CAL-27 xenografts. In addition, the synergistic anti-tumor effect of andrographolide with synergistic was due to an enhanced apoptosis. Moreover, the combination therapy upregulated the expression level of p-p53 in vitro and decreased Ki-67 expression in vivo. Our data indicate that the combination treatment of andrographolide and DDP results in synergistic anti-tumor growth activity against oral squamous cell carcinoma CAL-27 in vitro and in vivo. These results demonstrated that combination of andrographolide with DDP was likely to represent a potential therapeutic strategy for oral squamous cell carcinoma.

  4. Antitumor effects and mechanisms of Ganoderma extracts and spores oil.

    Chen, Chun; Li, Peng; Li, Ye; Yao, Guan; Xu, Jian-Hua

    2016-11-01

    Ganoderma lucidum is a popular herbal medicine used in China to promote health. Modern studies have disclosed that the active ingredients of Ganoderma can exhibit several effects, including antitumor effects and immunomodulation. The present study evaluated the antitumor effects of self-prepared Ganoderma extracts and spores oil, and investigated the possible underlying mechanisms by observing the effects of the extracts and oil on topoisomerases and the cell cycle. The results showed that Ganoderma extracts and spores oil presented dose-dependent inhibitory effects on tumor cells. The half maximal inhibitory concentration (IC 50 ) values of Ganoderma extracts on HL60, K562 and SGC-7901 cells for 24 h were 0.44, 0.39 and 0.90 mg/ml, respectively; for Ganoderma spores oil, the IC 50 values were 1.13, 2.27 and 6.29 mg/ml, respectively. In the in vivo study, the inhibitory rates of Ganoderma extracts (4 g/kg/d, intragastrically) on S180 and H22 cells were 39.1 and 44.6%, respectively, and for Ganoderma spores oil (1.2 g/kg/d, intragastrically) the inhibitory rates were 30.9 and 44.9%, respectively. Ganoderma extracts and spores oil inhibited the activities of topoisomerase I and II. Ganoderma spores oil was shown block the cell cycle at the transition between the G1 and S phases and induce a marked decrease in cyclin D1 levels in K562 cells, with no significant change in cyclin E level. These results suggest that the Ganoderma extracts and spores oil possessed antitumor effects in the in vitro and in vivo studies. The antitumor mechanisms of the extracts and spores oil were associated with inhibitory effects on topoisomerase I and II activities, and for Ganoderma spores oil, the antitumor effects may also be associated with decreased cyclin D1 levels, thus inducing G1 arrest in the cell cycle.

  5. Antitumor effects and mechanisms of Ganoderma extracts and spores oil

    Chen, Chun; Li, Peng; Li, Ye; Yao, Guan; Xu, Jian-Hua

    2016-01-01

    Ganoderma lucidum is a popular herbal medicine used in China to promote health. Modern studies have disclosed that the active ingredients of Ganoderma can exhibit several effects, including antitumor effects and immunomodulation. The present study evaluated the antitumor effects of self-prepared Ganoderma extracts and spores oil, and investigated the possible underlying mechanisms by observing the effects of the extracts and oil on topoisomerases and the cell cycle. The results showed that Ganoderma extracts and spores oil presented dose-dependent inhibitory effects on tumor cells. The half maximal inhibitory concentration (IC50) values of Ganoderma extracts on HL60, K562 and SGC-7901 cells for 24 h were 0.44, 0.39 and 0.90 mg/ml, respectively; for Ganoderma spores oil, the IC50 values were 1.13, 2.27 and 6.29 mg/ml, respectively. In the in vivo study, the inhibitory rates of Ganoderma extracts (4 g/kg/d, intragastrically) on S180 and H22 cells were 39.1 and 44.6%, respectively, and for Ganoderma spores oil (1.2 g/kg/d, intragastrically) the inhibitory rates were 30.9 and 44.9%, respectively. Ganoderma extracts and spores oil inhibited the activities of topoisomerase I and II. Ganoderma spores oil was shown block the cell cycle at the transition between the G1 and S phases and induce a marked decrease in cyclin D1 levels in K562 cells, with no significant change in cyclin E level. These results suggest that the Ganoderma extracts and spores oil possessed antitumor effects in the in vitro and in vivo studies. The antitumor mechanisms of the extracts and spores oil were associated with inhibitory effects on topoisomerase I and II activities, and for Ganoderma spores oil, the antitumor effects may also be associated with decreased cyclin D1 levels, thus inducing G1 arrest in the cell cycle. PMID:27900038

  6. Synergistic antitumor activity of oncolytic reovirus and chemotherapeutic agents in non-small cell lung cancer cells

    Coffey Matthew C

    2009-07-01

    Full Text Available Abstract Background Reovirus type 3 Dearing strain (ReoT3D has an inherent propensity to preferentially infect and destroy cancer cells. The oncolytic activity of ReoT3D as a single agent has been demonstrated in vitro and in vivo against various cancers, including colon, pancreatic, ovarian and breast cancers. Its human safety and potential efficacy are currently being investigated in early clinical trials. In this study, we investigated the in vitro combination effects of ReoT3D and chemotherapeutic agents against human non-small cell lung cancer (NSCLC. Results ReoT3D alone exerted significant cytolytic activity in 7 of 9 NSCLC cell lines examined, with the 50% effective dose, defined as the initial virus dose to achieve 50% cell killing after 48 hours of infection, ranging from 1.46 ± 0.12 ~2.68 ± 0.25 (mean ± SD log10 pfu/cell. Chou-Talalay analysis of the combination of ReoT3D with cisplatin, gemcitabine, or vinblastine demonstrated strong synergistic effects on cell killing, but only in cell lines that were sensitive to these compounds. In contrast, the combination of ReoT3D and paclitaxel was invariably synergistic in all cell lines tested, regardless of their levels of sensitivity to either agent. Treatment of NSCLC cell lines with the ReoT3D-paclitaxel combination resulted in increased poly (ADP-ribose polymerase cleavage and caspase activity compared to single therapy, indicating enhanced apoptosis induction in dually treated NSCLC cells. NSCLC cells treated with the ReoT3D-paclitaxel combination showed increased proportions of mitotic and apoptotic cells, and a more pronounced level of caspase-3 activation was demonstrated in mitotically arrested cells. Conclusion These data suggest that the oncolytic activity of ReoT3D can be potentiated by taxanes and other chemotherapeutic agents, and that the ReoT3D-taxane combination most effectively achieves synergy through accelerated apoptosis triggered by prolonged mitotic arrest.

  7. Synergistic neurotrophic effects of piracetam and thiotriazoline

    O. A. Gromova

    2016-01-01

    Full Text Available The paper considers the synergy between the nootropic drug piracetam and the metabolic agent thiotriazoline that maintains energy metabolism and survival of neurons and other types of cells. Piracetam, a nootropic drug, a chemical pyrrolidone derivative, is used in neurological, psychiatric, and narcological practice. There is evidence on the positive effect of piracetam in elderly and senile patients with coronary heart disease. This drug is supposed to stimulate redox processes, to enhance glucose utilization, and to improve regional blood flow in the ischemic brain regions. Due to its action, the drug activates glycolytic processes and elevates ATP concentrations in brain tissue. Thiotriazoline is a compound that has antioxidant, anti-ischemic properties. The co-administration of piracetam and thiothriazoline is an innovation area in the treatment of stroke and other brain damages, especially in insulin resistance and high blood glucose levels. The paper considers the neurobiological properties of thiotriazoline and piracetam, which synergistically exert neuroprotective and neurotrophic effects.

  8. Juglans regia Hexane Extract Exerts Antitumor Effect, Apoptosis ...

    Original Research Article. Juglans regia Hexane Extract Exerts Antitumor Effect,. Apoptosis Induction and Cell Circle Arrest in Prostate. Cancer Cells In vitro. Wei Li1, De-Yuan Li2*, ... composition of walnut is juglone (5-hydroxy-1, 4- naphthoquinone), the .... extract was confirmed by studying apoptotic body formation using ...

  9. The antitumor effect of arsenic trioxide on hepatocellular carcinoma is enhanced by andrographolide.

    Duan, Xuhua; Li, Tengfei; Han, Xinwei; Ren, Jianzhuang; Chen, Pengfei; Li, Hao; Gong, Shaojun

    2017-10-31

    High concentrations of arsenic trioxide (As 2 O 3 ) are used to treat acute promyelocytic leukemia and solid tumors, with negative side effects to normal cells. Andrographolide is a traditional Chinese medicine that exerts anti-cancer, anti-inflammatory, anti-virus, and anti-diabetic effects. Here, we tested the effects of combined andrographolide with As 2 O 3 against hepatocellular carcinoma (HCC). We found that by increasing apoptosis, andrographolide synergistically enhanced the anti-tumor effects of As2O3 in HepG2 cells in vitro and in vivo . Furthermore, results from our microarray assays and experiments with mouse xenografts showed that EphB4 was downregulated by the combination of As 2 O 3 plus andrographolide. These findings suggest that the combination of andrographolide and As 2 O 3 could yield therapeutic benefits in the treatment of HCC.

  10. Antitumor effect of malaria parasite infection in a murine Lewis lung cancer model through induction of innate and adaptive immunity.

    Chen, Lili; He, Zhengxiang; Qin, Li; Li, Qinyan; Shi, Xibao; Zhao, Siting; Chen, Ling; Zhong, Nanshan; Chen, Xiaoping

    2011-01-01

    Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL) staining and decreased Ki-67 expression in tumors. Through natural killer (NK) cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8(+) T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria parasite may provide a novel strategy or therapeutic vaccine vector for anti-lung cancer

  11. Antitumor effect of malaria parasite infection in a murine Lewis lung cancer model through induction of innate and adaptive immunity.

    Lili Chen

    Full Text Available BACKGROUND: Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL staining and decreased Ki-67 expression in tumors. Through natural killer (NK cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8(+ T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. CONCLUSIONS/SIGNIFICANCE: Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria

  12. Studies on anti-tumor effect of electromagnetic waves

    Kadota, Ikuhito; Wakabayashi, Toshio; Ogoshi, Kyoji; Kamijo, Akemi

    1995-01-01

    Hyperthermia have treated cancer with thermal effect of electromagnetic waves for biological systems, but the expected effect is not shown. Also non-thermal effect of electromagnetic waves is out of consideration. If irradiation conditions of electromagnetic waves with non-thermal anti-tumor effect are obtained, we can expect newly spread in cancer therapy. We had in vivo experiments that electromagnetic waves were irradiated to mice. In some irradiation conditions, the non-thermal anti-tumor effect of electromagnetic waves showed. In order to specify the irradiation conditions, we had in vitro experiments. We found that activity ratio of tumor cells which was measured by MTT method depended on irradiation time and power of electromagnetic waves. These results are useful for the cancer therapy. (author)

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

    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.

  14. Synergistic effect of aqueous extract of Telfaria occidentalis on the ...

    Synergistic effect of aqueous extract of Telfaria occidentalis on the biological activities of ... Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ibadan. 2. ... development of resistance to most of the earlier drugs.

  15. Synergistic effect of Elephantopus scaber L and Sauropus ...

    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.

  16. The anti-tumor effect and biological activities of the extract JMM6 ...

    Juglans mandshurica Maxim is a traditional herbal medicines in China, and its anti-tumor bioactivities are of research interest. Bioassay-guided fractionation method was employed to isolate anti-tumor compounds from the stem barks of the Juglans mandshurica Maxim. The anti-tumor effect and biological activities of the ...

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

    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

  18. Synergistic effect of Ebselen and gamma radiation on breast cancer cells.

    Thabet, Noura M; Moustafa, Enas M

    2017-08-01

    To explore the synergistic effect of a seleno-organic compound Ebselen (Ebs) and/or γ-radiation to exert antitumor effects on human breast cancer (MCF-7) cell line in vitro. Ebs cytotoxicity at various concentrations (10, 25, 50 and 75 μg), cell proliferation and clonogenic assay of Ebs and/or γ-radiation (at 1, 3 and 6 Gy), expression of p-IκBα and NF-κB, inflammatory cytokines levels (TNF-α, IL-2, INF-γ, IL-10 and TGF-β), apoptotic factors (Caspase-3, Granzyme-B and TRAIL) and angiogenic factor (VEGF) were investigated. The results showed that the effective dosage of this combination was observed at 25 μg/ml of Ebs with γ-radiation at 6 Gy. Data displayed a significant reduction in NF-κB mRNA along with an elevation in granzyme-B mRNA and TRAIL mRNA expression. Furthermore, protein expression of caspase-3 was elevated, whereas p-IκBα and p-NF-κB(p65) protein expression was reduced significantly. Also, a significant decline in TNF-α, IL-2, INF-γ, TGF-β with a significant increase in IL-10 levels were revealed. Meanwhile, a significant decrease in VEGF level and proliferation capacity were observed. We conclude that a combination of Ebs with radiotherapy has a major antitumor efficiency in inducing apoptosis and inhibiting cancer cell progression, due to the synergistic effect in regulating gene and protein expression, and in a modulating response of pro-and anti-inflammatory cytokines.

  19. Ethacrynic acid improves the antitumor effects of irreversible epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer.

    Liu, Bing; Huang, XinPing; Hu, YunLong; Chen, TingTing; Peng, BoYa; Gao, NingNing; Jin, ZhenChao; Jia, TieLiu; Zhang, Na; Wang, ZhuLin; Jin, GuangYi

    2016-09-06

    Prolonged treatment of breast cancer with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) often results in acquired resistance and a narrow therapeutic index. One strategy to improve the therapeutic effects of EGFR TKIs is to combine them with drugs used for other clinical indications. Ethacrynic acid (EA) is an FDA approved drug that may have antitumor effects and may enhance the cytotoxicity of chemotherapeutic agents by binding to glutathione and inhibiting WNT signaling. While the α,β-unsaturated-keto structure of EA is similar to that of irreversible TKIs, the mechanism of action of EA when combined with irreversible EGFR TKIs in breast cancer remains unknown. We therefore investigated the combination of irreversible EGFR TKIs and EA. We found that irreversible EGFR TKIs and EA synergistically inhibit breast cancer both in vitro and in vivo. The combination of EGFR TKIs and EA induces necrosis and cell cycle arrest and represses WNT/β-catenin signaling as well as MAPK-ERK1/2 signaling. We conclude that EA synergistically enhances the antitumor effects of irreversible EGFR TKIs in breast cancer.

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

    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.)

  1. Synergistic effects between catalase inhibitors and modulators of nitric oxide metabolism on tumor cell apoptosis.

    Scheit, Katrin; Bauer, Georg

    2014-10-01

    Inhibitors of catalase (such as ascorbate, methyldopa, salicylic acid and neutralizing antibodies) synergize with modulators of nitric oxide (NO) metabolism (such as arginine, arginase inhibitor, NO synthase-inducing interferons and NO dioxygenase inhibitors) in the singlet oxygen-mediated inactivation of tumor cell protective catalase. This is followed by reactive oxygen species (ROS)-dependent apoptosis induction. TGF-beta, NADPH oxidase-1, NO synthase, dual oxidase-1 and caspase-9 are characterized as essential catalysts in this process. The FAS receptor and caspase-8 are required for amplification of ROS signaling triggered by individual compounds, but are dispensable when the synergistic effect is established. Our findings explain the antitumor effects of catalase inhibitors and of compounds that target NO metabolism, as well as their synergy. These data may have an impact on epidemiological studies related to secondary plant compounds and open new perspectives for the establishment of novel antitumor drugs and for the improvement of established chemotherapeutics. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  2. Contrast-induced nephrotoxicity: possible synergistic effect of stress hyperglycemia.

    O'Donnell, David H

    2010-07-01

    Oxidative stress on the renal tubules has been implicated as a mechanism of injury in both stress hyperglycemia and contrast-induced nephrotoxicity. The purpose of this study was to determine whether the combination of these effects has a synergistic effect on accentuating renal tubular apoptosis and therefore increasing the risk of contrast-induced nephrotoxicity.

  3. Antitumor effects of Marginisporum crassissimum (Rhodophyceae), a marine red alga.

    Hiroishi, S; Sugie, K; Yoshida, T; Morimoto, J; Taniguchi, Y; Imai, S; Kurebayashi, J

    2001-06-26

    Marginisporum crassissimum (Yendo) Ganesan, a marine red alga found in the ordinal coastal sea around Japan, revealed antitumor (antimetastatic) effects in vitro and in vivo. In in vitro experiments, extracts of this alga inhibited not only the growth of several tumor cell lines, such as B16-BL6 (a mouse melanoma cell line), JYG-B (a mouse mammary carcinoma cell line) and KPL-1 (a human mammary carcinoma cell line), but also invasion of B16-BL6 cells in a culture system. In in vivo experiments, the lung metastasis of B16-BL6 cells inoculated to the tail vein of B57BL/6J mice was inhibited by intraperitoneal administration of an extract from the alga. In addition, life prolongation of B57BL/6J mice inoculated with B16-BL6 cells was also observed by the intraperitoneal administration of the extract. An effective substance showing B16-BL6 growth inhibition in vitro was partially purified by filtration and hydrophobic column chromatography, and was revealed to be sensitive to trypsin-digestion and heat-treatment. The molecular weight of the substance was greater than 100 kDa. This is the first study demonstrating antitumor (antimetastatic) effects of M. crassissimum.

  4. Synergistic anti-tumor therapy by a comb-like multifunctional antibody nanoarray with exceptionally potent activity

    Li, Huafei; Sun, Yun; Chen, Di; Zhao, He; Zhao, Mengxin; Zhu, Xiandi; Ke, Changhong; Zhang, Ge; Jiang, Cheng; Zhang, Li; Zhang, Fulei; Wei, Huafeng; Li, Wei

    2015-10-01

    Simultaneously blocking multiple mediators offers new hope for the treatment of complex diseases. However, the curative potential of current combination therapy by chronological administration of separate monoclonal antibodies (mAbs) or multi-specific mAbs is still moderate due to inconvenient manipulation, low cooperative effectors, poor pharmacokinetics and insufficient tumor accumulation. Here, we describe a facile strategy that arms distinct mAbs with cooperative effectors onto a long chain to form a multicomponent comb-like nano mAb. Unlike dissociative parental mAbs, the multifunctional mAb nanoarray (PL-RB) constructed from type I/II anti-CD20 mAbs shows good pharmacokinetics. This PL-RB simultaneously targets distinct epitopes on a single antigen (Ag) and neighboring Ags on different lymphocytes. This unique intra- and intercellular Ag cross-linking endows the multifunctional mAb nanoarray with potent apoptosis activity. The exceptional apoptosis, complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) that are synchronously evoked by the nano PL-RB are further synergistically promoted via enhanced permeability and retention (EPR), which resulted in high intratumor accumulation and excellent anti-lymphoma efficiency.

  5. Synergistic effects of irradiation of waste-water

    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. Polypeptide-based nanogels co-encapsulating a synergistic combination of doxorubicin with 17-AAG show potent anti-tumor activity in ErbB2-driven breast cancer models.

    Desale, Swapnil S; Raja, Srikumar M; Kim, Jong Oh; Mohapatra, Bhopal; Soni, Kruti S; Luan, Haitao; Williams, Stetson H; Bielecki, Timothy A; Feng, Dan; Storck, Matthew; Band, Vimla; Cohen, Samuel M; Band, Hamid; Bronich, Tatiana K

    2015-06-28

    ErbB2-driven breast cancers constitute 20-25% of the cases diagnosed within the USA. The humanized anti-ErbB2 monoclonal antibody, Trastuzumab (Herceptin™; Genentech), with chemotherapy is the current standard of treatment. Novel agents and strategies continue to be explored, given the challenges posed by Trastuzumab-resistance development in most patients. The HSP90 inhibitor, 17-allylaminodemethoxygeldanamycin (17-AAG), which induces ErbB2 degradation and attenuates downstream oncogenic signaling, is one such agent that showed significant promise in early phase I and II clinical trials. Its low water solubility, potential toxicities and undesirable side effects observed in patients, partly due to the Cremophor-based formulation, have been discouraging factors in the advancement of this promising drug into clinical use. Encapsulation of 17-AAG into polymeric nanoparticle formulations, particularly in synergistic combination with conventional chemotherapeutics, represents an alternative approach to overcome these problems. Herein, we report an efficient co-encapsulation of 17-AAG and doxorubicin, a clinically well-established and effective modality in breast cancer treatment, into biodegradable and biocompatible polypeptide-based nanogels. Dual drug-loaded nanogels displayed potent cytotoxicity in a breast cancer cell panel and exerted selective synergistic anticancer activity against ErbB2-overexpressing breast cancer cell lines. Analysis of ErbB2 degradation confirmed efficient 17-AAG release from nanogels with activity comparable to free 17-AAG. Furthermore, nanogels containing both 17-AAG and doxorubicin exhibited superior antitumor efficacy in vivo in an ErbB2-driven xenograft model compared to the combination of free drugs. These studies demonstrate that polypeptide-based nanogels can serve as novel nanocarriers for encapsulating 17-AAG along with other chemotherapeutics, providing an opportunity to overcome solubility issues and thereby exploit its full

  7. Comparative study of the antitumor effect of natural monoterpenes: relationship to cell cycle analysis

    Abdeslam Jaafari

    2012-06-01

    Full Text Available Monoterpenes have been identified as responsible of important therapeutic effects of plant-extracts. In this work, we try to compare the cytotoxic effect of six monoterpenes (carvacrol, thymol, carveol, carvone, eugenol and isopulegol as well as their molecular mechanisms. The in vitro antitumor activity of the tested products, evaluated against five tumor cell lines, show that the carvacrol is the most cytotoxic monoterpene. The investigation of an eventual synergistic effect of the six natural monoterpenes with two anticancer drugs revealed that there is a significant synergy between them (p<5%. On the other hand, the effect of the tested products on cell cycle progression was examined by flow cytometry after DNA staining in order to investigate the molecular mechanism of their cytotoxic activity. The results revealed that carvacrol and carveol stopped the cell cycle progression in S phase; however, thymol and isopulegol stopped it in G0/G1 phase. Regarding carvone and eugenol, no effect on cell cycle was observed.

  8. Antitumor effects of radioiodinated antisense oligonucleotide mediated by VIP receptor

    Ou Xiaohong; Tan Tianzhi; Li Yunchun; Kuang Anren

    2004-01-01

    Purpose: we had constructed a targeting delivery system based on intestinal peptide (VIP) for antisense oligonucleotide (ASON) transfer into VIP receptor-positive cells in previous study. The aims of present studies are to observe the antitumor effect of VIP-131I-ASON in HT29 human colon adenocarcinoma xenografts. Methods: A 15-met phosphorothioate ASON, which was complementary to the translation start region of the C-myc oncogene mRNA, was labeled with 131I and the labelled compound was linked to the VIP bound covalently 'to a polylysine chain so as to deliver oligonucleotide into tumor cells. Distribution experiments for evaluating the radiolabeled antisense complexe uptake in tumor tissue were performed in BALB/c nude mice bearing with HT29 tumor xenografts. Nude mice beating HT29 tumor xenografts were adminstered VIP-131I-ASON (3.7,7.4 MBq) or 131I-ASON (3.7 MBq), 131I labeled control sense and nosense DNA (3.7 MBq), or saline. Antitumor effects were assessed using endpoints of tumor growth delay. C-myc-encoded protein expression of tumor was measured by immunocytohistochemical staining. Results: Distribution experiment performed with athymic mice bearing human colon tumor xenografts revealed maximal accumulation of conjugated ASON in the tumor tissue 2 h after administration and significantly higher than that in nude mice injected unconjngated ASON [(5.89±1.03)%ID/g and(1.56±0.31)%ID/g, respectively; t=7.7954 P<0.001]. The radioratio of tumor to muscle was peaked 4h after administration. VIP-131I-ASON exhibited strong antitumor effects against HT29 xenografts, decreasing their growth rate 7-fold compare with that in saline-treated mice(tumor growth delay, 25.4±0.89 day). The antitumor effects of unconjugated 131I-ASON were much less profound than VIP-131I-ASON (tumor growth delay, 3.2±1.3 and 25.4±0.89 day, respectively; q=51.4126 P<0.01). Sense, nosense control ON with VIP carder caused no therapeutic effect. There was no progressive weight loss or

  9. Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation.

    Sachiko Hirai

    Full Text Available Up-regulated sirtuin 1 (SIRT1, an NAD+-dependent class III histone deacetylase, deacetylates p53 and inhibits its transcriptional activity, leading to cell survival. SIRT1 overexpression has been reported to predict poor survival in some malignancies, including gastric cancer. However, the antitumor effect of SIRT1 inhibition remains elusive in gastric cancer. Here, we investigated the antitumor mechanisms of a sirtuin inhibitor, tenovin-6, in seven human gastric cancer cell lines (four cell lines with wild-type TP53, two with mutant-type TP53, and one with null TP53. Interestingly, tenovin-6 induced apoptosis in all cell lines, not only those with wild-type TP53, but also mutant-type and null versions, accompanied by up-regulation of death receptor 5 (DR5. In the KatoIII cell line (TP53-null, DR5 silencing markedly attenuated tenovin-6-induced apoptosis, suggesting that the pivotal mechanism behind its antitumor effects is based on activation of the death receptor signal pathway. Although endoplasmic reticulum stress caused by sirtuin inhibitors was reported to induce DR5 up-regulation in other cancer cell lines, we could not find marked activation of its related molecules, such as ATF6, PERK, and CHOP, in gastric cancer cells treated with tenovin-6. Tenovin-6 in combination with docetaxel or SN-38 exerted a slight to moderate synergistic cytotoxicity against gastric cancer cells. In conclusion, tenovin-6 has potent antitumor activity against human gastric cancer cells via DR5 up-regulation. Our results should be helpful for the future clinical development of sirtuin inhibitors.

  10. Synergistic Antimicrobial Effect of Tribulus terrestris and Bitter Almond Extracts

    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.

  11. Antitumor bystander effect induced by radiation-inducible target gene therapy combined with α particle irradiation

    Liu Hui; Jin Chufeng; Wu Yican; Ge Shenfang; Wu Lijun; FDS Team

    2012-01-01

    In this work, we investigated the bystander effect of the tumor and normal cells surrounding the target region caused by radiation-inducible target gene therapy combined with α-particle irradiation. The receptor tumor cell A549 and normal cell MRC-5 were co-cultured with the donor cells irradiated to 0.5 Gy or the non-irradiated donor cells, and their survival and apoptosis fractions were evaluated. The results showed that the combined treatment of Ad-ET and particle irradiation could induce synergistic antitumor effect on A549 tumor cell, and the survival fraction of receptor cells co-cultured with the irradiated cells decreased by 6%, compared with receptor cells co-cultured with non-irradiated cells, and the apoptosis fraction increased in the same circumstance, but no difference was observed with the normal cells. This study demonstrates that Ad-ET combined with α-particle irradiation can significantly cause the bystander effect on neighboring tumor cells by inhibiting cell growth and inducing apoptosis, without obvious toxicity to normal cells. This suggests that combining radiation-inducible TRAIL gene therapy and irradiation may improve tumor treatment efficacy by specifically targeting tumor cells and even involving the neighboring tumor cells. (authors)

  12. IL-6 Inhibition Reduces STAT3 Activation and Enhances the Antitumor Effect of Carboplatin

    Zhi-Yong Wang

    2016-01-01

    Full Text Available Recent studies suggest that tumor-associated macrophage-produced IL-6 is an important mediator within the tumor microenvironment that promotes tumor growth. The activation of IL-6/STAT3 axis has been associated with chemoresistance and poor prognosis of a variety of cancers including colorectal carcinoma and thus serves as a potential immunotherapeutic target for cancer treatment. However, it is not fully understood whether anticytokine therapy could reverse chemosensitivity and enhance the suppressive effect of chemotherapy on tumor growth. In this study, we aimed to investigate the effect of IL-6 inhibition therapy on the antitumor effect of carboplatin. Enhanced expression of IL-6 and activation of STAT3 were observed in human colorectal carcinoma samples compared to normal colorectal tissue, with higher levels of IL-6/STAT3 in low grade carcinomas. Treatment of carboplatin (CBP dose-dependently increased IL-6 production and STAT3 activation in human colorectal LoVo cells. Blockade of IL-6 with neutralizing antibody enhanced chemosensitivity of LoVo cells to carboplatin as evidenced by increased cell apoptosis. IL-6 blockade abolished carboplatin-induced STAT3 activation. IL-6 blockade and carboplatin synergistically reduced cyclin D1 expression and enhanced caspase-3 activity in LoVo cells. Our results suggest that inhibition of IL-6 may enhance chemosensitivity of colon cancers with overactive STAT3 to platinum agents.

  13. Synergistic effect of Glomus fasciculatum and Trichoderma ...

    Firdaus-e-Bareen

    2011-05-30

    May 30, 2011 ... The effect of two soil amendments of tannery sludge (10% and 20%) on growth and metal uptake of. Helianthus annuus L. ... heavy metal polluted soils (Terry and Bañuelos, 2000). Although it is ..... remediation unit to treat contaminated soils containing a .... such as zinc, cadmium, lead, and arsenic. Rev.

  14. Synergistic antiosteoporotic effect of Lepidium Sativum and ...

    Alendronate belongs to a class of drugs called bisphosphonates. Bisphosphonates (BP) therapy is a vital option to reduce the risk of bone fracture in people who suffer from osteoporosis. Yet, bisphosphonate have displayed several side effects. Lepidium sativum (LS) seeds have been used in traditional folk medicine to ...

  15. The synergistic effect between coal macerals during hydropyrolysis

    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. Antitumor Effects and Biological Mechanism of Action of the Aqueous Extract of the Camptotheca acuminata Fruit in Human Endometrial Carcinoma Cells

    Chi-Shian Lin

    2014-01-01

    Full Text Available The aqueous extracts of the leaves and fruit of Camptotheca acuminata have long been used in traditional Chinese medicine (TCM for treating cancer patients. The chemotherapeutic drug, camptothecin (CPT, and related analogs were first isolated from C. acuminata in the 1970s. Although the antitumor effects of CPT have been characterized in recent years, the antitumor effects of aqueous extracts of C. acuminata have not been clarified. The aims of our current study were to determine the tumor-suppression efficiency of an aqueous extract of the fruit of C. acuminata (AE-CA in the human endometrial carcinoma cell lines, HEC-1A, HEC-1B, and KLE, and compare its antitumor effects with those of CPT. Cell viability assays indicated that a dosage of AE-CA containing 0.28 mg/mL of CPT demonstrated enhanced cytotoxicity, compared with CPT treatment. The effects of AE-CA on the induction of cell cycle arrest, the accumulation of cyclin-A2 and -B1, and the activation of caspase-3 and caspase-7 were similar to those of CPT. Furthermore, AE-CA exhibited a synergistic effect on the cytotoxicity of cisplatin in HEC-1A and HEC-1B cells. These results indicated that AE-CA is a potent antitumor agent and can be combined with cisplatin for the treatment of human endometrial cancer.

  17. In vitro synergistic antitumor efficacy of sequentially combined chemotherapy/icotinib in non‑small cell lung cancer cell lines.

    Wang, Min-Cong; Liang, Xuan; Liu, Zhi-Yan; Cui, Jie; Liu, Ying; Jing, Li; Jiang, Li-Li; Ma, Jie-Qun; Han, Li-Li; Guo, Qian-Qian; Yang, Cheng-Cheng; Wang, Jing; Wu, Tao; Nan, Ke-Jun; Yao, Yu

    2015-01-01

    The concurrent administration of chemotherapy and epidermal growth factor receptor‑tyrosine kinase inhibitors (EGFR‑TKIs) has previously produced a negative interaction and failed to confer a survival benefit to non‑small cell lung cancer (NSCLC) patients compared with first‑line cytotoxic chemotherapy. The present study aimed to investigate the optimal schedule of the combined treatment of cisplatin/paclitaxel and icotinib in NSCLC cell lines and clarify the underlying mechanisms. HCC827, H1975, H1299 and A549 human NSCLC cell lines with wild‑type and mutant EGFR genes were used as in vitro models to define the differential effects of various schedules of cisplatin/paclitaxel with icotinib treatments on cell growth, proliferation, cell cycle distribution, apoptosis, and EGFR signaling pathway. Sequence‑dependent antiproliferative effects differed among the four NSCLC cell lines, and were not associated with EGFR mutation, constitutive expression levels of EGFR or downstream signaling molecules. The antiproliferative effect of cisplatin plus paclitaxel followed by icotinib was superior to that of cisplatin or paclitaxel followed by icotinib in the HCC827, H1975, H1299 and A549 cell lines, and induced more cell apoptosis and G0/G1 phase arrest. Cisplatin and paclitaxel significantly increased the expression of EGFR phosphorylation in the HCC827 cell line. However, only paclitaxel increased the expression of EGFR phosphorylation in the H1975 cell line. Cisplatin/paclitaxel followed by icotinib influenced the expression of p‑EGFR and p‑AKT, although the expression of p‑ERK1/2 remained unchanged. The results suggest that the optimal schedule of the combined treatment of cisplatin/paclitaxel and icotinib differed among the NSCLC cell lines. The results also provide molecular evidence to support clinical treatment strategies for NSCLC patients.

  18. Synergistic effect of casein glycomacropeptide on sodium caseinate foaming properties.

    Morales, R; Martinez, M J; Pilosof, A M R

    2017-11-01

    Several strategies to improve the interfacial properties and foaming properties of proteins may be developed; among them, the use of mixtures of biopolymers that exhibit synergistic interactions. The aim of the present work was to evaluate the effect of casein glycomacropeptide (CMP) on foaming and surface properties of sodium caseinate (NaCas) and to establish the role of protein interactions in the aqueous phase. To this end particles size, interfacial and foaming properties of CMP, NaCas and NaCas-CMP mixtures at pH 5.5 and 7 were determined. At both pH, the interaction between CMP and NaCas induced a decrease in the aggregation state of NaCas. Single CMP foams showed the highest and NaCas the lowest foam overrun (FO) and the mixture exhibited intermediate values. CMP foam quickly drained. The drainage profile of mixed foams was closer to NaCas foams; at pH 5.5, mixed foams drained even slower than NaCas foam, exhibiting a synergistic performance. Additionally, a strong synergism was observed on the collapse of mixed foams at pH 5.5. Finally, a model to explain the synergistic effect observed on foaming properties in CMP-NaCas mixtures has been proposed; the reduced aggregation state of NaCas in the presence of CMP, made it more efficient for foam stabilization. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Zoledronic acid produces combinatory anti-tumor effects with cisplatin on mesothelioma by increasing p53 expression levels.

    Shinya Okamoto

    Full Text Available We examined anti-tumor effects of zoledronic acid (ZOL, one of the bisphosphonates agents clinically used for preventing loss of bone mass, on human mesothelioma cells bearing the wild-type p53 gene. ZOL-treated cells showed activation of caspase-3/7, -8 and -9, and increased sub-G1 phase fractions. A combinatory use of ZOL and cisplatin (CDDP, one of the first-line anti-cancer agents for mesothelioma, synergistically or additively produced the cytotoxicity on mesothelioma cells. Moreover, the combination achieved greater anti-tumor effects on mesothelioma developed in the pleural cavity than administration of either ZOL or CDDP alone. ZOL-treated cells as well as CDDP-treated cells induced p53 phosphorylation at Ser 15, a marker of p53 activation, and up-regulated p53 protein expression levels. Down-regulation of p53 levels with siRNA however did not influence the ZOL-mediated cytotoxicity but negated the combinatory effects by ZOL and CDDP. In addition, ZOL treatments augmented cytotoxicity of adenoviruses expressing the p53 gene on mesothelioma. These data demonstrated that ZOL-mediated augmentation of p53, which was not linked with ZOL-induced cytotoxicity, played a role in the combinatory effects with a p53 up-regulating agent, and suggests a possible clinical use of ZOL to mesothelioma with anti-cancer agents.

  20. Synergistic anti-glioma effect of a coloaded nano-drug delivery system

    Xu H

    2016-12-01

    Full Text Available Huae Xu,1,* Feng Jia,2,* Pankaj Kumar Singh,3 Shu Ruan,4 Hao Zhang,5,* Xiaolin Li5 1Department of Pharmacy, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 2Department of Neurosurgery, Yancheng City No 1 People’s Hospital, The Fourth Affiliated Hospital of Nantong Medical College, Yancheng, People’s Republic of China; 3Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Department of Endocrinology, Yancheng Third Hospital, The Affiliated Hospital of Southeast University Medical College, Yancheng, 5Department of Geriatrics, The First Affiliated Hospital with Nanjing Medical University, Nanjing, People’s Republic of China *These authors contributed equally to this work Abstract: The anti-glioma effect of temozolomide (Tem is sometimes undermined by the emerging resistance. Recently, resveratrol (Res, herbal medicine extracted from grape seeds, has been demonstrated for its potential use in chemosensitization. In the current study, both these drugs were loaded simultaneously into nanoparticles with methoxy poly(ethylene glycol-poly epsilon caprolactone (mPEG-PCL as drug carriers in order to achieve better antitumor efficiency. Tem/Res-coloaded mPEG-PCL nanoparticles were constructed, characterized, and tested for antitumor effect on glioma cells by using in vitro and xenograft model system. The nanoparticle constructs were satisfactory with drug loading content (Res =~12.4%; Tem =~9.3% and encapsulation capacity of >85% for both the drugs. In addition, the coencapsulation led to better in vitro stability of the nanoparticles than Tem-loaded nanoparticles. An in vitro uptake study demonstrated a high uptake efficiency of the nanoparticles by glioma cells. The synergistic antitumor effect against glioma cells was observed in the combinational treatment of Res and Tem. Tem/Res-coloaded nanoparticles induced higher apoptosis in U87 glioma cells as

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

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

    2017-01-01

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

  2. Curcumin exerts its antitumor effects in a context dependent fashion.

    Kreutz, Dominique; Sinthuvanich, Chomdao; Bileck, Andrea; Janker, Lukas; Muqaku, Besnik; Slany, Astrid; Gerner, Christopher

    2018-06-30

    Proteome profiling profoundly contributes to the understanding of cell response mechanisms to drug actions. Such knowledge may become a key to improve personalized medicine. In the present study, the effects of the natural remedy curcumin on breast cancer model systems were investigated. MCF-7, ZR-75-1 and TGF-β1 pretreated fibroblasts, mimicking cancer-associated fibroblasts (CAFs), were treated independently as well as in tumor cell/CAF co-cultures. Remarkably, co-culturing with CAF-like cells (CLCs) induced different proteome alterations in MCF-7 and ZR-75-1 cells, respectively. Curcumin significantly induced HMOX1 in single cell type models and co-cultures. However, other curcumin effects differed. In the MCF-7/CLC co-culture, curcumin significantly down-regulated RC3H1, a repressor of inflammatory signaling. In the ZR-75-1/CLC co-culture, curcumin significantly down-regulated PEG10, an anti-apoptotic protein, and induced RRAGA, a pro-apoptotic protein involved in TNF-alpha signaling. Furthermore, curcumin induced AKR1C2, an important enzyme for progesterone metabolism. None of these specific curcumin effects were observed in single cell type cultures. All high-resolution mass spectrometry data are available via ProteomeXchange with the identifier PXD008719. The present data demonstrate that curcumin induces proteome alterations, potentially accounting for its known antitumor effects, in a strongly context-dependent fashion. Better means to understand and potentially predict individual variations of drug effects are urgently required. The present proteome profiling study of curcumin effects demonstrates the massive impact of the cell microenvironment on cell responses to drug action. Co-culture models apparently provide more biologically relevant information regarding curcumin effects than single cell type cultures. Copyright © 2018. Published by Elsevier B.V.

  3. Amplexicaule A exerts anti-tumor effects by inducing apoptosis in human breast cancer

    Shu, Guangwen; Wan, Dingrong; He, Feng; Loaec, Morgann; Ding, Yali; Li, Jun; Dovat, Sinisa; Yang, Gaungzhong; Song, Chunhua

    2016-01-01

    Chemotherapy is the main treatment for patients with breast cancer metastases, but natural alternatives have been receiving attention for their potential as novel anti-tumor reagents. Amplexicaule A (APA) is a flavonoid glucoside isolated from rhizomes of Polygonum amplexicaule D. Don var. sinense Forb (PADF). We found that APA has anti-tumor effects in a breast cancer xenograft mouse model and induces apoptosis in breast cancer cell lines. APA increased levels of cleaved caspase-3,-8,-9 and PARP, which resulted from suppression of MCL-1 and BCL-2 expression in the cells. APA also inactivated the Akt/mTOR pathway in breast cancer cells. Thus, APA exerts a strong anti-tumor effect on breast cancer cells, most likely through induction of apoptosis. Our study is the first to identify this novel anti-tumor compound and provides a new strategy for isolation and separation of single compounds from herbs. PMID:26943775

  4. Amplexicaule A exerts anti-tumor effects by inducing apoptosis in human breast cancer

    Xiang, Meixian; Su, Hanwen; Shu, Guangwen; Wan, Dingrong; He, Feng; Loaec, Morgann; Ding, Yali; Li, Jun; Dovat, Sinisa; Yang, Gaungzhong; Song, Chunhua

    2016-01-01

    Chemotherapy is the main treatment for patients with breast cancer metastases, but natural alternatives have been receiving attention for their potential as novel anti-tumor reagents. Amplexicaule A (APA) is a flavonoid glucoside isolated from rhizomes of Polygonum amplexicaule D. Don var. sinense Forb (PADF). We found that APA has anti-tumor effects in a breast cancer xenograft mouse model and induces apoptosis in breast cancer cell lines. APA increased levels of cleaved caspase-3,-8,-9 and ...

  5. FOXO3a reactivation mediates the synergistic cytotoxic effects of rapamycin and cisplatin in oral squamous cell carcinoma cells

    Fang Liang; Wang Huiming; Zhou Lin; Yu Da

    2011-01-01

    FOXO3a, a well-known transcriptional regulator, controls a wide spectrum of biological processes. The Phosphoinositide-3-kinase (PI3K)/Akt signaling pathway inactivates FOXO3a via phosphorylation-induced nuclear exclusion and degradation. A loss or gain of FOXO3a activity has been correlated with efficiency of chemotherapies in various cancers including oral squamous cell carcinoma (OSCC). Therefore, in the current study, we have investigated the FOXO3a activity modulating and antitumor effects of rapamycin and cisplatin in OSCC cells. Cisplatin inhibited proliferation and induced apoptosis in a dose-dependent way in OSCC Tca8113 cells. Rapamycin alone had no effect on cell proliferation and apoptosis. Rapamycin downregulated the expression of S-phase kinase associated protein-2 (Skp2) and increased the FOXO3a protein stability but induced the upregulation of feedback Akt activation-mediated FOXO3a phosphorylation. Cisplatin decreased the phosphorylation of FOXO3a via Akt inhibition. Rapamycin combined with cisplatin as its feedback Akt activation inhibitor revealed the most dramatic FOXO3a nuclear localization and reactivation with the prevention of its feedback loop and exposed significant synergistic effects of decreased cell proliferation and increased apoptosis in vitro and decreased tumor size in vivo. Furthermore, the downstream effects of FOXO3a reactivation were found to be accumulation of p27 and Bim. In conclusion, rapamycin/cisplatin combination therapy boosts synergistic antitumor effects through the significant FOXO3a reactivation in OSCC cells. These results may represent a novel mechanism by which rapamycin/cisplatin combination therapy proves to be a potent molecular-targeted strategy for OSCC.

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

    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. Non-equilibrium synergistic effects in atmospheric pressure plasmas.

    Guo, Heng; Zhang, Xiao-Ning; Chen, Jian; Li, He-Ping; Ostrikov, Kostya Ken

    2018-03-19

    Non-equilibrium is one of the important features of an atmospheric gas discharge plasma. It involves complicated physical-chemical processes and plays a key role in various actual plasma processing. In this report, a novel complete non-equilibrium model is developed to reveal the non-equilibrium synergistic effects for the atmospheric-pressure low-temperature plasmas (AP-LTPs). It combines a thermal-chemical non-equilibrium fluid model for the quasi-neutral plasma region and a simplified sheath model for the electrode sheath region. The free-burning argon arc is selected as a model system because both the electrical-thermal-chemical equilibrium and non-equilibrium regions are involved simultaneously in this arc plasma system. The modeling results indicate for the first time that it is the strong and synergistic interactions among the mass, momentum and energy transfer processes that determine the self-consistent non-equilibrium characteristics of the AP-LTPs. An energy transfer process related to the non-uniform spatial distributions of the electron-to-heavy-particle temperature ratio has also been discovered for the first time. It has a significant influence for self-consistently predicting the transition region between the "hot" and "cold" equilibrium regions of an AP-LTP system. The modeling results would provide an instructive guidance for predicting and possibly controlling the non-equilibrium particle-energy transportation process in various AP-LTPs in future.

  8. A NOTCH-sensitive uPAR-regulated oncolytic adenovirus effectively suppresses pancreatic tumor growth and triggers synergistic anticancer effects with gemcitabine and nab-paclitaxel.

    Mato-Berciano, Ana; Raimondi, Giulia; Maliandi, Maria Victoria; Alemany, Ramon; Montoliu, Lluis; Fillat, Cristina

    2017-04-04

    Notch signaling pathway is an embryonic program that becomes reactivated in pancreatic cancer and contributes to cancer stem cell (CSC) maintenance. We explored the concept of oncolytic adenoviral activity in response to Notch activation signaling, in the context of a chimeric promoter with uPAR regulatory sequences, as a strategy to drive its activity in neoplastic and CSC. We explored the advantages of a chemo-virotherapy approach based on synergistic combinations. Regulatory sequences recognized by the transcriptional factor CSL upstream a minimal uPAR promoter were engineered in adenoviral vectors and in the oncolytic adenovirus AdNuPARmE1A. Viral response to Notch signaling, and viral potency in cell lines and pancreatic cancer stem cells (PCSC) was tested. Preclinical toxicity and antitumor efficacy in xenografts and Patient-derived xenografts (PDX) mouse models was evaluated, as unimodal or in combination with gemcitabine+nab-paclitaxel. Mechanistic studies were conducted to explore the synergism of combined therapies.We demonstrate that CSL-binding site optimized-engineered sequences respond to Notch activation in AdNuPARmLuc and AdNuPARmE1A. AdNuPARmE1A showed strong lytic effects in pancreatic cancer cell lines and PCSC. AdNuPARmE1A displayed attenuated activity in normal tissues, but robust antitumor effects in xenograft and PDX models, leading to a reduced capacity of treated tumors to form tumorspheres. Chemo-virotherapy treatment enlarged therapeutic response in both tumor models. Synergistic effects of the combination resulted from viral sensitization of apoptotic cell death triggered by chemotherapy.In summary we present a novel effective oncolytic adenovirus, AdNuPARmE1A that reduces PCSC and presents synergistic effects with gemcitabine and nab-paclitaxel, supporting further clinical development.

  9. Antitumor Effects of Palladium-α-Lipoic Acid Complex Formulation as an Adjunct in Radiotherapy.

    Veena, Ravindran Kalathil; Ajith, Thekkuttuparambil Ananthanarayanan; Janardhanan, Kainoor Krishnankutty; Antonawich, Francis

    2016-01-01

    Several investigations have been initiated to enhance the antitumor effect of radiation and ameliorate its adverse effects such as reducing blood cell counts and causing DNA damage in normal cells. Compounds that enhance the antitumor activity of radiation without reducing blood cell counts or damaging DNA in normal cells can be of immense use as an adjunct in radiotherapy. We evaluated the antitumor effect of a specific set of minerals, vitamins, and amino acids (Poly-MVA) (2 mL/kg, per os), with and without radiation, against Dalton's lymphoma ascites (DLA) and Ehrlich's ascites carcinoma (EAC) cell lines that were transplanted in a solid-tumor model. Whole-body γ-radiation exposure (2 Gy) was performed using 60Co. Poly-MVA enhanced the antitumor effect of radiation when administered beforehand. Furthermore, Poly-MVA administered once daily for 2 wk, immediately after 4 Gy irradiation, protected DNA damage in peripheral blood. It also rendered protection against the radiation-induced reduction of platelet count. The unique electronic and redox properties of palladium-α-lipoic acid complex in Poly-MVA appear to be responsible for the exhibited effect. The results conclude that the antitumor-enhancing and normal cell-protective effect of Poly-MVA warrants additional studies for its potential clinical application.

  10. Low-dose cyclophosphamide administered as daily or single dose enhances the antitumor effects of a therapeutic HPV vaccine

    Peng, Shiwen; Lyford-Pike, Sofia; Akpeng, Belinda; Wu, Annie; Hung, Chien-Fu; Hannaman, Drew; Saunders, John R.; Wu, T.-C.

    2012-01-01

    Although therapeutic HPV vaccines are able to elicit systemic HPV-specific immunity, clinical responses have not always correlated with levels of vaccine-induced CD8+ T cells in human clinical trials. This observed discrepancy may be attributable to an immunosuppressive tumor microenvironment in which the CD8+ T cells are recruited. Regulatory T cells (Tregs) are cells that can dampen cytotoxic CD8+ T-cell function. Cyclophosphamide (CTX) is a systemic chemotherapeutic agent, which can eradicate immune cells, including inhibitory Tregs. The optimal dose and schedule of CTX administration in combination with immunotherapy to eliminate the Treg population without adversely affecting vaccine-induced T-cell responses is unknown. Therefore, we investigated various dosing and administration schedules of CTX in combination with a therapeutic HPV vaccine in a preclinical tumor model. HPV tumor-bearing mice received either a single preconditioning dose or a daily dose of CTX in combination with the pNGVL4a-CRT/E7(detox) DNA vaccine. Both single and daily dosing of CTX in combination with vaccine had a synergistic anti-tumor effect as compared to monotherapy alone. The potent antitumor responses were attributed to the reduction in Treg frequency and increased infiltration of HPV16 E7-specific CD8+ T cells, which led to higher ratios of CD8+/Treg and CD8+/CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs). There was an observed trend toward decreased vaccine-induced CD8+ T-cell frequency with daily dosing of CTX. We recommend a single, preconditioning dose of CTX prior to vaccination due to its efficacy, ease of administration, and reduced cumulative adverse effect on vaccine-induced T cells. PMID:23011589

  11. Synergistic anti-tumor effects of nitroreductase mutants and p53

    Mahboobeh Razmkhah

    2014-01-01

    Conclusion: Combination of T41L/F70A NTR with p53 may have more advantages for treatment of different types of cancers compared to the other NTRs and p53 alone. The present study results may open new windows for getting desired outcome in gene therapy of different types of cancer.

  12. Potential Antitumor Effects of Pomegranates and Its Ingredients.

    Rahmani, Arshad H; Alsahli, Mohammed A; Almatroodi, Saleh A

    2017-01-01

    The treatment based on plant or plant derivatives is a promising strategy in the killing of cancers cells. Moreover, wide-ranging finding has established that medicinal plant and its ingredient modulate several cells signaling pathways or inhibiting the carcinogenesis process. In this vista, pomegranates fruits, seeds and peels illustrate cancer preventive role seems to be due to rich source of antioxidant and other valuable ingredients. Furthermore, anti-tumour activities of pomegranates have been evidences through the modulation of cell signaling pathways including transcription factor, apoptosis and angiogenesis. In this review article, anti-tumor activity of pomegranates and its components or its different type of extracts are described to understand the mechanism of action of pomegranates in cancer therapy.

  13. On effect of diluent nature on synergistic extraction

    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

  14. [Effective productions of plant secondary metabolites having antitumor activity by plant cell and tissue cultures].

    Taniguchi, Shoko

    2005-06-01

    Methods for the effective production of plant secondary metabolites with antitumor activity using plant cell and tissue cultures were developed. The factors in tannin productivity were investigated using culture strains producing different types of hydrolyzable tannins, i.e., gallotannins (mixture of galloylglucoses), ellagi-, and dehydroellagitannins. Production of ellagi- and dehydroellagitannins was affected by the concentrations and ratio of nitrogen sources in the medium. The formation of oligomeric ellagitannins in shoots of Oenothera tetraptera was correlated with the differentiation of tissues. Cultured cells of Eriobotrya japonica producing ursane- and oleanane-type triterpenes with antitumor activities were also established.

  15. Synergistic effects of metformin, resveratrol, and hydroxymethylbutyrate on insulin sensitivity

    Bruckbauer A

    2013-02-01

    Full Text Available Antje Bruckbauer,1 Michael B Zemel1,21NuSirt Sciences Inc, 2Department of Nutrition, University of Tennessee, Knoxville, TN, USABackground: The purpose of this study was to determine whether a mixture of the polyphenol, resveratrol, and the leucine metabolite, hydroxymethylbutyrate (HMB, acts synergistically with low doses of metformin to impact insulin sensitivity and AMP-activated protein kinase-dependent outcomes in cell culture and in diabetic mice.Methods: C2C12 skeletal myotubes and 3T3-L1 adipocytes were treated with resveratrol 0.2 µM, HMB 5 µM, and metformin 0.1 mM alone or in combination. db/db mice were treated for 2 weeks with high (1.5 g/kg diet, low (0.75 g/kg diet, or very low (0.25 g/kg diet doses of metformin alone or in combination with a diet containing resveratrol 12.5 mg and CaHMB 2 g/kg.Results: The combination of metformin-resveratrol-HMB significantly increased fat oxidation, AMP-activated protein kinase, and Sirt1 activity in muscle cells compared with metformin or resveratrol-HMB alone. A similar trend was found in 3T3L1 adipocytes. In mice, the two lower doses of metformin exerted no independent effect but, when combined with resveratrol-HMB, both low-dose and very low-dose metformin improved insulin sensitivity (HOMAIR, plasma insulin levels, and insulin tolerance test response to a level comparable with that found for high-dose metformin. In addition, the metformin-resveratrol-HMB combination decreased visceral fat and liver weight in mice.Conclusion: Resveratrol-HMB combined with metformin may act synergistically on AMP-activated protein kinase-dependent pathways, leading to increased insulin sensitivity, which may reduce the therapeutic doses of metformin necessary in the treatment of diabetes.Keywords: diabetes, AMP-activated protein kinase, Sirt1, fat oxidation

  16. Combining antiangiogenic therapy with adoptive cell immunotherapy exerts better antitumor effects in non-small cell lung cancer models.

    Shujing Shi

    Full Text Available INTRODUCTION: Cytokine-induced killer cells (CIK cells are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment. METHODS: We combined recombinant human endostatin (rh-endostatin and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells. RESULTS: Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments. CONCLUSIONS: Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells

  17. Antioxidants Impair Anti-Tumoral Effects of Vorinostat, but Not Anti-Neoplastic Effects of Vorinostat and Caspase-8 Downregulation

    Bergadà, Laura; Yeramian, Andree; Sorolla, Annabel; Matias-Guiu, Xavier; Dolcet, Xavier

    2014-01-01

    We have recently demonstrated that histone deacetylase inhibitor, Vorinostat, applied as a single therapy or in combination with caspase-8 downregulation exhibits high anti-tumoral activity on endometrial carcinoma cell lines. In the present study, we have assessed the signalling processes underlying anti-tumoral effects of Vorinostat. Increasing evidence suggests that reactive oxygen species are responsible for histone deacetylase inhibitor-induced cell killing. We have found that Vorinostat...

  18. Antitumor effects of traditional Chinese medicine targeting the cellular apoptotic pathway

    Xu HL

    2015-05-01

    Full Text Available Huanli Xu,1 Xin Zhao,2 Xiaohui Liu,1 Pingxiang Xu,1 Keming Zhang,2 Xiukun Lin11Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, 2Department of Hepatobiliary Surgery, 302 Hospital of Chinese People’s Liberation Army, Beijing, People’s Republic of ChinaAbstract: Defects in apoptosis are common phenomena in many types of cancer and are also a critical step in tumorigenesis. Targeting the apoptotic pathway has been considered an intriguing strategy for cancer therapy. Traditional Chinese medicine (TCM has been used in the People’s Republic of China for thousands of years, and many of the medicines have been confirmed to be effective in the treatment of a number of tumors. With increasing cancer rates worldwide, the antitumor effects of TCMs have attracted more and more attention globally. Many of the TCMs have been shown to have antitumor activity through multiple targets, and apoptosis pathway-related targets have been extensively studied and defined to be promising. This review focuses on several antitumor TCMs, especially those with clinical efficacy, based on their effects on the apoptotic signaling pathway. The problems with and prospects of development of TCMs as anticancer agents are also presented.Keywords: traditional Chinese medicine, antitumor effects, apoptotic pathway

  19. Antitumor and biological effects of black pine (Pinus nigra) pollen nuclease

    Lipovová, P.; Podzimek, T.; Orctová, Lidmila; Matoušek, Jaroslav; Poučková, P.; Souček, J.; Matoušek, Josef

    2008-01-01

    Roč. 55, - (2008), s. 158-164 ISSN 0028-2685 Institutional research plan: CEZ:AV0Z50510513; CEZ:AV0Z50450515 Keywords : pollen nuclease * Antitumor effect Subject RIV: FD - Oncology ; Hematology Impact factor: 1.179, year: 2008

  20. Antitumor and apoptotic effects of cucurbitacin a in A-549 lung ...

    Background: The main aim of this study was to demonstrate the antitumor potential of cucurbitacin A on A-549 NSCLC (non-small cell lung cancer cells). The effects of Cucurbitacin A on apoptotic induction, cell physic, cell cycle failure and m-TOR/PI3K/Akt signalling pathway were also investigated in the present study.

  1. Immunological and antitumor effects of IL-23 as a cancer vaccine adjuvant

    Overwijk, Willem W.; de Visser, Karin E.; Tirion, Felicia H.; de Jong, Laurina A.; Pols, Thijs W. H.; van der Velden, Yme U.; van den Boorn, Jasper G.; Keller, Anna M.; Buurman, Wim A.; Theoret, Marc R.; Blom, Bianca; Restifo, Nicholas P.; Kruisbeek, Ada M.; Kastelein, Robert A.; Haanen, John B. A. G.

    2006-01-01

    The promising, but modest, clinical results of many human cancer vaccines indicate a need for vaccine adjuvants that can increase both the quantity and the quality of vaccine-induced, tumor-specific T cells. In this study we tested the immunological and antitumor effects of the proinflammatory

  2. Evaluation of Anti-tumor and Chemoresistance-lowering Effects of ...

    Evaluation of Anti-tumor and Chemoresistance-lowering Effects of Pectolinarigenin from Cirsium japonicum Fisch ex DC in Breast Cancer. Mingqian Lu, Xinhua Xu, Hongda Lu, Zhongxin Lu, Bingqing Xu, Chao Tan, Kezhi Shi, Rong Guo, Qingzhi Kong ...

  3. Curcuma increasing antitumor effect of Rhizoma paridis saponins through absorptive enhancement of paridis saponins.

    Man, Shuli; Li, Yuanyuan; Fan, Wei; Gao, Wenyuan; Liu, Zhen; Li, Nan; Zhang, Yao; Liu, Changxiao

    2013-09-15

    Rhizoma paridis saponins (RPS) played a good antitumor role in many clinical applications. However, low oral bioavailability limited its application. In this research, water extract of Curcuma (CW) significantly increased antitumor effect of Rhizoma paridis saponins (RPS). GC-MS was used to identify its polar composition. HPLC was applied for determination of the content of curcuminoids in CW. As a result, 47 analytes with 0.65% of curcuminoids were identified in CW. According to the in vivo anti-tumor data, the best proportion of curcuminoids in CW with RPS was 16:500 (w/w). Using this ratio, curcuminoids significantly increased absorption of RPS in the everted rat duodenum sac system. In addition, curcuminoids decreased the promotion of RPS on rhodamine 123 efflux. The effect of curcuminoids was similar to that of the P-gp inhibitor, cyclosporin A in combination with RPS. In conclusion, drug combination of water extract of Curcuma with RPS was a good method to increase the antitumor effect of RPS. This combination would be a potent anticancer agent used in the prospective application. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

  4. Targeting Gene-Viro-Therapy with AFP driving Apoptin gene shows potent antitumor effect in hepatocarcinoma

    Zhang Kang-Jian

    2012-02-01

    Full Text Available Abstract Background Gene therapy and viral therapy are used for cancer therapy for many years, but the results are less than satisfactory. Our aim was to construct a new recombinant adenovirus which is more efficient to kill hepatocarcinoma cells but more safe to normal cells. Methods By using the Cancer Targeting Gene-Viro-Therapy strategy, Apoptin, a promising cancer therapeutic gene was inserted into the double-regulated oncolytic adenovirus AD55 in which E1A gene was driven by alpha fetoprotein promoter along with a 55 kDa deletion in E1B gene to form AD55-Apoptin. The anti-tumor effects and safety were examined by western blotting, virus yield assay, real time polymerase chain reaction, 3-(4,5-dimethylthiazol-2-yl-2, 5-diphenyltetrazolium bromide assay, Hoechst33342 staining, Fluorescence-activated cell sorting, xenograft tumor model, Immunohistochemical assay, liver function analysis and Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling assay. Results The recombinant virus AD55-Apoptin has more significant antitumor effect for hepatocelluar carcinoma cell lines (in vitro than that of AD55 and even ONYX-015 but no or little impair on normal cell lines. Furthermore, it also shows an obvious in vivo antitumor effect on the Huh-7 liver carcinoma xenograft in nude mice with bigger beginning tumor volume till about 425 mm3 but has no any damage on the function of liver. The induction of apoptosis is involved in AD55-Apoptin induced antitumor effects. Conclusion The AD55-Apoptin can be a potential anti-hepatoma agent with remarkable antitumor efficacy as well as higher safety in cancer targeting gene-viro-therapy system.

  5. Synergistic effect of Murraya koenigii and Telfairia occidentalis ...

    Larger zones of inhibition were observed for M. Koenigii extract than T. occidentalis extract, and larger zones of inhibition were observed by their synergy than on their separate use. Synergistic antibacterial activity of the extract ranged from 0 mm to 20.0 ± 0.03 mm, zone of inhibition of M. koenigii extract ranged from 0 mm ...

  6. Effects of immune synergist of Chinese medicinal herbs on the ...

    AJL

    2012-01-19

    Jan 19, 2012 ... 1Institute of Animal Husbandry and Veterinary Sciences, Shanxi Academy of Agricultural Sciences, Taiyuan 030032, China. 2Modern ... Two-month-old piglets were fed with 1, 1.5 and 2% immune synergist of Chinese medicinal herbs together with ..... saponins that are capable of activating immune system.

  7. Towards enhancing photocatalytic hydrogen generation: Which is more important, alloy synergistic effect or plasmonic effect?

    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.

  8. Study on fluorouracil–chitosan nanoparticle preparation and its antitumor effect

    Gaimin Chen

    2016-05-01

    Full Text Available To successfully prepare fluorouracil–chitosan nanoparticles, and further analyze its anti-tumor activity mechanism, this paper makes a comprehensive study of existing preparation prescription and makes a detailed analysis of fluorouracil–chitosan in vitro release and pharmacodynamic behavior of animals. Two-step synthesis method is adopted to prepare 5-FU–CS–mPEG prodrugs, and infrared, 1H NMR and differential thermal analysis are adopted to analyze characterization synthetic products of prepared drugs. To ensure clinical efficacy of prepared drugs, UV spectrophotometry is adopted for determination of drug loading capacity of prepared drugs, transmission electron microscopy is adopted to observe the appearance, dynamic dialysis method is used to observe in vitro drug release of prepared drugs and fitting of various release models is done. Anti-tumor effect is studied via level of animal pharmacodynamics. After the end of the experiment, tumor inhibition rate, spleen index and thymus index of drugs are calculated. Experimental results show that the prepared drugs are qualified in terms of regular shape, dispersion, drug content, etc. Animal pharmacodynamics experiments have shown that concentration level of drug loading capacity of prepared drugs has a direct impact on anti-tumor rate. The higher the concentration, the higher the anti-tumor rate. Results of pathological tissue sections of mice show that the prepared drugs cause varying degrees of damage to receptor cells, resulting in cell necrosis or apoptosis problem. It can thus be concluded that ion gel method is an effective method to prepare drug-loading nanoparticles, with prepared nanoparticles evenly distributed in regular shape which demonstrate good slow-release characteristics in receptor vitro and vivo. At the same time, after completion of drug preparation, relatively strong anti-tumor activity can be generated for the receptor, so this mode of preparation enjoys broad

  9. The in vitro sustained release profile and antitumor effect of etoposide-layered double hydroxide nanohybrids

    Qin LL

    2013-05-01

    Full Text Available Lili Qin,1 Mei Wang,2 Rongrong Zhu,3 Songhui You,1 Ping Zhou,1 Shilong Wang31Department of Physical Education, Tongji University, Shanghai, People's Republic of China; 2Department of Chemistry, Tongji University, Shanghai, People's Republic of China; 3School of Life Science and Technology, Tongji University, Shanghai, People's Republic of ChinaAbstract: Magnesium-aluminum layered double hydroxides intercalated with antitumor drug etoposide (VP16 were prepared for the first time using a two-step procedure. The X-ray powder diffraction data suggested the intercalation of VP16 into layers with the increased basal spacing from 0.84–1.18 nm was successful. Then, it was characterized by X-ray powder diffraction, Fourier transform infrared spectroscopy, thermogravimetry and differential thermal analysis, and transmission electron microscopy. The prepared nanoparticles, VP16-LDH, showed an average diameter of 62.5 nm with a zeta potential of 20.5 mV. Evaluation of the buffering effect of VP16-LDH indicated that the nanohybrids were ideal for administration of the drugs that treat human stomach irritation. The loading amount of intercalated VP16 was 21.94% and possessed a profile of sustained release. The mechanism of VP16-LDH release in the phosphate buffered saline solution at pH 7.4 is likely controlled by the diffusion of VP16 anions from inside to the surface of LDH particles. The in vitro cytotoxicity and antitumor assays indicated that VP16-LDH hybrids were less toxic to GES-1 cells while exhibiting better antitumor efficacy on MKN45 and SGC-7901 cells. These results imply that VP16-LDH is a potential antitumor drug for a broad range of gastric cancer therapeutic applications.Keywords: layered double hydroxides, etoposide, drug delivery, antitumor effect, sustained release

  10. Pharmacokinetic-Pharmacodynamic Modeling of the Anti-Tumor Effect of Sunitinib Combined with Dopamine in the Human Non-Small Cell Lung Cancer Xenograft.

    Hao, Fangran; Wang, Siyuan; Zhu, Xiao; Xue, Junsheng; Li, Jingyun; Wang, Lijie; Li, Jian; Lu, Wei; Zhou, Tianyan

    2017-02-01

    To investigate the anti-tumor effect of sunitinib in combination with dopamine in the treatment of nu/nu nude mice bearing non-small cell lung cancer (NSCLC) A549 cells and to develop the combination PK/PD model. Further, simulations were conducted to optimize the administration regimens. A PK/PD model was developed based on our preclinical experiment to explore the relationship between plasma concentration and drug effect quantitatively. Further, the model was evaluated and validated. By fixing the parameters obtained from the PK/PD model, simulations were built to predict the tumor suppression under various regimens. The synergistic effect was observed between sunitinib and dopamine in the study, which was confirmed by the effect constant (GAMA, estimated as 2.49). The enhanced potency of dopamine on sunitinib was exerted by on/off effect in the PK/PD model. The optimal dose regimen was selected as sunitinib (120 mg/kg, q3d) in combination with dopamine (2 mg/kg, q3d) based on the simulation study. The synergistic effect of sunitinib and dopamine was demonstrated by the preclinical experiment and confirmed by the developed PK/PD model. In addition, the regimens were optimized by means of modeling as well as simulation, which may be conducive to clinical study.

  11. Host-mediated antitumor effect of DMG, a degraded D-manno-D-glucan from Microellobosporia grisea culture fluid.

    Nakajima, H; Hashimoto, S; Nagao, S; Kita, Y; Khono, M; Ogawa, H; Abe, S; Mizuno, D

    1984-03-01

    DMG, a new polysaccharide with a well-characterized structure, isolated from the culture filtrate of an actinomycetes and then degraded by acid treatment, was tested for antitumor activity on allogeneic and syngeneic tumors in mice. In the allogeneic Ehrlich solid tumor system, DMG showed antitumor activity over a wide dose range, its optimal dose being 10-100 mg/kg. The optimal time of DMG administration was 1-2 weeks after tumor inoculation, but DMG was also effective when given before tumor inoculation. DMG was effective when given ip, sc, it (intratumorally) or iv. DMG also had antitumor effects on syngeneic tumors. It rapidly inhibited the growth of MM46 mammary carcinoma, MH134 hepatoma, and Meth A fibrosarcoma, and also inhibited spontaneous pulmonary metastases of B16-BL6 melanoma. However, it had no direct cytocidal action on tumor cells in vitro. Its antitumor activity was much less in athymic nude mice and in mice immunosuppressed by whole-body X-irradiation than in normal hosts.Thus, DMG was shown to exert antitumor activity via host-mediated mechanisms. Its antitumor activity is discussed in comparison with those of other antitumor polysaccharides.

  12. T lymphocytes derived from human cord blood provide effective antitumor immunotherapy against a human tumor

    Kim Tae-Sik

    2011-06-01

    Full Text Available Abstract Background Although the graft-versus-tumor (GVT effect of donor-derived T cells after allogeneic hematopoietic stem cell transplantation has been used as an effective adoptive immunotherapy, the antitumor effects of cord blood (CB transplantation have not been well studied. Methods We established the animal model by transplantation of CB mononuclear cells and/or tumor cells into NOD/SCID mice. The presence of CB derived T cells in NOD/SCID mice or tumor tissues were determined by flow cytometric and immunohistochemical analysis. The anti-tumor effects of CB derived T cells against tumor was determined by tumor size and weight, and by the cytotoxicity assay and ELISPOT assay of T cells. Results We found dramatic tumor remission following transfer of CB mononuclear cells into NOD/SCID mice with human cervical tumors with a high infiltration of CD3+ T cells in tumors. NOD/SCID mice that receive neonatal CB transplants have reconstituted T cells with significant antitumor effects against human cervical and lung tumors, with a high infiltration of CD3+ T cells showing dramatic induction of apoptotic cell death. We also confirmed that T cells showed tumor specific antigen cytotoxicity in vitro. In adoptive transfer of CD3+ T cells into mice with pre-established tumors, we observed much higher antitumor effects of HPV-specific T cells by ELISPOT assays. Conclusions Our results show that CB derived T lymphocytes will be useful for novel immunotherapeutic candidate cells for therapy of several tumors in clinic.

  13. Immunomodulatory and antitumor effects in vivo by the cytoplasmic fraction of Lactobacillus casei and Bifidobacterium longum.

    Lee, Jung-Woo; Shin, Jung-Gul; Kim, Eun Hee; Kang, Hae Eun; Yim, In Been; Kim, Ji Yeon; Joo, Hong-Gu; Woo, Hee Jong

    2004-03-01

    The immunomodulatory and antitumor effects of lactic acid bacteria (LABs) were investigated. Cytoplasmic fraction of Lactobacillus acidophilus, Lactobacillus casei and Bifidobacterium longum were tested for the antiproliferative activity in vitro to SNUC2A, SNU1, NIH/3T3 and Jurkat cell lines by crystal violet assay. All cytoplasmic fraction suppressed proliferation of tumor cells, though L. casei and B. longum were more effective. From these results, cytoplasmic fraction of L. casei and B. longum with Y400 as a control were administered as dietary supplements to Balb/c mice for 2, and 4 consecutive wks. Administration for 4 wks enhanced the number of total T cells, NK cells and MHC class II+ cells, and CD4-CD8+ T cells in flow cytometry analysis. To determine of antitumor activity of LABs preparation in vivo, F9 teratocarcinoma cells were inoculated on mice at 14th day. Body weight was decreased with increased survival rate in all groups with the cytoplasm of LABs. Our results showed that cytoplasmic fraction of LABs had direct antiproliferative effects on tumor cell lines in vitro, effects on immune cells in vivo, and antitumor effects on tumor-bearing mice with prolonged survival periods.

  14. Increasing antitumor effects of chemoradiotherapy by drug efflux inhibition with encapsulated anti-RLIP-76

    Harada, Satoshi; Ehara, Shigeru; Ishii, Keizo

    2011-01-01

    Microencapsulated anti-RLIP76 was tested in vivo using C3He/J mice to determine the increasing of antitumor effects by chemotherapeutic agent efflux inhibition during chemoradiotherapy. Microcapsules were produced by spraying a mixture of 3.0% hyaluronic acid, 2.0% alginate, 3.0% H 2 O 2 , and 0.3 mmol carboplatin onto a mixture of 0.3 mol FeCl 2 and 0.15 mol CaCl 2 . Microcapsules were subcutaneously injected into MM46 tumors previously inoculated into the left hind legs of C3He/J mice. Subsequent radiotherapy consisted of tumor irradiation with 10 Gy or 20 Gy 60 Co. The antitumor effects of microcapsules were tested by measuring tumor size and monitoring tumor growth. Three types of adverse effects were considered: fuzzy hair, loss of body weight, and mortality. Carboplatin levels were monitored using particle-induced X-ray emission (PIXE) and a micro-PIXE camera. Anti-RLIP76 inhibited the efflux of carboplatin from tumor tissue, which led to an increase in the concentration of carboplatin. Higher carboplatin concentration significantly increased the combined antitumor effect of radiation and chemotherapy. A significant decrease in adverse effects was also observed with microencapsulated anti-RLIP76. (author)

  15. Antioxidant synergistic effects of Osmanthus fragrans flowers with green tea and their major contributed antioxidant compounds

    Mao, Shuqin; Wang, Kaidi; Lei, Yukun; Yao, Shuting; Lu, Baiyi; Huang, Weisu

    2017-01-01

    The antioxidant synergistic effects of Osmanthus fragrans flowers with green tea were evaluated, and their major antioxidant compounds contributed to the total amount of synergy were determined. The antioxidant compounds in O. fragrans flowers with green tea were identified by LC-MS and quantified by UPLC-PDA. The synergistic antioxidant interactions between O. fragrans flowers with green tea and their antioxidant compounds were tested using the Prieto?s model after the simulated digestion. T...

  16. Anti-tumor effect of a recombinant plasmid expressing human interleukin-12: an initial research

    Zheng Chuansheng; Xia Xiangwen; Feng Gansheng; Li Xin; Liang Huimin; Liang Bin

    2010-01-01

    Objective: To study the anti-tumor effect of a recombinant plasmid expressing human interleukin-12 (pEGFP-CI I L- 12) in vivo and in vitro. Methods: We transduct the recombinant gene (pEGFP-CI I L-12) to liver cancer cell HepG 2 in vitro, and detect reproductive activity of the cell using MTT and the activity of expressing vascular endothelial growth factor(VEGF) using semiquantitative PCR. And then, we deliver the gene to rabbit liver tumor tissue intraarterial and combine with chemoembolization to observe the anti- tumor effect to VX 2 tumor in vivo. Results: There are no statistical difference compared With control group in activity of reproductive and expressing VEGF in vitro. In vivo, tumor growth rate significantly reduce in gene therapy combined with chemoembolization group. Conclusion: Recombinant gene (pEGFP-Cl I L-12) exhibit significant anti-tumor effect in vivo but not in vitro, perhaps the anti-tumor effect is associated with an indirect pathway instead of a direct pathway. (authors)

  17. The Therapeutic Effect of the Antitumor Drug 11 Beta and Related Molecules on Polycystic Kidney Disease

    2017-10-01

    models (Somlo, Yale). Preparation work to assemble a collection of probes specific for oxidative stress genes and other PKD specific genes (as part... Worked : 6 Contribution to Project: Performance of experiments including those related to mitochondrial biology in vivo and unfolded protein...1 AWARD NUMBER: W81XWH-15-1-0364 TITLE: THE THERAPEUTIC EFFECT OF THE ANTITUMOR DRUG 11 BETA AND RELATED MOLECULES ON POLYYSTIC KIDNEY DISEASE

  18. An oncolytic adenovirus enhances antiangiogenic and antitumoral effects of a replication-deficient adenovirus encoding endostatin by rescuing its selective replication in nasopharyngeal carcinoma cells

    Liu, Ran-yi; Zhou, Ling; Zhang, Yan-ling; Huang, Bi-jun; Ke, Miao-la; Chen, Jie-min; Li, Li-xia; Fu, Xiang; Wu, Jiang-xue; Huang, Wenlin

    2013-01-01

    Highlights: •H101 promotes endostatin expression by Ad-Endo via rescuing Ad-Endo replication. •H101 rescued Ad-Endo replication by supplying E1A and E1B19k proteins. •Ad-Endo enhanced the cytotoxicity of H101 in NPC cells. •Ad-Endo and oncolytic Ad H101 have synergistic antitumor effects on NPC. -- Abstract: A replication-deficient adenovirus (Ad) encoding secreted human endostatin (Ad-Endo) has been demonstrated to have promising antiangiogenic and antitumoral effects. The E1B55k-deleted Ad H101 can selectively lyse cancer cells. In this study, we explored the antitumor effects and cross-interactions of Ad-Endo and H101 on nasopharyngeal carcinoma (NPC). The results showed that H101 dramatically promoted endostatin expression by Ad-Endo via rescuing Ad-Endo replication in NPC cells, and the expressed endostatin proteins significantly inhibited the proliferation of human umbilical vein endothelial cells. E1A and E1B19k products are required for the rescuing of H101 to Ad-Endo replication in CNE-1 and CNE-2 cells, but not in C666-1 cells. On the other hand, Ad-Endo enhanced the cytotoxicity of H101 by enhancing Ad replication in NPC cells. The combination of H101 and Ad-Endo significantly inhibited CNE-2 xenografts growth through the increased endostatin expression and Ad replication. These findings indicate that the combination of Ad-Endo gene therapy and oncolytic Ad therapeutics could be promising in comprehensive treatment of NPC

  19. An oncolytic adenovirus enhances antiangiogenic and antitumoral effects of a replication-deficient adenovirus encoding endostatin by rescuing its selective replication in nasopharyngeal carcinoma cells

    Liu, Ran-yi, E-mail: liuranyi@mail.sysu.edu.cn [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Zhou, Ling [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Zhang, Yan-ling [School of Biotechnology, Southern Medical University, Guangzhou 510515 (China); Huang, Bi-jun; Ke, Miao-la; Chen, Jie-min [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Li, Li-xia [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); General Hospital of Guangzhou Military Command of PLA, Guangzhou 510010 (China); Fu, Xiang; Wu, Jiang-xue [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Huang, Wenlin, E-mail: hwenl@mail.sysu.edu.cn [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Guangdong Provincial Key Laboratory of Tumor-Targeted Drug, Doublle Bioproducts Inc., Guangzhou 510663 (China)

    2013-12-13

    Highlights: •H101 promotes endostatin expression by Ad-Endo via rescuing Ad-Endo replication. •H101 rescued Ad-Endo replication by supplying E1A and E1B19k proteins. •Ad-Endo enhanced the cytotoxicity of H101 in NPC cells. •Ad-Endo and oncolytic Ad H101 have synergistic antitumor effects on NPC. -- Abstract: A replication-deficient adenovirus (Ad) encoding secreted human endostatin (Ad-Endo) has been demonstrated to have promising antiangiogenic and antitumoral effects. The E1B55k-deleted Ad H101 can selectively lyse cancer cells. In this study, we explored the antitumor effects and cross-interactions of Ad-Endo and H101 on nasopharyngeal carcinoma (NPC). The results showed that H101 dramatically promoted endostatin expression by Ad-Endo via rescuing Ad-Endo replication in NPC cells, and the expressed endostatin proteins significantly inhibited the proliferation of human umbilical vein endothelial cells. E1A and E1B19k products are required for the rescuing of H101 to Ad-Endo replication in CNE-1 and CNE-2 cells, but not in C666-1 cells. On the other hand, Ad-Endo enhanced the cytotoxicity of H101 by enhancing Ad replication in NPC cells. The combination of H101 and Ad-Endo significantly inhibited CNE-2 xenografts growth through the increased endostatin expression and Ad replication. These findings indicate that the combination of Ad-Endo gene therapy and oncolytic Ad therapeutics could be promising in comprehensive treatment of NPC.

  20. Transcutaneous carbon dioxide enhances the antitumor effect of radiotherapy on oral squamous cell carcinoma.

    Iwata, Eiji; Hasegawa, Takumi; Ueha, Takeshi; Takeda, Daisuke; Saito, Izumi; Kawamoto, Teruya; Akisue, Toshihiro; Sakai, Yoshitada; Sasaki, Ryohei; Kuroda, Ryosuke; Komori, Takahide

    2018-05-16

    Radiotherapy (RT) is one of the main treatment modalities for oral squamous cell carcinoma (OSCC), however, radioresistance is a major impediment to its clinical success and poses as a concern that needs to be addressed. Tumor hypoxia is known to be significantly associated with radioresistance in various malignancies, hence, resolving the hypoxic state of a tumor may improve the antitumor effect of RT on OSCC. We have previously revealed that transcutaneous CO2 induced mitochondrial apoptosis and suppressed tumor growth in OSCC by resolving hypoxia. Considering the previous study, we hypothesized that transcutaneous CO2 may enhance the antitumor effect of RT on OSCC by improving intratumoral hypoxia, thereby overcoming radioresistance. In the present study, the combination of transcutaneous CO2 and RT significantly inhibited tumor growth compared with other treatments. This combination therapy also led to decreased expression of HIF-1α in parallel with increased expression of the cleaved forms of caspase-3-8-9 and PARP, which play essential roles in mitochondrial apoptosis. Additionally, the combination therapy increased the expression of ROS modulator 1 and subsequent mitochondrial ROS production, compared to RT alone. These results indicated that transcutaneous CO2 could potentially improve the antitumor effect of RT by decreasing the intratumoral hypoxia and increasing the mitochondrial apoptosis. Our findings indicated that CO2 therapy may be a novel adjuvant therapy in combination with RT for OSCC.

  1. Vaccination with OK-432 followed by TC-1 tumor lysate leads to significant antitumor effects.

    Chen, I-Ju; Yen, Chih-Feng; Lin, Kun-Ju; Lee, Chyi-Long; Soong, Yung-Kuei; Lai, Chyong-Huey; Lin, Cheng-Tao

    2011-07-01

    Human papillomavirus (HPV) infects large numbers of women worldwide and is present in more than 99% of all cervical cancer. TC-1 cell is a cell line with high expression of E7 antigen of HPV type 16 and its cell lysate has been demonstrated as an ideal inducer of E7-specific, antitumor immunity. OK-432 (Picibanil), a penicillin-killed Streptococcus pyogenes, has been reported with potent immunomodulation properties in cancer treatment by stimulating the maturation of dendritic cells (DCs) and secretion of Th-1 type cytokines. The current study demonstrated that a protocol to immunize the C57BL/6 mice with OK-432 followed by treatment with TC-1 lysate can generate markedly increased immune responses of E7-specific CD4(+) T cells and a moderate increase of natural killer (NK) cell, as well as a satisfactorily protective and therapeutic antitumor effect by triggering the DCs to prime T cells. Depletion of lymphocyte subset in vivo suggested that the antitumor effects could be dominantly executed by CD8+ T cells and followed by NK cells, and both of these reactions were induced by the generation of robust E7-specific CD4(+) T helper cell response. These findings warrant OK-432 combination with tumor-lysate as an effective and safe vaccine in future clinical application of cervical cancer.

  2. Antitumor Effects of Saffron-Derived Carotenoids in Prostate Cancer Cell Models

    Claudio Festuccia

    2014-01-01

    Full Text Available Crocus sativus L. extracts (saffron are rich in carotenoids. Preclinical studies have shown that dietary intake of carotenoids has antitumor effects suggesting their potential preventive and/or therapeutic roles. We have recently reported that saffron (SE and crocin (CR exhibit anticancer activity by promoting cell cycle arrest in prostate cancer (PCa cells. It has also been demonstrated that crocetin esters are produced after SE gastrointestinal digestion by CR hydrolysis. The aim of the present report was to investigate if SE, crocetin (CCT, and CR affected in vivo tumor growth of two aggressive PCa cell lines (PC3 and 22rv1 which were xenografted in male nude mice treated by oral gavage with SE, CR, and CCT. We demonstrated that the antitumor effects of CCT were higher when compared to CR and SE and treatments reverted the epithelial-mesenchymal transdifferentiation (EMT as attested by the significant reduction of N-cadherin and beta-catenin expression and the increased expression of E-cadherin. Additionally, SE, CR, and CCT inhibited PCa cell invasion and migration through the downmodulation of metalloproteinase and urokinase expression/activity suggesting that these agents may affect metastatic processes. Our findings suggest that CR and CCT may be dietary phytochemicals with potential antitumor effects in biologically aggressive PCa cells.

  3. Characterization and anti-tumor effects of chondroitin sulfate-chitosan nanoparticles delivery system

    Hu, Chieh-Shen; Tang, Sung-Ling; Chiang, Chiao-Hsi; Hosseinkhani, Hossein; Hong, Po-Da; Yeh, Ming-Kung

    2014-11-01

    We prepared chondroitin sulfate (ChS)-chitosan (CS) nanoparticles (NPs) as a delivery carrier, and doxorubicin (Dox) was used as a model drug. The physicochemical properties and biological activities of the Dox-ChS-CS NPs including the release profile, cell cytotoxicity, cellular internalization, and in vivo anti-tumor effects were evaluated. The ChS-CS NPs and Dox-ChS-CS NPs had a mean size of 262.0 ± 15.0 and 369.4 ± 77.4 nm, and a zeta potential of 30.2 ± 0.9 and 20.6 ± 3.1 mV, respectively. In vitro release tests showed that the 50 % release time for the Dox-ChS-CS NPs was 20 h. Two hepatoma cell models, HepG2 and HuH6, were used for evaluating the cytotoxicity and cell uptake efficiency of the Dox-ChS-CS NPs. A significant difference was observed between doxorubicin solution and the Dox-ChS-CS NPs in the cellular uptake within 60 min ( p < 0.01). For the in vivo human xenograft-nude mouse model, the Dox-ChS-CS NPs were more effective with less body weight loss and anti-tumor growth suppression in comparison with the Dox solution. The prepared Dox-ChS-CS NPs offer a new effective targeting nanoparticle delivery system platform for anti-tumor therapy.

  4. Intensification of the antitumoral effect of ionizing radiations in combined use of metronidazole and hyperglycemia

    Vinskaya, N.P.; Voloshina, E.A.; Vygodskaya, A.L.; Yarmonenko, S.P.

    1984-01-01

    The authors have shown that a more pronounced antitumor effect of radiation in the combined use of metronidazole and induced short-term hyperglycemia (STH) may result not only from the summation of the two effects: the sensitizing effect of metronidazole and decreased viability of irradiated cells caused by STH but also from the intensified cytotoxic effect of metronidazole on hypoxic tumor cells. It was also noted that when hypoxic cells subjected to the sensitizing effect of electron acceptor sensitizers are found in the normal (skin) and tumorous tissues, STH use following irradiation in the presence of metronidazole enchances selectively the tumor radiation effect

  5. Synergistic effects of concurrent blockade of PI3K and MEK pathways in pancreatic cancer preclinical models.

    Hua Zhong

    Full Text Available Patients with pancreatic cancer have dismal prognoses, and novel therapies are urgently needed. Mutations of the KRAS oncogene occur frequently in pancreatic cancer and represent an attractive target. Direct targeting of the predominant KRAS pathways have been challenging and research into therapeutic strategies have been now refocused on pathways downstream of KRAS, phosphoinositide 3-kinase (PI3K and mitogen-activated protein kinase (MAPK [MEK]. We hypothesized that concurrent inhibition of the PI3K and MEK pathways would result in synergistic antitumor activity, as it would circumvent the compensatory feedback loop between the two pathways. We investigated the combined effect of the PI3K inhibitor, GDC0941, and the MEK inhibitor, AZD6244, on cell viability, apoptosis and cell signaling in a panel of pancreatic cancer cell lines. An in vivo analysis was conducted on pancreatic cancer xenografts. While BxPC-3 (KRAS wild type and MIA PaCa-2 (KRAS mutated cell lines were sensitive to GDC0941 and AZD6244 as single agents, synergistic inhibition of tumor cell growth and induction of apoptosis were observed in both cell lines when the two drugs were combined. Interestingly, phosphorylation of the cap-dependent translational components, 4E-binding protein (p-4E-BP1 and S6 was found to be closely associated with sensitivity to GDC0941 and AZD6244. In BxPC-3 cell xenografts, survival differences were observed between the control and the AZD6244, GDC0941, and combination groups. Our study provides the rationale for concurrent targeting of the PI3K and MEK pathways, regardless of KRAS status, and suggests that phosphorylation of 4E-BP1and S6 can serve as a predictive biomarker for response to treatment.

  6. Clinical pharmacology of CAR-T cells: Linking cellular pharmacodynamics to pharmacokinetics and antitumor effects.

    Norelli, M; Casucci, M; Bonini, C; Bondanza, A

    2016-01-01

    Adoptive cell transfer of T cells genetically modified with tumor-reactive chimeric antigen receptors (CARs) is a rapidly emerging field in oncology, which in preliminary clinical trials has already shown striking antitumor efficacy. Despite these premises, there are still a number of open issues related to CAR-T cells, spanning from their exact mechanism of action (pharmacodynamics), to the factors associated with their in vivo persistence (pharmacokinetics), and, finally, to the relative contribution of each of the two in determining the antitumor effects and accompanying toxicities. In light of the unprecedented curative potential of CAR-T cells and of their predicted wide availability in the next few years, in this review we will summarize the current knowledge on the clinical pharmacology aspects of what is anticipated to be a brand new class of biopharmaceuticals to join the therapeutic armamentarium of cancer doctors. Copyright © 2015. Published by Elsevier B.V.

  7. Proton pump inhibitors while belonging to the same family of generic drugs show different anti-tumor effect.

    Lugini, Luana; Federici, Cristina; Borghi, Martina; Azzarito, Tommaso; Marino, Maria Lucia; Cesolini, Albino; Spugnini, Enrico Pierluigi; Fais, Stefano

    2016-08-01

    Tumor acidity represents a major cause of chemoresistance. Proton pump inhibitors (PPIs) can neutralize tumor acidity, sensitizing cancer cells to chemotherapy. To compare the anti-tumor efficacy of different PPIs in vitro and in vivo. In vitro experiments PPIs anti-tumor efficacy in terms of cell proliferation and cell death/apoptosis/necrosis evaluation were performed. In vivo PPIs efficacy experiments were carried out using melanoma xenograft model in SCID mice. Lansoprazole showed higher anti-tumor effect when compared to the other PPIs. The lansoprazole effect lasted even upon drug removal from the cell culture medium and it was independent from the lipophilicity of the PPIs formulation. These PPIs have shown different anti-tumoral efficacy, and the most effective at low dose was lansoprazole. The possibility to contrast tumor acidity by off-label using PPIs opens a new field of oncology investigation.

  8. Effects of Different Temperatures on the Chemical Structure and Antitumor Activities of Polysaccharides from Cordyceps militaris

    Eliyas Nurmamat

    2018-04-01

    Full Text Available The effects of different extraction temperatures (4 and 80 °C on the physicochemical properties and antitumor activity of water soluble polysaccharides (CMPs-4 and CMPs-80 from Cordyceps militaris (C. militaris were evaluated in this study. The results of gas chromatography (GC and high-performance gel permeation chromatography (HPGPC showed that a higher extraction temperature could degrade the polysaccharides with 188 kDa, mainly composed of glucose, and increase the dissolution rate of polysaccharides about 308 kDa, mainly consisting of rhamnose and galactose. In addition, the CMPs displayed the same sugar ring and category of glycosidic linkage based on Fourier-transform infrared spectroscopy (FTIR analysis, however, their invisible structural difference occurred in the specific rotation and conformational characteristics according to the results of specific optical rotation measurement and Congo red test. In vitro antitumor experiments indicated that CMPs-4 possessed stronger inhibitory effects on human esophagus cancer Eca-109 cells by inducing cell apoptosis more than CMPs-80 did. These findings demonstrated that the polysaccharides extracted with cold water (4 °C could be applied as a novel alternative chemotherapeutic agent or dietary supplement with its underlying antitumor property.

  9. Experimental study on anti-tumor effect of pcEgr-IFNγ gene-radiotherapy

    Wu Congmei; Li Xiuyi; Liu Shuzheng

    2001-01-01

    Objective: To study the anti-tumor effect of IFN γ gene-radiotherapy to murine melanoma and its immunologic mechanism. Methods: pcEgr-IFNγ plasmids were injected locally into tumor, and 36 hours later, the tumors were given 20 Gy X-ray irradiation. Tumor growth at different time, IFN γ expression 3 days later and immunologic indexes 15 days later were detected. Results: At 3-15 days after pcEgr-IFNγ gene-radiotherapy, the tumor growth rate was lower than that of irradiation alone group. It was also lower than that of gene therapy alone group and control plasmid combined with X-ray irradiation group significantly. Day 3 tumor IFN γ expression was higher than that of plasmid treatment alone group. NK activity, IL-2 and IFN γ secretion activities were higher than those of gene therapy alone and irradiation alone groups significantly. Conclusion: The antitumor effect of IFN γ gene-radiotherapy is better than that of either of them applied solely. Its mechanism might be concerned with the higher expression of IFN γ induced by irradiation in tumors and activation of anti-tumor immunologic functions

  10. Evaluation of the antitumor effects of vitamin K2 (menaquinone-7) nanoemulsions modified with sialic acid-cholesterol conjugate.

    Shi, Jia; Zhou, Songlei; Kang, Le; Ling, Hu; Chen, Jiepeng; Duan, Lili; Song, Yanzhi; Deng, Yihui

    2018-02-01

    Numerous studies have recently shown that vitamin K 2 (VK 2 ) has antitumor effects in a variety of tumor cells, but there are few reports demonstrating antitumor effects of VK 2 in vivo. The antitumor effects of VK 2 in nanoemulsions are currently not known. Therefore, we sought to characterize the antitumor potential of VK 2 nanoemulsions in S180 tumor cells in the present study. Furthermore, a ligand conjugate sialic acid-cholesterol, with enhanced affinity towards the membrane receptors overexpressed in tumors, was anchored on the surface of the nanoemulsions to increase VK 2 distribution to the tumor tissue. VK 2 was encapsulated in oil-in-water nanoemulsions, and the physical and chemical stability of the nanoemulsions were characterized during storage at 25 °C. At 25 °C, all nanoemulsions remained physically and chemically stable with little change in particle size. An in vivo study using syngeneic mice with subcutaneously established S180 tumors demonstrated that intravenous or intragastric administration of VK 2 nanoemulsions significantly suppressed the tumor growth. The VK 2 nanoemulsions modified with sialic acid-cholesterol conjugate showed higher tumor growth suppression than the VK 2 nanoemulsions, while neither of them exhibited signs of drug toxicity. In summary, VK 2 exerted effective antitumor effects in vivo, and VK 2 nanoemulsions modified with sialic acid-cholesterol conjugate enhanced the antitumor activity, suggesting that these VK 2 may be promising agents for the prevention or treatment of tumor in patients.

  11. Antitumor effects evaluation of a novel porphyrin derivative in photodynamic therapy.

    Li, Jian-Wei; Wu, Zhong-Ming; Magetic, Davor; Zhang, Li-Jun; Chen, Zhi-Long

    2015-12-01

    In this paper, the antitumor activity of a novel porphyrin-based photosensitizer 5,10,15,20-tetrakis[(5-diethylamino)pentyl] porphyrin (TDPP) was reported in vitro and in vivo. The photophysical and cellular properties of TDPP were investigated. The singlet oxygen generation quantum yield of TDPP was detected; it showed a high singlet oxygen quantum yield of 0.52. The intracellular distribution of photosensitizer was detected with laser scanning confocal microscopy. The efficiency of TDPP-photodynamic therapy (PDT) in vitro was analyzed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and in situ trypan blue exclusion test. Treated with a 630-nm laser, TDPP can kill cultured human esophageal cancer cell line (Eca-109) cells and reduce the growth of Eca-109 xenograft tumors significantly in BABL/c nude mice. And histopathological study was also used to confirm the antitumor effect. It has the perspective to be developed as a new antitumor drug in photodynamic therapy and deserves further investigation.

  12. Effect of immunomodifier on radiation-induced antitumor immunity following local irradiation to tumor, 2

    Mukae, Shiro; Norimura, Toshiyuki; Tsuchiya, Takehiko

    1988-01-01

    This study was carried out to clarify whether or not the antitumor cell-mediated immunity of host is more effectively induced by the combined use of mouse interferon-α/β (MuIFN-α/β) with local irradiation than by simple local irradiation to tumor. C3H/He female mice, MM46 tumor cells and mouse interferon-α/β (MuIFN-α/β) were used in the experiment. Antitumor activity in mice was evaluated by the inhibition of tumor growth and mean survival days after treatment. Spleen cell killing activity to MM46 tumor cells was measured to evaluate the antitumor activity in vitro. In the case of single use of MuIFN-α/β, tumor growth was more rapid than in the non-treated group (control) in vivo. The mean survival days were also reduced. There was no siginificant difference in tumor growth inhibition between combined therapy using X-irradiation and MuIFN-α/β, and single therapy by local irradiation. However, in the case of administration of MuIFN-α/β after irradiation, the mean survival days was significantly increased compared with the group receiving X-ray irradiation only. (author)

  13. Enhanced antitumor effects by combining an IL-12/anti-DNA fusion protein with avelumab, an anti-PD-L1 antibody.

    Fallon, Jonathan K; Vandeveer, Amanda J; Schlom, Jeffrey; Greiner, John W

    2017-03-28

    The combined therapeutic potential of an immunocytokine designed to deliver IL-12 to the necrotic regions of solid tumors with an anti-PD-L1 antibody that disrupts the immunosuppressive PD-1/PD-L1 axis yielded a combinatorial benefit in multiple murine tumor models. The murine version of the immunocytokine, NHS-muIL12, consists of an antibody (NHS76) recognizing DNA/DNA-histone complexes, fused with two molecules of murine IL-12 (NHS-muIL12). By its recognition of exposed DNA, NHS-muIL12 targets IL-12 to the necrotic portions of tumors; it has a longer plasma half-life and better antitumor efficacy against murine tumors than recombinant murine IL-12. It is shown here that NHS-muIL12, in an IFN-γ‒dependent mechanism, upregulates mPD-L1 expression on mouse tumors, which could be construed as an immunosuppressive action. Yet concurrent therapy with NHS-muIL12 and an anti-PD-L1 antibody resulted in additive/synergistic antitumor effects in PD-L1‒expressing subcutaneously transplanted tumors (MC38, MB49) and in an intravesical bladder tumor model (MB49). Antitumor efficacy correlated with (a) with a higher frequency of tumor antigen-specific splenic CD8+ T cells and (b) enhanced T cell activation over a wide range of NHS-muIL12 concentrations. These findings suggest that combining NHS-muIL12 and an anti-PD-L1 antibody enhances T cell activation and T cell effector functions within the tumor microenvironment, significantly improving overall tumor regression. These results should provide the rationale to examine the combination of these agents in clinical studies.

  14. Radiotherapy and antitumor immunity. An immunomodifying effect of ionizing radiation

    Klimovich, V.B.

    1983-01-01

    It has been found that a tumor is formed and spread under the influence of opposite but not mutually exlusive immune reactions. Radiation effect along with direct injury of tumoral cells and feeding neoplasms vessels changes the established equilibrium of immunologic factors, therefore it should be considered as immunomodifying one. The wide spread opinion according to which the therapeutic effect in case of radiotherapy is attained despite its depressive effect on immunity, should be revised as not corresponding to the facts. The data available allow one to assume that immunologic factors may play an essential role in realization of therapeutic effect of irradiation as well as in limitation of its efficiency. Investigations into immunologic aspects of oncology and radiology should be therefore directed to the search of methods of control of immune reactions of organism - the tumor bearer. This may discover considerable reserves of increasing radiotherapeutic efficiency

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

    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.

  16. Specific internalization and synergistic anticancer effect of docetaxel-encapsulated chitosan-modified polymeric nanocarriers: a novel approach in cancer chemotherapy

    Asthana, Shalini; Gupta, Pramod K.; Konwar, Rituraj; Chourasia, Manish K.

    2013-01-01

    Nanocarriers can be surface engineered to increase endocytosis for applications in delivery of chemotherapeutics. This study investigated the chitosan (CS)-mediated effects on the anticancer efficacy and uptake of docetaxel-loaded nanometric particles ( 5-fold) in intracellular uptake as well as antitumor efficacy of modified nanoparticles (NPs) that explicate the possibility of saccharide marker-mediated tumor targeting along with synergism via proapoptotic effect of CS. Additionally, high positivity of optimized tailored nanocarrier (+23.3 ± 2.02 mV, 242.8 ± 9.42 nm) may have accounted for the increased adsorption-mediated endocytosis, preferably toward tumor cells with negative potential. Developed drug carrier system showed high stability in human blood which is in compliance with mucoadhesive property of CS. Transmission electron microscopy technique was applied to observe shape and morphological features of NPs. Furthermore, in vivo tissue toxicity study revealed safe use of drug at 20 mg/kg dose in nanoparticulate form. Moreover, the enhanced in vitro uptake of these NPs and their cytotoxicity against the tumor cells along with synergistic effect of CS clearly suggest that CS-modified carrier system is a promising candidate for preclinical studies to achieve wider anti-tumor therapeutic window and lower side effects

  17. Synergistic effects of iron powder on intumescent flame retardant polypropylene system

    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.

  18. Antioxidants impair anti-tumoral effects of Vorinostat, but not anti-neoplastic effects of Vorinostat and caspase-8 downregulation.

    Bergadà, Laura; Yeramian, Andree; Sorolla, Annabel; Matias-Guiu, Xavier; Dolcet, Xavier

    2014-01-01

    We have recently demonstrated that histone deacetylase inhibitor, Vorinostat, applied as a single therapy or in combination with caspase-8 downregulation exhibits high anti-tumoral activity on endometrial carcinoma cell lines. In the present study, we have assessed the signalling processes underlying anti-tumoral effects of Vorinostat. Increasing evidence suggests that reactive oxygen species are responsible for histone deacetylase inhibitor-induced cell killing. We have found that Vorinostat induces formation of reactive oxygen species and DNA damage. To investigate the role of oxidative stress as anti-neoplastic mechanism, we have evaluated the effects of different antioxidants (Bha, Nac and Tiron) on endometrial carcinoma cell line Ishikawa treated with Vorinostat. We show that Bha, Nac and Tiron markedly inhibited the cytotoxic effects of Vorinostat, increasing cell viability in vitro. We found that all three antioxidants did not inhibited accumulation of acetyl Histone H4, so that antioxidants did not inhibit Vorinostat activity. Finally, we have evaluated the effects of antioxidants on anti-tumoral activity of Vorinostat as monotherapy or in combination with caspase-8 downregulation in vivo. Interestingly, antioxidants blocked the reduction of tumour growth caused by Vorinostat, but they were unable to inhibit anti-tumoral activity of Vorinostat plus caspase-8 inhibition.

  19. Antitumor Effect of KX-01 through Inhibiting Src Family Kinases and Mitosis.

    Kim, Seongyeong; Min, Ahrum; Lee, Kyung-Hun; Yang, Yaewon; Kim, Tae-Yong; Lim, Jee Min; Park, So Jung; Nam, Hyun-Jin; Kim, Jung Eun; Song, Sang-Hyun; Han, Sae-Won; Oh, Do-Youn; Kim, Jee Hyun; Kim, Tae-You; Hangauer, David; Lau, Johnson Yiu-Nam; Im, Kyongok; Lee, Dong Soon; Bang, Yung-Jue; Im, Seock-Ah

    2017-07-01

    KX-01 is a novel dual inhibitor of Src and tubulin. Unlike previous Src inhibitors that failed to show clinical benefit during treatment of breast cancer, KX-01 can potentially overcome the therapeutic limitations of current Src inhibitors through inhibition of both Src and tubulin. The present study further evaluates the activity and mechanism of KX-01 in vitro and in vivo . The antitumor effect of KX-01 in triple negative breast cancer (TNBC) cell lines was determined by MTT assay. Wound healing and immunofluorescence assays were performed to evaluate the action mechanisms of KX-01. Changes in the cell cycle and molecular changes induced by KX-01 were also evaluated. A MDA-MB-231 mouse xenograft model was used to demonstrate the in vivo effects. KX-01 effectively inhibited the growth of breast cancer cell lines. The expression of phospho-Src and proliferative-signaling molecules were down-regulated in KX-01-sensitive TNBC cell lines. In addition, migration inhibition was observed by wound healing assay. KX-01-induced G2/M cell cycle arrest and increased the aneuploid cell population in KX-01-sensitive cell lines. Multi-nucleated cells were significantly increased after KX-01 treatment. Furthermore, KX-01 effectively delayed tumor growth in a MDA-MB-231 mouse xenograft model. KX-01 effectively inhibited cell growth and migration of TNBC cells. Moreover, this study demonstrated that KX-01 showed antitumor effects through the inhibition of Src signaling and the induction of mitotic catastrophe. The antitumor effects of KX-01 were also demonstrated in vivo using a mouse xenograft model.

  20. Linalool Exhibits Cytotoxic Effects by Activating Antitumor Immunity

    Mei-Yin Chang

    2014-05-01

    Full Text Available According to recent studies, the Plantaginaceae, which are traditional Chinese herbal remedies, have potential for use in viral infection treatment and cancer therapy. Linalool and p-coumaric acid are two of the biologically active compounds that can be isolated from the Plantaginaceae. This study mainly focused on investigating the bioactivity of linalool as well as the bioactivity of p-coumaric acid in terms of their cytotoxic effects on cancer cells. Whether the mechanisms of such effects are generated through apoptosis and immunoregulatory activity were also investigated. By using WST-1 analysis, it was shown that linalool and p-coumaric acid have good inhibitory effects against breast, colorectal and liver cancer cells. The IC50 values of linalool for those cancer cell types were 224 μM, 222 μM, and 290 μM, respectively, and the IC50 values of p-coumaric acid were 693 μM, 215 μM and 87 μM, respectively. Cell cycle analysis also confirmed that linalool and p-coumaric acid can lead to apoptosis. By using flow cytometry, it was determined that treatment with linalool rather than p-coumaric acid significantly increased the sub-G1 phase and that there were more cells concentrated in the G1 phase. Furthermore, by using cytokine array analysis, we found that linalool can stimulate IFN-γ, IL-13, IL-2, IL-21, IL-21R, IL-4, IL-6sR and TNF-α secretion. This demonstrated that in addition to the bidirectional regulation capabilities found in linalool, it also induces Th1 cellular immune response in T-47D cells. These results showed that linalool holds great potential for use in cancer therapy, and we believe that it could provide an alternative way to take action against tumors.

  1. Anti-tumor effect of low dose radiation in mice

    Fan Zhengping; Lu Jiaben; Zhu Bingchai

    1997-01-01

    The author reports the effects of the total body irradiation of low dose radiation (LDR) and/or the local irradiation of large dose on average tumor weights and tumor inhibitory rates in 170 mice inoculated S 180 sarcoma cell, and the influence of LDR on average longevity in 40 tumor-bearing animals. Results show (1) LDR in the range of 75∼250 mGy can inhibit tumor growth to some extent; (2) fractionated irradiation of 75 mGy and local irradiation of 10 Gy may produce a synergism in tumor growth inhibition; and (3)LDR may enhance average longevity in ascitic tumor-bearing mice

  2. Synergistic effects of Chinese herbal medicine: a comprehensive review of methodology and current research

    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.

  3. The synergistic effect of complex ligands for radioactive metal salts decontamination in supercritical CO2

    Go, M. S.; Park, K. H.; Kim, H. W.; Kim, H. D.

    2004-01-01

    The organophosphorus and dithiocarbamate ligands were used to extract five metal ions (Cd 2+ , Co 2+ , Cu 2+ , Pb 2+ , Zn 2+ ) in supercritical CO 2 so as to decontaminate the radioactive contaminants. The experiments confirmed that the ligands mixed together in a variety of the mixing ratios efficiently extracted all metal ions by more than 90% due to its synergistic effect. The UV-Vis spectrometer installed in a high-pressurized cell showed that the NaDDC was decomposed in supercritical CO 2 containing the water. It also proved that the synergistic effect improved the deprotonation of the organophosphorus ligand when NaDDC was used together with. In addition, we mixed organophosphorus ligand together with diethylamine, the decomposed NaDDC, to obtain the same extraction result of more than 90% as with NaDDC. The enhanced extraction efficiency shows the synergistic effect that is produced by combining two ligands together

  4. Antiangiogenic and Antitumor Effects of Src Inhibition in Ovarian Carcinoma

    Han, Liz Y.; Landen, Charles N.; Trevino, Jose G.; Halder, Jyotsnabaran; Lin, Yvonne G.; Kamat, Aparna A.; Kim, Tae-Jin; Merritt, William M.; Coleman, Robert L.; Gershenson, David M.; Shakespeare, William C.; Wang, Yihan; Sundaramoorth, Raji; Metcalf, Chester A.; Dalgarno, David C.; Sawyer, Tomi K.; Gallick, Gary E.; Sood, Anil K.

    2011-01-01

    Src, a nonreceptor tyrosine kinase, is a key mediator for multiple signaling pathways that regulate critical cellular functions and is often aberrantly activated in a number of solid tumors, including ovarian carcinoma. The purpose of this study was to determine the role of activated Src inhibition on tumor growth in an orthotopic murine model of ovarian carcinoma. In vitro studies on HeyA8 and SKOV3ip1 cell lines revealed that Src inhibition by the Src-selective inhibitor, AP23846, occurred within 1 hour and responded in a dose-dependent manner. Furthermore, Src inhibition enhanced the cytotoxicity of docetaxel in both chemosensitive and chemoresistant ovarian cancer cell lines, HeyA8 and HeyA8-MDR, respectively. In vivo, Src inhibition by AP23994, an orally bioavailable analogue of AP23846, significantly decreased tumor burden in HeyA8 (P = 0.02), SKOV3ip1 (P = 0.01), as well as HeyA8-MDR (P < 0.03) relative to the untreated controls. However, the greatest effect on tumor reduction was observed in combination therapy with docetaxel (P < 0.001, P = 0.002, and P = 0.01, for the above models, respectively). Proliferating cell nuclear antigen staining showed that Src inhibition alone (P = 0.02) and in combination with docetaxel (P = 0.007) significantly reduced tumor proliferation. In addition, Src inhibition alone and in combination with docetaxel significantly down-regulated tumoral production of vascular endothelial growth factor and interleukin 8, whereas combination therapy decreased the microvessel density (P = 0.02) and significantly affected vascular permeability (P < 0.05). In summary, Src inhibition with AP23994 has potent antiangiogenic effects and significantly reduces tumor burden in preclinical ovarian cancer models. Thus, Src inhibition may be an attractive therapeutic approach for patients with ovarian carcinoma. PMID:16951177

  5. Cytotoxic and Antitumor Effects of Curzerene from Curcuma longa.

    Wang, Youdi; Li, Jiahong; Guo, Jiquan; Wang, Qiyou; Zhu, Shuguang; Gao, Siyuan; Yang, Chen; Wei, Min; Pan, Xuediao; Zhu, Wei; Ding, Dongmei; Gao, Ruiping; Zhang, Wei; Wang, Junye; Zang, Linquan

    2017-01-01

    Curzerene is a sesquiterpene and component used in oriental medicine. It was originally isolated from the traditional Chinese herbal medicine Curcuma rhizomes. In this study, anticancer activity of curzerene was examined in both in vitro and in vivo models. The result of the MTT assay showed that curzerene exhibited antiproliferative effects in SPC-A1 human lung adenocarcinoma cells in a time-dependent and dose-dependent manner. The anticancer IC 50 s were 403.8, 154.8, and 47.0 µM for 24, 48, and 72 hours, respectively. The flow cytometry analysis indicated curzerene arrested the cells in the G2/M cell cycle and promoted or induced apoptosis of SPC-A1 cells. The percentage of cells arrested in the G2/M phase increased from 9.26 % in the control group cells to 17.57 % in the cells treated with the highest dose (100 µM) of curzerene. Western blot and RT-PCR analysis demonstrated that curzerene induced the downregulation of GSTA1 protein and mRNA expressions in SPC-A1 cells. Tumor growth was significantly inhibited in SPC-A1 cell-bearing nude mice by using curzerene (135 mg/kg daily), meanwhile, curzerene did not significantly affect body mass and the organs of the mice, which may indicate that curzerene has limited toxicity and side effects in vivo . In conclusion, curzerene could inhibit the proliferation of SPC-A1 human lung adenocarcinoma cells line in both in vitro and in vivo models. Focusing on its relationship with GSTA1, curzerene could induce the downregulation of GSTA1 protein and mRNA expressions in SPC-A1 cells. Curzerene might be used as an anti-lung adenocarcinoma drug candidate compound for further development. Georg Thieme Verlag KG Stuttgart · New York.

  6. Synergistic effect of mixed neutron and gamma irradiation in bipolar operational amplifier OP07

    Yan, Liu, E-mail: liuyan@nint.ac.cn [State Key Laboratory of Intense Pulsed Irradiation Simulation and Effect, Northwest Institute of Nuclear Technology, P.O.Box 69-10, Xi’an 710024 (China); School of Nuclear Science and Technology, Xi’an Jiaotong University, Xi’an 710049 (China); Wei, Chen; Shanchao, Yang; Xiaoming, Jin [State Key Laboratory of Intense Pulsed Irradiation Simulation and Effect, Northwest Institute of Nuclear Technology, P.O.Box 69-10, Xi’an 710024 (China); Chaohui, He [School of Nuclear Science and Technology, Xi’an Jiaotong University, Xi’an 710049 (China)

    2016-09-21

    This paper presents the synergistic effects in bipolar operational amplifier OP07. The radiation effects are studied by neutron beam, gamma ray, and mixed neutron/gamma ray environments. The characterateristics of the synergistic effects are studied through comparison of different experiment results. The results show that the bipolar operational amplifier OP07 exhibited significant synergistic effects in the mixed neutron and gamma irradiation. The bipolar transistor is identified as the most radiation sensitive unit of the operational amplifier. In this paper, a series of simulations are performed on bipolar transistors in different radiation environments. In the theoretical simulation, the geometric model and calculations based on the Medici toolkit are built to study the radiation effects in bipolar components. The effect of mixed neutron and gamma irradiation is simulated based on the understanding of the underlying mechanisms of radiation effects in bipolar transistors. The simulated results agree well with the experimental data. The results of the experiments and simulation indicate that the radiation effects in the bipolar devices subjected to mixed neutron and gamma environments is not a simple combination of total ionizing dose (TID) effects and displacement damage. The data suggests that the TID effect could enhance the displacement damage. The synergistic effect should not be neglected in complex radiation environments.

  7. Selective potentiation of the antitumor radiation effect by means of short-term hyperglycemia

    Yarmonenko, S.P.; Shapot, V.S.; Voloshina, E.A.; Gorozhanskaya, Eh.G.; Dyuskaliev, Zh.D.; Krimker, V.M.

    1981-01-01

    Experiments on mice have shown that short-term induced hyperglycemia caused by 5-fold intraperitoneal administration of glucose at a dose of 2.6 and 1.3 g/kg increases notably the radiation injury to a solid type of Ehrlich carcinoma. Short-term induced hyperglycemia is mostly effective after irradiation. During irradiation together with its antitumor effect enhanced in the presence of short-term induced hyperglycemia there is observed selective protection of the normal tissues resulting from a decrease of oxygen pressure in them

  8. Anti-tumor effects of an engineered 'killer' transfer RNA

    Zhou, Dong-hui [Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637 (United States); Lee, Jiyoung; Frankenberger, Casey [Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637 (United States); Geslain, Renaud, E-mail: rgeslain@depaul.edu [Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637 (United States); Department of Biology, DePaul University, Chicago, IL 60614 (United States); Rosner, Marsha, E-mail: m-rosner@uchicago.edu [Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637 (United States); Pan, Tao, E-mail: taopan@uchicago.edu [Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637 (United States)

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer tRNA with anti-cancer effects. Black-Right-Pointing-Pointer tRNA induced protein misfolding. Black-Right-Pointing-Pointer tRNA as anti-tumor agent. -- Abstract: A hallmark of cancer cells is their ability to continuously divide; and rapid proliferation requires increased protein translation. Elevating levels of misfolded proteins can elicit growth arrest due to ER stress and decreased global translation. Failure to correct prolonged ER stress eventually results in cell death via apoptosis. tRNA{sup Ser}(AAU) is an engineered human tRNA{sup Ser} with an anticodon coding for isoleucine. Here we test the possibility that tRNA{sup Ser}(AAU) can be an effective killing agent of breast cancer cells and can effectively inhibit tumor-formation in mice. We found that tRNA{sup Ser}(AAU) exert strong effects on breast cancer translation activity, cell viability, and tumor formation. Translation is strongly inhibited by tRNA{sup Ser}(AAU) in both tumorigenic and non-tumorigenic cells. tRNA{sup Ser}(AAU) significantly decreased the number of viable cells over time. A short time treatment with tRNA{sup Ser}(AAU) was sufficient to eliminate breast tumor formation in a xenograft mouse model. Our results indicate that tRNA{sup Ser}(AAU) can inhibit breast cancer metabolism, growth and tumor formation. This RNA has strong anti-cancer effects and presents an opportunity for its development into an anti-tumor agent. Because tRNA{sup Ser}(AAU) corrupts the protein synthesis mechanism that is an integral component of the cell, it would be extremely difficult for tumor cells to evolve and develop resistance against this anti-tumor agent.

  9. Anti-tumor effects of an engineered “killer” transfer RNA

    Zhou, Dong-hui; Lee, Jiyoung; Frankenberger, Casey; Geslain, Renaud; Rosner, Marsha; Pan, Tao

    2012-01-01

    Highlights: ► tRNA with anti-cancer effects. ► tRNA induced protein misfolding. ► tRNA as anti-tumor agent. -- Abstract: A hallmark of cancer cells is their ability to continuously divide; and rapid proliferation requires increased protein translation. Elevating levels of misfolded proteins can elicit growth arrest due to ER stress and decreased global translation. Failure to correct prolonged ER stress eventually results in cell death via apoptosis. tRNA Ser (AAU) is an engineered human tRNA Ser with an anticodon coding for isoleucine. Here we test the possibility that tRNA Ser (AAU) can be an effective killing agent of breast cancer cells and can effectively inhibit tumor-formation in mice. We found that tRNA Ser (AAU) exert strong effects on breast cancer translation activity, cell viability, and tumor formation. Translation is strongly inhibited by tRNA Ser (AAU) in both tumorigenic and non-tumorigenic cells. tRNA Ser (AAU) significantly decreased the number of viable cells over time. A short time treatment with tRNA Ser (AAU) was sufficient to eliminate breast tumor formation in a xenograft mouse model. Our results indicate that tRNA Ser (AAU) can inhibit breast cancer metabolism, growth and tumor formation. This RNA has strong anti-cancer effects and presents an opportunity for its development into an anti-tumor agent. Because tRNA Ser (AAU) corrupts the protein synthesis mechanism that is an integral component of the cell, it would be extremely difficult for tumor cells to evolve and develop resistance against this anti-tumor agent.

  10. Antitussive arabinogalactan of Andrographis paniculata demonstrates synergistic effect with andrographolide.

    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.

  11. Rhenium–platinum antitumor systems

    A. V. Shtemenko

    2017-04-01

    Full Text Available This review provides an overlook of design (in short, antitumor and other biological activity of quadruple-bonded cluster dirhenium(III compounds and their synergism with cisplatin. In particular, we describe the work of the rhenium-platinum antitumor system (introduction of rhenium and platinum compounds. Among known metal-based anticancer drugs and drug candidates dirhenium(III compounds differ profoundly due to their strong antiradical and antioxidant properties determined by quadruple bond unsaturation. Such advantages of metal complexes as more expressed redox chemical propertie should be exploited for creating more efficient anticancer drugs. Combination of drugs leads to synergistic effects and/or to lowe­ring toxicity of platinides and is very promising in cancer chemotherapy. The review covers the follo­wing items: design of quadruple bonded dirhenium(III clusters, their spectral and antiradical properties (in short; interaction of the dirhenium(III compounds with lipids and formation of liposomes; interaction of the dirhenium(III compounds with erythrocytes and their antihemolytic activity in the models of hemolytic anemia; anticancer activity of dirhenium clusters and work of the rhenium-platinum antitumor system; antianemic and antioxidant properties of the dirhenium(III compounds in the model of tumor growth; interaction of the dirhenium(III compounds with nucleobases and DNA. Some modern trends in the field of bioinorganic and medicinal chemi­stry are also considered regarding their connection to the rhenium-platinum system efficiency: use of combinational therapy and nanomaterials; involvement of some biologically active ligands and redox-activation strategy, etc.

  12. Synergistic Effect of Simvastatin Plus Radiation in Gastric Cancer and Colorectal Cancer: Implications of BIRC5 and Connective Tissue Growth Factor.

    Lim, Taekyu; Lee, Inkyoung; Kim, Jungmin; Kang, Won Ki

    2015-10-01

    We investigated the synergistic effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor plus radiation therapy, on the proliferation and survival of gastric cancer (GC) and colorectal cancer (CRC) cells. We also studied several genes involved in the simvastatin/radiation-induced effects. Gastric cancer (AGS, SNU601, MKN1, and MKN28) and CRC (CoLo320, SW48, HT29, and HCT8) cell lines were treated with 0.2 μM simvastatin alone, or in combination with 0 to 4 Gy of radiation, and subjected to clonogenic survival and proliferation assays in vitro. To assess the molecular mechanism of the combination treatment, we performed microarray analysis, immunoblot assays, small interfering RNA knockdown experiments, and plasmid rescue assays. The antitumoral effects of simvastatin and radiation were evaluated in vivo using xenograft models. The combination therapy of simvastatin plus radiation inhibited basal clonogenic survival and proliferation of GC and CRC cells in vitro. Simvastatin suppressed the expression of BIRC5 and CTGF genes in these cancer cells. In vivo, the combined treatment with simvastatin and radiation significantly reduced the growth of xenograft tumors compared with treatment with radiation alone. We suggest that simvastatin has a synergistic effect with radiation on GC and CRC through the induction of apoptosis, which may be mediated by a simultaneous inhibition of BIRC5 and CTGF expression. A clinical trial of simvastatin in combination with radiation in patients with GC or CRC is warranted. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Synergistic effects of antimicrobial peptide DP7 combined with antibiotics against multidrug-resistant bacteria

    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

  14. Synergistic effect of oridonin and a PI3K/mTOR inhibitor on the non-germinal center B cell-like subtype of diffuse large B cell lymphoma

    Kai Qing

    2016-08-01

    Full Text Available Abstract We demonstrate the synergistic antitumor effect of oridonin and the PI3K/mTOR inhibitor NVP-BEZ235 on the non-germinal center B cell-like subtype of diffuse large B cell lymphoma (non-GCB DLBCL both in vitro and in vivo. The underlying mechanism may be multifunctional, involving apoptosis, AKT/mTOR and NF-kB inactivation, and ROS-mediated DNA damage response. Our findings pave the way for a new potential treatment option for non-GCB DLBCL with the combination of oridonin and NVP-BEZ235.

  15. Assessment of antitumoral and antimicrobial effects of a maslinic acid derivative

    Ioana Z. Pavel

    2016-12-01

    Full Text Available INTRODUCTION Maslinic acid, a naturally occurring triterpene, has been reported to possess several therapeutic effects including antioxidant, anti-inflammatory and antiparasitic properties. Structural changes of the compound led to the development of new derivatives in order to expand the spectrum of activities. OBJECTIVES AND BACKGROUND The present study was purposed to assess the in vitro antitumoral and antibacterial effects of a maslinic acid derivative, namely benzyl (2α, 3β 2,3-diacetoxy-olean-12- en-28-amide (EM2. MATERIALS AND METHODS Four compound concentrations (12.5, 25, 50 and 100 µM were evaluated for their cytotoxic effect on A375 human melanoma and B164A5 murine melanoma cell lines using the MTT assay. Furthermore, EM2 was tested on ten bacterial strains by means of agar disk diffusion method with the assessment of the inhibition zone diameters at 24h period of time. RESULTS EM2 elicited a dose-dependent cytotoxic effect on both melanoma cell lines. Regarding the antibacterial activity, EM2 determined a significant growth inhibition on Streptococcus pyogenes (20 ± 0.26 mm and Staphylococcus aureus (13 ± 0.19 mm. CONCLUSIONS The tested maslinic acid derivative is a promising antitumoral agent against skin cancer and antimicrobial agent against cocci bacteria. Graphical abstract: EM2 in vitro effects

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

    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

  17. Antitumor and Immunomodulatory Effects of Polysaccharides from Broken-Spore of Ganoderma lucidum

    Peng-Yun eWang

    2012-07-01

    Full Text Available The antitumor activity of Gl-BSP, a polysaccharide isolated from boiling water extract of the broken-spores of Ganoderma lucidum (Leyss ex Fr Karst. and its possible mechanism were investigated in vivo and in vitro. It was showed that Gl-BSP (50, 100, 200 mg/kg exhibited antitumor effect against Sarcoma 180 (S180 in BALB/c mice. The Gl-BSP was not cytotoxicity in S180 cells and PG cells (human lung carcinoma cell in vitro. However, Gl-BSP-treated serum potently inhibited S180 cells and PG cells proliferation in vitro. Moreover, Gl-BSP could promote the splenic lymphocyte proliferation induced by Con A or LPS, enhance nature killer cell (NK cell cytotoxic activity, augment the percentage of neutral red (NR phagocytosis by macrophages, and increase the percentage of the CD4+ or CD8+ subset in S180-bearing BALB/c mice. The level of IFN-γ, TNF-α and NO of serum apparently was increased by Gl-BSP. Gl-BSP also showed immunomodulatory activities in tumor-bearing mice. Furthermore,It was proved that neutralization with anti-TNF-α and/or anti-IFN-γ significantly diminished growth inhibition induced by Gl-BSP –treated serum in S180 or PG cells. Blocking effect was noted in the combination of anti-TNF-α and anti-IFN-γ. These observations suggest that the antitumor activity of Gl-BSP may mainly relate to the activation of the immune response of the host organism by the stimulation of NK cells, T cells, and macrophages.

  18. Effect of electron beam-irradiation to b-glucan on its immunomodulating and antitumor activity

    Jung, Yeon Hwan; Lee, Jung Lim; Yoo, Yung Choon [Konyand Univ., Daejeon (Korea, Republic of); Kim, Jae Hoon; Lee, Ju Woon [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2010-07-01

    In this study, in order investigated the effect of electron beam irradiation to b-glucan on its biological activities, we compared immunomodulating and antitumor activity between non-irradiated and electron beam-irradiated b-glucan. EB-glucan was irradiated by electron beam with 10, 30 and 50 kGy. Treatment with EB-glucan resulted in a slight increase of the proliferation of ConA-stimulated splenocytes, and the strongest activity was seen in 50 kGy-treated EB-glucan. EB-glucan teated with 50 kGy also showed increased secretion of cytokines such as IL-2 IFN-{gamma} and IL-6 from ConA-stimulated splenocytes. The activity of EB-glucan to enhance the proliferation of splenocytes and cytokine secretion from ConA-stimulated splenocytes was higher than that of NI-glucan. Furthermore, EB-glucan treated with 50 kGy showed higher activity to activate RAW 264.7 macrophages, comparing with that of NI-glucan. In experiments of antitumor activity, EB-glucan treated with 50 kGy prior to tumor inoculation inhibited an experimental lung metastasis produced by B16-BL6 melanoma cells in mice. But NI-glucan did show no effect. In addition, EB-glucan treated with 50 kGy induced a decrease a decrease of tumor growth in tumor-bearing mice. Collectivelt, these results indicates that electron beam irradiation {beta}-glucan leads its biological functions to enhance immunomodulating and antitumor activity.

  19. Effect of electron beam-irradiation to b-glucan on its immunomodulating and antitumor activity

    Jung, Yeon Hwan; Lee, Jung Lim; Yoo, Yung Choon; Kim, Jae Hoon; Lee, Ju Woon

    2010-01-01

    In this study, in order investigated the effect of electron beam irradiation to b-glucan on its biological activities, we compared immunomodulating and antitumor activity between non-irradiated and electron beam-irradiated b-glucan. EB-glucan was irradiated by electron beam with 10, 30 and 50 kGy. Treatment with EB-glucan resulted in a slight increase of the proliferation of ConA-stimulated splenocytes, and the strongest activity was seen in 50 kGy-treated EB-glucan. EB-glucan teated with 50 kGy also showed increased secretion of cytokines such as IL-2 IFN-γ and IL-6 from ConA-stimulated splenocytes. The activity of EB-glucan to enhance the proliferation of splenocytes and cytokine secretion from ConA-stimulated splenocytes was higher than that of NI-glucan. Furthermore, EB-glucan treated with 50 kGy showed higher activity to activate RAW 264.7 macrophages, comparing with that of NI-glucan. In experiments of antitumor activity, EB-glucan treated with 50 kGy prior to tumor inoculation inhibited an experimental lung metastasis produced by B16-BL6 melanoma cells in mice. But NI-glucan did show no effect. In addition, EB-glucan treated with 50 kGy induced a decrease a decrease of tumor growth in tumor-bearing mice. Collectivelt, these results indicates that electron beam irradiation β-glucan leads its biological functions to enhance immunomodulating and antitumor activity

  20. Participation of MT3 melatonin receptors in the synergistic effect of melatonin on cytotoxic and apoptotic actions evoked by chemotherapeutics.

    Pariente, Roberto; Bejarano, Ignacio; Espino, Javier; Rodríguez, Ana B; Pariente, José A

    2017-11-01

    Melatonin has antitumor activity via several mechanisms including its antiproliferative and proapoptotic effects in addition to its potent antioxidant actions. Therefore, melatonin may be useful in the treatment of tumors in association with chemotherapy drugs. This study was performed to study the role of melatonin receptors on the cytotoxicity and apoptosis induced by the chemotherapeutic agents cisplatin and 5-fluorouracil in two tumor cell lines, such as human colorectal cancer HT-29 cells and cervical cancer HeLa cells. We found that both melatonin and the two chemotherapeutic agents tested induced a decrease in HT-29 and HeLa cell viability. Furthermore, melatonin significantly increased the cytotoxic effect of chemotherapeutic agents, particularly, in 5-fluorouracil-challenged cells. Stimulation of cells with either of the two chemotherapeutic agents in the presence of melatonin further increased caspase-3 activation. Concomitant treatments with melatonin and chemotherapeutic agents augmented the population of apoptotic cells compared to the treatments with chemotherapeutics alone. Blockade of MT1 and/or MT2 receptors with luzindole or 4-P-PDOT was unable to reverse the enhancing effects of melatonin on both cytotoxicity, caspase-3 activation and the amount of apoptotic cells evoked by the chemotherapeutic agents, whereas when MT3 receptors were blocked with prazosin, the synergistic effect of melatonin with chemotherapy on cytotoxicity and apoptosis was reversed. Our findings provided evidence that in vitro melatonin strongly enhances chemotherapeutic-induced cytotoxicity and apoptosis in two tumor cell lines, namely HT-29 and HeLa cells and, this potentiating effect of melatonin is mediated by MT3 receptor stimulation.

  1. Synergistic Effect of Molybdate and Monoethanolamine on Corrosion Inhibition of Ductile Cast Iron in Tap Water

    Kim, K. T.; Kim, Y. S. [Andong National University, Andong (Korea, Republic of); Chang, H. Y.; Lim, B. T.; Park, H. B. [KEPCO Engineering and Construction Company, Gimcheon (Korea, Republic of)

    2017-02-15

    A synergistic effect was observed in the combination of nitrite and ethanolamines. Ethanolamine is one of the representative organic corrosion inhibitors and can be categorized as adsorption type. However, nitrosamines can form when amines mix with sodium nitrite. Since nitrosamine is a carcinogen, the co-addition of nitrite and ethanolamine will be not practical, and thus, a non-toxic combination of inhibitors shall be needed. In order to maximize the effect of monoethanolamine, we focused on the addition of molybdate. Molybdate has been used to alternate the addition of chromate, but it showed insufficient oxidizing power relative to corrosion inhibitors. This work evaluated the synergistic effect of the co-addition of molybdate and monoethanolamine, and its corrosion mechanism was elucidated. A high concentration of molybdate or monoethanolamine was needed to inhibit the corrosion of ductile cast iron in tap water, but in the case of the co-addition of molybdate and monoethanolamine, a synergistic effect was observed. This synergistic effect could be attributed to the molybdate that partly oxidizes the metallic surface and the monoethanolamine that is simultaneously adsorbed on the graphite surface. This adsorbed layer then acts as the barrier layer that mitigates galvanic corrosion between the graphite and the matrix.

  2. Antitumor effect of the essential oil from leaves of Guatteria pogonopus (Annonaceae).

    do N Fontes, José Eraldo; Ferraz, Rosana P C; Britto, Anny C S; Carvalho, Adriana A; Moraes, Manoel O; Pessoa, Claudia; Costa, Emmanoel V; Bezerra, Daniel P

    2013-04-01

    Guatteria pogonopus Martius, a plant belonging to the Annonaceae family, is found in the remaining Brazilian Atlantic Forest. In this study, the chemical composition and antitumor effects of the essential oil isolated from leaves of G. pogonopus was investigated. The chemical composition of the oil was determined by GC-FID and GC/MS analyses. The in vitro cytotoxicity was evaluated against three different tumor cell lines (OVCAR-8, NCI-H358M, and PC-3M), and the in vivo antitumor activity was tested in mice bearing sarcoma 180 tumor. A total of 29 compounds was identified and quantified in the oil. The major compounds were γ-patchoulene (13.55%), (E)-caryophyllene (11.36%), β-pinene (10.37%), germacrene D (6.72%), bicyclogermacrene (5.97%), α-pinene (5.33%), and germacrene B (4.69%). The essential oil, but neither (E)-caryophyllene nor β-pinene, displayed in vitro cytotoxicity against all three tumor cell lines tested. The obtained average IC50 values ranged from 3.8 to 20.8 μg/ml. The lowest and highest values were obtained against the NCI-H358M and the OVCAR-8 cell lines, respectively. The in vivo tumor-growth-inhibition rates in the tumor-bearing mice treated with essential oil (50 and 100 mg/kg/d) were 25.3 and 42.6%, respectively. Hence, the essential oil showed significant in vitro and in vivo antitumor activity. Copyright © 2013 Verlag Helvetica Chimica Acta AG, Zürich.

  3. The antitumor effect of bromophenol derivatives in vitro and Leathesia nana extract in vivo

    Shi, Dayong; Li, Jing; Guo, Shuju; Su, Hua; Fan, Xiao

    2009-05-01

    To investigate the antitumor effect of bromophenol derivatives in vitro and Leathesia nana extract in vivo, six bromophenol derivatives 6-(2,3-dibromo-4,5-dihydroxybenzyl)-2,3-dibromo-4,5-dihydroxy benzyl methyl ether (1), (+)-3-(2,3-dibromo-4,5-dihydroxyphenyl)-4-bromo-5,6-dihydroxy-1,3-dihydroisobenzofuran (2), 3-bromo-4-(2,3-dibromo-4,5-dihydroxybenzyl)-5-methoxymethyl-pyrocatechol (3), 2,2',3,3'-tetrabromo-4,4',5,5'-tetrahydroxy-diphenylmethane (4), bis(2,3-dibromo-4,5-dihydroxybenzyl) ether (5), 2,2',3-tribromo-3',4,4',5-tetrahydroxy-6'-ethyloxymethyldiphenylmethane (6) were isolated from brown alga Leathesia nana, and their cytotoxicity were tested by MTT assays in human cancer cell lines A549, BGC-823, MCF-7, B16-BL6, HT-1080, A2780, Bel7402 and HCT-8. Their inhibitory activity against protein tyrosine kinase (PTK) with over-expression of c-kit was analyzed also by ELISA. The antitumor activity of ethanolic extraction of Leathesia nana (EELN) was evaluated on S180-bearing mice. All compounds showed very potent cytotoxicity against all of the eight cancer cell lines with IC50 below 10 μg/mL. In PTK inhibition study, all bromophenol derivatives showed moderate inhibitory activity and compounds 2, 5 and 6 showed significant bioactivity with the inhibition ratio of 77.5%, 80.1% and 71.4%, respectively. Pharmacological studies reveal that EELN could inhibit the growth of Sarcoma 180 tumor and increase the indices of thymus and spleen to improve the immune system remarkably in vivo. Results indicated that the bromophenol derivatives and EELN can be used as potent antitumor agents for PTK over-expression of c-kit and considered in a new therapeutic strategy for treatment of cancer.

  4. Antioxidant Activity, Antitumor Effect, and Antiaging Property of Proanthocyanidins Extracted from Kunlun Chrysanthemum Flowers

    Siqun Jing

    2015-01-01

    Full Text Available The objective of the present study was to evaluate the antioxidant activity, antitumor effect, and antiaging property of proanthocyanidins from Kunlun Chrysanthemum flowers (PKCF grown in Xinjiang. In vitro antioxidant experiments results showed that the total antioxidant activity and the scavenging capacity of hydroxyl radicals (•OH and 1,1-diphenyl-2-picrylhydrazyl (DPPH• radicals increased in a concentration-dependent manner and were stronger than those of vitamin C. To investigate the antioxidant activity of PKCF in vivo, we used serum, liver, and kidney from mouse for the measurement of superoxide dismutase (SOD, malondialdehyde (MDA, and total antioxidant capacity (T-AOC. Results indicated that PKCF had antioxidative effect in vivo which significantly improved the activity of SOD and T-AOC and decreased MDA content. To investigate the antitumor activity of PKCF, we used H22 cells, HeLa cells, and Eca-109 cells with Vero cells as control. Inhibition ratio and IC50 values were measured by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay; PKCF showed great inhibitory activity on H22 cells and HeLa cells. We also used fruit flies as a model for analyzing the anti-aging property of PKCF. Results showed that PKCF has antiaging effect on Drosophila. Results of the present study demonstrated that PKCF could be a promising agent that may find applications in health care, medicine, and cosmetics.

  5. Increased oxidative stress mediates the antitumor effect of PARP inhibition in ovarian cancer

    Dong Hou

    2018-07-01

    Full Text Available PARP inhibitors have been widely tested in clinical trials, especially for the treatment of breast cancer and ovarian cancer, and were shown to be highly successful. Because PARP primarily functions in sensing and repairing DNA strand breaks, the therapeutic effect of PARP inhibition is generally believed to be attributed to impaired DNA repair. We here report that oxidative stress is also increased by PARP inhibition and mediates the antitumor effect. We showed that PARP1 is highly expressed in specimens of high grade serous ovarian carcinoma and its activity is required for unperturbed proliferation of ovarian cancer cells. Inhibition or depletion of PARP leads to not only an increase in DNA damage, but also an elevation in the levels of reactive oxygen species (ROS. Importantly, antioxidant N-acetylcysteine (NAC significantly attenuated the induction of DNA damage and the perturbation of proliferation by PARP inhibition or depletion. We further showed that NADPH oxidases 1 and 4 were significantly upregulated by PARP inhibition and were partially responsible for the induction of oxidative stress. Depletion of NOX1 and NOX4 partially rescued the growth inhibition of PARP1-deficient tumor xenografts. Our findings suggest that in addition to compromising the repair of DNA damage, PARP inhibition or depletion may exert extra antitumor effect by elevating oxidative stress in ovarian cancer cells. Keywords: PARP1, Oxidative stress, NADPH oxidases, Ovarian cancer

  6. Proton pump inhibitors induce a caspase-independent antitumor effect against human multiple myeloma.

    Canitano, Andrea; Iessi, Elisabetta; Spugnini, Enrico Pierluigi; Federici, Cristina; Fais, Stefano

    2016-07-01

    Multiple Myeloma (MM) is the second most common hematological malignancy and is responsive to a limited number of drugs. Unfortunately, to date, despite the introduction of novel drugs, no relevant increase in survival rates has been obtained. Proton pump inhibitors (PPIs) have been shown to have significant antitumor action as single agents as well as in combination with chemotherapy. This study investigates the potential anti-tumor effectiveness of two PPIs, Lansoprazole and Omeprazole, against human MM cells. We found that Lansoprazole exerts straightforward efficacy against myeloma cells, even at suboptimal concentrations (50 µM), while Omeprazole has limited cytotoxic action. The Lansoprazole anti-MM effect was mostly mediated by a caspase-independent apoptotic-like cytotoxicity, with only a secondary anti-proliferative action. This study provides clear evidence supporting the use of Lansoprazole in the strive against MM with an efficacy proven much higher than current therapeutical approaches and without reported side effects. It is however conceivable that, consistent with the results obtained in other human tumors, Lansoprazole may well be combined with existing anti-myeloma therapies with the aim to improve the low level of efficacy of the current strategies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. Gold namoprtices enhance anti-tumor effect of radiotherapy to hypoxic tumor

    Kim, Mi Sun; Lee, Eun Jung; Kim, Jae Won; Keum, Ki Chang; Koom, Woong Sub; Chung, Ui Seok; Koh, Won Gun

    2016-01-01

    Hypoxia can impair the therapeutic efficacy of radiotherapy (RT). Therefore, a new strategy is necessary for enhancing the response to RT. In this study, we investigated whether the combination of nanoparticles and RT is effective in eliminating the radioresistance of hypoxic tumors. Gold nanoparticles (GNPs) consisting of a silica core with a gold shell were used. CT26 colon cancer mouse model was developed to study whether the combination of RT and GNPs reduced hypoxia-induced radioresistance. Hypoxia inducible factor-1α (HIF-1α) was used as a hypoxia marker. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were conducted to evaluate cell death. Hypoxic tumor cells had an impaired response to RT. GNPs combined with RT enhanced anti-tumor effect in hypoxic tumor compared with RT alone. The combination of GNPs and RT decreased tumor cell viability compare to RT alone in vitro. Under hypoxia, tumors treated with GNPs + RT showed a higher response than that shown by tumors treated with RT alone. When a reactive oxygen species (ROS) scavenger was added, the enhanced antitumor effect of GNPs + RT was diminished. In the present study, hypoxic tumors treated with GNPs + RT showed favorable responses, which might be attributable to the ROS production induced by GNPs + RT. Taken together, GNPs combined with RT seems to be potential modality for enhancing the response to RT in hypoxic tumors

  8. Antitumor effects of pristimerin on human osteosarcoma cells in vitro and in vivo

    Mori Y

    2017-11-01

    Full Text Available Yuki Mori,1 Toshiharu Shirai,1 Ryu Terauchi,1 Shinji Tsuchida,1 Naoki Mizoshiri,1 Daichi Hayashi,1 Yuji Arai,2 Tunao Kishida,3 Osam Mazda,3 Toshikazu Kubo1 1Department of Orthopaedics, 2Department of Sports and Para-Sports Medicine, 3Department of Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan Abstract: There are very few treatments for musculoskeletal tumors, compared to other cancers; thus, novel therapeutic drugs are needed. Pristimerin (PM is a triterpene compound isolated from plant extracts that reportedly has antitumor effects on various cancers, such as of the breast and prostate. The purpose of this study was to evaluate the antitumor effects of PM on human osteosarcoma cells. Treatment of the human osteosarcoma cell lines, MNNG and 143B, with PM led to a dose-dependent decrease in cell viability. The effects of PM on apoptosis were evaluated with the Annexin V/propidium iodide assay and analysis of caspases 3, 8, and 9 activities. Western blot analysis showed that PM caused a decrease in the expression of Akt, mTOR, and NF-κB. The volumes and weights of human osteosarcoma xenografts decreased significantly with PM treatment. The results of this study revealed that PM can inhibit human osteosarcoma growth in vitro and in vivo, and may be a novel therapeutic agent for the disease. Keywords: pristimerin, osteosarcoma, apoptosis, caspase, Akt 

  9. Antitumor effects of pristimerin on human osteosarcoma cells in vitro and in vivo.

    Mori, Yuki; Shirai, Toshiharu; Terauchi, Ryu; Tsuchida, Shinji; Mizoshiri, Naoki; Hayashi, Daichi; Arai, Yuji; Kishida, Tunao; Mazda, Osam; Kubo, Toshikazu

    2017-01-01

    There are very few treatments for musculoskeletal tumors, compared to other cancers; thus, novel therapeutic drugs are needed. Pristimerin (PM) is a triterpene compound isolated from plant extracts that reportedly has antitumor effects on various cancers, such as of the breast and prostate. The purpose of this study was to evaluate the antitumor effects of PM on human osteosarcoma cells. Treatment of the human osteosarcoma cell lines, MNNG and 143B, with PM led to a dose-dependent decrease in cell viability. The effects of PM on apoptosis were evaluated with the Annexin V/propidium iodide assay and analysis of caspases 3, 8, and 9 activities. Western blot analysis showed that PM caused a decrease in the expression of Akt, mTOR, and NF-κB. The volumes and weights of human osteosarcoma xenografts decreased significantly with PM treatment. The results of this study revealed that PM can inhibit human osteosarcoma growth in vitro and in vivo, and may be a novel therapeutic agent for the disease.

  10. Macrophage PPARγ inhibits Gpr132 to mediate the anti-tumor effects of rosiglitazone

    Cheng, Wing Yin; Huynh, HoangDinh; Chen, Peiwen; Peña-Llopis, Samuel; Wan, Yihong

    2016-01-01

    Tumor-associated macrophage (TAM) significantly contributes to cancer progression. Human cancer is enhanced by PPARγ loss-of-function mutations, but inhibited by PPARγ agonists such as TZD diabetes drugs including rosiglitazone. However, it remains enigmatic whether and how macrophage contributes to PPARγ tumor-suppressive functions. Here we report that macrophage PPARγ deletion in mice not only exacerbates mammary tumor development but also impairs the anti-tumor effects of rosiglitazone. Mechanistically, we identify Gpr132 as a novel direct PPARγ target in macrophage whose expression is enhanced by PPARγ loss but repressed by PPARγ activation. Functionally, macrophage Gpr132 is pro-inflammatory and pro-tumor. Genetic Gpr132 deletion not only retards inflammation and cancer growth but also abrogates the anti-tumor effects of PPARγ and rosiglitazone. Pharmacological Gpr132 inhibition significantly impedes mammary tumor malignancy. These findings uncover macrophage PPARγ and Gpr132 as critical TAM modulators, new cancer therapeutic targets, and essential mediators of TZD anti-cancer effects. DOI: http://dx.doi.org/10.7554/eLife.18501.001 PMID:27692066

  11. Gold namoprtices enhance anti-tumor effect of radiotherapy to hypoxic tumor

    Kim, Mi Sun; Lee, Eun Jung; Kim, Jae Won; Keum, Ki Chang; Koom, Woong Sub [Dept. of Radiation Oncology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Chung, Ui Seok; Koh, Won Gun [Dept. of Chemical and Biomolecular Engineering, Yonsei University, Seoul (Korea, Republic of)

    2016-09-15

    Hypoxia can impair the therapeutic efficacy of radiotherapy (RT). Therefore, a new strategy is necessary for enhancing the response to RT. In this study, we investigated whether the combination of nanoparticles and RT is effective in eliminating the radioresistance of hypoxic tumors. Gold nanoparticles (GNPs) consisting of a silica core with a gold shell were used. CT26 colon cancer mouse model was developed to study whether the combination of RT and GNPs reduced hypoxia-induced radioresistance. Hypoxia inducible factor-1α (HIF-1α) was used as a hypoxia marker. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were conducted to evaluate cell death. Hypoxic tumor cells had an impaired response to RT. GNPs combined with RT enhanced anti-tumor effect in hypoxic tumor compared with RT alone. The combination of GNPs and RT decreased tumor cell viability compare to RT alone in vitro. Under hypoxia, tumors treated with GNPs + RT showed a higher response than that shown by tumors treated with RT alone. When a reactive oxygen species (ROS) scavenger was added, the enhanced antitumor effect of GNPs + RT was diminished. In the present study, hypoxic tumors treated with GNPs + RT showed favorable responses, which might be attributable to the ROS production induced by GNPs + RT. Taken together, GNPs combined with RT seems to be potential modality for enhancing the response to RT in hypoxic tumors.

  12. Supercritical-Carbon Dioxide Fluid Extract from Chrysanthemum indicum Enhances Anti-Tumor Effect and Reduces Toxicity of Bleomycin in Tumor-Bearing Mice

    Hong-Mei Yang

    2017-02-01

    Full Text Available Bleomycin (BLM, a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum, an edible flower, possesses abundant bioactivities; the supercritical-carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE have strong anti-inflammatory, anti-oxidant, and lung protective effects. However, the role of CISCFE combined with BLM treatment on tumor-bearing mice remains unclear. The present study aimed to investigate the potential synergistic effect and the underlying mechanism of CISCFE combined with BLM in the treatment of hepatoma 22 (H22 tumor-bearing mice. The results suggested that the oral administration of CISCFE combined with BLM could markedly prolong the life span, attenuate the BLM-induced pulmonary fibrosis, suppress the production of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor-α, activities of myeloperoxidase, and malondiadehyde. Moreover, CISCFE combined with BLM promoted the ascites cell apoptosis, the activities of caspases 3 and 8, and up-regulated the protein expression of p53 and down-regulated the transforming growth factor-β1 by activating the gene expression of miR-29b. Taken together, these results indicated that CISCFE could enhance the anti-cancer activity of BLM and reduce the BLM-induced pulmonary injury in H22 tumor-bearing mice, rendering it as a potential adjuvant drug with chemotherapy after further investigation in the future.

  13. Degradation by synergistic effect in synthetic insulators; Degradacion por efecto sinergico en aisladores sinteticos

    Garza M, Anibal; Montesinos S, Jose I. [Instituto de Investigaciones Electricas, Cuernavaca (Mexico)

    1991-12-31

    A study is presented of the main degradation phenomena experimented by synthetic insulators and the simultaneous participation of such phenomena to propitiate a synergistic effect. [Espanol] Se presenta un estudio de los principales fenomenos de degradacion que sufren los aisladores sinteticos y la participacion simultanea de dichos fenomenos para propiciar un efecto sinergico.

  14. Degradation by synergistic effect in synthetic insulators; Degradacion por efecto sinergico en aisladores sinteticos

    Garza M, Anibal; Montesinos S, Jose I [Instituto de Investigaciones Electricas, Cuernavaca (Mexico)

    1992-12-31

    A study is presented of the main degradation phenomena experimented by synthetic insulators and the simultaneous participation of such phenomena to propitiate a synergistic effect. [Espanol] Se presenta un estudio de los principales fenomenos de degradacion que sufren los aisladores sinteticos y la participacion simultanea de dichos fenomenos para propiciar un efecto sinergico.

  15. Synergistic effects in mechanical properties of PLA/PCL blends with optimized composition, processing, and morphology

    Ostafinska, Aleksandra; Fortelný, Ivan; Nevoralová, Martina; Hodan, Jiří; Kredatusová, Jana; Šlouf, Miroslav

    2015-01-01

    Roč. 5, č. 120 (2015), s. 98971-98982 ISSN 2046-2069 R&D Projects: GA ČR(CZ) GA14-17921S; GA MŠk(CZ) LO1507 Institutional support: RVO:61389013 Keywords : biodegradable polymer blends * synergistic effects * impact strength Subject RIV: JJ - Other Materials Impact factor: 3.289, year: 2015

  16. Antitumor effect of combination of the inhibitors of two new oncotargets: proton pumps and reverse transcriptase.

    Lugini, Luana; Sciamanna, Ilaria; Federici, Cristina; Iessi, Elisabetta; Spugnini, Enrico Pierluigi; Fais, Stefano

    2017-01-17

    Tumor therapy needs new approaches in order to improve efficacy and reduce toxicity of the current treatments. The acidic microenvironment and the expression of high levels of endogenous non-telomerase reverse transcriptase (RT) are common features of malignant tumor cells. The anti-acidic proton pump inhibitor Lansoprazole (LAN) and the non-nucleoside RT inhibitor Efavirenz (EFV) have shown independent antitumor efficacy. LAN has shown to counteract drug tumor resistance. We tested the hypothesis that combination of LAN and EFV may improve the overall antitumor effects. We thus pretreated human metastatic melanoma cells with LAN and then with EFV, both in 2D and 3D spheroid models. We evaluated the treatment effect by proliferation and cell death/apoptosis assays in classical and in pulse administration experiments. The action of EFV was negatively affected by the tumor microenvironmental acidity, and LAN pretreatment overcame the problem. LAN potentiated the cytotoxicity of EFV to melanoma cells and, when administered during the drug interruption period, prevented the replacement of tumor cell growth.This study supports the implementation of the current therapies with combination of Proton Pumps and Reverse Transcriptase inhibitors.

  17. Melittin exerts an antitumor effect on non‑small cell lung cancer cells.

    Zhang, Su-Fang; Chen, Zhe

    2017-09-01

    Lung cancer accounts for a significant percentage of all cancer‑associated mortalities in men and women, with non‑small cell lung cancer being the most frequently occurring type of lung cancer. Melittin is the principal active component of apitoxin (bee venom) that has been reported to exert anti‑chronic inflammatory and anti‑cancer effects. In the present study, the antitumor effect of melittin was evaluated using in vivo and in vitro analyses. The results demonstrated that melittin significantly inhibited the epidermal growth factor‑induced invasion and migration of non‑small cell lung cancer cells. Subcutaneous injection of melittin at doses of 1 and 10 mg/kg significantly suppressed non‑small cell lung cancer tumor growth by 27 and 61%, respectively. In addition, melittin significantly inhibited the secretion of vascular endothelial growth factor (VEGF) in non‑small cell lung cancer cells. Furthermore, melittin decreased the protein expression of VEGF and hypoxia‑inducible factor 1‑α. Therefore, the antitumor activity of melittin may be associated with the anti‑angiogenic actions of inhibiting the VEGF and hypoxia‑inducible factor signaling pathways.

  18. Carcinogenic and antitumor effects of aminotriazole on acatalasemic and normal catalase mice

    Feinstein, R.N.; Fry, R.J.M.; Staffeidt, E.F.

    1978-01-01

    Dietary 3-amino-1H-1,2,4-triazole (AT), although carcinogenic when administered alone, was an antitumor agent when combined with certain other carcinogenic stimuli. The carcinogenic effect was prominent in the livers of C3H mice; thyroid tumors were less common because they required a longer period of development, and the life-span of the animal was shortened by the AT diet. The antitumor effects of AT included: delay in appearance of mammary tumors, striking reduction in γ-radiation-induced lymphomas, and sharp reduction in neutron radiation-induced harderian gland and ovarian tumors. On an AT diet, the inbred C3H acatalasemic mouse substrain developed more liver tumors, starting earlier, than did the C3H normal catalase substrain. We suggest that our findings pointed to a possible relevance of catalase and H 2 O 2 in carcinogenesis. The most probable mechanism for the increased incidence of liver tumors in AT-treated acatalasemic mice was the diminished rate of degradation of endogenous H 2 O 2

  19. Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin Lymphomas.

    Sarah K Knutson

    Full Text Available Patients with non-Hodgkin lymphoma (NHL are treated today with a cocktail of drugs referred to as CHOP (Cyclophosphamide, Hydroxyldaunorubicin, Oncovin, and Prednisone. Subsets of patients with NHL of germinal center origin bear oncogenic mutations in the EZH2 histone methyltransferase. Clinical testing of the EZH2 inhibitor EPZ-6438 has recently begun in patients. We report here that combining EPZ-6438 with CHOP in preclinical cell culture and mouse models results in dramatic synergy for cell killing in EZH2 mutant germinal center NHL cells. Surprisingly, we observe that much of this synergy is due to Prednisolone - a glucocorticoid receptor agonist (GRag component of CHOP. Dramatic synergy was observed when EPZ-6438 is combined with Prednisolone alone, and a similar effect was observed with Dexamethasone, another GRag. Remarkably, the anti-proliferative effect of the EPZ-6438+GRag combination extends beyond EZH2 mutant-bearing cells to more generally impact germinal center NHL. These preclinical data reveal an unanticipated biological intersection between GR-mediated gene regulation and EZH2-mediated chromatin remodeling. The data also suggest the possibility of a significant and practical benefit of combining EZH2 inhibitors and GRag that warrants further investigation in a clinical setting.

  20. Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin Lymphomas.

    Knutson, Sarah K; Warholic, Natalie M; Johnston, L Danielle; Klaus, Christine R; Wigle, Tim J; Iwanowicz, Dorothy; Littlefield, Bruce A; Porter-Scott, Margaret; Smith, Jesse J; Moyer, Mikel P; Copeland, Robert A; Pollock, Roy M; Kuntz, Kevin W; Raimondi, Alejandra; Keilhack, Heike

    2014-01-01

    Patients with non-Hodgkin lymphoma (NHL) are treated today with a cocktail of drugs referred to as CHOP (Cyclophosphamide, Hydroxyldaunorubicin, Oncovin, and Prednisone). Subsets of patients with NHL of germinal center origin bear oncogenic mutations in the EZH2 histone methyltransferase. Clinical testing of the EZH2 inhibitor EPZ-6438 has recently begun in patients. We report here that combining EPZ-6438 with CHOP in preclinical cell culture and mouse models results in dramatic synergy for cell killing in EZH2 mutant germinal center NHL cells. Surprisingly, we observe that much of this synergy is due to Prednisolone - a glucocorticoid receptor agonist (GRag) component of CHOP. Dramatic synergy was observed when EPZ-6438 is combined with Prednisolone alone, and a similar effect was observed with Dexamethasone, another GRag. Remarkably, the anti-proliferative effect of the EPZ-6438+GRag combination extends beyond EZH2 mutant-bearing cells to more generally impact germinal center NHL. These preclinical data reveal an unanticipated biological intersection between GR-mediated gene regulation and EZH2-mediated chromatin remodeling. The data also suggest the possibility of a significant and practical benefit of combining EZH2 inhibitors and GRag that warrants further investigation in a clinical setting.

  1. Tretinoin-loaded lipid-core nanocapsules overcome the triple-negative breast cancer cell resistance to tretinoin and show synergistic effect on cytotoxicity induced by doxorubicin and 5-fluororacil.

    Schultze, Eduarda; Buss, Julieti; Coradini, Karine; Begnini, Karine Rech; Guterres, Silvia S; Collares, Tiago; Beck, Ruy Carlos Ruver; Pohlmann, Adriana R; Seixas, Fabiana Kömmling

    2017-12-01

    Nanostructured drug delivery systems have been extensively studied, mainly for applications in cancer therapy. The advantages of these materials include protection against drug degradation and improvement in both the relative solubility of poorly water soluble drugs as in targeting of therapy, due to the enhanced permeability and retention effect on tumor sites. In this work, we evaluate the antitumor activity of tretinoin-loaded lipid core nanocapsules (TT-LNC) in a tretinoin-resistant breast cancer cell-line, MDA-MB- 231, as well as the synergistic effect of combination of this treatment with 5-FU or DOXO. The inhibition of cell growth was assayed by MTT reduction. Live/Dead assay and DAPI staining evaluated cytotoxicity. Apoptosis was evaluated by Annexin V-PE/7AAD and the effect of chronic exposure was evaluated by colony formation assay. TT-LNC reduced the cell viability even at lower concentrations (1μM) and displayed synergistic effect with 5-FU or DOXO on cytotoxicity and colony formation inhibition. Our work shows a possibility of using nanocapsules to improve the antitumoral activity of TT for its use either alone or in combination with other chemotherapeutic drugs, especially considering the chronic effect. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  2. Synergistic antitumor cytotoxic actions of ascorbate and menadione on human prostate (DU145) cancer cells in vitro: nucleus and other injuries preceding cell death by autoschizis.

    Gilloteaux, Jacques; Jamison, James M; Neal, Deborah; Summers, Jack L

    2014-04-01

    Scanning (SEM) and transmission electron microscopy (TEM) were used to characterize the cytotoxic effects of ascorbate (VC), menadione (VK3), or a VC:VK3 combination on a human prostate carcinoma cell line (DU145) following a 1-h vitamin treatment and a subsequent 24-h incubation in culture medium. Cell alterations examined by light and electron microscopy were treatment-dependent with VC + VK3 >VK3 > VC > Sham. Oxidative stress-induced damage was found in most organelles. This report describes injuries in the tumor cell nucleus (chromatin and nucleolus), mitochondria, endomembranes, lysosomal bodies (autophagocytoses) and inclusions. Morphologic alterations suggest that cytoskeleton damage is likely responsible for the superficial cytoplasmic changes, including major changes in cell shape and size and the self-excising phenomena. Unlike apoptotic bodies, the excised pieces contain ribonucleoproteins, but not organelles. These deleterious events cause a progressive, significant reduction in the tumor cell size. During nuclear alterations, the nuclei maintain their envelope during chromatolysis and karyolysis until cell death, while nucleoli undergo a characteristic segregation of their components. In addition, changes in fat and glycogen storage are consistent the cytotoxic and metabolic alterations caused by the respective treatments. All cellular ultrastructural changes are consistent with cell death by autoschizis and not apoptosis or other kinds of cell death.

  3. The Antitumor Effects of Triterpenoid Saponins from the Anemone flaccida and the Underlying Mechanism

    Lin-Tao Han

    2013-01-01

    Full Text Available Anemone flaccida Fr. Schmidt, a family of ancient hopanoids, have been used as traditional Asian herbs for the treatments of inflammation and convulsant diseases. Previous study on HeLa cells suggested that triterpenoid saponins from Anemone flaccida Fr. Schmidt may have potential antitumor effect due to their apoptotic activities. Here, we confirmed the apoptotic activities of the following five triterpenoid saponins: glycoside St-I4a (1, glycoside St-J (2, anhuienoside E (3, hedera saponin B (4, and flaccidoside II (5 on human BEL-7402 and HepG2 hepatoma cell lines, as well as the model of HeLa cells treated with lipopolysaccharide (LPS. We found that COX-2/PGE2 signaling pathway, which plays key roles in the development of cancer, is involved in the antitumor activities of these saponins. These data provide the evidence that triterpenoid saponins can induce apoptosis via COX-2/PGE2 pathway, implying a preventive role of saponins from Anemone flaccida in tumor.

  4. Synergistic Cancer Growth-Inhibitory Effect of Emodin and Low ...

    against human gastric cancer (SNU-5), including their effects on cell cycle phase distribution, apoptosis and cancer ... chemotherapy in cancer. ... is restricted due to harmful side effects such as ..... Our study provides ... Curcumin enhances the effect of cisplatin in suppression of head and neck squamous cell carcinoma via.

  5. Mechanisms Underlying the Anti-Aging and Anti-Tumor Effects of Lithocholic Bile Acid

    Anthony Arlia-Ciommo

    2014-09-01

    Full Text Available Bile acids are cholesterol-derived bioactive lipids that play essential roles in the maintenance of a heathy lifespan. These amphipathic molecules with detergent-like properties display numerous beneficial effects on various longevity- and healthspan-promoting processes in evolutionarily distant organisms. Recent studies revealed that lithocholic bile acid not only causes a considerable lifespan extension in yeast, but also exhibits a substantial cytotoxic effect in cultured cancer cells derived from different tissues and organisms. The molecular and cellular mechanisms underlying the robust anti-aging and anti-tumor effects of lithocholic acid have emerged. This review summarizes the current knowledge of these mechanisms, outlines the most important unanswered questions and suggests directions for future research.

  6. Decreasing size of radiosensitive capsules from micro to nano, and its increased antitumor effect and decreasing adverse effect

    Harada, S.; Ehara, S.; Ishii, K.; Yamazaki, H.; Matsuyama, S.; Sato, Takahiro; Kamiya, Tomihiro; Sera, K.; Saito, Y.

    2012-01-01

    We have been developing microcapsules that release anticancer drug with response to radiation. We attempted to decrease the diameter of capsules. Then, two categories were tested in VIVO in C3He mice: (1) the antitumor effect in combination with radiation and subcutaneously injected nanocapsules, (2) the kidnetics of nanocapsules when they were injected intravenously. Microcapsules were produced by spraying a mixture of 3.0 % hyaluronic acid, 2.0 % alginate, 3.0 % H 2 O 2 , and 0.3 mmol carboplatin (Pt containing anticancer drug) onto a mixture of vibrated 0.3 mol FeCl 2 and 0.15 mol CaCl 2 . The antitumor effect was measured by measuring tumor diameter every day. The kinetics of microcapsules were expressed as the numbers of capsules in 5 views (25 x 25 μm) of micro PIXE camera and Pt concentration of quantiative PIXE. The generated microcapsules 752 ± 64 nm, which were significantly downsized relative to previous capsules. The accumulations of capsules in lungs, liver, and kidneys were decreased by downsizing, whereas those of tumors were increased. By adjusting Pt concentration in tumor, there were no significant differences in antitumor effect between not downsized and downsized microcapsules with combination with radiation. Decreased trapping of downsized microcapsules to lungs, liver, and kidneys, also increased trapping in tumors will lead to new targeted chemoradiotherapy via intravenous injection of microcapsules. (author)

  7. Combination of TRAIL and actinomycin D liposomes enhances antitumor effect in non-small cell lung cancer

    Guo LG

    2012-03-01

    Full Text Available Liangran Guo1,2,4, Li Fan1,2, Jinfeng Ren1,2, Zhiqing Pang1,2, Yulong Ren1,2, Jingwei Li1,2, Ziyi Wen1,3, Yong Qian1,2, Lin Zhang1,2, Hang Ma4, Xinguo Jiang1,2 1School of Pharmacy, Fudan University, Zhangheng Road, Shanghai, 2Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Shanghai, 3School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China; 4College of Pharmacy, University of Rhode Island, RI, USAAbstract: The intractability of non-small cell lung cancer (NSCLC to multimodality treatments plays a large part in its extremely poor prognosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL is a promising cytokine for selective induction of apoptosis in cancer cells; however, many NSCLC cell lines are resistant to TRAIL-induced apoptosis. The therapeutic effect can be restored by treatments combining TRAIL with chemotherapeutic agents. Actinomycin D (ActD can sensitize NSCLC cells to TRAIL-induced apoptosis by upregulation of death receptor 4 (DR4 or 5 (DR5. However, the use of ActD has significant drawbacks due to the side effects that result from its nonspecific biodistribution in vivo. In addition, the short half-life of TRAIL in serum also limits the antitumor effect of treatments combining TRAIL and ActD. In this study, we designed a combination treatment of long-circulating TRAIL liposomes and ActD liposomes with the aim of resolving these problems. The combination of TRAIL liposomes and ActD liposomes had a synergistic cytotoxic effect against A-549 cells. The mechanism behind this combination treatment includes both increased expression of DR5 and caspase activation. Moreover, systemic administration of the combination of TRAIL liposomes and ActD liposomes suppressed both tumor formation and growth of established subcutaneous NSCLC xenografts in nude mice, inducing apoptosis without causing significant general toxicity. These results provide preclinical proof

  8. [Antitumor effect of recombinant Xenopus laevis vascular endothelial growth factor (VEGF) as a vaccine combined with adriamycin on EL4 lymphoma in mice].

    Niu, Ting; Liu, Ting; Jia, Yong-Qian; Liu, Ji-Yan; Wu, Yang; Hu, Bing; Tian, Ling; Yang, Li; Kan, Bing; Wei, Yu-Quan

    2005-09-01

    To explore the antitumor effect of immunotherapy with recombinant Xenopus laevis vascular endothelial growth factor (xVEGF) as a vaccine combined with adriamycin on lymphoma model in mice. EL4 lymphoma model was established in C57BL/6 mice. Mice were randomized into four groups: combination therapy, adriamycin alone, xVEGF alone and normal saline (NS) groups, and then were given relevant treatments. The growth of tumor, the survival rate of tumor-bearing mice, and the potential toxicity of regimens above were observed. Anti-VEGF antibody-producing B cells (APBCs) were detected by enzyme-linked immunospot (ELISPOT) assay. In addition, microvessel density (MVD) of tumor was detected by immunohistochemistry, and tumor cell apoptosis was also detected by TUNEL staining. The tumor volumes of mice were significantly smaller in combination group than those in other three groups (P < 0.05). Complete regression of tumor was observed in 3 of 10 mice in combination group. Forty-eight days after inoculation of tumor cells, the survival rate of mice was significantly higher in combination group than in NS group (P < 0.01). The anti-VEGF APBC count in combination group or xVEGF group was significantly higher, compared with that in adriamycin group or NS group (P < 0.01). MVD in tumor tissues was significantly lower in combination group than those in other three groups (P < 0.05). Moreover, tumor cell apoptosis was significantly higher in combination group than those in other three groups (P < 0.05). In this experimental study, the use of xVEGF vaccine and adriamycin as a combination of immunotherapy with chemotherapy has sucessfully produced synergistic antitumor effect on lymphoma in mice.

  9. In vitro and in vivo antitumor effects of chloroquine on oral squamous cell carcinoma

    Jia, Lihua; Wang, Juan; Wu, Tong; Wu, Jinan; Ling, Junqi; Cheng, Bin

    2017-01-01

    Chloroquine, which is a widely used antimalarial drug, has been reported to exert anticancer activity in some tumor types; however, its potential effects on oral squamous cell carcinoma (OSCC) remain unclear. The present study aimed to explore the effects and possible underlying mechanisms of chloroquine against OSCC. MTT and clonogenic assays were conducted to evaluate the effects of chloroquine on the human OSCC cell lines SCC25 and CAL27. Cell cycle progression and apoptosis were detected using flow cytometry. Autophagy was monitored using microtubule-associated protein 1A/1B-light chain 3 as an autophagosomal marker. In order to determine the in vivo antitumor effects of chloroquine on OSCC, a CAL27 xenograft model was used. The results demonstrated that chloroquine markedly inhibited the proliferation and the colony-forming ability of both OSCC cell lines in a dose- and time-dependent manner in vitro. Chloroquine also disrupted the cell cycle, resulting in the cell cycle arrest of CAL27 and SCC25 cells at G0/G1 phase, via downregulation of cyclin D1. In addition, chloroquine inhibited autophagy, and induced autophagosome and autolysosome accumulation in the cytoplasm, thus interfering with degradation; however, OSCC apoptosis was barely affected by chloroquine. The results of the in vivo study demonstrated that chloroquine effectively inhibited OSCC tumor growth in the CAL27 xenograft model. In conclusion, the present study reported the in vitro and in vivo antitumor effects of chloroquine on OSCC, and the results indicated that chloroquine may be considered a potent therapeutic agent against human OSCC. PMID:28849182

  10. Synergistic effect of fisetin combined with sorafenib in human cervical cancer HeLa cells through activation of death receptor-5 mediated caspase-8/caspase-3 and the mitochondria-dependent apoptotic pathway.

    Lin, Ming-Te; Lin, Chia-Liang; Lin, Tzu-Yu; Cheng, Chun-Wen; Yang, Shun-Fa; Lin, Chu-Liang; Wu, Chih-Chien; Hsieh, Yi-Hsien; Tsai, Jen-Pi

    2016-05-01

    Combining antitumor agents with bioactive compounds is a potential strategy for improving the effect of chemotherapy on cancer cells. The goal of this study was to elucidate the antitumor effect of the flavonoid, fisetin, combined with the multikinase inhibitor, sorafenib, against human cervical cancer cells in vitro and in vivo. The combination of fisetin and sorafenib synergistically induced apoptosis in HeLa cells, which is accompanied by a marked increase in loss of mitochondrial membrane potential. Apoptosis induction was achieved by caspase-3 and caspase-8 activation which increased the ratio of Bax/Bcl-2 and caused the subsequent cleavage of PARP level while disrupting the mitochondrial membrane potential in HeLa cells. Decreased Bax/Bcl-2 ratio level and mitochondrial membrane potential were also observed in siDR5-treated HeLa cells. In addition, in vivo studies revealed that the combined fisetin and sorafenib treatment was clearly superior to sorafenib treatment alone using a HeLa xenograft model. Our study showed that the combination of fisetin and sorafenib exerted better synergistic effects in vitro and in vivo than either agent used alone against human cervical cancer, and this synergism was based on apoptotic potential through a mitochondrial- and DR5-dependent caspase-8/caspase-3 signaling pathway. This combined fisetin and sorafenib treatment represents a novel therapeutic strategy for further clinical developments in advanced cervical cancer.

  11. Synergistic anticonvulsant effects of pregabalin and amlodipine on acute seizure model of epilepsy in mice.

    Qureshi, Itefaq Hussain; Riaz, Azra; Khan, Rafeeq Alam; Siddiqui, Afaq Ahmed

    2017-08-01

    Status epilepticus is a life threatening neurological medical emergency. It may cause serious damage to the brain and even death in many cases if not treated properly. There is limited choice of drugs for the short term and long term management of status epilepticus and the dugs recommended for status epilepticus possess various side effects. The present study was designed to investigate synergistic anticonvulsant effects of pregabalin with amlodipine on acute seizure model of epilepsy in mice. Pentylenetetrazole was used to induce acute seizures which mimic status epilepticus. Pregabalin and amlodipine were used in combination to evaluate synergistic anti-seizure effects on acute seizure model of epilepsy in mice. Diazepam and valproate were used as reference dugs. The acute anti-convulsive activity of pregabalin with amlodipine was evaluated in vivo by the chemical induced seizures and their anti-seizure effects were compared with pentylenetetrazole, reference drugs and to their individual effects. The anti-seizure effects of tested drugs were recorded in seconds on seizure characteristics such as latency of onset of threshold seizures, rearing and fallings and Hind limbs tonic extensions. The seizure protection and mortality to the animals exhibited by the drugs were recorded in percentage. Combination regimen of pregabalin with amlodipine exhibited dose dependent significant synergistic anticonvulsant effects on acute seizures which were superior to their individual effects and equivalent to reference drugs.

  12. Synergistic effects in radiation-induced particle ejection from solid surfaces

    Itoh, Noriaki

    1990-01-01

    A description is given on radiation-induced particle ejection from solid surfaces, emphasizing synergistic effects arising from multi-species particle irradiation and from irradiation under complex environments. First, it is pointed out that synergisms can be treated by introducing the effects of material modification on radiation-induced particle ejection. As examples of the effects of surface modification on the sputtering induced by elastic encounters, sputtering of alloys and chemical sputtering of graphite are briefly discussed. Then the particle ejection induced by electronic encounters is explained emphasizing the difference in the behaviors from materials to materials. The possible synergistic effects of electronic and elastic encounters are also described. Lastly, we point out the importance of understanding the elementary processes of material-particle interaction and of developing computer codes describing material behaviors under irradiation. (author)

  13. Snake venom L-amino acid oxidases: an overview on their antitumor effects

    2014-01-01

    The L-amino acid oxidases (LAAOs) constitute a major component of snake venoms and have been widely studied due to their widespread presence and various effects, such as apoptosis induction, cytotoxicity, induction and/or inhibition of platelet aggregation, hemorrhage, hemolysis, edema, as well as antimicrobial, antiparasitic and anti-HIV activities. The isolated and characterized snake venom LAAOs have become important research targets due to their potential biotechnological applications in pursuit for new drugs of interest in the scientific and medical fields. The current study discusses the antitumor effects of snake venom LAAOs described in the literature to date, highlighting the mechanisms of apoptosis induction proposed for this class of proteins. PMID:24940304

  14. [Anti-tumor effects of DDP-PLLA-CNTs on human cholangiocarcinoma cell line in vitro].

    Li, Maolan; Lu, Wei; Zhang, Fei; Ding, Qichen; Wu, Xiangsong; Tan, Zhujun; Wu, Wenguang; Weng, Hao; Wang, Xuefeng; Shi, Weibin; Dong, Ping; Gu, Jun; Liu, Yingbin

    2014-11-04

    To explore the antitumor effects of DDP-PLLA-CNTs on human cholangiocarcinoma cell line. DDP-PLLA-CNTs were prepared with the method of ultrasound emulsification. The morphology of DDP-PLLA-CNTs was determined by scanning electron microscope (SEM). And its drug loading and drug release curve in vitro was detected by UV-Vis-NIR spectrophotometer. CCK8 was used to test the cytotoxic effects of DDP-PLLA-CNTs at different concentrations on QBC939 cell proliferation.Flow cytometry was employed to measure the changes of apoptotic rate. With excellent controlled-release characteristic of in vitro drug release, DDP-PLLA-CNTs inhibited the proliferation and significantly increased the apoptotic rate of QBC939 cell line. DDP-PLLA-CNTs have drug sustained-release characteristics and can significantly inhibit the proliferation of QBC939 cell line.

  15. Antitumor and immunomodulatory effects of the naphthoquinone 5-methoxy-3,4-dehydroxanthomegnin

    Rodrigo Rezende Kitagawa

    2011-12-01

    Full Text Available Large number of quinones has been associated with antitumor, antibacterial, antimalarial and antifungal activities. In this work we describe the effect of the naphthoquinone, 5-methoxy-3,4-dehydroxanthomegnin, on murine tumor cells (LP07 and LM2 and its immunomodulatory effect on nitric oxide (NO production on LPS-stimulated macrophages. The results have shown that 5-methoxy-3,4-dehydroxanthomegnin was a significant inhibitor of LPS-stimulated NO generation from macrophage (inhibition percentage ranged from 97.4 to 98.9% and a strong cytotoxic agent against both tumor cells LP07 and LM2 (CI50 6.2±0.36 µM and 74.6±1.9 µM, respectively. These results indicate that the 5-methoxy-3,4-dehydroxanthomegnin may show promising activity in the treatment of murine breast and lung cancer by immunomodulatory and antiproliferative activities.

  16. Antitumor and immunomodulatory effects of the naphthoquinone 5-methoxy-3,4-dehydroxanthomegnin

    Rodrigo Rezende Kitagawa

    2011-08-01

    Full Text Available Large number of quinones has been associated with antitumor, antibacterial, antimalarial and antifungal activities. In this work we describe the effect of the naphthoquinone, 5-methoxy-3,4-dehydroxanthomegnin, on murine tumor cells (LP07 and LM2 and its immunomodulatory effect on nitric oxide (NO production on LPS-stimulated macrophages. The results have shown that 5-methoxy-3,4-dehydroxanthomegnin was a significant inhibitor of LPS-stimulated NO generation from macrophage (inhibition percentage ranged from 97.4 to 98.9% and a strong cytotoxic agent against both tumor cells LP07 and LM2 (CI50 6.2±0.36 µM and 74.6±1.9 µM, respectively. These results indicate that the 5-methoxy-3,4-dehydroxanthomegnin may show promising activity in the treatment of murine breast and lung cancer by immunomodulatory and antiproliferative activities.

  17. Human harvest, climate change and their synergistic effects drove the Chinese Crested Tern to the brink of extinction

    Shuihua Chen

    2015-07-01

    Full Text Available Synergistic effect refers to simultaneous actions of separate factors which have a greater total effect than the sum of the individual factor effects. However, there has been a limited knowledge on how synergistic effects occur and individual roles of different drivers are not often considered. Therefore, it becomes quite challenging to manage multiple threatening processes simultaneously in order to mitigate biodiversity loss. In this regard, our hypothesis is, if the traits actually play different roles in the synergistic interaction, conservation efforts could be made more effectively. To understand the synergistic effect and test our hypothesis, we examined the processes associated with the endangerment of critically endangered Chinese Crested Tern (Thalasseus bernsteini, whose total population number was estimated no more than 50. Through monitoring of breeding colonies and investigations into causative factors, combined with other data on human activities, we found that widespread human harvest of seabird eggs and increasing frequency of typhoons are the major factors that threatened the Chinese Crested Tern. Furthermore, 28 percent of breeding failures were due to the synergistic effects in which egg harvest-induced renestings suffered the higher frequent typhoons. In such combined interactions, the egg harvest has clearly served as a proximal factor for the population decline, and the superimposition of enhanced typhoon activity further accelerated the species toward imminent extinction. Our findings suggest that species endangerment, on one hand, should be treated as a synergistic process, while conservation efforts, on the other hand, should focus principally on combatting the threat that triggers synergistic effects.

  18. Aspirin Has Antitumor Effects via Expression of Calpain Gene in Cervical Cancer Cells

    Sang Koo Lee

    2008-01-01

    Full Text Available Aspirin and other nonsteroidal anti-inflammatory drugs show efficacy in the prevention of cancers. It is known that they can inhibit cyclooxygenases, and some studies have shown that they can induce apoptosis. Our objective in this study was to investigate the mechanism by which aspirin exerts its apoptosis effects in human cervical cancer HeLa cells. The effect of aspirin on the gene expression was studied by differential mRNA display RT-PCR. Among the isolated genes, mu-type calpain gene was upregulated by aspirin treatment. To examine whether calpain mediates the antitumor effects, HeLa cells were stably transfected with the mammalian expression vector pCR3.1 containing mu-type calpain cDNA (pCRCAL/HeLa, and tumor formations were measured in nude mice. When tumor burden was measured by day 49, HeLa cells and pCR/HeLa cells (vector control produced tumors of 2126 mm3 and 1638 mm3, respectively, while pCRCAL/HeLa cells produced markedly smaller tumor of 434 mm3 in volume. The caspase-3 activity was markedly elevated in pCRCAL/HeLa cells. The increased activity levels of caspase-3 in pCRCAL/HeLa cells, in parallel with the decreased tumor formation, suggest a correlation between caspase-3 activity and calpain protein. Therefore, we conclude that aspirin-induced calpain mediates an antitumor effect via caspase-3 in cervical cancer cells.

  19. Higher Performance of DSSC with Dyes from Cladophora sp. as Mixed Cosensitizer through Synergistic Effect.

    Lim, Andery; Haji Manaf, Noramaliyana; Tennakoon, Kushan; Chandrakanthi, R L N; Lim, Linda Biaw Leng; Bandara, J M R Sarath; Ekanayake, Piyasiri

    2015-01-01

    Chlorophyll and xanthophyll dyes extracted from a single source of filamentous freshwater green algae (Cladophora sp.) were used to sensitize dye sensitized solar cells and their performances were investigated. A more positive interaction is expected as the derived dyes come from a single natural source because they work mutually in nature. Cell sensitized with mixed chlorophyll and xanthophyll showed synergistic activity with improved cell performance of 1.5- to 2-fold higher than that sensitized with any individual dye. The effect of temperature and the stability of these dyes were also investigated. Xanthophyll dye was found to be more stable compared to chlorophyll that is attributed in the ability of xanthophyll to dissipate extra energy via reversible structural changes. Mixing the dyes resulted to an increase in effective electron life time and reduced the process of electron recombination during solar cell operation, hence exhibiting a synergistic effect.

  20. The synergistic antinociceptive effect of lornoxicam in combination with tramadol

    Amela Saračević

    2013-12-01

    Full Text Available Introduction: One of the most important priorities in therapy is pain control. Therefore, many different groups of drugs are being used for this purpose, primarily opioid analgesics and non-steroidal anti-inflammatory drugs (NSAIDs. Opioid analgesic tramadol, by binding to specific receptors, modulates the perception and response to painful stimuli and inhibits transmitting and further processing of pain impulses. Lornoxicam, which belongs to the oxicam class of NSAIDs, is a non-selective cyclooxygenase inhibitor with strong analgesic and anti-inflammatory effects, and better tolerance profile. Preliminary research, which requires further verification, suggests that lornoxicam may be a better alternative or adjunctive therapy to opioid analgesics in the treatment of moderate to severe pain. The aim of this study was to investigate antinociceptive effects of lornoxicam, as well as the combination of lornoxicam with tramadol.Methods: Analgesic effect of combination of lornoxicam and tramadol or lornoxicam applied alone was examined on female albino mice, using a hot plate method. Measurements were made 30, 60, 90 and 120 minutes after intraperitoneal and subcutaneous administration, in dose of 10 mg/kg.Results: Combination of lornoxicam and tramadol, applied intraperitoneally, increases the threshold of sensitivity to painful stimuli, which was not the case with subcutaneous administration.Conclusions: Lornoxicam significantly increases analgesic effect when applied intraperitoneally in combination with tramadol. On the other hand, lornoxicam in combination with tramadol, did not increase the threshold of sensitivity to painful stimuli with significant difference, after subcutaneous administration

  1. Effects of local and global network connectivity on synergistic epidemics

    Broder-Rodgers, David; Pérez-Reche, Francisco J.; Taraskin, Sergei N.

    2015-12-01

    Epidemics in networks can be affected by cooperation in transmission of infection and also connectivity between nodes. An interplay between these two properties and their influence on epidemic spread are addressed in the paper. A particular type of cooperative effects (called synergy effects) is considered, where the transmission rate between a pair of nodes depends on the number of infected neighbors. The connectivity effects are studied by constructing networks of different topology, starting with lattices with only local connectivity and then with networks that have both local and global connectivity obtained by random bond-rewiring to nodes within a certain distance. The susceptible-infected-removed epidemics were found to exhibit several interesting effects: (i) for epidemics with strong constructive synergy spreading in networks with high local connectivity, the bond rewiring has a negative role in epidemic spread, i.e., it reduces invasion probability; (ii) in contrast, for epidemics with destructive or weak constructive synergy spreading on networks of arbitrary local connectivity, rewiring helps epidemics to spread; (iii) and, finally, rewiring always enhances the spread of epidemics, independent of synergy, if the local connectivity is low.

  2. Synergistic effect of radiation and traditional Chinese medicine ...

    Results: Our data showed that Rhizoma typhonii (RT) obviously inhibited the proliferations of Lewis cells in time and dose dependent manners by MTT assay and enhanced radiosensitivity by colony formation assay. The effects of RT to Ionizing radiation (IR) therapy were demonstrated radiosensitivity on tumors xenograft ...

  3. Cytotoxicity and anti-tumor effects of new ruthenium complexes on triple negative breast cancer cells.

    Cecília P Popolin

    Full Text Available Triple-negative breast cancer (TNBC is a highly aggressive breast cancer subtype. The high rate of metastasis associated to the fact that these cells frequently display multidrug resistance, make the treatment of metastatic disease difficult. Development of antitumor metal-based drugs was started with the discovery of cisplatin, however, the severe side effects represent a limitation for its clinical use. Ruthenium (Ru complexes with different ligands have been successfully studied as prospective antitumor drugs. In this work, we demonstrated the activity of a series of biphosphine bipyridine Ru complexes (1 [Ru(SO4(dppb(bipy], (2 [Ru(CO3(dppb(bipy], (3 [Ru(C2O4(dppb(bipy] and (4 [Ru(CH3CO2(dppb(bipy]PF6 [where dppb = 1,4-bis(diphenylphosphinobutane and bipy = 2,2'-bipyridine], on proliferation of TNBC (MDA-MB-231, estrogen-dependent breast tumor cells (MCF-7 and a non-tumor breast cell line (MCF-10A. Complex (4 was most effective among the complexes and was selected to be further investigated on effects on tumor cell adhesion, migration, invasion and in apoptosis. Moreover, DNA and HSA binding properties of this complex were also investigated. Results show that complex (4 was more efficient inhibiting proliferation of MDA-MB-231 cells over non-tumor cells. In addition, complex (4 was able to inhibit MDA-MB231 cells adhesion, migration and invasion and to induce apoptosis and inhibit MMP-9 secretion in TNBC cells. Complex (4 should be further investigated in vivo in order to stablish its potential to improve breast cancer treatment.

  4. Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines.

    Massi, Paola; Vaccani, Angelo; Ceruti, Stefania; Colombo, Arianna; Abbracchio, Maria P; Parolaro, Daniela

    2004-03-01

    Recently, cannabinoids (CBs) have been shown to possess antitumor properties. Because the psychoactivity of cannabinoid compounds limits their medicinal usage, we undertook the present study to evaluate the in vitro antiproliferative ability of cannabidiol (CBD), a nonpsychoactive cannabinoid compound, on U87 and U373 human glioma cell lines. The addition of CBD to the culture medium led to a dramatic drop of mitochondrial oxidative metabolism [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide test] and viability in glioma cells, in a concentration-dependent manner that was already evident 24 h after CBD exposure, with an apparent IC(50) of 25 microM. The antiproliferative effect of CBD was partially prevented by the CB2 receptor antagonist N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; SR2) and alpha-tocopherol. By contrast, the CB1 cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716; SR1), capsazepine (vanilloid receptor antagonist), the inhibitors of ceramide generation, or pertussis toxin did not counteract CBD effects. We also show, for the first time, that the antiproliferative effect of CBD was correlated to induction of apoptosis, as determined by cytofluorimetric analysis and single-strand DNA staining, which was not reverted by cannabinoid antagonists. Finally, CBD, administered s.c. to nude mice at the dose of 0.5 mg/mouse, significantly inhibited the growth of subcutaneously implanted U87 human glioma cells. In conclusion, the nonpsychoactive CBD was able to produce a significant antitumor activity both in vitro and in vivo, thus suggesting a possible application of CBD as an antineoplastic agent.

  5. Triclosan treatment decreased the antitumor effect of sorafenib on hepatocellular carcinoma cells

    Wu M

    2018-05-01

    Full Text Available Man Wu,1,2 Guanren Zhao,2 Xiaomei Zhuang,1 Tianhong Zhang,1 Ce Zhang,2 Wenpeng Zhang,1 Zhenqing Zhang1 1State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China; 2Department of Pharmacy, The 309th Hospital of PLA, Beijing, China Background: Triclosan is a widely applied antimicrobial agent which affects the endocrine system and homeostasis; it may also promote the cirrhosis and hepatocellular carcinoma (HCC growth in a mice model. The exact roles of triclosan in regulating human hepatocellular carcinoma development and treatment remain unknown. Methods: MHCC97-H, a highly aggressive HCC cell line, was treated with indicated concentration of triclosan or sorafenib. The expression of drug-resistance genes was examined by qPCR. The clearance or metabolism of sorafenib was determined by liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS. MTT assay was used to examine the MHCC97-H cell proliferation. Nude mice were used to exam the anti-tumor effect of sorafenib on subcutaneous and intrahepatic growth of MHCC97-H cells. Results: In the present study, triclosan could induce the expression of drug-resistance genes in MHCC97-H cells (a highly aggressive HCC cell line, accelerate the clearance of sorafenib, and attenuate the anti-proliferation effect of this molecular targeted agent in MHCC97-H cells. Triclosan decreased the antitumor effect of sorafenib on subcutaneous and intrahepatic growth of MHCC97-H in nude mice. Conclusion: By discovering the fact that triclosan treatment enhances sorafenib resistance in HCC cells, this work suggests exposure of triclosan is detrimental to HCC patients during chemotherapy. Keywords: HCC, triclosan, sorafenib resistance, drug clearance 

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

    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

  7. Solvent effects in the synergistic solvent extraction of Co2+

    Kandil, A.T.; Ramadan, A.

    1979-01-01

    The extraction of Co 2+ from a 0.1M ionic strength aqueous phase (Na + , CH 3 COOH) of pH = 5.1 was studied using thenoyltrifluoroacetone, HTTA, in eight different solvents and HTTA + trioctylphosphine oxide, TOPO, in the same solvents. A comparison of the effect of solvent dielectric constant on the equilibrium constant shows a synergism as a result of the increased hydrophobic character imparted to the metal complex due to the formation of the TOPO adduct. (author)

  8. Regulatory T cell effects in antitumor laser immunotherapy: a mathematical model and analysis

    Dawkins, Bryan A.; Laverty, Sean M.

    2016-03-01

    Regulatory T cells (Tregs) have tremendous influence on treatment outcomes in patients receiving immunotherapy for cancerous tumors. We present a mathematical model incorporating the primary cellular and molecular components of antitumor laser immunotherapy. We explicitly model developmental classes of dendritic cells (DCs), cytotoxic T cells (CTLs), primary and metastatic tumor cells, and tumor antigen. Regulatory T cells have been shown to kill antigen presenting cells, to influence dendritic cell maturation and migration, to kill activated killer CTLs in the tumor microenvironment, and to influence CTL proliferation. Since Tregs affect explicitly modeled cells, but we do not explicitly model dynamics of Treg themselves, we use model parameters to analyze effects of Treg immunosuppressive activity. We will outline a systematic method for assigning clinical outcomes to model simulations and use this condition to associate simulated patient treatment outcome with Treg activity.

  9. A PAH growth mechanism and synergistic effect on PAH formation in counterflow diffusion flames

    Wang, Yu

    2013-09-01

    A reaction mechanism having molecular growth up to benzene for hydrocarbon fuels with up to four carbon-atoms was extended to include the formation and growth of polycyclic aromatic hydrocarbons (PAHs) up to coronene (C24H12). The new mechanism was tested for ethylene premixed flames at low (20torr) and atmospheric pressures by comparing experimentally observed species concentrations with those of the computed ones for small chemical species and PAHs. As compared to several existing mechanisms in the literature, the newly developed mechanism showed an appreciable improvement in the predicted profiles of PAHs. The new mechanism was also used to simulate PAH formation in counterflow diffusion flames of ethylene to study the effects of mixing propane and benzene in the fuel stream. In the ethylene-propane flames, existing experimental results showed a synergistic effect in PAH concentrations, i.e. PAH concentrations first increased and then decreased with increasing propane mixing. This PAH behavior was successfully captured by the new mechanism. The synergistic effect was predicted to be more pronounced for larger PAH molecules as compared to the smaller ones, which is in agreement with experimental observations. In the experimental study in which the fuel stream of ethylene-propane flames was doped with benzene, a synergistic effect was mitigated for benzene, but was observed for large PAHs. This effect was also predicted in the computed PAH profiles for these flames. To explain these responses of PAHs in the flames of mixture fuels, a pathway analysis has been conducted, which show that several resonantly stabilized species as well as C4H4 and H atom contribute to the enhanced synergistic behaviors of larger PAHs as compared to the small ones in the flames of mixture fuels. © 2013 The Combustion Institute.

  10. Synergistic Antibacterial Effects of Polyphenolic Compounds from Olive Mill Wastewater

    Ahmed Tafesh

    2011-01-01

    Full Text Available Polyphenols or phenolic compounds are groups of secondary metabolites widely distributed in plants and found in olive mill wastewater (OMW. Phenolic compounds as well as OMW extracts were evaluated in vitro for their antimicrobial activity against Gram-positive (Streptococcus pyogenes and Staphylococcus aureus and Gram-negative bacteria (Escherichia coli and Klebsiella pneumoniae. Most of the tested phenols were not effective against the four bacterial strains when tested as single compounds at concentrations of up to 1000 μg mL−1. Hydroxytyrosol at 400 μg mL−1 caused complete growth inhibition of the four strains. Gallic acid was effective at 200, and 400 μg mL−1 against S. aureus, and S. pyogenes, respectively, but not against the gram negative bacteria. An OMW fraction called AntiSolvent was obtained after the addition of ethanol to the crude OMW. HPLC analysis of AntiSolvent fraction revealed that this fraction contains mainly hydroxytyrosol (10.3%, verbascoside (7.4%, and tyrosol (2.6%. The combinations of AntiSolvent/gallic acid were tested using the low minimal inhibitory concentrations which revealed that 50/100–100/100 μg mL−1 caused complete growth inhibition of the four strains. These results suggest that OMW specific fractions augmented with natural phenolic ingredients may be utilized as a source of bioactive compounds to control pathogenic bacteria.

  11. Composition and mechanism of anti-tumor effects of Hericium erinaceus mushroom extracts in tumor-bearing mice

    We investigated anti-tumor effects of the following four extracts of freeze-dried Hericium erinaceus mushrooms in Balb/c mice intracutaneously transplanted on the backs with CT-26 colon cancer cells: HWE, hot-water extraction by boiling in water for 3 h; MWE, microwaving in 50% ethanol/water at 60 W...

  12. Antitumor effects of cecropin B-LHRH’ on drug-resistant ovarian and endometrial cancer cells

    Li, Xiaoyong; Shen, Bo; Chen, Qi; Zhang, Xiaohui; Ye, Yiqing; Wang, Fengmei; Zhang, Xinmei

    2016-01-01

    Luteinizing hormone-releasing hormone receptor (LHRHr) represents a promising therapeutic target for treating sex hormone-dependent tumors. We coupled cecropin B, an antimicrobial peptide, to LHRH’, a form of LHRH modified at carboxyl-terminal residues 4–10, which binds to LHRHr without interfering with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. This study aimed to assess the antitumor effects of cecropin B-LHRH’ (CB-LHRH’) in drug-resistant ovarian and endometrial cancers. To evaluate the antitumor effects of CB-LHRH’, three drug resistant ovarian cancer cell lines (SKOV-3, ES-2, NIH:OVCAR-3) and an endometrial cancer cell line (HEC-1A) were treated with CB-LHRH’. Cell morphology changes were assessed using inverted and electron microscopes. In addition, cell growth and cell cytotoxicity were measured by MTT assay and LDH release, respectively. In addition, hemolysis was measured. Furthermore, radioligand receptor binding, hypersensitization and minimal inhibitory concentrations (against Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae, Pseudomonas aeruginosa, and Acinetobacter baumannii) were determined. Finally, the impact on tumor growth in BALB/c-nu mice was assessed in an ES-2 xenograft model. CB-LHRH’ bound LHRHr with high-affinity (dissociation constant, Kd = 0.252 ± 0.061nM). Interestingly, CB-LHRH’ significantly inhibited the cell viability of SKOV-3, ES-2, NIH:OVCAR-3 and HEC-1A, but not that of normal eukaryotic cells. CB-LHRH’ was active against bacteria at micromolar concentrations, and caused no hypersensitivity in guinea pigs. Furthermore, CB-LHRH’ inhibited tumor growth with a 23.8 and 20.4 % reduction in tumor weight at 50 and 25 mg/kg.d, respectively. CB-LHRH’ is a candidate for targeted chemotherapy against ovarian and endometrial cancers

  13. Synergistic Effect of Carbon Nanotubes and Graphene on Diopside Scaffolds.

    Liu, Tingting; Wu, Ping; Gao, Chengde; Feng, Pei; Xiao, Tao; Deng, Youwen; Shuai, Cijun; Peng, Shuping

    2016-01-01

    A synergetic effect between carbon nanotubes (CNTs) and graphene on diopside (Di) scaffolds was demonstrated. 3D network architecture in the matrix was formed through the 1D CNTs inlaid among the 2D graphene platelets (GNPs). The mechanical properties of the CNTs/GNPs/Di scaffolds were significantly improved compared with the CNTs/Di scaffolds and GNPs/Di scaffolds. In addition, the scaffolds exhibited excellent apatite-forming ability, a modest degradation rate, and stable mechanical properties in simulated body fluid (SBF). Moreover, cell culturing tests indicated that the scaffolds supported the cells attachment and proliferation. Taken together, the CNTs/GNPs/Di scaffolds offered great potential for bone tissue engineering.

  14. Immunotherapeutic effect of Concholepas hemocyanin in the murine bladder cancer model: evidence for conserved antitumor properties among hemocyanins.

    Moltedo, Bruno; Faunes, Fernando; Haussmann, Denise; De Ioannes, Pablo; De Ioannes, Alfredo E; Puente, Javier; Becker, María Inés

    2006-12-01

    We determined the antitumor properties of a newly available hemocyanin obtained from the Chilean gastropod Concholepas concholepas (Biosonda Corp., Santiago, Chile) in a syngeneic heterotopic mouse bladder carcinoma model. Since keyhole limpet hemocyanin (Pierce, Rockford, Illinois) is used increasingly in biomedicine as a carrier for vaccines and an immunotherapeutic agent for bladder transitional cell carcinoma, there is a growing interest in finding new substances that share its potent immunomodulatory properties. Considering that keyhole limpet hemocyanin and Concholepas concholepas hemocyanin differ significantly, it was not possible to predict a priori the antitumor properties of Concholepas concholepas hemocyanin. C3H/He mice were primed with Concholepas concholepas hemocyanin before subcutaneous implantation of mouse bladder tumor-2 cells. Treatment consisted of a subcutaneous dose of Concholepas concholepas hemocyanin (1 mg or 100 mug) at different intervals after implantation. Keyhole limpet hemocyanin and phosphate buffered saline served as positive and negative controls, respectively. In addition, experiments were designed to determine which elements of the immune response were involved in its adjuvant immunostimulatory effect. Mice treated with Concholepas concholepas hemocyanin showed a significant antitumor effect, as demonstrated by decreased tumor growth and incidence, prolonged survival and lack of toxic effects. These effects were similar to those achieved with keyhole limpet hemocyanin. We found that each hemocyanin increased natural killer cell activity but the effect of Concholepas concholepas hemocyanin was stronger. Analysis of serum from treated mice showed an increased interferon-gamma and low interleukin-4, which correlated with antibody isotypes, confirming that hemocyanins induce a T helper type 1 cytokine profile. To our knowledge our results are the first demonstration of the antitumor effect of a hemocyanin other than keyhole limpet

  15. Synergistic effect of fluorination on molecular energy level modulation in highly efficient photovoltaic polymers.

    Zhang, Maojie; Guo, Xia; Zhang, Shaoqing; Hou, Jianhui

    2014-02-01

    The synergistic effect of fluorination on molecular energy level modulation is realized by introducing fluorine atoms onto both the donor and the acceptor moieties in a D-A polymer, and as a result, the polymer solar cell device based on the trifluorinated polymer, PBT-3F, shows a high efficiency of 8.6%, under illumination of AM 1.5G, 100 mW cm(-) (2) . © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Coordinate and synergistic effects of extensive treadmill exercise and ovariectomy on articular cartilage degeneration

    Miyatake, Kazumasa; Muneta, Takeshi; Ojima, Miyoko; Yamada, Jun; Matsukura, Yu; Abula, Kahaer; Sekiya, Ichiro; Tsuji, Kunikazu

    2016-01-01

    Background Although osteoarthritis (OA) is a multifactorial disease, little has been reported regarding the cooperative interaction among these factors on cartilage metabolism. Here we examined the synergistic effect of ovariectomy (OVX) and excessive mechanical stress (forced running) on articular cartilage homeostasis in a mouse model resembling a human postmenopausal condition. Methods Mice were randomly divided into four groups, I: Sham, II: OVX, III: Sham and forced running (60?km in 6?w...

  17. Seasonal variation of Brazilian red propolis: Antibacterial activity, synergistic effect and phytochemical screening.

    Regueira, M S; Tintino, Saulo Relison; da Silva, Ana Raquel Pereira; Costa, Maria do Socorro; Boligon, Aline Augusti; Matias, Edinardo F F; de Queiroz Balbino, Valdir; Menezes, Irwin R A; Melo Coutinho, Henrique Douglas

    2017-09-01

    The aim of this study was to investigate the effect of the dry and rainy season on the antibacterial activity and chemical composition of the Brazilian red propolis. The samples were collected in rainy (RP-PER) and dry (RP-PED) seasons and analyzed by HPLC-DAD. The extracts were tested alone and in association with antibiotics against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. The HPLC analysis identified luteolin and quercetin as the main compounds. Seasonal variation was observed according to concentrations of the compounds. The MIC values against E. coli ranged from 128 μg/mL to 512 μg/mL (EC 06 and EC ATCC). The red propolis showed MIC values of 512 μg/mL against both strains of P. aeruginosa used in our study (PA03 and PA24) and against strains of Gram-positive bacteria S. aureus the MICs ranged from 64 μg/mL to ≥1024 μg/mL (SA10). A synergistic effect was observed when we combined the RP-PED with gentamicin against all the strains tested. When we combined the RP-PED with Imipenem, we only observed synergistic effect against P. aeruginosa. According to our synergistic activity results, the utilization of red propolis collected in the drier periods can be used as an adjuvant against multiresistant bacterial infections. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

    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.

  19. Synergistic effect of ultrasonic pre-treatment combined with UV irradiation for secondary effluent disinfection.

    Jin, Xin; Li, Zifu; Xie, Lanlan; Zhao, Yuan; Wang, Tingting

    2013-11-01

    The ultraviolet (UV) disinfection efficiency is often affected by suspended solids (SS). Given their high concentration or large particle size, SS can scatter UV light and provide shielding for bacteria. Thus, ultrasound is often employed as a pre-treatment process to improve UV disinfection. This work investigated the synergistic effect of ultrasound combined with UV for secondary effluent disinfection. Bench-scale experiments were conducted in using samples obtained from secondary sedimentation tanks. These tanks belonged to three wastewater treatment plants in Beijing that use different kinds of biological treatment methods. Several parameters may contribute to the changes in the efficiency of ultrasound and UV disinfection. Thus, the frequency and energy density of ultrasound, as well as the SS, were investigated. Results demonstrated that samples which have relatively higher SS concentrations or higher percentages of larger particles have less disinfection efficiency using UV disinfection alone. However, the presence of ultrasound could improve the disinfection efficiency because it has synergistic effect. Changes in the particle size distribution and SS concentration notably affected the efficiency of UV disinfection. The efficiency of Escherichia coli elimination can be decreased by 1.2 log units as the SS concentration increases from 16.9 mg/l to 25.4 mg/l at a UV energy density of 40 mJ/cm(2). UV disinfection alone reduced the E. coli population by 3.4 log units. However, the synergistic disinfection of ultrasound and UV could reach 5.4 log units during the reduction of E. coli at a 40 kHz frequency and an energy density of 2.64 kJ/l. The additional synergistic effect is 1.1 log units. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Improving aqueous solubility and antitumor effects by nanosized gambogic acid-mPEG2000 micelles

    Cai LL

    2013-12-01

    Full Text Available Lulu Cai,1,* Neng Qiu,2,* Mingli Xiang,3,* Rongsheng Tong,1 Junfeng Yan,1 Lin He,1 Jianyou Shi,1 Tao Chen,4 Jiaolin Wen,3 Wenwen Wang,3 Lijuan Chen31Department of Pharmacy, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, 2College of Materials and Chemistry and Chemical Engineering, Chengdu University of Technology, 3State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China; 4Faculty of Pharmacy, University of Montreal, Montreal, QC, Canada *These authors contributed equally to this paperAbstract: The clinical application of gambogic acid, a natural component with promising antitumor activity, is limited due to its extremely poor aqueous solubility, short half-life in blood, and severe systemic toxicity. To solve these problems, an amphiphilic polymer-drug conjugate was prepared by attachment of low molecular weight (ie, 2 kDa methoxy poly(ethylene glycol methyl ether (mPEG to gambogic acid (GA-mPEG2000 through an ester linkage and characterized by 1H nuclear magnetic resonance. The GA-mPEG2000 conjugates self-assembled to form nanosized micelles, with mean diameters of less than 50 nm, and a very narrow particle size distribution. The properties of the GA-mPEG2000 micelles, including morphology, stability, molecular modeling, and drug release profile, were evaluated. MTT (3-(4,5-dimethylthiazol-2-yl-2,5 diphenyl tetrazolium bromide tests demonstrated that the GA-mPEG2000 micelle formulation had obvious cytotoxicity to tumor cells and human umbilical vein endothelial cells. Further, GA-mPEG2000 micelles were effective in inhibiting tumor growth and prolonged survival in subcutaneous B16-F10 and C26 tumor models. Our findings suggest that GA-mPEG2000 micelles may have promising applications in tumor therapy.Keywords: gambogic acid, poly(ethylene glycol-drug conjugate, micelle, antitumor, toxicity

  1. Phosphorus doped and defects engineered graphene for improved electrochemical sensing: synergistic effect of dopants and defects

    Chu, Ke; Wang, Fan; Tian, Ye; Wei, Zhen

    2017-01-01

    Heteroatom-doped graphene materials emerged as promising metal-free catalysts have recently attracted a growing interest in electrochemical sensing applications. However, their catalytic activity and sensing performances still need to be further improved. Herein, we reported the development of unique phosphorus (P)-doped and plasma-etched graphene (denoted as PG-E) as an efficient metal-free electrocatalyst for dopamine (DA) sensing. It was demonstrated that introducing both P-dopants and plasma-engineered defects in graphene could synergistically improve the activity toward electrocatalytic oxidation of DA by increasing the accessible active sites and promoting the electron transport capability. The resulting PG-E modified electrode showed exceptional DA sensing performances with low detection limit, high selectivity and good stability. These results suggested that the synergistic effect of dopants and defects might be an important factor for developing the advanced graphene-based metal-free catalysts for electrochemical sensing.

  2. In vitro and in vivo antitumor effects of 50 to 100-KDa components from B16 melanoma culture supernatant.

    Qin, Ying-Song; Zhang, X U; Zhang, Xiang-Yu

    2015-07-01

    The development of immunological therapies for melanoma has been of considerable concern in recent years. Whole tumor cell lysates have been used to develop antitumor vaccines, but the effective components of the lysates have not been identified. In the present study, protein elements were purified from the B16 supernatant to analyze the in vitro chemotaxis towards mouse spleen lymphocytes using a Boyden chamber. Prior to establishing a B16 melanoma model, C57BL/6 mice were vaccinated with these proteins, and melanoma growth, tumor appearance time and behavioral changes were observed. Next, the cytotoxicity and subsets of the tumor infiltrating lymphocytes, and the histological characteristics of the melanoma were analyzed. The isolated purified fragments of B16 melanoma culture supernatant had strong antitumor effects. The possible antitumor mechanism was delineated, and was identified to possibly be through the activation of cluster of differentiation 8-positive T cells and the promotion of B16 cell differentiation. These methods will provide a novel insight into understanding antitumor immunological mechanisms and provide a potential avenue for immunotherapy.

  3. In vitro synergistic effects of fisetin and norfloxacin against aquatic isolates of Serratia marcescens.

    Dong, Jing; Ruan, Jing; Xu, Ning; Yang, Yibin; Ai, Xiaohui

    2016-01-01

    Serratia marcescens is a common pathogenic bacterium that can cause infections in both humans and animals. It can cause a range of diseases, from slight wound infections to life-threatening bacteraemia and pneumonia. The emergence of antimicrobial resistance has limited the treatment of the diseases caused by the bacterium to a great extent. Consequently, there is an urgent need to develop novel antimicrobial strategies against this pathogen. Synergistic strategy is a new approach to treat the infections caused by drug-resistant bacteria. In this paper, we isolated and identified the first multi-resistant pathogenic Serratia marcescens strain from diseased soft-shelled turtles (Pelodiscus sinensis) in China. We then performed a checkerboard assay; the results showed that out of 10 tested natural products fisetin had synergistic effects against S. marcescens when combined with norfloxacin. The time-kill curve assay further confirmed the results of the checkerboard assay. We found that this novel synergistic effect could significantly reduce the dosage of norfloxacin against S. marcescens. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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

    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

  5. Co-administration of morphine and gabapentin leads to dose dependent synergistic effects in a rat model of postoperative pain

    Papathanasiou, Theodoros; Juul, Rasmus Vestergaard; Heegaard, Anne-Marie

    2016-01-01

    dose combinations and investigate whether co-administration leads to synergistic effects in a preclinical model of postoperative pain. The pharmacodynamic effects of morphine (1, 3 and 7 mg/kg), gabapentin (10, 30 and 100 mg/kg) or their combination (9 combinations in total) were evaluated in the rat...... plantar incision model using an electronic von Frey device. The percentage of maximum possible effect (%MPE) and the area under the response curve (AUC) were used for evaluation of the antihyperalgesic effects of the drugs. Identification of synergistic interactions was based on Loewe additivity response...... surface analyses. The combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects in a preclinical model of postoperative pain. The synergistic interactions were found to be dose dependent and the increase in observed response compared to the theoretical additive response...

  6. Combined treatment of xenon and hypothermia in newborn rats--additive or synergistic effect?

    Hemmen Sabir

    Full Text Available Breathing the inert gas Xenon (Xe enhances hypothermic (HT neuroprotection after hypoxia-ischemia (HI in small and large newborn animal models. The underlying mechanism of the enhancement is not yet fully understood, but the combined effect of Xe and HT could either be synergistic (larger than the two effects added or simply additive. A previously published study, using unilateral carotid ligation followed by hypoxia in seven day old (P7 rats, showed that the combination of mild HT (35°C and low Xe concentration (20%, both not being neuroprotective alone, had a synergistic effect and was neuroprotective when both were started with a 4 h delay after a moderate HI insult. To examine whether another laboratory could confirm this finding, we repeated key aspects of the study.After the HI-insult 120 pups were exposed to different post-insult treatments: three temperatures (normothermia (NT NT37°C, HT35°C, HT32°C or Xe concentrations (0%, 20% or 50% starting either immediately or with a 4 h delay. To assess the synergistic potency of Xe-HT, a second set (n = 101 of P7 pups were exposed to either HT35°C+Xe0%, NT+Xe20% or a combination of HT35°C+Xe20% starting with a 4 h delay after the insult. Brain damage was analyzed using relative hemispheric (ligated side/unligated side brain tissue area loss after seven day survival.Immediate HT32°C (p = 0.042, but not HT35°C significantly reduced brain injury compared to NT37°C. As previously shown, adding immediate Xe50% to HT32°C increased protection. Neither 4 h-delayed Xe20%, nor Xe50% at 37°C significantly reduced brain injury (p>0.050. In addition, neither 4 h-delayed HT35°C alone, nor HT35°C+Xe20% reduced brain injury. We found no synergistic effect of the combined treatments in this experimental model.Combining two treatments that individually were ineffective (delayed HT35°C and delayed Xe20% did not exert neuroprotection when combined, and therefore did not show a synergistic

  7. Synergistic effects of rmhTRAIL and 17-AAG on the proliferation and apoptosis of multiple myeloma cells.

    Wang, Jing; Li, Yun; Sun, Wei; Liu, Jing; Chen, Wenming

    2018-03-22

    This study aimed to investigate synergistic effects of recombinant mutant human tumor necrosis factor-related apoptosis-inducing ligand (rmhTRAIL) and heat-shock protein 90 (HSP90) inhibitor (geldanamycin derivative 17 -allylamino- 17-demethoxy -geldanamycin, 17-AAG) on the proliferation and apoptosis of multiple myeloma (MM) cells. MTT assays evaluated inhibitory effects of rmhTRAIL and 17-AAG in different concentrations and treatment durations on the proliferation of RPMI8226 and U266 cells. The half maximal inhibitory concentration was calculated using OriginPro7.5. Synergistic effects of rmhTRAIL and 17-AAG on apoptosis of MM cells were detected using flow cytometry at 24 and 48 h post-treatment. To evaluate synergistic effects of rmhTRAIL and 17-AAG, the Q-value was calculated using King's formula. rmhTRAIL exhibited significant inhibitory effects on the proliferation of RPMI8226 cells in a dose- and time-dependent manner (>50%), whereas U266 cells were not sensitive to rmhTRAIL (80%). Significant synergistic effects of rmhTRAIL and 17-AAG on the proliferation of RPMI8226 cells were revealed (Q-value > 1.15), whereas synergistic effects were not evident on the proliferation of U266 cells (Q-value effects on apoptosis of RPMI8226 and U266 cells (Q-value > 1.15). The combined application of rmhTRAIL and 17-AAG revealed favorable synergistic effects in the treatment of MM.

  8. Antagonistic and synergistic effects of light irradiation on the effects of copper on Chlamydomonas reinhardtii

    Cheloni, Giulia; Cosio, Claudia; Slaveykova, Vera I., E-mail: vera.slaveykova@unige.ch

    2014-10-15

    Highlights: • Light intensity and spectral composition affect Cu uptake and effects to C. reinhardtii. • High light (HL) reduced Cu effect on growth inhibition, oxidative stress and damage. • HL in combination with Cu up-regulated genes involved in the antioxidant responses. • HL with increased UVB radiation exacerbated Cu uptake and Cu-induced toxic effects. - Abstract: The present study showed the important role of light intensity and spectral composition on Cu uptake and effects on green alga Chlamydomonas reinhardtii. High-intenisty light (HL) increased cellular Cu concentrations, but mitigated the Cu-induced decrease in chlorophyll fluorescence, oxidative stress and lipid peroxidation at high Cu concentrations, indicating that Cu and HL interact in an antagonistic manner. HL up-regulated the transcription of genes involved in the antioxidant response in C. reinhardtii and thus reduced the oxidative stress upon exposure to Cu and HL. Combined exposure to Cu and UVBR resulted in an increase of cellular Cu contents and caused severe oxidative damage to the cells. The observed effects were higher than the sum of the effects corresponding to exposure to UVBR or Cu alone suggesting a synergistic interaction.

  9. Effects of extraction methods on the yield, chemical structure and anti-tumor activity of polysaccharides from Cordyceps gunnii mycelia.

    Zhu, Zhen-Yuan; Dong, Fengying; Liu, Xiaocui; Lv, Qian; YingYang; Liu, Fei; Chen, Ling; Wang, Tiantian; Wang, Zheng; Zhang, Yongmin

    2016-04-20

    This study was to investigate the effects of different extraction methods on the yield, chemical structure and antitumor activity of polysaccharides from Cordyceps gunnii (C. gunnii) mycelia. Five extraction methods were used to extract crude polysaccharides (CPS), which include room-temperature water extraction (RWE), hot-water extraction (HWE), microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE) and cellulase-assisted extraction (CAE). Then Sephadex G-100 was used for purification of CPS. As a result, the antitumor activities of CPS and PPS on S180 cells were evaluated. Five CPS and purified polysaccharides (PPS) were obtained. The yield of CPS by microwave-assisted extraction (CPSMAE) was the highest and its anti-tumor activity was the best and its macromolecular polysaccharide (3000-1000kDa) ratio was the largest. The PPS had the same monosaccharide composition, but their obvious difference was in the antitumor activity and the physicochemical characteristics, such as intrinsic viscosity, specific rotation, scanning electron microscopy and circular dichroism spectra. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    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.

  11. The synergistic effect between vanillin and doxorubicin in ehrlich ascites carcinoma solid tumor and MCF-7 human breast cancer cell line.

    Elsherbiny, Nehal M; Younis, Nahla N; Shaheen, Mohamed A; Elseweidy, Mohamed M

    2016-09-01

    Despite the remarkable anti-tumor activity of doxorubicin (DOX), its clinical application is limited due to multiple organ toxicities. Products with less side effects are therefore highly requested. The current study investigated the anti-cancer activities of vanillin against breast cancer and possible synergistic potentiation of DOX chemotherapeutic effects by vanillin. Vanillin (100mg/kg), DOX (2mg/kg) and their combination were administered i.p. to solid Ehrlich tumor-bearing mice for 21days. MCF-7 human breast cancer cell line was treated with vanillin (1 and 2mM), DOX (100μM) or their combination. Protection against DOX-induced nephrotoxicity was studied in rats that received vanillin (100mg/kg, ip) for 10days with a single dose of DOX (15mg/kg) on day 6. Vanillin exerted anticancer effects comparable to DOX and synergesticlly potentiated DOX anticancer effects both in-vivo and in-vitro. The anticancer potency of vanillin in-vivo was mediated via apoptosis and antioxidant capacity. It also offered an in-vitro growth inhibitory effect and cytotoxicity mediated by apoptosis (increased caspase-9 and Bax:Bcl-2 ratio) along with anti-metasasis effect. Vanillin protected against DOX-induced nephrotoxicity in rats. In conclusion, vanillin can be a potential lead molecule for the development of non-toxic agents for the treatment of breast cancer either alone or combined with DOX. Copyright © 2016. Published by Elsevier GmbH.

  12. Synergistic Effect of Simvastatin Plus Radiation in Gastric Cancer and Colorectal Cancer: Implications of BIRC5 and Connective Tissue Growth Factor

    Lim, Taekyu [Division of Hematology-Oncology, Department of Internal Medicine, VHS Medical Center, Seoul (Korea, Republic of); Lee, Inkyoung [Biomedical Research Institute, Samsung Medical Center, Seoul (Korea, Republic of); Kim, Jungmin [Changduk Girls' High School, Seoul (Korea, Republic of); Kang, Won Ki, E-mail: wonki.kang@samsung.com [Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2015-10-01

    Purpose: We investigated the synergistic effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor plus radiation therapy, on the proliferation and survival of gastric cancer (GC) and colorectal cancer (CRC) cells. We also studied several genes involved in the simvastatin/radiation-induced effects. Methods and Materials: Gastric cancer (AGS, SNU601, MKN1, and MKN28) and CRC (CoLo320, SW48, HT29, and HCT8) cell lines were treated with 0.2 μM simvastatin alone, or in combination with 0 to 4 Gy of radiation, and subjected to clonogenic survival and proliferation assays in vitro. To assess the molecular mechanism of the combination treatment, we performed microarray analysis, immunoblot assays, small interfering RNA knockdown experiments, and plasmid rescue assays. The antitumoral effects of simvastatin and radiation were evaluated in vivo using xenograft models. Results: The combination therapy of simvastatin plus radiation inhibited basal clonogenic survival and proliferation of GC and CRC cells in vitro. Simvastatin suppressed the expression of BIRC5 and CTGF genes in these cancer cells. In vivo, the combined treatment with simvastatin and radiation significantly reduced the growth of xenograft tumors compared with treatment with radiation alone. Conclusion: We suggest that simvastatin has a synergistic effect with radiation on GC and CRC through the induction of apoptosis, which may be mediated by a simultaneous inhibition of BIRC5 and CTGF expression. A clinical trial of simvastatin in combination with radiation in patients with GC or CRC is warranted.

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

    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. Anti-tumor effects of brucine immuno-nanoparticles on hepatocellular carcinoma

    Qin JM

    2012-01-01

    Full Text Available Jian-Min Qin1, Pei-Hao Yin1, Qi Li1, Zhong-Qiu Sa1, Xia Sheng1, Lin Yang1, Tao Huang1, Min Zhang1, Ke-Pan Gao2, Qing-Hua Chen2, Jing-Wei Ma3, He-Bai Shen31Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, 2National Pharmaceutical Engineering Research Center; Shanghai Institute of Pharmaceutical Industry, 3Department of Physical Chemistry, Shanghai Normal University, Shanghai, People's Republic of ChinaBackground: Hepatocellular carcinoma is difficult to diagnose early, and most patients are already in the late stages of the disease when they are admitted to hospital. The total 5-year survival rate is less than 5%. Recent studies have showed that brucine has a good anti-tumor effect, but high toxicity, poor water solubility, short half-life, narrow therapeutic window, and a toxic dose that is close to the therapeutic dose, which all limit its clinical application. This study evaluated the effects of brucine immuno-nanoparticles (BIN on hepatocellular carcinoma.Materials and methods: Anionic polymerization, chemical modification technology, and phacoemulsification technology were used to prepare a carboxylated polyethylene glycol-polylactic acid copolymer carrier material. Chemical coupling technology was utilized to develop anti-human AFP McAb-polyethylene glycol-polylactic acid copolymer BIN. The size, shape, zeta potential, drug loading, encapsulation efficiency, and release of these immune-nanoparticles were studied in vitro. The targeting, and growth, invasion, and metastasis inhibitory effects of this treatment on liver cancer SMMC-7721 cells were tested.Results: BIN were of uniform size with an average particle size of 249 ± 77 nm and zeta potential of -18.7 ± 4.19 mV. The encapsulation efficiency was 76.0% ± 2.3% and the drug load was 5.6% ± 0.2%. Complete uptake and even distribution around the liver cancer cell membrane were observed.Conclusion: BIN had even size distribution, was

  15. Synergistic effect of cisplatin and synchrotron irradiation on F98 gliomas growing in nude mice

    Ricard, Clement; Fernandez, Manuel [Grenoble Institut des Neurosciences, Grenoble (France); Université Joseph Fourier, Grenoble (France); Requardt, Herwig [European Synchrotron Radiation Facility, Grenoble (France); Wion, Didier [Grenoble Institut des Neurosciences, Grenoble (France); Université Joseph Fourier, Grenoble (France); Vial, Jean-Claude [Université Joseph Fourier, Grenoble (France); Laboratoire Interdisciplinaire de Physique, St Martin d’Hères (France); Segebarth, Christoph; Sanden, Boudewijn van der, E-mail: boudewijn.vandersanden@ujf-grenoble.fr [Grenoble Institut des Neurosciences, Grenoble (France); Université Joseph Fourier, Grenoble (France)

    2013-09-01

    Synchrotron photoactivation therapy of cisplatin relies on a synergistic effect of synchrotron X-rays and platinum and leads to tumor-cell-killing effects and reduction of the tumor blood perfusion. Among brain tumors, glioblastoma multiforme appears as one of the most aggressive forms of cancer with poor prognosis and no curative treatment available. Recently, a new kind of radio-chemotherapy has been developed using synchrotron irradiation for the photoactivation of molecules with high-Z elements such as cisplatin (PAT-Plat). This protocol showed a cure of 33% of rats bearing the F98 glioma but the efficiency of the treatment was only measured in terms of overall survival. Here, characterization of the effects of the PAT-Plat on tumor volume and tumor blood perfusion are proposed. Changes in these parameters may predict the overall survival. Firstly, changes in tumor growth of the F98 glioma implanted in the hindlimb of nude mice after the PAT-Plat treatment and its different modalities have been characterized. Secondly, the effects of the treatment on tumor blood perfusion have been observed by intravital two-photon microscopy. Cisplatin alone had no detectable effect on the tumor volume. A reduction of tumor growth was measured after a 15 Gy synchrotron irradiation, but the whole therapy (15 Gy irradiation + cisplatin) showed the largest decrease in tumor growth, indicating a synergistic effect of both synchrotron irradiation and cisplatin treatment. A high number of unperfused vessels (52%) were observed in the peritumoral area in comparison with untreated controls. In the PAT-Plat protocol the transient tumor growth reduction may be due to synergistic interactions of tumor-cell-killing effects and reduction of the tumor blood perfusion.

  16. Anti-tumor and Chemoprotective Effect of Bauhinia tomentosa by Regulating Growth Factors and Inflammatory Mediators.

    Kannan, Narayanan; Sakthivel, Kunnathur Murugesan; Guruvayoorappan, Chandrasekaran

    2015-01-01

    Cancer is a leading cause of death worldwide. Due to the toxic side effects of the commonly used chemotherapeutic drug cyclophosphamide (CTX), the use of herbal medicines with fewer side effects but having potential use as inducing anti-cancer outcomes in situ has become increasingly popular. The present study sought to investigate the effects of a methanolic extract of Bauhinia tomentosa against Dalton's ascites lymphoma (DAL) induced ascites as well as solid tumors in BALB/c mice. Specifically, B. tomentosa extract was administered intraperitonealy (IP) at 10 mg/kg. BW body weight starting just after tumor cell implantation and thereafter for 10 consecutive days. In the ascites tumor model hosts, administration of extract resulted in a 52% increase in the life span. In solid tumor models, co-administration of extract and CTX significantly reduced tumor volume (relative to in untreated hosts) by 73% compared to just by 52% when the extract alone was provided. Co-administration of the extract also mitigated CTX-induced toxicity, including decreases in WBC count, and in bone marrow cellularity and α-esterase activity. Extract treatment also attenuated any increases in serum levels of TNFα, iNOS, IL-1β, IL-6, GM-CSF, and VEGF seen in tumor-bearing hosts. This study confirmed that, the potent antitumor activity of B.tomentosa extract may be associated with immune modulatory effects by regulating anti-oxidants and cytokine levels.

  17. Hypoxia-targeted suicidal gene therapy system enhances antitumor effects of radiotherapy

    Liu Junye; Guo Yao; Guo Guozhen

    2006-01-01

    Objective: To explore the effects of hypoxia-targeted suicidal gene therapy system combined with radiotherapy on pancreatic cancer. Methods: The recombinant adenovirus Ad-5HRE/hCMVmp-BCD was constructed by DNA recombinant technique. Western blot was used to detect hypoxia-induced expression of bacterial cytosine deaminase (BCD). Cell growth inhibition assay was used to determine the sensitivity of human pancreatic cancer cells MIA-PACA2 to 5-fluorocytosine (5-FC). Tumor xenograft growth delay assays was used to evaluate the effects of Ad-5HRE/hCMVmp-BCD/5-FC combined with radiotherapy on pancreatic cancer. Results: Western blot analysis demonstrated that hypoxia-induced BCD protein expression was achieved in MIA-PACA2 cells infected with Ad-5HRE/hCMVmp-BCD. With hypoxia treatment, the sensitivity of MIA-PACA2 cells infected with Ad-5HRE/hCMVmp-BCD to 5-FC significantly increased. Administration of either Ad-5HRE/hCMVmp-BCD/5-FC or radiotherapy could inhibit the growth of MIA-PACA2 xenografts in nude mice. Moreover, combination of Ad-5HRE/hCMVmp-BCD/5-FC could significantly enhance suppressing effects of radiotherapy on MIA-PACA2 xenografts. Conclusion: Hypoxia-targeted suicidal gene therapy system Ad-5HRE/hCMVmp-BCD/5-FC could enhance antitumor effects of radiotherapy on pancreatic cancer and can be used as a powerful adjunct to conventional radiotherapy. (authors)

  18. Anti-tumor Effects of Plasma Activated Media and Correlation with Hydrogen Peroxide Concentration

    Laroussi, Mounir; Mohades, Soheila; Barekzi, Nazir; Maruthamuthu, Venkat; Razavi, Hamid

    2016-09-01

    Plasma activated media (PAM) can induce death in cancer cells. In our research, PAM is produced by exposing liquid culture medium to a helium plasma pencil. Reactive oxygen and nitrogen species in the aqueous state are known factors in anti-tumor effects of PAM. The duration of plasma exposure determines the concentrations of reactive species produced in PAM. Stability of the plasma generated reactive species and their lifetime depend on parameters such as the chemical composition of the medium. Here, a complete cell culture medium was employed to make PAM. Later, PAM was used to treat SCaBER cancer cells either as an immediate PAM (right after exposure) or as an aged-PAM (after storage). SCaBER (ATCC®HTB-3™) is an epithelial cell line from a human bladder with the squamous carcinoma disease. A normal epithelial cell line from a kidney tissue of a dog - MDCK (ATCC®CCL-34™) - was used to analyze the selective effect of PAM. Correspondingly, we measured the concentration of hydrogen peroxide- as a stable species with biological impact on cell viability- in both immediate PAM and aged-PAM. In addition, we report on the effect of serum supplemented in PAM on the H2O2 concentration measured by Amplex red assay kit. Finally, we evaluate the effects of PAM on growth and morphological changes in MDCK cells using fluorescence microscopy.

  19. Antitumor effects of celecoxib in COX-2 expressing and non-expressing canine melanoma cell lines.

    Seo, Kyoung-Won; Coh, Ye-Rin; Rebhun, Robert B; Ahn, Jin-Ok; Han, Sei-Myung; Lee, Hee-Woo; Youn, Hwa-Young

    2014-06-01

    Cyclooxygenase-2 (COX-2) is a potential target for chemoprevention and cancer therapy. Celecoxib, a selective COX-2 inhibitor, inhibits cell growth of various types of human cancer including malignant melanoma. In dogs, oral malignant melanoma represents the most common oral tumor and is often a fatal disease. Therefore, there is a desperate need to develop additional therapeutic strategies. The purpose of this study was to investigate the anticancer effects of celecoxib on canine malignant melanoma cell lines that express varying levels of COX-2. Celecoxib induced a significant anti-proliferative effect in both LMeC and CMeC-1 cells. In the CMeC cells, treatment of 50 μM celecoxib caused an increase in cells in the G0/G1 and a decreased proportion of cells in G-2 phase. In the LMeC cells, 50 μM of celecoxib led to an increase in the percentage of cells in the sub-G1 phase and a significant activation of caspase-3 when compared to CMeC-1 cells. In conclusion, these results demonstrate that celecoxib exhibits antitumor effects on canine melanoma LMeC and CMeC-1 cells by induction of G1-S cell cycle arrest and apoptosis. Our data suggest that celecoxib might be effective as a chemotherapeutic agent against canine malignant melanoma. Copyright © 2014. Published by Elsevier Ltd.

  20. Evaluation of antitumor effects of folate-conjugated methyl-β-cyclodextrin in melanoma.

    Motoyama, Keiichi; Onodera, Risako; Tanaka, Nao; Kameyama, Kazuhisa; Higashi, Taishi; Kariya, Ryusho; Okada, Seiji; Arima, Hidetoshi

    2015-01-01

    Melanoma is a life-threatening disorder and its incidence is increasing gradually. Despite the numerous treatment approaches, conventional systemic chemotherapy has not reduced the mortality rate among melanoma patients, probably due to the induction of toxicity to normal tissues. Recently, we have developed folate-conjugated methyl-β-cyclodextrin (FA-M-β-CyD) and clarified its potential as a new antitumor agent involved in autophagic cell death. However, it remains uncertain whether FA-M-β-CyD exerts anticancer effects against melanomas. Therefore, in this study, we investigated the effects of FA-M-β-CyD on the folate receptor-α (FR-α)-expressing melanoma cell-selective cytotoxic effect. FA-M-β-CyD showed cytotoxic effects in Ihara cells, a human melanoma cell line expressing FR-α. In sharp contrast to methyl-β-cyclodextrin, FA-M-β-CyD entered Ihara cells [FR-α(+)] through FR-α-mediated endocytosis. Additionally, FA-M-β-CyD elicited the formation of autophagosomes in Ihara cells. Notably, FA-M-β-CyD suppressed melanoma growth in BALB/c nude recombinase-activating gene-2 (Rag-2)/Janus kinase 3 (Jak3) double deficient mice bearing Ihara cells. Therefore, these results suggest that FA-M-β-CyD could be utilized as a potent anticancer agent for melanoma chemotherapy by regulating autophagy.

  1. Synergistic effects of fire and elephants on arboreal animals in an African savanna.

    Pringle, Robert M; Kimuyu, Duncan M; Sensenig, Ryan L; Palmer, Todd M; Riginos, Corinna; Veblen, Kari E; Young, Truman P

    2015-11-01

    Disturbance is a crucial determinant of animal abundance, distribution and community structure in many ecosystems, but the ways in which multiple disturbance types interact remain poorly understood. The effects of multiple-disturbance interactions can be additive, subadditive or super-additive (synergistic). Synergistic effects in particular can accelerate ecological change; thus, characterizing such synergies, the conditions under which they arise, and how long they persist has been identified as a major goal of ecology. We factorially manipulated two principal sources of disturbance in African savannas, fire and elephants, and measured their independent and interactive effects on the numerically dominant vertebrate (the arboreal gekkonid lizard Lygodactylus keniensis) and invertebrate (a guild of symbiotic Acacia ants) animal species in a semi-arid Kenyan savanna. Elephant exclusion alone (minus fire) had negligible effects on gecko density. Fire alone (minus elephants) had negligible effects on gecko density after 4 months, but increased gecko density twofold after 16 months, likely because the decay of fire-damaged woody biomass created refuges and nest sites for geckos. In the presence of elephants, fire increased gecko density nearly threefold within 4 months of the experimental burn; this occurred because fire increased the incidence of elephant damage to trees, which in turn improved microhabitat quality for geckos. However, this synergistic positive effect of fire and elephants attenuated over the ensuing year, such that only the main effect of fire was evident after 16 months. Fire also altered the structure of symbiotic plant-ant assemblages occupying the dominant tree species (Acacia drepanolobium); this influenced gecko habitat selection but did not explain the synergistic effect of fire and elephants. However, fire-driven shifts in plant-ant occupancy may have indirectly mediated this effect by increasing trees' susceptibility to elephant damage. Our

  2. Antitumor effect of degalactosylated gc-globulin on orthotopic grafted lung cancer in mice.

    Hirota, Keiji; Nakagawa, Yoshinori; Takeuchi, Ryota; Uto, Yoshihiro; Hori, Hitoshi; Onizuka, Shinya; Terada, Hiroshi

    2013-07-01

    Group-specific component (Gc)-globulin-derived macrophage-activating factor (GcMAF) generated by a cascade of catalytic reactions with deglycosidase enzymes exerts antitumor activity. We hypothesized that degalactosyl Gc-globulin (DG3), a precursor of GcMAF, also plays a role in recovery from cancer as well as GcMAF due to progression of deglycosylation by generally resident sialidases and mannosidases. We prepared the subtypes of DG3, such as 1f1f and 1s1s and its 22 homodimers, by using vitamin D3-binding Sepharose CL-6B and examined their antitumor activity in mice bearing Lewis lung carcinoma cells, by counting the number of nodules formed in their lungs. Antitumor activity of DG3 was observed regardless of its subtype, being equivalent to that of GcMAF. The injection route of DG3 affected its antitumor activity, with subcutaneous and intramuscular administration being more favorable than the intraperitoneal or intravenous route. In order to obtain significant antitumor activity, more than 160 ng/kg of DG3 were required. DG3 proved to be promising as an antitumor agent, similarly to GcMAF.

  3. Beneficial synergistic effects of microdose lithium with pyrroloquinoline quinone in an Alzheimer's disease mouse model.

    Zhao, Lei; Gong, Neng; Liu, Meng; Pan, Xiaoli; Sang, Shaoming; Sun, Xiaojing; Yu, Zhe; Fang, Qi; Zhao, Na; Fei, Guoqiang; Jin, Lirong; Zhong, Chunjiu; Xu, Tianle

    2014-12-01

    Alzheimer's disease (AD) is a complicated, neurodegenerative disorder involving multifactorial pathogeneses and still lacks effective clinical treatment. Recent studies show that lithium exerts disease-modifying effects against AD. However, the intolerant side effects at conventional effective dosage limit the clinical use of lithium in treating AD. To explore a novel AD treatment strategy with microdose lithium, we designed and synthesized a new chemical, tri-lithium pyrroloquinoline quinone (Li3PQQ), to study the synergistic effects of low-dose lithium and pyrroloquinoline quinone, a native compound with powerful antioxidation and mitochondrial amelioration. The results showed that Li3PQQ at a relative low dose (6 and 12 mg/kg) exhibited more powerful effects in restoring the impairment of learning and memory, facilitating hippocampal long-term potentiation, and reducing cerebral amyloid deposition and phosphorylated tau level in APP/PS1 transgenic mice than that of lithium chloride at both low and high dose (5 and 100 mg/kg). We further found that Li3PQQ inhibited the activity of glycogen synthase kinase-3 and increased the activity of β-amyloid-binding alcohol dehydrogenase, which might underlie the beneficial effects of Li3PQQ on APP/PS1 transgenic mice. Our study demonstrated the efficacy of a novel AD therapeutic strategy targeting at multiple disease-causing mechanisms through the synergistic effects of microdose lithium and pyrroloquinoline quinone. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Combined effects of irritants and allergens. Synergistic effects of nickel and sodium lauryl sulfate in nickel- sensitized individuals

    Agner, Tove; Johansen, Jeanne Duus; Overgaard, Lene

    2002-01-01

    (nickel chloride) and sodium lauryl sulfate (SLS) alone and in combination. Evaluation of skin reactions was performed by colorimetry, measurement of transepidermal water loss and clinical evaluation, and the data were analyzed by logistic dose-response models. A synergistic effect was found of combined...

  5. Some regularities of manifestation of synergistic effects of microplasticity under electrolytic iron hydpidation

    Skryabina, N.E.; Spivak, L.V.; Volyntsev, A.B.

    1984-01-01

    Effect of the crystalline lattice type, material chemical composition, kinds of strain and regimes of cathode polarization on the fact of appearance and magnitude of the microplastic aftereffect deformation (MAD) has been studied. Investigation of some factors determining the MAD strengthening during the electrolytic metal hydridation allows one to define the following necessary conditions for manifestation of those synergistic effects: a sufficiently high hydrogen permeability; an existence of strains gradient and hydrogen concentration across sample cross section, an existence of some specific structural state

  6. Synergistic immunosuppressive effects of the mTOR inhibitor sirolimus and the phytochemical curcumin.

    Deters, M; Hütten, H; Kaever, V

    2013-01-15

    The immunosuppressant sirolimus and curcumin, the main principle of the turmeric spice, have shown antiproliferative effects on many human and not-human cell lines. Whereas the antiproliferative effect of sirolimus is mainly mediated by inhibition of mTOR, curcumin is described to affect many molecular targets which makes it unpredictable to appraise if the effects of these both substances on cell proliferation and especially on immunosuppression are additive or synergistic. To answer this question we investigated the interaction of both these substances on OKT3-induced human peripheral blood mononuclear cell (PBMC) proliferation. OKT3-induced human PBMC proliferation was determined by measuring (3)H-thymidine incorporation. Influence of curcumin on interleukin-2 (IL-2) release and IκB-phosphorylation in PBMC was determined by ELISA and western blot, respectively. Curcumin-induced apoptosis and necrosis was analyzed by FACS analysis. Whereas curcumin completely inhibited OKT3-induced PBMC proliferation in a dose-dependent manner with an IC(50) of 2.8 μM, sirolimus could reduce PBMC proliferation dose-dependently only to a minimum of 28% at a concentration of 5 ng/ml (IC(50) 1.1 ng/ml). When curcumin was combined at concentrations of 1.25-2.5 μM with sirolimus at concentrations from 0.63 to 1.25 ng/ml the effects were synergistic. Combination of curcumin (1.25-2.5 μM) with sirolimus (5 ng/ml) showed additive effects. The effects after combination of curcumin at 5 μM with each sirolimus concentration and sirolimus at 10 ng/ml with each curcumin concentration were presumably antagonistic. We conclude that the immunosuppressive effects of curcumin and sirolimus in low concentrations are synergistic in OKT3-activated PBMC. Whether curcumin and sirolimus have also synergistic antiproliferative effects in tumor cells has to be shown in further experiments including animal models. Copyright © 2012 Elsevier GmbH. All rights reserved.

  7. Some regularities of manifestation of synergistic effects of microplasticity under electrolytic iron hydridation

    Skryabina, N.E.; Spivak, L.V.; Volyntsev, A.B.

    Effect of the crystalline lattice type, material chemical composition, kinds of strain and regimes of cathode polarization on the fact of appearance and magnitude of the microplastic aftereffect deformation (MAD) has been studied. Investigation of some factors determining the MAD strengthening during the electrolytic metal hydridation allows one to define the following necessary conditions for manifestation of those synergistic effects: a sufficiently high hydrogen permeability; an existence of strains gradient and hydrogen concentration across sample cross section, an existence of some specific structural state.

  8. Evaluation of a novel photosensitizing drug having antitumor effect for advanced prostate cancer

    Saito, Sachiko; Inai, Mizuho; Honda, Norihiro; Hazama, Hisanao; Kaneda, Yasufumi; Awazu, Kunio

    2017-07-01

    Prostate cancer is the second most frequently diagnosed cancer among men worldwide and a novel treatment for the disease is required. Replication-deficient virus particles, hemagglutinating virus of Japan envelope (HVJ-E), has cytotoxicity to cancer cells. To enhance the therapeutic effect of HVJ-E by photodynamic therapy (PDT) as a trigger of HVJ-E's anti-tumor effect, talaporfin sodium (Laserphyrin) used for PDT was encapsulated into HVJ-E to produce a novel photosensitizing drug, named Laserphyrin ®-HVJ-E, and its therapeutic effect for prostate cancer cells (PC-3) was evaluated. As the results, direct cytotoxicities of HVJ-E and Laserphyrin ®-HVJ-E for PC-3 after an administration time of 48 h were almost the same. Cell survival rates of PC-3, which were irradiated 2 h after administration of Laserphyrin ®-HVJ-E, were about 7.8%. Although further study is needed to find an optimal PDT condition, these results suggest that Laserphyrin ®-HVJ-E is useful for treatment of prostate cancer due to the combination of cytotoxicities of HVJ-E and PDT.

  9. Tramadol and propentofylline coadministration exerted synergistic effects on rat spinal nerve ligation-induced neuropathic pain.

    Zhang, Jin; Wu, Dan; Xie, Cheng; Wang, Huan; Wang, Wei; Zhang, Hui; Liu, Rui; Xu, Li-Xian; Mei, Xiao-Peng

    2013-01-01

    Neuropathic pain is an intractable clinical problem. Drug treatments such as tramadol have been reported to effectively decrease neuropathic pain by inhibiting the activity of nociceptive neurons. It has also been reported that modulating glial activation could also prevent or reverse neuropathic pain via the administration of a glial modulator or inhibitor, such as propentofylline. Thus far, there has been no clinical strategy incorporating both neuronal and glial participation for treating neuropathic pain. Therefore, the present research study was designed to assess whether coadministration of tramadol and propentofylline, as neuronal and glial activation inhibitors, respectively, would exert a synergistic effect on the reduction of rat spinal nerve ligation (SNL)-induced neuropathic pain. Rats underwent SNL surgery to induce neuropathic pain. Pain behavioral tests were conducted to ascertain the effect of drugs on SNL-induced mechanical allodynia with von-Frey hairs. Proinflammatory factor interleukin-1β (IL-1β) expression was also detected by Real-time RT-PCR. Intrathecal tramadol and propentofylline administered alone relieved SNL-induced mechanical allodynia in a dose-dependent manner. Tramadol and propentofylline coadministration exerted a more potent effect in a synergistic and dose dependent manner than the intrathecal administration of either drug alone. Real-time RT-PCR demonstrated IL-1β up-expression in the ipsilateral spinal dorsal horn after the lesion, which was significantly decreased by tramadol and propentofylline coadministration. Inhibiting proinflammatory factor IL-1β contributed to the synergistic effects of tramadol and propentofylline coadministration on rat peripheral nerve injury-induced neuropathic pain. Thus, our study provided a rationale for utilizing a novel strategy for treating neuropathic pain by blocking the proinflammatory factor related pathways in the central nervous system.

  10. Isolated and synergistic effects of PM10 and average temperature on cardiovascular and respiratory mortality.

    Pinheiro, Samya de Lara Lins de Araujo; Saldiva, Paulo Hilário Nascimento; Schwartz, Joel; Zanobetti, Antonella

    2014-12-01

    OBJECTIVE To analyze the effect of air pollution and temperature on mortality due to cardiovascular and respiratory diseases. METHODS We evaluated the isolated and synergistic effects of temperature and particulate matter with aerodynamic diameter mortality of individuals > 40 years old due to cardiovascular disease and that of individuals > 60 years old due to respiratory diseases in Sao Paulo, SP, Southeastern Brazil, between 1998 and 2008. Three methodologies were used to evaluate the isolated association: time-series analysis using Poisson regression model, bidirectional case-crossover analysis matched by period, and case-crossover analysis matched by the confounding factor, i.e., average temperature or pollutant concentration. The graphical representation of the response surface, generated by the interaction term between these factors added to the Poisson regression model, was interpreted to evaluate the synergistic effect of the risk factors. RESULTS No differences were observed between the results of the case-crossover and time-series analyses. The percentage change in the relative risk of cardiovascular and respiratory mortality was 0.85% (0.45;1.25) and 1.60% (0.74;2.46), respectively, due to an increase of 10 μg/m3 in the PM10 concentration. The pattern of correlation of the temperature with cardiovascular mortality was U-shaped and that with respiratory mortality was J-shaped, indicating an increased relative risk at high temperatures. The values for the interaction term indicated a higher relative risk for cardiovascular and respiratory mortalities at low temperatures and high temperatures, respectively, when the pollution levels reached approximately 60 μg/m3. CONCLUSIONS The positive association standardized in the Poisson regression model for pollutant concentration is not confounded by temperature, and the effect of temperature is not confounded by the pollutant levels in the time-series analysis. The simultaneous exposure to different levels of

  11. Isolated and synergistic effects of PM10 and average temperature on cardiovascular and respiratory mortality

    Samya de Lara Lins de Araujo Pinheiro

    2014-12-01

    Full Text Available OBJECTIVE To analyze the effect of air pollution and temperature on mortality due to cardiovascular and respiratory diseases. METHODS We evaluated the isolated and synergistic effects of temperature and particulate matter with aerodynamic diameter 40 years old due to cardiovascular disease and that of individuals > 60 years old due to respiratory diseases in Sao Paulo, SP, Southeastern Brazil, between 1998 and 2008. Three methodologies were used to evaluate the isolated association: time-series analysis using Poisson regression model, bidirectional case-crossover analysis matched by period, and case-crossover analysis matched by the confounding factor, i.e., average temperature or pollutant concentration. The graphical representation of the response surface, generated by the interaction term between these factors added to the Poisson regression model, was interpreted to evaluate the synergistic effect of the risk factors. RESULTS No differences were observed between the results of the case-crossover and time-series analyses. The percentage change in the relative risk of cardiovascular and respiratory mortality was 0.85% (0.45;1.25 and 1.60% (0.74;2.46, respectively, due to an increase of 10 μg/m3 in the PM10 concentration. The pattern of correlation of the temperature with cardiovascular mortality was U-shaped and that with respiratory mortality was J-shaped, indicating an increased relative risk at high temperatures. The values for the interaction term indicated a higher relative risk for cardiovascular and respiratory mortalities at low temperatures and high temperatures, respectively, when the pollution levels reached approximately 60 μg/m3. CONCLUSIONS The positive association standardized in the Poisson regression model for pollutant concentration is not confounded by temperature, and the effect of temperature is not confounded by the pollutant levels in the time-series analysis. The simultaneous exposure to different levels of

  12. Synergistic Effects of SAM and Selenium Compounds on Proliferation, Migration and Adhesion of HeLa Cells.

    Sun, Licui; Zhang, Jianxin; Yang, Qiu; Si, Yang; Liu, Yiqun; Wang, Qin; Han, Feng; Huang, Zhenwu

    2017-08-01

    To determine the antitumor activities and molecular mechanism of selenium compounds in HeLa cells. Western blotting was used to detect ERK and AKT activation in HeLa cells induced by selenium compounds selenomethionine (SeMet), methylselenocysteine (MeSeCys) and methylseleninic acids (MeSeA). Using MTT, wound-healing and Matrigel adhesion assays, the antitumor effects of SAM and selenium compounds were evaluated in HeLa cells. MeSeA inhibited ERK and AKT signaling pathways and suppressed the proliferation (peffects compared to the other treatments. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  13. Synergistic inhibitory effect of hyperbaric oxygen combined with sorafenib on hepatoma cells.

    Hai-Shan Peng

    Full Text Available OBJECTIVES: Hypoxia is a common phenomenon in solid tumors, associated with chemotherapy and radiotherapy resistance, recurrence and metastasis. Hyperbaric oxygen (HBO therapy can increase tissue oxygen pressure and content to prevent the resistance, recurrence and metastasis of cancer. Presently, Sorafenib is a first-line drug, targeted for hepatocellular carcinoma (HCC but effective in only a small portion of patients and can induce hypoxia. The purpose of this study is to investigate the effect of HBO in combination with sorafenib on hepatoma cells. METHODS: Hepatoma cell lines (BEL-7402 and SK-Hep1 were treated with HBO at 2 atmosphere absolute pressure for 80 min per day or combined with sorafenib or cisplatin. At different time points, cells were tested for cell growth, colony formation, apoptosis, cell cycle and migration. Finally, miRNA from the hepatoma cells was detected by microRNA array and validated by qRT-PCR. RESULTS: Although HBO, sorafenib or cisplatin alone could inhibit growth of hepatoma cells, HBO combined with sorafenib or cisplatin resulted in much greater synergistic growth inhibition (cell proliferation and colony formation in hepatoma cells. Similarly, the synergistic effect of HBO and sorafenib on induction of apoptosis was also observed in hepatoma cells. HBO induced G1 arrest in SK-Hep1 not in BEL-7402 cells, but enhanced cell cycle arrest induced by sorafenib in BEL-7402 treated cells. However, HBO had no obvious effect on the migration of hepatoma cells, and microRNA array analysis showed that hepatoma cells with HBO treatment had significantly different microRNA expression profiles from those with blank control. CONCLUSIONS: We show for the first time that HBO combined with sorafenib results in synergistic growth inhibition and apoptosis in hepatoma cells, suggesting a potential application of HBO combined with sorafenib in HCC patients. Additionally, we also show that HBO significantly altered microRNA expression

  14. Synergistic Effects of Sulfated Polysaccharides from Mexican Seaweeds against Measles Virus

    Karla Morán-Santibañez

    2016-01-01

    Full Text Available Sulfated polysaccharides (SPs extracted from five seaweed samples collected or cultivated in Mexico (Macrocystis pyrifera, Eisenia arborea, Pelvetia compressa, Ulva intestinalis, and Solieria filiformis were tested in this study in order to evaluate their effect on measles virus in vitro. All polysaccharides showed antiviral activity (as measured by the reduction of syncytia formation and low cytotoxicity (MTT assay at inhibitory concentrations. SPs from Eisenia arborea and Solieria filiformis showed the highest antiviral activities (confirmed by qPCR and were selected to determine their combined effect. Their synergistic effect was observed at low concentrations (0.0274 μg/mL and 0.011 μg/mL of E. arborea and S. filiformis SPs, resp., which exhibited by far a higher inhibitory effect (96% syncytia reduction in comparison to the individual SP effects (50% inhibition with 0.275 μg/mL and 0.985 μg/mL of E. arborea and S. filiformis, resp.. Time of addition experiments and viral penetration assays suggest that best activities of these SPs occur at different stages of infection. The synergistic effect would allow reducing the treatment dose and toxicity and minimizing or delaying the induction of antiviral resistance; sulfated polysaccharides of the tested seaweed species thus appear as promising candidates for the development of natural antiviral agents.

  15. An evaluation of anti-tumor effect and toxicity of PEGylated ursolic acid liposomes

    Wang, Qianqian; Zhao, Tingting; Liu, Yanping; Xing, Shanshan; Li, Lei; Gao, Dawei, E-mail: dwgao@ysu.edu.cn [Yanshan University, Applying Chemistry Key Lab of Hebei Province, Department of Bioengineer (China)

    2016-02-15

    Therapy of solid tumors mediated by nano-drug delivery has attracted considerable interest. In our previous study, ursolic acid (UA) was successfully encapsulated into PEGylated liposomes. The study aimed to evaluate the tumor inhibition effect and cytotoxicity of the PEGylated UA liposomes by U14 cervical carcinoma-bearing mice. The liposomes were spherical particles with mean particle diameters of 127.2 nm. The tumor inhibition rate of PEGylated UA liposomes was 53.60 % on U14 cervical carcinoma-bearing mice, which was greater than those of the UA solution (18.25 %) and traditional UA liposome groups (40.75 %). The tumor cells apoptosis rate of PEGylated UA liposomes was 25.81 %, which was significantly higher than that of the traditional UA liposomes (13.37 %). Moreover, the kidney and liver did not emerge the pathological changes in UA therapeutic mice by histopathological analysis, while there were significant differences on tumor tissues among three UA formulation groups. The PEGylated UA liposomes exhibited higher anti-tumor activity and lower cytotoxicity, and the main reason was that the coating PEG layer improved UA liposome properties, such as enhancing the stability of liposomes, promoting the effect of slow release, and prolonging the time of blood circulation. This may shed light on the development of PEGylated nano-vehicles.

  16. Synergistic Enhancement of Cancer Therapy Using a Combination of Ceramide and Docetaxel

    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.

  17. Synergistic Effect of Co-utilization of Coal and Biomass Char: An Overview

    Paiman, M. E. S.; Hamzah, N. S.; Idris, S. S.; Rahman, N. A.; Ismail, K.

    2018-05-01

    Global concerns on impact of greenhouse gases emission, mostly released from coal-fired power plant, and the depletion of fossil fuel particularly coal, has led the production of electricity from alternatives resources such as co-utilization technologies. Previous studies proved that the co-utilization of coal and biomass/biomass chars has significantly reduced the emission of greenhouse gases either during the pyrolysis, combustion or gasification process in laboratories, pilots as well as in the industrial scales. Interestingly, most of the studies reported the presence of synergistic effect during the co-utilization processes particularly between coal and biomass char while some are not. Biomass chars were found to have porous and highly disorder carbon structure and belong to the class of most reactive carbon material, resulting to be more reactive than those hard coal and lignite. Up to date, microwave assisted pyrolysis is one of the best and latest techniques employed to produce better quality of biomass chars and it is also reduce the processing cost. Lot of works has been done regarding on the existence of synergistic effects during its co-utilization. However, the knowledge is limited to thermal and product characteristics so far. Even so, the specific reasons behind its existence are yet to understand well. Therefore, in this paper, the emphasis will be given on the synergistic effects on emission characteristics of co-utilization of coal and biomass chars so that it can be apply in energy-based industries to help in reduction of the greenhouse gases emission.

  18. Coordinate and synergistic effects of extensive treadmill exercise and ovariectomy on articular cartilage degeneration.

    Miyatake, Kazumasa; Muneta, Takeshi; Ojima, Miyoko; Yamada, Jun; Matsukura, Yu; Abula, Kahaer; Sekiya, Ichiro; Tsuji, Kunikazu

    2016-05-31

    Although osteoarthritis (OA) is a multifactorial disease, little has been reported regarding the cooperative interaction among these factors on cartilage metabolism. Here we examined the synergistic effect of ovariectomy (OVX) and excessive mechanical stress (forced running) on articular cartilage homeostasis in a mouse model resembling a human postmenopausal condition. Mice were randomly divided into four groups, I: Sham, II: OVX, III: Sham and forced running (60 km in 6 weeks), and IV: OVX and forced running. Histological and immunohistochemical analyses were performed to evaluate the degeneration of articular cartilage and synovitis in the knee joint. Morphological changes of subchondral bone were analyzed by micro-CT. Micro-CT analyses showed significant loss of metaphyseal trabecular bone volume/tissue volume (BV/TV) after OVX as described previously. Forced running increased the trabecular BV/TV in all mice. In the epiphyseal region, no visible alteration in bone morphology or osteophyte formation was observed in any of the four groups. Histological analysis revealed that OVX or forced running respectively had subtle effects on cartilage degeneration. However, the combination of OVX and forced running synergistically enhanced synovitis and articular cartilage degeneration. Although morphological changes in chondrocytes were observed during OA initiation, no signs of bone marrow edema were observed in any of the four experimental groups. We report the coordinate and synergistic effects of extensive treadmill exercise and ovariectomy on articular cartilage degeneration. Since no surgical procedure was performed on the knee joint directly in this model, this model is useful in addressing the molecular pathogenesis of naturally occurring OA.

  19. Synergistic effects of non-thermal plasma-assisted catalyst and ultrasound on toluene removal.

    Sun, Yongli; Zhou, Libo; Zhang, Luhong; Sui, Hong

    2012-01-01

    A wire-mesh catalyst coated by La0.8Sr0.2MnO3 was combined with a dielectric barrier discharge (DBD) reactor for toluene removal at atmospheric pressure. It was found that toluene removal efficiency and carbon dioxide selectivity were enhanced in the catalytic packed-bed reactor. In addition, ozone and nitrogen monoxide from the gas effluent byproducts decreased. This is the first time that ultrasound combined with plasma has been used for toluene removal. A synergistic effect on toluene removal was observed in the plasma-assisted ultrasound system. At the same time, the system increased toluene conversion and reduced ozone emission.

  20. COMBINATION OF MORPHINE AND GABAPENTIN LEADS TO SYNERGISTIC EFFECTS IN A RAT MODEL OF POSTOPERATIVE PAIN

    Papathanasiou, Theodoros; Juul, Rasmus Vestergaard; Heegaard, Anne-Marie

    Postoperative pain is a complex clinical condition that is still inadequately managed. Opioids remain the first line agents for the management of postoperative pain despite their side effects. Combination treatment with non-opioid agents that act at different sites within the central and peripheral...... of hindpaw withdrawal thresholds, after subcutaneous administration of morphine (0, 1, 3 and 7 mg/kg), gabapentin (0, 10, 30 and 100 mg/kg) or their combination (9 combinations of the above doses) were obtained using an electronic von Frey device. Surface of synergistic interaction (SSI) analysis was used...

  1. Evaluation of antitumor, immunomodulatory and free radical scavenging effects of a new herbal prescription seaweed complex preparation

    Liu, Xin; Shao, Changlun; Kong, Wenwen; Fang, Yuchun; Wang, Changyun

    2013-09-01

    Seaweed Complex Preparation (SCP) is a clinical traditional Chinese medicine preparation which is composed of seven traditional Chinese herbs, and it has been used for treatment of lung cancer, liver cancer and digestive cancer. However, little information is available about the pharmacodynamic basis. The antitumor, immunomodulatory and free radical scavenging effects of SCP were evaluated in this study. Transplanted tumor in vivo method was used to determine the antitumor effect. The effects on splenocyte proliferation and phagocytosis of macrophages in tumor-bearing mice were measured by the MTT method and the phagocytizing cock red blood cell (CRBC) method respectively. The scavenging activities of SCP on DPPH and hydroxyl radicals in vitro were investigated. It was found that the medium-dose and high-dose of SCP could significantly inhibit the growth of transplanted hepatic tumor of murine hepatocarcinoma cell line H22, and promote proliferation of splenocytes and phagocytosis of macrophages. SCP possessed noticeable scavenging activities on DPPH and hydroxyl radicals. The antitumor effects of SCP might be achieved by improving immune system and scavenging free radicals, which is in accordance with the viewpoint of traditional Chinese medicine in promoting the body resistance and eliminating pathogenic factors for cancer treatment.

  2. Anti-tumor effects of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase α

    Maeda, Naoki; Kokai, Yasuo; Ohtani, Seiji; Sahara, Hiroeki; Kuriyama, Isoko; Kamisuki, Shinji; Takahashi, Shunya; Sakaguchi, Kengo; Sugawara, Fumio; Yoshida, Hiromi; Sato, Noriyuki; Mizushina, Yoshiyuki

    2007-01-01

    In the screening of selective inhibitors of eukaryotic DNA polymerases (pols), dehydroaltenusin was found to be an inhibitor of pol α from a fungus (Alternaria tennuis). We succeeded in chemically synthesizing dehydroaltenusin, and the compound inhibited only mammalian pol α with IC 50 value of 0.5 μM, and did not influence the activities of other replicative pols such as pols δ and ε, but also showed no effect on pol α activity from another vertebrate, fish, or from a plant species. Dehydroaltenusin also had no influence on the other pols and DNA metabolic enzymes tested. The compound also inhibited the proliferation of human cancer cells with LD 50 values of 38.0-44.4 μM. In an in vivo anti-tumor assay on nude mice bearing solid tumors of HeLa cells, dehydroaltenusin was shown to be a promising suppressor of solid tumors. Histopathological examination revealed that increased tumor necrosis and decreased mitotic index were apparently detected by the compound in vivo. Therefore, dehydroaltenusin could be of interest as not only a mammalian pol α-specific inhibitor, but also as a candidate drug for anti-cancer treatment

  3. [Antitumor effects of matrix protein of vesicular stomatic virus on EL4 lymphoma mice].

    Lin, Shi-jia; Yu, Qin-mei; Meng, Wen-tong; Wen, Yan-jun; Chen, Li-juan; Niu, Ting

    2011-03-01

    To explore antitumor effects of plasmid pcDNA3. 1-MP encoding matrix protein of vesicular stomatitis virus (VSV) complexed with cationic liposome (DOTAP:CHOL) in mice with EL4 lymphoma. C57BL/6 mouse model with EL4 lymphoma was established. Sixty mice bearing EL4 lymphoma were divided randomly into five groups including Lip-MP, Lip-pVAX, Lip, ADM and NS groups, which were intravenously injected with liposome-pcDNA 3. 1-MP complex, liposome-pVAX complex, empty liposome, Adriamycin and normal saline respectively every three days. Tumor volumes and survival time were monitored. Microvessel density and tumor proliferative index in tumor tissues were determined by CD31, Ki-67 immunohistochemistry staining, meanwhile the tumor apoptosis index was measured by TUNEL method. From 6 days after treatments on, the tumor volume in Lip-MP group was much smaller than that in Lip-pVAX, Lip and NS group (P EL4 tumor cells in vivo (P EL4 lymphoma, which may be related to the induction of tumor cell apoptosis, inhibition of tumor angiogenesis, and suppression of tumor cell proliferation.

  4. Ukrain, a plant derived semi-synthetic compound, exerts antitumor effects against murine and human breast cancer and induce protective antitumor immunity in mice.

    Bozeman, E N; Srivatsan, S; Mohammadi, H; Daniels, D; Shashidharamurthy, R; Selvaraj, P

    2012-12-01

    Despite the recent advances in anti-cancer therapies, breast cancer accounts for the highest percentage of estimated new cases among female cancer patients. The anti-cancer drug Ukrain, a plant-derived semi-synthetic compound, has been shown to be effective in a variety of tumor models including colon, brain, ovarian, melanoma and lymphoma. However, the direct cytotoxic effects of Ukrain have yet to be investigated in breast cancer models. Herein, we investigated the in vitro and in vivo cytotoxicity of Ukrain using murine (4T07 and TUBO) and human (SKBR-3) breast cancer cell lines. Cells were treated with varying concentrations of Ukrain for up to 72 h and analyzed for viability by trypan blue exclusion, apoptosis by intracellular caspase 3 and Annexin V staining, and proliferative potential by a clonogenic assay. Female BALB/c mice were challenged subcutaneously (s.c.) with 4T07-RG cells and administered 5 mg/kg or 12.5 mg/kg body weight Ukrain intravenously (i.v.) on the same day and 3 days later. Protective immune responses were determined following re-challenge of tumor-free mice 35 days post primary challenge. Ukrain exposure induced apoptosis in a dose and time-dependent manner with 50 µg/mL Ukrain leading to >50% cell death after 48 h exposure for all three breast cancer cell lines. Ukrain administration (12.5 mg/kg) led to significant inhibition of 4T07 tumor growth in vivo and sustained protective anti-tumor immunity following secondary challenge. Our findings demonstrate the in vitro and in vivo cytotoxic effects of Ukrain on breast cancer cells and may provide insight into designing Ukrain-based therapies for breast cancer patients.

  5. Synergistic effect of tungsten carbide and palladium on graphene for promoted ethanol electrooxidation.

    Yang, Jun; Xie, Ying; Wang, Ruihong; Jiang, Baojiang; Tian, Chungui; Mu, Guang; Yin, Jie; Wang, Bo; Fu, Honggang

    2013-07-24

    The synergistic effect of WC and Pd has large benefit for ethanol electrooxidation. The small-sized Pd nanoparticles (NPs) decorated tungsten carbide on graphene (Pd-WC/GN) will be a promising anode catalyst for the direct ethanol fuel cells. The density functional theory (DFT) calculations reveal that the strong interaction exists at the interface between Pd and WC, which induces the electron transfer from WC to Pd. Fortunately, the nanoscale architecture of Pd-WC/GN has been successfully fabricated in our experiments. X-ray photoelectron spectrum further confirms the existence of electron transfer from WC to Pd in a Pd-WC/GN nanohybrid. Notably, electrochemical tests show that the Pd-WC/GN catalyst exhibits low onset potential, a large electrochemical surface area, high activity, and stability for ethanol electrooxidation in alkaline solution compared with Pd/graphene and Pd/commercial Vulcan 72R carbon catalysts. The enhancement can be attributed to the synergistic effect of Pd and WC on graphene. At the interface between Pd and WC, the electron transfer from WC to Pd leads to the increased electron densities of surface Pd, which is available for weakening adsorption of intermediate oxygen-containing species such as CO and activating catalyst. Meanwhile, the increased tungsten oxide induced by electron transfer can facilitate the effective removal of intermediate species adsorbed on the Pd surface through a bifunctional mechanism or hydrogen spillover effect.

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

    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 effect on co-gasification reactivity of biomass-petroleum coke blended char.

    Wei, Juntao; Guo, Qinghua; Gong, Yan; Ding, Lu; Yu, Guangsuo

    2017-06-01

    In this work, effects of gasification temperature (900°C-1100°C) and blended ratio (3:1, 1:1, 1:3) on reactivity of petroleum coke and biomass co-gasification were studied in TGA. Quantification analysis of active AAEM transformation and in situ investigation of morphological structure variations in gasification were conducted respectively using inductively coupled plasma optical emission spectrometer and heating stage microscope to explore synergistic effect on co-gasification reactivity. The results indicated that char gasification reactivity was enhanced with increasing biomass proportion and gasification temperature. Synergistic effect on co-gasification reactivity was presented after complete generation of biomass ash, and gradually weakened with increasing temperature from 1000°C to 1100°C after reaching the most significant value at 1000°C. This phenomenon was well related with the appearance of molten biomass ash rich in glassy state potassium and the weakest inhibition effect on active potassium transformation during co-gasification at the temperature higher than 1000°C. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Synergistic effects of radiation and immobilization of hind limb on bone in rats

    Fukuda, Satoshi; Ikeda, Mizuyo; Nakamura, Mariko

    2008-01-01

    Synergistic effects of radiation (x-ray) and immobilization of hind limbs on bone in rats were examined, and the preventive effect of milk basic protein (MBP) on radiation effects was tested. One hundred and twenty female rats were divided into three large groups and then each group was divided into four small groups such as the no treatment, oral administered MBP, immobilization (IM) of hind limb, and IM+MBP groups. The rats of two large groups were exposed to a whole-body dose of 3 Gy or 6 Gy of x-ray. Half of the rats of each large group were sacrificed at 1 and 3 months, respectively. Muscle weights and bone mineral density decreased significantly in the IM groups following radiation, and bone volume in the proximal metaphysis of the tibia decreased significantly in all of the radiation groups and most in the radiation+IM group at 1 month. The bone volume recovered in all of the radiation groups except for the radiation+IM groups. The results indicated that the bone damages increased more as a result of the synergistic effects of radiation and IM than as a result of either of IM or radiation alone, and the harmful damage caused by IM was much greater than that of radiation. (author)

  9. A visualized investigation at the atomic scale of the antitumor effect of magnetic nanomedicine on gastric cancer cells.

    Liu, Xiaokang; Deng, Xia; Li, Xinghua; Xue, Desheng; Zhang, Haoli; Liu, Tao; Liu, Qingfang; Mellors, Nigel J; Li, Yumin; Peng, Yong

    2014-07-01

    Discovering which anticancer drugs attack which organelle(s) of cancer cells is essential and significant, not only for understanding their therapeutic and adverse effects, but also to enable the development of new-generation therapeutics. Here, we show that novel Fe3O4-carboxymethyl cellulose-5-fluorouracil (Fe3O4-CMC-5FU) nanomedicine can apparently enhance the antitumor effect on gastric cancer cells, and its mechanism of killing the SGC-7901 gastric cancer cells can be directly observed at the atomic scale. The novel nanomedicine was prepared using the traditional antitumor drug 5FU to chemically bond onto the functionalized Fe3O4 nanoparticles (Fe3O4-CMC-5FU nanomedicine), and then was fed into SGC-7901 gastric cancer cells. The inorganic Fe3O4 nanoparticles were used to track the distribution and antitumor effect of the nanomedicine within individual SGC-7901 gastric cancer cells. Atomic-level observation and tracking the elemental distribution inside individual cells proved that the magnetic nanomedicine killed the gastric cells mainly by attacking their mitochondria. The enhanced therapeutic efficacy derives from the localized high concentration and poor mobility of the aggregated Fe3O4-CMC-5FU nanomedicine in the cytoplasm. A brand new mechanism of Fe3O4-CMC-5FU nanomedicine killing SGC-7901 gastric cancer cells by attacking their mitochondria was discovered, which is different from the classical mechanism utilized by traditional medicine 5FU, which kills gastric cancer cells by damaging their DNA. Our work might provide a partial solution in nanomedicines or even modern anticancer medicine for the visualized investigation of their antitumor effect.

  10. 2-methoxyestradiol-mediated anti-tumor effect increases osteoprotegerin expression in osteosarcoma cells.

    Benedikt, Michaela B; Mahlum, Eric W; Shogren, Kristen L; Subramaniam, Malayannan; Spelsberg, Thomas C; Yaszemski, Michael J; Maran, Avudaiappan

    2010-04-01

    Osteosarcoma is a bone tumor that frequently develops during adolescence. 2-Methoxyestradiol (2-ME), a naturally occurring metabolite of 17beta-estradiol, induces cell cycle arrest and cell death in human osteosarcoma cells. To investigate whether the osteoprotegrin (OPG) protein plays a role in 2-ME actions, we studied the effect of 2-ME treatment on OPG gene expression in human osteosarcoma cells. 2-ME treatment induced OPG gene promoter activity and mRNA levels. Also, Western blot analysis showed that 2-ME treatment increased OPG protein levels in MG63, KHOS, 143B and LM7 osteosarcoma cells by 3-, 1.9-, 2.8-, and 2.5-fold, respectively, but did not affect OPG expression in normal bone cells. In addition, increases in OPG protein levels were observed in osteosarcoma cell culture media after 3 days of 2-ME treatment. The effect of 2-ME on osteosarcoma cells was ligand-specific as parent estrogen, 17beta-estradiol and a tumorigenic estrogen metabolite, 16alpha-hydroxyestradiol, which do not affect osteosarcoma cell cycle and cell death, had no effect on OPG protein expression. Furthermore, co-treating osteosarcoma cells with OPG protein did not further enhance 2-ME-mediated anti-tumor effects. OPG-released in 2-ME-treated cultures led to an increase in osteoblastic activity and a decrease in osteoclast number, respectively. These findings suggest that OPG is not directly involved in 2-ME-mediated anti-proliferative effects in osteosarcoma cells, but rather participates in anti-resorptive functions of 2-ME in bone tumor environment. Copyright 2010 Wiley-Liss, Inc.

  11. Anti-Tumor Effects of Ketogenic Diets in Mice: A Meta-Analysis.

    Rainer J Klement

    Full Text Available Currently ketogenic diets (KDs are hyped as an anti-tumor intervention aimed at exploiting the metabolic abnormalities of cancer cells. However, while data in humans is sparse, translation of murine tumor models to the clinic is further hampered by small sample sizes, heterogeneous settings and mixed results concerning tumor growth retardation. The aim was therefore to synthesize the evidence for a growth inhibiting effect of KDs when used as a monotherapy in mice.We conducted a Bayesian random effects meta-analysis on all studies assessing the survival (defined as the time to reach a pre-defined endpoint such as tumor volume of mice on an unrestricted KD compared to a high carbohydrate standard diet (SD. For 12 studies meeting the inclusion criteria either a mean survival time ratio (MR or hazard ratio (HR between the KD and SD groups could be obtained. The posterior estimates for the MR and HR averaged over four priors on the between-study heterogeneity τ2 were MR = 0.85 (95% highest posterior density interval (HPDI = [0.73, 0.97] and HR = 0.55 (95% HPDI = [0.26, 0.87], indicating a significant overall benefit of the KD in terms of prolonged mean survival times and reduced hazard rate. All studies that used a brain tumor model also chose a late starting point for the KD (at least one day after tumor initiation which accounted for 26% of the heterogeneity. In this subgroup the KD was less effective (MR = 0.89, 95% HPDI = [0.76, 1.04].There was an overall tumor growth delaying effect of unrestricted KDs in mice. Future experiments should aim at differentiating the effects of KD timing versus tumor location, since external evidence is currently consistent with an influence of both of these factors.

  12. In vitro effectiveness of triterpenoids and their synergistic effect with antibiotics against Staphylococcus aureus strains.

    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.

  13. Study on the Immunomodulation Effect of Isodon japonicus Extract via Splenocyte Function and NK Anti-Tumor Activity

    Kyung-A Hwang

    2012-04-01

    Full Text Available Here we investigated the potential immune-enhancing activity of Isodon japonicus on murine splenocyte and natural-killer (NK cells in vitro. The ethanol extract of I. japonicus significantly enhanced the proliferation of splenocyte and induced the significant enhancement of NK cells’ activity against tumor cells (YAC-1. In addition, I. japonicus increased the production of interferon (IFN-γ and tumor necrosis factor (TNF-α, suggesting that the increase in NK cell cytotoxicity could be due to the enhancement of the NK cell production of both cytokines. Taken together, I. japonicus extract inhibited the growth of human leukemia cells (K562 by 74%. Our observation indicated that the anti-tumor effects of I. japonicus may be attributed to its ability to serve as a stimulant of NK anti-tumor activity. In addition, our results support the development of functional food studies on I. japonicus.

  14. Ionizing/displacement synergistic effects induced by gamma and neutron irradiation in gate-controlled lateral PNP bipolar transistors

    Wang, Chenhui, E-mail: wangchenhui@nint.ac.cn [State Key Laboratory of Intense Pulsed Irradiation Simulation and Effect, Northwest Institute of Nuclear Technology, P.O. Box 69-10, Xi’an 710024 (China); Chen, Wei; Yao, Zhibin; Jin, Xiaoming; Liu, Yan; Yang, Shanchao [State Key Laboratory of Intense Pulsed Irradiation Simulation and Effect, Northwest Institute of Nuclear Technology, P.O. Box 69-10, Xi’an 710024 (China); Wang, Zhikuan [State Key Laboratory of Analog Integrated Circuit, Chongqing 400060 (China)

    2016-09-21

    A kind of gate-controlled lateral PNP bipolar transistor has been specially designed to do experimental validations and studies on the ionizing/displacement synergistic effects in the lateral PNP bipolar transistor. The individual and mixed irradiation experiments of gamma rays and neutrons are accomplished on the transistors. The common emitter current gain, gate sweep characteristics and sub-threshold sweep characteristics are measured after each exposure. The results indicate that under the sequential irradiation of gamma rays and neutrons, the response of the gate-controlled lateral PNP bipolar transistor does exhibit ionizing/displacement synergistic effects and base current degradation is more severe than the simple artificial sum of those under the individual gamma and neutron irradiation. Enough attention should be paid to this phenomenon in radiation damage evaluation. - Highlights: • A kind of gate-controlled lateral PNP bipolar transistor has been specially designed to facilitate the analysis of ionizing/displacement synergistic effects induced by the mixed irradiation of gamma and neutron. • The difference between ionizing/displacement synergistic effects and the simple sum of TID and displacement effects is analyzed. • The physical mechanisms of synergistic effects are explained.

  15. Toxic effect of nonylphenol on the marine macroalgae Gracilaria lemaneiformis (Gracilariales, Rhodophyta): antioxidant system and antitumor activity.

    Zhong, Mingqin; Yin, Pinghe; Zhao, Ling

    2017-04-01

    The objective of the present work was to evaluate the toxic effect of nonylphenol (NP) on the antioxidant response and antitumor activity of Gracilaria lemaneiformis. An obvious oxidative damage was observed in this study. The thallus exposed to NP showed 1.2-2.0-fold increase in lipid peroxide and displayed a maximum level of 16.58 μmol g -1 Fw on 0.6 mg L -1 for 15-day exposure. The activities of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) enhanced significantly by 1.1-3.2-fold and subsequently diminished at the high concentrations and prolonged exposure. The results of DNA damage in comet assay also supported that NP was obviously toxic on G. lemaneiformis with increasing the percentage of tail DNA in a dose-dependent manner. Furthermore, the ethanol extract of G. lemaneiformis (EEGL) did exhibit antitumor potential against HepG-2 cells. While decreased in cell inhibition, ROS generation, apoptosis, and caspase-3 in HepG-2 cells treated with the EEGL were observed when G. lemaneiformis was exposed to NP for 15 days, and which were related to exposure concentration of NP. These suggested that NP has strongly toxic effect on the antitumor activity of G. lemaneiformis. The results revealed in this study imply that macroalgae can be useful biomarkers to evaluate marine pollutions.

  16. A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases

    Hayakawa, F; Sugimoto, K; Harada, Y; Hashimoto, N; Ohi, N; Kurahashi, S; Naoe, T

    2013-01-01

    Signal transduction and activator of transcription (STAT) proteins are extracellular ligand-responsive transcription factors that mediate cell proliferation, apoptosis, differentiation, development and the immune response. Aberrant signals of STAT induce uncontrolled cell proliferation and apoptosis resistance and are strongly involved in cancer. STAT has been identified as a promising target for antitumor drugs, but to date most trials have not been successful. Here, we demonstrated that a novel STAT inhibitor, OPB-31121, strongly inhibited STAT3 and STAT5 phosphorylation without upstream kinase inhibition, and induced significant growth inhibition in various hematopoietic malignant cells. Investigation of various cell lines suggested that OPB-31121 is particularly effective against multiple myeloma, Burkitt lymphoma and leukemia harboring BCR–ABL, FLT3/ITD and JAK2 V617F, oncokinases with their oncogenicities dependent on STAT3/5. Using an immunodeficient mouse transplantation system, we showed the significant antitumor effect of OPB-31121 against primary human leukemia cells harboring these aberrant kinases and its safety for normal human cord blood cells. Finally, we demonstrated a model to overcome drug resistance to upstream kinase inhibitors with a STAT inhibitor. These results suggested that OPB-31121 is a promising antitumor drug. Phase I trials have been performed in Korea and Hong Kong, and a phase I/II trial is underway in Japan

  17. Effect of the antitumoral alkylating agent 3-bromopyruvate on mitochondrial respiration: role of mitochondrially bound hexokinase.

    Rodrigues-Ferreira, Clara; da Silva, Ana Paula Pereira; Galina, Antonio

    2012-02-01

    The alkylating agent 3-Bromopyruvate (3-BrPA) has been used as an anti-tumoral drug due to its anti-proliferative property in hepatomas cells. This propriety is believed to disturb glycolysis and respiration, which leads to a decreased rate of ATP synthesis. In this study, we evaluated the effects of the alkylating agent 3-BrPA on the respiratory states and the metabolic steps of the mitochondria of mice liver, brain and in human hepatocarcinoma cell line HepG2. The mitochondrial membrane potential (ΔΨ(m)), O(2) consumption and dehydrogenase activities were rapidly dissipated/or inhibited by 3-BrPA in respiration medium containing ADP and succinate as respiratory substrate. 3-BrPA inhibition was reverted by reduced glutathione (GSH). Respiration induced by yeast soluble hexokinase (HK) was rapidly inhibited by 3-BrPA. Similar results were observed using mice brain mitochondria that present HK naturally bound to the outer mitochondrial membrane. When the adenine nucleotide transporter (ANT) was blocked by the carboxyatractiloside, the 3-BrPA effect was significantly delayed. In permeabilized human hepatoma HepG2 cells that present HK type II bound to mitochondria (mt-HK II), the inhibiting effect occurred faster when the endogenous HK activity was activated by 2-deoxyglucose (2-DOG). Inhibition of mt-HK II by glucose-6-phosphate retards the mitochondria to react with 3-BrPA. The HK activities recovered in HepG2 cells treated or not with 3-BrPA were practically the same. These results suggest that mitochondrially bound HK supporting the ADP/ATP exchange activity levels facilitates the 3-BrPA inhibition reaction in tumors mitochondria by a proton motive force-dependent dynamic equilibrium between sensitive and less sensitive SDH in the electron transport system.

  18. Effect of administration of some antitumor extracts on Ehrlich ascites carcinoma-bearing mice

    Mesalam, N.M.A.

    2013-01-01

    Cancer is considered one of the most common causes of morbidity and mortality worldwide. Many researches have been studied on the discovery of natural and synthetic compounds that can be used in the prevention and/or treatment of cancer. Many chemo preventive agents have been associated with antiproliferative and apoptotic effects on cancer cells because of their high antioxidant activity. The present study was undertaken to investigate the antioxidant and antitumor effects of three natural extracts including (propolis, green tea and Chlorella vulgaris) without or with radiation exposure in Ehrlich ascites carcinoma (EAC) - bearing female albino mice. The animals were randomly distributed into three major groups as follows:- Group A (control group).This group consists of 10 mice kept on normal standard rodent diet without any treatment and housed in two cages: mice of the first cage served as control for non tumor-bearing group and the second cage served as control for tumor-bearing group. Group B (Non tumor - bearing group).This group consists of 30 mice and used to study the effect of the vehicle solutions (gum acacia, DMSO), propolis, green tea, Chlorella vulgaris and gamma irradiation on normal mice. Mice of this group were equally distributed into six subgroups receiving gum acacia, DMSO, propolis, green tea and Chlorella vulgaris for two weeks and whole body gamma irradiated. Group C (Tumor- bearing group): This group consists of 160 mice randomly and equally distributed into 8 subgroups: Ehrlich ascites carcinoma(mice were inoculated with 2.5 x 10 6 intra-peretoneally(i.p), Ehrlich ascites carcinoma and 2 Gy irradiated, Ehrlich ascites carcinoma and propolis treated (150 mg/kg b.w), Ehrlich ascites carcinoma, propolis treated and irradiated, Ehrlich ascites carcinoma and green tea treated (150 mg/kg b.w), Ehrlich ascites carcinoma, green tea treated and irradiated, Ehrlich ascites carcinoma and Chlorella vulgaris treated (150 mg/kg b.w) and Ehrlich ascites

  19. Antitumor effects of vitamins K1, K2 and K3 on hepatocellular carcinoma in vitro and in vivo.

    Hitomi, Misuzu; Yokoyama, Fumi; Kita, Yuko; Nonomura, Takako; Masaki, Tsutomu; Yoshiji, Hitoshi; Inoue, Hideyuki; Kinekawa, Fumihiko; Kurokohchi, Kazutaka; Uchida, Naohito; Watanabe, Seishiro; Kuriyama, Shigeki

    2005-03-01

    A number of studies have shown that various K vitamins, specifically vitamins K2 and K3, possess antitumor activity on various types of rodent- and human-derived neoplastic cell lines. In the present study, we examined the antitumor effects of vitamins K1, K2 and K3 on PLC/PRF/5 human hepatocellular carcinoma (HCC) cells in vitro and in vivo. Furthermore, we examined the mechanisms of antitumor actions of these vitamins in vitro and in vivo. Although vitamin K1 did not inhibit proliferation of PLC/PRF/5 cells at a 90-microM concentration (the highest tested), vitamins K2 and K3 suppressed proliferation of the cells at concentrations of 90 and 9 microM, respectively. By flow cytometric analysis, it was shown that not only vitamin K1, but also vitamin K2 did not induce apoptosis or cell cycle arrest on PLC/PRF/5 cells. In contrast, vitamin K3 induced G1 arrest, but not apoptosis on PLC/PRF/5 cells. Subsequent in vivo study using subcutaneous HCC-bearing athymic nude mice demonstrated that both vitamins K2 and K3 markedly suppressed the growth of HCC tumors to similar extent. Protein expression of cyclin D1 and cyclin-dependent kinase 4 (Cdk4), but not p16INK4a Cdk inhibitor in the tumor was significantly reduced by vitamin K2 or K3 treatment, indicating that vitamins K2 and K3 may induce G1 arrest of cell cycle on PLC/PRF/5 cells in vivo. Taken collectively, vitamins K2 and K3 were able to induce potent antitumor effects on HCC in vitro and in vivo, at least in part, by inducing G1 arrest of the cell cycle. The results indicate that vitamins K2 and K3 may be useful agents for the treatment of patients with HCC.

  20. Synergistic electron transfer effect-based signal amplification strategy for the ultrasensitive detection of dopamine.

    Lu, Qiujun; Chen, Xiaogen; Liu, Dan; Wu, Cuiyan; Liu, Meiling; Li, Haitao; Zhang, Youyu; Yao, Shouzhuo

    2018-05-15

    The selective and sensitive detection of dopamine (DA) is of great significance for the identification of schizophrenia, Huntington's disease, and Parkinson's disease from the perspective of molecular diagnostics. So far, most of DA fluorescence sensors are based on the electron transfer from the fluorescence nanomaterials to DA-quinone. However, the limited electron transfer ability of the DA-quinone affects the level of detection sensitivity of these sensors. In this work, based on the DA can reduce Ag + into AgNPs followed by oxidized to DA-quinone, we developed a novel silicon nanoparticles-based electron transfer fluorescent sensor for the detection of DA. As electron transfer acceptor, the AgNPs and DA-quinone can quench the fluorescence of silicon nanoparticles effectively through the synergistic electron transfer effect. Compared with traditional fluorescence DA sensors, the proposed synergistic electron transfer-based sensor improves the detection sensitivity to a great extent (at least 10-fold improvement). The proposed sensor shows a low detection limit of DA, which is as low as 0.1 nM under the optimal conditions. This sensor has potential applicability for the detection of DA in practical sample. This work has been demonstrated to contribute to a substantial improvement in the sensitivity of the sensors. It also gives new insight into design electron transfer-based sensors. Copyright © 2018. Published by Elsevier B.V.

  1. Insights into the Synergistic Effect of Fungi and Bacteria for Reactive Red Decolorization

    Dandan Zhou

    2014-01-01

    Full Text Available Bacterial contamination is a prevalent problem in fungal dye wastewater decolorization that prevents the development of this technology in practical engineering. New insight into the relationship between fungi and bacteria is given in terms of settleability, bioadsorption, and biodegradation, which all confirm their synergistic effect. Sterilization is implied to be not the only mechanism for fungi decolorization. When the fungi and bacteria isolated from the activated sludge were cocultured, fungi removed more than 70% of the reactive red through sole bioadsorption in 5 min and enhanced the settleability of the bacteria group from 7.7 to 18.4 in the aggregation index. Subsequently, the bacteria played a more significant role in dye biodegradation according to the ultraviolet-visible spectrum analysis. They further enhanced the decolorization efficiency to over 80% when cocultured with fungi. Therefore, the advanced bioadsorption and settleability of fungi, combined with the good dye biodegradation ability of bacteria, results in the synergistic effect of the coculture microorganisms.

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

    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.

  3. Synergistic effects of hollow structure and surface fluorination on the photocatalytic activity of titania

    Lv Kangle; Yu Jiaguo; Deng Kejian; Sun Jie; Zhao Yanxi; Du Dongyun; Li Mei

    2010-01-01

    To study the synergistic effects of hollow structure and surface fluorination on the photoactivity of TiO 2 , TiO 2 hollow microspheres were synthesized by a hydrolysis-precipitate method using sulfonated polystyrene (PS) as templates and tetrabutylorthotitanate (TBOT) as precursor, and then calcined at 500 o C for 2 h. The calcined samples were characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy and N 2 sorption. Photocatalytic activity was evaluated using reactive brilliant red X3B, an anionic organic dye, as a model pollutant in water. The results show that the photocatalytic activity of TiO 2 hollow microspheres is significantly higher than that of TiO 2 nanoparticles prepared in the same experimental conditions. At pH 7 and 3, the apparent rate constants of the former exceed that of the latter by a factor of 3.38 and 3.15, respectively. After surface fluorination at pH 3, the photoactivity of hollow microspheres and nanoparticles further increases for another 1.61 and 2.19 times, respectively. The synergistic effect of surface fluorination and hollow structure can also be used to prepare other highly efficient photocatalyst.

  4. Synergistic effect of rhenium and ruthenium in nickel-based single-crystal superalloys

    Yu, X.X. [Department of Physics, Tsinghua University, Beijing 100084 (China); Department of Materials Science and Engineering, Tsinghua University, Beijing 100084 (China); Wang, C.Y., E-mail: cywang@mail.tsinghua.edu.cn [Department of Physics, Tsinghua University, Beijing 100084 (China); Central Iron and Steel Research Institute, Beijing 100081 (China); Zhang, X.N. [Institute of Microstructure and Property of Advanced Materials, Beijing University of Technology, Beijing 100124 (China); Yan, P. [Central Iron and Steel Research Institute, Beijing 100081 (China); Zhang, Z., E-mail: zezhang@zju.edu.cn [State Key Laboratory of Silicon Materials, Department of Materials Science and Engineering, Zhejiang University, Hangzhou 310027 (China)

    2014-01-05

    Highlights: • Re and Ru synergistic effects in nickel-based superalloys are investigated. • The Al site occupation of Re atom in the γ′ phase is observed directly. • The addition of Ru results in the repartitioning of Re to γ phase. -- Abstract: The microstructures of ternary Ni–Al–Re and quaternary Ni–Al–Re–Ru single-crystal alloys were investigated at atomic and electronic levels to clarify the synergistic effect of Re and Ru in nickel-based single-crystal superalloys. In the Ni–Al–Re alloy, it was directly observed that Re atom occupied the Al site of γ′ phase. In the Ni–Al–Re–Ru alloy, the mechanisms of Re repartition between γ and γ′ phases were proposed. In the dendritic cores, high concentrations of Re exceeded the solubility limit of γ′ phase and partitioned to γ phase, which led to the homogenization. In the interdendritic regions, Ru resulted in the repartitioning of Re to γ phase which was proved by transmission electron microscopy and first-principles calculations.

  5. Analysis of the effects of simulated synergistic LEO environment on solar panels

    Allegri, G.; Corradi, S.; Marchetti, M.; Scaglione, S.

    2007-02-01

    The effects due to the LEO environment exposure of a solar array primary structure are here presented and discussed in detail. The synergistic damaging components featuring LEO environment are high vacuum, thermal cycling, neutral gas, ultraviolet (UV) radiation and cold plasma. The synergistic effects due to these environmental elements are simulated by "on ground" tests, performed in the Space Environment Simulator (SAS) at the University of Rome "La Sapienza"; numerical simulations are performed by the Space Environment Information System (SPENVIS), developed by the European Space Agency (ESA). A "safe life" design for a solar array primary structure is developed, taking into consideration the combined damaging action of the LEO environment components; therefore results from both numerical and experimental simulations are coupled within the framework of a standard finite element method (FEM) based design. The expected durability of the solar array primary structure, made of laminated sandwich composite, is evaluated assuming that the loads exerted on the structure itself are essentially dependent on thermo-elastic stresses. The optical degradation of surface materials and the stiffness and strength degradation of structural elements are taken into account to assess the global structural durability of the solar array under characteristic operative conditions in LEO environment.

  6. Anti-tumor effect of bisphosphonate (YM529 on non-small cell lung cancer cell lines

    Date Hiroshi

    2007-01-01

    Full Text Available Abstract Background YM529 is a newly developed nitrogen-containing bisphosphonate (BP classified as a third-generation BP that shows a 100-fold greater potency against bone resorption than pamidronate, a second-generation BP. This agent is, therefore expected to be extremely useful clinically for the treatment of osteoporosis and hypercalcemia. Recently, YM529 as well as other third-generation BPs have also been shown to exert anti-tumor effects against various types of cancer cells both in vitro or/and in vivo. In this study, we investigate the anti-tumor effect of YM529 on non-small cell lung cancer (NSCLC. Methods Direct anti-tumor effect of YM529 against 8 NSCLC cell lines (adenocarcinoma: H23, H1299, NCI-H1819, NCI-H2009, H44, A549, adenosquamous cell carcinoma: NCI-H125, squamous cell carcinoma: NCI-H157 were measured by MTS assay and calculated inhibition concentration 50 % (IC50 values. YM529 induced apoptosis of NCI-H1819 was examined by DNA fragmentation of 2 % agarose gel electrophoresis and flowcytometric analysis (sub-G1 method. We examined where YM529 given effect to apoptosis of NSCLC cells in signaling pathway of the mevalonate pathway by western blotting analysis. Results We found that there was direct anti-tumor effect of YM529 on 8 NSCLC cell lines in a dose-dependent manner and their IC50 values were 2.1 to 7.9 μM and YM529 induced apoptosis and G1 arrest cell cycle with dose-dependent manner and YM529 caused down regulation of phospholyration of ERK1/2 in signaling pathways of NSCLC cell line (NCI-H1819. Conclusion Our study demonstrate that YM529 showed direct anti-tumor effect on NSCLC cell lines in vitro, which supports the possibility that third-generation BPs including YM529 can be one of therapeutic options for NSCLC.

  7. Synergistic antibacterial effects of β-lactam antibiotic combined with silver nanoparticles

    Li, Ping; Li, Juan; Wu, Changzhu; Wu, Qingsheng; Li, Jian

    2005-09-01

    The bactericidal action of silver (0) nanoparticles and amoxicillin on Escherichia coli is studied, respectively. Increasing concentration of both amoxicillin (0-0.525 mg ml-1) and silver nanoparticles (0-40 µg ml-1) showed a higher antibacterial effect in Luria-Bertani (LB) medium. Escherichia coli cells have different bactericidal sensitivity to them. When amoxicillin and silver nanoparticles are combined, it results in greater bactericidal efficiency on Escherichia coli cells than when they were applied separately. Dynamic tests on bacterial growth indicated that exponential and stationary phases are greatly decreased and delayed in the synergistic effect of amoxicillin and silver nanoparticles. In addition, the effect induced by a preincubation with silver nanoparticles is examined. The results show that solutions with more silver nanoparticles have better antimicrobial effects. One hypothesized mechanism is proposed to explain this phenomenon.

  8. Antitumor effects of regorafenib and sorafenib in preclinical models of hepatocellular carcinoma.

    Kissel, Maria; Berndt, Sandra; Fiebig, Lukas; Kling, Simon; Ji, Qunsheng; Gu, Qingyang; Lang, Tina; Hafner, Frank-Thorsten; Teufel, Michael; Zopf, Dieter

    2017-12-05

    The purpose of this study was to investigate the antitumor activity of regorafenib and sorafenib in preclinical models of HCC and to assess their mechanism of action by associated changes in protein expression in a HCC-PDX mouse model. Both drugs were administered orally once daily at 10 mg/kg (regorafenib) or 30 mg/kg (sorafenib), which recapitulate the human exposure at the maximally tolerated dose in mice. In a H129 hepatoma model, survival times differed significantly between regorafenib versus vehicle (p=0.0269; median survival times 36 vs 27 days), but not between sorafenib versus vehicle (p=0.1961; 33 vs 28 days). Effects on tumor growth were assessed in 10 patient-derived HCC xenograft (HCC-PDX) models. Significant tumor growth inhibition was observed in 8/10 models with regorafenib and 7/10 with sorafenib; in four models, superior response was observed with regorafenib versus sorafenib which was deemed not to be due to lower sorafenib exposure. Bead-based multiplex western blot analysis was performed with total protein lysates from drug- and vehicle-treated HCC-PDX xenografts. Protein expression was substantially different in regorafenib- and sorafenib-treated samples compared with vehicle. The pattern of upregulated proteins was similar with both drugs and indicates an activated RAF/MEK/ERK pathway, but more proteins were downregulated with sorafenib versus regorafenib. Overall, both regorafenib and sorafenib were effective in mouse models of HCC, although several cases showed better regorafenib activity which may explain the observed efficacy of regorafenib in sorafenib-refractory patients.

  9. [The Antitumor Effects of Fisetin on Ovarian Cancer in vitro and in vivo.

    Meng, Yi-Bo; Xiao, Chao; Chen, Xin-Lian; Bai, Peng; Yao, Yuan; Wang, He; Xiao, Xue

    2016-11-01

    We attempted to survey the inhibit effect of fisetin with human ovarian cancer cell line SKOV3 and the xenograft and the mechanism of the effect. The ovarian cancer cell line SKOV3 treated by fisetin were observed directly under the transmission electronmicroscope (TEM);MTT assay was used to determine cell viability.Flow cytometry was used to analyze the apoptosis in ovarian cancer cell line SKOV3.In addition,we established an ovarian cancer athymicnude rat model.We observed the neoplasia and progression after fisetin treatment.The proliferation and apoptosis of athymic nude rat model were evaluated by testing Bcl-2,Bax and poly-ADP-ribose polyerase (PARP) expression through Western blot. The chromatin were brought together and the apoptotic bodies were detected in SKOV3 cells under transmission electron microscope after the treatment by fisetin.MTT assay indicated that fisetin inhibited ovarian cancer cell proliferation in a dose-dependent manner.The flow cytometry data demonstrated that the apoptosis might induct in SKOV3 cells after treatment by fisetin.In athymic rude rat model,under the influence of fisetin,tumor volume and tumor mass were significantly decreased.Western blot demonstrated that treatment with higher concentration of fisetin resulted in a significant decrease of Bcl-2 and a significant increase of Bax.The apoptosis proteins PARP was cut apparently. The results provided the first insight into antitumor anti-proliferative and the induction of apoptosis efficacy of fisetin against ovarian cancer in vitro and in vivo .All data suggested a safe promising therapeutic potential of fisetin in ovarian cancer treatment.

  10. Effectiveness and Safety of Immunomodulators With Anti-Tumor Necrosis Factor Therapy in Crohn's Disease.

    Osterman, Mark T; Haynes, Kevin; Delzell, Elizabeth; Zhang, Jie; Bewtra, Meenakshi; Brensinger, Colleen M; Chen, Lang; Xie, Fenglong; Curtis, Jeffrey R; Lewis, James D

    2015-07-01

    The benefit of continuing immunomodulators when "stepping up" to anti-tumor necrosis factor (anti-TNF) therapy for Crohn's disease (CD) is uncertain. This study assessed the effectiveness and safety of immunomodulators with anti-TNF therapy in CD. We conducted a retrospective cohort study of new users of anti-TNF therapy for CD in Medicare. Users of anti-TNF combination therapy with immunomodulators were matched to up to 3 users of anti-TNF monotherapy via propensity score and compared by using 3 metrics of effectiveness-surgery, hospitalization, and discontinuation of anti-TNF therapy or surgery-and 2 metrics of safety-serious infection and non-Candida opportunistic infection. Cox regression was used for all analyses. Among new users of infliximab, we matched 381 users of combination therapy to 912 users of monotherapy; among new users of adalimumab, we matched 196 users of combination therapy to 505 users of monotherapy. Combination therapy occurred predominantly as "step up" after thiopurine therapy. The rates of surgery (hazard ratio [HR], 1.20; 95% confidence interval, 0.73-1.96), hospitalization (HR, 0.82; 0.57-1.19), discontinuation of anti-TNF therapy or surgery (HR, 1.09; 0.88-1.34), and serious infection (HR, 0.93; 0.88-1.34) did not differ between users of anti-TNF combination therapy and monotherapy. However, the risks of opportunistic infection (HR, 2.64; 1.21-5.73) and herpes zoster (HR, 3.16; 1.25-7.97) were increased with combination therapy. We found that continuation of immunomodulators after "stepping up" to anti-TNF therapy did not improve outcomes but was associated with an increased risk of opportunistic infection. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

  11. Dll4 blockade potentiates the anti-tumor effects of VEGF inhibition in renal cell carcinoma patient-derived xenografts.

    Kiersten Marie Miles

    Full Text Available The Notch ligand Delta-like 4 (Dll4 is highly expressed in vascular endothelium and has been shown to play a pivotal role in regulating tumor angiogenesis. Blockade of the Dll4-Notch pathway in preclinical cancer models has been associated with non-productive angiogenesis and reduced tumor growth. Given the cross-talk between the vascular endothelial growth factor (VEGF and Delta-Notch pathways in tumor angiogenesis, we examined the activity of a function-blocking Dll4 antibody, REGN1035, alone and in combination with anti-VEGF therapy in renal cell carcinoma (RCC.Severe combined immunodeficiency (SCID mice bearing patient-derived clear cell RCC xenografts were treated with REGN1035 and in combination with the multi-targeted tyrosine kinase inhibitor sunitinib or the VEGF blocker ziv-aflibercept. Immunohistochemical and immunofluorescent analyses were carried out, as well as magnetic resonance imaging (MRI examinations pre and 24 hours and 2 weeks post treatment. Single agent treatment with REGN1035 resulted in significant tumor growth inhibition (36-62% that was equivalent to or exceeded the single agent anti-tumor activity of the VEGF pathway inhibitors sunitinib (38-54% and ziv-aflibercept (46%. Importantly, combination treatments with REGN1035 plus VEGF inhibitors resulted in enhanced anti-tumor effects (72-80% growth inhibition, including some tumor regression. Magnetic resonance imaging showed a marked decrease in tumor perfusion in all treatment groups. Interestingly, anti-tumor efficacy of the combination of REGN1035 and ziv-aflibercept was also observed in a sunitinib resistant ccRCC model.Overall, these findings demonstrate the potent anti-tumor activity of Dll4 blockade in RCC patient-derived tumors and a combination benefit for the simultaneous targeting of the Dll4 and VEGF signaling pathways, highlighting the therapeutic potential of this treatment modality in RCC.

  12. Effects of antitumor derivatives of ineffective transplatin on bacterial cells: Is DNA a pharmacological target?

    Kašpárková, Jana; Brabec, Viktor

    2015-01-01

    Roč. 153, DEC2015 (2015), s. 206-210 ISSN 0162-0134 R&D Projects: GA ČR(CZ) GA14-21053S; GA MŠk(CZ) LD14019 Institutional support: RVO:68081707 Keywords : Transplatinum * Antitumor * Cellular target Subject RIV: BO - Biophysics Impact factor: 3.205, year: 2015

  13. Effect of Paris saponin on antitumor and immune function in U14 ...

    bearing mice, and reduced the serum IL-4 level. The Paris saponin can inhibit U14 cell growth and prolong survival time of mice; it is speculated that the Paris saponin may express its anti-tumor activity by improving the body's immune system.

  14. Synergistic sub-lethal effects of a biocide mixture on the springtail Folsomia fimetaria

    Schnug, Lisbeth; Leinaas, Hans Petter; Jensen, John

    2014-01-01

    The toxicity of three biocides, esfenvalerate, picoxystrobin and triclosan, on adult survival and recruitment of juveniles was studied in the springtail Folsomia fimetaria, both in single and mixture experiments. Recruitment of juveniles was more sensitive to biocide exposure than adult survival. The concepts of concentration addition and independent action returned almost identical toxicity predictions, though both models failed to predict the observed toxicity due to synergistic deviations at high exposure concentrations. A comparison with a similar study on earthworms showed that response-patterns were species-specific. Consequently, there is no single reference concept which is applicable for all species of one ecosystem, which in turn questions the usefulness of such mixture prediction concepts in ecological risk assessment. -- Highlights: • Toxicity of esfenvalerate, picoxystrobin and triclosan to Folsomia fimetaria was assessed. • Both, the single biocides and the mixture affected recruitment stronger than survival. • Concentration addition and independent action predictions were almost identical. • Inhibition of recruitment after mixture exposure was stronger than predicted. • Comparison with an earthworm study showed that responses are species-specific. -- The concepts of concentration addition and independent action failed to predict mixture toxicity due to dose-dependent synergistic effects

  15. SYNERGISTIC EFFECTS OF TOTAL QUALITY MANAGEMENT AND OPERATIONAL RISK MANAGEMENT IN CENTRAL BANKS

    Radoica Luburić

    2012-12-01

    Full Text Available This paper focuses on two very important and current approaches to management: Total Quality Management (TQM and Operational Risk Management (ORM. As a paradigm of business success, TQM provides the key assumptions for survival, development and success of an organisation, regardless of any limitations whatsoever. ORM, on the other hand, is predetermined to be an irreplaceable managerial tool that enables organisations to survive in any environment. In times of accelerated political, economic and technological changes, frequent natural disasters, acts of terrorism and other external events, a successful risk management has been gaining importance and becomes one of the key competitive advantages of an organisation. The ultimate objective is to make TQM and ORM, as two rather compatible and complementary approaches to risk management, harmonized, efficient and functional in order to get their synergistic effects in an organisation in full swing and practice. Various organisations, and thus central banks as conservative institutions, have an innovative opportunity to timely minimize their operational risk through preventive, comprehensive and synergistic operation of TQM and ORM and thus significantly contribute to improving their business performance.

  16. Synergistic effects of interstitial impurities and radiation defects on mechanical characteristics of ferritic steels

    Charit, I.; Seok, C.S.; Murty, K.L.

    2007-01-01

    Ferritic steels are generally used in pressure vessels and various reactor support structures in light water reactors. They are known to exhibit radiation embrittlement in terms of decreased toughness and increased ductile-brittle transition temperature as a result of exposure to neutron radiation. The superimposed effects of strain aging due to interstitial impurity atoms on radiation embrittlement were considered first by Wechsler, Hall and others. Here we summarize some of our efforts on the investigation of synergistic effects between interstitial impurity atoms (IIAs) and radiation-induced point defects, which result in interesting effects at appropriate temperature and strain rate conditions. Two materials, a mild steel and a pressure vessel steel (A516 Gr.70), are evaluated using tensile and three-point bend tests

  17. Multilineage hematopoietic recovery with concomitant antitumor effects using low dose Interleukin-12 in myelosuppressed tumor-bearing mice

    Miller Joseph D

    2008-05-01

    Full Text Available Abstract Background Interleukin-12 (IL-12 is a cytokine well known for its role in immunity. A lesser known function of IL-12 is its role in hematopoiesis. The promising data obtained in the preclinical models of antitumor immunotherapy raised hope that IL-12 could be a powerful therapeutic agent against cancer. However, excessive clinical toxicity, largely due to repeat dose regimens, and modest clinical response observed in the clinical trials have pointed to the necessity to design protocols that minimize toxicity without affecting the anti-tumor effect of IL-12. We have focused on the lesser known role of IL-12 in hematopoiesis and hypothesized that an important clinical role for IL-12 in cancer may be as an adjuvant hematological cancer therapy. In this putative clinical function, IL-12 is utilized for the prevention of cancer therapy-related cytopenias, while providing concomitant anti-tumor responses over and above responses observed with the primary therapy alone. This putative clinical function of IL-12 focuses on the dual role of IL-12 in hematopoiesis and immunity. Methods We assessed the ability of IL-12 to facilitate hematopoietic recovery from radiation (625 rad and chemotherapy (cyclophosphamide in two tumor-bearing murine models, namely the EL4 lymphoma and the Lewis lung cancer models. Antitumor effects and changes in bone marrow cellularity were also assessed. Results We show herein that carefully designed protocols, in mice, utilizing IL-12 as an adjuvant to radiation or chemotherapy yield facile and consistent, multilineage hematopoietic recovery from cancer therapy-induced cytopenias, as compared to vehicle and the clinically-utilized cytokine granulocyte colony-stimulating factor (G-CSF (positive control, while still providing concomitant antitumor responses over and above the effects of the primary therapy alone. Moreover, our protocol design utilizes single, low doses of IL-12 that did not yield any apparent toxicity

  18. Synergistic Antibacterial Effects of Nanoparticles Encapsulated with Scutellaria baicalensis and Pure Chlorhexidine on Oral Bacterial Biofilms

    Ken Cham-Fai Leung

    2016-04-01

    Full Text Available Scutellaria baicalensis (SB is a traditional Chinese medicine for treating infectious and inflammatory diseases. Our recent study shows potent antibacterial effects of nanoparticle-encapsulated chlorhexidine (Nano-CHX. Herein, we explored the synergistic effects of the nanoparticle-encapsulated SB (Nano-SB and Nano-CHX on oral bacterial biofilms. Loading efficiency of Nano-SB was determined by thermogravimetric analysis, and its releasing profile was assessed by high-performance liquid chromatographyusing baicalin (a flavonoid compound of SB as the marker. The mucosal diffusion assay on Nano-SB was undertaken in a porcine model. The antibacterial effects of the mixed nanoparticles (Nano-MIX of Nano-SB and Nano-CHX at 9:1 (w/w ratio were analyzed in both planktonic and biofilm modes of representative oral bacteria. The Nano-MIX was effective on the mono-species biofilms of Streptococcus (S. mutans, S. sobrinus, Fusobacterium (F. nucleatum, and Aggregatibacter (A. actinomycetemcomitans (MIC 50 μg/mL at 24 h, and exhibited an enhanced effect against the multi-species biofilms such as S. mutans, F. nucleatum, A. actinomycetemcomitans, and Porphyromonas (P. gingivalis (MIC 12.5 μg/mL at 24 h that was supported by the findings of both scanning electron microscopy (SEM and confocal scanning laser microscopy (CLSM. This study shows enhanced synergistic antibacterial effects of the Nano-MIX on common oral bacterial biofilms, which could be potentially developed as a novel antimicrobial agent for clinical oral/periodontal care.

  19. Theory of synergistic effects: Hill-type response surfaces as 'null-interaction' models for mixtures.

    Schindler, Michael

    2017-08-02

    The classification of effects caused by mixtures of agents as synergistic, antagonistic or additive depends critically on the reference model of 'null interaction'. Two main approaches are currently in use, the Additive Dose (ADM) or concentration addition (CA) and the Multiplicative Survival (MSM) or independent action (IA) models. We compare several response surface models to a newly developed Hill response surface, obtained by solving a logistic partial differential equation (PDE). Assuming that a mixture of chemicals with individual Hill-type dose-response curves can be described by an n-dimensional logistic function, Hill's differential equation for pure agents is replaced by a PDE for mixtures whose solution provides Hill surfaces as 'null-interaction' models and relies neither on Bliss independence or Loewe additivity nor uses Chou's unified general theory. An n-dimensional logistic PDE decribing the Hill-type response of n-component mixtures is solved. Appropriate boundary conditions ensure the correct asymptotic behaviour. Mathematica 11 (Wolfram, Mathematica Version 11.0, 2016) is used for the mathematics and graphics presented in this article. The Hill response surface ansatz can be applied to mixtures of compounds with arbitrary Hill parameters. Restrictions which are required when deriving analytical expressions for response surfaces from other principles, are unnecessary. Many approaches based on Loewe additivity turn out be special cases of the Hill approach whose increased flexibility permits a better description of 'null-effect' responses. Missing sham-compliance of Bliss IA, known as Colby's model in agrochemistry, leads to incompatibility with the Hill surface ansatz. Examples of binary and ternary mixtures illustrate the differences between the approaches. For Hill-slopes close to one and doses below the half-maximum effect doses MSM (Colby, Bliss, Finney, Abbott) predicts synergistic effects where the Hill model indicates 'null

  20. Anti-tumor effects of nitrosylcobalamin against spontaneous tumors in dogs.

    Bauer, Joseph A; Frye, Gerald; Bahr, Anne; Gieg, Jennifer; Brofman, Peter

    2010-10-01

    Given the limited options available to treat canine cancers, the use of companion animals for evaluating new drugs may identify better therapies for veterinary and human oncology. The anti-tumor effects of nitrosylcobalamin (NO-Cbl), an apoptosis-inducing, vitamin B12-based carrier of nitric oxide (NO), was evaluated in four dogs with spontaneous cancer. (1) A 13 year-old female spayed Giant Schnauzer with inoperable thyroid carcinoma and hypercalcemia. (2) A 6 year-old male neutered Golden Retriever with a malignant peripheral nerve sheath tumor (MPNST). (3) A ten yr-old neutered male Bichon Frise with apocrine gland anal sac adenocarcinoma (AGACA). (4) A 7 year-old female spayed Labrador mix with spinal meningioma following partial surgical resection. Tumor regression was measured by physical exam and verified using ultrasound (case 1) and MRI (case 2-4). Serum chemistries and hematologic parameters were monitored throughout the studies. (1) The Giant Schnauzer demonstrated a 77% reduction in tumor volume after ten weeks of daily NO-Cbl treatment. (2) The Golden Retriever demonstrated a 53% reduction in tumor volume after 15 months of daily NO-Cbl therapy. (3) The Bichon Frise demonstrated a 43% regression of the primary tumor and a 90% regression of an iliac lymph node measured by MRI after 15 months of treatment. After 61 months, the dog currently has stable disease, normal liver enzymes, CBC analysis, and no evidence of toxicity. (4) The Labrador demonstrated complete regression of the residual tumor after 6 months of treatment. We have shown previously that NO-Cbl is endocytosed by malignant cells, resulting in intra-tumoral NO release. In this study, we have shown that daily long-term use of NO-Cbl induced responses in all dogs without any signs of toxicity. The use of NO-Cbl capitalizes on the tumor-specific properties of the vitamin B12 receptor and represents a promising anti-cancer therapy.

  1. Antioxidative and Antitumor Effects of Isoflavones Isolated from the Leaves of Maackia fauriei .

    Ki Hoon Yoon

    2016-01-01

    Full Text Available The flowers of Maackia fauriei have traditionally been used to treat hypertension, apoplexy, hemostasis, vaginal bleeding, and dystocia; moreover, the bark of this plant has been used as a natural dye. In the present study, activity-guided isolation of the leaves of M. fauriei yielded five isoflavones [genistein (1, pratensein (2, genistin (3, 2'-hydroxygenistein-7-O-β-D-glucopyranoside (4, and 2,3-dehydrokievitone (5]; three pterocarpans [medicarpin (6, maackiain (7, and 4-hydroxy maackiain (8]; and one flavonol [isoquercitrin (9]. To evaluate the anti-oxidative effects of these compounds, their 1,1-diphenyl-2-picryl-hydrazyl (DPPH radical scavenging assays and nitrotetrazolium blue chloride (NBT superoxide scavenging assays were measured. And the anti-tumor activity against human cancer cell lines in genital system, LNCaP, PC-3,HeLa and OVCAR-3 cells were evaluated by MTT method. Furthermore, the apoptosis of the PC-3 and HeLa cells were determined by by annexin V-FITC and PI their fluorescence was analyzed by flow cytometry. The flavonol (9, isoquercitrin and pterocarpan (8, 4-hydroxymaackiain showed strong anti-oxidative activities. Besides, the isoflavones (1-5 did not showed anti-oxidative activity and the isoflavones (1-5 and pterocarpans (6-8 generally showed the potent cytotoxic activity against all of four human genital cancer cells. Especially, 2,3-dehydrokievitone (5 which had a prenyl group at C-8 position of the A-ring exhibited strong cytotoxic activity and induced apoptosis efficiently in cancer cells.

  2. Electrosensitization Increases Antitumor Effectiveness of Nanosecond Pulsed Electric Fields In Vivo.

    Muratori, Claudia; Pakhomov, Andrei G; Heller, Loree; Casciola, Maura; Gianulis, Elena; Grigoryev, Sergey; Xiao, Shu; Pakhomova, O N

    2017-01-01

    Nanosecond pulsed electric fields are emerging as a new modality for tissue and tumor ablation. We previously reported that cells exposed to pulsed electric fields develop hypersensitivity to subsequent pulsed electric field applications. This phenomenon, named electrosensitization, is evoked by splitting the pulsed electric field treatment in fractions (split-dose treatments) and causes in vitro a 2- to 3-fold increase in cytotoxicity. The aim of this study was to show the benefit of split-dose treatments for in vivo tumor ablation by nanosecond pulsed electric field. KLN 205 squamous carcinoma cells were embedded in an agarose gel or grown subcutaneously as tumors in mice. Nanosecond pulsed electric field ablations were produced using a 2-needle probe with a 6.5-mm interelectrode distance. In agarose gel, splitting a pulsed electric field dose of 300, 300-ns pulses (20 Hz, 4.4-6.4 kV) in 2 equal fractions increased cell death up to 3-fold compared to single-train treatments. We then compared the antitumor effectiveness of these treatments in vivo. At 24 hours after treatment, sensitizing tumors by a split-dose pulsed electric field exposure (150 + 150, 300-ns pulses, 20 Hz, 6.4 kV) caused a 4- and 2-fold tumor volume reduction as compared to sham and single-train treatments, respectively. Tumor volume reduction that exceeds 75% was 43% for split-dose-treated animals compared to only 12% for single-dose treatments. The difference between the 2 experimental groups remained statistically significant for at least 1 week after the treatment. The results show that electrosensitization occurs in vivo and can be exploited to assist in vivo cancer ablation.

  3. Pharmacological targeting of p53 through RITA is an effective antitumoral strategy for malignant pleural mesothelioma.

    Di Marzo, Domenico; Forte, Iris Maria; Indovina, Paola; Di Gennaro, Elena; Rizzo, Valeria; Giorgi, Francesca; Mattioli, Eliseo; Iannuzzi, Carmelina Antonella; Budillon, Alfredo; Giordano, Antonio; Pentimalli, Francesca

    2014-01-01

    Malignant mesothelioma, a very aggressive tumor associated to asbestos exposure, is expected to increase in incidence, and unfortunately, no curative modality exists. Reactivation of p53 is a new attractive antitumoral strategy. p53 is rarely mutated in mesothelioma, but it is inactivated in most tumors by the lack of p14(ARF). Here, we evaluated the feasibility of this approach in pleural mesothelioma by testing RITA and nutlin-3, two molecules able to restore p53 function through a different mechanism, on a panel of mesothelioma cell lines representing the epithelioid (NCI-H28, NCI-H2452, IST-MES 2), biphasic (MSTO-211H), and sarcomatoid (NCI-H2052) histotypes compared with the normal mesothelial HMC-hTERT. RITA triggered robust caspase-dependent apoptosis specifically in epithelioid and biphasic mesothelioma cell lines, both through wild-type and mutant p53, concomitant to p21 downregulation. Conversely, nutlin-3 induced a p21-dependent growth arrest, rather than apoptosis, and was slightly toxic on HMC-hTERT.   Interestingly, we identified a previously undetected point mutation of p53 (p.Arg249Ser) in IST-MES 2, and showed that RITA is also able to reactivate this p53 mutant protein and its apoptotic function. RITA reduced tumor growth in a MSTO-211H-derived xenograft model of mesothelioma and synergized with cisplatin, which is the mainstay of treatment for this tumor. Our data indicate that reactivation of p53 and concomitant p21 downregulation effectively induce cell death in mesothelioma, a tumor characterized by a high intrinsic resistance to apoptosis. Altogether, our findings provide the preclinical framework supporting the use of p53-reactivating agents alone, or in combination regimens, to improve the outcome of patients with mesothelioma.

  4. Expression of Momordica charantia MAP30 and its antitumor effect on bladder cancer cells.

    Hlin, Hao; Zhi-Guo, Zhang; Cong-Hui, Han; Yan, Zhao; Qing, Liang; Bo, Jiang; Hou-Guang, He; Jun-Jie, Zhang; Pei-Ying, Zhang

    2016-06-01

    Momordica charantia (MC) is an edible medicinal plant that is known for its diversified biological functions. Momordica Antiviral Protein 30kD (MAP30) is a type I single chain ribosome-inactivating protein (RIP) isolated from the mature fruit and seeds of MC. Since MAP30 content in MC is limited, the study aim was to generate the recombinant MAP30 protein using prokaryotic expression system and determine its apoptotic/growth inhibitory effects on bladder cancer 5637 cells. MAP30 gene was amplified by PCR from MC genomic DNA and identified by sequencing. The target gene was inserted into pET-28a (+) vector and transformed into E. coli BL21 (DE3) cells. Positive clones were selected by PCR. Recombinant protein was efficiently expressed under induction with 1.0 mM Isopropylthio-β-D-galactoside (IPTG) at 30° C for 4 hours. Cytotoxicity studies were performed using MTT assay by treating 5637 bladder cancer cells with 100 µg/mL, 200 µg/mL, and 400 µg/mL concentrations of MAP30 for 24 hours and 48 hours, respectively. Flow cytometry was used to measure the apoptosis of MAP30-treatedcells in time course experiments. Full-length MAP30 gene was successfully expressed in Escherichia coli (E. coli) BL21 strain and MAP30 recombinant protein inhibited the growth of bladder cancer 5637 cells at 200 µg/mL and 400 µg/mL concentrations by inducing apoptosis of target cells in a dose- and time-dependent manner. It was, therefore, concluded that the MAP30 recombinant protein displayed potent antitumor activity in vitro.

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

    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.

  6. Synergistic effects of atmospheric pressure plasma-emitted components on DNA oligomers: a Raman spectroscopic study.

    Edengeiser, Eugen; Lackmann, Jan-Wilm; Bründermann, Erik; Schneider, Simon; Benedikt, Jan; Bandow, Julia E; Havenith, Martina

    2015-11-01

    Cold atmospheric-pressure plasmas have become of increasing importance in sterilization processes especially with the growing prevalence of multi-resistant bacteria. Albeit the potential for technological application is obvious, much less is known about the molecular mechanisms underlying bacterial inactivation. X-jet technology separates plasma-generated reactive particles and photons, thus allowing the investigation of their individual and joint effects on DNA. Raman spectroscopy shows that particles and photons cause different modifications in DNA single and double strands. The treatment with the combination of particles and photons does not only result in cumulative, but in synergistic effects. Profilometry confirms that etching is a minor contributor to the observed DNA damage in vitro. Schematics of DNA oligomer treatment with cold atmospheric-pressure plasma. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

    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

  8. Synergistic effect of alkaline pretreatment and Fe dosing on batch anaerobic digestion of maize straw

    Khatri, Shailendra; Wu, Shubiao; Kizito, Simon; Zhang, Wanqin; Li, Jiaxi; Dong, Renjie

    2015-01-01

    Highlights: • Synergistic effect of NaOH treatment and Fe dosage to maize straw was investigated. • Combining NaOH treatment and Fe dosing resulted in 57% and 56% higher biogas and methane yield respectively. • Combined treatment shortened the technical digestion time from 48 days to 7 days. • Methane content did not differ significantly among the straw treatments. - Abstract: The synergistic effect of alkaline pretreatment and Fe dosing on anaerobic digestion of maize straw was investigated using mesophilic batch reactors. Three straw treatments were investigated as follows: NaOH (4% and 6%) pretreatment, Fe dosage (50, 200, 1000 and 2000 mg/L), and combined NaOH pretreatment and Fe dosage. Compared to the control, NaOH pretreatment alone increased methane yield by 3.5% (313.3 mL CH_4/gVS) and 22.5% (370.9 mL CH_4/gVS) and shortened the technical digestion time (TDT) from 48 days to 19 days and 10 days in 4% NaOH and 6% NaOH pretreatment respectively. Moreover, Fe dosing (200–1000 mg/L) alone gave a methane yield higher (9.4%) than that obtained from 4% NaOH and 7.5% less than the methane yield from 6% NaOH pretreatment; however, the TDT was 10 days longer. Combining NaOH pretreatment and Fe dosage (200–1000 mg/L) significantly increased the methane yield even further to 21.8% (368.8 mL CH_4/gVS) and 56.2% (472.9 mL CH_4/gVS), and shortened TDT from 48 days to 13 days and 7 days in 4% NaOH and 6% NaOH pretreatment respectively. This synergistic effect may be attributed to the fact that the alkaline treatment improved accessibility of the biodegradable fraction of the straw while Fe contributed to increased microbial enzyme activity.

  9. Synergistic effects of some essential oils against fungal spoilage on pear fruit.

    Nikkhah, Mehdi; Hashemi, Maryam; Habibi Najafi, Mohammad B; Farhoosh, Reza

    2017-09-18

    The development of natural protective agents as alternatives to chemical fungicides is currently in the spotlight. In the present investigation, chemical composition and antifungal activities of thyme, cinnamon, rosemary and marjoram essential oils (EO), as well as synergism of their possible double and triple combinations were investigated. The compositions of the oils were determined by GC/MS. For determination of antifungal activity against Penicillium expansum and Botrytis cinerea, a broth microdilution method was used. The possible interactions of some essential oil combinations were performed by the two and three-dimensional checkerboard assay and isobologram construction. An in vivo antifungal assay was performed by artificial wounding of pear fruits. The maximum antifungal activity was demonstrated by thyme and cinnamon oils which displayed lower MIC values whereas rosemary and marjoram oils with MIC range between 2500 and 10,000μg/mL exhibited weak antifungal activities against tested fungi. In synergy testing, some double combinations (thyme/cinnamon, thyme/rosemary, cinnamon/rosemary) were found to be synergistic (FICi≤0.5). The triple combination of thyme, cinnamon and rosemary was synergistic for B. cinerea and P. expansum (FICi values of 0.5 and 0.375, respectively); while combination of cinnamon, marjoram and thyme exhibited additive and synergistic effect against P. expansum (FIC=0.625) and B. cinerea (FIC=0.375) respectively. The usage of a mathematical Gompertz model in relation to fungal kinetics, showed that the model could be used to predict growth curves (R 2 =0.993±0.05). For B. cinerea, Gompertz parameters for double and triple combination treatments showed significant increase in lag phase (1.92 and 2.92days, respectively) compared to single treatments. Increase lag time up to 2.82days (P<0.05) also observed in P. expansum treated by triple combination of EOs. Base on the results, the lowest maximum growth rate (0.37mm/day) was observed

  10. Anomalous water dynamics at surfaces and interfaces: synergistic effects of confinement and surface interactions

    Biswas, Rajib; Bagchi, Biman

    2018-01-01

    In nature, water is often found in contact with surfaces that are extended on the scale of molecule size but small on a macroscopic scale. Examples include lipid bilayers and reverse micelles as well as biomolecules like proteins, DNA and zeolites, to name a few. While the presence of surfaces and interfaces interrupts the continuous hydrogen bond network of liquid water, confinement on a mesoscopic scale introduces new features. Even when extended on a molecular scale, natural and biological surfaces often have features (like charge, hydrophobicity) that vary on the scale of the molecular diameter of water. As a result, many new and exotic features, which are not seen in the bulk, appear in the dynamics of water close to the surface. These different behaviors bear the signature of both water-surface interactions and of confinement. In other words, the altered properties are the result of the synergistic effects of surface-water interactions and confinement. Ultrafast spectroscopy, theoretical modeling and computer simulations together form powerful synergistic approaches towards an understanding of the properties of confined water in such systems as nanocavities, reverse micelles (RMs), water inside and outside biomolecules like proteins and DNA, and also between two hydrophobic walls. We shall review the experimental results and place them in the context of theory and simulations. For water confined within RMs, we discuss the possible interference effects propagating from opposite surfaces. Similar interference is found to give rise to an effective attractive force between two hydrophobic surfaces immersed and kept fixed at a separation of d, with the force showing an exponential dependence on this distance. For protein and DNA hydration, we shall examine a multitude of timescales that arise from frustration effects due to the inherent heterogeneity of these surfaces. We pay particular attention to the role of orientational correlations and modification of the

  11. Synergistic bactericidal effect by combined exposure to Ag nanoparticles and UVA

    Zhao, Xiaoxu; Toyooka, Tatsushi; Ibuki, Yuko, E-mail: ibuki@u-shizuoka-ken.ac.jp

    2013-08-01

    Broad and strong antimicrobial properties of silver (Ag) have been used for biomedical applications, water treatment, etc. In this study, a synergistic antibacterial effect between Ag nanoparticles (AgNPs) and ultraviolet (UV) light was examined. AgNPs (< 0.1 μm) with subsequent exposure to UVA (320–400 nm) showed pronounced toxicity in Escherichia coli, but micro-sized Ag particles (> 1 μm) with UVA and AgNPs with UVB (280–325 nm) did not. As significant bactericidal activity was also exhibited by hydrogen peroxide-treated AgNPs, the surface oxidation of AgNPs caused by UVA irradiation was considered to contribute to the enhanced antibacterial effect. Although no difference in NP-incorporation rates was observed with or without the surface oxidation of AgNPs, a particle size of less than 0.1 μm was a factor for AgNPs uptake and an essential requirement for the antimicrobial function of Ag particles. Incorporated AgNPs oxidized by UVA irradiation released larger amounts of Ag ion inside cells than reduced AgNPs, which reacted with intercellular molecules having –SH groups such as glutathione. The synergistic use of AgNPs and UVA could become a powerful tool with broad antimicrobial applications. Highlights: • Combined treatment with AgNPs and UV achieved a remarkable antibacterial effect in E. coli. • For the antibacterial effect, it is necessary to satisfy the following requirements: • 1) Translocation of nano-sized Ag particles inside E. coli. • 2) Oxidation of AgNPs by UVA, and extensive and persistent release of Ag{sup +} inside E. coli. • Ag{sup +} released inside cells reacted with intercellular molecules having –SH groups such as GSH.

  12. Synergistic effects of tacrolimus and azole antifungal compounds in fluconazole-susceptible and fluconazole-resistant Candida glabrata isolates

    Laura Bedin Denardi

    2015-03-01

    Full Text Available In vitro interaction between tacrolimus (FK506 and four azoles (fluconazole, ketoconazole, itraconazole and voriconazole against thirty clinical isolates of both fluconazole susceptible and -resistant Candida glabrata were evaluated by the checkerboard microdilution method. Synergistic, indifferent or antagonism interactions were found for combinations of the antifungal agents and FK506. A larger synergistic effect was observed for the combinations of FK506 with itraconazole and voriconazole (43%, followed by that of the combination with ketoconazole (37%, against fluconazole-susceptible isolates. For fluconazole-resistant C. glabrata, a higher synergistic effect was obtained from FK506 combined with ketoconazole (77%, itraconazole (73%, voriconazole (63% and fluconazole (60%. The synergisms that we observed in vitro, notably against fluconazole-resistant C. glabrata isolates, are promising and warrant further analysis of their applications in experimental in vivo studies.

  13. Synergistic effects of remote perconditioning with terminal blood cardioplegia in an in vivo piglet model.

    Abe, Takayuki; Morita, Kiyozo; Shinohara, Gen; Hashimoto, Kazuhiro; Nishikawa, Masako

    2017-09-01

    This study tested the hypothesis that remote perconditioning offers effective and synergistic cardioprotection to terminal warm blood cardioplegia for prompt ventricular recovery after prolonged cardioplegic arrest in an in vivo piglet model. Twenty-four piglets were subjected to 120 min of single-dose cardioplegic arrest and were divided into 4 groups according to the mode of reperfusion: control (simple aortic unclamp), remote perconditioning, terminal warm blood cardioplegia or remote perconditioning + terminal warm blood cardioplegia; remote perconditioning (4 cycles of 5-min ischaemia-reperfusion of the lower limb) was applied prior to aortic unclamping. Left ventricular systolic and diastolic functions were assessed by pressure-volume loop analysis at baseline and after 60 min of reperfusion. Biochemical injury was evaluated by plasma troponin T level. The control group showed decreased end-systolic elastance, preload recruitable stroke work and inverse of end-diastolic pressure-volume relationship of 51.3 ± 14.0%, 46.1 ± 22.5% and 34.8 ± 14.9%, respectively. Percentage recovery of end-systolic elastance and preload recruitable stroke work were significantly better with terminal warm blood cardioplegia (with or without remote perconditioning) (end-systolic elastance: 95% confidence interval, 38.6-84.1; preload recruitable stroke work: 95% confidence interval, 0.4-54.3). Percentage recovery of inverse of end-diastolic pressure-volume relationship was significantly better in the remote perconditioning groups (with or without terminal warm blood cardioplegia) (95% confidence interval, 1.6-41.6). No synergistic effects of remote perconditioning and terminal warm blood cardioplegia on troponin T release were noted. Remote perconditioning offers promising synergistic cardioprotection to terminal warm blood cardioplegia, implicating potential clinical benefit by contributing to prompt left ventricular functional recovery during paediatric open

  14. Characterization of silver nanoparticles synthesized using Urtica dioica Linn. leaves and their synergistic effects with antibiotics

    Kumari Jyoti

    2016-07-01

    Full Text Available In continuation of the efforts for synthesizing silver nanoparticles (AgNPs by green chemistry route, here we report a facile bottom-up ‘green’ route for the synthesis of AgNPs using aqueous leaves extract of Urtica dioica (Linn.. The synthesized AgNPs were characterized by UV-vis spectroscopy, X-ray diffraction (XRD, Fourier transform-infrared spectroscopy (FTIR, Zeta-sizer and Zeta-potential, Scanning electron microscopy (SEM, Energy dispersive X-ray (EDX spectroscopy, Transmission electron microscopy (TEM and Selected area electron diffraction (SAED. The results obtained from various characterizations revealed that AgNPs were in the size range of 20–30 nm and crystallized in face-centered-cubic structure. The antibacterial activity against Gram-positive (Bacillus cereus, Bacillus subtilis, Staphylococcus aureus and Staphylococcus epidermidis and Gram-negative (Escherichia coli, Klebsiella pneumoniae, Serratia marcescens and Salmonella typhimurium bacterial pathogens was demonstrated by synthesized nanoparticles. Further, synergistic effects of AgNPs with various antibiotics were evaluated against above mentioned bacterial pathogens. The results showed that AgNPs in combination with antibiotics have better antibacterial effect as compared with AgNPs alone and hence can be used in the treatment of infectious diseases caused by bacteria. The maximum effect, with a 17.8 fold increase in inhibition zone, was observed for amoxicillin with AgNPs against S. marcescens proving the synergistic role of AgNPs. Therefore, it may be used to augment the activities of antibiotics.

  15. Synergistic effect of solar radiation and solar heating to disinfect drinking water sources.

    Rijal, G K; Fujioka, R S

    2001-01-01

    Waterborne diseases are still common in developing countries as drinking water sources are contaminated and feasible means to reliably treat and disinfect these waters are not available. Many of these developing countries are in the tropical regions of the world where sunlight is plentiful. The objective of this study was to evaluate the effectiveness of combining solar radiation and solar heating to disinfect contaminated water using a modified Family Sol*Saver System (FSP). The non-UV transmittable cover sheet of the former FSP system was replaced with an UV transmittable plastic cover sheet to enable more wavelengths of sunlight to treat the water. Disinfection efficiency of both systems was evaluated based on reduction of the natural populations of faecal coliform, E. coli, enterococci, C. perfringens, total heterotrophic bacteria, hydrogen sulphide producing bacteria and FRNA virus. The results showed that under sunny and partly sunny conditions, water was heated to critical temperature (60 degrees C) in both the FSP systems inactivating more than 3 log (99.9%) of the concentrations of faecal coliform and E. coli to undetectable levels of heat worked synergistically to enhance the inactivation of faecal indicator bacteria. The relative log removal of indicator microorganism in the FSP treated water was total heterotrophic bacteria heat and radiation effects of sunlight were important in disinfecting water by solar units. The data indicated that direct radiation of sunlight worked synergistically with solar heating of the water to disinfect the water. Thus, effective disinfection was observed even when the water temperature did not reach 60 degrees C. Finally, the hydrogen sulphide test is a simple and reliable test that householders can use to determine whether their water had been sufficiently disinfected.

  16. Synergistic effect of some essential oils on toxicity and knockdown effects, against mosquitos, cockroaches and housefly

    Idin Zibaee

    2015-12-01

    Full Text Available The toxicity and knockdown effect of Eucalyptus globulus, Rosmarinus officinalis essential oils and their mixed formulation on Periplaneta Americana (L., Blattella germanica (L., Supella longipalpa, Culex pipiens, Anopheles stephensi and Musca domestica were evaluated in a series of laboratory experiments. In all bioassay five different doses (0.625, 1.25, 2.5, 5 and 10% were used by filter paper (cm2 and aerosol (cm3 bioassay methods, all essential oils was toxic to cockroaches, mosquitos and housefly species the lowest and the highest LC50 belong to mixed formulation on B. germanica (LC50 6.1 and E. globulus on P. americana (LC50 27.7 respectively. In continuous exposure experiments, Mortality (LT50 values for cockroaches ranged from 1403.3 min with 0.625% E. globulus (for P. americana to 2.2 min with 10% mixed formulation for A. stephensi. The KT50 values ranged from 0.1 to 1090.8 min for 10% and 0.625 for mixed formulation and R. officinalis respectively. The mortality after 24 h for mixed formulation was 100% but for single essential oils ranged from 81.5 to 98.3 for P. americana treated with R. officinalis and A. stephensi treated with E. globulus respectively. Studies on persistence of essential oils on impregnated paper revealed that it has more adulticidal activity for longer period at low storage temperature. Gas chromatographic-mass spectrometric analysis of essential oil showed 14 and 16 peaks for E. globules and R. officinalis respectively. α-Pinene (39.8%, 1, 8-Cineole (13.2%, Camphene (9.1% and Borneol (3.7% were present in major amounts for R. officinalis and 1,8-Cineole (31.4%, α-Pinene (15.3%, d-Limonene (9.7% and α-Terpinolen (5.3% were present in major amounts for E. globulus respectively. Our results showed that two surveyed essential oils has compatible with synergistic effect on various insect species, furthermore it is useful for applying as integrated pest management tool for studied insects management, especially in

  17. Intelligently targeted drug delivery and enhanced antitumor effect by gelatinase-responsive nanoparticles.

    Rutian Li

    Full Text Available AIMS: The matrix metalloproteinase (MMP 2/9, also known as collagenases IV and gelatinases A/B, play a key role in cancer invasion and metastasis. However, the clinical trials of the MMP inhibitors (MMPIs ended up with disappointing results. In this paper, we synthesized a gelatinase-responsive copolymer (mPEG-PCL by inserting a gelatinase cleavable peptide (PVGLIG between mPEG and PCL blocks of mPEG-PCL for anticancer drug delivery to make use of MMP2/9 as an intelligent target for drug delivery. MATERIALS AND METHODS: mPEG-pep-PCL copolymer was synthesized via ring-opening copolymerization and double-amidation. To evaluate whether Nanoparticles (NPs prepared from this copolymer are superior to NPs prepared from mPEG-PCL, NPs prepared from mPEG-PCL copolymer were used as positive control. Docetaxel-loading NPs using mPEG-pep-PCL and mPEG-PCL were prepared by nano-precipitation method, mentioned as Gel-NPs and Con-NPs, respectively. The morphologic changes of the NPs after treatment with gelatinases were observed macroscopically by spectrophotometer and microscopically by transmission electron microscopy (TEM and atomic force microscopy (AFM. The cellular uptake amount and cytotoxicity of Gel-NPs and Con-NPs, respectively, in cell lines with different levels of gelatinase expression were studied. Moreover, the cytotoxicity study on the primary cancer cells isolated from pericardial fluids from a patient with late-stage lung cancer was conducted. RESULTS: The Gel-NPs aggregated in response to gelatinases, which was confirmed macroscopically and microscopically. The cellular uptake amount of Gel-NPs was correlated with the level of gelatinases. The in vitro antitumor effect of Gel-NPs was also correlated with the level of gelatinases and was superior to Taxotere (commercially available docetaxel as well as the Con-NPs. The cytotoxicity study on the primary lung cancer cells also confirmed the effectiveness of Gel-NPs. CONCLUSION: The results in

  18. Antitumor and radiation protection effects of β-1,3-D-glucan extracted from yeast (saccharomyces cerevisiae)

    Yoshimura, Akinobu; Hasegawa, Takeo; Monzen, Hajime; Takahashi, Tohru

    2003-01-01

    Various natural extracts are manufactured and on sale as health food products, which are raising popular consciousness of being fit, because they are considered effective or suppressible for cancer. In the current experiment, we measured the immunological activity, antitumor effects, and radioprotective effects of β-1,3-D-glucan (Macroglucan) extracted from bread yeast. Macroglucan of 0, 200, 400, and 800 mg/kg were administered intraperitoneally to C3H/HeJ mice, respectively. The antitumor effects of Macroglucan were examined by measuring natural killer (NK) and lymphokine activated killer (LAK) cell activity and tumor volume. Change in weight, survival, and microscopic manifestation of the intestine were evaluated in the C3H/HeJ mice received total body irradiation to measure radioprotective effect of Macroglucan. According to measurements of cellular cytotoxicity, levels of NK and LAK cell activity were significantly higher in the group administered Macroglucan than in the control group. Macroglucan's role in immunological activity was suggested by the observed suppression of tumor growth in the Macroglucan-administered group. That group also experienced suppression of weight loss after irradiation in the experiment for radioprotection, and a consequent increase in the survival rate compared with the control group. Protective effects appeared in photomicrographs of the intestinal cells. These results confirmed Macroglucan's radioprotective effects. These effects may be related to the suppression of infection accompanying immunological activation due to Macroglucan administration, antioxidant activity, and radical scavenging capacity. (author)

  19. Synergistic Effect of Auto-Activation and Small RNA Regulation on Gene Expression

    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.

  20. Synergistic Effect of Auto-Activation and Small RNA Regulation on Gene Expression

    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

  1. Synergistic effects of zinc borate and aluminium trihydroxide on flammability behaviour of aerospace epoxy system

    2009-06-01

    Full Text Available The flame retardancy of mono-component epoxy resin (RTM6, widely used for aerospace composites, treated with zinc borate (ZB, aluminium trihydroxide (ATH and their mixtures at different concentrations have been investigated by morphological and thermal characterization. Cone calorimeter data reveal that combustion behaviour, heat release rate peak (PHRR and heat release rate average (HRR Average of RTM6 resin decrease substantially when synergistic effects of zinc borate and aluminium trihydroxide intervene. Thermogravimetric (TGA results and analysis of the residue show that addition higher than 20% w/w of ZB, ATH, and their mixture greatly promotes RTM6 char formation acting as a barrier layer for the fire development. Depending upon the different used flame additives, SEM micrographs indicate that the morphology of residual char could vary from a compact amalgam-like structure, for the RTM6+ZB system, to a granular structure, characterized by very small particles of degraded resin and additive for the ATH.

  2. Synergistic Effect of Copper and Cobalt in Cu-Co-O Composite Nanocatalyst for Catalytic Ozonation

    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

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

    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.

  4. Synergistic effects of altered salinity and temperature on estuarine eelgrass (Zostera marina) seedlings and clonal shoots

    Salo, Tiina Elina; Pedersen, Morten Foldager

    2014-01-01

    investigated experimentally how different combinations of salinity and temperature affect the physiological performance of adult eelgrass (Zostera marina) shoots and seedlings. Plants were exposed to different combinations of salinity (salinity 5, 12.5 and 20) and temperature (15, 20 and 25 °C) in a 5-week...... and temperature. Seedlings had higher absolute mortality, while adult shoots were relatively more sensitive to unfavorable levels of salinity. Leaf tissue sucrose concentrations in both life stages decreased at low salinity, whereas salinity and temperature resulted in contrasting starch concentrations between...... seedlings and adult shoots. Our results show that altered salinity and temperature may have negative synergistic effects on eelgrass performance. Future climate changes may thus have serious impacts on eelgrass survival and performance....

  5. Synergistic Effect of Combined Hollow Viscus Injuries on Intra-Abdominal Abscess Formation.

    Paulus, Elena M; Croce, Martin A; Shahan, Charles P; Zarzaur, Ben L; Sharpe, John P; Dileepan, Amirtha; Boyd, Brandon S; Fabian, Timothy C

    2015-07-01

    The strong association between penetrating colon injuries and intra-abdominal abscess (IAA) formation is well established and attributed to high colon bacterial counts. Since trauma patients are rarely fasting at injury, stomach and small bowel colony counts are also elevated. We hypothesized that there is a synergistic effect of increased IAA formation with concomitant stomach and/or colon injuries when compared to small bowel injuries alone. Consecutive patients at a level one trauma center with penetrating small bowel (SB), stomach (S), and/or colon (C) injuries from 1996 to 2012 were reviewed. Logistic regression determined associations with IAA, adjusting for age, gender, Injury Severity Score (ISS), admission Glasgow Coma Score, transfusions, and concurrent pancreas or liver injury. A total of 1518 patients (91% male, ISS = 15.9 ± 8.4) were identified: 496 (33%) SB, 231 (15%) S, 288 (19%) C, 40 (3%) S + SB, 69 (5%) S + C, 338 (22%) C + SB, and 56 (4%) S + C + SB. 148 (10%) patients developed IAA: 4 per cent SB, 9 per cent S, 10 per cent C, 5 per cent S + SB, 22 per cent S + C, 13 per cent C + SB, and 25 per cent S + C + SB. Multiple logistic regression demonstrated that ISS, 24 hour blood transfusions, and concomitant pancreatic or liver injuries were associated with IAA. Compared with reference SB, S or S + SB injuries were no more likely to develop IAA. However, S + C, SB + C, and S + C + SB injuries were significantly more likely to have IAA. In conclusion, combined stomach + colon, small bowel + colon, and stomach, colon, + small bowel injuries have a synergistic effect leading to increased IAA formation after penetrating injuries. Heightened clinical suspicion for IAA formation is necessary in these combined hollow viscus injury patients.

  6. Radioactive EGFR Antibody Cetuximab in Multimodal Cancer Treatment: Stability and Synergistic Effects With Radiotherapy

    Rades, Dirk; Wolff, Christian; Nadrowitz, Roger; Breunig, Christian; Schild, Steven E.; Baehre, Manfred; Meller, Birgit

    2009-01-01

    Purpose: Systemic therapies when added to whole brain radiotherapy have failed to improve the survival of patients with multiple brain metastases. The epidermal growth factor receptor antibody cetuximab is an attractive option, if it is able to cross the blood-brain barrier. This might be proven with molecular imaging if the radiolabeled antibody is stable long enough to be effective. This study investigated the stability of radiolabeled cetuximab (Erbitux) ( 131 I-Erbi) and potential synergistic effects with radiotherapy in vitro. Methods and Materials: Two cell lines were investigated, A431 with numerous epidermal growth factor receptors, and JIMT without epidermal growth factor receptors. We labeled 0.4 mg cetuximab with 50 MBq of [ 131 I] iodide. Stability was determined for 72 h. The cell cultures were incubated with 131 I-Erbi or cold cetuximab for 72 h. Uptake and cell proliferation were measured every 24 h after no radiotherapy or irradiation with 2, 4, or 10 Gy. Results: The radiolabeling yield of 131 I-Erbi was always >80%. The radiochemical purity was still 93.6% after 72 h. A431 cells showed a 131 I-Erbi uptake about 100-fold greater than the JIMT controls. After 48 h, the A431 cultures showed significantly decreased proliferation. At 72 h after irradiation, 131 I-Erbi resulted in more pronounced inhibition of cell proliferation than the cold antibody in all radiation dose groups. Conclusion: 131 I-Erbi was stable for ≤72 h. Radiotherapy led to increased tumor cell uptake of 131 I-Erbi. Radiotherapy and 131 I-Erbi synergistically inhibited tumor cell proliferation. These results provide the prerequisite data for a planned in vivo study of whole brain radiotherapy plus cetuximab for brain metastases.

  7. Antitumor effects of regorafenib and sorafenib in preclinical models of hepatocellular carcinoma

    Kissel, Maria; Berndt, Sandra; Fiebig, Lukas; Kling, Simon; Ji, Qunsheng; Gu, Qingyang; Lang, Tina; Hafner, Frank-Thorsten; Teufel, Michael; Zopf, Dieter

    2017-01-01

    The purpose of this study was to investigate the antitumor activity of regorafenib and sorafenib in preclinical models of HCC and to assess their mechanism of action by associated changes in protein expression in a HCC-PDX mouse model. Both drugs were administered orally once daily at 10 mg/kg (regorafenib) or 30 mg/kg (sorafenib), which recapitulate the human exposure at the maximally tolerated dose in mice. In a H129 hepatoma model, survival times differed significantly between regorafenib ...

  8. Effects of a piperidine ligand on DNA modification by antitumor cisplatin analogues

    Kašpárková, Jana; Nováková, Olga; Najajreh, Y.; Gibson, D.; Perez, J.M.; Brabec, Viktor

    2003-01-01

    Roč. 16, č. 11 (2003), s. 1424-1432 ISSN 0893-228X R&D Projects: GA ČR GA305/02/1552; GA AV ČR KJB5004301; GA AV ČR IBS5004009 Institutional research plan: CEZ:AV0Z5004920 Keywords : DNA * piperidine ligand * antitumor cisplatin analogues Subject RIV: BO - Biophysics Impact factor: 3.332, year: 2003

  9. Antitumor activity and systemic effects of PVM/MA-shelled selol nanocapsules in lung adenocarcinoma-bearing mice

    De Souza, Ludmilla Regina; Muehlmann, Luis Alexandre; Matos, Lívia Carneiro; Lacava, Zulmira Guerreiro Marques; Báo, Sônia Nair; Azevedo, Ricardo Bentes; Simón-Vázquez, Rosana; González-Fernández, África; De-Paula, Alfredo Maurício Batista; Mosiniewicz-Szablewska, Ewa; Suchocki, Piotr; Morais, Paulo César

    2015-01-01

    Selol is a semi-synthetic compound containing selenite that is effective against cancerous cells and safer for clinical applications in comparison with other inorganic forms of selenite. Recently, we have developed a formulation of poly(methyl vinyl ether-co-maleic anhydride)-shelled selol nanocapsules (SPN), which reduced the proliferative activity of lung adenocarcinoma cells and presented little deleterious effects on normal cells in in vitro studies. In this study, we report on the antitumor activity and systemic effects induced by this formulation in chemically induced lung adenocarcinoma-bearing mice. The in vivo antitumor activity of the SPN was verified by macroscopic quantification, immunohistochemistry and morphological analyses. Toxicity analyses were performed by evaluations of the kidney, liver, and spleen; analyses of hemogram and plasma levels of alanine aminotransferase, aspartate transaminase, urea, and creatinine; and DNA fragmentation and cell cycle activity of the bone marrow cells. Furthermore, we investigated the potential of the SPN formulation to cause hemolysis, activate the complement system, provoke an inflammatory response and change the conformation of the plasma proteins. Our results showed that the SPN reduced the area of the surface tumor nodules but not the total number of tumor nodules. The biochemical and hematological findings were suggestive of the low systemic toxicity of the SPN formulation. The surface properties of the selol nanocapsules point to characteristics that are consistent with the treatment of the tumors in vivo: low hemolytic activity, weak inflammatory reaction with no activation of the complement system, and mild or absent conformational changes of the plasma proteins. In conclusion, this report suggests that the SPN formulation investigated herein exhibits anti-tumoral effects against lung adenocarcinoma in vivo and is associated with low systemic toxicity and high biocompatibility. (paper)

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

    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.

  11. Strong and Nonspecific Synergistic Antibacterial Efficiency of Antibiotics Combined with Silver Nanoparticles at Very Low Concentrations Showing No Cytotoxic Effect.

    Panáček, Aleš; Smékalová, Monika; Kilianová, Martina; Prucek, Robert; Bogdanová, Kateřina; Večeřová, Renata; Kolář, Milan; Havrdová, Markéta; Płaza, Grażyna Anna; Chojniak, Joanna; Zbořil, Radek; Kvítek, Libor

    2015-12-28

    The resistance of bacteria towards traditional antibiotics currently constitutes one of the most important health care issues with serious negative impacts in practice. Overcoming this issue can be achieved by using antibacterial agents with multimode antibacterial action. Silver nano-particles (AgNPs) are one of the well-known antibacterial substances showing such multimode antibacterial action. Therefore, AgNPs are suitable candidates for use in combinations with traditional antibiotics in order to improve their antibacterial action. In this work, a systematic study quantifying the synergistic effects of antibiotics with different modes of action and different chemical structures in combination with AgNPs against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus was performed. Employing the microdilution method as more suitable and reliable than the disc diffusion method, strong synergistic effects were shown for all tested antibiotics combined with AgNPs at very low concentrations of both antibiotics and AgNPs. No trends were observed for synergistic effects of antibiotics with different modes of action and different chemical structures in combination with AgNPs, indicating non-specific synergistic effects. Moreover, a very low amount of silver is needed for effective antibacterial action of the antibiotics, which represents an important finding for potential medical applications due to the negligible cytotoxic effect of AgNPs towards human cells at these concentration levels.

  12. Antitumor effect of novel anti-podoplanin antibody NZ-12 against malignant pleural mesothelioma in an orthotopic xenograft model.

    Abe, Shinji; Kaneko, Mika Kato; Tsuchihashi, Yuki; Izumi, Toshihiro; Ogasawara, Satoshi; Okada, Naoto; Sato, Chiemi; Tobiume, Makoto; Otsuka, Kenji; Miyamoto, Licht; Tsuchiya, Koichiro; Kawazoe, Kazuyoshi; Kato, Yukinari; Nishioka, Yasuhiko

    2016-09-01

    Podoplanin (aggrus) is highly expressed in several types of cancers, including malignant pleural mesothelioma (MPM). Previously, we developed a rat anti-human podoplanin mAb, NZ-1, and a rat-human chimeric anti-human podoplanin antibody, NZ-8, derived from NZ-1, which induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against podoplanin-positive MPM cell lines. In this study, we showed the antitumor effect of NZ-1, NZ-8, and NZ-12, a novel rat-human chimeric anti-human podoplanin antibody derived from NZ-1, in an MPM orthotopic xenograft SCID mouse model. Treatment with NZ-1 and rat NK (CD161a(+) ) cells inhibited the growth of tumors and the production of pleural effusion in NCI-H290/PDPN or NCI-H226 orthotopic xenograft mouse models. NZ-8 and human natural killer (NK) (CD56(+) ) cells also inhibited tumor growth and pleural effusion in MPM orthotopic xenograft mice. Furthermore, NZ-12 induced potent ADCC mediated by human MNC, compared with either NZ-1 or NZ-8. Antitumor effects were observed following treatment with NZ-12 and human NK (CD56(+) ) cells in MPM orthotopic xenograft mice. In addition, combined immunotherapy using the ADCC activity of NZ-12 mediated by human NK (CD56(+) ) cells with pemetrexed, led to enhanced antitumor effects in MPM orthotopic xenograft mice. These results strongly suggest that combination therapy with podoplanin-targeting immunotherapy using both NZ-12 and pemetrexed might provide an efficacious therapeutic strategy for the treatment of MPM. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  13. Studies on The Synergistic Effect of Some Irradiated Essential Oils in Some Food Products

    Hanafy, M.A.A.

    2013-01-01

    Cumin, rosemary and thyme essential oils were gamma irradiated. Then, antibacterial and antioxidant activities were studied to measure the synergistic effect of their essential oils mixtures. 4, 6 and 4 kGy were the recommended doses for cumin, rosemary and thyme, respectively according to antimicrobial activity (agar well-diffusion) against S. typhimurium, S. aureus, B. cereus and E. coli. There were no changes in the physiochemical properties due to irradiation but, some changes occurred in the GC/MS analysis where, the amount of oxygenated compounds increased in cumin and thyme essential oils while, the oxygenated compounds decreased in rosemary essential oil. The mixture made from non-irradiated cumin (C 0 ) and rosemary (R 0 ) essential oils were showed the highest antimicrobial activity against E. coil and B. cereus at 50 μl. Mixtures made from non-irradiated cumin and thyme (T 0 ) essential oils showed the highest antimicrobial activity against B. cereus. Mixtures made form irradiated cumin at dose 4 kGy (C 4 ) and rosemary at dose 6 kGy (R 6 ) essential oils introduced promising antimicrobial activity as well as C 0 XR 0 mixture. Fraction inhibitory concentrations (FIC) were studied against selected four bacterial strains for measuring synergistic activity however, (FIC) represented indifference in all essential oils mixtures but, the C 0 X R 0 mixture against B. cereus (0.375) and E. coli (0.375) was synergy (below 0.5). Furthermore, the FIC shows addition in case of R 0 XT 0 , C 2 XR 6 , C 4 XR 6 and R 6 XT 4 against B. cereus. And in case of C 4 XR 6 against S. typhimurium. Preliminary experiment represented that 0.2, 0.4 and 0.1% were the acceptable odor in sunflower oil supplemented with rosemary, cumin and thyme essential oils, respectively.

  14. Synergistic effects of F and Fe in co-doped TiO{sub 2} nanoparticles

    Zhang, Yufei, E-mail: zhang.yu.fei@stu.xjtu.edu.cn; Shen, Huiyuan; Liu, Yanhua, E-mail: yhliu@mail.xjtu.edu.cn [Xi’an Jiaotong University, Department of Building Environment and Services Engineering, School of Human Settlements and Civil Engineering (China)

    2016-03-15

    TiO{sub 2} photocatalysts co-doped with F and Fe were synthesized by a sol–gel method. Synergistic effects of F and Fe in the co-doped TiO{sub 2} were verified by NH{sub 3} decomposition, X-ray diffraction (XRD), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), X-ray photoelectron spectroscopy (XPS) and ultraviolet–visible (UV–Vis) absorption spectroscopy, and was analyzed by the simulation based on the density functional theory (DFT). The results from NH{sub 3} decomposition confirmed that the cooperation of F and Fe broadened the optical response of TiO{sub 2} to visible light region and also enhanced the photocatalytic activity of TiO{sub 2} under ultraviolet light. XRD patterns, SEM and HRTEM images showed that the co-doped samples were nanometric anatase with an average particle size of 25 nm. Co-doping with F and Fe inhibited the grain growth of TiO{sub 2} from anatase to rutile and resulted in a larger lattice defect. XPS analysis exhibited that the doped F and Fe atoms were into the TiO{sub 2} lattice. UV–Vis absorption spectra showed that its optical absorption edge was moved up to approximately 617 nm and its ultraviolet absorption was also enhanced. The DFT results indicated that the cooperation of Fe 3d and O 2p orbits narrowed the band gap of TiO{sub 2} and F 2p orbit widened the upper valence bands. The synergistic electron density around F and Fe in co-doped TiO{sub 2} was capable to enhance the photo-chemical stability of TiO{sub 2}.

  15. Predicting synergistic effects of resources and predators on foraging decisions by juvenile Steller sea lions.

    Frid, Alejandro; Burns, Jennifer; Baker, Gregory G; Thorne, Richard E

    2009-01-01

    Many theoretical and experimental studies suggest that synergistic interactions between resources and predators influence foraging decisions and their fitness consequences. This framework, however, has been ignored almost completely by hypotheses on causes of the population decline of Steller sea lions (SSLs) (Eumetopias jubatus) in western Alaska. By comparing predictions from a dynamic state variable model to empirical data on the behaviour of individuals instrumented with satellite-linked time-at-depth recorders, we develop and find preliminary support for the hypothesis that, during winter in Prince William Sound, juvenile SSLs (a) underutilise walleye pollock, a predictable resource in deep strata, due to predation risk from Pacific sleeper sharks, and (b) underutilise the potential energy bonanza of inshore aggregations of Pacific herring due to risk from either killer whales, larger conspecifics, or both. Further, under conditions of resource scarcity-induced by overfishing, long-term oceanographic cycles, or their combination-trade-offs between mortality risk and energy gain may influence demographic parameters. Accordingly, computer simulations illustrated the theoretical plausibility that a decline of Pacific herring in shallow strata would greatly increase the number of deep foraging dives, thereby increasing exposure to sleeper sharks and mortality rates. These results suggest that hypotheses on the decline of SSLs should consider synergistic effects of predators and resources on behaviour and mortality rates. Empirical support for our model, however, is limited and we outline tasks for empirical research that emerge from these limitations. More generally, in the context of today's conservation crises, our work illustrates that the greater the dearth of system-specific data, the greater the need to apply principles of behavioural ecology toward the understanding and management of large-scale marine systems.

  16. Enhanced antitumor effects of novel intracellular delivery of an active form of menaquinone-4, menahydroquinone-4, into hepatocellular carcinoma.

    Setoguchi, Shuichi; Watase, Daisuke; Matsunaga, Kazuhisa; Matsubara, Misa; Kubo, Yohei; Kusuda, Mariko; Nagata-Akaho, Nami; Enjoji, Munechika; Nakashima, Manabu; Takeshita, Morishige; Karube, Yoshiharu; Takata, Jiro

    2015-02-01

    Reduced cellular uptake of menaquinone-4 (MK-4), a vitamin K2 homolog, in human hepatocellular carcinoma (HCC) limits its usefulness as a safe long-term antitumor agent for recurrent HCC and produces des-γ-carboxy prothrombin (DCP). We hypothesized that effective delivery of menahydroquinone-4 (MKH), the active form of MK-4 for γ-glutamyl carboxylation, into HCC cells is critical for regulating HCC growth, and may enable it to be applied as a safe antitumor agent. In this study, we verified this hypothesis using menahydroquinone-4 1,4-bis-N,N-dimethylglycinate hydrochloride (MKH-DMG), a prodrug of MKH, and demonstrated its effectiveness. Intracellular delivery of MKH and subsequent growth inhibition of PLC/PRF/5 and Hep3B (DCP-positive) and SK-Hep-1 (DCP-negative) cells after MKH-DMG administration were determined and compared with MK-4. The activity of MKH-DMG against tumor progression in the liver alongside DCP formation was determined in a spleen-liver metastasis mouse model. MKH-DMG exhibited greater intracellular delivery of MKH in vitro (AUC0-72 hour of MKH) and increased growth-inhibitory activity against both DCP-positive and DCP-negative HCC cell lines. The phenomena of MKH delivery into cells in parallel with simultaneous growth inhibition suggested that MKH is the active form for growth inhibition of HCC cells. Cell-cycle arrest was determined to be involved in the growth inhibition mechanisms of MKH-DMG. Furthermore, MKH-DMG showed significant inhibition of tumor progression in the liver, and a substantial decrease in plasma DCP levels in the spleen-liver metastasis mouse model. Our results suggest that MKH-DMG is a promising new candidate antitumor agent for safe long-term treatment of HCC. ©2014 American Association for Cancer Research.

  17. Synergistic effect of sevoflurane and isoflurane on inhibition of the adult-type muscle nicotinic acetylcholine receptor by rocuronium.

    Liu, Li; Li, Wei; Wei, Ke; Cao, Jun; Luo, Jie; Wang, Bin; Min, Su

    2013-06-01

    Inhaled anesthetics increase the incidence of postoperative residual neuromuscular blockade, and the mechanism is still unclear. We have investigated the synergistic effect of low-concentration inhaled anesthetics and rocuronium on inhibition of the inward current of the adult-type muscle nicotinic acetylcholine receptor (ε-nAChR). Adult-type mouse muscle ε-nAChR was expressed in HEK293 cells by liposome transfection. The inward current of the ε-nAChR was activated by use of 10 μmol/L acetylcholine alone or in combination with different concentrations of sevoflurane, isoflurane, or rocuronium. The concentration-response curves of five cells were constructed, and the data yielded the 5, 25, and 50 % inhibitory concentrations (IC5, IC25, and IC50, respectively) for single-drug application. Subsequently, the functional channels were perfused by adding 0.5 IC5 of either sevoflurane or isoflurane (aqueous concentrations 140 and 100 μmol/L, respectively) to the solution, followed by addition of IC5, IC25, or IC50 rocuronium. The amount of inhibition was calculated to quantify their synergistic effect. The inhibitory effect of rocuronium was enhanced by sevoflurane or isoflurane in a concentration-dependent manner. Sevoflurane or isoflurane (0.5 IC5) with rocuronium at IC5, IC25, and IC50 synergistically inhibited the current amplitude of adult-type muscle ε-nAChR. When the IC5 of rocuronium was used, isoflurane had a stronger synergistic effect than sevoflurane (p rocuronium was applied at higher concentrations (IC25 and IC50), sevoflurane had an effect similar to that of isoflurane. For both inhaled anesthetics, the synergistic effect was more intense for rocuronium at IC5 than for rocuronium at IC25 or IC50. Residual-concentration sevoflurane or isoflurane has a strong synergistic effect with rocuronium at clinically relevant residual concentrations. A lower rocuronium concentration resulted in a stronger synergistic effect.

  18. Antitumor Effect of Selenium and Modified Pectin Nano Particles and Gamma Radiation on Ehrilch Solid Tumor in Female Mice

    Mansour, S. Z.; Anis, L.M.; EI- Batal, A.I.

    2010-01-01

    Selenium nano particle (Nano- Se) is a novel Se species with novel biological activities with low toxicity. The aim of the present work was to evaluate the antitumor activity of a novel Nano- Se compound with or without gamma irradiation of female mice. Selenium size- controlled Nano-Se was prepared by a simple method by adding modified pectin to the selenious acid and ascorbic acid. The antitumor activity of Selenium and Modified Pectin Nano Particles (Se-Mp- NPs) were evaluated against Ehrilch ascites carcinoma (In vitro) and Ehrilch solid tumor model (In vivo). The antioxidant states of the novel compound were assessed measuring parameters in blood and tumor tissue of female mice. Malonaldehydoyl (MDA) end product of lipid peroxidation was evaluated in plasma and tumor tissue. Glutathione -S- transferase (GST) and cytochrome P450 (Cyto P450) were determined in tumor tissue homogenate. Tumor necrosis factor alpha (TNF- a) concentration and interleukin 10 (IL- 10) concentrations was evaluated in plasma of female mice. The effect of tumor inoculation and different treatments on liver enzymes (ALT and AST) and kidney Function (urea and creatinine) were detected in the plasma of animals. Apoptosis was shown and estimated in tumor tissue of animals histopathological of tumor in different groups of mice were examined. Ehrilch solid tumor induced a significant increase in MDA content, GSH-Px and GST activities level and in the amount of metabolites of CYP 450. Moreover, a significant decrease was observed in GSH content, SOD activity level in the tumor tissue, INF- a concentration, IL- 10 concentration in the plasma. Also, a significant alteration in kidney and liver functions was occurred as compared to control group. The results showed a significant antitumor activity of selenium and Modified Pectin Nano Particles (Se-Mp- NPs) at the concentration 2.25 μg / ml was 70%

  19. Effect of anhydrosophoradiol-3-acetate of Calotropis gigantea (Linn.) flower as antitumoric agent against Ehrlich's ascites carcinoma in mice.

    Habib, Muhammad R; Karim, Muhammad R

    2013-01-01

    Over 60% of currently used anti-cancer agents are derived in one-way or another from natural sources, including plants, marine organisms and microorganisms. Calotropis gigantea (Linn.) (Family: Asclepiadaceae) is a perennial shrub and it is used as a traditional folk medicine for the treatment of various health complications. But there is no report on isolation of anticancerous chemicals from the flower of Calotropis gigantea. The objective of the present study is to explore the antitumor effect of anhydrosophoradiol-3-acetate (A3A), isolated from the flower of Calotropis gigantea (Linn.) against Ehrlich's ascites carcinoma (EAC) in Swiss albino mice. Antitumoric effect of A3A was assessed by evaluating viable tumor cell count, survival time, body weight gain due to tumor burden, hematological and biochemical (glucose, cholesterol, triglyceride, blood urea, SALP, SGPT and SGOT) parameters of EAC bearing host at doses of 10 and 20 mg/kg body weight. Treatment with A3A decreased the viable tumor cells and body weight gain thereby increasing the life span of EAC bearing mice. A3A also brought back the altered hematological (Hb, total RBC and total WBC) and biochemical parameters more or less to normal level. Results of this study conclude that in vivo the A3A was effective in inhibiting the growth of EAC with improving in cancer induced complications.

  20. GSK-3 inhibition in vitro and in vivo enhances antitumor effect of sorafenib in renal cell carcinoma (RCC)

    Kawazoe, Hisashi; Bilim, Vladimir N. [Laboratory of Molecular Oncology, Department of Urology, Yamagata University School of Medicine, Iida-nishi 2-2-2, Yamagata 990-9585 (Japan); Ugolkov, Andrey V., E-mail: ugolkov@northwestern.edu [Tumor Biology Core, Center for Developmental Therapeutics, Chemistry of Life Processes Institute, Silverman Hall B733, Northwestern University, Evanston, IL (United States); Yuuki, Kaori; Naito, Sei; Nagaoka, Akira; Kato, Tomoyuki [Laboratory of Molecular Oncology, Department of Urology, Yamagata University School of Medicine, Iida-nishi 2-2-2, Yamagata 990-9585 (Japan); Tomita, Yoshihiko, E-mail: ytomita@med.id.yamagata-u.ac.jp [Laboratory of Molecular Oncology, Department of Urology, Yamagata University School of Medicine, Iida-nishi 2-2-2, Yamagata 990-9585 (Japan)

    2012-07-06

    Highlights: Black-Right-Pointing-Pointer Sorafenib treatment upregulated GSK-3{beta} levels in RCC cells. Black-Right-Pointing-Pointer Pharmacologic inhibition of GSK-3 suppressed xenograft RCC tumor growth. Black-Right-Pointing-Pointer Inhibition of GSK-3 enhanced antitumor effect of sorafenib in vitro and in vivo. -- Abstract: Sorafenib is a multikinase inhibitor approved for the systemic treatment of renal cell carcinoma (RCC). However, sorafenib treatment has a limited effect due to acquired chemoresistance of RCC. Previously, we identified glycogen synthase kinase-3 (GSK-3) as a new therapeutic target in RCC. Here, we observed that sorafenib inhibits proliferation and survival of RCC cells. Significantly, we revealed that sorafenib enhances GSK-3 activity in RCC cells, which could be a potential mechanism of acquired chemoresistance. We found that pharmacological inhibition of GSK-3 potentiates sorafenib antitumor effect in vitro and in vivo. Our results suggest that combining GSK-3 inhibitor and sorafenib might be a potential new therapeutic approach for RCC treatment.

  1. Synergistic effect of DHT and IGF-1 hyperstimulation in human peripheral blood lymphocytes.

    Imperlini, Esther; Spaziani, Sara; Mancini, Annamaria; Caterino, Marianna; Buono, Pasqualina; Orrù, Stefania

    2015-06-01

    The abuse of mixed or combined performance-enhancing drugs is widespread among athletes and amateurs, adults and adolescents. Clinical studies demonstrated that misuse of these doping agents is associated with serious adverse effects to many organs in human. Previously, we demonstrated in human peripheral blood lymphocytes that high doses of anabolic androgenic steroids, such as dihydrotestosterone (DHT) and growth factors, such as insulin-like growth factor-1 (IGF-1), have effects at gene and protein levels. Supraphysiological treatments of DHT and IGF-1 affected the expression of genes involved in skeletal muscle disorders as well as in cell-mediated immunological response. At protein level, DHT hyperdosage affects cell motility and apoptosis; IGF-1 hyperstimulation triggers an active cytoskeletal reorganization and an overproduction of immune response- and inflammation-related cytokines. In this study, we investigate the combined effects of DHT and IGF-1 hyperdosage in peripheral blood lymphocytes using a differential proteomic approach. DHT and IGF-1 combined treatment affects cell adhesion, migration, and survival through modulation of expression levels of cytokines and paxillin-signaling-related proteins, and activation of several pathways downstream focal adhesion kinase. Our results indicate a synergistic effect of DHT and IGF-1 which has potential implications for health risk factors. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

    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.

  3. How synergistic or antagonistic effects may influence the mutual hazard ranking of chemicals

    Lars Carlsen

    2015-04-01

    Full Text Available The presence of various agents, including humic materials, nanomaterials, microplastics, or simply specific chemical compounds, may cause changes in the apparent persistence, bioaccumulation, and/or toxicity (PBT of a chemical compound leading to an either increased or decreased PBT characteristics and thus an increased or decreased hazard evaluation. In the present paper, a series chloro-containing obsolete pesticides is studied as an illustrative example. Partial order methodology is used to quantify how changed P, B, or T characteristics of methoxychlor (MEC influences the measure of the hazard of MEC, relative to the other 11 compounds in the series investigated. Not surprisingly, an increase in one of the three indicators (P, B, or T lead to an increased average order and thus an increased relative hazard as a result of a synergistic effect. A decrease in one of the indicator values analogously causes a decreased average order/relative hazard through an antagonistic effect; the effect, however, being less pronounced. It is further seen that the effect of changing the apparent value of the three indicators is different. Thus, persistence apparently is more important that bioaccumulation which again appears more important than toxicity, which is in agreement with previous work. The results are discussed with reference to the European chemicals framework on registration, evaluation and authorization of chemicals (REACH framework.

  4. [Synergistic effect of cell kinetics-directed chemo-endocrine therapy on experimental mammary tumors].

    Ueki, H

    1987-11-01

    We tried to demonstrate that the cell kinetics-directed chemoendocrine therapy is more effective on hormone dependent breast cancer than empirical combination of the endocrine therapy and chemotherapy. Cell kinetics of each tumor was measured by flow cytometric analysis. Estrogen dependent human breast cancer cell line MCF-7 was used in vitro. In vivo, androgen dependent SC-115 carcinoma was transplanted to DDS mice. In vitro, tamoxifen was administered as the endocrine therapy. In vivo, we carried out testectomy on DDS mice. Effect of the endocrine therapy on the cell kinetics of the tumor was thought to be G1-S depression. High density 5FU was administered as the chemotherapeutic agents, whose content was 1 microgram/ml in vitro and 40 mg/kg in vivo. 5FU brought temporary decrease of cells in S phase. Only anteceding 5FU administration had synergistic effect in combination of 5FU and the endocrine therapy. 5FU was convinced to act more effectively on cells in S phase, so it was shown that cell kinetics-directed schedule was superior to the empirical treatment schedule in chemoendocrine therapy.

  5. Synergistic Effect of Nanophotocatalysis and Nonthermal Plasma on the Removal of Indoor HCHO

    Yuanwei Lu

    2012-01-01

    Full Text Available Photocatalysis is an effective method of air purification at the condition of a higher pollutant concentration. However, its wide application in indoor air cleaning is limited due to the low level of indoor air contaminants. Immobilizing the nanosized TiO2 particles on the surface of activated carbon filter (TiO2/AC film could increase the photocatalytic reaction rate as a local high pollutant concentration can be formed on the surface of TiO2 by the adsorption of AC. However, the pollutant removal still decreased quickly with the increase in flow velocity, which results in a decrease in air treatment capacity. In order to improve the air treatment capacity by the photocatalytic oxidation (PCO method, this paper used formaldehyde (HCHO as a contaminant to study the effect of combination of PCO with nonthermal plasma technology (NTP on the removal of HCHO. The experimental results show that HCHO removal is more effective with line-to-plate electrode discharge reactor; the HCHO removal and the reaction rate can be enhanced and the amount of air that needs to be cleaned can be improved. Meanwhile, the results show that there is the synergistic effect on the indoor air purification by the combination of PCO with NTP.

  6. Synergistic effects of plasma-activated medium and chemotherapeutic drugs in cancer treatment

    Chen, Chao-Yu; Cheng, Yun-Chien; Cheng, Yi-Jing

    2018-04-01

    Chemotherapy is an important treatment method for metastatic cancer, but the drug-uptake efficiency of cancer cells needs to be enhanced in order to diminish the side effects of chemotherapeutic drugs and improve survival. The use of a nonequilibrium low-temperature atmospheric-pressure plasma jet (APPJ) has been demonstrated to exert selective effects in cancer therapy and to be able to enhance the uptake of molecules by cells, which makes an APPJ a good candidate adjuvant in combination chemotherapy. This study estimated the effects of direct helium-based APPJ (He-APPJ) exposure (DE) and He-APPJ-activated RPMI medium (PAM) on cell viability and migration. Both of these treatments decreased cell viability and inhibited cell migration, but to different degrees in different cell types. The use of PAM as a culture medium resulted in the dialkylcarbocyanine (DiI) fluorescent dye entering the cells more efficiently. PAM was combined with the anticancer drug doxorubicin (Doxo) to treat human heptocellular carcinoma HepG2 cells and human adenocarcinomic alveolar basal epithelial A549 cells. The results showed that the synergistic effects of combined PAM and Doxo treatment resulted in stronger lethality in cancer cells than did PAM or Doxo treatment alone. To sum up, PAM has potential as an adjuvant in combination with other drugs to improve curative cancer therapies.

  7. Synergistic and additive effects of hydrostatic pressure and growth factors on tissue formation.

    Benjamin D Elder

    2008-06-01

    Full Text Available Hydrostatic pressure (HP is a significant factor in the function of many tissues, including cartilage, knee meniscus, temporomandibular joint disc, intervertebral disc, bone, bladder, and vasculature. Though studies have been performed in assessing the role of HP in tissue biochemistry, to the best of our knowledge, no studies have demonstrated enhanced mechanical properties from HP application in any tissue.The objective of this study was to determine the effects of hydrostatic pressure (HP, with and without growth factors, on the biomechanical and biochemical properties of engineered articular cartilage constructs, using a two-phased approach. In phase I, a 3x3 full-factorial design of HP magnitude (1, 5, 10 MPa and frequency (0, 0.1, 1 Hz was used, and the best two treatments were selected for use in phase II. Static HP at 5 MPa and 10 MPa resulted in significant 95% and 96% increases, respectively, in aggregate modulus (H(A, with corresponding increases in GAG content. These regimens also resulted in significant 101% and 92% increases in Young's modulus (E(Y, with corresponding increases in collagen content. Phase II employed a 3x3 full-factorial design of HP (no HP, 5 MPa static, 10 MPa static and growth factor application (no GF, BMP-2+IGF-I, TGF-beta1. The combination of 10 MPa static HP and TGF-beta1 treatment had an additive effect on both H(A and E(Y, as well as a synergistic effect on collagen content. This group demonstrated a 164% increase in H(A, a 231% increase in E(Y, an 85% increase in GAG/wet weight (WW, and a 173% increase in collagen/WW, relative to control.To our knowledge, this is the first study to demonstrate increases in the biomechanical properties of tissue from pure HP application, using a cartilage model. Furthermore, it is the only study to demonstrate additive or synergistic effects between HP and growth factors on tissue functional properties. These findings are exciting as coupling HP stimulation with growth

  8. Combined anti-tumor therapeutic effect of targeted gene, hyperthermia, radionuclide brachytherapy in breast carcinoma

    Chen Daozhen; Tang Qiusha; Xiang Jingying; Xu Fei; Zhang Li; Wang Junfeng

    2011-01-01

    Objective: To investigate the antitumor therapeutic effect of combined therapy of magnetic induction heating by nano-magnetic particles, herpes simplex virus thymidine kinase gene (HSV-tk suicide gene) and internal radiation in mice bearing MCF-7 breast carcinoma. Methods: The transfection reagents, plasmids heat shock protein-HSV-tk (pHSP-HSV-tk), ferroso-ferric oxide nano-magnetic fluid flow and 188 Re-ganciclovir-bovine serum albumin-nanopaticles (GCV-BSA-NP) were prepared. The heating experiments in vivo were carried out using ferroso-ferric oxide nano-magnetic fluid flow. Sixty mice tumor models bearing MCF-7 breast carcinoma were established and randomly divided into six groups. Group A was the control group, B was gene transfection therapy group, C was hyperthermia group, D was gene transfection therapy combined with radionuclide brachytherapy group, E was gene therapy combined with hyperthermia group, and F was gene therapy, hyperthermia combined with radionuclide brachytherapy group. The tumor growth, tumor mass and histopathological changes were evaluated. The expression of HSV-tk in the groups of B, D, E and F was detected by RT-PCR. Poisson distribution and one-way analysis of variance (ANOVA) were used for statistical analysis by SPSS 10.0 software. Results: In the animal heating experiments, the temperature of tumor increased up to 39.6 degree C, 43.2 degree C, and 48.1 degree C quickly with different injected doses (2, 4 and 6 mg respectively) of nano-magnetic particles and maintained for 40 min. The temperature of tumor tissue reduced to 36.8 degree C, 37.5 degree C and 37.8 degree C in 10 min when alternating magnetic field (AMF) stopped. The tumor mass in Groups C ((452.50±30.29) mg), D ((240.98±35.32)mg), E((231.87±27.41) mg) and F ((141.55±23.78) mg) were much lower than that in Group A ((719.12±22.65) mg) (F=800.07, P<0.01), with the most significant treatment effect in Group F.The tumor mass in Group B((684.05±24.02) mg) was higher than

  9. Synergistic effects of oncolytic reovirus and docetaxel chemotherapy in prostate cancer

    Prestwich Robin

    2011-06-01

    Full Text Available Abstract Background Reovirus type 3 Dearing (T3D has demonstrated oncolytic activity in vitro, in in vivo murine models and in early clinical trials. However the true potential of oncolytic viruses may only be realized fully in combination with other modalities such as chemotherapy, targeted therapy and radiotherapy. In this study, we examine the oncolytic activity of reovirus T3D and chemotherapeutic agents against human prostate cancer cell lines, with particular focus on the highly metastatic cell line PC3 and the chemotherapeutic agent docetaxel. Docetaxel is the standard of care for metastatic prostate cancer and acts by disrupting the normal process of microtubule assembly and disassembly. Reoviruses have been shown to associate with microtubules and may require this association for efficient viral replication. Methods The effects of reovirus and chemotherapy on in vitro cytotoxicity were investigated in PC3 and Du 145 cells and the interactions between agents were assessed by combination index analysis. An Annexin V/propidium iodide fluorescence-activated cell sorting-based assay was used to determine mode of cell death. The effects of reovirus and docetaxel administered as single agent or combination therapy were tested in vivo in a murine model. The effects of docetaxel and reovirus, alone and together, on microtubule stabilisation were investigated by Western blot analysis. Results Variable degrees of synergistic cytotoxicity were observed in PC3 and Du 145 cells exposed to live reovirus and several chemotherapy agents. Combination of reovirus infection with docetaxel exposure led to increased late apoptotic/necrotic cell populations. Reovirus/docetaxel combined therapy led to reduced tumour growth and increased survival in a PC3 tumour bearing mouse model. Microtubule stabilization was enhanced in PC3 cells treated with reovirus/docetaxel combined therapy compared to other reovirus/chemotherapy combinations. Conclusions The co

  10. Synergistic effects of radiation and caffeine on embryonic development in mice

    Kusama, Tomoko; Yoshizawa, Yasuo (Tokyo Univ. (Japan). Faculty of Medicine)

    1984-09-01

    The combined action of radiation with caffeine has been studied in mouse embryos. Radiation and/or caffeine were administered to ICR mice on day 7 of gestation, at which time the embryos were in the early stage of organogenesis. Intrauterine death, gross malformation, body weight and sex ratio were selected as indicators of effects. Doses of gamma irradiation were 0.5, 1.0 and 2.0 Gy and those of caffeine were 0.10 and 0.25 mg/g of body weight. Intrauterine mortality increased with increasing radiation dose and this trend was more remarkable in combination with caffeine. The malformation such as parietal hernia, exencephalia, hydrocephalia and cleft palate appeared frequently in the fetuses treated with both radiation and caffeine compared to the fetuses treated with each agent separately. Fetal body weight was a sensitive indicator of the effects on growth retardation of radiation and/or caffeine. The sex ratio of live fetuses did not change by means of treatment with radiation and/or caffeine. Intrauterine mortality and frequency of malformations in mice treated with both radiation and caffeine were higher than the sum of those induced by radiation and those by caffeine separately. The results demonstrated that the combined effects of radiation and caffeine were synergistic.

  11. The synergistic effects of radiation and caffeine on embryonic development in mice

    Kusama, Tomoko; Yoshizawa, Yasuo

    1984-01-01

    The combined action of radiation with caffeine has been studied in mouse embryos. Radiation and/or caffeine were administered to ICR mice on day 7 of gestation, at which time the embryos were in the early stage of organogenesis. Intrauterine death, gross malformation, body weight and sex ratio were selected as indicators of effects. Doses of gamma irradiation were 0.5, 1.0 and 2.0 Gy and those of caffeine were 0.10 and 0.25 mg/g of body weight. Intrauterine mortality increased with increasing radiation dose and this trend was more remarkable in combination with caffeine. The malformation such as parietal hernia, exencephalia, hydrocephalia and cleft palate appeared frequently in the fetuses treated with both radiation and caffeine compared to the fetuses treated with each agent separately. Fetal body weight was a sensitive indicator of the effects on growth retardation of radiation and/or caffeine. The sex ratio of live fetuses did not change by means of treatment with radiation and/or caffeine. Intrauterine mortality and frequency of malformations in mice treated with both radiation and caffeine were higher than the sum of those induced by radiation and those by caffeine separately. The results demonstrated that the combined effects of radiation and caffeine were synergistic. (author)

  12. A pharmacoproteomic study confirms the synergistic effect of chondroitin sulfate and glucosamine.

    Calamia, Valentina; Mateos, Jesús; Fernández-Puente, Patricia; Lourido, Lucía; Rocha, Beatriz; Fernández-Costa, Carolina; Montell, Eulalia; Vergés, Josep; Ruiz-Romero, Cristina; Blanco, Francisco J

    2014-06-10

    Osteoarthritis (OA) is the most common age-related rheumatic disease. Chondrocytes play a primary role in mediating cartilage destruction and extracellular matrix (ECM) breakdown, which are main features of the OA joint. Quantitative proteomics technologies are demonstrating a very interesting power for studying the molecular effects of some drugs currently used to treat OA patients, such as chondroitin sulfate (CS) and glucosamine (GlcN). In this work, we employed the iTRAQ (isobaric tags for relative and absolute quantitation) technique to assess the effect of CS and GlcN, both alone and in combination, in modifying cartilage ECM metabolism by the analysis of OA chondrocytes secretome. 186 different proteins secreted by the treated OA chondrocytes were identified. 36 of them presented statistically significant differences (p ≤ 0.05) between untreated and treated samples: 32 were increased and 4 decreased. The synergistic chondroprotective effect of CS and GlcN, firstly reported by our group at the intracellular level, is now demonstrated also at the extracellular level.

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

    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.

  14. Synergistic effects of hypoxia and increasing CO2 on benthic invertebrates of the central Chilean coast

    Steckbauer, Alexandra

    2015-07-10

    Ocean acidification (OA) and hypoxic events are an increasing worldwide problem, but the synergetic effects of these factors are seldom explored. However, this synergetic occurrence of stressors is prevalent. The coastline of Chile not only suffers from coastal hypoxia but the cold, oxygen-poor waters in upwelling events are also supersaturated in CO2, a study site to explore the combined effect of OA and hypoxia. We experimentally evaluated the metabolic response of different invertebrate species (2 anthozoans, 9 molluscs, 4 crustaceans, 2 echinoderms) of the coastline of central Chile (33°30′S, 71°37′W) to hypoxia and OA within predicted levels and in a full factorial design. Organisms were exposed to 4 different treatments (ambient, low oxygen, high CO2, and the combination of low oxygen and high CO2) and metabolism was measured after 3 and 6 days. We show that the combination of hypoxia and increased pCO2 reduces the respiration significantly, compared to a single stressor. The evaluation of synergistic pressures, a more realistic scenario than single stressors, is crucial to evaluate the effect of future changes for coastal species and our results provide the first insight on what might happen in the next 100 years.

  15. Synergistic Effect of MiR-146a Mimic and Cetuximab on Hepatocellular Carcinoma Cells

    Suning Huang

    2014-01-01

    Full Text Available Previously, we found that the expression of microRNA-146a (miR-146a was downregulated in hepatocellular carcinoma (HCC formalin-fixed paraffin-embedded (FFPE tissues compared to the adjacent noncancerous hepatic tissues. In the current study, we have explored the in vitro effect of miR-146a on the malignant phenotypes of HCC cells. MiR-146a mimic could suppress cell growth and increase cellular apoptosis in HCC cell lines HepG2, HepB3, and SNU449, as assessed by spectrophotometry, fluorimetry, and fluorescence microscopy, respectively. Furthermore, western blot showed that miR-146a mimic downregulated EGFR, ERK1/2, and stat5 signalings. These effects were less potent compared to that of a siRNA targeting EGFR, a known target gene of miR-146a. Moreover, miR-146a mimic could enhance the cell growth inhibition and apoptosis induction impact of various EGFR targeting agents. The most potent combination was miR-146a mimic with cetuximab, presenting a synergistic effect. In conclusion, miR-146a plays a vital role in the cell growth and apoptosis of HCC cells and inducing miR-146a level might be a critical targeted molecular therapy strategy for HCC.

  16. Effect of Eugenol against Streptococcus agalactiae and Synergistic Interaction with Biologically Produced Silver Nanoparticles

    Renata Perugini Biasi-Garbin

    2015-01-01

    Full Text Available Streptococcus agalactiae (group B streptococci (GBS is an important infections agent in newborns associated with maternal vaginal colonization. Intrapartum antibiotic prophylaxis in GBS-colonized pregnant women has led to a significant reduction in the incidence of early neonatal infection in various geographic regions. However, this strategy may lead to resistance selecting among GBS, indicating the need for new alternatives to prevent bacterial transmission and even to treat GBS infections. This study reported for the first time the effect of eugenol on GBS isolated from colonized women, alone and in combination with silver nanoparticles produced by Fusarium oxysporum (AgNPbio. Eugenol showed a bactericidal effect against planktonic cells of all GBS strains, and this effect appeared to be time-dependent as judged by the time-kill curves and viability analysis. Combination of eugenol with AgNPbio resulted in a strong synergistic activity, significantly reducing the minimum inhibitory concentration values of both compounds. Scanning and transmission electron microscopy revealed fragmented cells and changes in bacterial morphology after incubation with eugenol. In addition, eugenol inhibited the viability of sessile cells during biofilm formation and in mature biofilms. These results indicate the potential of eugenol as an alternative for controlling GBS infections.

  17. Synergistic anticancer effects of the 9.2.27PE immunotoxin and ABT-737 in melanoma.

    Karianne Risberg

    Full Text Available In cancer, combinations of drugs targeting different cellular functions is well accepted to improve tumor control. We studied the effects of a Pseudomonas exotoxin A (PE-based immunotoxin, the 9.2.27PE, and the BH-3 mimetic compound ABT-737 in a panel of melanoma cell lines. The drug combination resulted in synergistic cytotoxicity, and the cell death observed was associated with apoptosis, as activation of caspase-3, inactivation of Poly (ADP-ribose polymerase (PARP and increased DNA fragmentation could be prevented by pre-treatment with caspase and cathepsin inhibitors. We further show that ABT-737 caused endoplasmic reticulum (ER stress with increased GRP78 and phosphorylated eIF2α protein levels. Moreover, treatment with ABT-737 increased the intracellular calcium levels, an effect which was enhanced by 9.2.27PE, which as a single entity drug had minimal effect on calcium release from the ER. In addition, silencing of Mcl-1 by short hairpin RNA (shRNA enhanced the intracellular calcium levels and cytotoxicity caused by ABT-737. Notably, the combination of 9.2.27PE and ABT-737 caused growth delay in a human melanoma xenograft mice model, supporting further investigations of this particular drug combination.

  18. Synergistic effect of MiR-146a mimic and cetuximab on hepatocellular carcinoma cells.

    Huang, Suning; He, Rongquan; Rong, Minhua; Dang, Yiwu; Chen, Gang

    2014-01-01

    Previously, we found that the expression of microRNA-146a (miR-146a) was downregulated in hepatocellular carcinoma (HCC) formalin-fixed paraffin-embedded (FFPE) tissues compared to the adjacent noncancerous hepatic tissues. In the current study, we have explored the in vitro effect of miR-146a on the malignant phenotypes of HCC cells. MiR-146a mimic could suppress cell growth and increase cellular apoptosis in HCC cell lines HepG2, HepB3, and SNU449, as assessed by spectrophotometry, fluorimetry, and fluorescence microscopy, respectively. Furthermore, western blot showed that miR-146a mimic downregulated EGFR, ERK1/2, and stat5 signalings. These effects were less potent compared to that of a siRNA targeting EGFR, a known target gene of miR-146a. Moreover, miR-146a mimic could enhance the cell growth inhibition and apoptosis induction impact of various EGFR targeting agents. The most potent combination was miR-146a mimic with cetuximab, presenting a synergistic effect. In conclusion, miR-146a plays a vital role in the cell growth and apoptosis of HCC cells and inducing miR-146a level might be a critical targeted molecular therapy strategy for HCC.

  19. Synergistic effects of hypoxia and increasing CO2 on benthic invertebrates of the central Chilean coast

    Steckbauer, Alexandra; Ramajo, Laura; Hendriks, Iris E.; Fernandez, Miriam; Lagos, Nelson A.; Prado, Luis; Duarte, Carlos M.

    2015-01-01

    Ocean acidification (OA) and hypoxic events are an increasing worldwide problem, but the synergetic effects of these factors are seldom explored. However, this synergetic occurrence of stressors is prevalent. The coastline of Chile not only suffers from coastal hypoxia but the cold, oxygen-poor waters in upwelling events are also supersaturated in CO2, a study site to explore the combined effect of OA and hypoxia. We experimentally evaluated the metabolic response of different invertebrate species (2 anthozoans, 9 molluscs, 4 crustaceans, 2 echinoderms) of the coastline of central Chile (33°30′S, 71°37′W) to hypoxia and OA within predicted levels and in a full factorial design. Organisms were exposed to 4 different treatments (ambient, low oxygen, high CO2, and the combination of low oxygen and high CO2) and metabolism was measured after 3 and 6 days. We show that the combination of hypoxia and increased pCO2 reduces the respiration significantly, compared to a single stressor. The evaluation of synergistic pressures, a more realistic scenario than single stressors, is crucial to evaluate the effect of future changes for coastal species and our results provide the first insight on what might happen in the next 100 years.

  20. Synergistic Effect of Rapamycin and Metformin Against Age-Dependent Oxidative Stress in Rat Erythrocytes.

    Singh, Abhishek Kumar; Garg, Geetika; Singh, Sandeep; Rizvi, Syed Ibrahim

    2017-10-01

    Erythrocytes are particularly vulnerable toward age-dependent oxidative stress-mediated damage. Caloric restriction mimetics (CRMs) may provide a novel strategy for the maintenance of redox balance as well as effective treatment of age-associated diseases. Herein, we have investigated the beneficial effect of cotreatment with CRM-candidate drugs, rapamycin (an immunosuppressant drug and inhibitor of mammalian target of rapamycin) and metformin (an antidiabetic biguanide and activator of adenosine monophosphate kinase), against aging-induced oxidative stress in erythrocytes and plasma of aging rats. Male Wistar rats of age 4 (young) and 24 months (old) were coexposed to rapamycin (0.5 mg/kg body weight [b.w.]) and metformin (300 mg/kg b.w.), and data were compared with the response of rats receiving an independent exposure to these chemicals at similar doses. The exposure of individual candidate drugs significantly reversed the age-dependent alterations in the endpoints associated with oxidative stress such as reactive oxygen species, ferric reducing ability of plasma, malondialdehyde, reduced glutathione, plasma membrane redox system, plasma protein carbonyl, and acetyl cholinesterase in erythrocytes and plasma of aging rats. However, the cotreatment with rapamycin and metformin showed a significant augmented effect compared with individual drug interventions on reversal of these age-dependent biomarkers of oxidative stress, suggesting a synergistic response. Thus, the findings open up further possibilities for the design of new combinatorial therapies to prevent oxidative stress- and age-associated health problems.

  1. Immunotherapy with Dendritic Cells Modified with Tumor-Associated Antigen Gene Demonstrates Enhanced Antitumor Effect Against Lung Cancer

    Tao Jiang

    2017-04-01

    Full Text Available BACKGROUND: Immunotherapy using dendritic cell (DC vaccine has the potential to overcome the bottleneck of cancer therapy. METHODS: We engineered Lewis lung cancer cells (LLCs and bone marrow–derived DCs to express tumor-associated antigen (TAA ovalbumin (OVA via lentiviral vector plasmid encoding OVA gene. We then tested the antitumor effect of modified DCs both in vitro and in vivo. RESULTS: The results demonstrated that in vitro modified DCs could dramatically enhance T-cell proliferation (P < .01 and killing of LLCs than control groups (P < .05. Moreover, modified DCs could reduce tumor size and prolong the survival of LLC tumor-bearing mice than control groups (P < .01 and P < .01, respectively. Mechanistically, modified DCs demonstrated enhanced homing to T-cell–rich compartments and triggered more naive T cells to become cytotoxic T lymphocytes, which exhibited significant infiltration into the tumors. Interestingly, modified DCs also markedly reduced tumor cells harboring stem cell markers in mice (P < .05, suggesting the potential role on cancer stem-like cells. CONCLUSION: These findings suggested that DCs bioengineered with TAA could enhance antitumor effect and therefore represent a novel anticancer strategy that is worth further exploration.

  2. Cytotoxic, Antitumor and Immunomodulatory Effects of the Water-Soluble Polysaccharides from Lotus (Nelumbo nucifera Gaertn. Seeds

    Yafeng Zheng

    2016-11-01

    Full Text Available Lotus is an edible and medicinal plant, and the extracts from its different parts exhibit various bioactivities. In the present study, the hot water–soluble polysaccharides from lotus seeds (LSPS were evaluated for their cancer cell cytotoxicity, immunomodulatory and antitumor activities. LSPS showed significant inhibitory effects on the mouse gastric cancer MFC cells, human liver cancer HuH-7 cells and mouse hepatocarcinoma H22 cells. The animal studies showed that LSPS inhibited tumor growth in H22 tumor-bearing mice with the highest inhibition rate of 45.36%, which is comparable to that induced by cyclophosphamide (30 mg/kg treatment (50.79%. The concentrations of white blood cells were significantly reduced in cyclophosphamide-treated groups (p < 0.01, while LSPS showed much fewer side effects according to the hematology analysis. LSPS improved the immune response in H22 tumor-bearing mice by enhancing the spleen and thymus indexes, and increasing the levels of serum cytokines including tumor necrosis factor-α and interleukin-2. Moreover, LSPS also showed in vivo antioxidant activity by increasing superoxide dismutase activity, thus reducing the malondialdehyde level in the liver tissue. These results suggested that LSPS can be used as an antitumor and immunomodulatory agent.

  3. In Situ TEM Multi-Beam Ion Irradiation as a Technique for Elucidating Synergistic Radiation Effects

    Taylor, Caitlin; Bufford, Daniel; Muntifering, Brittany; Senor, David; Steckbeck, Mackenzie; Davis, Justin; Doyle, Barney; Buller, Daniel; Hattar, Khalid

    2017-09-29

    Materials designed for nuclear reactors undergo microstructural changes resulting from a combination of several environmental factors, including neutron irradiation damage, gas accumulation and elevated temperatures. Typical ion beam irradiation experiments designed for simulating a neutron irradiation environment involve irradiating the sample with a single ion beam and subsequent characterization of the resulting microstructure, often by transmission electron microscopy (TEM). This method does not allow for examination of microstructural effects due to simultaneous gas accumulation and displacement cascade damage, which occurs in a reactor. Sandia’s in situ ion irradiation TEM (I3TEM) offers the unique ability to observe microstructural changes due to irradiation damage caused by concurrent multi-beam ion irradiation in real time. This allows for time-dependent microstructure analysis. A plethora of additional in situ stages can be coupled with these experiments, e.g., for more accurately simulating defect kinetics at elevated reactor temperatures. This work outlines experiments showing synergistic effects in Au using in situ ion irradiation with various combinations of helium, deuterium and Au ions, as well as some initial work on materials utilized in tritium-producing burnable absorber rods (TPBARs): zirconium alloys and LiAlO2.

  4. Synergistic effects of bioremediation and electrokinetics in the remediation of petroleum-contaminated soil.

    Guo, Shuhai; Fan, Ruijuan; Li, Tingting; Hartog, Niels; Li, Fengmei; Yang, Xuelian

    2014-08-01

    The present study evaluated the coupling interactions between bioremediation (BIO) and electrokinetics (EK) in the remediation of total petroleum hydrocarbons (TPH) by using bio-electrokinetics (BIO-EK) with a rotatory 2-D electric field. The results demonstrated an obvious positive correlation between the degradation extents of TPH and electric intensity both in the EK and BIO-EK tests. The use of BIO-EK showed a significant improvement in degradation of TPH as compared to BIO or EK alone. The actual degradation curve in BIO-EK tests fitted well with the simulated curve obtained by combining the degradation curves in BIO- and EK-only tests during the first 60 d, indicating a superimposed effect of biological degradation and electrochemical stimulation. The synergistic effect was particularly expressed during the later phase of the experiment, concurrent with changes in the microbial community structure. The community composition changed mainly according to the duration of the electric field, leading to a reduction in diversity. No significant spatial shifts in microbial community composition and bacterial numbers were detected among different sampling positions. Soil pH was uniform during the experimental process, soil temperature showed no variations between the soil chambers with and without an electric field. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Synergistic effect of multiple indoor allergen sources on atopic symptoms in primary school children

    Chen, W-Y.; Tseng, H-I.; Wu, M-T.; Hung, H-C.; Wu, H-T.; Chen, H-L.; Lu, C.-C.

    2003-01-01

    Accumulating data show that the complex modern indoor environment contributes to increasing prevalence of atopic diseases. However, the dose-response relationship between allergic symptoms and complexity of indoor environmental allergen sources (IEAS) has not been clearly evaluated before. Therefore, we designed this study to investigate the overall effect of multiple IEAS on appearance of asthma (AS), allergic rhinitis (AR), and eczema (EC) symptoms in 1472 primary school children. Among various IEAS analyzed, only stuffed toys, cockroaches, and mold patches fit the model of 'more IEAS, higher odds ratio (OR) of association'. The association of IEAS and AR increased stepwise as more IEAS appeared in the environment (1.71, 2.47, to 2.86). In AS and EC, the association was significant only when all three IEAS were present (1.42, 1.98, to 4.11 in AS; 1.40, 1.76, to 2.95 in EC). These results showed that different IEAS had a synergistic effect on their association with atopic symptoms and also suggest that there is a dose-response relationship between kinds of IEAS and risk of appearance of atopic diseases

  6. In Situ TEM Multi-Beam Ion Irradiation as a Technique for Elucidating Synergistic Radiation Effects

    Caitlin Anne Taylor

    2017-09-01

    Full Text Available Materials designed for nuclear reactors undergo microstructural changes resulting from a combination of several environmental factors, including neutron irradiation damage, gas accumulation and elevated temperatures. Typical ion beam irradiation experiments designed for simulating a neutron irradiation environment involve irradiating the sample with a single ion beam and subsequent characterization of the resulting microstructure, often by transmission electron microscopy (TEM. This method does not allow for examination of microstructural effects due to simultaneous gas accumulation and displacement cascade damage, which occurs in a reactor. Sandia’s in situ ion irradiation TEM (I3TEM offers the unique ability to observe microstructural changes due to irradiation damage caused by concurrent multi-beam ion irradiation in real time. This allows for time-dependent microstructure analysis. A plethora of additional in situ stages can be coupled with these experiments, e.g., for more accurately simulating defect kinetics at elevated reactor temperatures. This work outlines experiments showing synergistic effects in Au using in situ ion irradiation with various combinations of helium, deuterium and Au ions, as well as some initial work on materials utilized in tritium-producing burnable absorber rods (TPBARs: zirconium alloys and LiAlO2.

  7. Synergistic protective effect of picrorhiza with honey in acetaminophen induced hepatic injury.

    Gupta, Prashant; Tripathi, Alok; Agrawal, Tripti; Narayan, Chandradeo; Singh, B M; Kumar, Mohan; Kumar, Arvind

    2016-08-01

    Rhizome of picrorhiza along with honey prevents hepatic damage and cure the acetaminophen (paracetamol) induced hepatotoxicity by modulating the activity of hepatic enzymes. Here, we studied the in vivo effects of Picrorhiza kurroa and honey on acetaminophen induced hepatotoxicity Balb/c mice model. Hepatic histopathological observations of acetaminophen fed (day-6) group showed more congestion, hemorrhage, necrosis, distorted hepatic architecture and nuclear inclusion. Such damages were recompensed to normal by picrorhiza or honey alone or both in combinations. We observed increased activity of SGPT and SGOT in injured liver tissues, and that too was compensated to normal with picrorhiza or honey alone or both in combinations. We observed 1.27 and 1.23-fold enhanced activity of SGPT in serum and liver lysate, respectively while SGOT showed 1.66 and 1.11 fold enhanced activity. These two enzymes are signature enzymes of liver damage. Thus, our results support that honey may be used with drug picrorhiza due to its synergistic role to enhance hepatoprotective and hepatoregenerative ability along with allopathic drugs to mitigate the hepatotoxic effects.

  8. Arctigenin in combination with quercetin synergistically enhances the anti-proliferative effect in prostate cancer cells

    Wang, Piwen; Phan, Tien; Gordon, David; Chung, Seyung; Henning, Susanne M.; Vadgama, Jaydutt V.

    2014-01-01

    Scope We investigated whether a combination of two promising chemopreventive agents arctigenin and quercetin increases the anti-carcinogenic potency at lower concentrations than necessary when used individually in prostate cancer. Methods and results Androgen-dependent LAPC-4 and LNCaP prostate cancer cells were treated with low doses of arctigenin and quercetin alone or in combination for 48h. The anti-proliferative activity of arctigenin was 10-20 fold stronger than quercetin in both cell lines. Their combination synergistically enhanced the anti-proliferative effect, with a stronger effect in androgen receptor (AR) wild-type LAPC-4 cells than in AR mutated LNCaP cells. Arctigenin demonstrated a strong ability to inhibit AR protein expression in LAPC-4 cells. The combination treatment significantly inhibited both AR and PI3K/Akt pathways compared to control. A protein array analysis revealed that the mixture targets multiple pathways particularly in LAPC-4 cells including Stat3 pathway. The mixture significantly inhibited the expression of several oncogenic microRNAs including miR-21, miR-19b, and miR-148a compared to control. The mixture also enhanced the inhibition of cell migration in both cell lines compared to individual compounds tested. Conclusion The combination of arctigenin and quercetin, that target similar pathways, at low physiological doses, provides a novel regimen with enhanced chemoprevention in prostate cancer. PMID:25380086

  9. Arctigenin in combination with quercetin synergistically enhances the antiproliferative effect in prostate cancer cells.

    Wang, Piwen; Phan, Tien; Gordon, David; Chung, Seyung; Henning, Susanne M; Vadgama, Jaydutt V

    2015-02-01

    We investigated whether a combination of two promising chemopreventive agents arctigenin (Arc) and quercetin (Q) increases the anticarcinogenic potency at lower concentrations than necessary when used individually in prostate cancer. Androgen-dependent LAPC-4 and LNCaP prostate cancer cells were treated with low doses of Arc and Q alone or in combination for 48 h. The antiproliferative activity of Arc was 10- to 20-fold stronger than Q in both cell lines. Their combination synergistically enhanced the antiproliferative effect, with a stronger effect in androgen receptor (AR) wild-type LAPC-4 cells than in AR mutated LNCaP cells. Arc demonstrated a strong ability to inhibit AR protein expression in LAPC-4 cells. The combination treatment significantly inhibited both AR and PI3K/Akt pathways compared to control. A protein array analysis revealed that the mixture targets multiple pathways particularly in LAPC-4 cells including Stat3 pathway. The mixture significantly inhibited the expression of several oncogenic microRNAs including miR-21, miR-19b, and miR-148a compared to control. The mixture also enhanced the inhibition of cell migration in both cell lines compared to individual compounds tested. The combination of Arc and Q that target similar pathways, at low physiological doses, provides a novel regimen with enhanced chemoprevention in prostate cancer. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Synergistic Effect of Hybrid Multilayer In2Se3 and Nanodiamonds for Highly Sensitive Photodetectors.

    Zheng, Zhaoqiang; Yao, Jiandong; Xiao, Jun; Yang, Guowei

    2016-08-10

    Layered materials have rapidly established themselves as intriguing building blocks for next-generation photodetection platforms in view of their exotic electronic and optical attributes. However, both relatively low mobility and heavier electron effective mass limit layered materials for high-performance applications. Herein, we employed nanodiamonds (NDs) to promote the performance of multilayer In2Se3 photodetectors for the first time. This hybrid NDs-In2Se3 photodetector showed a tremendous promotion of photodetection performance in comparison to pristine In2Se3 ones. This hybrid devices exhibited remarkable detectivity (5.12 × 10(12) jones), fast response speed (less than 16.6 ms), and decent current on/off ratio (∼2285) simultaneously. These parameters are superior to most reported layered materials based photodetectors and even comparable to the state-of-the-art commercial photodetectors. Meanwhile, we attributed this excellent performance to the synergistic effect between NDs and the In2Se3. They can greatly enhance the broad spectrum absorption and promote the injection of photoexcited carrier in NDs to In2Se3. These results actually open up a new scenario for designing and fabricating innovative optoelectronic systems.

  11. Synergistic effect of certain insecticides combined with Bacillus thuringiensis on mosquito larvae

    C.P. Narkhede

    2017-04-01

    Full Text Available For effective vector control it is essential to formulate new preparations having multiple action against the vector pest. Developing combined formulation of biopesticide and chemical pesticide is one of the novel concept to fight against the vectors with new weapons; however, compatibility of biopesticide i.e. Bacillus thuringiensis (Bt and chemical pesticide is a real hurdle. In this investigation, local isolate Bacillus thuringiensis SV2 (BtSV2 was tested for its compatibility with various available mosquito larvicides. Temephos was most compatible with BtSV2 than with other tested pesticides. These two compatible agents were tested for larvicidal potential. Our study revealed that the synergistic effect of both agents reduces LC50 value by 30.68 and 22.36% against the Ae. aegypti and An. stephensi, respectively. The larvicidal potential increased when compared to individual pesticides. It was also observed a biochemical change in larvae after the TBT (Temephos + Bacillus thuringiensis combination treatment; it involves decreased level of alpha esterase, acetylcholine esterase and protein while level of beta esterase and acid phosphatase was unchanged and alkaline phosphatase activity was increased. Increased potential of combined formulation may be due to altered physiological condition.

  12. Finding stable cellulase and xylanase: evaluation of the synergistic effect of pH and temperature.

    Farinas, Cristiane S; Loyo, Marcel Moitas; Baraldo, Anderson; Tardioli, Paulo W; Neto, Victor Bertucci; Couri, Sonia

    2010-12-31

    Ethanol from lignocellulosic biomass has been recognized as one of the most promising alternatives for the production of renewable and sustainable energy. However, one of the major bottlenecks holding back its commercialization is the high costs of the enzymes needed for biomass conversion. In this work, we studied the enzymes produced from a selected strain of Aspergillus niger under solid state fermentation. The cellulase and xylanase enzymatic cocktail was characterized in terms of pH and temperature by using response surface methodology. Thermostability and kinetic parameters were also determined. The statistical analysis of pH and temperature effects on enzymatic activity showed a synergistic interaction of these two variables, thus enabling to find a pH and temperature range in which the enzymes have a higher activity. The results obtained allowed the construction of mathematical models used to predict endoglucanase, β-glucosidase and xylanase activities under different pH and temperature conditions. Optimum temperature values for all three enzymes were found to be in the range between 35°C and 60°C, and the optimum pH range was found between 4 and 5.5. The methodology employed here was very effective in estimating enzyme behavior under different process conditions. Copyright © 2010 Elsevier B.V. All rights reserved.

  13. Synergistic effects of leflunomide and benazepril in streptozotocin-induced diabetic nephropathy.

    Jin, Hua; Piao, Shang Guo; Jin, Ji Zhe; Jin, Ying Shun; Cui, Zhen Hua; Jin, Hai Feng; Zheng, Hai Lan; Li, Jin Ji; Jiang, Yu Ji; Yang, Chul Woo; Li, Can

    2014-01-01

    Leflunomide (LEF) and benazepril have renoprotective effects on diabetic nephropathy (DN) through their anti-inflammatory and anti-fibrotic activities. This study investigated whether combined treatment using LEF and benazepril affords superior protection compared with the respective monotherapies. Diabetes was induced with streptozotocin (STZ, 65 mg/kg) by intraperitoneal injection in male Wistar rats. Two weeks after STZ injection, diabetic rats were treated daily for 12 weeks with LEF (10 mg/kg), benazepril (10 mg/kg), or a combination of both. Basic parameters (body weight, fasting blood glucose level, and 24 h urinary protein excretion), histopathology, inflammatory [inflammatory cell infiltration (ED-1), monocyte chemoattractant protein-1 (MCP-1), and Toll-like receptor-2 (TLR-2)] and glomerulosclerotic factors [transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF)], and oxidative stress (8-hydroxy-2'-deoxyguanosine, 8-OHdG) were studied. Benazepril or LEF treatment significantly prevented body weight loss and 24 h urinary protein excretion induced by diabetes; combined treatment with LEF and benazepril further improved these parameters compared with giving each drug alone (all p benazepril and was further reduced by the combined administration of the two drugs (p benazepril provides synergistic effects in preventing DN. 2014 S. Karger AG, Basel

  14. Inoculum and zeolite synergistic effect on anaerobic digestion of poultry manure.

    Fotidis, Ioannis A; Kougias, Panagiotis G; Zaganas, Ioannis D; Kotsopoulos, Thomas A; Martzopoulos, Gerasimos G

    2014-01-01

    Poultry manure is an ammonia-rich substrate due to its high content of proteins and amino acids. Ammonia is the major inhibitor of anaerobic digestion (AD) process, affecting biogas production and causing great economic losses to the biogas plants. In this study, the effect of different natural zeolite dosages on the mesophilic AD of poultry manure inoculated with a non-acclimatized to ammonia inoculum (dairy manure) was investigated. Additionally, a comparative analysis was performed between the data extracted from this study and the results of a previous study, which has been conducted under the same experimental conditions but with the use of ammonia acclimatized inoculum (swine manure). At 5 and 10 g zeolite L(-1), the methane yield of poultry manure was 43.4% and 80.3% higher compared with the experimental set without zeolite addition. However, the ammonia non-acclimatized inoculum was not efficient in digesting poultry manure even in the presence of 10 g zeolite L(-1), due to low methane production (only 39%) compared with the maximum theoretical yield. Finally, ammonia acclimatized inoculum and zeolite have demonstrated a possible 'synergistic effect', which led to a more efficient AD of poultry manure. The results of this study could potentially been used by the biogas plant operators to efficiently digest poultry manure.

  15. Synergistic effects of the combination of galangin with gentamicin against methicillin-resistant Staphylococcus aureus.

    Lee, Young-Seob; Kang, Ok-Hwa; Choi, Jang-Gi; Oh, You-Chang; Chae, Hee-Sung; Kim, Jong Hak; Park, Hyun; Sohn, Dong Hwan; Wang, Zheng-Tao; Kwon, Dong-Yeul

    2008-06-01

    The antimicrobial killing activity toward methicillin-resistant Staphylococcus aureus (MRSA) has been a serious emerging global issue. New effective antimicrobials and/or new approaches to settle this issue are urgently needed. The oriental herb, Alpinia officinarum, has been used in Korea for several hundreds of years to treat various infectious diseases. As it is well known, one of the active constituents of Alpinia officinarum is galangin. Against the 17 strains, the minimum inhibitory concentrations (MICs) of galangin (GAL) were in the range of 62.5 ~ 125 microg/ml, and the MICs of gentamicin (GEN) ranged from 1.9 microg/ml to 2,000 microg/ml. The fractional inhibitory concentrations (FICs) of GAL, in combination with GEN, against 3 test strains were 0.4, 3.9, and 250 microg/ml, and were all 15.62 microg/ml in GEN. The FIC index showed marked synergism in the value range of 0.19 to 0.25. By determining time-kill curves, also confirmed the low synergism of the GAL and GEN combination against 4 h, 8 h, 12 h, and 24 h cultured MRSA. The time-kill study results indicated a low synergistic effect against 3 test strains. Thus, the mixture of GAL and GEN could lead to the development of new combination antibiotics against MRSA infection.

  16. Characteristics and synergistic effects of co-combustion of carbonaceous wastes with coal.

    Onenc, Sermin; Retschitzegger, Stefan; Evic, Nikola; Kienzl, Norbert; Yanik, Jale

    2018-01-01

    This study presents combustion behavior and emission results obtained for different fuels: poultry litter (PL) and its char (PLC), scrap tires (ST) and its char (STC) and blends of char/lignite (PLC/LIG and STC/LIG). The combustion parameters and emissions were investigated via a non-isothermal thermogravimetric method and experiments in a lab-scale reactor. Fuel indexes were used for the prediction of high temperature corrosion risks and slagging potentials of the fuels used. The addition of chars to lignite caused a lowering of the combustion reactivity (anti-synergistic effect). There was a linear correlation between the NO x emissions and the N content of the fuel. The form of S and the concentrations of alkali metals in the fuel had a strong effect on the extent of SO 2 emissions. The use of PL and PLC in blends reduced SO 2 emissions and sulphur compounds in the fly ash. The 2S/Cl ratio in the fuel showed that only PLC and STC/PLC would show a risk of corrosion during combustion. The ratio of basic to acidic oxides in fuel indicated that ST, STC and STC/LIG have low slagging potential. The molar (Si+P+K)/(Ca+Mg) ratio, which was used for PL, PLC and PLC containing blends, showed that the ash melting temperatures of these fuels would be higher than 1000 °C. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Anti-tumor effect and mechanism of cyclooxygenase-2 inhibitor through matrix metalloproteinase 14 pathway in PANC-1 cells.

    Li, Siyuan; Gu, Zhuoyu; Xiao, Zhiwei; Zhou, Ting; Li, Jun; Sun, Kan

    2015-01-01

    To investigate whether celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, can attenuate proliferation, migration, invasion and MMP-14 expression in pancreatic cancer cells PANC-1 and the possible anti-tumor mechanism of celecoxib. Human pancreatic cancer cell line PANC-1 cells were treated with diverse concentrations of celecoxib (20, 60, 100 μmol/L). Cell proliferation, invasion and migration capabilities were measured by MTT colorimetry, transwell invasion assay, and scratch assay separately. At the same time, the protein expression of COX-2 and MMP-14 was assessed by ELISA. The capabilities of proliferation, invasion and migration in PANC-1 cells were attenuated in a concentration-dependent manner after treated with celecoxib, followed by the down-regulation of the protein expression of COX-2 and MMP-14. In addition, MMP-14 expression was significantly positively correlated with COX-2 expression. COX-2 inhibitor celecoxib can inhibit the proliferation, invasion and migration of PANC-1 cells via down-regulating the expression of MMP-14 in a concentration-dependent manner, thus contributing to its anti-tumor effect in pancreatic cancer.

  18. Synergistic effect of pyrazoles derivatives and doxorubicin in claudin-low breast cancer subtype.

    Saueressig, Silvia; Tessmann, Josiane; Mastelari, Rosiane; da Silva, Liziane Pereira; Buss, Julieti; Segatto, Natalia Vieira; Begnini, Karine Rech; Pacheco, Bruna; de Pereira, Cláudio Martin Pereira; Collares, Tiago; Seixas, Fabiana Kömmling

    2018-02-01

    Breast cancer is a global public health problem. For some subtypes, such as Claudin-low, the prognosis is poorer and the treatment is still a challenge. Pyrazoles are an important class of heterocyclic compounds and are promising anticancer agents based on their chemical properties. The present study was aimed not only at testing pyrazoles previously prepared by our research group in two breast cancer cell lines characterized by intermediated response to conventional chemotherapy but also at analyzing the possible synergistic effect of these pyrazoles associated with doxorubicin. Four 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-1H pyrazoles were tested for the first time in MCF-7 and MDA-MB-231 culture cells. The pyrazoles with best results in cytotoxicity were used in combination with doxorubicin and compared with this drug alone as standard. The synergic effect was analyzed using Combination Index method. In addition, cell death and apoptosis assays were carried out. Two pyrazoles with cytotoxic effect in MCF-7 and especially in MDA-MB-231 were identified. This activity was markedly higher in pyrazoles containing bromine and chlorine substituents. The combination of these pyrazoles with doxorubicin had a significant synergic effect in both cells tested and mainly in MDA-MB-231. These data were confirmed with apoptosis and cell death analysis. The synergic effect observed with combination of these pyrazoles and doxorubicin deserves special attention in Claudin-low breast cancer subtype. This should be explored in order to improve treatment results and minimize side effects. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  19. Classification of suppressor additives based on synergistic and antagonistic ensemble effects

    Broekmann, P., E-mail: peter.broekmann@iac.unibe.ch [BASF SE, Global Business Unit Electronic Materials, 67056 Ludwigshafen (Germany); Department of Chemistry and Biochemistry, University of Bern, Bern (Switzerland); Fluegel, A.; Emnet, C.; Arnold, M.; Roeger-Goepfert, C.; Wagner, A. [BASF SE, Global Business Unit Electronic Materials, 67056 Ludwigshafen (Germany); Hai, N.T.M. [Department of Chemistry and Biochemistry, University of Bern, Bern (Switzerland); Mayer, D. [BASF SE, Global Business Unit Electronic Materials, 67056 Ludwigshafen (Germany)

    2011-05-01

    Highlights: > Three fundamental types of suppressor additives for copper electroplating could be identified by means of potential transient measurements. > These suppressor additives differ in their synergistic and antagonistic interplay with anions that are chemisorbed on the metallic copper surface during electrodeposition. > In addition these suppressor chemistries reveal different barrier properties with respect to cupric ions and plating additives (Cl, SPS). - Abstract: Three fundamental types of suppressor additives for copper electroplating could be identified by means of potential transient measurements. These suppressor additives differ in their synergistic and antagonistic interplay with anions that are chemisorbed on the metallic copper surface during electrodeposition. In addition these suppressor chemistries reveal different barrier properties with respect to cupric ions and plating additives (Cl, SPS). While the type-I suppressor selectively forms efficient barriers for copper inter-diffusion on chloride-terminated electrode surfaces we identified a type-II suppressor that interacts non-selectively with any kind of anions chemisorbed on copper (chloride, sulfate, sulfonate). Type-I suppressors are vital for the superconformal copper growth mode in Damascene processing and show an antagonistic interaction with SPS (Bis-Sodium-Sulfopropyl-Disulfide) which involves the deactivation of this suppressor chemistry. This suppressor deactivation is rationalized in terms of compositional changes in the layer of the chemisorbed anions due to the competition of chloride and MPS (Mercaptopropane Sulfonic Acid) for adsorption sites on the metallic copper surface. MPS is the product of the dissociative SPS adsorption within the preexisting chloride matrix on the copper surface. The non-selectivity in the adsorption behavior of the type-II suppressor is rationalized in terms of anion/cation pairing effects of the poly-cationic suppressor and the anion-modified copper

  20. New Mechanism on Synergistic Effect of Nitrite and Triethanolamine Addition on the Corrosion of Ductile Cast Iron

    K. T. Kim

    2016-01-01

    Full Text Available In general, we compared the different inhibition mechanisms of organic inhibitor with that of anodic inhibitor. When triethanolamine or nitrite was added separately to tap water for inhibiting the corrosion of ductile cast iron, large amounts of inhibitor were needed. This is because the corrosion inhibitors had to overcome the galvanic corrosion that occurs between graphite and matrix. In this work, we investigated the corrosion of ductile cast iron in tap water with/without inhibitors. The corrosion rate was measured using chemical immersion test and electrochemical methods, including anodic polarization test. The inhibited surface was analyzed using EPMA and XPS. Test solutions were analyzed by performing FT-IR measurement. When triethanolamine and nitrite coexisted in tap water, synergistic effect built up, and the inhibition effect was ca. 30 times more effective than witnessed with single addition. This work focused on the synergistic effect brought about by nitrite and triethanolamine and its novel mechanism was also proposed.

  1. A new extract of the plant calendula officinalis produces a dual in vitro effect: cytotoxic anti-tumor activity and lymphocyte activation

    Jiménez-Medina, Eva; Garcia-Lora, Angel; Paco, Laura; Algarra, Ignacio; Collado, Antonia; Garrido, Federico

    2006-01-01

    Phytopharmacological studies of different Calendula extracts have shown anti-inflamatory, anti-viral and anti-genotoxic properties of therapeutic interest. In this study, we evaluated the in vitro cytotoxic anti-tumor and immunomodulatory activities and in vivo anti-tumor effect of Laser Activated Calendula Extract (LACE), a novel extract of the plant Calendula Officinalis (Asteraceae). An aqueous extract of Calendula Officinalis was obtained by a novel extraction method in order to measure its anti-tumor and immunomodulatory activities in vitro. Tumor cell lines derived from leukemias, melanomas, fibrosarcomas and cancers of breast, prostate, cervix, lung, pancreas and colorectal were used and tumor cell proliferation in vitro was measured by BrdU incorporation and viable cell count. Effect of LACE on human peripheral blood lymphocyte (PBL) proliferation in vitro was also analyzed. Studies of cell cycle and apoptosis were performed in LACE-treated cells. In vivo anti-tumor activity was evaluated in nude mice bearing subcutaneously human Ando-2 melanoma cells. The LACE extract showed a potent in vitro inhibition of tumor cell proliferation when tested on a wide variety of human and murine tumor cell lines. The inhibition ranged from 70 to 100%. Mechanisms of inhibition were identified as cell cycle arrest in G0/G1 phase and Caspase-3-induced apoptosis. Interestingly, the same extract showed an opposite effect when tested on PBLs and NKL cell line, in which in vitro induction of proliferation and activation of these cells was observed. The intraperitoneal injection or oral administration of LACE extract in nude mice inhibits in vivo tumor growth of Ando-2 melanoma cells and prolongs the survival day of the mice. These results indicate that LACE aqueous extract has two complementary activities in vitro with potential anti-tumor therapeutic effect: cytotoxic tumor cell activity and lymphocyte activation. The LACE extract presented in vivo anti-tumoral activity in nude

  2. Synergistic effect of the interaction between curcumin and diclofenac on the formalin test in rats.

    De Paz-Campos, Marco A; Ortiz, Mario I; Chávez Piña, Aracely E; Zazueta-Beltrán, Liliana; Castañeda-Hernández, Gilberto

    2014-10-15

    The association of non-steroidal anti-inflammatory drugs with certain plant extracts can increase antinociceptive activity, permitting the use of lower doses and thus limiting side effects. Therefore, the aim objective of the current study was to examine the effects of curcumin on the nociception and pharmacokinetics of diclofenac in rats. Antinociception was assessed using the formalin test. Diluted formalin was injected subcutaneously into the dorsal surface of the right hind paw. Nociceptive behavior was quantified as the number of flinches of the injected paw during 60 min after injection, and a reduction in formalin-induced flinching was interpreted as an antinociceptive response. Rats were treated with oral diclofenac (1-31 mg/kg), curcumin (3.1-100 mg/kg) or the diclofenac-curcumin combination (2.4-38.4 mg/kg). To determine the possibility of a pharmacokinetic interaction, the oral bioavailability of diclofenac (10 mg/kg) was studied in presence and the absence of curcumin (31 mg/kg). Diclofenac, curcumin, or diclofenac-curcumin combination produced an antinociceptive effect on the formalin test. ED30 values were estimated for the individual drugs, and an isobologram was constructed. The derived theoretical ED30 for the antinociceptive effect (19.2 mg/kg) was significantly different from the observed experimental ED30 value (9.8 mg/kg); hence, the interaction between diclofenac and curcumin that mediates the antinociceptive effect was synergistic. Notwithstanding, the interaction does not appear to involve pharmacokinetic mechanisms, as oral curcumin failed to produce any significant alteration in oral diclofenac bioavailability. Data suggest that the diclofenac-curcumin combination can interact at the systemic level and may have therapeutic advantages for the clinical treatment of inflammatory pain. Copyright © 2014 Elsevier GmbH. All rights reserved.

  3. Evaluation of synergistic effect in vacuum pack, refrigeration and irradiated treatments of minimally processed cassava

    Pedroso, Bianca Maria

    2005-01-01

    Cassava is cultivated almost all over the world and it is considered one of the most important nutritious sources of calories in the human diet. Cassava is a viable food against starvation in several poor areas of the world because it is an extremely resistant culture and may reach satisfactory economical yield. We utilized vacuum packed industrialized cassava irradiated with 0,1 kGy, 3kGy and 5kGy and stored under refrigeration for 1, 21, 30 and 50 days. Our objective was to analyse the synergistic effect of vacuum packing, irradiation and refrigeration on the preservation of minimally processed cassava. The samples were analyzed for pH, acidity, weight, humidity, texture and color. The irradiation did not affect the chemical characteristics of the cassava. Neither the pH nor the acidity, the most relevant variables to verify deterioration in cassava, presented significant alterations during the period of storage. Comparing the irradiated treatments, the dose of 1kGy and 3kGy affected the physic-chemical characteristics of the cassava the least during the period of storage and refrigeration for 50 days; the doses of 1kGy,3kGy and 5kGy scored the highest rates the sensorial analysis during the period of storage for 21 days. (author)

  4. Tree growth acceleration and expansion of alpine forests: The synergistic effect of atmospheric and edaphic change.

    Silva, Lucas C R; Sun, Geng; Zhu-Barker, Xia; Liang, Qianlong; Wu, Ning; Horwath, William R

    2016-08-01

    Many forest ecosystems have experienced recent declines in productivity; however, in some alpine regions, tree growth and forest expansion are increasing at marked rates. Dendrochronological analyses at the upper limit of alpine forests in the Tibetan Plateau show a steady increase in tree growth since the early 1900s, which intensified during the 1930s and 1960s, and have reached unprecedented levels since 1760. This recent growth acceleration was observed in small/young and large/old trees and coincided with the establishment of trees outside the forest range, reflecting a connection between the physiological performance of dominant species and shifts in forest distribution. Measurements of stable isotopes (carbon, oxygen, and nitrogen) in tree rings indicate that tree growth has been stimulated by the synergistic effect of rising atmospheric CO2 and a warming-induced increase in water and nutrient availability from thawing permafrost. These findings illustrate the importance of considering soil-plant-atmosphere interactions to understand current and anticipate future changes in productivity and distribution of forest ecosystems.

  5. Synergistic effect of Candida maltosa HY-35 and Enterobacter aerogenes W-23 on hydrogen production

    Lu, Wenyu; Wen, Jianping; Chen, Yu.; Sun, Bing; Jia, Xiaoqiang; Liu, Minghui; Caiyin, Qinggele [Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072 (China)

    2007-06-15

    An aciduric high-yielding hydrogen yeast named Candida maltosa HY-35 was screened, which can grow and produce hydrogen at pH 1.3. Further research was carried out batchwise to measure the hydrogen-producing ability of a mixed culture of C. maltosa HY-35 and a facultative anaerobe Enterobacter aerogenes W-23. In this method, with the mixed culture of these two strains at 35 {sup circle} C for 28 h, the hydrogen yield was 1735 ml/l, which was 17.15% and 119.90% higher than those of the monoculture of E. aerogenes W-23 and C. maltosa HY-35, respectively. Meanwhile, the average hydrogen production rate with the mixed culture was 261.1 ml/h/l, which was 7.85% and 146.23% higher than those of the monoculture of E. aerogenes W-23 and C. maltosa HY-35, respectively. The results suggested that mixed culture of these two strains had the synergistic effect on hydrogen production. The optimum fermentation medium and operation conditions for hydrogen production with mixed culture were also investigated. (author)

  6. Assembly of graphene oxide on nonconductive nonwovens by the synergistic effect of interception and electrophoresis

    Jiao, Kunyan; Zhu, Ting; Li, Xianhua; Shan, Mingjing; Xu, Zhiwei, E-mail: xuzhiwei@tjpu.edu.cn; Jiao, Yanan [Tianjin Polytechnic University, Key Laboratory of Advanced Braided Composites, Ministry of Education (China)

    2015-09-15

    Electrophoretic deposition has always been an attractive method to deposit nanoparticles on conductive materials, while most fiber-based materials have poor conductivity which limits the application of electrophoretic deposition in assembling nanoparticles onto fiber-based materials. A new approach to assemble graphene oxide (GO) nanosheets on nonconductive nonwovens via the synergistic effect of electrophoresis and fiber interception was reported in this study. To improve surface wettability, polypropylene (PP) nonwovens were modified by acrylic acid and subsequent N{sub 2} plasma treatment. Then GO nanosheets were anchored onto modified nonwovens by electrophoresis process and nonwoven interception. The results of scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) manifested that etching and grafting simultaneously occurred on the surface of modified PP nonwovens, resulting in a great improvement of nonwoven hydrophily, which corresponded to the results of water contact angle. Furthermore, the results of X-ray diffraction, energy dispersive X-ray, SEM, and FTIR indicated that different amounts of GO nanosheets were successfully assembled onto modified PP nonwovens. This method provides a new avenue for incorporating carbon nanoparticles with nonconductive fiber-based materials, and modified PP nonwovens assembled with GO nanosheets show good air filtration performance for sodium chloride aerosol with a filtration efficiency of 87.9 % and a pressure drop of 36.4 mmH{sub 2}O, and the reduced GO/PP composite nonwovens exhibit enhanced conductivity.

  7. Synergistic effects of iodine and silver ions co-implanted in 6H-SiC

    Kuhudzai, R. J.; Malherbe, J. B.; Hlatshwayo, T. T.; van der Berg, N. G.; Devaraj, A.; Zhu, Z.; Nandasiri, M.

    2015-12-01

    Motivated by the aim of understanding the release of fission products through the SiC coating of fuel kernels in modern high temperature nuclear reactors, a fundamental investigation is conducted to understand the synergistic effects of implanted silver (Ag) and iodine (I) in 6H-SiC. The implantation of the individual species, as well as the co-implantation of 360 keV ions of I and Ag at room temperature in 6H-SiC and their subsequent annealing behaviour has been investigated by Secondary Ion Mass Spectrometry (SIMS), Atom Probe Tomography (APT) and X-ray Photoelectron Spectroscopy (XPS). SIMS and APT measurements indicated the presence of Ag in the co-implanted samples after annealing at 1500 °C for 30 h in sharp contrast to the samples implanted with Ag only. In samples implanted with Ag only, complete loss of the implanted Ag was observed. However, for I only implanted samples, some iodine was retained. APT of annealed co-implanted 6H-SiC showed clear spatial association of Ag and I clusters in SiC, which can be attributed to the observed I assisted retention of Ag after annealing. Such detailed studies will be necessary to identify the fundamental mechanism of fission products migration through SiC coatings.

  8. Homogeneous sonophotolysis of food processing industry wastewater: Study of synergistic effects, mineralization and toxicity removal.

    Durán, A; Monteagudo, J M; Sanmartín, I; Gómez, P

    2013-03-01

    The mineralization of industrial wastewater coming from food industry using an emerging homogeneous sonophotolytic oxidation process was evaluated as an alternative to or a rapid pretreatment step for conventional anaerobic digestion with the aim of considerably reducing the total treatment time. At the selected operation conditions ([H(2)O(2)]=11,750ppm, pH=8, amplitude=50%, pulse length (cycles)=1), 60% of TOC is removed after 60min and 98% after 180min when treating an industrial effluent with 2114ppm of total organic carbon (TOC). This process removed completely the toxicity generated during storing or due to intermediate compounds. An important synergistic effect between sonolysis and photolysis (H(2)O(2)/UV) was observed. Thus the sonophotolysis (ultrasound/H(2)O(2)/UV) technique significantly increases TOC removal when compared with each individual process. Finally, a preliminary economical analysis confirms that the sono-photolysis with H(2)O(2) and pretreated water is a profitable system when compared with the same process without using ultrasound waves and with no pretreatment. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. Synergistic effects of mica and wollastonite fillers on thermal performance of intumescent fire retardant coating

    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.

  10. Synergistic effects of surface erosion on tritium inventory and permeation in metallic plasma facing armours

    Federici, G.; Holland, D. F.; Matera, R.

    1996-10-01

    In the next generation of DT fuelled tokamaks, i.e., the International Thermonuclear Experimental Reactor (ITER) implantation of energetic DT particles on some portions of the plasma facing components (PFCs) will take place along with significant erosion of the armour surfaces. As a result of the simultaneous removal of material from the front surface, the build-up of tritium inventory and the start of permeation originating in the presence of large densities of neutron-induced traps is expected to be influenced considerably and special provisions could be required to minimise the consequences on the design. This paper reports on the results of a tritium transport modelling study based on a new model which describes the migration of implanted tritium across the bulk of metallic plasma facing materials containing neutron-induced traps which can capture it and includes the synergistic effects of surface erosion. The physical basis of the model is summarised, but emphasis is on the discussion of the results of a comparative study performed for beryllium and tungsten armours for ranges of design and operation conditions similar to those anticipated in the divertor of ITER.

  11. Synergistic effect of high pressure processing and Lactobacillus casei antimicrobial activity against pressure resistant Listeria monocytogenes.

    Chung, Hyun-Jung; Yousef, Ahmed E

    2010-09-30

    The purpose of this study was to evaluate combinations of high pressure processing (HPP) and Lactobacillus casei antimicrobial activity against Listeria monocytogenes strains with variation in pressure resistance in culture and in a food model. In culture, combination of HPP (350 MPa, for 1-20 min) and Lb. casei cell extract (CE, 32 CEAU/ml) showed a significant synergistic bactericidal effect (P5 log(10)CFU/ml. Synergy between CE and HPP was most evident in the pressure-resistant strain, OSY-8578. Similar result was observed in meat products where high pressure (500 MPa for 1 min), and high-activity CE (100 CEAU/g) caused >5 log reduction in the viability of L. monocytogenes Scott A. The combination treatment resulted in the absence of peaks associated with cellular components in DSC thermogram suggesting that the presence of CE may have caused a considerable damage to cellular components during the high pressure treatment. Copyright 2010 Elsevier B.V. All rights reserved.

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

    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.

  13. Red blood cell antibodies in pregnancy and their clinical consequences: synergistic effects of multiple specificities.

    Nordvall, Maria; Dziegiel, Morten; Hegaard, Hanne Kristine; Bidstrup, Mogens; Jonsbo, Finn; Christensen, Birgit; Hedegaard, Morten

    2009-10-01

    The objective was to determine clinical consequences of various specificities for the infant/fetus. The population was patients referred between 1998 and 2005 to the tertiary center because of detected red blood cell (RBC) alloimmunization. Altogether 455 infants were delivered by 390 alloimmunized women. This was a retrospective cohort study. Data were obtained from the blood bank register and the obstetric and neonatal database. As indicators of hemolytic activity of the antibodies, the frequency of the therapeutic interventions intrauterine transfusion, exchange transfusion, and simple transfusion was used. Anti-D was the most common antibody (46.6%), followed by anti-K (15.4%). A combination of antibodies was detected in 27%. All three types of therapeutic intervention were significantly more frequent in women with anti-D plus an additional antibody than in women with anti-D as the sole antibody. The anti-D titer closely paralleled the clinical importance of the antibody. One case of anti-s with a titer of 512 required all three types of transfusion. Anti-D was the single most frequent and harmful specificity closely followed by anti-K. Combinations of antibody specificities were more harmful than single specificities, and a potentially synergistic effect should be considered.

  14. Why Do Lithium-Oxygen Batteries Fail: Parasitic Chemical Reactions and Their Synergistic Effect.

    Yao, Xiahui; Dong, Qi; Cheng, Qingmei; Wang, Dunwei

    2016-09-12

    As an electrochemical energy-storage technology with the highest theoretical capacity, lithium-oxygen batteries face critical challenges in terms of poor stabilities and low charge/discharge round-trip efficiencies. It is generally recognized that these issues are connected to the parasitic chemical reactions at the anode, electrolyte, and cathode. While the detailed mechanisms of these reactions have been studied separately, the possible synergistic effects between these reactions remain poorly understood. To fill in the knowledge gap, this Minireview examines literature reports on the parasitic chemical reactions and finds the reactive oxygen species a key chemical mediator that participates in or facilitates nearly all parasitic chemical reactions. Given the ubiquitous presence of oxygen in all test cells, this finding is important. It offers new insights into how to stabilize various components of lithium-oxygen batteries for high-performance operations and how to eventually materialize the full potentials of this promising technology. © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

  15. Synergistic effects of surface erosion on tritium inventory and permeation in metallic plasma facing armours

    Federici, G.; Holland, D.F.; Matera, R.

    1996-01-01

    In the next generation of DT fuelled tokamaks, i.e., the international thermonuclear experimental reactor (ITER) implantation of energetic DT particles on some portions of the plasma facing components (PFCs) will take place along with significant erosion of the armour surfaces. As a result of the simultaneous removal of material from the front surface, the build-up of tritium inventory and the start of permeation originating in the presence of large densities of neutron-induced traps is expected to be influenced considerably and special provisions could be required to minimise the consequences on the design. This paper reports on the results of a tritium transport modelling study based on a new model which describes the migration of implanted tritium across the bulk of metallic plasma facing materials containing neutron-induced traps which can capture it and includes the synergistic effects of surface erosion. The physical basis of the model is summarised, but emphasis is on the discussion of the results of a comparative study performed for beryllium and tungsten armours for ranges of design and operation conditions similar to those anticipated in the divertor of ITER. (orig.)

  16. THE SYNERGISTIC EFFECT OF HYBRID FLAME RETARDANTS ON PYROLYSIS BEHAVIOUR OF HYBRID COMPOSITE MATERIALS

    M. T. ALBDIRY

    2012-06-01

    Full Text Available The aim of this investigation is to comprehensively understand the polymeric composite behavior under direct fire sources. The synergistic effects of hybrid flame retardant material on inhabiting the pyrolysis of hybrid reinforced fibers, woven roving (0°- 45° carbon and kevlar (50/50 wt/wt, and an araldite resin composites were studied. The composites were synthesised and coated primarily by zinc borate (2ZnO.3B2O3.3.5H2O and modified by antimony trioxide (Sb2O3 with different amounts (10-30 wt% of flame retardant materials. In the experiments, the composite samples were exposed to a direct flame source generated by oxyacetylene flame (~3000ºC at variable exposure distances of 10-20 mm. The synergic flame retardants role of antimony trioxide and zinc borate on the composite surface noticeably improves the flame resistance of the composite which is attributed to forming a protective mass and heat barrier on the composite surface and increasing the melt viscosity.

  17. Synergistic effects of pyrrolizidine alkaloids and lipopolysaccharide on preterm delivery and intrauterine fetal death in mice.

    Guo, Yu; Ma, Zhenguo; Kou, Hao; Sun, Rongze; Yang, Hanxiao; Smith, Charles Vincent; Zheng, Jiang; Wang, Hui

    2013-08-29

    Preterm birth is the leading cause of death for newborn infants, and lipopolysaccharide (LPS) is commonly used to induce preterm delivery in experimental animals. Pyrrolizidine alkaloids (PAs) are widespread and occur in foods, herbs, and other plants. This study was to investigate the synergistic effects of LPS and two representative PAs, retrorsine (RTS) and monocrotaline (MCT), on preterm delivery and fetal death. Pregnant Kunming mice were divided into seven groups: control, RTS, MCT, LPS, RTS+LPS and two MCT+LPS groups. Animals in PAs and PAs+LPS groups were dosed intragastrically with RTS (10mg/kg) or MCT (20 mg/kg or 60 mg/kg) from gestational day (GD) 9 to GD16; mice given LPS were injected intraperitoneally with 150 μg/kg on GD15.5. Latencies to delivery, numbers of pups live and dead at birth were recorded, and livers of live neonates were collected. The incidence of LPS-induced preterm birth was enhanced in dams pretreated with MCT, and combination of PAs and LPS increased fetal mortality from PAs. The enhancement of LPS-induced preterm delivery and fetal demise in animals exposed chronically to PAs and other substances found in foods and beverages consumed widely by humans merits further focused investigation. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

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

    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.

  19. Synergistic antiviral effect in vitro of azidothymidine and amphotericin B methyl ester in combination on HIV infection

    Hansen, J E; Nielsen, C; Svenningsen, A

    1992-01-01

    The nucleoside analogue azidothymidine (AZT) and the methyl ester of amphotericin B (AME) were assayed for antiviral effect on HIV infection singly and in combination. Both compounds were effective in inhibiting HIV infection of MT-4 cells. At concentrations where either compound alone had no sig...... synergistic antiviral properties. Amphotericin B itself significantly reduced HIV infectivity in vitro and should not be used as an antifungal agent in cultures intended to propagate HIV....

  20. Synergistic enhancing effect of N+C alloying on cyclic deformation behaviors in austenitic steel

    Kang, J. [State Key Laboratory of Metastable Materials Science and Technology, Yanshan University, Qinhuangdao 066004 (China); Zhang, F.C., E-mail: zfc@ysu.edu.cn [State Key Laboratory of Metastable Materials Science and Technology, Yanshan University, Qinhuangdao 066004 (China); Long, X.Y. [State Key Laboratory of Metastable Materials Science and Technology, Yanshan University, Qinhuangdao 066004 (China); Yang, Z.N. [National Engineering Research Center for Equipment and Technology of Cold Strip Rolling, Yanshan University, Qinhuangdao 066004 (China)

    2014-07-29

    Cyclic plastic and elastic strain controlled deformation behaviors of Mn18Cr7 austenitic steel with N0.6C0.3 synergistic enhancing alloying have been investigated using tension-compression low cycle fatigue and three-point bending high cycle fatigue testing. Results of cyclic deformation characteristic and fatigue damage mechanism have been compared to that in Mn12C1.2 steel. Mn18Cr7N0.6C0.3 steel always shows cyclic softening caused by enhanced planar sliding due to the interaction between N+C and the substitutional atoms as well as the dislocation, which is totally different from cyclic hardening in Mn12C1.2 steel caused by the interaction between C members of C–Mn couples with the dislocation. Enhanced effective stress is obtained due to the solid solution strengthening effect caused by the short range order at low strain amplitude while this effect does not work at high strain amplitude. Internal stress contributes most to the cyclic softening with the increase of strain amplitudes. Significant planar slip characteristic can be observed resulting from low stacking fault energy and high short range order effects in Mn18Cr7N0.6C0.3 steel and finally the parallel or intersecting thin sheets with dislocation tangles separated by dislocation free sheets are obtained with the prolonged cycles under cyclic elastic or plastic strain controlled fatigue testing. There exist amounts of small cracks on the surface of the Mn18Cr7N0.6C0.3 steel because fatigue crack initiation is promoted by the cyclic plastic strain localization. However, the zigzag configuration of the cracks reveals that the fatigue crack propagation is highly inhibited by the planar slip characteristic, which eventually improves the fatigue life.

  1. Chimeric HCMV/HSV-1 and Δγ134.5 oncolytic herpes simplex virus elicit immune mediated antigliomal effect and antitumor memory

    Mohammed G. Ghonime

    2018-02-01

    Full Text Available Malignant gliomas are the most common primary brain tumor and are characterized by rapid and highly invasive growth. Because of their poor prognosis, new therapeutic strategies are needed. Oncolytic virotherapy (OV is a promising strategy for treating cancer that incorporates both direct viral replication mediated and immune mediated mechanisms to kill tumor cells. C134 is a next generation Δγ134.5 oHSV-1 with improved intratumoral viral replication. It remains safe in the CNS environment by inducing early IFN signaling which restricts its replication in non-malignant cells. We sought to identify how C134 performed in an immunocompetent tumor model that restricts its replication advantage over first generation viruses. To achieve this we identified tumors that have intact IFN signaling responses that restrict C134 and first generation virus replication similarly. Our results show that both viruses elicit a T cell mediated anti-tumor effect and improved animal survival but that subtle difference exist between the viruses effect on median survival despite equivalent in vivo viral replication. To further investigate this we examined the anti-tumor activity in immunodeficient mice and in syngeneic models with re-challenge. These studies show that the T cell response is integral to C134 replication independent anti-tumor response and that OV therapy elicits a durable and circulating anti-tumor memory. The studies also show that repeated intratumoral administration can extend both OV anti-tumor effects and induce durable anti-tumor memory that is superior to tumor antigen exposure alone.

  2. Synergistic Effects of NDRG2 Overexpression and Radiotherapy on Cell Death of Human Prostate LNCaP Cells.

    Alizadeh Zarei, M; Takhshid, M A; Behzad Behbahani, A; Hosseini, S Y; Okhovat, M A; Rafiee Dehbidi, Gh R; Mosleh Shirazi, M A

    2017-09-01

    Radiation therapy is among the most conventional cancer therapeutic modalities with effective local tumor control. However, due to the development of radio-resistance, tumor recurrence and metastasis often occur following radiation therapy. In recent years, combination of radiotherapy and gene therapy has been suggested to overcome this problem. The aim of the current study was to explore the potential synergistic effects of N-Myc Downstream-Regulated Gene 2 (NDRG2) overexpression, a newly identified candidate tumor suppressor gene, with radiotherapy against proliferation of prostate LNCaP cell line. In this study, LNCaP cells were exposed to X-ray radiation in the presence or absence of NDRG2 overexpression using plasmid PSES- pAdenoVator-PSA-NDRG2-IRES-GFP. The effects of NDRG2 overexpression, X-ray radiation or combination of both on the cell proliferation and apoptosis of LNCaP cells were then analyzed using MTT assay and flow cytometery, respectively. Results of MTT assay showed that NDRG2 overexpression and X-ray radiation had a synergistic effect against proliferation of LNCaP cells. Moreover, NDRG2 overexpression increased apoptotic effect of X-ray radiation in LNCaP cells synergistically. Our findings suggested that NDRG2 overexpression in combination with radiotherapy may be an effective therapeutic option against prostate cancer.

  3. Synergistic Effect of the Lactoperoxidase System and Cinnamon Essential Oil on Total Flora and Salmonella Growth Inhibition in Raw Milk

    Chiraz Abbes

    2018-01-01

    Full Text Available Despite its antibacterial and antipathogenic effects, the heat treatment of milk induces undesirable changes that can be noted in the overall properties of ultrahigh temperature (UHT milk, such as changes in nutritional and organoleptic properties. Our goal is to find new nonthermal antibacterial technologies for the preservation of raw milk (RM. This study investigates the possible synergistic effect of using a combination of the lactoperoxidase system (LS and 3 μg mL−1 of cinnamon essential oil (cinnamon EO to inactivate the total flora of milk and Salmonella Hadar (S. Hadar. The LS was activated with 30 mg L−1 sodium percarbonate and 14 mg L−1 of sodium thiocyanate. Using this approach, we obtained a synergistic effect with a complete inhibition of the activity of the total flora of the milk and S. Hadar after 12 hours at 25°C. In addition, the attainment of synergy was defined when the inhibitory effect of the two compounds together was greater than the effect observed by each compound added alone. Moreover, the monitoring of the synergistic effect at 4°C for 5 days showed complete inhibition of total flora for 3 days and for S. Hadar it was up to 5 days. To summarize, the current study clearly identified a new inhibitory combination that may be used in food-based applications.

  4. Low dose radiation enhance the anti-tumor effect of high dose radiation on human glioma cell U251

    Wang Chang; Wang Guanjun; Tan Yehui; Jiang Hongyu; Li Wei

    2008-01-01

    Objective: To detect the effect on the growth of human glioma cell U251 induced by low dose irradiation and low dose irradiation combined with large dose irradiation. Methods: Human glioma cell line U251 and nude mice carried with human glioma were used. The tumor cells and the mice were treated with low dose, high dose, and low dose combined high dose radiation. Cells growth curve, MTT and flow cytometry were used to detect the proliferation, cell cycle and apoptosis of the cells; and the tumor inhibition rate was used to assess the growth of tumor in vivo. Results: After low dose irradiation, there was no difference between experimental group and control group in cell count, MTT and flow cytometry. Single high dose group and low dose combined high dose group both show significantly the suppressing effect on tumor cells, the apoptosis increased and there was cell cycle blocked in G 2 period, but there was no difference between two groups. In vivo apparent anti-tumor effect in high dose radiation group and the combining group was observed, and that was more significant in the combining group; the prior low dose radiation alleviated the injury of hematological system. There was no difference between single low dose radiation group and control. Conclusions: There is no significant effect on human glioma cell induced by low dose radiation, and low dose radiation could not induce adaptive response. But in vivo experience, low dose radiation could enhance the anti-tumor effect of high dose radiation and alleviated the injury of hematological system. (authors)

  5. Effects of Lactobacillus salivarius, Lactobacillus reuteri, and Pediococcus acidilactici on the nematode Caenorhabditis elegans include possible antitumor activity.

    Fasseas, Michael K; Fasseas, Costas; Mountzouris, Konstantinos C; Syntichaki, Popi

    2013-03-01

    This study examined the effects of three lactic acid bacteria (LAB) strains on the nematode Caenorhabditis elegans. Lactobacillus salivarius, Lactobacillus reuteri, and Pediococcus acidilactici were found to inhibit the development and growth of the worm. Compared to Escherichia coli used as the control, L. reuteri and P. acidilactici reduced the lifespan of wild-type and short-lived daf-16 worms. On the contrary, L. salivarius extended the lifespan of daf-16 worms when used live, but reduced it as UV-killed bacteria. The three LAB induced the expression of genes involved in pathogen response and inhibited the growth of tumor-like germ cells, without affecting DAF16 localization or increasing corpse cells. Our results suggest the possible use of C. elegans as a model for studying the antitumor attributes of LAB. The negative effects of these LAB strains on the nematode also indicate their potential use against parasitic nematodes.

  6. The Antitumor Effect of Single-domain Antibodies Directed Towards Membrane-associated Catalase and Superoxide Dismutase.

    Bauer, Georg; Motz, Manfred

    2016-11-01

    Neutralizing single-domain antibodies directed towards catalase or superoxide dismutase (SOD) caused efficient reactivation of intercellular reactive oxygen species/reactive nitrogen species (ROS/RNS)-dependent apoptosis-inducing signaling specifically in human tumor cells. Single-domain antibodies targeted tumor cell-specific membrane-associated SOD and catalase, but not the corresponding intracellular enzymes. They were shown to be about 200-fold more effective than corresponding classical recombinant antigen-binding fragments and more than four log steps more efficient than monoclonal antibodies. Combined addition of single-domain antibodies against catalase and SOD caused a remarkable synergistic effect. Proof-of-concept experiments in immunocompromised mice using human tumor xenografts and single-domain antibodies directed towards SOD showed an inhibition of tumor growth. Neutralizing single-domain antibodies directed to catalase and SOD also caused a very strong synergistic effect with the established chemotherapeutic agent taxol, indicating an overlap of signaling pathways. This effect might also be useful in order to avoid unwanted side-effects and to drastically lower the costs for taxol-based therapy. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  7. Liposomal n-butylidenephthalide protects the drug from oxidation and enhances its antitumor effects in glioblastoma multiforme

    Lin YL

    2015-09-01

    Full Text Available Yu-Ling Lin,1,2,* Kai-Fu Chang,3,* Xiao-Fan Huang,3 Che-Lun Hung,4 Shyh-Chang Chen,5 Wan-Ru Chao,6,7 Kuang-Wen Liao,1,8 Nu-Man Tsai3,9 1College of Biological Science and Technology, 2Center for Bioinformatics Research, National Chiao Tung University, Hsinchu, 3School of Medical Laboratory and Biotechnology, Chung Shan Medical University, 4Department of Computer Science and Communication Engineering, Providence University, 5Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, 6Institute of Medicine, Chung Shan Medical University, 7Department of Pathology, Chung Shan Medical University and Chung Shan Medical University Hospital, Taichung, 8Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, 9Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan *These authors contributed equally to this work Background: The natural compound n-butylidenephthalide (BP can pass through the blood–brain barrier to inhibit the growth of glioblastoma multiforme tumors. However, BP has an unstable structure that reduces its antitumor activity and half-life in vivo.Objective: The aim of this study is to design a drug delivery system to encapsulate BP to enhance its efficacy by improving its protection and delivery.Methods: To protect its structural stability against protein-rich and peroxide solutions, BP was encapsulated into a lipo-PEG-PEI complex (LPPC. Then, the cytotoxicity of BP/LPPC following preincubation in protein-rich, acid/alkaline, and peroxide solutions was analyzed by MTT. Cell uptake of BP/LPPC was also measured by confocal microscopy. The therapeutic effects of BP/LPPC were analyzed in xenograft mice following intratumoral and intravenous injections.Results: When BP was encapsulated in LPPC, its cytotoxicity was maintained following preincubation in protein-rich, acid/alkaline, and peroxide solutions. The cytotoxic activity of encapsulated BP was higher than

  8. Synergistic effects of seasonal rainfall, parasites and demography on fluctuations in springbok body condition

    Turner, Wendy C.; Versfeld, Wilferd D.; Kilian, J. Werner; Getz, Wayne M.

    2011-01-01

    Summary 1. Seasonality of rainfall can exert a strong influence on animal condition and on host-parasite interactions. The body condition of ruminants fluctuates seasonally in response to changes in energy requirements, foraging patterns and resource availability, and seasonal variation in parasite infections may further alter ruminant body condition. 2. This study disentangles effects of rainfall and gastrointestinal parasite infections on springbok (Antidorcas marsupialis) body condition and determines how these factors vary among demographic groups. 3. Using data from four years and three study areas, we investigated i) the influence of rainfall variation, demographic factors and parasite interactions on parasite prevalence or infection intensity, ii) whether parasitism or rainfall is a more important predictor of springbok body condition and iii) how parasitism and condition vary among study areas along a rainfall gradient. 4. We found that increased parasite intensity is associated with reduced body condition only for adult females. For all other demographic groups, body condition was significantly related to prior rainfall and not to parasitism. Rainfall lagged by two months had a positive effect on body condition. 5. Adult females showed evidence of a “periparturient rise” in parasite intensity, and had higher parasite intensity and lower body condition than adult males after parturition and during early lactation. After juveniles were weaned, adult females had lower parasite intensity than adult males. Sex differences in parasitism and condition may be due to differences between adult females and males in the seasonal timing of reproductive effort and its effects on host immunity, as well as documented sex differences in vulnerability to predation. 6. Our results highlight that parasites and the environment can synergistically affect host populations, but that these interactions might be masked by their interwoven relationships, their differential

  9. Reversal of fluconazole resistance induced by a synergistic effect with Acca sellowiana in Candida glabrata strains.

    R M Machado, Gabriella da; Pippi, Bruna; Dalla Lana, Daiane Flores; Amaral, Ana Paula S; Teixeira, Mário Lettieri; Souza, Kellen C B de; Fuentefria, Alexandre M

    2016-11-01

    The increased incidence of non-albicans Candida (NAC) resistant to fluconazole (FLZ) makes it necessary to use new therapeutic alternatives. Acca sellowiana (O.berg) Burret (Myrtaceae) is a guava with several proven biological activities. The interaction with fluconazole can be a feasible alternative to overcome this resistance. This study evaluates the in vitro antifungal activity of fractions obtained from the lyophilized aqueous extract of the leaves of A. sellowiana against resistant strains of NAC. The antifungal activity of the fractions was evaluated at 500 μg/mL by microdilution method. Checkerboard assay was performed to determine the effect of the combination of the F2 fraction and antifungal at concentrations: MIC/4, MIC/2, MIC, MIC × 2 and MIC × 4. Candida glabrata showed the lowest MIC values (500-3.90 μg/mL) and the F2 active fraction was the most effective. The association of F2 with FLZ showed a strong synergistic effect (FICI ≤ 0.5) against 100% of C. glabrata resistant isolates. Moreover, the F2 active fraction has demonstrated that probably acts in the cell wall of these yeasts. There was no observed acute dermal toxicity of lyophilized aqueous extract of leaves of A. sellowiana on pig ear skin cells. The interaction between substances present in the F2 active fraction is possibly responsible for the antifungal activity presented by this fraction. This study is unprecedented and suggests that the combination of F2 active fraction and FLZ might be used as an alternative treatment for mucocutaneus infections caused by C. glabrata resistant.

  10. The Synergistic Effects of Almond Protection Fungicides on Honey Bee (Hymenoptera: Apidae) Forager Survival.

    Fisher, Adrian; Coleman, Chet; Hoffmann, Clint; Fritz, Brad; Rangel, Juliana

    2017-06-01

    The honey bee (Apis mellifera L.) contributes ∼$17 billion annually to the United States economy, primarily by pollinating major agricultural crops including almond, which is completely dependent on honey bee pollination for nut set. Almond growers face constant challenges to crop productivity owing to pests and pathogens, which are often controlled with a multitude of agrochemicals. For example, fungicides are often applied in combination with other products to control fungal pathogens during almond bloom. However, the effects of fungicides on honey bee health have been so far understudied. To assess the effects of some of the top fungicides used during the 2012 California almond bloom on honey bee forager mortality, we collected foragers from a local apiary and exposed them to fungicides (alone and in various combinations) at the label dose, or at doses ranging from 0.25 to 2 times the label dose rate. These fungicides were Iprodione 2SE Select, Pristine, and Quadris. We utilized a wind tunnel and atomizer set up with a wind speed of 2.9 m/s to simulate field-relevant exposure of honey bees to these agrochemicals during aerial application in almond fields. Groups of 40-50 foragers exposed to either untreated controls or fungicide-laden treatments were monitored daily over a 10-d period. Our results showed a significant decrease in forager survival resulting from exposure to simulated tank mixes of Iprodione 2SE Select, as well as synergistic detrimental effects of Iprodione 2SE Select in combination with Pristine and Quadris on forager survival. © The Authors 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. Synergistic effects of Combined Therapy: nonfocused ultrasound plus Aussie current for noninvasive body contouring.

    Canela, Vivianne Carvalho; Crivelaro, Cinthia Nicoletti; Ferla, Luciane Zacchi; Pelozo, Gisele Marques; Azevedo, Juliana; Liebano, Richard Eloin; Nogueira, Caroline; Guidi, Renata Michelini; Grecco, Clóvis; Sant'Ana, Estela

    2018-01-01

    Nowadays, there are several noninvasive technologies being used for improving of body contouring. The objectives of this pilot study were to verify the effectiveness of the Heccus ® device, emphasizing the synergism between nonfocused ultrasound plus Aussie current in the improvement of body contour, and to determine if the association of this therapy with whole-body vibration exercises can have additional positive effects in the results of the treatments. Twenty healthy women aged 20-40 years participated in the study. Ten patients received Combined Therapy treatment (G1) and the other 10 participants received Combined Therapy with additional vibratory platform treatment (G2). Anthropometric and standardized photography analysis, ultrasonography, cutometry and self-adminestered questionnaires of tolerance and satisfaction levels with the treatment were used. Compared with baseline values, reduction of fat thickness was observed by ultrasonography in the posterior thigh area in the G1 group ( P <0.05) and in the buttocks ( P <0.05) and the posterior thigh areas ( P <0.05) in the G2. All the treated areas in both groups showed reduction in cellulite degree in the buttocks, G1 ( P <0.05) and G2 ( P <0.05), and in posterior thigh areas, G1 ( P <0.05) and G2 ( P <0.05). Optimal improvement of skin firmness (G1, P <0.0001; G2, P =0.0034) in the treated areas was observed in both groups. We conclude that the synergistic effects of the Combined Therapy (nonfocused ultrasound plus Aussie current) might be a good option with noninvasive body contouring treatment for improving the aspect of the cellulite, skin firmness and localized fat. If used in association with the whole-body vibratory platform, the results can be better, especially in the treatment of localized fat. Further studies with larger sample size should be performed to confirm these results.

  12. The Role of Bystander Effects in the Antitumor Activity of the Hypoxia-Activated Prodrug PR-104

    Foehrenbacher, Annika; Patel, Kashyap; Abbattista, Maria R.; Guise, Chris P.; Secomb, Timothy W.; Wilson, William R.; Hicks, Kevin O.

    2013-01-01

    Activation of prodrugs in tumors (e.g., by bioreduction in hypoxic zones) has the potential to generate active metabolites that can diffuse within the tumor microenvironment. Such “bystander effects” may offset spatial heterogeneity in prodrug activation but the relative importance of this effect is not understood. Here, we quantify the contribution of bystander effects to antitumor activity for the first time, by developing a spatially resolved pharmacokinetic/pharmacodynamic (SR-PK/PD) model for PR-104, a phosphate ester pre-prodrug that is converted systemically to the hypoxia-activated prodrug PR-104A. Using Green’s function methods we calculated concentrations of oxygen, PR-104A and its active metabolites, and resultant cell killing, at each point of a mapped three-dimensional tumor microregion. Model parameters were determined in vitro, using single cell suspensions to determine relationships between PR-104A metabolism and clonogenic cell killing, and multicellular layer (MCL) cultures to measure tissue diffusion coefficients. LC-MS/MS detection of active metabolites in the extracellular medium following exposure of anoxic single cell suspensions and MCLs to PR-104A confirmed that metabolites can diffuse out of cells and through a tissue-like environment. The SR-PK/PD model estimated that bystander effects contribute 30 and 50% of PR-104 activity in SiHa and HCT116 tumors, respectively. Testing the model by modulating PR-104A-activating reductases and hypoxia in tumor xenografts showed overall clonogenic killing broadly consistent with model predictions. Overall, our data suggest that bystander effects are important in PR-104 antitumor activity, although their reach may be limited by macroregional heterogeneity in hypoxia and reductase expression in tumors. The reported computational and experimental techniques are broadly applicable to all targeted anticancer prodrugs and could be used to identify strategies for rational prodrug optimization. PMID

  13. Synergistic effects of heat and irradiation treatment (thermoradiation) in the sterilization of medical products

    Trauth, C.A. Jr.; Sivinski, H.D.

    1975-01-01

    This paper describes a generic class of sterilization processes is which properly chosen combinations of radiation and heat synergistically inactivate many bacteria and viruses. Treatments with optimal combinations are shown to offer the possibility of using lower total doses and lower temperatures than would be required separately for sterilization. This results from easier elimination of heat-labile, radioresistant organisms and radiolabile, heat-resistant organisms, and from synergistic inactivation of organisms which are both radioresistant and heat resistant. These processes depend upon temperature, dose-rate, and time in fairly complex ways; therefore, an analytical framework in which they can be defined is also presented. (author)

  14. The in vitro synergistic inhibitory effect of human amniotic fluid and gentamicin on growth of Escherichia coli.

    Miglioli, P A; Schoffel, U; Gianfranceschi, L

    1996-01-01

    The activity of serum and its synergistic effect with many antibiotics against bacteria are well known. Few reports are available on similar phenomena produced by human amniotic fluid (HAF). Thus we investigated the antibacterial activity of HAF and the presence of a synergistic effect with gentamicin (GM) against Escherichia coli strains. Antimicrobial activity was evaluated as a delay of the growth curve, using a turbidimetric method. E. coli ATCC 10798 and E. coli SC 12155 were employed as test micro-organisms in nutrient broth, and GM was used at a subinhibitory concentration. HAF exerted antibacterial activity and, cooperating with GM at subinhibitory concentration, enhanced its antibiotic activity against E. coli. The presence of Schlievert's glycoprotein in HAF could explain these results.

  15. Combination of Tramadol with Minocycline Exerted Synergistic Effects on a Rat Model of Nerve Injury-Induced Neuropathic Pain

    Xiao-Peng Mei

    2012-09-01

    Full Text Available Neuropathic pain is a refractory clinical problem. Certain drugs, such as tramadol, proved useful for the treatment of neuropathic pain by inhibiting the activity of nociceptive neurons. Moreover, studies indicated that suppression or modulation of glial activation could prevent or reverse neuropathic pain, for example with the microglia inhibitor minocycline. However, few present clinical therapeutics focused on both neuronal and glial participation when treating neuropathic pain. Therefore, the present study hypothesized that combination of tramadol with minocycline as neuronal and glial activation inhibitor may exert some synergistic effects on spinal nerve ligation (SNL-induced neuropathic pain. Intrathecal tramadol or minocycline relieved SNL-induced mechanical allodynia in a dose-dependent manner. SNL-induced spinal dorsal horn Fos or OX42 expression was downregulated by intrathecal tramadol or minocycline. Combination of tramadol with minocycline exerted powerful and synergistic effects on SNL-induced neuropathic pain also in a dose-dependent manner. Moreover, the drug combination enhanced the suppression effects on SNL-induced spinal dorsal horn Fos and OX42 expression, compared to either drug administered alone. These results indicated that combination of tramadol with minocycline could exert synergistic effects on peripheral nerve injury-induced neuropathic pain; thus, a new strategy for treating neuropathic pain by breaking the interaction between neurons and glia bilaterally was also proposed.

  16. Synergistic effect of heat and solar UV on DNA damage and water disinfection of E. coli and bacteriophage MS2.

    Theitler, Dana Jennifer; Nasser, Abid; Gerchman, Yoram; Kribus, Abraham; Mamane, Hadas

    2012-12-01

    The response of a representative virus and indicator bacteria to heating, solar irradiation, or their combination, was investigated in a controlled solar simulator and under real sun conditions. Heating showed higher inactivation of Escherichia coli compared to the bacteriophage MS2. Heating combined with natural or simulated solar irradiation demonstrated a synergistic effect on the inactivation of E. coli, with up to 3-log difference for 50 °C and natural sun insolation of 2,000 kJ m(-2) (compared to the sum of the separate treatments). Similar synergistic effect was also evident when solar-UV induced DNA damage to E. coli was assessed using the endonuclease sensitive site assay (ESS). MS2 was found to be highly resistant to irradiation and heat, with a slightly synergistic effect observed only at 59 °C and natural sun insolation of 5,580 kJ m(-2). Heat treatment also hindered light-dependent recovery of E. coli making the treatment much more effective.

  17. Synergistic effect of oral corticosteroids use on risk of hepatocellular carcinoma in high risk populations.

    Lai, Shih-Wei; Lin, Cheng-Li; Liao, Kuan-Fu

    2018-06-01

    Little evidence is available on the relationship between oral corticosteroids use and hepatocellular carcinoma. The objective of this study was to investigate whether oral corticosteroids use correlates with the risk of hepatocellular carcinoma in high risk populations in Taiwan. Using representative claims database established from the Taiwan National Health Insurance Program with a population coverage rate of 99.6%, we identified 102,182 subjects aged 20-84 years with newly diagnosed hepatocellular carcinoma in 2000-2011 as the cases and 102,182 randomly selected subjects aged 20-84 years without hepatocellular carcinoma as the matched controls. In subjects with any one of comorbidities including alcohol-related disease, chronic liver disease, and diabetes mellitus, the adjusted OR of hepatocellular carcinoma was 29.9 (95% CI 28.7, 31.1) for subjects with never use of oral corticosteroids, and the adjusted OR would increase to 33.7 (95% CI 32.3, 35.3) for those with ever use of oral corticosteroids. The adjusted OR of hepatocellular carcinoma was 1.03 for subjects with increasing cumulative duration of oral corticosteroids use for every one year (95% CI 1.01, 1.06), with a duration-dependent effect. The largest OR occurred in subjects with ever use of oral corticosteroids and concurrently comorbid with alcohol-related disease, chronic liver disease, and diabetes mellitus (adjusted OR 122.7, 95% CI 108.5, 138.8). There is a synergistic effect between oral corticosteroids use and the traditional risk factors on the risk of hepatocellular carcinoma. People with risk factors for hepatocellular carcinoma should receive regular ultrasound surveillance, particularly when they currently use oral corticosteroids. Copyright © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  18. Antibiotic activity and synergistic effect of antimicrobial peptide against pathogens from a patient with gallstones

    Park, Yoonkyung; Park, Soon Nang; Park, Seong-Cheol; Park, Joon Yong; Park, Yong Ha; Hahm, Joon Soo; Hahm, Kyung-Soo

    2004-01-01

    HP (2-20) is a peptide derived from the N-terminus of Helicobacter pylori ribosomal protein L1 that has been shown to have antimicrobial activity against various species of bacteria. When we tested the effects of HP (2-20), we found that this peptide displayed strong activity against pathogens from a patient with gallstones, but it did not have hemolytic activity against human erythrocytes. We also found that HP (2-20) had potent activity against cefazolin sodium-resistant bacterial cell lines, and that HP (2-20) and cefazolin sodium had synergistic effects against cell lines resistant to the latter. To investigate the mechanism of action of HP (2-20), we performed fluorescence activated flow cytometry using pathogens from the patient with gallstones. As determined by propidium iodide (PI) staining, pathogenic bacteria treated with HP (2-20) showed higher fluorescence intensity than untreated cells, similar to melittin-treated cells, and that HP (2-20) acted in an energy- and salt-dependent manner. Scanning electron microscopy showed that HP (2-20) caused significant morphological alterations in the cell surface of pathogens from the patient with gallstones. By determining their 16S rDNA sequences, we found that both the pathogens from the patient with gallstones and the cefazolin sodium-resistant cell lines showed 100% homology with sequences from Pseudomonas aeruginosa. Taken together, these results suggest that HP (2-20) has antibiotic activity and that it may be used as a lead drug for the treatment of acquired pathogens from patients with gallstones and antibiotic-resistant cell lines

  19. Synergistic effect of tungsten disulfide and cenosphere combination on braking performance of composite friction materials

    Kachhap, Rakesh K.; Satapathy, Bhabani K.

    2014-01-01

    Graphical abstract: Graphical abstract showing correlation between enhanced frictional stability and enhanced visc-oelastic energy dissipation. - Highlights: • Developed new class of brake composites based on WS 2 and cenosphere. • Synergistic effect of WS 2 and cenosphere for enhanced friction stability. • Wear surface morphology revealed composition specific topography. • Friction fade-recovery performance remained optimal. - Abstract: Tungsten disulfide (WS 2 /TDS) based cenosphere (Cn) filled friction composites with varying cenosphere to WS 2 ratio (Cn/TDS) were fabricated by compression molding of phenolic resin based dry formulation mix and evaluated for their thermal, thermo-mechanical and tribological performances. The loss and revival of braking friction effectiveness due to heating or cooling of the disc termed as fade and recovery performance have been characterized on a Krauss friction testing machine following ECE R-90 industrial standards. The fade performance remained dependent on Cn/TDS, where enhanced fading could be correlated to lower Cn/TDS value accompanied with broader frictional fluctuations i.e. μ max –μ min . A decrease in the frictional-recovery response ensued with increase in Cn/TDS. Dynamic mechanical analysis revealed an increase in storage modulus till 2.5 wt.% of TDS loading followed by consistent decrease whereas two distinct peaks in loss modulus plots that are composition independent have been observed. Scanning electron microscopy revealed the worn surface morphology associated with the dynamics of contact patches formation and deformation vis-a-vis friction layer formation as integrally responsible for the observed friction performance. Energy dispersive analysis of X-rays (EDX) enabled compositional analysis of the friction layer viz. Fe, W, Si, and Al content which may have a mechanistic role in controlling phenomena like, disc rubbing, lubricity, porosity, and hardness of friction layer formed during braking

  20. The effect of anti-tumor necrosis factor alpha agents on postoperative anastomotic complications in Crohn's disease

    El-Hussuna, Alaa Abdul-Hussein H; Krag, Aleksander; Olaison, Gunnar

    2013-01-01

    Patients with Crohn's disease treated with anti-tumor necrosis factor alpha agents may have an increased risk of surgical complications.......Patients with Crohn's disease treated with anti-tumor necrosis factor alpha agents may have an increased risk of surgical complications....

  1. An experimental study on the antitumor effect of 131I-17-AAG in vitro and in vivo.

    Wenyong, Tu; Lu, Liu; Daozhen, Chen; Weidong, Yin; Ying, Huang

    2009-02-01

    To observe the antitumor effect of (131)I-17-allylamino-17-demethoxygeldanamycin ((131)I-17-AAG) in vitro/in vivo and explore its antitumor mechanism with a view to its potential therapeutic application. (131)I-17-AAG was prepared by the reaction of 17-AAG with Na [(131)I] in the presence of hydrogen peroxide. The effects of (131)17-AAG on cell growth inhibition and cell cycle distribution in vitro were studied in BEL-7402 cells lines. Following BEL-7402 tumor implantation by subcutaneous xenografts into nude mice, the reagents were injected through the tail vein, and the tumor volume was measured and analyzed. At the end of the experiment, tumor specimens were processed for histopathological analysis. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was used to investigate apoptosis. The expression change of Akt2 was tested by Western-blot analysis. Methyl-thiazolyl-tetrazolium assay showed inhibition rates of 27.7 +/- 5.3%, 57.3 +/- 4.3%, and 63.7 +/- 3.1%, in Na(131)I group, 17-AAG group, and (131)I-17-AAG group, respectively. The inhibition rate in the (131)I-17-AAG group differed significantly between N(a131)I group and 17-AAG group (F = 229.49, P AAG group, and (131)I-17-AAG group, respectively. Following infusion for 32 days, the tumor volumes in the (131)I-17-AAG group were significantly smaller than those in the DMSO group (F = 24.18, P AAG inhibited the proliferation of tumor cells and induced apoptosis. The expression of Akt2 in (131)I-17-AAG was significantly lower than that in the DMSO group or (131)I group. (131)I-17-AAG can effectively inhibit the growth of BEL-7402 tumor cells in vitro and in vivo. (131)I-17-AAG is a promising agent for the treatment of BEL-7402 cell tumor.

  2. Effects of oxygen radical scavengers on the inactivation of SS phi X174 DNA by the semi-quinone free radical of the antitumor agent etoposide

    van Maanen, M.J.; Mans, D.R.A.; Lafleur, M.V.M.; Van Schaik, M A; de Vries, J; Vermeulen, N P; Retèl, J.; Lankelma, J

    1990-01-01

    We have studied the effects of oxygen radical scavengers on the inactivation of ss phi X174 DNA by the semi-quinone free radical of the antitumor agent etoposide (VP 16-213), which was generated from the ortho-quinone of etoposide at pH greater than or equal to 7.4. A semi-quinone free radical of

  3. Synergistic effect of the integration of the organizational culture and social capital

    Лариса Анатоліївна Янковська

    2015-06-01

    Full Text Available The paper describes the organizational culture as part of the management system of control subject aimed at the formation and development of social capital organization, helping improve the management system. It is determined an interaction of organizational culture and social capital in the synergistic approach to management. Views of scientists on organizational culture and its relationship to social capital are systemized

  4. Anti-tumor effects of a novel chimeric peptide on S180 and H22 xenografts bearing nude mice.

    Wu, Dongdong; Gao, Yanfeng; Chen, Lixiang; Qi, Yuanming; Kang, Qiaozhen; Wang, Haili; Zhu, Linyu; Ye, Yong; Zhai, Mingxia

    2010-05-01

    In recent years, many endogenous peptides have been identified by screening combinatory phage display peptide library, which play important roles in the process of angiogenesis. A heptapeptide, ATWLPPR, binds specifically to NRP-1 and selectively inhibits VEGF165 binding to VEGFR-2. Another heptapeptide, NLLMAAS, blocks both Ang-1 and Ang-2 binding to Tie-2 in a dose-dependent manner. In the present study, we aimed to connect ATWLPPR (V1) with NLLMAAS (V2) via a flexible linker, Ala-Ala, to reconstruct a novel peptide ATWLPPRAANLLMAAS (V3). We firstly investigated the anti-tumor and anti-angiogenic effects of peptide V3 on sarcoma S180 and hepatoma H22 bearing BALB/c nude mice. Mice were continuously subcutaneously administrated with normal saline, V1 (320microg/kg/d), V2 (320microg/kg/d), V1+V2 (320microg/kg/d), and V3 (160, 320 and 480microg/kg/d), for 7 days. Treatment with peptide V3 could significantly reduce the tumor weight and volume. Pathological examination showed that the tumors treated with peptide V3 had a larger region of necrosis than that of peptide V1, V2, and V1+V2 at the same dose. A significant decrease of microvessel density (MVD) in a dose-dependent manner was observed in each group of peptide V3. The results of pathological examination on normal tissue, lung, heart, liver, spleen, kidney and white blood cells showed that peptide V3 might have no significant toxicity. In conclusion, our results demonstrated that peptide V3 could be more effective on inhibiting tumor growth and angiogenesis than that of V1, V2, and V1+V2. Peptide V3 could be considered as a novel chimeric peptide with potent anti-tumor activity. Copyright (c) 2010 Elsevier Inc. All rights reserved.

  5. Anti-tumor effects of flavonoids from the ethnic medicine Docynia delavayi (Franch.) Schneid. and its possible mechanism.

    Deng, Xukun; Zhao, Xiangpei; Lan, Zhou; Jiang, Jie; Yin, Wu; Chen, Lvyi

    2014-07-01

    This study investigated the active components and the anti-tumor efficacy and mechanisms of the flavonoids from Docynia delavayi (Franch.) Schneid. (DDS). MTT assay was used to examine the growth inhibitory effects of the four flavonoids, including chrysin, quercetin, naringenin, and avicularin that were isolated from the rhizome of DDS, on human hematomas cell (HepG2), esophageal carcinoma cell (EC109), human cervical adenocarcinoma cell (Hela), human colon adenocarcinoma cell (SW480), and African green monkey kidney cell (Vero cells). The anti-tumor mechanism of chrysin on HepG2 was further investigated by the methods of fluorescence staining, flow cytometry, and immunoblotting. The results showed that the inhibitory activity of chrysin was much stronger than the other three flavonoids on HepG2, EC109, Hela, and SW480 cells for 48 h treatment in vitro. Moreover, no inhibiting effect of chrysin on the proliferation of normal cells (Vero cells) was observed. Further study revealed that chrysin caused HepG2 cell shrinkage, membrane blebbing, and apoptotic body formation, all of which were typical characteristics of apoptosis programmed cell death. Flow cytometric analysis demonstrated that chrysin increased the sub G0/G1 population, which indicated the increased cell apoptosis, thus preventing cells from entering the S phase as the population in G2/M or S phase declined; whereas in G0/G1 phase, it increased. In addition, immunoblot results showed that chrysin significantly increased the expression levels of caspase-3 and Bax proteins, and it decreased the expression level of B-cell lymphoma/leukemia-2 (Bcl-2) protein. These findings indicate that chrysin is the major flavonoid present in DDS, and it induces HepG2 cell death via apoptosis, probably through the participation of caspase-3, Bax, and Bcl-2 proteins.

  6. Synergistic effects of ELMs and steady state H and H/He irradiation on tungsten

    Lemahieu, Nathan; Greuner, Henri; Linke, Jochen; Maier, Hans; Pintsuk, Gerald; Van Oost, Guido; Wirtz, Marius

    2015-01-01

    Highlights: • Tungsten was first exposed to H or H/He fluxes and then to ELM-like transients. • The influence of particle exposure on the thermal shock behaviour was studied. • There was no deterioration of thermal shock behaviour compared to reference material. • Some combinations of loading conditions resulted in an improved material behaviour. - Abstract: To investigate synergistic effects of high heat flux loading on H and H/He loaded tungsten surfaces, specimens were exposed to a 30 keV steady-state H or H/He beam and subsequently loaded with an electron beam to simulate ELMs. The heat flux during the H and H/He loading was 10.5 MW m"−"2, while a 2 × 10"2"5 m"−"2 fluence was reached. After exposure, all specimens exhibited an altered surface morphology. The H/He samples with a surface temperature of 1000 °C and 1500 °C had a multitude of surface extrusions. Afterwards the particle loaded samples were exposed to 100 ELM-like pulses around the material's damage threshold. Transient heat fluxes of 190 MW m"−"2 and 380 MW m"−"2 were applied at room temperature and 400 °C for a duration of 1 ms. Post-mortem analysis showed no deterioration of thermal shock resistance in comparison with polished material. For some tests the reference specimens roughened or cracked while the H or H/He exposed material had no damage. The H-content and the H/He-induced cavities and/or extrusions are suggested as two potential causes for this change in material behaviour.

  7. Correlations between water-soluble organic aerosol and water vapor: a synergistic effect from biogenic emissions?

    Hennigan, Christopher J; Bergin, Michael H; Weber, Rodney J

    2008-12-15

    Ground-based measurements of meteorological parameters and water-soluble organic carbon in the gas(WSOCg) and particle (WSOCp) phases were carried out in Atlanta, Georgia, from May to September 2007. Fourteen separate events were observed throughout the summer in which WSOCp and water vapor concentrations were highly correlated (average WSOCp-water vapor r = 0.92); however, for the entire summer, no well-defined relationship existed between the two. The correlation events, which lasted on average 19 h, were characterized by a wide range of WSOCp and water vapor concentrations. Several hypotheses for the correlation are explored, including heterogeneous liquid phase SOA formation and the co-emission of biogenic VOCs and water vapor. The data provide supporting evidence for contributions from both and suggest the possibility of a synergistic effect between the co-emission of water vapor and VOCs from biogenic sources on SOA formation. Median WSOCp concentrations were also correlated with elemental carbon (EC), although this correlation extended over the entire summer. Despite the emission of water vapor from anthropogenic mobile sources and the WSOCp-EC correlation, mobile sources were not considered a potential cause for the WSOCp-water vapor correlations because of their low contribution to the water vapor budget. Meteorology could perhaps have influenced the WSOCp-EC correlation, but other factors are implicated as well. Overall, the results suggest that the temperature-dependent co-emission of water vapor through evapotranspiration and SOA precursor-VOCs by vegetation may be an important process contributing to SOA in some environments.

  8. Synergistic effect of polymorphisms of paraoxonase gene cluster and arsenic exposure on electrocardiogram abnormality

    Liao, Y.-T.; Li, W.-F.; Chen, C.-J.; Prineas, Ronald J.; Chen, Wei J.; Zhang Zhuming; Sun, C.-W.; Wang, S.-L.

    2009-01-01

    Arsenic has been linked to increased prevalence of cancer and cardiovascular disease (CVD), but the long-term impact of arsenic exposure remains unclear. Human paraoxonase (PON1) is a high-density lipoprotein-associated antioxidant enzyme which hydrolyzes oxidized lipids and is thought to be protective against atherosclerosis, but evidence remains limited to case-control studies. Only recently have genes encoding enzymes responsible for arsenic metabolism, such as AS3MT and GSTO, been cloned and characterized. This study was designed to evaluate the synergistic interaction of genetic factors and arsenic exposure on electrocardiogram abnormality. A total of 216 residents from three tap water implemented villages of previous arseniasis-hyperendemic regions in Taiwan were prospectively followed for an average of 8 years. For each resident, a 12-lead conventional electrocardiogram (ECG) was recorded and coded by Minnesota Code standard criteria. Eight functional polymorphisms of PON1, PON2, AS3MT, GSTO1, and GSTO2 were examined for genetic susceptibility to ECG abnormality. Among 42 incident cases with ECG deterioration identified among 121 baseline-normal subjects, arsenic exposure was significantly correlated with incidence of ECG abnormality. In addition, polymorphisms in two paraoxonase genes were also found associated with the incidence of ECG abnormality. A haplotype R-C-S constituted by polymorphisms of PON1 Q192R, -108C/T and PON2 C311S was linked to the increased risk. Subjects exposed to high levels of As (cumulative As exposure > 14.7 ppm-year or drinking artesian well water > 21 years) and carrying the R-C-S haplotype had significantly increased risks for ECG abnormality over those with only one risk factor. Results of this study showed a long-term arsenic effect on ECG abnormality and significant gene-gene and gene-environment interactions linked to the incidence of CVD. This finding might have important implications for a novel and potentially useful

  9. Antimalarial activity of Garcinia mangostana L rind and its synergistic effect with artemisinin in vitro.

    Tjahjani, Susy

    2017-02-28

    Malaria especially falciparum malaria still causes high morbidity and mortality in tropical countries. Several factors have been linked to this situation and the most important one is the rapid spread of parasite resistance to the currently available antimalarials, including artemisinin. Artemisinin is the main component of the currently recommended antimalarial, artemisinin based combination therapy (ACT), and it is a free radical generating antimalarial. Garcinia mangostana L (mangosteen) rind contain a lot of xanthone compounds acting as an antioxidant and exhibited antimalarial activity. The aim of this study was to evaluate the antimalarial activity of mangosteen rind extract and its fractions and their interaction with artemisinin against the 3D7 clone of Plasmodium falciparum in vitro. Dry ripe mangosteen rind was extracted with ethanol followed by fractionation with hexane, ethylacetate, buthanol, and water consecutively to get ethanol extract, hexane, athylacetate, buthanol, and water fractions. Each of these substances was diluted in DMSO and examined for antimalarial activity either singly or in combination with artemisinin in vitro against Plasmodium falciparum 3D7 clone. Synergism between these substances with artemisinin was evaluated according to certain formula to get the sum of fractional inhibitory concentration 50 (∑FIC 50 ). Analysis of the parasite growth in vitro indicated that IC 50 of these mangosteen rind extract, hexane, ethylacetate, buthanol, and water fraction ranged from 0.41 to > 100 μg/mL. All of the ∑FIC50 were antimalarial activity of the extract and fractions of G.mangostana L rind and its synergistic effect with artemisinin. Further study using lead compound(s) isolated from extract and fractions should be performed to identify more accurately their mechanism of antimalarial activities.

  10. Synergistic effects of fenbendazole and metronidazole against Giardia muris in Swiss mice naturally infected.

    Bezagio, Renata Coltro; Colli, Cristiane Maria; Romera, Liara Izabela Lopes; Ferreira, Érika Cristina; Falavigna-Guilherme, Ana Lúcia; Gomes, Mônica Lúcia

    2017-03-01

    In this study were proposed different protocols for the treatment of mice naturally infected with Giardia muris. Male Swiss mice were divided into seven groups, with five animals each, in a blind, controlled, randomized by drawing lots and once-repeated experiment. Parasite detection and cure control were performed using the Faust method and search by trophozoites in the intestinal mucosa. Clinical parameters (weight, water and feed consumption, elimination of excreta, aspect of the fur and feces) were also evaluated. All animals were treated with metronidazole (M), fenbendazole (F), and probiotics (P), administered intragastrically, during 7 days. M1, FM1, and F1 groups were treated 1×/day; M3, FM3, and PM3 groups 3×/day; and ST (control group) received only water. After the 5th and 7th days of treatment, the animals in FM1/FM3 and PM3/M3 groups presented, respectively, negative results and remained negative in the following 10 days. Animals in F1 group consumed less water (p = 0.00010) compared with FM1/FM3/PM3. The animals in M1 group compared with FM3/M3, F1 compared with M3, and ST compared with FM1/FM3/M3/PM3 consumed a larger amount of feed (p = 0.00001). The animals in F1 group compared with FM3/M1/M3/PM3, FM1 compared with FM3, and ST compared with FM3/M1/M3/PM3 eliminated lower volume of excreta (p = 0.00001). The results show that the association between F and M potentiates the effects, indicating a synergistic action of these two drugs, and FM1 is the best protocol due to early negativity in the animals, lower concentrations of the drugs, lower risk of toxicity and stress, and less alterations in clinical parameters.

  11. Menin and p53 have non-synergistic effects on tumorigenesis in mice

    Loffler, Kelly A; Mould, Arne W; Waring, Paul M; Hayward, Nicholas K; Kay, Graham F

    2012-01-01

    While it is now more than a decade since the first description of the gene mutation underlying the tumour predisposition syndrome multiple endocrine neoplasia type 1 (MEN1), the mechanism by which its protein product menin acts to prevent development of tumours is still poorly understood. We undertook a genetic experiment to assess whether menin synergises with p53. Mice carrying various combinations of Men1 and Trp53 mutations were generated then survival and pathology assessed. While homozygous loss of Trp53 in mice resulted in early onset, aggressive tumours and profoundly reduced lifespan, heterozygous loss of either Trp53 or Men1 caused later onset disease, with a spectrum of tumours characteristic of each tumour suppressor gene. Loss of one copy of Men1 in animals also lacking both alleles of Trp53 did not exacerbate phenotype, based on survival, animal weight or sites of pathology, compared to Trp53 deletion alone. Dual heterozygous deletion of Men1 and Trp53 resulted in a small reduction in lifespan compared to the individual mutations, without new tumour sites. In the adrenal, we observed development of cortical tumours in dual heterozygous animals, as we have previously seen in Men1 +/− animals, and there was loss of heterozygosity at the Men1 allele in these tumours. Median number of pathology observations per animal was increased in dual heterozygous animals compared with heterozygous loss of Trp53 alone. Simultaneous heterozygous deletion of Men1 in animals with either heterozygous or homozygous deletion of Trp53 did not result in formation of tumours at any new sites, implying additive rather than synergistic effects of these pathways. Mice that were Men1 +/− in addition to Trp53 +/− had tumours in endocrine as well as other sites, implying that increase in total tumour burden, at sites typically associated with either Men1 or Trp53 loss, contributed to the slight decrease in survival in Men1 +/− : Trp53 +/− animals in comparison with their

  12. Synergistic effects of iodine and silver ions co-implanted in 6H–SiC

    Kuhudzai, R.J.; Malherbe, J.B.; Hlatshwayo, T.T.; Berg, N.G. van der; Devaraj, A.; Zhu, Z.; Nandasiri, M.

    2015-01-01

    Motivated by the aim of understanding the release of fission products through the SiC coating of fuel kernels in modern high temperature nuclear reactors, a fundamental investigation is conducted to understand the synergistic effects of implanted silver (Ag) and iodine (I) in 6H–SiC. The implantation of the individual species, as well as the co-implantation of 360 keV ions of I and Ag at room temperature in 6H–SiC and their subsequent annealing behaviour has been investigated by Secondary Ion Mass Spectrometry (SIMS), Atom Probe Tomography (APT) and X-ray Photoelectron Spectroscopy (XPS). SIMS and APT measurements indicated the presence of Ag in the co-implanted samples after annealing at 1500 °C for 30 h in sharp contrast to the samples implanted with Ag only. In samples implanted with Ag only, complete loss of the implanted Ag was observed. However, for I only implanted samples, some iodine was retained. APT of annealed co-implanted 6H–SiC showed clear spatial association of Ag and I clusters in SiC, which can be attributed to the observed I assisted retention of Ag after annealing. Such detailed studies will be necessary to identify the fundamental mechanism of fission products migration through SiC coatings. - Highlights: • Co-implantation of Ag and I ions in 6H–SiC was performed. • Clear spatial association of Ag and I clusters observed after annealing. • Complete loss of Ag after high temperature annealing of silver only sample. • Iodine was retained in iodine only sample after high temperature annealing. • Iodine was found to play a role in the retention of Ag in the co-implanted samples.

  13. Unprecedented carbon accumulation in mined soils: the synergistic effect of resource input and plant species invasion.

    Silva, Lucas C R; Corrêa, Rodrigo S; Doane, Timothy A; Pereira, Engil I P; Horwath, William R

    2013-09-01

    Opencast mining causes severe impacts on natural environments, often resulting in permanent damage to soils and vegetation. In the present study we use a 14-year restoration chronosequence to investigate how resource input and spontaneous plant colonization promote the revegetation and reconstruction of mined soils in central Brazil. Using a multi-proxy approach, combining vegetation surveys with the analysis of plant and soil isotopic abundances (delta13C and delta15N) and chemical and physical fractionation of organic matter in soil profiles, we show that: (1) after several decades without vegetation cover, the input of nutrient-rich biosolids into exposed regoliths prompted the establishment of a diverse plant community (> 30 species); (2) the synergistic effect of resource input and plant colonization yielded unprecedented increases in soil carbon, accumulating as chemically stable compounds in occluded physical fractions and reaching much higher levels than observed in undisturbed ecosystems; and (3) invasive grasses progressively excluded native species, limiting nutrient availability, but contributing more than 65% of the total accumulated soil organic carbon. These results show that soil-plant feedbacks regulate the amount of available resources, determining successional trajectories and alternative stable equilibria in degraded areas undergoing restoration. External inputs promote plant colonization, soil formation, and carbon sequestration, at the cost of excluding native species. The introduction of native woody species would suppress invasive grasses and increase nutrient availability, bringing the system closer to its original state. However, it is difficult to predict whether soil carbon levels could be maintained without the exotic grass cover. We discuss theoretical and practical implications of these findings, describing how the combination of resource manipulation and management of invasive species could be used to optimize restoration strategies

  14. Synergistic effects of ELMs and steady state H and H/He irradiation on tungsten

    Lemahieu, Nathan, E-mail: n.lemahieu@fz-juelich.de [Institute for Energy and Climate Research, Forschungszentrum Jülich, 52425 Jülich (Germany); Department of Applied Physics, Ghent University, Sint-Pietersnieuwstraat 41 B4, 9000 Gent (Belgium); Institute of Interfacial Process Engineering and Plasma Technology IGVP, Universität Stuttgart, Pfaffenwaldring 31, 70569 Stuttgart (Germany); Greuner, Henri [Max Planck Institute for Plasma Physics, Boltzmannstraße 2, 85748 Garching (Germany); Linke, Jochen [Institute for Energy and Climate Research, Forschungszentrum Jülich, 52425 Jülich (Germany); Maier, Hans [Max Planck Institute for Plasma Physics, Boltzmannstraße 2, 85748 Garching (Germany); Pintsuk, Gerald [Institute for Energy and Climate Research, Forschungszentrum Jülich, 52425 Jülich (Germany); Van Oost, Guido [Department of Applied Physics, Ghent University, Sint-Pietersnieuwstraat 41 B4, 9000 Gent (Belgium); Wirtz, Marius [Institute for Energy and Climate Research, Forschungszentrum Jülich, 52425 Jülich (Germany)

    2015-10-15

    Highlights: • Tungsten was first exposed to H or H/He fluxes and then to ELM-like transients. • The influence of particle exposure on the thermal shock behaviour was studied. • There was no deterioration of thermal shock behaviour compared to reference material. • Some combinations of loading conditions resulted in an improved material behaviour. - Abstract: To investigate synergistic effects of high heat flux loading on H and H/He loaded tungsten surfaces, specimens were exposed to a 30 keV steady-state H or H/He beam and subsequently loaded with an electron beam to simulate ELMs. The heat flux during the H and H/He loading was 10.5 MW m{sup −2}, while a 2 × 10{sup 25} m{sup −2} fluence was reached. After exposure, all specimens exhibited an altered surface morphology. The H/He samples with a surface temperature of 1000 °C and 1500 °C had a multitude of surface extrusions. Afterwards the particle loaded samples were exposed to 100 ELM-like pulses around the material's damage threshold. Transient heat fluxes of 190 MW m{sup −2} and 380 MW m{sup −2} were applied at room temperature and 400 °C for a duration of 1 ms. Post-mortem analysis showed no deterioration of thermal shock resistance in comparison with polished material. For some tests the reference specimens roughened or cracked while the H or H/He exposed material had no damage. The H-content and the H/He-induced cavities and/or extrusions are suggested as two potential causes for this change in material behaviour.

  15. Copyrolysis of Biomass and Coal: A Review of Effects of Copyrolysis Parameters, Product Properties, and Synergistic Mechanisms

    2016-01-01

    Concerns in the last few decades regarding the environmental and socioeconomic impacts of the dependence on fossil fuels have resulted in calls for more renewable and alternative energy sources. This has led to recent interest in copyrolysis of biomass and coal. Numerous reviews have been found related to individual pyrolysis of coal and biomass. This review deals mainly with the copyrolysis of coal and biomass and then compares their results with those obtained using coal and biomass pyrolysis in detail. It is controversial whether there are synergistic or additive behaviours when coal and biomass are blended during copyrolysis. In this review, the effects of reaction parameters such as feedstock types, blending ratio, heating rate, temperature, and reactor types on the occurrence of synergy are discussed. Also, the main properties of the copyrolytic products are pointed out. Some possible synergistic mechanisms are also suggested. Additionally, several outlooks based on studies in the literature are also presented in this paper. PMID:27722171

  16. The enhanced inhibitory effect of different antitumor agents in self-microemulsifying drug delivery systems on human cervical cancer HeLa cells.

    Ujhelyi, Zoltán; Kalantari, Azin; Vecsernyés, Miklós; Róka, Eszter; Fenyvesi, Ferenc; Póka, Róbert; Kozma, Bence; Bácskay, Ildikó

    2015-07-21

    The aim of this study was to develop topical self-microemulsifying drug delivery systems (SMEDDS) containing antitumor agents (bleomycin, cisplatin and ifosfamide) and to investigate their inhibitory potential in SMEDDS on human cervical cancer HeLa cells. The physicochemical properties of cytostatic drug loaded SMEDDS were characterized. The cytotoxicity of main components of SMEDDS was also investigated. Their IC50 values were determined. HeLa cells were treated by different concentrations of cisplatin, bleomycin and ifosfamide alone and in various SMEDDS. The inhibitory effect on cell growth was analyzed by MTT cell viability assay. Inflammation is a driving force that accelerates cancer development. The inhibitory effect of these antitumor agents has also been tested on HeLa cells in the presence of inflammatory mediators (IL-1-β, TNF-α) as an in vitro model of inflamed human cervix. Significant differences in the cytotoxicity of cytostatic drugs alone and in SMEDDS have been found in a concentration-dependent manner. The self-micro emulsifying system may potentiate the effectiveness of bleomycin, cisplatin and ifosfamide topically. The effect of SMEDDS containing antitumor agents was decreased significantly in the presence of inflammatory mediators. According to our experiments, the optimal SMEDDS formulation is 1:1:2:6:2 ratios of Isopropyl myristate, Capryol 90, Kolliphor RH 40, Cremophor RH40, Transcutol HP and Labrasol. It can be concluded that SMEDDS may increase the inhibitory effect of bleomycin, ifosfamide and cisplatin on human cervical cancer HeLa cells. Inflammation on HeLa cells hinders the effectiveness of SMEDDS containing antitumor agents. Our results might ensure useful data for development of optimal antitumor formulations.

  17. Synergistic effect of cellulose nanocrystals/graphene oxide nanosheets as functional hybrid nanofiller for enhancing properties of PVA nanocomposites.

    El Miri, Nassima; El Achaby, Mounir; Fihri, Aziz; Larzek, Mohamed; Zahouily, Mohamed; Abdelouahdi, Karima; Barakat, Abdellatif; Solhy, Abderrahim

    2016-02-10

    Novel functional hybrid nanofillers composed of cellulose nanocrystals (CNC) and graphene oxide nanosheets (GON), at different weight ratios (2:1, 1:1 and 1:2), were successfully prepared and characterized, and their synergistic effect in enhancing the properties of poly(vinyl alcohol) (PVA) nanocomposites was investigated. Due to the synergistic reinforcement, it was found that the Young's modulus, tensile strength and toughness of the PVA nanocomposite containing 5 wt% hybrid nanofiller (1:2) were significantly improved by 320%, 124% and 159%, respectively; and the elongation at break basically remained compared to the neat PVA matrix. In addition, the glass and melting temperatures as well as the moisture sorption of nanocomposites were also enhanced. This synergistic effect improved the dispersion homogeneity by avoiding the agglomeration phenomenon of nanofillers within the polymer matrix, resulting in nanocomposites with largely enhanced properties compared to those prepared from single nanofiller (CNC or GON). The preparation of these hybrid nanofillers and their incorporation into a polymer provided a novel method for the development of novel multifunctional nanocomposites based on the combination of existing nanomaterials. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. The synergistic effects of 2,4-D dimethyl amine and propanil herbicides on weed population in rice agroecosystem

    Nashriyah Mat; Ramli Ishak; Sabri Junoh; Ismail Sahid

    2002-01-01

    Four treatments with the herbicides 2,4-D dimethyl amine and propanil were carried out in two consecutive rice planting seasons, to study the synergistic effect of 2,4-D dimethyl amine and propanil on rice weed populations at Pasir Panjang, the Northwest Selangor Project (PBLS), Projek Barat Laut Selangor) rice granary area. The treatments were control, 1x recommended rate (single dose), 2x recommended rate (double dose) of 2,4-D dimethyl amine and farmer practice. In all plots, propanil herbicide was applied at similar rate. Among the ecological indices measured were Simpson Index of diversity and importance (I.V.). A total number of 19 weed species was identified and the most common important weed was Najas graminae Del. The second most commonly found important weed was Scirpus lateriflorus Gmel. Other important weeds frequently found were Echinochloa crus-galli (L.) Beauv. and Fimbristylis miliacea (L.) Vahl. In the rice agroecosystem, species diversity of weeds was affected but total weed biomass was not affected synergistically by the mixture of 2,4-D dimethyl amine and propanil. The negative synergistic effect of 2,4-D dimethyl amine and propanil was to increase the total biomass of Scirpus lateriflorus, at 2x recommended dose rate of 2,4-D dimethyl amine. (Author)

  19. Synergistic Effects of Natural Medicinal Plant Extracts on Growth Inhibition of Carcinoma (KB) Cells under Oxidative Stress

    Kim, Jeong Hee; Ju, Eun Mi; Kim, Jin Kyu

    2000-01-01

    Medicinal plants with synergistic effects on growth inhibition of cancer cells under oxidative stress were screened in this study. Methanol extracts from 51 natural medicinal plants, which were reported to have anticancer effect on hepatoma, stomach cancer or colon cancers which are frequently found in Korean, were prepared and screened for their synergistic activity on growth inhibition of cancer cells under chemically-induced oxidative stress by using MTT assay. Twenty seven samples showed synergistic activity on the growth inhibition in various extent under chemically-induced oxidative stress. Among those samples, eleven samples, such as Melia azedarach, Agastache rugosa, Catalpa ovata, Prunus persica, Sinomenium acutum, Pulsatilla koreana, Oldenlandia diffiusa, Anthriscus sylvestris, Schizandra chinensis, Gleditsia sinensis, Cridium officinale, showed decrease in IC 50 values more than 50%, other 16 samples showed decrease in IC 50 values between 50-25%, compared with the value acquired when medicinal plant sample was used alone. Among those 11 samples, extract of Catalpa ovata showed the highest activity. IC 50 values were decrease to 61% and 28% when carcinoma cells were treated with Catalpa ovata extract in combination of 75 and 100 μM of hydrogen peroxide, respectively

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

    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.

  1. The effect of microneedles on the skin permeability and antitumor activity of topical 5-fluorouracil

    Youssef W. Naguib

    2014-02-01

    Full Text Available Topical 5-fluorouracil (5-FU is approved for the treatment of superficial basal cell carcinoma and actinic keratosis. However, 5-FU suffers from poor skin permeation. Microneedles have been successfully applied to improve the skin permeability of small and large molecules, and even nanoparticles, by creating micron-sized pores in the stratum corneum layer of the skin. In this report, the feasibility of using microneedles to increase the skin permeability of 5-FU was tested. Using full thickness mouse skin mounted on Franz diffusion apparatus, it was shown that the flux of 5-FU through the skin was increased by up to 4.5-fold when the skin was pretreated with microneedles (500 μm in length, 50 μm in base diameter. In a mouse model with B16-F10 mouse melanoma cells implanted in the subcutaneous space, the antitumor activity of a commercially available 5-FU topical cream (5% was significantly enhanced when the cream was applied on a skin area that was pretreated with microneedles, as compared to when the cream was simply applied on a skin area, underneath which the tumor cells were implanted, and without pretreatment of the skin with microneedles. Fluorouracil is not approved for melanoma therapy, but the clinical efficacy of topical 5-FU against tumors such as basal cell carcinoma may be improved by integrating microneedle technology into the therapy.

  2. Synergistic effects of leucine and resveratrol on insulin sensitivity and fat metabolism in adipocytes and mice

    Bruckbauer Antje

    2012-08-01

    Full Text Available Abstract Background Sirtuins are important regulators of glucose and fat metabolism, and sirtuin activation has been proposed as a therapeutic target for insulin resistance and diabetes. We have shown leucine to increase mitochondrial biogenesis and fat oxidation via Sirt1 dependent pathways. Resveratrol is a widely recognized activator of Sirt; however, the biologically-effective high concentrations used in cell and animal studies are generally impractical or difficult to achieve in humans. Accordingly, we sought to determine whether leucine would exhibit synergy with low levels of resveratrol on sirtuin-dependent outcomes in adipocytes and in diet-induced obese (DIO mice. Methods 3T3-L1 mouse adipocytes were treated with Leucine (0.5 mM, β-hydroxy-β-methyl butyrate (HMB (5 μM or Resveratrol (200 nM alone or in combination. In addition, diet-induced obese mice were treated for 6-weeks with low (2 g/kg diet or high (10 g/kg diet dose HMB, Leucine (24 g/kg diet; 200% of normal level or low (12.5 mg/kg diet or high (225 mg/kg diet dose resveratrol, alone or as combination with leucine-resveratrol or HMB-resveratrol. Results Fatty acid oxidation, AMPK, Sirt1 and Sirt3 activity in 3T3-L1 adipocytes and in muscle cells, were significantly increased by the combinations compared to the individual treatments. Similarly, 6-week feeding of low-dose resveratrol combined with either leucine or its metabolite HMB to DIO mice increased adipose Sirt1 activity, muscle glucose and palmitate uptake (measured via PET/CT, insulin sensitivity (HOMAIR, improved inflammatory stress biomarkers (CRP, IL-6, MCP-1, adiponectin and reduced adiposity comparable to the effects of high dose resveratrol, while low-dose resveratrol exerted no independent effect. Conclusion These data demonstrate that either leucine or its metabolite HMB may be combined with a low concentration of resveratrol to exert synergistic effects on Sirt1-dependent outcomes; this may result in more

  3. The Synergistic Effect between Electrical and Chemical Factors in Plasma Gene/Molecule-Transfection

    Jinno, Masafumi

    2016-09-01

    This study has been done to know what kind of factors in plasma and processes on cells promote plasma gene/molecule transfection. We have discovered a new plasma source using a microcapillary electrode which enables high transfection efficiency and high cell survivability simultaneously. However, the mechanism of the transfection by plasma was not clear. To clarify the transfection mechanisms by micro plasma, we focused on the effects of electrical (current, charge, field, etc.) and chemical (radicals, RONS, etc.) factors generated by the micro plasma and evaluated the contribution weight of three groups of the effects and processes, i.e. electrical, chemical and biochemical ones. At first, the necessity of the electrical factors was estimated by the laser produced plasma (LPP). Mouse L-929 fibroblast cell was cultured on a 96-well plate or 12-well micro slide chamber. Plasmids pCX-EGFP in Tris-EDTA buffer was dropped on the cells and they were exposed to the capillary discharge plasma (CDP) or the LPP. In the case of the CDP, the plasma was generated between the tip of the capillary electrode and the cells so that both electrical and chemical factors were supplied to the cells. In this setup, about 20% of average transfection efficiency was obtained. In the case of the LPP, the plasma was generated apart from the cells so that electrical factors were not supplied to the cells. In this setup, no transfection was observed. These results show that the electrical factors are necessary for the plasma gene transfection. Next, the necessity of the chemical factors was estimated the effect of catalase to remove H2O2 in CDP. The transfection efficiency decreased to 0.4 by scavenging H2O2 with catalase. However, only the solution of H2O2 caused no gene transfection in cells. These results shows that H2O2 is important species to cause gene/molecule transfection but still needs a synergistic effect with electrical or other chemical factors. This work was partly supported by

  4. Carbon and TiO{sub 2} synergistic effect on methylene blue adsorption

    Simonetti, Evelyn Alves Nunes, E-mail: evelynalvesnunes@yahoo.com.br; Simone Cividanes, Luciana de; Campos, Tiago Moreira Bastos; Rossi Canuto de Menezes, Beatriz; Brito, Felipe Sales; Thim, Gilmar Patrocínio

    2016-07-01

    Due to its high efficiency, low cost and a simple operation, the adsorption process is an important and widely used technique for industrial wastewater treatment. Recent studies on the removal of artificial dyes by adsorption include a large number of adsorbents, such as: activated carbon, silicates, carbon nanotube, graphene, fibers, titanates and doped titanates. The carbon insertion in the TiO{sub 2} structure promotes a synergistic effect on the adsorbent composite, improving the adsorption and the charge-transfer efficiency rates. However, there are few studies regarding the adsorption capacity of TiO{sub 2}/Carbon composites with the carbon concentration. This study evaluates the effect of carbon (resorcinol/formaldehyde) insertion on TiO{sub 2} structure through the adsorption process. Adsorbents were prepared by varying the carbon weight percentages using the sol-gel method. The physicochemical properties of the catalysts prepared, such as crystallinity, particle size, surface morphology, specific surface area and pore volume were investigated. The kinetic study, adsorption isotherm, pH effect and thermodynamic study were examined in batch experiments using methylene blue as organic molecule. In addition, the effect of carbon phase on the adsorption capacity of TiO{sub 2}-carbon composite was deeply investigated. SEM micrographs showed that TiO{sub 2} phase grows along the carbon phase and FT-IR results showed the presence of Ti−O−C chemical bonding. The experiments indicate that the carbon phase acted as a nucleation agent for the growth of TiO{sub 2} during the sol-gel step, with a TiO{sub 2} structure suitable for blue methylene adsorption, resulting in a material with large surface area and slit-like or wedge-shaped pores. Further experiments will show the best carbon concentration for methylene blue adsorption using a TiO{sub 2} based material. - Highlights: • This article deals with the adsorption of methylene blue onto TiO{sub 2}-Carbon

  5. Carbon and TiO_2 synergistic effect on methylene blue adsorption

    Simonetti, Evelyn Alves Nunes; Simone Cividanes, Luciana de; Campos, Tiago Moreira Bastos; Rossi Canuto de Menezes, Beatriz; Brito, Felipe Sales; Thim, Gilmar Patrocínio

    2016-01-01

    Due to its high efficiency, low cost and a simple operation, the adsorption process is an important and widely used technique for industrial wastewater treatment. Recent studies on the removal of artificial dyes by adsorption include a large number of adsorbents, such as: activated carbon, silicates, carbon nanotube, graphene, fibers, titanates and doped titanates. The carbon insertion in the TiO_2 structure promotes a synergistic effect on the adsorbent composite, improving the adsorption and the charge-transfer efficiency rates. However, there are few studies regarding the adsorption capacity of TiO_2/Carbon composites with the carbon concentration. This study evaluates the effect of carbon (resorcinol/formaldehyde) insertion on TiO_2 structure through the adsorption process. Adsorbents were prepared by varying the carbon weight percentages using the sol-gel method. The physicochemical properties of the catalysts prepared, such as crystallinity, particle size, surface morphology, specific surface area and pore volume were investigated. The kinetic study, adsorption isotherm, pH effect and thermodynamic study were examined in batch experiments using methylene blue as organic molecule. In addition, the effect of carbon phase on the adsorption capacity of TiO_2-carbon composite was deeply investigated. SEM micrographs showed that TiO_2 phase grows along the carbon phase and FT-IR results showed the presence of Ti−O−C chemical bonding. The experiments indicate that the carbon phase acted as a nucleation agent for the growth of TiO_2 during the sol-gel step, with a TiO_2 structure suitable for blue methylene adsorption, resulting in a material with large surface area and slit-like or wedge-shaped pores. Further experiments will show the best carbon concentration for methylene blue adsorption using a TiO_2 based material. - Highlights: • This article deals with the adsorption of methylene blue onto TiO_2-Carbon composite. • The sol-gel synthesis was efficient

  6. Synergistic Effects of Citalopram and Morphine in the Renal Colic Pain Relief; a Randomized Clinical Trial

    Mehrdad Esmailian

    2014-03-01

    Full Text Available Introduction: Although the synergistic effects of opioids and other analgesic drugs such as non-steroidal anti-inflammatory drugs (NSAIDs have been established in relieving acute pain due to renal calculi, no studies today have evaluated the concomitant administration of opiates and other drugs with analgesic effects, such as serotonin re-uptake inhibitors. Considering the high prevalence of renal colic, the present study was carried out to compare the effect of concomitant prescription of morphine and a placebo with that of morphine and citalopram on the management of acute pain due to renal calculi. Methods: The present double-blind randomized clinical trial was carried out from October 2012 to March 2013 in the Al-Zahra educational Hospital in Isfahan, Iran. A total of 90 patients with acute renal colic pain were randomly divided into two groups of 45 subjects. The subjects in one group received morphine/ placebo and another one morphine/citalopram. The patients’ pain severity was determined by visual analogue scale (VAS before and 20 minutes after administration of medications. In case of persistent pain the second or even third dose was administered and the pain severity was once again determined. Data were analyzed with STATA 11.0 using chi-squared, two-way ANOVA, Bonferroni post hoc test, and log rank test. Results: The decrease in pain severity in the morphine/citalopram group was significantly compared to the morphine/placebo group and the time before administration of the medications (p<0.001. In contrast, administration of morphine/placebo did not have a significant effect on pain severity at this interval (p=0.32. Kaplan-Meier curve showed that the first injection was successful in relieving pain in 15 (33.3% and 26 (57.8% subjects in the morphine/placebo and morphine/citalopram groups, respectively. The second injection of these medications resulted in therapeutic success in 35 (87.8% and 42 (95.6% subjects in the above groups

  7. Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells.

    Ogawa, Mutsumi; Nakai, Seiji; Deguchi, Akihiro; Nonomura, Takako; Masaki, Tsutomu; Uchida, Naohito; Yoshiji, Hitoshi; Kuriyama, Shigeki

    2007-08-01

    Although a number of studies have shown that vitamin K possesses antitumor activities on various neoplastic cell lines, there are few reports demonstrating in vivo antitumor effects of vitamin K, and the antitumor effect on colorectal cancer (CRC) remains to be examined. Therefore, antitumor effects of vitamin K on CRC were examined both in vitro and in vivo. Vitamins K2, K3 and K5 suppressed the proliferation of colon 26 cells in a dose-dependent manner, while vitamin K1 did not. On flow cytometry, induction of apoptosis by vitamins K2, K3 and K5 was suggested by population in sub-G1 phase of the cell cycle. Hoechst 33342 staining and a two-color flow cytometric assay using fluorescein isothiocyanate-conjugated annexin V and propidium iodide confirmed that vitamins K2, K3 and K5 induced apoptotic death of colon 26 cells. Enzymatic activity of caspase-3 in colon 26 cells was significantly up-regulated by vitamins K2, K3 and K5. The pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, substantially prevented vitamin K-mediated apoptosis. In vivo study using syngeneic mice with subcutaneously established colon 26 tumors demonstrated that intravenous administration of vitamins K2, K3 and K5 significantly suppressed the tumor growth. The number of apoptotic tumor cells was significantly larger in the vitamin K-treated groups than in the control group. These results suggest that vitamins K2, K3 and K5 exerted effective antitumor effects on CRC in vitro and in vivo by inducing caspase-dependent apoptotic death of tumor cells, suggesting that these K vitamins may be promising agents for the treatment of patients with CRC.

  8. The synergistic effect of cigarette taxes on the consumption of cigarettes, alcohol and betel nuts

    Lee Jie-Min

    2007-06-01

    Full Text Available Abstract Background Consumption of cigarettes and alcoholic beverages creates serious health consequences for individuals and overwhelming financial burdens for governments around the world. In Asia, a third stimulant – betel nuts – increases this burden exponentially. For example, individuals who simultaneously smoke, chew betel nuts and drink alcohol are approximately 123 times more likely to develop oral, pharyngeal and laryngeal cancer than are those who do not. To discourage consumption of cigarettes, the government of Taiwan has imposed three taxes over the last two decades. It now wishes to lower consumption of betel nuts. To assist in this effort, our study poses two questions: 1 Will the imposition of an NT$10 Health Tax on cigarettes effectively reduce cigarette consumption? and 2 Will this cigarette tax also reduce consumption of alcoholic beverages and betel nuts? To answer these questions, we analyze the effect of the NT$10 tax on overall cigarette consumption as well as the cross price elasticities of cigarettes, betel nuts, and alcoholic beverages. Methods To establish the Central Bureau of Statistics demand function, we used cigarette, betel nut, and alcoholic beverage price and sales volume data for the years 1972–2002. To estimate the overall demand price elasticity of cigarettes, betel nuts, and alcoholic beverages, we used a seemingly unrelated regression analysis. Results We find that the NT$10 health tax on cigarettes will reduce cigarette consumption by a significant 27.22%. We also find that cigarettes, betel nuts, and alcoholic beverages have similar inherent price elasticities of -0.6571, -0.5871, and -0.6261 respectively. Because of this complementary relationship, the NT$10 health tax on cigarettes will reduce betel nut consumption by 20.07% and alcohol consumption by 7.5%. Conclusion The assessment of a health tax on cigarettes as a smoking control policy tool yields a win-win outcome for both government and

  9. Synergistic effect of age and body mass index on mortality and morbidity in general surgery.

    Yanquez, Federico J; Clements, John M; Grauf, Dawn; Merchant, Aziz M

    2013-09-01

    The elderly population (aged 65 y and older) is expected to be the dominant age group in the United States by 2030. In addition, the prevalence of obesity in the United States is growing exponentially. Obese elderly patients are increasingly undergoing elective or emergent general surgery. There are few, if any, studies highlighting the combined effect of age and body mass index (BMI) on surgical outcomes. We hypothesize that increasing age and BMI synergistically impact morbidity and mortality in general surgery. We collected individual-level, de-identified patient data from the Michigan Surgical Quality Collaborative. Subjects underwent general surgery with general anesthetic, were >18 y, and had a BMI between 19 and 60. Primary and secondary outcomes were 30-d "Any morbidity" and mortality (from wound, respiratory, genitourinary, central nervous system, and cardiac systems), respectively. Preoperative risk variables included diabetes, dialysis, steroid use, cardiac risk, wound classification, American Society of Anesthesiology class, emergent cases, and 13 other variables. We conducted binary logistic regression models for 30-d morbidity and mortality to determine independent effects of age, BMI, interaction between both age and BMI, and a saturated model for all independent variables. We identified 149,853 patients. The average age was 54.6 y, and the average BMI was 30.9. Overall 30-d mortality was 2%, and morbidity was 6.7%. Age was a positive predictor for mortality and morbidity, and BMI was negatively associated with mortality and not significantly associated with morbidity. Age combined with higher BMI was positively associated with morbidity and mortality when the higher age groups were analyzed. Saturated models revealed age and American Society of Anesthesiology class as highest predictors of poor outcomes. Although BMI itself was not a major independent factor predicting 30-d major morbidity or mortality, the morbidly obese, elderly (>50 and 70 y

  10. Melatonin enhances the anti-tumor effect of fisetin by inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways.

    Canhui Yi

    Full Text Available Melatonin is a hormone identified in plants and pineal glands of mammals and possesses diverse physiological functions. Fisetin is a bio-flavonoid widely found in plants and exerts antitumor activity in several types of human cancers. However, the combinational effect of melatonin and fisetin on antitumor activity, especially in melanoma treatment, remains unclear. Here, we tested the hypothesis that melatonin could enhance the antitumor activity of fisetin in melanoma cells and identified the underlying molecular mechanisms. The combinational treatment of melanoma cells with fisetin and melatonin significantly enhanced the inhibitions of cell viability, cell migration and clone formation, and the induction of apoptosis when compared with the treatment of fisetin alone. Moreover, such enhancement of antitumor effect by melatonin was found to be mediated through the modulation of the multiply signaling pathways in melanoma cells. The combinational treatment of fisetin with melatonin increased the cleavage of PARP proteins, triggered more release of cytochrome-c from the mitochondrial inter-membrane, enhanced the inhibition of COX-2 and iNOS expression, repressed the nuclear localization of p300 and NF-κB proteins, and abrogated the binding of NF-κB on COX-2 promoter. Thus, these results demonstrated that melatonin potentiated the anti-tumor effect of fisetin in melanoma cells by activating cytochrome-c-dependent apoptotic pathway and inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways, and our study suggests the potential of such a combinational treatment of natural products in melanoma therapy.

  11. Melatonin Enhances the Anti-Tumor Effect of Fisetin by Inhibiting COX-2/iNOS and NF-κB/p300 Signaling Pathways

    Yu, Zhenlong; Xiao, Yao; Wang, Jingshu; Qiu, Huijuan; Yu, Wendan; Tang, Ranran; Yuan, Yuhui; Guo, Wei; Deng, Wuguo

    2014-01-01

    Melatonin is a hormone identified in plants and pineal glands of mammals and possesses diverse physiological functions. Fisetin is a bio-flavonoid widely found in plants and exerts antitumor activity in several types of human cancers. However, the combinational effect of melatonin and fisetin on antitumor activity, especially in melanoma treatment, remains unclear. Here, we tested the hypothesis that melatonin could enhance the antitumor activity of fisetin in melanoma cells and identified the underlying molecular mechanisms. The combinational treatment of melanoma cells with fisetin and melatonin significantly enhanced the inhibitions of cell viability, cell migration and clone formation, and the induction of apoptosis when compared with the treatment of fisetin alone. Moreover, such enhancement of antitumor effect by melatonin was found to be mediated through the modulation of the multiply signaling pathways in melanoma cells. The combinational treatment of fisetin with melatonin increased the cleavage of PARP proteins, triggered more release of cytochrome-c from the mitochondrial inter-membrane, enhanced the inhibition of COX-2 and iNOS expression, repressed the nuclear localization of p300 and NF-κB proteins, and abrogated the binding of NF-κB on COX-2 promoter. Thus, these results demonstrated that melatonin potentiated the anti-tumor effect of fisetin in melanoma cells by activating cytochrome-c-dependent apoptotic pathway and inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways, and our study suggests the potential of such a combinational treatment of natural products in melanoma therapy. PMID:25000190

  12. New benzimidazoles and their antitumor effects with Aurora A kinase and KSP inhibitory activities.

    Abd El-All, Amira S; Magd-El-Din, Asmaa A; Ragab, Fatma A F; ElHefnawi, Mahmoud; Abdalla, Mohamed M; Galal, Shadia A; El-Rashedy, Ahmed A

    2015-07-01

    A newly synthesized series of anticancer compounds comprising thiazolo[3,2-a]pyrimidine derivatives 6a-q bearing a benzimidazole moiety was produced via a one-pot reaction of N-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-2-cyanoacetamide 5 with 2-aminothiazole and an appropriate aromatic aldehyde. Compound 7 was obtained via the reaction of 4-(1H-benzo[d]imidazol-2yl)benzenamide 1 with carbon disulphide and methyl iodide in the presence of concentrated aqueous solution of NaOH, then treated with o-phenylenediamine to give N-(4-1H-benzo[d]imidazol-2-yl)phenyl)-1H-benzo[d]imidazol-2-amine 8. The structures of the newly synthesized compounds were confirmed by analytical and spectroscopic measurements (IR, MS, and (1) H NMR). The synthesized products were screened and studied for their in vitro antitumor activity against three human cancer cell lines (namely colorectal cancer cell line HCT116, human liver cancer cell line HepG2, and human ovarian cancer cell line A2780) and their Aurora A kinase and KSP inhibitory activities. All newly synthesized compounds revealed marked results comparable with the standard drug CK0106023. The compounds 6e and 6k of the thiazolopyrimidine derivatives were the most active compounds when tested against the three cell lines in comparison with the standard drug CK0106023, and showed potent dual KSP and Aurora A kinase inhibition. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Synergistic inhibitory effect of berberine and d-limonene on human gastric carcinoma cell line MGC803.

    Zhang, Xiu-Zhen; Wang, Ling; Liu, Dong-Wu; Tang, Guang-Yan; Zhang, Hong-Yu

    2014-09-01

    This study aims at evaluating the anticancer effects of berberine hydrochloride (berberine) and d-limonene, alone and in combination, on human gastric carcinoma cell line MGC803 to determine whether berberine and d-limonene work synergistically and elucidate their mechanisms. MGC803 cells were treated with berberine and d-limonene, alone and in combination, for 24-48 h. The inhibitory effects of these drugs on growth were determined by MTT assay. The combination index and drug reduction index were calculated with the Chou-Talalay method based on the median-effect principle. Flow cytometry and laser scanning confocal microscopy were employed to evaluate the effects of both drugs on cell-cycle perturbation and apoptosis, generation of reactive oxygen species (ROS), mitochondrial membrane potential, and expression of Bcl-2 and caspase-3 in MGC803 cells. Berberine or d-limonene alone can inhibit the growth of MGC803 cells in a dose- and time-dependent manner. Berberine and d-limonene at a combination ratio of 1:4 exhibited a synergistic effect on anti-MGC803 cells. The two drugs distinctly induced intracellular ROS generation, reduced the mitochondrial transmembrane potential (ΔΨm), enhanced the expression of caspase-3, and decreased the expression of Bcl-2. The combination of berberine and d-limonene showed more remarkable effects compared with drugs used singly in MGC803 cells. The combination of berberine and d-limonene exerted synergistic anticancer effects on MGC803 cells by cell-cycle arrest, ROS production, and apoptosis induction through the mitochondria-mediated intrinsic pathway.

  14. Synergistic effect of CART (cocaine- and amphetamine-regulated transcript peptide and cholecystokinin on food intake regulation in lean mice

    Kiss Alexander

    2008-10-01

    Full Text Available Abstract Background CART (cocaine- and amphetamine-regulated transcript peptide and cholecystokinin (CCK are neuromodulators involved in feeding behavior. This study is based on previously found synergistic effect of leptin and CCK on food intake and our hypothesis on a co-operation of the CART peptide and CCK in food intake regulation and Fos activation in their common targets, the nucleus tractus solitarii of the brainstem (NTS, the paraventricular nucleus (PVN, and the dorsomedial nucleus (DMH of the hypothalamus. Results In fasted C57BL/6 mice, the anorexigenic effect of CART(61-102 in the doses of 0.1 or 0.5 μg/mouse was significantly enhanced by low doses of CCK-8 of 0.4 or 4 μg/kg, while 1 mg/kg dose of CCK-A receptor antagonist devazepide blocked the effect of CART(61-102 on food intake. After simultaneous administration of 0.1 μg/mouse CART(61-102 and of 4 μg/kg of CCK-8, the number of Fos-positive neurons in NTS, PVN, and DMH was significantly higher than after administration of each particular peptide. Besides, CART(61-102 and CCK-8 showed an additive effect on inhibition of the locomotor activity of mice in an open field test. Conclusion The synergistic and long-lasting effect of the CART peptide and CCK on food intake and their additive effect on Fos immunoreactivity in their common targets suggest a co-operative action of CART peptide and CCK which could be related to synergistic effect of leptin on CCK satiety.

  15. Antitumor effect of cordycepin (3'-deoxyadenosine) on mouse melanoma and lung carcinoma cells involves adenosine A3 receptor stimulation.

    Nakamura, Kazuki; Yoshikawa, Noriko; Yamaguchi, Yu; Kagota, Satomi; Shinozuka, Kazumasa; Kunitomo, Masaru

    2006-01-01

    An attempt was made to elucidate the molecular targetfor the antitumor effects of cordycepin (3'-deoxyadenosine) using non-selective and selective adenosine A1, A2a, A2b and A3 receptor agonists and antagonists. Although adenosine and 2'-deoxyadenosine (up to 100 microM) had no effect, cordycepin showed remarkable inhibitory effects on the growth curves of B16-BL6 mouse melanoma (IC50= 39 microM) and mouse Lewis lung carcinoma (IC50 = 48 microM) cell lines in vitro. Among the adenosine receptor agonists and antagonists used (up to 100 microM), only 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA), a selective adenosine A3 receptor agonist, notably inhibited the growth of both mouse tumor cell lines (B16-BL6; IC50 = 5 microM, LLC; 14 microM). In addition, the tumor growth inhibitory effect of cordycepin was antagonized by 3-ethyl 5-benzyl 2-methyl-6-phenyl-4-phenylethynyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS1191), a selective adenosine A3 receptor antagonist. These results suggest that cordycepin exerts inhibitory effects on the growth of mouse melanoma and lung carcinoma cells by stimulating adenosine A3 receptors on tumor cells.

  16. Synergistic Effect of Nitrogen and Molybdenum on Localized Corrosion of Stainless Steels

    Kim, Y. S.

    2010-01-01

    According to the bipolar model, ion selectivity of some species in the passive film is important factor to control the passivation. An increase of cation selectivity of outer layer of the passive film can stabilize the film and improves the corrosion resistance. Therefore, the formation and roles of ionic species in the passive film should be elucidated. In this work, two types of solution (hydrochloric or sulfuric acid) were used to test high N and Mo-bearing stainless steels. The objective of this work was to investigate the formation of oxyanions in the passive film and the roles of oxyanions in passivation of stainless steel. Nitrogen exists as atomic nitrogen, nitric oxide, nitro-oxyanions (NO x - ), and N-H species, not nitride in the passive film. Because of its high mobility, the enriched atomic nitrogen can act as a reservoir. The formation of N-H species buffers the film pH and facilitates the formation of oxyanions in the film. NO x - species improve the cation selectivity of the film, increasing the oxide content and film density. NO x - acts similar to a strong inhibitor both in the passive film and at active sites. This facilitates the formation of chromium oxide. Also, NO x - can make more molybdate and nitric oxide by reacting with Mo. The role of Mo addition on the passivation characteristics of stainless steel may differ with the test environment. Mo exists as metallic molybdenum, Molybdenum oxide, and molybdate and the latter facilitates the oxide formation. When nitrogen and molybdenum coexist in stainless steel, corrosion resistance in chloride solutions is drastically increased. This synergistic effect of N and Mo in a chloride solution is mainly due to the formation of nitro-oxyanions and molybdate ion. Oxyanions can be formed by a 'solid state reaction' in the passive film, resulting in the formation of more molybdate and nitric oxide. These oxyanions improve the cation selectivity of the outer layer and from more oxide and increase the

  17. CYP24A1 inhibition facilitates the anti-tumor effect of vitamin D3 on colorectal cancer cells

    Kósa, János P; Horváth, Péter; Wölfling, János; Kovács, Dóra; Balla, Bernadett; Mátyus, Péter; Horváth, Evelin; Speer, Gábor; Takács, István; Nagy, Zsolt; Horváth, Henrik; Lakatos, Péter

    2013-01-01

    AIM: The effects of vitamin D3 have been investigated on various tumors, including colorectal cancer (CRC). 25-hydroxyvitamin-D3-24-hydroxylase (CYP24A1), the enzyme that inactivates the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 (1,25-D3), is considered to be the main enzyme determining the biological half-life of 1,25-D3. During colorectal carcinogenesis, the expression and concentration of CYP24A1 increases significantly, suggesting that this phenomenon could be responsible for the proposed efficacy of 1,25-D3 in the treatment of CRC. The aim of this study was to investigate the anti-tumor effects of vitamin D3 on the human CRC cell line Caco-2 after inhibition of the cytochrome P450 component of CYP24A1 activity. METHODS: We examined the expression of CYP24A1 mRNA and the effects of 1,25-D3 on the cell line Caco-2 after inhibition of CYP24A1. Cell viability and proliferation were determined by means of sulforhodamine-B staining and bromodeoxyuridine incorporation, respectively, while cytotoxicity was estimated via the lactate dehydrogenase content of the cell culture supernatant. CYP24A1 expression was measured by real-time reverse transcription polymerase chain reaction. A number of tetralone compounds were synthesized to investigate their CP24A1 inhibitory activity. RESULTS: In response to 1,25-D3, CYP24A1 mRNA expression was enhanced significantly, in a time- and dose-dependent manner. Caco-2 cell viability and proliferation were not influenced by the administration of 1,25-D3 alone, but were markedly reduced by co-administration of 1,25-D3 and KD-35, a CYP24A1-inhibiting tetralone. Our data suggest that the mechanism of action of co-administered KD-35 and 1,25-D3 does not involve a direct cytotoxic effect, but rather the inhibition of cell proliferation. CONCLUSION: These findings demonstrate that the selective inhibition of CYP24A1 by compounds such as KD-35 may be a new approach for enhancement of the anti-tumor effect of 1,25-D3 on CRC. PMID

  18. Synergistic effects of total ionizing dose on single event upset sensitivity in static random access memory under proton irradiation

    Xiao Yao; Guo Hong-Xia; Zhang Feng-Qi; Zhao Wen; Wang Yan-Ping; Zhang Ke-Ying; Ding Li-Li; Luo Yin-Hong; Wang Yuan-Ming; Fan Xue

    2014-01-01

    Synergistic effects of the total ionizing dose (TID) on the single event upset (SEU) sensitivity in static random access memories (SRAMs) were studied by using protons. The total dose was cumulated with high flux protons during the TID exposure, and the SEU cross section was tested with low flux protons at several cumulated dose steps. Because of the radiation-induced off-state leakage current increase of the CMOS transistors, the noise margin became asymmetric and the memory imprint effect was observed. (interdisciplinary physics and related areas of science and technology)

  19. Antibiotic and synergistic effect of Leu-Lys rich peptide against antibiotic resistant microorganisms isolated from patients with cholelithiasis.

    Jeong, Nari; Kim, Jin-Young; Park, Seong-Cheol; Lee, Jong-Kook; Gopal, Ramamourthy; Yoo, Suyeon; Son, Byoung Kwan; Hahm, Joon Soo; Park, Yoonkyung; Hahm, Kyung-Soo

    2010-09-03

    Pseudomonas aeruginosa has eventually developed resistance against flomoxef sodium, isepamicin and cefpiramide. Therefore, in this study, the antibacterial activity and synergistic effects of the amphipathic-derived P5-18mer antimicrobial peptide were tested against pathogens associated with cholelithiasis that have developed resistance against commonly used antibiotics. The results were then compared with the activities of the amphipathic-derived peptide, P5-18mer, melittin and common antibiotics. Growth inhibition of planktonic bacteria was tested using the National Committee for Clinical Laboratory Standards (NCCLS). The bactericidal activity of the antimicrobial peptides was measured using time-kill curves. Synergistic effects were evaluated by testing the effects of P5-18mer alone and in combination with flomoxef sodium, isepamicin or cefpiramide at 0.5xMIC. P5-18mer peptide displayed strong activity against pathogens and flomoxef sodium, isepamicin and cefpiramide-resistant bacteria cell lines obtained from a patient with gallstones; however, it did not exert cytotoxicity against the human keratinocyte HaCat cell line. In addition, the results of time-kill curves indicated that P5-18mer peptide exerted bactericidal activity against four strains of P. aeruginosa. Finally, the use of P5-18mer and antibiotics exerted synergistic effects against cell lines that were resistant to commonly used antibiotics. These results indicate that this class of peptides has a rapid microbicidal effect on flomoxef sodium, isepamicin and cefpiramide-resistant strains of P. aeruginosa. Therefore, these peptides may be used as a lead drug for the treatment of acquired pathogens from patients with cholelithiasis who are affected with antibiotic-resistant bacteria. Copyright 2010 Elsevier Inc. All rights reserved.

  20. Hydrogel-PLGA delivery system prolongs 2-methoxyestradiol-mediated anti-tumor effects in osteosarcoma cells.

    Maran, Avudaiappan; Dadsetan, Mahrokh; Buenz, Colleen M; Shogren, Kristen L; Lu, Lichun; Yaszemski, Michael J

    2013-09-01

    Osteosarcoma is a bone tumor that affects children and young adults. 2-Methoxyestradiol (2-ME), a naturally occurring estrogen metabolite, kills osteosarcoma cells, but does not affect normal osteoblasts. In order to effectively target osteosarcoma and improve the therapeutic index of the drug 2-ME, we have encapsulated 2-ME in a composite of oligo-(polyethylene glycol) fumarate (OPF) hydrogel and poly (lactic-co-glycolic acid) (PLGA) microspheres and investigated the effect of polymer composition on 2-ME release kinetics and osteosarcoma cell survival. The in vitro study shows that 2-ME can be released in a controlled manner over 21-days. The initial burst releases observed on day 1 were 50% and 32% for OPF and OPF/PLGA composites, respectively. The extended release kinetics show that 100% of the encapsulated 2-ME is released by day 12 from OPF, whereas the OPF/PLGA composites showed a release of 85% on day 21. 2-ME released from the polymers was biologically active and blocked osteosarcoma cell proliferation in vitro. Also, comparison of 2-ME delivery in osteosarcoma cells in culture, shows that direct treatment has no effect after 3 days, whereas polymer-mediated delivery produces anti-tumor effects that could be sustained for 21 days. These findings show that the OPF and PLGA polymeric system may prove to be useful in controlled and sustained delivery of 2-ME and could be further explored in the treatment of osteosarcoma. Copyright © 2012 Wiley Periodicals, Inc.

  1. Poly-S-Nitrosated Albumin as a Safe and Effective Multifunctional Antitumor Agent: Characterization, Biochemistry and Possible Future Therapeutic Applications

    Yu Ishima

    2013-01-01

    Full Text Available Nitric oxide (NO is a ubiquitous molecule involved in multiple cellular functions. Inappropriate production of NO may lead to disease states. To date, pharmacologically active compounds that release NO within the body, such as organic nitrates, have been used as therapeutic agents, but their efficacy is significantly limited by unwanted side effects. Therefore, novel NO donors with better pharmacological and pharmacokinetic properties are highly desirable. The S-nitrosothiol fraction in plasma is largely composed of endogenous S-nitrosated human serum albumin (Mono-SNO-HSA, and that is why we are testing whether this albumin form can be therapeutically useful. Recently, we developed SNO-HSA analogs such as SNO-HSA with many conjugated SNO groups (Poly-SNO-HSA which were prepared using chemical modification. Unexpectedly, we found striking inverse effects between Poly-SNO-HSA and Mono-SNO-HSA. Despite the fact that Mono-SNO-HSA inhibits apoptosis, Poly-SNO-HSA possesses very strong proapoptotic effects against tumor cells. Furthermore, Poly-SNO-HSA can reduce or perhaps completely eliminate the multidrug resistance often developed by cancer cells. In this review, we forward the possibility that Poly-SNO-HSA can be used as a safe and effective multifunctional antitumor agent.

  2. Studies on Preparation of Photosensitizer Loaded Magnetic Silica Nanoparticles and Their Anti-Tumor Effects for Targeting Photodynamic Therapy

    Chen Zhi-Long

    2009-01-01

    Full Text Available Abstract As a fast developing alternative of traditional therapeutics, photodynamic therapy (PDT is an effective, noninvasive, nontoxic therapeutics for cancer, senile macular degeneration, and so on. But the efficacy of PDT was compromised by insufficient selectivity and low solubility. In this study, novel multifunctional silica-based magnetic nanoparticles (SMNPs were strategically designed and prepared as targeting drug delivery system to achieve higher specificity and better solubility. 2,7,12,18-Tetramethyl-3,8-di-(1-propoxyethyl-13,17-bis-(3-hydroxypropyl porphyrin, shorted as PHPP, was used as photosensitizer, which was first synthesized by our lab with good PDT effects. Magnetite nanoparticles (Fe3O4 and PHPP were incorporated into silica nanoparticles by microemulsion and sol–gel methods. The prepared nanoparticles were characterized by transmission electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy and fluorescence spectroscopy. The nanoparticles were approximately spherical with 20–30 nm diameter. Intense fluorescence of PHPP was monitored in the cytoplasm of SW480 cells. The nanoparticles possessed good biocompatibility and could generate singlet oxygen to cause remarkable photodynamic anti-tumor effects. These suggested that PHPP-SMNPs had great potential as effective drug delivery system in targeting photodynamic therapy, diagnostic magnetic resonance imaging and magnetic hyperthermia therapy.

  3. Ganoderma lucidum exerts anti-tumor effects on ovarian cancer cells and enhances their sensitivity to cisplatin.

    Zhao, Sufen; Ye, Gang; Fu, Guodong; Cheng, Jian-Xin; Yang, Burton B; Peng, Chun

    2011-05-01

    Ganoderma lucidum is a herbal mushroom known to have many health benefits, including the inhibition of tumor cell growth. However, the effect of Ganoderma lucidum on epithelial ovarian cancer (EOC), the most fatal gynecological malignancy, has not yet been reported. In this study, we determined whether Ganoderma lucidum regulates EOC cell activity. Using several cell lines derived from EOC, we found that Ganoderma lucidum strongly decreased cell numbers in a dose-dependent manner. Ganoderma lucidum also inhibited colony formation, cell migration and spheroid formation. In particular, Ganoderma lucidum was effective in inhibiting cell growth in both chemosensitive and chemoresistant cells and the treatment with Ganoderma lucidum significantly enhanced the effect of cisplatin on EOC cells. Furthermore, Ganoderma lucidum induced cell cycle arrest at the G2/M phase and also induced apoptosis by activating caspase 3. Finally, Ganoderma lucidum increased p53 but inhibited Akt expression. Taken together, these findings suggest that Ganoderma lucidum exerts multiple anti-tumor effects on ovarian cancer cells and can enhance the sensitivity of EOC cells to cisplatin.

  4. An experimental study on the antitumor effect of 131I-17-AAG in vitro and in vivo

    Tu Wenyong; Liu Lu; Chen Daozhen; Huang Ying; Yin Weidong

    2009-01-01

    The objective of this study was to observe the antitumor effect of 131 I-17-allylamino-17-demethoxygeldanamycin ( 131 I-17-AAG) in vitro/in vivo and explore its antitumor mechanism with a view to its potential therapeutic application. 131 I-17-AAG was prepared by the reaction of 17-AAG with Na [ 131 I] in the presence of hydrogen peroxide. The effects of 131 17-AAG on cell growth inhibition and cell cycle distribution in vitro were studied in BEL-7402 cells lines. Following BEL-7402 tumor implantation by subcutaneous xenografts into nude mice, the reagents were injected through the tail vein, and the tumor volume was measured and analyzed. At the end of the experiment, tumor specimens were processed for histopathological analysis. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was used to investigate apoptosis. The expression change of Akt2 was tested by Western-blot analysis. Methyl-thiazolyl-tetrazolium assay showed inhibition rates of 27.7±5.3%, 57.3±4.3%, and 63.7±3.1%, in Na 131 I group, 17-AAG group, and 131 I-17-AAG group, respectively. The inhibition rate in the 131 I-17-AAG group differed significantly between Na 131 I group and 17-AAG group (F=229.49, P 131 I group, 17-AAG group, and 131 I-17-AAG group, respectively. Following infusion for 32 days, the tumor volumes in the 131 I-17-AAG group were significantly smaller than those in the DMSO group (F=24.18, P 131 I group (F=20.68, P 131 I-17-AAG inhibited the proliferation of tumor cells and induced apoptosis. The expression of Akt2 in 131 I-17-AAG was significantly lower than that in the DMSO group or 131 I group. 131 I-17-AAG can effectively inhibit the growth of BEL-7402 tumor cells in vitro and in vivo. 131 I-17-AAG is a promising agent for the treatment of BEL-7402 cell tumor. (author)