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Sample records for suppress ovarian activity

  1. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer.

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    Pagani, Olivia; Regan, Meredith M; Walley, Barbara A; Fleming, Gini F; Colleoni, Marco; Láng, István; Gomez, Henry L; Tondini, Carlo; Burstein, Harold J; Perez, Edith A; Ciruelos, Eva; Stearns, Vered; Bonnefoi, Hervé R; Martino, Silvana; Geyer, Charles E; Pinotti, Graziella; Puglisi, Fabio; Crivellari, Diana; Ruhstaller, Thomas; Winer, Eric P; Rabaglio-Poretti, Manuela; Maibach, Rudolf; Ruepp, Barbara; Giobbie-Hurder, Anita; Price, Karen N; Bernhard, Jürg; Luo, Weixiu; Ribi, Karin; Viale, Giuseppe; Coates, Alan S; Gelber, Richard D; Goldhirsch, Aron; Francis, Prudence A

    2014-07-10

    Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor-positive breast cancer. In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor-positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials. After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane-ovarian suppression group and 87.3% in the tamoxifen-ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane-ovarian suppression group, as compared with 88.8% in the tamoxifen-ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane-ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P=0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane-ovarian suppression group and 29.4% of those in the tamoxifen-ovarian suppression group, with profiles similar to those for postmenopausal women. In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT ClinicalTrials.gov numbers, NCT00066703 and NCT00066690, respectively.).

  2. Tumor suppressive effects of bromodomain-containing protein 7 (BRD7) in epithelial ovarian carcinoma.

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    Park, Young-Ae; Lee, Jeong-Won; Kim, Hye-Sun; Lee, Yoo-Young; Kim, Tae-Joong; Choi, Chel Hun; Choi, Jung-Joo; Jeon, Hye-Kyung; Cho, Young Jae; Ryu, Ji Yoon; Kim, Byoung-Gie; Bae, Duk-Soo

    2014-02-01

    Bromodomain-containing protein 7 (BRD7), which is a subunit of SWI/SNF complex, has been recently suggested as a novel tumor suppressor in several cancers. In this study, we investigated the tumor suppressive effect of BRD7 in epithelial ovarian cancer. We analyzed the expression of BRD7 in human ovarian tissues with real-time PCR. To investigate the functional role of BRD7, we transfected ovarian cancer cells (A2780 and SKOV3) with BRD7 plasmid and checked the cell viability, apoptosis, and invasion. The activities of BRD7 in the signaling pathways associated with carcinogenesis were also tested. In addition, we used the orthotopic mouse model for ovarian cancer to evaluate tumor growth-inhibiting effect by administration of BRD7 plasmid. The BRD7 expression was downregulated in the ovarian cancer tissues compared with normal (P p53-wild) or SKOV3 (p53-null) ovarian cancer cells showed the tumor suppressive effects assessed by cell viability, apoptosis, and invasion assay and especially significantly decreased tumor weight in orthotopic mouse model (A2780). Moreover, we found that tumor suppressive effects of BRD7 are independent to the presence of p53 activity in ovarian cancer cells. BRD7 negatively regulated β-catenin pathway, resulting in decreased its accumulation in the nucleus. These results suggested that BRD7 acts as a tumor suppressor in epithelial ovarian cancers independently of p53 activity, via negative regulation of β-catenin pathway. ©2013 AACR.

  3. Suppression of ovarian activity with a low-dose 21/7-day regimen oral contraceptive containing ethinylestradiol 20 mcg/drospirenone 3 mg in Japanese and Caucasian women.

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    Anzai, Yuzuru; Heger-Mahn, Doris; Schellschmidt, Ilka; Marr, Joachim

    2012-07-01

    Two studies assessed the effect of a low-estrogen-dose 21/7-day oral contraceptive containing ethinylestradiol and drospirenone (EE 20 mcg/drsp 3 mg) on ovarian activity in Japanese and Caucasian women. Study 1 was conducted in Japanese women (20-35 years), and Study 2 was conducted in Caucasian women (18-35 years). All women received EE 20 mcg/drsp 3 mg in a 21-day active pill regimen. The primary endpoint was the proportion of women with ovulation inhibition (Hoogland score day regimen provides comparable ovarian suppression in Japanese and Caucasian women, with normal ovarian function resuming shortly after treatment end in both populations. Copyright © 2012 Elsevier Inc. All rights reserved.

  4. Dietary compounds galangin and myricetin suppress ovarian cancer cell angiogenesis.

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    Huang, Haizhi; Chen, Allen Y; Rojanasakul, Yon; Ye, Xingqian; Rankin, Gary O; Chen, Yi Charlie

    2015-05-01

    Galangin and myricetin are flavonoids isolated from vegetables and fruits which exhibit anti-proliferative activity in human cancer cells. In this study, their anti-angiogenic effects were investigated with in vitro (HUVEC) and in vivo (CAM) models, which showed that galangin and myricetin inhibited angiogenesis induced by OVCAR-3 cells. The molecular mechanisms through which galangin and myricetin suppress angiogenesis were also studied. It was observed that galangin and myricetin inhibited secretion of the key angiogenesis mediator vascular endothelial growth factor (VEGF) and decreased levels of p-Akt, p-70S6K and hypoxia-inducible factor-1α (HIF-1α) proteins in A2780/CP70 and OVCAR-3 cells. Transient transfection experiments showed that galangin and myricetin inhibited secretion of VEGF by the Akt/p70S6K/ HIF-1α pathway. Moreover, a novel pathway, p21/HIF-1α/VEGF, was found to be involved in the inhibitory effect of myricetin on angiogenesis in OVCAR-3 cells. These data suggest that galangin and myricetin might serve as potential anti-angiogenic agents in the prevention of ovarian cancers dependent on new blood vessel networks.

  5. SIRT1 activator (SRT1720) improves the follicle reserve and prolongs the ovarian lifespan of diet-induced obesity in female mice via activating SIRT1 and suppressing mTOR signaling.

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    Zhou, Xiao-Ling; Xu, Jin-Jie; Ni, Yan-Hong; Chen, Xiao-Chun; Zhang, Hong-Xia; Zhang, Xing-Mei; Liu, Wei-Juan; Luo, Li-Li; Fu, Yu-Cai

    2014-10-21

    SRT1720 may improve the follicle pool reserve in HF diet-induced obese female mice via activating SIRT1 signaling and suppressing mTOR signaling, thus extending the ovarian lifespan.

  6. Mevalonate Pathway Antagonist Suppresses Formation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models.

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    Kobayashi, Yusuke; Kashima, Hiroyasu; Wu, Ren-Chin; Jung, Jin-Gyoung; Kuan, Jen-Chun; Gu, Jinghua; Xuan, Jianhua; Sokoll, Lori; Visvanathan, Kala; Shih, Ie-Ming; Wang, Tian-Li

    2015-10-15

    Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with TP53 mutations. Because TP53 mutations occur in almost all ovarian high-grade serous carcinoma (HGSC), we determined whether statins suppressed tumor growth in animal models of ovarian cancer. Two ovarian cancer mouse models were used. The first one was a genetically engineered model, mogp-TAg, in which the promoter of oviduct glycoprotein-1 was used to drive the expression of SV40 T-antigen in gynecologic tissues. These mice spontaneously developed serous tubal intraepithelial carcinomas (STICs), which are known as ovarian cancer precursor lesions. The second model was a xenograft tumor model in which human ovarian cancer cells were inoculated into immunocompromised mice. Mice in both models were treated with lovastatin, and effects on tumor growth were monitored. The molecular mechanisms underlying the antitumor effects of lovastatin were also investigated. Lovastatin significantly reduced the development of STICs in mogp-TAg mice and inhibited ovarian tumor growth in the mouse xenograft model. Knockdown of prenylation enzymes in the mevalonate pathway recapitulated the lovastatin-induced antiproliferative phenotype. Transcriptome analysis indicated that lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways, suggesting that statins have pleiotropic effects on tumor cells. The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease. ©2015 American Association for Cancer Research.

  7. AG490, a Jak2 inhibitor, suppressed the progression of murine ovarian cancer.

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    Kobayashi, Aya; Tanizaki, Yuko; Kimura, Akihiko; Ishida, Yuko; Nosaka, Mizuho; Toujima, Saori; Kuninaka, Yumi; Minami, Sawako; Ino, Kazuhiko; Kondo, Toshikazu

    2015-11-05

    Ovarian cancer is the major cause of cancer death among female genital malignancies, and requires developing novel therapeutic measures. Immune escape and acquisition of tolerance by tumor cells are essential for cancer growth and progression. An immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) overexpression in tumors is essential for host immune tolerance. Janus-activated kinase-signal transducer and activator of transcription (JAK-STAT) pathway is involved in various kinds of tumor biology. Thus, we examined the effects of STAT1 inhibition by AG490 (a JAK2 inhibitor) on ovarian cancer progression in mice. In vitro study, IFN-γ treatment up-regulated Ido mRNA expression with STAT1 activation in OV2944-HM-1 cells, whereas AG490 treatment significantly inhibited this effect with the suppression of STAT1 phosphorylation. In vivo model, OV2944-HM-1 cells were intraperitoneally/subcutaneously transplanted into syngeneic immunocompetent female mice. AG490 treatment significantly suppressed subcutaneous tumor growth, compared with control. Consistently, in mice intraperitoneally inoculated HM-1 cells, the same treatment significantly improved survival rate with the reduced number of intraperitoneal tumors. Actually, intratumoral IDO expression was significantly suppressed with the reduction of STAT1 activation in AG490-treated mice. Moreover, in tumor microenvironment of mice treated with AG490, the accumulation of anti-tumor leukocytes such as CD8(+) T-cells, M1 macrophages, and NK cells was apparently exaggerated with the reciprocal reduction of regulatory T cells. Furthermore, intratumoral expression of anti-tumor cytokines such as IL-1α, IL-1β and IL-12 expression was significantly enhanced in mice treated with AG490. Collectively, JAK/STAT signal pathways may be good molecular target for immunotherapy of ovarian cancer. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Knockdown of eIF4E suppresses cell proliferation, invasion and enhances cisplatin cytotoxicity in human ovarian cancer cells.

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    Wan, Jing; Shi, Fang; Xu, Zhanzhan; Zhao, Min

    2015-12-01

    Eukaryotic initiation factor 4E (eIF4E) plays an important role in cap-dependent translation. The overexpression of eIF4E gene has been found in a variety of human malignancies. In this study, we attempted to identify the potential effects of eIF4E and explore the possibility of eIF4E as a therapeutic target for the treatment of human ovarian cancer. First the activation of eIF4E protein was detected with m7-GTP cap binding assays in ovarian cancer and control cells. Next, the eIF4E-shRNA expression plasmids were used to specifically inhibit eIF4E activity in ovarian cancer cells line A2780 and C200. The effects of knockdown eIF4E gene on cell proliferation, migration and invasion were investigated in vitro. Moreover, the changes of cell cycle and apoptosis of ovarian cancer cells were detected by flow cytometry. Finally, we investigated the effect of knockdown of eIF4E on the chemosensitivity of ovarian cancer cells to cisplatin in vitro. Our results show there is elevated activation of eIF4E in ovarian cancer cells compared with normal human ovarian epithelial cell line. The results of BrdU incorporation and FCM assay indicate that knockdown of eIF4E efficiently suppressed cell growth and induce cell cycle arrest in G1 phase and subsequent apoptosis in ovarian cancer cells. From Transwell assay analysis, knockdown eIF4E significantly decrease cellular migration and invasion of ovarian cancer cells. We also confirmed that knockdown eIF4E could synergistically enhance the cytotoxicity effects of cisplatin to cancer cells and sensitized cisplatin-resistant C200 cells in vitro. This study demonstrates that the activation of eIF4E gene is an essential component of the malignant phenotype in ovarian cancer, and aberration of eIF4E expression is associated with proliferation, migration, invasion and chemosensitivity to cisplatin in ovarian cancer cells. Knockdown eIF4E gene can be used as a potential therapeutic target for the treatment of human ovarian cancer.

  9. Serum arylesterase and paraoxonase activities in patients with ovarian tumors

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    Slawomir Michalak

    2014-12-01

    Conclusion: ARE activity is higher in patients with ovarian cancer than in patients with benign ovarian tumors; however, the serum activity of ARE is similar between patients with cancer and healthy individuals.

  10. Isoflurane promotes glucose metabolism through up-regulation ofmiR-21and suppresses mitochondrial oxidative phosphorylation in ovarian cancer cells.

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    Guo, Nai-Liang; Zhang, Jia-Xin; Wu, Jing-Ping; Xu, Ying-Hua

    2017-12-22

    Ovarian cancer is one of the most lethal gynecologic malignancies in women. Isoflurane is one of the volatile anesthetics used extensively for inhalational anesthesia and gynecological surgery. However, the effects of isoflurane on ovarian cancer have not been fully elucidated. It is widely studied that one of the biochemical fingerprints of cancer cells is the altered energy metabolism which is characterized by preferential dependence on glycolysis for energy production in an oxygen-independent manner. In the present study, we explored the roles of isoflurane in the regulation of cellular metabolism of ovarian cancer cells. We observed the glucose uptake, lactate production and extracellular acidification of two ovarian cancer cell lines, SKOV3 and TOV21G were significantly stimulated by isoflurane treatments at 1 and 2 h. The glycolysis enzymes, HK2, PKM2, and LDHA were up-regulated by isoflurane. We report that miR-21 was induced by isoflurane treatments in ovarian cancer cells, leading to the elevated AKT phosphorylation and up-regulation of glycolysis enzymes. In contrast, the mitochondrial functions were suppressed by isoflurane treatments: the oxygen consumption, mitochondrial membrane potential (MMP), and activities of complex I, II, and IV on the electron transport chain were significantly decreased under isoflurane treatments. Importantly, ovarian cancer cells become hypersensitive to glycolysis inhibitors with isoflurane pretreatments. The present study demonstrates that isoflurane treatments drive a metabolic switch of ovarian cancer cells and contributes to the discovery and development of clinical therapeutic agents against ovarian cancer. © 2017 The Author(s).

  11. Signaling Circuits and Regulation of Immune Suppression by Ovarian Tumor-Associated Macrophages

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    Martin J. Cannon

    2015-05-01

    Full Text Available The barriers presented by immune suppression in the ovarian tumor microenvironment present one of the biggest challenges to development of successful tumor vaccine strategies for prevention of disease recurrence and progression following primary surgery and chemotherapy. New insights gained over the last decade have revealed multiple mechanisms of immune regulation, with ovarian tumor-associated macrophages/DC likely to fulfill a central role in creating a highly immunosuppressive milieu that supports disease progression and blocks anti-tumor immunity. This review provides an appraisal of some of the key signaling pathways that may contribute to immune suppression in ovarian cancer, with a particular focus on the potential involvement of the c-KIT/PI3K/AKT, wnt/β-catenin, IL-6/STAT3 and AhR signaling pathways in regulation of indoleamine 2,3-dioxygenase expression in tumor-associated macrophages. Knowledge of intercellular and intracellular circuits that shape immune suppression may afford insights for development of adjuvant treatments that alleviate immunosuppression in the tumor microenvironment and enhance the clinical efficacy of ovarian tumor vaccines.

  12. MiR-23b targets cyclin G1 and suppresses ovarian cancer tumorigenesis and progression.

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    Yan, Jing; Jiang, Jing-yi; Meng, Xiao-Na; Xiu, Yin-Ling; Zong, Zhi-Hong

    2016-02-13

    It has been proposed that cyclin G1 (CCNG1) participates in p53-dependent G1-S and G2 checkpoints and might function as an oncogenic protein in the initiation and metastasis of ovarian carcinoma. MicroRNA 23b (miR-23b) is a critical regulatory factor in the progression of many cancer cell types that targets the relevant genes. MiR-23b expression in ovarian tissues was quantified by quantitative reverse transcription-PCR. The ovarian cancer cell lines OVCAR3, HO8910-PM, and SKOV3/DDP were transfected with miR-23b, after we assayed the cell phenotype and expression of the relevant molecules. Dual-luciferase reporter assay and a xenograft mouse model were used to examine the expression of miR-23b and its target gene CCNG1. MIR23B mRNA expression was significantly lower in epithelial ovarian carcinoma and borderline tumors than in normal ovarian tissues and benign tumors, and miR-23b expression among ages and pathological subtypes was significantly different. CCNG1 mRNA expression was significantly lower in normal ovarian tissues than in benign tumors, borderline tumors, and ovarian carcinomas, and expression among pathological subtypes was significantly different. MiR-23b overexpression inhibited ovarian cancer cell proliferation, invasion, and migration, and induced apoptosis. Dual-luciferase reporter assay showed that miR-23b bound with the 3' untranslated region of CCNG1. MiR-23b overexpression significantly downregulated CCNG1, urokinase, survivin, Bcl-xL, P70S6K, and matrix metallopeptidase-9 (MMP9) mRNA and protein expression. Furthermore, miR-23b inhibited tumor growth and suppressed CCNG1 expression in vitro. Our findings show that miR-23b may inhibit ovarian cancer tumorigenesis and progression by downregulating CCNG1 and the expression of the relevant genes. MiR-23b is a potentially novel application for regulating ovarian carcinoma progression.

  13. Minocycline suppresses interleukine-6, its receptor system and signaling pathways and impairs migration, invasion and adhesion capacity of ovarian cancer cells: in vitro and in vivo studies.

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    Parvin Ataie-Kachoie

    Full Text Available Interleukin (IL-6 has been shown to be a major contributing factor in growth and progression of ovarian cancer. The cytokine exerts pro-tumorigenic activity through activation of several signaling pathways in particular signal transducer and activator of transcription (STAT3 and extracellular signal-regulated kinase (ERK1/2. Hence, targeting IL-6 is becoming increasingly attractive as a treatment option in ovarian cancer. Here, we investigated the effects of minocycline on IL-6 and its signaling pathways in ovarian cancer. In vitro, minocycline was found to significantly suppress both constitutive and IL-1β or 4-hydroxyestradiol (4-OH-E2-stimulated IL-6 expression in human ovarian cancer cells; OVCAR-3, SKOV-3 and CAOV-3. Moreover, minocycline down-regulated two major components of IL-6 receptor system (IL-6Rα and gp130 and blocked the activation of STAT3 and ERK1/2 pathways leading to suppression of the downstream product MCL-1. In female nude mice bearing intraperitoneal OVCAR-3 tumors, acute administration (4 and 24 h of minocycline (30 mg/kg led to suppression of IL-6. Even single dose of minocycline was effective at significantly lowering plasma and tumor IL-6 levels. In line with this, tumoral expression of p-STAT3, p-ERK1/2 and MCL-1 were decreased in minocycline-treated mice. Evaluation of the functional implication of minocycline on metastatic activity revealed the capacity of minocycline to inhibit cellular migration, invasion and adhesion associated with down-regulation of matrix metalloproteinases (MMP-2 and 9. Thus, the data suggest a potential role for minocycline in suppressing IL-6 expression and activity. These effects may prove to be an important attribute to the upcoming clinical trials of minocycline in ovarian cancer.

  14. Tetramethoxychalcone, a chalcone derivative, suppresses proliferation, blocks cell cycle progression, and induces apoptosis of human ovarian cancer cells.

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    Qi, Zihao; Liu, Mingming; Liu, Yang; Zhang, Meiqin; Yang, Gong

    2014-01-01

    In the present study, we investigated the in vitro antitumor functions of a synthetic chalcone derivative 4,3',4',5'- tetramethoxychalcone (TMOC) in ovarian cancer cells. We found that TMOC inhibited the proliferation and colony formation of cisplatin sensitive cell line A2780 and resistant cell line A2780/CDDP, as well as ovarian cancer cell line SKOV3 in a time- and dose-dependent manner. Treatment of A2780 cells with TMOC resulted in G0/G1 cell cycle arrest through the down-regulation of cyclin D1 and CDK4, and the up-regulation of p16, p21 and p27 proteins. We demonstrated that TMOC might induce cell apoptosis through suppressing Bcl-2 and Bcl-xL, but enhancing the expression of Bax and the cleavage of PARP-1. Treatment of TMOC also reduced the invasion and migration of A2780 cells. Finally, we found that TMOC inhibited the constitutive activation of STAT3 signaling pathway and induced the expression of the tumor suppressor PTEN regardless of the p53 status in cell lines. These data suggest that TMOC may be developed as a potential chemotherapeutic agent to effectively treat certain cancers including ovarian cancer.

  15. Follistatin during pregnancy and its potential role as an ovarian suppressing agent.

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    Köninger, Angela; Schmidt, Börge; Damaske, Daniela; Birdir, Cahit; Enekwe, Antje; Kimmig, Rainer; Strowitzki, Thomas; Gellhaus, Alexandra

    2017-05-01

    Ovarian quiescence is a common condition during pregnancy. In vitro, follistatin, an antagonist of follicle-stimulating hormone, blocks follicular development at early stages, and its serum levels increase during pregnancy. A possible surrogate biomarker of ovarian arrest during pregnancy is a decrease in anti-mullerian hormone (AMH) levels followed by an increase in these levels on the second day after labor. The purpose of this study was to determine whether follistatin could act as an ovarian-suppressing agent during pregnancy. Follistatin levels and AMH levels were determined at various stages of pregnancy and postpartum. The follistatin and AMH levels of 69 patients were retrospectively determined with the AMH Gen II ELISA and with the Human Follistatin Quantikine ELISA Kit. For 49 patients, samples were available from various trimesters for cross-sectional analysis; for the other 20, samples were available longitudinally from day one before labor and then daily on days 1 through 4 after labor. Statistical significance was determined with linear regression, the Friedman rank sum test and the Wilcoxon-Nemenyi-McDonald-Thompson post hoc test. The behavior of follistatin levels was exactly opposite that of AMH levels: Follistatin levels increased significantly during pregnancy and on the first day after parturition but declined afterwards, whereas AMH levels decreased significantly during pregnancy and increased after labor. Follistatin can induce ovarian arrest during pregnancy. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Adjuvant Tamoxifen Plus Ovarian Function Suppression Versus Tamoxifen Alone in Premenopausal Women With Early Breast Cancer: Patient-Reported Outcomes in the Suppression of Ovarian Function Trial

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    Luo, Weixiu; Bernhard, Jürg; Francis, Prudence A.; Burstein, Harold J.; Ciruelos, Eva; Bellet, Meritxell; Pavesi, Lorenzo; Lluch, Ana; Visini, Marilena; Parmar, Vani; Tondini, Carlo; Kerbrat, Pierre; Perelló, Antonia; Neven, Patrick; Torres, Roberto; Lombardi, Davide; Puglisi, Fabio; Karlsson, Per; Ruhstaller, Thomas; Colleoni, Marco; Coates, Alan S.; Goldhirsch, Aron; Price, Karen N.; Gelber, Richard D.; Regan, Meredith M.; Fleming, Gini F.

    2016-01-01

    Purpose The Suppression of Ovarian Function trial showed improved disease control for tamoxifen plus ovarian function suppression (OFS) compared with tamoxifen alone for the cohort of premenopausal patients who received prior chemotherapy. We present the patient-reported outcomes. Patients and Methods The quality-of-life (QoL) analysis includes 1,722 of 2,045 premenopausal patients with hormone receptor–positive breast cancer randomly assigned to receive adjuvant treatment with 5 years of tamoxifen plus OFS or tamoxifen alone. Chemotherapy use before enrollment was optional. Patients completed a QoL form consisting of global and symptom indicators at baseline, every 6 months for 24 months, and annually during years 3 to 6. Differences in the change of QoL from baseline between the two treatments were tested at 6, 24, and 60 months with mixed models for repeated measures with and without chemotherapy and overall. Results Patients on tamoxifen plus OFS were more affected than patients on tamoxifen alone by hot flushes at 6 and 24 months, by loss of sexual interest and sleep disturbance at 6 months, and by vaginal dryness up to 60 months. Without prior chemotherapy, patients on tamoxifen alone reported more vaginal discharge over the 5 years than patients on tamoxifen plus OFS. Symptom-specific treatment differences at 6 months were less pronounced in patients with prior chemotherapy. Changes in global QoL indicators from baseline were small and similar between treatments over the whole treatment period. Conclusion Overall, OFS added to tamoxifen resulted in worse endocrine symptoms and sexual functioning during the first 2 years of treatment, with variable magnitudes of treatment differences. Short-term differences in symptom-specific QoL, treatment burden, and coping effort between treatment groups were less pronounced for patients with prior chemotherapy, the cohort that benefited most from OFS in terms of disease control. PMID:27022111

  17. Antigen-specific active immunotherapy for ovarian cancer

    NARCIS (Netherlands)

    Leffers, Ninke; Daemen, Toos; Helfrich, Wijnand; Boezen, H. Marike; Cohlen, Ben J.; Melief, Cornelis J. M.; Nijman, Hans W.

    2014-01-01

    BACKGROUND: Despite advances in chemotherapy, prognosis of ovarian cancer remains poor. Antigen-specific active immunotherapy aims to induce tumour-antigen-specific anti-tumour immune responses as an alternative treatment for ovarian cancer. OBJECTIVES: To assess the feasibility of antigen-specific

  18. Antigen-specific active immunotherapy for ovarian cancer

    NARCIS (Netherlands)

    Leffers, N.; Daemen, T.; Helfrich, W.; Boezen, H. M.; Cohlen, B. J.; Melief, Cornelis; Nijman, H. W.

    2010-01-01

    BACKGROUND: Despite advances in chemotherapy, prognosis of ovarian cancer remains poor. Antigen-specific active immunotherapy aims to induce a tumour-antigen-specific anti-tumour immune responses as an alternative treatment for ovarian cancer. OBJECTIVES: To assess feasibility of antigen-specific

  19. Telomerase Activity in Human Ovarian Carcinoma

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    Counter, Christopher M.; Hirte, Hal W.; Bacchetti, Silvia; Harley, Calvin B.

    1994-04-01

    Telomeres fulfill the dual function of protecting eukaryotic chromosomes from illegitimate recombination and degradation and may aid in chromosome attachment to the nuclear membrane. We have previously shown that telomerase, the enzyme which synthesizes telomeric DNA, is not detected in normal somatic cells and that telomeres shorten with replicative age. In cells immortalized in vitro, activation of telomerase apparently stabilizes telomere length, preventing a critical destabilization of chromosomes, and cell proliferation continues even when telomeres are short. In vivo, telomeres of most tumors are shorter than telomeres of control tissues, suggesting an analogous role for the enzyme. To assess the relevance of telomerase and telomere stability in the development and progression of tumors, we have measured enzyme activity and telomere length in metastatic cells of epithelial ovarian carcinoma. We report that extremely short telomeres are maintained in these cells and that tumor cells, but not isogenic nonmalignant cells, express telomerase. Our findings suggest that progression of malignancy is ultimately dependent upon activation of telomerase and that telomerase inhibitors may be effective antitumor drugs.

  20. Tumour suppressive function and modulation of programmed cell death 4 (PDCD4 in ovarian cancer.

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    Na Wei

    Full Text Available BACKGROUND: Programmed cell death 4 (PDCD4, originally identified as the neoplastic transformation inhibitor, was attenuated in various cancer types. Our previous study demonstrated a continuous down-regulation of PDCD4 expression in the sequence of normal-borderline-malignant ovarian tissue samples and a significant correlation of PDCD4 expression with disease-free survival. The objective of the current study was to further investigate the function and modulation of PDCD4 in ovarian cancer cells. PRINCIPAL FINDINGS: We demonstrated that ectopic PDCD4 expression significantly inhibited cell proliferation by inducing cell cycle arrest at G(1 stage and up-regulation of cell cycle inhibitors of p27 and p21. Cell migration and invasion were also inhibited by PDCD4. PDCD4 over-expressing cells exhibited elevated phosphatase and tensin homolog (PTEN and inhibited protein kinase B (p-Akt. In addition, the expression of PDCD4 was up-regulated and it was exported to the cytoplasm upon serum withdrawal treatment, but it was rapidly depleted via proteasomal degradation upon serum re-administration. Treatment of a phosphoinositide 3-kinase (PI3K inhibitor prevented the degradation of PDCD4, indicating the involvement of PI3K-Akt pathway in the modulation of PDCD4. CONCLUSION: PDCD4 may play a critical function in arresting cell cycle progression at key checkpoint, thus inhibiting cell proliferation, as well as suppressing tumour metastasis. The PI3K-Akt pathway was implied to be involved in the regulation of PDCD4 degradation in ovarian cancer cells. In response to the stress condition, endogenous PDCD4 was able to shuttle between cell compartments to perform its diverted functions.

  1. Rspo1-activated signalling molecules are sufficient to induce ovarian differentiation in XY medaka (Oryzias latipes).

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    Zhou, Linyan; Charkraborty, Tapas; Zhou, Qian; Mohapatra, Sipra; Nagahama, Yoshitaka; Zhang, Yueguang

    2016-01-19

    In contrast to our understanding of testicular differentiation, ovarian differentiation is less well understood in vertebrates. In mammals, R-spondin1 (Rspo1), an activator of Wnt/β-catenin signaling pathway, is located upstream of the female sex determination pathway. However, the functions of Rspo1 in ovarian differentiation remain unclear in non-mammalian species. In order to elucidate the detailed functions of Rspo/Wnt signaling pathway in fish sex determination/differentiation, the ectopic expression of the Rspo1 gene was performed in XY medaka (Oryzias latipes). The results obtained demonstrated that the gain of Rspo1 function induced femininity in XY fish. The overexpression of Rspo1 enhanced Wnt4b and β-catenin transcription, and completely suppressed the expression of male-biased genes (Dmy, Gsdf, Sox9a2 and Dmrt1) as well as testicular differentiation. Gonadal reprograming of Rspo1-over-expressed-XY (Rspo1-OV-XY) fish, induced the production of female-biased genes (Cyp19a1a and Foxl2), estradiol-17β production and further female type secondary sexuality. Moreover, Rspo1-OV-XY females were fertile and produced successive generations. Promoter analyses showed that Rspo1 transcription was directly regulated by DM domain genes (Dmy, the sex-determining gene, and Dmrt1) and remained unresponsive to Foxl2. Taken together, our results strongly suggest that Rspo1 is sufficient to activate ovarian development and plays a decisive role in the ovarian differentiation in medaka.

  2. OESTRT}S AND OVARIAN ACTIVITY IN LACTATING BEEF COWS ...

    African Journals Online (AJOL)

    Prolactin may therefore be implicated in delaying the onset of ovarian activity in the post-partum cow. Bromocryptine (2-bromo- a -ergocryptine me- thansulphonate. CB-154 Sandoz Ltd. Basle. Switzer- land). administered in daily injections. of 100 mg, can effectively' block the release of prolactin {'rom the pituitarl' gland and ...

  3. Suppression of proliferation and oxidative stress by extracts of Ganoderma lucidum in the ovarian cancer cell line OVCAR-3.

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    Hsieh, Tze-Chen; Wu, Joseph M

    2011-12-01

    Lingzhi (LZ) is a medical mushroom also known as Ganoderma lucidum, which has been used in traditional Chinese medicine for more than 4,000 years and moreover, due to its presumed health benefits and apparent absence of side-effects it has also been widely consumed as a dietary supplement by cancer patients and by individuals diagnosed with various chronic diseases. The reported benefits of Ganoderma lucidum may be largely ascribed to its biologically active constituent polysaccharides and triterpenes known as ganoderic acids having structural similarity to steroid hormones. Laboratory studies have shown that Ganoderma lucidum enhances immune functions and also inhibits growth of various cancer cells both in vitro and in vivo. However, the mechanism by which Ganoderma lucidum exerts its chemopreventive activities remains unknown. In this study, we investigated whether Ganoderma lucidum elicits its anti-tumor effects by suppressing cell growth and inducing antioxidative/detoxification activity in human ovarian OVCAR-3 cells. The results showed that Ganoderma lucidum inhibits cell growth and disruption of cell cycle progression via down regulation of cyclin D1. Chemopreventive activities elicited by Ganoderma lucidum were demonstrated by the induction of antioxidant SOD and catalase as well as the phase II detoxification enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione S-transferase P1 (GSTP1) via the Nrf2 mediated signaling pathway known to provide chemoprotection against carcinogenicity. These findings indicate that Ganoderma lucidum possesses chemopreventive potential contributing to its overall health effects and further suggest that Ganoderma lucidum may have clinical applications as an adjunct supplementary agent in chemotherapy.

  4. Potential of Targeting PDE1C/2A for Suppressing Metastatic Ovarian Cancers

    Science.gov (United States)

    2015-09-01

    Analysis of ovarian cancer cell lines using array-based comparative genomic hybridization . The Journal of pathology. 2005; 205:29-40. 4. Integrated...Analysis of gene amplification and prognostic markers in ovarian cancer using comparative genomic hybridization for microarrays and immunohistochemical...Signals triggered by these factors all converge on EMT-inducing transcriptional factors such as Snail , Slug, Twist and Zeb1/2 that diminish the

  5. Ovarian Hormones and Transdermal Nicotine Administration Independently and Synergistically Suppress Tobacco Withdrawal Symptoms and Smoking Reinstatement in the Human Laboratory.

    Science.gov (United States)

    Pang, Raina D; Liautaud, Madalyn M; Kirkpatrick, Matthew G; Huh, Jimi; Monterosso, John; Leventhal, Adam M

    2018-03-01

    Modeling intra-individual fluctuations in estradiol and progesterone may provide unique insight into the effects of ovarian hormones on the etiology and treatment of nicotine dependence. This randomized placebo-controlled laboratory study tested the independent and interactive effects of intra-individual ovarian hormone variation and nicotine on suppression of tobacco withdrawal symptoms and smoking behavior. Female smokers randomized to 21 mg nicotine (TNP; n=37) or placebo (PBO; n=43) transdermal patch following overnight abstinence completed three sessions occurring during hormonally distinct menstrual cycle phases. At each session, participants provided saliva for hormone assays and completed repeated self-report measures (ie, tobacco withdrawal symptoms, smoking urge, and negative affect (NA)) followed by an analog smoking reinstatement task for which participants could earn money to delay smoking and subsequently purchase cigarettes to smoke. Higher (vs lower) progesterone levels were associated with greater reductions in NA. Higher (vs lower) progesterone levels and progesterone to estradiol ratios were associated with reducing smoking urges over time to a greater extent with TNP compared to PBO. There was an interaction between Patch and estradiol on NA. With TNP, higher-than-usual estradiol was associated with greater decreases in NA. However with PBO, lower-than-usual estradiol was associated with greater decreases in NA. These results suggest that the effects of TNP on mood- and smoking-related outcomes may vary depending on the ovarian hormone levels.

  6. GnRH-agonist implants suppress reproductive function and affects ovarian LHR and FSHR expression in prepubertal female cats.

    Science.gov (United States)

    Mehl, N S; Srisuwatanasagul, S; Swangchan-Uthai, T; Sirivaidyapong, S; Khalid, M

    2017-01-01

    Effect of a GnRH-agonist (deslorelin) was studied on reproductive function and ovarian luteinizing hormone receptor (LHR) and follicle stimulating hormone receptor (FSHR) expression in prepubertal female cats that were either implanted with 4.7-mg deslorelin (implanted: n = 6) or not (controls: n = 18) or ovariohysterectomized at prepubertal age (prepubertal OVH: n = 6). Body weights, fecal estradiol, and sexual behavior of implanted and control cats were monitored for 48 weeks followed by collection of ovaries and uteri. Ovaries and uteri were collected from control cats at follicular, luteal, and inactive stage (n = 6/group) and from prepubertal OVH cats at prepubertal age. Ovaries and uteri were analyzed for anatomical/histological characteristics. Ovaries were also analyzed for LHR and FSHR expression. Statistical analysis showed higher (P ≤ 0.05) body weight in control than implanted cats only during 22nd to 26th weeks of the study. Estrus was observed in control cats only. Deslorelin reduced (P ≤ 0.05) ovarian weight and number of antral follicles but did not affect endometrial thickness and gland diameter. However, myometrial thickness of implanted cats was significantly lower than control cats at follicular and luteal stage. Ovarian LHR mRNA expression was lower (P ≤ 0.05) in implanted cats than control cats at follicular stage. FSHR mRNA and LHR protein expression did not differ among the three groups. FSHR protein expression was lower (P ≤ 0.05) in prepubertal OVH cats and was not affected by deslorelin. In conclusion, deslorelin suppresses reproductive function in prepubertal female cats for at least 48 weeks possibly through a change in the ovarian mRNA expression of LHR. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Sublethal concentrations of 17-AAG suppress homologous recombination DNA repair and enhance sensitivity to carboplatin and olaparib in HR proficient ovarian cancer cells.

    Science.gov (United States)

    Choi, Young Eun; Battelli, Chiara; Watson, Jacqueline; Liu, Joyce; Curtis, Jennifer; Morse, Alexander N; Matulonis, Ursula A; Chowdhury, Dipanjan; Konstantinopoulos, Panagiotis A

    2014-05-15

    The promise of PARP-inhibitors(PARPis) in the management of epithelial ovarian cancer(EOC) is tempered by the fact that approximately 50% of patients with homologous recombination (HR)-proficient tumors do not respond well to these agents. Combination of PARPis with agents that inhibit HR may represent an effective strategy to enhance their activity in HR-proficient tumors. Using a bioinformatics approach, we identified that heat shock protein 90 inhibitors(HSP90i) may suppress HR and thus revert HR-proficient to HR-deficient tumors. Analysis of publicly available gene expression data showed that exposure of HR-proficient breast cancer cell lines to HSP90i 17-AAG(17-allylamino-17-demethoxygeldanamycin) downregulated HR, ATM and Fanconi Anemia pathways. In HR-proficient EOC cells, 17-AAG suppressed HR as assessed using the RAD51 foci formation assay and this was further confirmed using the Direct Repeat-GFP reporter assay. Furthermore, 17-AAG downregulated BRCA1 and/or RAD51 protein levels, and induced significantly more γH2AX activation in combination with olaparib compared to olaparib alone. Finally, sublethal concentrations of 17-AAG sensitized HR-proficient EOC lines to olaparib and carboplatin but did not affect sensitivity of the HR-deficient OVCAR8 line arguing that the 17-AAG mediated sensitization is dependent on suppression of HR. These results provide a preclinical rationale for using a combination of olaparib/17-AAG in HR-proficient EOC.

  8. Monitoring and controlling ovarian activities in wild ungulates.

    Science.gov (United States)

    Sontakke, Sadanand D

    2018-03-15

    Reproductive success in females relies primarily upon better understanding of fundamental ovarian processes to facilitate captive reproductive management and ultimately the development of assisted reproductive technologies as an alternative tool for conservation breeding of endangered wildlife species. Wild ungulates (cervids and non-domestic bovids) are an extraordinarily diverse group of mammals with remarkable diversity in reproductive biology (anatomy, behaviour, physiology and seasonality). This indicates a clear need, and indeed a big challenge, for acquiring such basic reproductive knowledge in severely threatened ungulates before attempting even a simpler technology such as artificial insemination. Despite a few sporadic successes of artificial insemination technology in ungulates, there is much to learn, including optimizing estrus synchronization protocols and an animal-friendly fixed-time insemination procedure that would maximize breeding success with minimal stress to the animal. Recent advances in non-invasive methodologies for monitoring endocrine profiles and assessment of ovarian function in wildlife species enable us to understand and characterize basic reproductive events in a species. This review discusses non-invasive approaches being used for monitoring endocrine and ovarian activity in wild ungulates. Further, it reviews the effectiveness of different methodologies for control of estrus and ovulation in non-domestic bovids and cervids. Additionally, the challenges regarding their application in different ungulates as a standard routine practice like in livestock are addressed. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Reprogramming of the Ovarian Tumor Stroma by Activation of a Biomechanical ECM Switch

    Science.gov (United States)

    2016-09-01

    AWARD NUMBER: W81XWH-14-1-0178 TITLE: Reprogramming of the Ovarian Tumor Stroma by Activation of a Biomechanical ECM Switch PRINCIPAL...SUBTITLE 5a. CONTRACT NUMBER Reprogramming of the Ovarian Tumor Stroma by Activation of a Biomechanical ECM Switch 5b. GRANT NUMBER W81XWH-14-1...particular we, have characterized stromal cell infiltration of ovarian tumors and have shown extensive infiltration of tumor associated blood vessels as well

  10. Emodin suppresses proliferation, migration and invasion in ovarian cancer cells by down regulating ILK in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Lu JJ

    2017-07-01

    Full Text Available Jingjing Lu,1,2,* Ying Xu,1,* Zhe Zhao,1 Xiaoning Ke,2 Xuan Wei,1 Jia Kang,1 Xuan Zong,1 Hongluan Mao,1 Peishu Liu1 1Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Shandong, 2Department of Obstetrics and Gynecology, Handan Central Hospital, Handan, People’s Republic of China *These authors contributed equally to this work Objective: Although our previous studies have confirmed that 1, 3, 8-trihydroxy-6-methylanthraquinone (emodin inhibits migration and invasion in epithelial ovarian cancer (EOC cells, the underlying molecular mechanism remains unknown. Here, the aim was to investigate the effects of emodin on EOC cells and to study further the mechanism underlying this process, both in vitro and in vivo.Materials and methods: Cell proliferation was evaluated by the methylthiazolyl tetrazolium assay. Cell migration and invasion abilities were tested using the transwell assay. The expression of integrin-linked kinase (ILK and epithelial–mesenchymal transition (EMT-associated factors were measured with western blotting.Results: Exogenous ILK enhanced the proliferation, migration and invasion properties of A2780 and SK-OV-3 cells. After treatment with emodin, the survival rate of cells was gradually reduced, including those of SK-OV-3/pLVX-ILK and A2780/pLVX-ILK cells, with increasing emodin concentrations. The migration and invasion abilities of A2780 and SK-OV-3 cells were effectively increased by the transfection of pLVX-ILK, which could be abrogated by following this with 48 hours of emodin treatment. Treatment with emodin significantly downregulated the expression of ILK and EMT-related proteins. So, emodin suppressed proliferation, migration and invasion in ovarian cancer cells by downregulating ILK in vitro. SK-OV-3/pLVX-Con and SK-OV-3/pLVX-ILK cells were used to generate xenografts in nude mice. Tumors grew more rapidly in the SK-OV-3/pLVX-ILK group compared with the control group, and this could be

  11. Berberine inhibits the chemotherapy-induced repopulation by suppressing the arachidonic acid metabolic pathway and phosphorylation of FAK in ovarian cancer.

    Science.gov (United States)

    Zhao, Yawei; Cui, Lianzhi; Pan, Yue; Shao, Dan; Zheng, Xiao; Zhang, Fan; Zhang, Hansi; He, Kan; Chen, Li

    2017-12-01

    Cytotoxic chemotherapy is an effective and traditional treatment of ovarian cancer. However, chemotherapy-induced apoptosis may also trigger and ultimately accelerate the repopulation of the small number of adjacent surviving cells. This study mainly focused on the tumour cell repopulation caused by chemotherapy in ovarian cancer and the adjunctive/synergistic effect of Berberine on the prevention of tumour repopulation. The transwell system was used to mimic the co-culture of surviving ovarian cancer cells in the microenvironment of cytotoxic chemotherapy-treated dying cells. Tumour cell proliferation was observed by crystal violet staining. AA and PGE 2 levels were measured by ELISA, and changes of protein expression were analysed by Western blot. Chemotherapy drug VP16 treatment triggered AA pathway, leading to the elevated PGE 2 level, and ultimately enhanced the repopulation of ovarian cancer cells. Berberine can block the caspase 3-iPLA 2 -AA-COX-2-PGE 2 pathway by inhibiting the expression of iPLA 2 and COX-2. Berberine can also reverse the increased phosphorylation of FAK caused by abnormal PGE 2 level and thus reverse the repopulation of ovarian cancer cells after VP16 treatment. Our observation suggested that Berberine could inhibit the chemotherapy-induced repopulation of ovarian cancer cells by suppressing the AA pathway and phosphorylation of FAK. And these findings implicated a novel combined use of Berberine and chemotherapeutics, which might prevent ovarian cancer recurrence by abrogating early tumour repopulation. © 2017 John Wiley & Sons Ltd.

  12. [Ovarian activity of Agouti paca (Rodentia: Agoutidae) under captivity].

    Science.gov (United States)

    Montes Pérez, Rubén C; Cabrera Baz, Elsy A

    2006-09-01

    The ovarian activity of Agouti paca was characterized by hormonal profiles and ovarian structures. Samples of blood were taken from eight females (seven adults and one juvenile) at the breeding grounds of the Facultad de Medicina Veterinaria y Zootecnia in Yucatśn, Mexico. Sampling lasted approximately two months and was done every three and six days. Blood was collected from anesthetized animals, and the levels of progesterone (P4) and 17 beta estradiol (E2) were analized by radioimmunoassay technique. Macroscopic and microscopic analyses were carried out in ovaries of dead animals. The estrous cycle lasted 29+/-8.4 days, levels of 1.61+/-0.65 ng/ml for P4 and 39+/-24 pg/ml for E2 were observed for a follicular phase, 6.18+/-3.70 ng/ml and 29+/-16 pg/ml for P4 and E2 respectively in the luteal phase. Statistically significant differences were found between phases for P4 but not for E2. The presence of extragonadal steroids with levels of P4 of 1.9+/-0.77 ng/ml and E2 of 22+/-17 pg/ml were observed, which are not produced by the effects of managing stress. The changes in the levels of P4 during the cycle are indicators of luteal activity, with the intersticial tissue acting probably as active steroids-producing gland. Follicular growth was observed during the entire cycle.

  13. Influence of ovarian hormones on cortical spreading depression and its suppression by L-kynurenine in rat.

    Directory of Open Access Journals (Sweden)

    Virginie Chauvel

    Full Text Available Migraine is sexually dimorphic and associated in 20-30% of patients with an aura most likely caused by cortical spreading depression (CSD. We have previously shown that systemic L-kynurenine (L-KYN, the precursor of kynurenic acid, suppresses CSD and that this effect depends on the stage of the estrous cycle in female rats. The objectives here are to determine the influence of ovarian hormones on KCl-induced CSD and its suppression after L-KYN by directly modulating estradiol or progesterone levels in ovariectomized rats. Adult female rats were ovariectomized and subcutaneously implanted with silastic capsules filled with progesterone or 17β-estradiol mixed with cholesterol, with cholesterol only or left empty. Two weeks after the ovariectomy/capsule implantation, the animals received an i.p. injection of L-KYN (300 mg/kg or NaCl as control. Thirty minutes later CSDs were elicited by applying KCl over the occipital cortex and recorded by DC electrocorticogram for 1 hour. The results show that both estradiol and progesterone increase CSD frequency after ovariectomy. The suppressive effect of L-KYN on CSD frequency, previously reported in normal cycling females, is not found anymore after ovariectomy, but reappears after progesterone replacement therapy. Taken together, these results emphasize the complex role of sex hormones on cortical excitability. The CSD increase by estradiol and, more surprisingly, progesterone may explain why clinically migraine with aura appears or worsens during pregnancy or with combined hormonal treatments.

  14. Activation of the LKB1‑SIK1 signaling pathway inhibits the TGF‑β‑mediated epithelial‑mesenchymal transition and apoptosis resistance of ovarian carcinoma cells.

    Science.gov (United States)

    Hong, Bo; Zhang, Jianmei; Yang, Wenlan

    2018-02-01

    Ovarian cancer is the most common and lethal type of gynecological malignancy, due to its invasiveness. The present study aimed to analyze the molecular mechanism underlying chemoresistance in ovarian carcinoma cells, which may lead to local migration toward adjacent tissues and long‑distance metastasis to other organs. A total of 12 patients with ovarian fibroma were used to evaluate chemoresistance and chemosensitivity. The sensitivity and resistance of ovarian carcinoma cells was measured using apoptosis analysis, morphological observation, survival rate analysis, immunohistochemistry and immunostaining. The mechanism underlying the interaction between the epithelial‑mesenchymal transition (EMT) and liver kinase B1 (LKB1)‑salt‑inducible kinase 1 (SIK1) signaling pathways was additionally investigated in ovarian carcinoma. The results of the present study demonstrated that ovarian carcinoma cells isolated from patients exhibited apoptosis resistance. Inhibition of TGF‑β expression led to an inhibition of growth, migration and invasion, in addition to a promotion of apoptosis, in ovarian carcinoma cells treated with paclitaxel. Studies have indicated that the LKB1‑SIK1 signaling pathway may be suppressed in ovarian carcinoma cells compared with normal ovarian cells, leading to activation of the EMT signaling pathway. The results of the present study demonstrated that upregulation of LKB1 promoted SIK1 expression and markedly suppressed the growth and aggressiveness of ovarian cancer cells. Upregulation of LKB1 additionally promoted apoptosis in ovarian carcinoma cells. In addition, the results of the present study demonstrated that the knockdown of LKB1 further promoted the expression of transforming growth factor‑β and EMT, which downregulated the chemosensitivity of ovarian carcinoma cells. Additionally, overexpression of LKB1 in ovarian carcinoma cells increased chemosensitivity, resulting in a significant inhibition of migration and

  15. Microbial enrichment to enhance the disease suppressive activity of compost

    NARCIS (Netherlands)

    Postma, J.; Montenari, M.; Boogert, van den P.H.J.F.

    2003-01-01

    Compost amended soil has been found to be suppressive against plant diseases in various cropping systems. The level and reproducibility of disease suppressive properties of compost might be increased by the addition of antagonists. In the present study, the establishment and suppressive activity of

  16. A Rationally Designed Histone Deacetylase Inhibitor with Distinct Antitumor Activity against Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Ya-Ting Yang

    2009-06-01

    Full Text Available Histone deacetylase inhibitors (HDACIs are a class of antineoplastic agents previously demonstrating preclinical chemosensitizing activity against drug-resistant cancer cells and mouse xenografts. However, whereas clinical studies have shown efficacy against human hematologic malignancies, solid tumor trials have proved disappointing. We previously developed a novel HDACI, “OSU-HDAC42,” and herein examine its activity against ovarian cancer cell lines and xenografts. OSU-HDAC42, (i unlike most HDACIs, elicited a more than five-fold increase in G2-phase cells, at 2.5 µM, with G2 arrest followed by apoptosis; (ii at 1.0 µM, completely repressed messenger RNA expression of the cell cycle progression gene cdc2; (iii at low doses (0.25–1.0 µM for 24 hours, induced tumor cell epithelial differentiation, as evidenced by morphology changes and a more than five-fold up-regulation of epithelium-specific cytokeratins; (iv potently abrogated the growth of numerous ovarian cancer cells, with IC50 values of 0.5 to 1.0 µM, whereas also remaining eight-fold less toxic (IC50 of 8.6 µM to normal ovarian surface epithelial cells; and (v chemosensitizated platinum-resistant mouse xenografts to cisplatin. Compared with the clinically approved HDACI suberoylanilide hydroxamic acid (vorinostat, 1.0 µM OSU-HDAC42 was more biochemically potent (i.e., enzyme-inhibitory, as suggested by greater gene up-regulation and acetylation of both histone and nonhistone proteins. In p53-dysfunctional cells, however, OSU-HDAC42 was two- to eight-fold less inductive of p53-regulated genes, whereas also having a two-fold higher IC50 than p53-functional cells, demonstrating some interaction with p53 tumor-suppressive cascades. These findings establish OSU-HDAC42 as a promising therapeutic agent for drug-resistant ovarian cancer and justify its further investigation.

  17. Allergen-Removed Rhus verniciflua Extract Induces Ovarian Cancer Cell Death via JNK Activation.

    Science.gov (United States)

    Kang, Se-Hui; Hwang, In-Hu; Son, Eunju; Cho, Chong-Kwan; Choi, Jong-Soon; Park, Soo-Jung; Jang, Byeong-Churl; Lee, Kyung-Bok; Lee, Zee-Won; Lee, Jong Hoon; Yoo, Hwa-Seung; Jang, Ik-Soon

    2016-01-01

    Nuclear factor-[Formula: see text]B (NF-[Formula: see text]B)/Rel transcription factors are best known for their central roles in promoting cell survival in cancer. NF-[Formula: see text]B antagonizes tumor necrosis factor (TNF)-[Formula: see text]-induced apoptosis through a process involving attenuation of the c-Jun-N-terminal kinase (JNK). However, the role of JNK activation in apoptosis induced by negative regulation of NF-[Formula: see text]B is not completely understood. We found that allergen-removed Rhus verniciflua Stokes (aRVS) extract-mediated NF-[Formula: see text]B inhibition induces apoptosis in SKOV-3 ovarian cancer cells via the serial activation of caspases and SKOV-3 cells are most specifically suppressed by aRVS. Here, we show that in addition to activating caspases, aRVS extract negatively modulates the TNF-[Formula: see text]-mediated I[Formula: see text]B/NF-[Formula: see text]B pathway to promote JNK activation, which results in apoptosis. When the cytokine TNF-[Formula: see text] binds to the TNF receptor, I[Formula: see text]B dissociates from NF-[Formula: see text]B. As a result, the active NF-[Formula: see text]B translocates to the nucleus. aRVS extract (0.5[Formula: see text]mg/ml) clearly prevented NF-[Formula: see text]B from mobilizing to the nucleus, resulting in the upregulation of JNK phosphorylation. This subsequently increased Bax activation, leading to marked aRVS-induced apoptosis, whereas the JNK inhibitor SP600125 in aRVS extract treated SKOV-3 cells strongly inhibited Bax. Bax subfamily proteins induced apoptosis through caspase-3. Thus, these results indicate that aRVS extract contains components that inhibit NF-[Formula: see text]B signaling to upregulate JNK activation in ovarian cancer cells and support the potential of aRVS as a therapeutic agent for ovarian cancer.

  18. YAP/TEAD co-activator regulated pluripotency and chemoresistance in ovarian cancer initiated cells.

    Science.gov (United States)

    Xia, Yan; Zhang, Yin-Li; Yu, Chao; Chang, Ting; Fan, Heng-Yu

    2014-01-01

    Recent evidence suggests that some solid tumors, including ovarian cancer, contain distinct populations of stem cells that are responsible for tumor initiation, growth, chemo-resistance, and recurrence. The Hippo pathway has attracted considerable attention and some investigators have focused on YAP functions for maintaining stemness and cell differentiation. In this study, we successfully isolated the ovarian cancer initiating cells (OCICs) and demonstrated YAP promoted self-renewal of ovarian cancer initiated cell (OCIC) through its downstream co-activator TEAD. YAP and TEAD families were required for maintaining the expression of specific genes that may be involved in OCICs' stemness and chemoresistance. Taken together, our data first indicate that YAP/TEAD co-activator regulated ovarian cancer initiated cell pluripotency and chemo-resistance. It proposed a new mechanism on the drug resistance in cancer stem cell that Hippo-YAP signal pathway might serve as therapeutic targets for ovarian cancer treatment in clinical.

  19. YAP/TEAD co-activator regulated pluripotency and chemoresistance in ovarian cancer initiated cells.

    Directory of Open Access Journals (Sweden)

    Yan Xia

    Full Text Available Recent evidence suggests that some solid tumors, including ovarian cancer, contain distinct populations of stem cells that are responsible for tumor initiation, growth, chemo-resistance, and recurrence. The Hippo pathway has attracted considerable attention and some investigators have focused on YAP functions for maintaining stemness and cell differentiation. In this study, we successfully isolated the ovarian cancer initiating cells (OCICs and demonstrated YAP promoted self-renewal of ovarian cancer initiated cell (OCIC through its downstream co-activator TEAD. YAP and TEAD families were required for maintaining the expression of specific genes that may be involved in OCICs' stemness and chemoresistance. Taken together, our data first indicate that YAP/TEAD co-activator regulated ovarian cancer initiated cell pluripotency and chemo-resistance. It proposed a new mechanism on the drug resistance in cancer stem cell that Hippo-YAP signal pathway might serve as therapeutic targets for ovarian cancer treatment in clinical.

  20. A designed inhibitor of p53 aggregation rescues p53 tumor-suppression in ovarian carcinomas

    Science.gov (United States)

    Soragni, Alice; Janzen, Deanna M.; Johnson, Lisa M.; Lindgren, Anne G.; Nguyen, Anh Thai-Quynh; Tiourin, Ekaterina; Soriaga, Angela B.; Lu, Jing; Jiang, Lin; Faull, Kym F.; Pellegrini, Matteo; Memarzadeh, Sanaz; Eisenberg, David S.

    2015-01-01

    SUMMARY Half of all human cancers lose p53 function by missense mutations, with an unknown fraction of these containing p53 in a self-aggregated, amyloid-like state. Here we show that a cell-penetrating peptide, ReACp53, designed to inhibit p53 amyloid formation, rescues p53 function in cancer cell lines and in organoids derived from high-grade serous ovarian carcinomas (HGSOC), an aggressive cancer characterized by ubiquitous p53 mutations. Rescued p53 behaves similarly to its wild-type counterpart in regulating target genes, reducing cell proliferation and increasing cell death. Intraperitoneal administration decreases tumor proliferation and shrinks xenografts in vivo. Our data show the effectiveness of targeting a specific aggregation defect of p53 and its potential applicability to HGSOCs. PMID:26748848

  1. Abrogation of constitutive Stat3 activity circumvents cisplatin resistant ovarian cancer.

    Science.gov (United States)

    Ji, Teng; Gong, Danni; Han, Zhiqiang; Wei, Xiao; Yan, Yuting; Ye, Fei; Ding, Wencheng; Wang, Junnai; Xia, Xi; Li, Fei; Hu, Wencheng; Lu, Yunping; Wang, Shixuan; Zhou, Jianfeng; Ma, Ding; Gao, Qinglei

    2013-12-01

    The aim of the present study was to investigate the role of Stat3 in cisplatin resistant ovarian cancer. It was first demonstrated that higher activated Stat3 was detected in cisplatin-resistant ovarian cancer cell lines. To provide evidence that supported the hypothesis that phosphorylated-Stat3 expression may promote cisplatin resistance, ectopic Stat3 was expressed by IL-6 stimulation that partially abrogates Stat3, as opposed to the knock-down of Stat3 by specific siRNA that restores cisplatin sensitivity against ovarian cancer cells. This hypothesis was further confirmed by clinical tumor specimens of ovarian cancer obtained from patients with cisplatin-resistance. Based on these premises, Stattic, an effective small molecular inhibitor of Stat3, was used to inhibit Stat3 activation. The data presented here show that Stattic restored the sensitivity to cisplatin in chemoresistant ovarian cancer by significant reductions in the expression of the anti-apoptosis protein Bcl-2, Bcl-XL, Survivin protein and phosphorylated-Akt levels. Consistent with these observations, this experiment demonstrated the first evidence of Stattic circumvented cisplatin resistance of orthotopic xenograft ovarian cancer in vivo. Altogether, these findings emphasize the importance of Stat3 in cisplatin resistance in ovarian cancer and provide a further impetus to clinically evaluate biological modifiers that may circumvent cisplatin resistance in patients with chemoresistant ovarian cancer. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  2. 1α,25(OH2D3 Suppresses the Migration of Ovarian Cancer SKOV-3 Cells through the Inhibition of Epithelial–Mesenchymal Transition

    Directory of Open Access Journals (Sweden)

    Yong-Feng Hou

    2016-08-01

    Full Text Available Ovarian cancer is the most lethal gynecological malignancy due to its high metastatic ability. Epithelial-mesenchymal transition (EMT is essential during both follicular rupture and epithelium regeneration. However, it may also accelerate the progression of ovarian carcinomas. Experimental studies have found that 1α,25-dihydroxyvitamin-D3 [1α,25(OH2D3] can inhibit the proliferation of ovarian cancer cells. In this study, we investigated whether 1α,25(OH2D3 could inhibit the migration of ovarian cancer cells via regulating EMT. We established a model of transient transforming growth factor-β1(TGF-β1-induced EMT in human ovarian adenocarcinoma cell line SKOV-3 cells. Results showed that, compared with control, 1α,25(OH2D3 not only inhibited the migration and the invasion of SKOV-3 cells, but also promoted the acquisition of an epithelial phenotype of SKOV-3 cells treated with TGF-β1. We discovered that 1α,25(OH2D3 increased the expression of epithelial marker E-cadherin and decreased the level of mesenchymal marker, Vimentin, which was associated with the elevated expression of VDR. Moreover, 1α,25(OH2D3 reduced the expression level of transcription factors of EMT, such as slug, snail, and β-catenin. These results indicate that 1α,25(OH2D3 suppresses the migration and invasion of ovarian cancer cells by inhibiting EMT, implying that 1α,25(OH2D3 might be a potential therapeutic agent for the treatment of ovarian cancer.

  3. Combination of ciglitazone, a peroxisome proliferator-activated receptor gamma ligand, and cisplatin enhances the inhibition of growth of human ovarian cancers.

    Science.gov (United States)

    Yokoyama, Yoshihito; Xin, Bing; Shigeto, Tatsuhiko; Mizunuma, Hideki

    2011-08-01

    We have recently reported that peroxisome proliferator-activated receptor gamma (PPARγ) ligands produce antitumor effects against human ovarian cancer in conjunction with reduction in angiogenesis and induction of apoptosis via regulating prostaglandin (PG) E(2) level. In this study, we investigated the effects of combination of ciglitazone, a PPARγ ligand, and cisplatin, a cytotoxic anti-cancer drug, on growth of ovarian cancer. Tumor growth and survival were examined in female nu/nu mice xenografted with subcutaneous OVCAR-3 tumors or with intraperitoneal DISS tumors and treated with cisplatin alone (5 mg/kg intraperitoneally once on day 1), ciglitazone alone (15 mg/kg intraperitoneally once a week), or the combination. Ciglitazone alone, cisplatin alone, or their combination significantly suppressed the growth of OVCAR-3 tumors xenotransplated subcutaneously and prolonged the survival of mice with malignant ascites derived from DISS cells as compared with the control. Furthermore, the combination produced a significantly greater antitumor effect than cisplatin or ciglitazone alone and also significantly prolonged the survival time as compared with cisplatin or ciglitazone alone. The combination significantly decreased PGE(2) concentration in serum as well as in ascites, reduced vascular endothelial growth factor as well as microvessel density, and induced apoptosis in solid OVCAR-3 tumor as compared with cisplatin or ciglitazone alone. The combination remarkably decreased the expression of cyclooxygenase-2 (COX-2), microsomal PG E synthase (mPGES), and PG receptor 3 (EP3) in tumors. In vitro experiment showed that ciglitazone enhances the cytotoxicity of cisplatin against ovarian cancer cells. In conclusion, the combination inhibited the growth of ovarian cancer in conjunction with reduction in angiogenesis and induction of apoptosis resulting from suppression of PGE(2) activation through decreasing the expression of COX-2, mPGES, and EP3. The inhibitory

  4. Quality of life and sexuality comparison between sexually active ovarian cancer survivors and healthy women

    Science.gov (United States)

    Kim, Se Ik; Lee, Yumi; Joo, Jungnam; Park, KiByung; Lee, Dong Ock; Park, Sang-Yoon

    2015-01-01

    Objective compare quality of life (QoL) and sexual functioning between sexually active ovarian cancer survivors and healthy women. Methods A cross-sectional study was performed in 103 successfully treated ovarian cancer survivors and 220 healthy women. All women had engaged in sexual activity within the previous 3 months, and ovarian cancer survivors were under surveillance after primary treatment without evidence of disease. QoL and sexual functioning were assessed using three questionnaires; the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Ovarian Cancer Module (EORTC QLQ-OV28), and the Female Sexual Function Index (FSFI). Propensity score matching was used to adjust covariates between the ovarian cancer survivor and healthy women groups. In total, 73 ovarian cancer survivors and 73 healthy women were compared. Results Poorer social functioning (mean, 82.4 vs. 90.9; p=0.010) and more financial difficulties (mean, 16.4 vs. 7.8; p=0.019) were observed among ovarian cancer survivors than among healthy women. Sexuality, both in terms of desire, arousal, lubrication, orgasm, satisfaction, and pain and in terms of interest in sex, sexual activity, and enjoyment of sex (EORTC QLQ-OV28) were similar between the groups. However, vaginal dryness was more problematic in ovarian cancer survivors, with borderline statistical significance (p=0.081). Conclusion Sexuality was not impaired in ovarian cancer survivors who were without evidence of disease after primary treatment and having sexual activities, compared with healthy women, whereas social functioning and financial status did deteriorate. Prospective cohort studies are needed. PMID:25686396

  5. Microcell-mediated chromosome transfer identifies EPB41L3 as a functional suppressor of epithelial ovarian cancers

    DEFF Research Database (Denmark)

    Dafou, Dimitra; Grun, Barbara; Sinclair, John

    2010-01-01

    lines. Using immunohistochemistry, 66% of 794 invasive ovarian tumors showed no EPB41L3 expression compared with only 24% of benign ovarian tumors and 0% of normal ovarian epithelial tissues. EPB41L3 was extensively methylated in ovarian cancer cell lines and primary ovarian tumors compared with normal...... (erythrocyte membrane protein band 4.1-like 3, alternative names DAL-1 and 4.1B) was a candidate ovarian cancer-suppressor gene. Immunoblot analysis showed that EPB41L3 was activated in TOV21G(+18) hybrids, expressed in normal ovarian epithelial cell lines, but was absent in 15 (78%) of 19 ovarian cancer cell...... tissues (P = .00004), suggesting this may be the mechanism of gene inactivation in ovarian cancers. Constitutive reexpression of EPB41L3 in a three-dimensional multicellular spheroid model of ovarian cancer caused significant growth suppression and induced apoptosis. Transmission and scanning electron...

  6. BRCA1 expression, proliferative and apoptotic activities in ovarian epithelial inclusions

    OpenAIRE

    Wang, Yiying; Wang, Yue; Wei, Li; Hong, Shuhui; Zhao, Miaoqing; Zhang, Xi; Zheng, Wenxin

    2017-01-01

    Background The purpose of this study was to examine proliferative and apoptotic activity in relation with BRCA1 expression in ovarian epithelial inclusions (OEIs), the putative precursor lesions of ovarian epithelial cancer (OEC). Methods Benign ovaries from 95 patients were examined. Dual immunohistochemical staining for both BRCA1 and MIB-1 were performed to examine the relationship between BRCA1 and MIB-1 in OEI cells. Apoptotic activity was assessed on the parallel tissue sections by usin...

  7. LY2109761 enhances cisplatin antitumor activity in ovarian cancer cells.

    Science.gov (United States)

    Gao, Yuxiu; Shan, Ning; Zhao, Cheng; Wang, Yunhai; Xu, Fuliang; Li, Jiacun; Yu, Xiaoqian; Gao, Lifeng; Yi, Zhengjun

    2015-01-01

    Ovarian cancer is among the most lethal of all malignancies in women. While chemotherapy is the preferred treatment modality, chemoresistance severely limits treatment success. Because transforming growth factor-beta (TGF-β) could increase survival of ovarian cancer cells in the presence of cisplatin, we conducted a preclinical study of the antitumor effects of the TGF-β type I (TβRI) and type II (TβRII) kinase inhibitor LY2109761 in combination with cisplatin. SKOV3, OV-90 and SKOV3(DDP) cells were treated with LY2109761, and/or cisplatin, and cell viability, apoptosis mRNA and protein expression levels were then evaluated. Furthermore, the efficacy of LY2109761 combined with cisplatin was further examined in established xenograft models. LY2109761 was sufficient to induce spontaneous apoptosis of ovarian cancer cells. Combination with LY2109761 significantly augmented the cytotoxicity of cisplatin in both parental and cisplatin resistant ovarian cancer cells. LY2109761 significantly increased apoptotic cell death in cisplatin-resistant cells. Combination treatment of LY2109761 and cisplatin showed antiproliferative effects and induced a greater rate of apoptosis than the sum of the single-treatment rates and promoted tumor regression in established parental and cisplatin resistant ovarian cancer xenograft models. Chemotherapeutic approaches using LY2109761 might enhance the treatment benefit of the cisplatin in the treatment of ovarian cancer patients.

  8. ACTIVITY OF NATURAL KILLER CELLS IN BIOLOGICAL FLUIDS FROM PATIENTS WITH COLORECTAL AND OVARIAN CANCERS

    Directory of Open Access Journals (Sweden)

    N. V. Yunusova

    2017-01-01

    Full Text Available Objective. To compare the functional activity of natural killer cells in peripheral blood and ascites from patients with different stages of colorectal and ovarian cancers and benign ovarian tumors. Material and methods. The study included 10 patients with stage IIIC ovarian cancer (FIGO, 2009, 5 patients with benign ovarian tumors (BOTs, and 15 patients with colorectal cancer (T2–4N0–2M0 . The control group consisted of 5 healthy donors. To evaluate the number and functional activity of NK-cells in peripheral blood and ascites, the FACS Canto II Flow Cytometer was used. Results. In peripheral blood of patients with ovarian and colorectal cancers, the relative number of activated NK-cells capable of secreting granzyme B (GB (CD56 + CD107a + GB + PF- was significantly lower and the proportion of degranulated NK-cells (CD56 + CD107a + GB- PF- was higher than those of healthy donors. Low total NK-cell counts in peripheral blood were a distinctive feature of ovarian cancer patients (p<0.05. The proportion of activated peripheral blood NK-cells, containing granules of cytolytic enzymes GB and perforin (PF increased with tumor growth. However, lymph node metastasis in patients with colorectal cancer did not affect the level and activation of NK-cells. The comparative analysis of NK-populations in patients with benign and malignant ovarian tumors revealed that the level of CD56 + cells was significantly higher in tumor ascites compared to peripheral blood. In patients with BTs, the levels of CD56 + CD107a + and activated CD56 + CD107a + GB-PF-degranulated cells was higher in ascites than in blood. In patients with ovarian cancer, the level of degranulated cells was higher in peripheral blood than in malignant ascites. Conclusion. The tumor cells and tumor microenvironment were found to affect the number and the functional activity of NK-cells. The accumulation of free fluid within the peritoneal cavity in patients with both benign and malignant

  9. Dienogest, a selective progestin, reduces plasma estradiol level through induction of apoptosis of granulosa cells in the ovarian dominant follicle without follicle-stimulating hormone suppression in monkeys.

    Science.gov (United States)

    Sasagawa, S; Shimizu, Y; Nagaoka, T; Tokado, H; Imada, K; Mizuguchi, K

    2008-07-01

    Dienogest is a selective progestin that has been shown to arrest ovarian follicular development in women, without affecting gonadotropin secretion. As luteal progesterone or exogeneous progestins are known to suppress ovarian folliculogenesis via the inhibition of gonadotropin secretion, this action of dienogest on ovaries seems to be unique. To examine the underlying mechanism of the antifolliculogenic effect of dienogest, female cynomolgus monkeys were treated with a single oral dose of 0.1 mg/kg dienogest on day 7 of the menstrual cycle. Plasma FSH, estradiol (E2), and progesterone levels were measured up to 15 days after dosing. In an additional experiment, ovaries were excised 24 h after dosing for histological examinations. As a result, plasma E2 level declined within 24 h after dosing, while dienogest did not decreased FSH level prior to E2 decline. After decline of E2 level, the low level of E2 was sustained for more than 11 days. It is considered that a single oral dose of dienogest induced atresia of the dominant follicle. In the histological examination, two out of three animals showed decline in E2 level. The ovarian dominant follicles from these animals showed apoptotic changes in granulosa cells with scattered aromatase expression within 24 h after dosing. These results indicate that the induction of atresia of the ovarian dominant follicle by direct action would be a possible mechanism of dienogest to inhibit plasma E2 level.

  10. ROS-induced nanotherapeutic approach for ovarian cancer treatment based on the combinatorial effect of photodynamic therapy and DJ-1 gene suppression.

    Science.gov (United States)

    Schumann, Canan; Taratula, Olena; Khalimonchuk, Oleh; Palmer, Amy L; Cronk, Lauren M; Jones, Carson V; Escalante, Cesar A; Taratula, Oleh

    2015-11-01

    This study represents a novel approach for intraoperative ovarian cancer treatment based on the combinatorial effect of a targeted photodynamic therapy (PDT) associated with suppression of the DJ-1 protein, one of the key players in the ROS defense of cancer cells. To assess the potential of the developed therapy, dendrimer-based nanoplatforms for cancer-targeted delivery of near-infrared photosensitizer, phthalocyanine, and DJ-1 siRNA have been constructed. In vitro studies revealed that therapeutic efficacy of the combinatorial approach was enhanced when compared to PDT alone and this enhancement was more pronounced in ovarian carcinoma cells, which are characterized by higher basal levels of DJ-1 protein. Moreover, the ovarian cancer tumors exposed to a single dose of combinatorial therapy were completely eradicated from the mice and the treated animals showed no evidence of cancer recurrence. Thus, the developed therapeutic approach can be potentially employed intraoperatively to eradicate unresactable cancer cells. The complete clearance of microscopic residual tumor cells during excision surgery is important to improve survival of the patient. In this interesting paper, the authors developed a novel approach using targeted photodynamic therapy (PDT), combining a photosensitizer, phthalocyanine, and DJ-1 siRNA for the treatment of ovarian cancer. The data showed that this approach increased cancer cell killing and may pave way for future clinical studies. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Ovarian hyperstimulation syndrome prevention strategies: oral contraceptive pills-dual gonadotropin-releasing hormone agonist suppression with step-down gonadotropin protocols.

    Science.gov (United States)

    Damario, Mark A

    2010-11-01

    The identification of patients at high risk for excessive responses to ovarian stimulation for in vitro fertilization and embryo transfer is essential in the tailoring of safe and effective treatment strategies. Known factors associated with increased sensitivity to gonadotropins include polycystic ovary syndrome, young age, prior ovarian hyperstimulation syndrome (OHSS), high baseline antral follicle count, and high baseline ovarian volume. Although several treatment strategies have been proposed for these patients, this report describes the experience using the dual suppression with gonadotropin step-down protocol. This protocol uses oral contraceptive pretreatment in combination with a long gonadotropin-releasing hormone agonist followed by a programmed step-down in gonadotropin dosing. Hormonal characteristics of dual suppression include an improved luteinizing hormone-to-follicle-stimulating hormone ratio and lower serum androgens, particularly dehydroepiandrosterone sulfate. Clinical characteristics of the protocol include a lower cancellation rate and favorable clinical and ongoing pregnancy rates per initiated cycle while mitigating the risk of OHSS. © Thieme Medical Publishers.

  12. Emotion suppression reduces hippocampal activity during successful memory encoding.

    Science.gov (United States)

    Binder, Julia; de Quervain, Dominique J-F; Friese, Malte; Luechinger, Roger; Boesiger, Peter; Rasch, Björn

    2012-10-15

    People suppressing their emotions while facing an emotional event typically remember it less well. However, the neural mechanisms underlying the impairing effect of emotion suppression on successful memory encoding are not well understood. Because successful memory encoding relies on the hippocampus and the amygdala, we hypothesized that memory impairments due to emotion suppression are associated with down-regulated activity in these brain areas. 59 healthy females were instructed either to simply watch the pictures or to down-regulate their emotions by using a response-focused emotion suppression strategy. Brain activity was recorded using functional magnetic resonance imaging (fMRI), and free recall of pictures was tested afterwards. As expected, suppressing one's emotions resulted in impaired recall of the pictures. On the neural level, the memory impairments were associated with reduced activity in the right hippocampus during successful encoding. No significant effects were observed in the amygdala. In addition, functional connectivity between the hippocampus and the right dorsolateral prefrontal cortex was strongly reduced during emotion suppression, and these reductions predicted free-recall performance. Our results indicate that emotion suppression interferes with memory encoding on the hippocampal level, possibly by decoupling hippocampal and prefrontal encoding processes, suggesting that response-focused emotion suppression might be an adaptive strategy for impairing hippocampal memory formation in highly arousing situations. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53.

    Science.gov (United States)

    Park, See-Hyoung; Lee, Jung Han; Berek, Jonathan S; Hu, Mickey C-T

    2014-10-01

    Auranofin is a gold-containing compound classified by the World Health Organization as a clinically established rheumatoid arthritis therapeutic agent. Through drug screening for novel anticancer therapeutics, we unexpectedly identified auranofin as a potent anticancer agent against a p53-null ovarian carcinoma SKOV3 cell line. However, the molecular mechanism underlying auranofin-mediated anticancer activity in ovarian cancer cells is basically unknown. Here, we show that auranofin inhibits proliferation and survival of SKOV3 cells in a dose‑ and time‑dependent manner. Auranofin treatment activates the pro-apoptotic caspase-3, increases protein levels of apoptosis-inducing proteins Bax and Bim and reduces the expression of the anti-apoptotic mediator Bcl-2 in SKOV3 cells. Moreover, auranofin downregulates IκB kinase (IKK)-β and promotes nuclear localization and the activation of FOXO3 tumor suppressor, leading to cellular apoptosis in SKOV3 cells. In contrast, silencing FOXO3 diminishes the pro-apoptotic signaling of auranofin in SKOV3 cells. These results suggest that auranofin may induce caspase-3-mediated apoptosis in a FOXO3-dependent manner. The observed upregulation of pro-apoptotic genes and apoptosis in cancer cells without p53 in response to auranofin suggests a novel p53-independent mechanism underlying auranofin-induced apoptosis in ovarian cancer cells.

  14. Simultaneous suppression of epidermal growth factor receptor and c-erbB-2 reverses aneuploidy and malignant phenotype of a human ovarian carcinoma cell line.

    Science.gov (United States)

    Pack, Svetlana D; Alper, Ozgül M; Stromberg, Kurt; Augustus, Meena; Ozdemirli, Metin; Miermont, Anne M; Klus, Greg; Rusin, Marek; Slack, Rebecca; Hacker, Neville F; Ried, Thomas; Szallasi, Zoltan; Alper, Ozge

    2004-02-01

    Coexpression of epidermal growth factor receptor (EGFR) and c-erbB-2 in 47-68% of ovarian cancer cells indicate their strong association with tumor formation. We examined the effects of simultaneous antisense- or immunosuppression of EGFR and c-erbB-2 expression on the invasive phenotype, aneuploidy, and genotype of cultured human ovarian carcinoma cells (NIH:OVCAR-8). We report here that suppression of both EGFR and c-erbB-2 results in regression of aneuploidy and genomic imbalances in NIH:OVCAR-8 cells, restores a more normal phenotype, and results in a more normal gene expression profile. Combined with cytogenetic analysis, our data demonstrate that the regression of aneuploidy is due to the selective apoptosis of double antisense transfected cells with highly abnormal karyotype.

  15. Human chorionic gonadotropin suppresses human breast cancer cell growth directly via p53-mediated mitochondrial apoptotic pathway and indirectly via ovarian steroid secretion.

    Science.gov (United States)

    Yuri, Takashi; Kinoshita, Yuichi; Emoto, Yuko; Yoshizawa, Katsuhiko; Tsubura, Airo

    2014-03-01

    The tumor-suppressive effects of human chorionic gonadotropin (hCG) against human breast cancer cells were examined. In cell viability assays, hCG inhibited the growth of three human breast cancer cell lines (estrogen receptor (ER)-positive KPL-1 and MCF-7, and ER-negative MKL-F cells), and the growth inhibition activity of hCG was most pronounced against KPL-1 cells (luteinizing hormone/chorionic gonadotropin receptor (LHCGR)-positive and luminal-A subtype). In hCG-treated KPL-1 cells, immunoblotting analysis revealed the expression of tumor suppressor protein p53 peaking at 12 h following treatment, followed by cleavage of caspase-9 and caspase-3 at 24 h and 48 h, respectively. KPL-1-transplanted athymic mice were divided into 3 groups: a sham-treated group that received an inoculation of KPL-1 cells at 6 weeks of age followed by daily intraperitoneal (i.p.) injection of saline; an in vitro hCG-treated KPL-1 group that received an inoculation of KPL-1 cells pre-treated with 100 IU/ml hCG in vitro for 48 h at 6 weeks of age, followed by daily i.p. injection of saline; and an in vivo hCG-treated group that received an KPL-1 cell inoculation at 6 weeks of age, followed by daily i.p. injection of 100 IU hCG. The daily injections of saline or hCG continued until the end of the experiment when mice reached 11 weeks of age. KPL-1 tumor growth was retarded in in vitro and in vivo hCG-treated mice compared to sham-treated controls, and the final tumor volume and tumor weight tended to be suppressed in the in vitro hCG-treated group and were significantly suppressed in the in vivo hCG-treated group. In vivo 100-IU hCG injections for 5 weeks elevated serum estradiol levels (35.7 vs. 23.5 pg/ml); thus, the mechanisms of hCG action may be directly coordinated via the p53-mediated mitochondrial apoptotic pathway and indirectly through ovarian steroid secretion that elevates estrogen levels. It is thus concluded that hCG may be an attractive agent for treating human breast

  16. Cold suppresses agonist-induced activation of TRPV1.

    Science.gov (United States)

    Chung, M-K; Wang, S

    2011-09-01

    Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction.

  17. Relationship between metabolism and ovarian activity in dairy cows with different dry period lengths.

    Science.gov (United States)

    Chen, J; Soede, N M; van Dorland, H A; Remmelink, G J; Bruckmaier, R M; Kemp, B; van Knegsel, A T M

    2015-11-01

    The objectives of the present study were to evaluate the effects of dry period length on ovarian activity in cows fed a lipogenic or a glucogenic diet within 100 days in milk (DIM) and to determine relationships between ovarian activity and energy balance and metabolic status in early lactation. Holstein-Friesian dairy cows (n = 167) were randomly assigned to one of three dry period lengths (0, 30, or 60 days) and one of two diets in early lactation (glucogenic or lipogenic diet) resulting in a 3 × 2 factorial design. Cows were monitored for body condition score, milk yield, dry matter intake, and energy balance from calving to week 8 postpartum, and blood was sampled weekly from 95 cows from calving to week 8 postpartum. Milk samples were collected three times a week until 100 DIM postpartum for determination of progesterone concentration. At least two succeeding milk samples with progesterone concentration of 2 ng/mL or greater were used to indicate the occurrence of luteal activity. Normal resumption of ovarian cyclicity was defined as the onset of luteal activity (OLA) occurring at 45 DIM or less, followed by regular ovarian cycles of 18 to 24 days in length. Within 100 DIM postpartum, cows with a 0-day dry period had greater incidence of normal resumption of ovarian cyclicity (53.2%; 25 out of 47 cows) compared with cows with a 60-day dry period (26.0%; 13 out of 50 cows, P = 0.02). Independent of dry period length or diet, cows with OLA at less than 21 DIM had a greater body condition score during weeks 1 and 2 (P = 0.01) and weeks 1 through 8 (P = 0.01) postpartum compared with cows with OLA at greater than 30 DIM. Cows with the first ovarian cycle of medium length (18-24 days) had greater energy balance (P = 0.03), plasma concentrations of insulin (P = 0.03), glucose (P = 0.04), and insulin-like growth factor I (P = 0.04) than cows with long ovarian cycle lengths (>24 days) but had lower plasma β-hydroxybutyrate (P cows with

  18. Ovarian activity and early embryonic development in the rusty bat ...

    African Journals Online (AJOL)

    The reproductive pattern of the female rusty bat, Pipistrellus rusticus, was investigated by means of a histological examination of the ovarian follicles as well as early embryonic development. Bats were collected from two localities in Limpopo Province. Female rusty bats are seasonal monestrous breeders, initiating ...

  19. Ganoderma lucidum inhibits proliferation of human ovarian cancer cells by suppressing VEGF expression and up-regulating the expression of connexin 43.

    Science.gov (United States)

    Dai, Shuyan; Liu, Jingjing; Sun, Xiaofei; Wang, Ning

    2014-11-05

    Ganoderma lucidum (G. lucidum, Reishimax) is an herbal mushroom known to have inhibitory effect on tumor cell growth. However, the molecular mechanisms responsible for its anti-proliferative effects on the ovarian cancer have not been fully elucidated. Human ovarian cancer cells HO 8910 (HOCC) and human primary ovarian cells (HPOC) were treated with G. lucidum. Effects of G. lucidum treatment on cell proliferation were studied by MTT assay. The expression of vascular endothelial growth factor (VEGF) and connexin 43 (Cx43) were measured by immunohistochemistry and real time polymerase chain reaction. To study the molecular mechanism of CX43 mediated anti-tumor activity, small interference RNA (siRNA) was used to knockdown Cx43 expression in HOCC. G. lucidum treatment resulted in reduced proliferation of HOCC. Inhibition of proliferation was accompanied by a decrease in VEGF expression and increase in Cx43 expression in the cancer cells. The extent of immune-reactivity of Cx43 or VEGF in cancer cells were correlated with the concentrations of G. lucidum used for treatment. Furthermore, knockdown of Cx43 expression in HOCC abrogated the effect of G. lucidum on cell proliferation without alteration of G. lucidum-induced attenuation of VEGF expression. G. lucidum inhibits ovarian cancer by down-regulating the expression of VEGF and up-regulating the downstream Cx43 expression. G. lucidum may be a promising therapeutic agent for the treatment of ovarian cancer.

  20. Melatonin Suppresses the Growth of Ovarian Cancer Cell Lines (OVCAR-429 and PA-1 and Potentiates the Effect of G1 Arrest by Targeting CDKs

    Directory of Open Access Journals (Sweden)

    Ching-Ju Shen

    2016-01-01

    Full Text Available Melatonin is found in animals as well as plants. In animals, it is a hormone that anticipates the daily onset of darkness and regulates physiological functions, such as sleep timing, blood pressure, and reproduction. Melatonin has also been found to have anti-tumor properties. Malignant cancers are the most common cause of death, and the mortality rate of ovarian tumor is the highest among gynecological diseases. This study investigated the anti-tumor effects of melatonin on the ovarian cancer lines, OVCAR-429 and PA-1. We observed the accumulation of melatonin-treated cells in the G1 phase due to the down-regulation of CDK 2 and 4. Our results suggest that in addition to the known effects on prevention, melatonin may also provide anti-tumor activity in established ovarian cancer.

  1. MR findings of ovarian tumors with hormonal activity, with emphasis on tumors other than sex cord-stromal tumors

    International Nuclear Information System (INIS)

    Tanaka, Yumiko Oishi; Saida, Tsukasa Sasaki; Minami, Rie; Yagi, Takako; Tsunoda, Hajime; Yoshikawa, Hiroyuki; Minami, Manabu

    2007-01-01

    Sex cord-stromal tumors including granulosa cell tumor, thecoma, Sertoli stromal cell tumor and steroid cell tumor are noted for their hormonal activity. However, there are many kinds of ovarian tumors other than sex cord-stromal tumors and tumor-like conditions with endocrine manifestations. Cross-sectional imaging, especially MR, can provide precise features of ovarian tumors and uterine morphological change even in a clinically latent excess of estrogen. In this article, we demonstrate typical imaging findings of ovarian tumors with hormonal activity. We also shortly explain the mechanism of the virilization and hyperestrogenism caused by ovarian tumors and tumor-like conditions

  2. The effect of body condition on ovarian activity of free ranging tropical jennies (Equus asinus).

    Science.gov (United States)

    Lemma, A; Bekana, M; Schwartz, H J; Hildebrandt, T

    2006-02-01

    Serial ultrasonography was performed on seven jennies to study the effect of seasonally fluctuating body condition on ovarian activity during the dry, short rainy and long rainy seasons. Kendall Tau correlations and differences of least square mean values were compared. A distinct seasonal pattern was observed both in body condition and ovarian activity. The mean (+/-SD) Body Condition Score (BCS) was lowest during the dry season 2.6 +/- 0.45 when compared with 3.5 +/- 0.52 and 3.9 +/- 0.58 during the short and long rainy seasons, respectively. The mean (+/-SD) number of total follicles was also proportionally low 7.3 +/- 1.6 during the dry season compared with 9.6 +/- 2.4 and 11.3 +/- 3.3 found during the short and the long rainy seasons, respectively. The BCS was positively correlated to the total number of follicles and the diameter of the largest follicle during all seasons. Periods of increasing BCS and transition between seasons with both increasing and decreasing body conditions were strongly correlated to the number and size of ovarian follicles. Seasonal fluctuation in the body condition was found to be the result of variation in feed resource and ovarian activity was also closely following this seasonal pattern. The improvement in body condition has generally, a positive impact on emergence of small growing follicles there by having influence on the total count of ovarian follicles.

  3. Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling.

    Science.gov (United States)

    Sun, Yuanzhen; Fan, Xiaoli; Zhang, Qing; Shi, Xiaoyu; Xu, Guangwei; Zou, Cuimin

    2017-07-01

    Ovarian cancer is the most lethal gynecologic malignancy, due to its high propensity for metastasis. Cancer-associated fibroblasts, as the dominant component of tumor microenvironment, are crucial for tumor progression. However, the mechanisms underlying the regulation of ovarian cancer cells by cancer-associated fibroblasts remain little known. Here, we first isolated cancer-associated fibroblasts from patients' ovarian tissues and found that cancer-associated fibroblasts promoted SKOV3 cells' proliferation, migration, and invasion. Fibroblast growth factor-1 was identified as a highly increased factor in cancer-associated fibroblasts compared with normal fibroblasts by quantitative reverse transcription polymerase chain reaction (~4.6-fold, p fibroblast growth factor-1 in cancer-associated fibroblasts either naturally or through gene recombination led to phosphorylation of fibroblast growth factor receptor 4 in SKOV3 cells, which is followed by the activation of mitogen-activated protein kinase/extracellular signal-regulated protein kinase pathway and epithelial-to-mesenchymal transition-associated gene Snail1 and MMP3 expression. Moreover, treatment of SKOV3 cell with fibroblast growth factor receptor inhibitor PD173074 terminated cellular proliferation, migration, and invasion, reduced the phosphorylation level of fibroblast growth factor receptor 4, and suppressed the activation of mitogen-activated protein kinase/extracellular signal-regulated protein kinase pathway. In addition, the expression level of Snail1 and MMP3 was reduced, while the expression level of E-cadherin increased. These observations suggest a crucial role for cancer-associated fibroblasts and fibroblast growth factor-1/fibroblast growth factor receptor 4 signaling in the progression of ovarian cancer. Therefore, this fibroblast growth factor-1/fibroblast growth factor receptor 4 axis may become a potential target for the treatment of ovarian cancer.

  4. Senescence-associated β-galactosidase activity in the in vitro ovarian stromal fibroblasts

    Directory of Open Access Journals (Sweden)

    Lilian Chuaire-Noack

    2011-04-01

    Full Text Available A growing biological research field is the cellular senescence, a mechanism that has been associated, under certain circumstances, withmalignant transformation. Given the high incidence of ovarian cancerand its main origin from the ovarian surface epithelium, as well asthe possibility that an epithelial-mesenchymal transition occurs, weevaluated both the in vitro growth of stromal fibroblasts from the ovarian cortex and their β-galactosidase activity at pH 6,enzyme whose expression is considered as a marker of replicativesenescence. Methods: 48 samples of ovarian cortical fibroblasts fromdonors without a history of cancer were serially cultured untilthe end of their replicative life. β-galactosidase activity at pH 6was quantified in each passage by the chemiluminiscent method. Ascontrol, we used ovarian epithelial cell cultures from the samedonors. The enzyme activity was also evaluated in fibroblastspreviously induced to senescence by exposure to hydrogen peroxide.Results: The analysis of the enzyme activity and the replicativecapacity taken together showed that the fibroblast cultures reachedthe senescent state at passages 4-5, as what happened with the control epithelial cells. Fibroblasts induced to senescence showed high variability in the values of enzymatic activity. Conclusions:The similarity between both types of cells in reaching the senescent state deserves to be taken into account in relation to theepithelialmesenchymal transition that has been proposed to explaintheir behavior in the genesis of cancer arising from ovarian surfaceepithelium. Low β-galactosidase activity values at pH 6 would suggestpossible inactivation of the response pathways to oxidative stress.

  5. Next Generation Active Buffet Suppression System

    Science.gov (United States)

    Galea, Stephen C.; Ryall, Thomas G.; Henderson, Douglas A.; Moses, Robert W.; White, Edward V.; Zimcik, David G.

    2003-01-01

    Buffeting is an aeroelastic phenomenon that is common to high performance aircraft, especially those with twin vertical tails like the F/A-18, at high angles of attack. These loads result in significant random stresses, which may cause fatigue damage leading to restricted capabilities and availability of the aircraft. This paper describes an international collaborative research activity among Australia, Canada and the United States involving the use of active structural control to alleviate the damaging structural response to these loads. The research program is being co-ordinated by the Air Force Research Laboratory (AFRL) and is being conducted under the auspices of The Technical Cooperative Program (TTCP). This truly unique collaborative program has been developed to enable each participating country to contribute resources toward a program that coalesces a broad range of technical knowledge and expertise into a single investigation. This collaborative program is directed toward a full-scale test of an F/A-18 empennage, which is an extension of an earlier initial test. The current program aims at applying advanced directional piezoactuators, the aircraft rudder, switch mode amplifiers and advanced control strategies on a full-scale structure to demonstrate the enhanced performance and capability of the advanced active BLA control system in preparation for a flight test demonstration.

  6. Cisplatin-induced caspase activation mediates PTEN cleavage in ovarian cancer cells: a potential mechanism of chemoresistance

    International Nuclear Information System (INIS)

    Singh, Mohan; Chaudhry, Parvesh; Fabi, Francois; Asselin, Eric

    2013-01-01

    The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor protein is a central negative regulator of the PI3K/AKT signaling cascade and suppresses cell survival as well as cell proliferation. PTEN is found to be either inactivated or mutated in various human malignancies. In the present study, we have investigated the regulation of PTEN during cisplatin induced apoptosis in A2780, A270-CP (cisplatin resistant), OVCAR-3 and SKOV3 ovarian cancer cell lines. Cells were treated with 10μM of cisplatin for 24h. Transcript and protein levels were analysed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and western blotting, respectively. Immunofluorescence microscopy was used to assess the intracellular localization of PTEN. Proteasome inhibitor and various caspases inhibitors were used to find the mechanism of PTEN degradation. PTEN protein levels were found to be decreased significantly in A2780 cells; however, there was no change in PTEN protein levels in A2780-CP, OVCAR-3 and SKOV3 cells with cisplatin treatment. The decrease in PTEN protein was accompanied with an increase in the levels of AKT phosphorylation (pAKT) in A2780 cells and a decrease of BCL-2. Cisplatin treatment induced the activation/cleavage of caspase-3, -6, -7, -8, -9 in all cell lines tested in this study except the resistant variant A2780-CP cells. In A2780 cells, restoration of PTEN levels was achieved upon pre-treatment with Z-DEVD-FMK (broad range caspases inhibitor) and not with MG132 (proteasome inhibitor) and by overexpression of BCL-2, suggesting that caspases and BCL-2 are involved in the decrease of PTEN protein levels in A2780 cells. The decrease in pro-apoptotic PTEN protein levels and increase in survival factor pAKT in A2780 ovarian cancer cells suggest that cisplatin treatment could further exacerbate drug resistance in A2780 ovarian cancer cells

  7. Enhancement of anticancer activity by silibinin and paclitaxel combination on the ovarian cancer.

    Science.gov (United States)

    Pashaei-Asl, Fatima; Pashaei-Asl, Roghiyeh; Khodadadi, Khodadad; Akbarzadeh, Abolfazl; Ebrahimie, Esmaeil; Pashaiasl, Maryam

    2017-09-08

    Ovarian carcinoma is the most lethal cancer among all gynaecological malignancies. One of the most chemotherapy drugs used for ovarian cancer is paclitaxel which induces apoptosis. Paclitaxel has been used for many years. Similar to the most cancers this responds to chemotherapy initially but in a long run, drug resistance happens which fails the treatment procedure. Combination of chemotherapy drugs has been suggested to deal with this issue. Silibinin, a plant extraction, has been used from ancient time in traditional medicine and identified to have powerful antioxidant activity. The aim of this study was to examine the effect of paclitaxel and silibinin combination on SKOV-3 cancer cell line. The human epithelial ovarian cancer cell line, SKOV-3, was cultured and treated with paclitaxel, silibinin and paclitaxel plus silibinin for 48 hours. MTT assay was carried out to determine cell viability. For apoptotic process, we used real-time PCR to study P53 and P21 genes expression after drug treatment and network analysis was performed using Pathway Studio web tool (Elsevier). Cell growth was inhibited considerably (p PCR showed the significant up-regulation of two tumour suppressor genes, P53 and P21 in response to combination of silibinin and paclitaxel. In addition, computational network analysis demonstrated the crosstalk between paclitaxel, silibinin and ovarian cancer. Our results showed that combination of chemotherapy drugs of silibinin and paclitaxel can be more efficient in treatment of ovarian cancer cells.

  8. PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma

    DEFF Research Database (Denmark)

    Thomsen, Jacob; Hjortebjerg, Rikke; Espelund, Ulrick

    2015-01-01

    serum and ascites from 22 women with ovarian carcinoma. We found that ascites contained 46-fold higher PAPP-A levels as compared to serum (P ...Pregnancy-associated plasma protein-A (PAPP-A) stimulates insulin-like growth factor (IGF) action through proteolysis of IGF-binding protein (IGFBP)-4. In experimental animals, PAPP-A accelerates ovarian tumor growth by this mechanism. To investigate the effect of PAPP-A in humans, we compared...... of IGF-IR in all but one tumor, whereas all tumors expressed PAPP-A, IGFBP-4, IGF-I and IGF-II. Addition of recombinant PAPP-A to ascites increased the cleavage of IGFBP-4 and enhanced IGF-IR activation (P ovarian tumors express PAPP-A, IGFBP-4 and IGFs and these proteins...

  9. THE EFFECT OF RAPAMYCIN ON SECRETORY ACTIVITY OF THE RABBIT OVARIAN FRAGMENTS

    Directory of Open Access Journals (Sweden)

    Sushmita Nath

    2012-02-01

    Full Text Available The aim of our study was to examine the effect of rapamycin on secretory activity of the rabbit ovarian fragments. The secretion of steroid (progesterone, testosterone, estradiol and peptide (prolactine hormones by ovarian fragments after rapamycin addition at the doses 0, 1, 10, 100 μg.ml-1 was determined. Fragments were incubated with rapamycin for 48 hours. Hormones were determinated by RIA. The experimental data showed that, addition of rapamycin did not affect progesterone and prolactine release (at all doses. Estradiol secretion was inhibited by rapamycin at the doses of 1, 10 and 100 μg.ml-1. Testosterone was inhibited by the rapamycin at the doses of 1 and 10 μg.ml-1 but not at 100 μg.ml-1. In conclusion, our results suggest a direct effect of rapamycin on ovarian functionsand a possible involvement in the regulation of steroidogenesis.

  10. Immunohistochemical expression of MMP-14 and MMP-2, and MMP-2 activity during human ovarian follicular development

    NARCIS (Netherlands)

    Vos, M.C.; Wurff, A.A. van der; Last, J.T.; Boed, E.A. de; Smeenk, J.M.J.; Kuppevelt, T.H. van; Massuger, L.F.A.G.

    2014-01-01

    BACKGROUND: The aim of this study was to investigate the presence of MMP-14 and MMP-2 during human ovarian follicular development using immunohistochemistry, and the activity of MMP-2 in follicular fluid using zymography. METHODS: Ovarian tissue collected from the archives of the Department of

  11. Anticancer effect of genistein on BG-1 ovarian cancer growth induced by 17 β-estradiol or bisphenol A via the suppression of the crosstalk between estrogen receptor alpha and insulin-like growth factor-1 receptor signaling pathways

    International Nuclear Information System (INIS)

    Hwang, Kyung-A; Park, Min-Ah; Kang, Nam-Hee; Yi, Bo-Rim; Hyun, Sang-Hwan; Jeung, Eui-Bae; Choi, Kyung-Chul

    2013-01-01

    The interaction between estrogen receptor (ER) and insulin-like growth factor-1 receptor (IGF-1R) signaling pathway plays an important role in proliferation of and resistance to endocrine therapy to estrogen dependent cancers. Estrogen (E2) upregulates the expression of components of IGF-1 system and induces the downstream of mitogenic signaling cascades via phosphorylation of insulin receptor substrate-1 (IRS-1). In the present study, we evaluated the xenoestrogenic effect of bisphenol A (BPA) and antiproliferative activity of genistein (GEN) in accordance with the influence on this crosstalk. BPA was determined to affect this crosstalk by upregulating mRNA expressions of ERα and IGF-1R and inducing phosphorylation of IRS-1 and Akt in protein level in BG-1 ovarian cancer cells as E2 did. In the mouse model xenografted with BG-1 cells, BPA significantly increased a tumor burden of mice and expressions of ERα, pIRS-1, and cyclin D1 in tumor mass compared to vehicle, indicating that BPA induces ovarian cancer growth by promoting the crosstalk between ER and IGF-1R signals. On the other hand, GEN effectively reversed estrogenicity of BPA by reversing mRNA and protein expressions of ERα, IGF-1R, pIRS-1, and pAkt induced by BPA in cellular model and also significantly decreased tumor growth and in vivo expressions of ERα, pIRS-1, and pAkt in xenografted mouse model. Also, GEN was confirmed to have an antiproliferative effect by inducing apoptotic signaling cascades. Taken together, these results suggest that GEN effectively reversed the increased proliferation of BG-1 ovarian cancer by suppressing the crosstalk between ERα and IGF-1R signaling pathways upregulated by BPA or E2

  12. Anticancer effect of genistein on BG-1 ovarian cancer growth induced by 17 β-estradiol or bisphenol A via the suppression of the crosstalk between estrogen receptor alpha and insulin-like growth factor-1 receptor signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, Kyung-A; Park, Min-Ah; Kang, Nam-Hee; Yi, Bo-Rim; Hyun, Sang-Hwan; Jeung, Eui-Bae; Choi, Kyung-Chul, E-mail: kchoi@cbu.ac.kr

    2013-11-01

    The interaction between estrogen receptor (ER) and insulin-like growth factor-1 receptor (IGF-1R) signaling pathway plays an important role in proliferation of and resistance to endocrine therapy to estrogen dependent cancers. Estrogen (E2) upregulates the expression of components of IGF-1 system and induces the downstream of mitogenic signaling cascades via phosphorylation of insulin receptor substrate-1 (IRS-1). In the present study, we evaluated the xenoestrogenic effect of bisphenol A (BPA) and antiproliferative activity of genistein (GEN) in accordance with the influence on this crosstalk. BPA was determined to affect this crosstalk by upregulating mRNA expressions of ERα and IGF-1R and inducing phosphorylation of IRS-1 and Akt in protein level in BG-1 ovarian cancer cells as E2 did. In the mouse model xenografted with BG-1 cells, BPA significantly increased a tumor burden of mice and expressions of ERα, pIRS-1, and cyclin D1 in tumor mass compared to vehicle, indicating that BPA induces ovarian cancer growth by promoting the crosstalk between ER and IGF-1R signals. On the other hand, GEN effectively reversed estrogenicity of BPA by reversing mRNA and protein expressions of ERα, IGF-1R, pIRS-1, and pAkt induced by BPA in cellular model and also significantly decreased tumor growth and in vivo expressions of ERα, pIRS-1, and pAkt in xenografted mouse model. Also, GEN was confirmed to have an antiproliferative effect by inducing apoptotic signaling cascades. Taken together, these results suggest that GEN effectively reversed the increased proliferation of BG-1 ovarian cancer by suppressing the crosstalk between ERα and IGF-1R signaling pathways upregulated by BPA or E2.

  13. Genetic relationship between cyclic ovarian activity in heifers and cows and beef traits in males

    Directory of Open Access Journals (Sweden)

    Ménissier François

    2001-05-01

    Full Text Available Abstract Records were collected in an experimental herd over an 11-year period from purebred Charolais heifers (n = 351, cows (n = 615 and young entire bulls (n = 383. The objective of the study was to estimate the genetic relationship between the components of female ovarian activity (age at puberty and postpartum anoestrus length, their growth rate and body condition score and beef traits measured on related bulls. Two methods were used to estimate age at puberty and postpartum anoestrus length: the detection of oestrous behaviour and a test of cyclicity based on plasmatic progesterone assay. This study shows the existence of significant heritability estimates for the different cyclicity traits (h2 between 0.11 and 0.38. Most of the genetic correlation coefficients between ovarian activity and growth rate of females and males are negative and favourable (rg between -0.43 and 0.06. Cyclicity is also favourably related with body condition score in young or adult females (rg between -0.65 and -0.22. The genetic relationship between female ovarian activity and proportion of adipose tissue in the male carcass is, however, close to zero. These results show that an antagonism between male beef traits measured in this study and female ovarian activity is unlikely to be a cause for concern in the short term.

  14. External stimuli help restore post-partum ovarian activity in Pelibuey ...

    African Journals Online (AJOL)

    Your User Name

    2017-12-26

    Dec 26, 2017 ... ovarian activity and that the application of a metabolic restorative (Metabolase ®) and its combination with the male effect positively affect the reproductive variables of post-partum Pelibuey female sheep giving them an estrus induction protocol of five days. The objective was to evaluate the post-partum ...

  15. The influence of loss and gain of body mass on ovarian activity in ...

    African Journals Online (AJOL)

    Ovarian activity was studied in 36 dry, Bos taurus cows fed to achieve different rates of body mass loss and gain in a 2 x 2 factorial experiment. Cows were fed hay to supply either 70% (Treatments 1, 2) or 40% (Treatments. 3,4) of their ME requirements for maintenance until they became anoestrus. Following a 90-day ...

  16. Quantifying physical activity and the associated barriers for women with ovarian cancer.

    Science.gov (United States)

    Mizrahi, David; Naumann, Fiona; Broderick, Carolyn; Samara, Juliane; Ryan, Mary; Friedlander, Michael

    2015-05-01

    The purpose of this study was to quantify physical activity levels and determine the barriers to physical activity for women with ovarian cancer. Women with ovarian cancer from 3 oncology clinics enrolled in the cross-sectional study. Physical activity and barriers to physical activity were measured using the International Physical Activity Questionnaire and Perceived Physical Activity Barriers scale, respectively. Demographic, medical, and anthropometric data were obtained from medical records. Ninety-five women (response rate, 41%), with a mean (SD) age of 61 (10.6) years, a body mass index of 26.5 (6.8) kg/m², and 36.6 (28.2) months since diagnosis, participated in the study. The majority of the participants had stage III (32%) or IV (32%) ovarian cancer, were undergoing chemotherapy (41%), and had a history of chemotherapy (93%). The majority of the participants reduced their physical activity after diagnosis, with 19% meeting recommended physical activity guidelines. The participants undergoing treatment reported lower moderate-vigorous physical activity compared with those not undergoing active treatment (mean [SD], 42 [57] vs 104 [119] min/wk; P 0.4). The greatest barriers to physical activity included fatigue (37.8%), exercise not in routine (34.7%), lack of self-discipline (32.6%), and procrastination (27.4%). Women with ovarian cancer have low levels of physical activity. There are disease-specific general barriers to physical activity participation. The majority of the participants reduced their physical activity after diagnosis, with these patients reporting a higher number of total barriers. Behavioral strategies are required to increase physical activity adherence in this population to ensure that recommended guidelines are met to achieve the emerging known benefits of exercise oncology.

  17. Valeriana jatamansi constituent IVHD-valtrate as a novel therapeutic agent to human ovarian cancer: in vitro and in vivo activities and mechanisms.

    Science.gov (United States)

    Li, Xiaoguang; Chen, Tao; Lin, Sheng; Zhao, Jing; Chen, Peizhan; Ba, Qian; Guo, He; Liu, Yanling; Li, Jingquan; Chu, Ruiai; Shan, Lei; Zhang, Weidong; Wang, Hui

    2013-05-01

    Identification of novel chemotherapeutic agents from traditional medicines and elucidation of the molecular basis of their anticancer effects are critical and urgently needed for modern pharmacotherapy. We previously found that analogs of the compounds present in Valeriana jatamansi, a traditional medicine used to treat mental disorders, possess notable antitumor properties; however, the underlying molecular mechanisms have not been fully demonstrated. In this study, we evaluated the anticancer effects of IVHD-valtrate, one of the most active Valeriana jatamansi derivatives, against human ovarian cancer cells in vitro and in vivo. IVHD-valtrate inhibited the growth and proliferation of the A2780 and OVCAR-3 ovarian cancer cell lines in a concentration-dependent manner, while relatively low cytotoxicity to immortalized non-tumorigenic human ovarian surface epithelial cells (IOSE-144) was observed. Treatment with IVHD-valtrate arrested the ovarian cancer cells in the G2/M phase and induced apoptosis, and significantly suppressed the growth of A2780 and OVCAR3 xenograft tumors in a dose-dependent manner. The detailed in vitro and in vivo study on the molecular mechanisms of this compound demonstrated that IVHD-valtrate exposure modulated the expression of numerous molecules involved in cell cycle progression and apoptosis regardless of p53 status, leading to increase the level of p53, Rb, p21, p27 and decrease Mdm2, E2F1, Cyclin B1, Cdc25C and Cdc2. It also down-regulated Bcl-2/Bax and Bcl-2/Bad ratio and enhanced the cleavage of PARP and Caspases. Our preclinical results indicated IVHD-valtrate is a potential therapeutic agent for ovarian cancer, providing a basis for development of the compound as a novel chemotherapeutic agent.

  18. An Ultrasonographic Study of Ovarian Antral Follicular Dynamics in Prepubertal Gilts During the Expected Activation of the Hypothalamo-pituitary-ovarian Axis

    Science.gov (United States)

    SCHWARZ, Tomasz; MURAWSKI, Maciej; WIERZCHOŚ, Edward; BARTLEWSKI, Paweł

    2013-01-01

    Abstract Daily transrectal ultrasonography was carried out in eight 4–5-month-old Polish Large White × Polish Landrace gilts for 42 days to monitor the growth of individual ovarian antral follicles ≥2 mm in diameter. In total, 52.4 ± 16.2 and 123.0 ± 6.7 follicles per gilt (mean ± SD) that grew to ≥4 mm were identified during the first and second 21-day study periods, respectively (Pgilts. The number of follicles and maximum diameter they attain increase significantly during the expected activation of the hypothalamo-pituitary-ovarian axis in prepubescent gilts. PMID:23708742

  19. BRCA1 Expression is an Important Biomarker for Chemosensitivity: Suppression of BRCA1 Increases the Apoptosis via Up-regulation of p53 and p21 During Cisplatin Treatment in Ovarian Cancer Cells

    Directory of Open Access Journals (Sweden)

    Ikuo Konishi

    2006-01-01

    Full Text Available BRCA1 is a tumor suppressor which plays a crucial role in the repair of DNA double-strand breaks, and its abnormality is responsible for hereditary ovarian cancer syndrome. It has recently been reported that reduced expression of BRCA1 is also common in sporadic ovarian carcinoma via its promoter hypermethylation, and that ovarian carcinoma patients negative for BRCA1 expression showed favorable prognosis. To address if BRCA1 expression plays a role in the chemotherapeutic response, we analyzed the effect of BRCA1 suppression on the sensitivity to cisplatin and paclitaxel in ovarian cancer cells. Specific siRNA for BRCA1 gene was transfected into 3 ovarian cancer cell lines with various p53 status. Reduced expression of BRCA1 by transfection of BRCA1-siRNA resulted in a 5.3-fold increase in sensitivity to cisplatin in p53-wild A2780 cells, but not in p53-mutated A2780/CDDP and p53-deleted SKOV3 cells. Regarding the sensitivity to paclitaxel, BRCA1 suppression caused no significant changes in all the 3 cell lines. For ionizing radiation sensitivity, BRCA1 suppression also showed a significant higher sensitivity in A2780 cells. Growth curve and cell cycle analyses showed no signifi cant differences between BRCA1-siRNA-transfected A2780 cells and control cells. However, cisplatin treatment under suppression of BRCA1 showed a significantly increased apoptosis along with up-regulation of p53 and p21 in A2780 cells. Accordingly, reduced expression of BRCA1 enhances the cisplatin sensitivity and apoptosis via up-regulation of p53 and p21, but does not affect the paclitaxel sensitivity. Expression of BRCA1 might be an important biomarker for cisplatin resistance in ovarian carcinoma.

  20. Active Suppression of Rotating Stall Inception with Distributed Jet Actuation

    Directory of Open Access Journals (Sweden)

    Huu Duc Vo

    2007-01-01

    Full Text Available An analytical and experimental investigation of the effectiveness of full-span distributed jet actuation for active suppression of long length-scale rotating stall inception is carried out. Detailed modeling and experimental verification highlight the important effects of mass addition, discrete injectors, and feedback dynamics, which may be overlooked in preliminary theoretical studies of active control with jet injection. A model of the compression system incorporating nonideal injection and feedback dynamics is verified with forced response measurements to predict the right trends in the movement of the critical pole associated with the stall precursor. Active control experiments with proportional feedback control show that the predicted stall precursors are suppressed to give a 5.5% range extension in compressor flow coefficient. In addition, results suggest that the proposed model could be used to design a more sophisticated controller to further improve performance while reducing actuator bandwidth requirements.

  1. Regulation of Injury-Induced Ovarian Regeneration by Activation of Oogonial Stem Cells.

    Science.gov (United States)

    Erler, Piril; Sweeney, Alexandra; Monaghan, James R

    2017-01-01

    Some animals have the ability to generate large numbers of oocytes throughout life. This raises the question whether persistent adult germline stem cell populations drive continuous oogenesis and whether they are capable of mounting a regenerative response after injury. Here we demonstrate the presence of adult oogonial stem cells (OSCs) in the adult axolotl salamander ovary and show that ovarian injury induces OSC activation and functional regeneration of the ovaries to reproductive capability. Cells that have morphological similarities to germ cells were identified in the developing and adult ovaries via histological analysis. Genes involved in germ cell maintenance including Vasa, Oct4, Sox2, Nanog, Bmp15, Piwil1, Piwil2, Dazl, and Lhx8 were expressed in the presumptive OSCs. Colocalization of Vasa protein with H3 mitotic marker showed that both oogonial and spermatogonial adult stem cells were mitotically active. Providing evidence of stemness and viability of adult OSCs, enhanced green fluorescent protein (EGFP) adult OSCs grafted into white juvenile host gonads gave rise to EGFP OSCs, and oocytes. Last, the axolotl ovaries completely regenerated after partial ovariectomy injury. During regeneration, OSC activation resulted in rapid differentiation into new oocytes, which was demonstrated by Vasa + /BrdU + coexpression. Furthermore, follicle cell proliferation promoted follicle maturation during ovarian regeneration. Overall, these results show that adult oogenesis occurs via proliferation of endogenous OSCs in a tetrapod and mediates ovarian regeneration. This study lays the foundations to elucidate mechanisms of ovarian regeneration that will assist regenerative medicine in treating premature ovarian failure and reduced fertility. Stem Cells 2017;35:236-247. © 2016 AlphaMed Press.

  2. Activation of MAPK signalling results in resistance to saracatinib (AZD0530) in ovarian cancer.

    Science.gov (United States)

    McGivern, Niamh; El-Helali, Aya; Mullan, Paul; McNeish, Iain A; Paul Harkin, D; Kennedy, Richard D; McCabe, Nuala

    2018-01-12

    SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease. In this study we aimed to identify mechanisms of resistance to SRC inhibitors in ovarian cancer cells. Using two complementary strategies; a targeted tumour suppressor gene siRNA screen, and a phospho-receptor tyrosine kinase array, we demonstrate that activation of MAPK signalling, via a reduction in NF1 (neurofibromin) expression or overexpression of HER2 and the insulin receptor, can drive resistance to AZD0530. Knockdown of NF1 in two ovarian cancer cell lines resulted in resistance to AZD0530, and was accompanied with activated MEK and ERK signalling. We also show that silencing of HER2 and the insulin receptor can partially resensitize AZD0530 resistant cells, which was associated with decreased phosphorylation of MEK and ERK. Furthermore, we demonstrate a synergistic effect of combining SRC and MEK inhibitors in both AZD0530 sensitive and resistant cells, and that MEK inhibition is sufficient to completely resensitize AZD0530 resistant cells. This work provides a preclinical rationale for the combination of SRC and MEK inhibitors in the treatment of ovarian cancer, and also highlights the need for biomarker driven patient selection for clinical trials.

  3. Postoperative administration of dienogest for suppressing recurrence of disease and relieving pain in subjects with ovarian endometriomas.

    Science.gov (United States)

    Adachi, Kazushige; Takahashi, Kayo; Nakamura, Koji; Otake, Akiko; Sasamoto, Naoko; Miyoshi, Yukari; Shioji, Mitsunori; Yamamoto, Yoshimitsu; Fujitani, Mayumi; Wakimoto, Akinori; Tokuhira, Atsushi; Kobayashi, Eiji; Yoshimura, Akihiko; Sawada, Kenjiro; Kimura, Tadashi

    2016-08-01

    To assess the effect of dienogest on recurrence of ovarian endometriomas and severity of pain after laparoscopic surgery, a retrospective study of 81 patients was performed at three institutions in Osaka, Japan. Patients had a six-month minimum follow-up after laparoscopic surgery for ovarian endometriomas performed between June 2012 and August 2014. Patients who chose to receive 2 mg dienogest daily and those who were managed expectantly postoperatively were included. Recurrence was defined as the presence of endometriomas of more than 2 cm. A visual analog scale (VAS) was used to score the intensity of pelvic pain. The cumulative recurrence rate and absolute VAS score changes between the baseline and at 6, 12, 18 and 24 months after the start of administration were evaluated in both groups. The recurrence rate was 16.5% and 24.0% in the expectant management group at 12 and 24 months, respectively. No recurrences occurred in the dienogest treatment group. The rate of VAS score reduction was significantly higher in the dienogest than in the expectant management group. Dienogest is effective on the recurrence of ovarian endometrioma and relieving pelvic pain after laparoscopic surgery.

  4. Antitumor activity of the combination of synthetic retinoid ST1926 and cisplatin in ovarian carcinoma models.

    Science.gov (United States)

    Pisano, C; Vesci, L; Foderà, R; Ferrara, F F; Rossi, C; De Cesare, M; Zuco, V; Pratesi, G; Supino, R; Zunino, F

    2007-09-01

    The novel adamantyl retinoid ST1926 is a potent inducer of apoptosis in ovarian carcinoma cells. Since the pro-apoptotic effect is associated with activation of p53, in this study we have investigated the efficacy of combination of ST1926 with cisplatin, a DNA-damaging agent that is known to induce p53-dependent apoptosis. The efficacy of ST1926 and its combination with cisplatin was evaluated in human ovarian carcinoma models, including resistant tumors. Oral treatment with ST1926 alone caused a marginal tumor growth inhibition (cisplatin resulted in an improved efficacy, most evident in terms of tumor growth delay without a substantial increase of toxicity. The combination therapy achieved the best effects against the HOC18 ovarian carcinoma tumor, resulting in an appreciable number of animals without evidence of disease at the end of the experiment. In contrast to the marginal effect of ST1926 alone against the subcutaneous-growing tumors, loco-regional (intraperitoneal) treatment achieved a marked increase of survival of animals with ascitic IGROV-1 tumor. The present results document the efficacy of the combination of cisplatin with ST1926 and provide a rational basis for the design of novel, well-tolerated platinum-based treatment approaches in human ovarian carcinoma.

  5. Adaptive Active Noise Suppression Using Multiple Model Switching Strategy

    Directory of Open Access Journals (Sweden)

    Quanzhen Huang

    2017-01-01

    Full Text Available Active noise suppression for applications where the system response varies with time is a difficult problem. The computation burden for the existing control algorithms with online identification is heavy and easy to cause control system instability. A new active noise control algorithm is proposed in this paper by employing multiple model switching strategy for secondary path varying. The computation is significantly reduced. Firstly, a noise control system modeling method is proposed for duct-like applications. Then a multiple model adaptive control algorithm is proposed with a new multiple model switching strategy based on filter-u least mean square (FULMS algorithm. Finally, the proposed algorithm was implemented on Texas Instruments digital signal processor (DSP TMS320F28335 and real time experiments were done to test the proposed algorithm and FULMS algorithm with online identification. Experimental verification tests show that the proposed algorithm is effective with good noise suppression performance.

  6. MicroRNA activity profile in the ovarian cancer cell line OVCAR3 identifies a proapoptotic effect of miR-23a

    Directory of Open Access Journals (Sweden)

    Andikyan V

    2015-10-01

    Full Text Available Vaagn Andikyan,1 Gregory Mullokandov,2 Judith Agudo,2 Ravi Sachidanandam,3,4 David Fishman,1 Alessia Baccarini,2 Brian D Brown2,3 1Department of Obstetrics, Gynecology and Reproductive Science, 2Department of Genetics and Genomic Sciences, 3Tisch Cancer Institute, 4Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA Introduction: Molecular profiling has revealed that many microRNAs (miRNAs are highly expressed in ovarian carcinoma. However, it is not yet known which miRNAs are biologically active (ie, they suppress expression of a target gene in ovarian cancer cells. Here we set out to determine the most active miRNAs in ovarian cancer cells. Methods: We performed miRNA molecular profiling by quantitative polymerase chain reaction array, and measured miRNA activity using a library of sensor vectors for 291 different conserved miRNAs. We inhibited miR-23a activity using a lentiviral-based decoy, and measured the percentage of apoptotic cells by flow cytometry. Results: Our miRNA activity profiling identified 54 active miRNAs in OVCAR3 cells, and found that over 150 miRNAs had no detectable activity. To study the function of an active miRNA, we selected miR-23a for further analysis. We inhibited miR-23a in OVCAR3 cells using a decoy vector, and found that there was decreased cell death compared to control (7.4%±1.4% versus 11.2%±0.5%; P<0.05 when the cells were treated with cisplatin. Moreover, the percentage of apoptotic cells was significantly lower in miR-23a inhibited cells compared to control (2.3%±0.4% versus 9.4%±2.6%; P<0.05. Conclusion: This study identifies the active miRNAs in OVCAR3 cells, and suggests that miR-23a may help to regulate chemosensitivity of ovarian cancer cells. Keywords: ovarian cancer, OVCAR3, microRNA profiling, miR-23a, apoptosis

  7. Synergistic suppression effect on tumor growth of ovarian cancer by combining cisplatin with a manganese superoxide dismutase-armed oncolytic adenovirus.

    Science.gov (United States)

    Wang, Shibing; Shu, Jing; Chen, Li; Chen, Xiaopan; Zhao, Jianhong; Li, Shuangshuang; Mou, Xiaozhou; Tong, Xiangmin

    2016-01-01

    Gene therapy on the basis of oncolytic adenovirus is a novel approach for human cancer therapeutics. We aim to investigate whether it will synergistically reinforce their antiovarian cancer activities when the combined use of ZD55-manganese superoxide dismutase (MnSOD) and cisplatin was performed. The experiments in vitro showed that ZD55-MnSOD enhances cisplatin-induced apoptosis and causes remarkable ovarian cancer cell death. Apoptosis induction by treatment with ZD55-MnSOD and/or cisplatin was detected in SKOV-3 by apoptotic cell staining, flow cytometry, and western blot analysis. In addition, the cytotoxicity caused by ZD55-MnSOD to normal cells was examined by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay and western blot analysis. Animal experiment further confirmed that combination of ZD55-MnSOD and cisplatin achieved significant inhibition of SKOV-3 ovarian tumor xenografted growth. In summary, we have demonstrated that ZD55-MnSOD can sensitize human ovarian cancer cells to cisplatin-induced cell death and apoptosis in vitro and in vivo. These findings indicate that the combined treatment with ZD55-MnSOD and cisplatin could represent a rational approach for antiovarian cancer therapy.

  8. Synergistic suppression effect on tumor growth of ovarian cancer by combining cisplatin with a manganese superoxide dismutase-armed oncolytic adenovirus

    Directory of Open Access Journals (Sweden)

    Wang S

    2016-10-01

    Full Text Available Shibing Wang,1,2,* Jing Shu,3,* Li Chen,4 Xiaopan Chen,3 Jianhong Zhao,4 Shuangshuang Li,1,2 Xiaozhou Mou,1,2 Xiangmin Tong1,2 1Clinical Research Institute, Zhejiang Provincial People’s Hospital, 2Key Laboratory of Cancer Molecular Diagnosis and Individualized Therapy of Zhejiang Province, 3Department of Reproductive Endocrinology, Zhejiang Provincial People’s Hospital, 4Department of Obstetrics and Gynecology, Hangzhou Red Cross Hospital, Hangzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Gene therapy on the basis of oncolytic adenovirus is a novel approach for human cancer therapeutics. We aim to investigate whether it will synergistically reinforce their antiovarian cancer activities when the combined use of ZD55-manganese superoxide dismutase (MnSOD and cisplatin was performed. The experiments in vitro showed that ZD55-MnSOD enhances cisplatin-induced apoptosis and causes remarkable ovarian cancer cell death. Apoptosis induction by treatment with ZD55-MnSOD and/or cisplatin was detected in SKOV-3 by apoptotic cell staining, flow cytometry, and western blot analysis. In addition, the cytotoxicity caused by ZD55-MnSOD to normal cells was examined by the 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2-H-tetrazolium bromide assay and western blot analysis. Animal experiment further confirmed that combination of ZD55-MnSOD and cisplatin achieved significant inhibition of SKOV-3 ovarian tumor xenografted growth. In summary, we have demonstrated that ZD55-MnSOD can sensitize human ovarian cancer cells to cisplatin-induced cell death and apoptosis in vitro and in vivo. These findings indicate that the combined treatment with ZD55-MnSOD and cisplatin could represent a rational approach for antiovarian cancer therapy. Keywords: oncolytic adenovirus, MnSOD, cisplatin, ovarian cancer

  9. Exploiting MEK inhibitor-mediated activation of ERα for therapeutic intervention in ER-positive ovarian carcinoma.

    Directory of Open Access Journals (Sweden)

    June Y Hou

    Full Text Available While the clinical benefit of MEK inhibitor (MEKi-based therapy is well established in Raf mutant malignancies, its utility as a suppressor of hyperactive MAPK signaling in the absence of mutated Raf or Ras, is an area of ongoing research. MAPK activation is associated with loss of ERα expression and hormonal resistance in numerous malignancies. Herein, we demonstrate that MEKi induces a feedback response that results in ERα overexpression, phosphorylation and transcriptional activation of ER-regulated genes. Mechanistically, MEKi-mediated ERα overexpression is largely independent of erbB2 and AKT feedback activation, but is ERK-dependent. We subsequently exploit this phenomenon therapeutically by combining the ER-antagonist, fulvestrant with MEKi. This results in synergistic suppression of tumor growth, in vitro and potentiation of single agent activity in vivo in nude mice bearing xenografts. Thus, we demonstrate that exploiting adaptive feedback after MEKi can be used to sensitize ERα-positive tumors to hormonal therapy, and propose that this strategy may have broader clinical utility in ERα-positive ovarian carcinoma.

  10. Global suppression of electrocortical activity in unilateral perinatal thalamic stroke.

    LENUS (Irish Health Repository)

    Kharoshankaya, Liudmila

    2014-07-01

    We present an unusual case of persistent generalized electroencephalography (EEG) suppression and right-sided clonic seizures in a male infant born at 40(+2) weeks\\' gestation, birthweight 3240g, with an isolated unilateral thalamic stroke. The EEG at 13 hours after birth showed a generalized very low amplitude background pattern, which progressed to frequent electrographic seizures over the left hemisphere. The interictal background EEG pattern remained grossly abnormal over the next 48 hours, showing very low background amplitudes (<10μV). Magnetic resonance imaging revealed an isolated acute left-sided thalamic infarction. This is the first description of severe global EEG suppression caused by an isolated unilateral thalamic stroke and supports the role of the thalamus as the control centre for cortical electrical activity.

  11. Somatic Activation of rasK Gene in a Human Ovarian Carcinoma

    Science.gov (United States)

    Feig, L. A.; Bast, R. C.; Knapp, R. C.; Cooper, G. M.

    1984-02-01

    A tumor isolate from a patient with serous cystadenocarcinoma of the ovary contained an activated rasK gene detected by transfection of NIH/3T3 cells. In contrast, DNA from normal cells of the same patient lacked transforming activity, indicating that activation of this transforming gene was the consequence of somatic mutation in the neoplastic cells. The transforming gene product displayed an electrophoretic mobility in sodium dodecyl sulfate-polyacrylamide gels that differed from the mobilities of rasK transforming proteins in other tumors, indicating that a previously undescribed mutation was responsible for activation of rasK in this ovarian carcinoma.

  12. Clinicopathological and biological significance of aberrant activation of glycogen synthase kinase-3 in ovarian cancer

    Directory of Open Access Journals (Sweden)

    Fu Y

    2014-06-01

    survival. GSK-3 inhibition by lithium chloride, 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8, or GSK-3 small interfering RNA can decrease viability of SKOV3 and SKOV3-TR30 ovarian cancer cells. Additionally, lithium chloride-treated SKOV3 xenograft mice had a significant reduction in tumor growth compared with control-treated animals. Conclusion: Our findings suggest that overexpression and aberrant activation of GSK-3 may contribute to progression and poor prognosis in ovarian cancer. Inhibition of GSK-3 may be a potential therapy for ovarian cancer.Keywords: ovarian carcinoma, immunohistochemistry, lithium chloride, TDZD-8

  13. BRCA1 expression, proliferative and apoptotic activities in ovarian epithelial inclusions.

    Science.gov (United States)

    Wang, Yiying; Wang, Yue; Wei, Li; Hong, Shuhui; Zhao, Miaoqing; Zhang, Xi; Zheng, Wenxin

    2017-03-07

    The purpose of this study was to examine proliferative and apoptotic activity in relation with BRCA1 expression in ovarian epithelial inclusions (OEIs), the putative precursor lesions of ovarian epithelial cancer (OEC). Benign ovaries from 95 patients were examined. Dual immunohistochemical staining for both BRCA1 and MIB-1 were performed to examine the relationship between BRCA1 and MIB-1 in OEI cells. Apoptotic activity was assessed on the parallel tissue sections by using TUNEL assay. Patients' age, menstrual phase and menopausal status were analyzed. OEIs were present in the ovaries of 53% of the patients. OEIs were less frequently found in premenopausal (45%) than postmenopausal women (58%). BRCA1 and MIB-1 were found in 27 and 47% of the OEI-containing ovaries, respectively. All BRCA1 positive OEI cells are MIB-1 positive with dual staining method, although overall the percentage of positive cells was small. No significant difference was found for BRCA1 and MIB-1 expression in OEIs between menopausal status and menstrual phases. Apoptosis containing OEIs were seen in 70% of the ovaries. Compared to OEIs in proliferative menstrual phase and premenopausal status, significantly more apoptosis was found in OEIs from secretory phase and postmenopausal women. A small fraction of the epithelial cells within OEIs are proliferating or dying. Low estrogen and/or high progesterone levels may promote OEI cell turnover via induction of apoptosis. Imbalance between cell proliferation and death within OEIs under influence of hormones may play a role in the ovarian epithelial tumorigenesis.

  14. Fibroblast activation protein regulates tumor-associated fibroblasts and epithelial ovarian cancer cells.

    Science.gov (United States)

    Lai, Dongmei; Ma, Li; Wang, Fangyuan

    2012-08-01

    The fibroblast activation protein (FAP) is a cell surface serine protease which has emerged as a specific marker of tumor-associated fibroblasts (TAFs). FAP has been shown to have both in vitro dipeptidyl peptidase and collagenase activity. However, the biological function of FAP in the tumor microenvironment is largely unknown. In this study, we first show that TAFs isolated from ovarian cancer samples have the characteristics of stem cells. To explore the functional role of FAP, the protein was silenced by siRNA lentiviral vector transfection. FAP silencing inhibited the growth of TAFs in vitro, accompanied with cell cycle arrest at the G2 and S phase in TAFs. FAP silencing also reduced the stem cell marker gene expression in TAFs. SKOV3 cells do not express FAP. Although FAP-silenced SKOV3 cells induced ovarian tumors, the rate of tumor growth was significantly decreased, as shown in the xenograft mouse model. TAF phenotypes in the xenograft tumor tissues were further assayed by immunohistochemistry. The expression of TAF markers, including fibroblast-specific protein, FAP, smooth muscle actin, desmin, vascular endothelial growth factor and fibroblast growth factor was decreased in the tumor stroma induced by FAP-silenced SKOV3 cells. In conclusion, FAP is an important regulator of the microenvironment in tumor formation and targeting FAP is a potential therapeutic strategy to combat ovarian cancer.

  15. Optimal Active Vibration Suppression of Smart Composite Wind Turbine Blades

    Science.gov (United States)

    Abd El-Maksoud Mohamed, Sherif Ibrahim

    The purpose of this study is to apply active vibration control technique numerically for suppressing the vibrational level of a horizontal axis wind turbine blade. Two systems are studied to apply active vibration control on the wind turbine blade model, the first is a uniform cantilever beam and the other system is a non-uniform (tapered) cantilever beam. A single piezoelectric actuator and sensor are bonded on the upper and lower surface of the systems, respectively. The vibration analysis and dynamic characteristics of smart systems are obtained using approximate analytical methods. The entire structure is modeled in the state space form using the state space method, generalized coordinates and piezoelectric theory. Two types of controllers are designed to study the performance of the piezoelectric active controller. The first is a Proportional-Derivative (PD) controller and the other type is a Linear Quadratic Regulator (LQR). The Linear Quadratic Regulator (LQR) demonstrates better results for vibration suppression. The MATLAB code Simulink is used to simulate the different cases.

  16. Apamin suppresses biliary fibrosis and activation of hepatic stellate cells.

    Science.gov (United States)

    Kim, Jung-Yeon; An, Hyun-Jin; Kim, Woon-Hae; Park, Yoon-Yub; Park, Kyung Duck; Park, Kwan-Kyu

    2017-05-01

    Cholestatic liver disease is characterized by the progressive destruction of biliary epithelial cells (BECs) followed by fibrosis, cirrhosis and liver failure. Activated hepatic stellate cells (HSCs) and portal fibroblasts are the major cellular effectors of enhanced collagen deposition in biliary fibrosis. Apamin, an 18 amino acid peptide neurotoxin found in apitoxin (bee venom), is known to block Ca2+-activated K+ channels and prevent carbon tetrachloride-induced liver fibrosis. In the present study, we aimed to ascertain whether apamin inhibits biliary fibrosis and the proliferation of HSCs. Cholestatic liver fibrosis was established in mouse models with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding. Cellular assays were performed on HSC-T6 cells (rat immortalized HSCs). DDC feeding led to increased hepatic damage and proinflammtory cytokine levels. Notably, apamin treatment resulted in decreased liver injury and proinflammatory cytokine levels. Moreover, apamin suppressed the deposition of collagen, proliferation of BECs and expression of fibrogenic genes in the DDC-fed mice. In HSCs, apamin suppressed activation of HSCs by inhibiting the Smad signaling pathway. These data suggest that apamin may be a potential therapeutic target in cholestatic liver disease.

  17. Regulation of gene expression in ovarian cancer cells by luteinizing hormone receptor expression and activation

    International Nuclear Information System (INIS)

    Cui, Juan; Miner, Brooke M; Eldredge, Joanna B; Warrenfeltz, Susanne W; Dam, Phuongan; Xu, Ying; Puett, David

    2011-01-01

    Since a substantial percentage of ovarian cancers express gonadotropin receptors and are responsive to the relatively high concentrations of pituitary gonadotropins during the postmenopausal years, it has been suggested that receptor activation may contribute to the etiology and/or progression of the neoplasm. The goal of the present study was to develop a cell model to determine the impact of luteinizing hormone (LH) receptor (LHR) expression and LH-mediated LHR activation on gene expression and thus obtain insights into the mechanism of gonadotropin action on ovarian surface epithelial (OSE) carcinoma cells. The human ovarian cancer cell line, SKOV-3, was stably transfected to express functional LHR and incubated with LH for various periods of time (0-20 hours). Transcriptomic profiling was performed on these cells to identify LHR expression/activation-dependent changes in gene expression levels and pathways by microarray and qRT-PCR analyses. Through comparative analysis on the LHR-transfected SKOV-3 cells exposed to LH, we observed the differential expression of 1,783 genes in response to LH treatment, among which five significant families were enriched, including those of growth factors, translation regulators, transporters, G-protein coupled receptors, and ligand-dependent nuclear receptors. The most highly induced early and intermediate responses were found to occupy a network impacting transcriptional regulation, cell growth, apoptosis, and multiple signaling transductions, giving indications of LH-induced apoptosis and cell growth inhibition through the significant changes in, for example, tumor necrosis factor, Jun and many others, supportive of the observed cell growth reduction in in vitro assays. However, other observations, e.g. the substantial up-regulation of the genes encoding the endothelin-1 subtype A receptor, stromal cell-derived factor 1, and insulin-like growth factor II, all of which are potential therapeutic targets, may reflect a positive

  18. Anticancer activity of the intraperitoneal-delivered DFP-10825, the cationic liposome-conjugated RNAi molecule targeting thymidylate synthase, on peritoneal disseminated ovarian cancer xenograft model

    Directory of Open Access Journals (Sweden)

    Iizuka K

    2018-03-01

    Full Text Available Kenzo Iizuka, Cheng Jin, Kokoro Eshima, Mei Hua Hong, Kiyoshi Eshima, Masakazu Fukushima Division of Research and Development, Delta-Fly Pharma Inc., Tokushima, Japan Introduction: Peritoneal disseminated ovarian cancer is one of the most difficult cancers to treat with conventional anti-cancer drugs and the treatment options are very limited, although an intraperitoneal (ip paclitaxel has shown some clinical benefit. Therefore, treatment of peritoneal disseminated ovarian cancer is a highly unmet medical need and it is urgent to develop a new ip delivered drug regulating the fast DNA synthesis. Methods: We developed a unique RNAi molecule consisting of shRNA against the thymidylate synthase (TS and a cationic liposome (DFP-10825 and tested its antitumor activity and PK profile in peritoneally disseminated human ovarian cancer ascites models by the luciferase gene-transfected SCID mice. DFP-10825 alone, paclitaxel alone or combination with DFP-10825 and paclitaxel were administered in an ip route to the tumor-bearing mice. The TS expression level was measured by conventional RT-PCR. The anti-tumor activity and host survival benefit by DFP-10825 treatment on tumor-bearing mice were observed as resulting from the specific TS mRNA knock-down in tumors. Results: DFP-10825 alone significantly suppressed the growth of SKOV3-luc tumore ascites cells and further extended the survival time of these tumor-bearing mice. Combination with the ip paclitaxel augmented the antitumor efficacy of DFP-10825 and significantly prolonged the survival time in the tumor-bearing mice. Short-hairpin RNA for TS (TS shRNA levels derived from DFP-10825 in the ascetic fluid were maintained at a nM range across 24 hours but not detected in the plasma, suggesting that TS shRNA is relatively stable in the peritoneal cavity, to be able to exert its anti-tumor activity, but not in blood stream, indicating little or no systemic effect. Conclusion: Collectively, the ip delivery of

  19. [Suppression of cycling activity in sheep using parenteral progestagen treatment].

    Science.gov (United States)

    Janett, F; Camponovo, L; Lanker, U; Hässig, M; Thun, R

    2004-03-01

    The objective of this study was to evaluate the effect of two synthetic progestagen preparations Chlormadinone acetate (CAP, Chronosyn, Veterinaria AG Zürich) and Medroxyprogesterone acetate (MPA, Nadigest, G Streuli & Co. Uznach) on cycling activity and fertility in sheep. A flock of 28 non pregnant white alpine sheep was randomly divided into three groups, A (n = 10), B (n = 9) and C (n = 9). During a period of 4 weeks the cycling activity was confirmed by blood progesterone analysis. Thereafter, the animals of group A were treated with 50 mg CAP, those of group B with 140 mg MPA and those of group C with physiological saline solution. All injections were given intramuscularly. Suppression of endogenous progesterone secretion lasted from 28 to 49 days (mean = 39 days) in group A and from 42 to 70 days (mean = 50 days) in group B. The synchronization effect of both preparations was unsatisfactory as the occurrence of first estrus was distributed over a period of 3 weeks in group A and 4 weeks in group B. These findings could also be confirmed by the lambing period which lasted 52 days in group A and 36 days in group B. Control animals lambed within 9 days due to the synchronizing effect of the ram. The first fertile estrus was observed 36 days (group A) and 45 days (group B) after the treatment. In group A all 10 animals and in groups B and C 8 of 9 ewes each became pregnant. Parenteral progestagen application with CAP and MPA is a simple, safe and reversible method of estrus suppression in the sheep. The minimal suppressive duration of 4 (CAP) and 5 weeks (MPA) is not sufficient when a period of 3 months (alpine pasture period) is desired.

  20. Elevated β-catenin activity contributes to carboplatin resistance in A2780cp ovarian cancer cells

    International Nuclear Information System (INIS)

    Barghout, Samir H.; Zepeda, Nubia; Xu, Zhihua; Steed, Helen; Lee, Cheng-Han; Fu, YangXin

    2015-01-01

    Ovarian cancer is the fifth leading cause of cancer-related mortalities in women. Epithelial ovarian cancer (EOC) represents approximately 90% of all ovarian malignancies. Most EOC patients are diagnosed at advanced stages and current chemotherapy regimens are ineffective against advanced EOC due to the development of chemoresistance. It is important to better understand the molecular mechanisms underlying acquired resistance to effectively manage this disease. In this study, we examined the expression of the Wnt/β-catenin signaling components in the paired cisplatin-sensitive (A2780s) and cisplatin-resistant (A2780cp) EOC cell lines. Our results showed that several negative regulators of Wnt signaling are downregulated, whereas a few Wnt ligands and known Wnt/β-catenin target genes are upregulated in A2780cp cells compared to A2780s cells, suggesting that Wnt/β-catenin signaling is more active in A2780cp cells. Further analysis revealed nuclear localization of β-catenin and higher β-catenin transcriptional activity in A2780cp cells compared to A2780s cells. Finally, we demonstrated that chemical inhibition of β-catenin transcriptional activity by its inhibitor CCT036477 sensitized A2780cp cells to carboplatin, supporting a role for β-catenin in carboplatin resistance in A2780cp cells. In conclusion, our data suggest that increased Wnt/β-catenin signaling activity contributes to carboplatin resistance in A2780cp cells. - Highlights: • Wnt ligands and target genes are upregulated in cisplatin resistant A2780cp cells. • Negative regulators of Wnt signaling are down-regulated in A2780cp cells. • β-catenin transcriptional activity is higher in A2780cp cells compared to A2780s cells. • Inhibition of β-catenin activity increases carboplatin cytotoxicity in A2780cp cells.

  1. Elevated β-catenin activity contributes to carboplatin resistance in A2780cp ovarian cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Barghout, Samir H. [Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB (Canada); Zepeda, Nubia; Xu, Zhihua [Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB (Canada); Steed, Helen [Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB (Canada); Lee, Cheng-Han [Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB (Canada); Fu, YangXin, E-mail: yangxin@ualberta.ca [Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB (Canada); Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB (Canada)

    2015-12-04

    Ovarian cancer is the fifth leading cause of cancer-related mortalities in women. Epithelial ovarian cancer (EOC) represents approximately 90% of all ovarian malignancies. Most EOC patients are diagnosed at advanced stages and current chemotherapy regimens are ineffective against advanced EOC due to the development of chemoresistance. It is important to better understand the molecular mechanisms underlying acquired resistance to effectively manage this disease. In this study, we examined the expression of the Wnt/β-catenin signaling components in the paired cisplatin-sensitive (A2780s) and cisplatin-resistant (A2780cp) EOC cell lines. Our results showed that several negative regulators of Wnt signaling are downregulated, whereas a few Wnt ligands and known Wnt/β-catenin target genes are upregulated in A2780cp cells compared to A2780s cells, suggesting that Wnt/β-catenin signaling is more active in A2780cp cells. Further analysis revealed nuclear localization of β-catenin and higher β-catenin transcriptional activity in A2780cp cells compared to A2780s cells. Finally, we demonstrated that chemical inhibition of β-catenin transcriptional activity by its inhibitor CCT036477 sensitized A2780cp cells to carboplatin, supporting a role for β-catenin in carboplatin resistance in A2780cp cells. In conclusion, our data suggest that increased Wnt/β-catenin signaling activity contributes to carboplatin resistance in A2780cp cells. - Highlights: • Wnt ligands and target genes are upregulated in cisplatin resistant A2780cp cells. • Negative regulators of Wnt signaling are down-regulated in A2780cp cells. • β-catenin transcriptional activity is higher in A2780cp cells compared to A2780s cells. • Inhibition of β-catenin activity increases carboplatin cytotoxicity in A2780cp cells.

  2. Geranylgeranylacetone inhibits ovarian cancer progression in vitro and in vivo

    International Nuclear Information System (INIS)

    Hashimoto, Kae; Morishige, Ken-ichirou; Sawada, Kenjiro; Ogata, Seiji; Tahara, Masahiro; Shimizu, Shoko; Sakata, Masahiro; Tasaka, Keiichi; Kimura, Tadashi

    2007-01-01

    Geranylgeranylacetone (GGA), an isoprenoid compound, is an anti-ulcer drug developed in Japan. In our previous study, GGA was shown to inhibit ovarian cancer invasion by attenuating Rho activation [K. Hashimoto, K. Morishige, K. Sawada, M. Tahara, S. Shimizu, M. Sakata, K. Tasaka, Y. Murata, Geranylgeranylacetone inhibits lysophosphatidic acid-induced invasion of human ovarian carcinoma cells in vitro. Cancer 103 (2005) 1529-1536.]. In the present study, GGA treatment inhibited ovarian cancer progression in vitro and suppressed the tumor growth and ascites in the in vivo ovarian cancer model. In vitro analysis, treatment of cancer cells by GGA resulted in the inhibition of cancer cell proliferation, the inactivation of Ras, and the suppression of tyrosine phosphorylation of mitogen-activated protein kinase (MAPK). In conclusion, this is the first report that GGA inhibited ovarian cancer progression and the anti-tumor effect by GGA is, at least in part, derived not only from the suppression of Rho activation but also Ras-MAPK activation

  3. Quantification of activity by alpha-camera imaging and small-scale dosimetry within ovarian carcinoma micrometastases treated with targeted alpha therapy

    DEFF Research Database (Denmark)

    Chouin, N; Lindegren, S; Jensen, Holger

    2012-01-01

    the activity distribution of an alpha-particle emitter radiolabelled antibody within >100-µm micrometastases in a murine ovarian carcinoma model. Nude mice bearing ovarian micrometastases were injected intra-peritoneally with 211At-MX35 (total injected activity 6 MBq, specific activity 650 MBq/mg). Animals...

  4. Isolation and characterization of genes functionally involved in ovarian development of the giant tiger shrimp Penaeus monodon by suppression subtractive hybridization (SSH).

    Science.gov (United States)

    Preechaphol, Rachanimuk; Klinbunga, Sirawut; Khamnamtong, Bavornlak; Menasveta, Piamsak

    2010-10-01

    Suppression subtractive hybridization (SSH) libraries between cDNA in stages I (previtellogenic) and III (cortical rod) ovaries of the giant tiger shrimp (Penaeus monodon) were established. In all, 452 ESTs were unidirectionally sequenced. Sequence assembly generated 28 contigs and 201 singletons, 109 of which (48.0%) corresponding to known sequences previously deposited in GenBank. Several reproduction-related transcripts were identified. The full-length cDNA of anaphase promoting complex subunit 11 (PmAPC11; 600 bp with an ORF of 255 bp corresponding to a polypeptide of 84 amino acids) and selenoprotein Mprecursor (PmSePM; 904 bp with an ORF of 396 bp corresponding to a polypeptide of 131 amino acids) were characterized and reported for the first time in penaeid shrimp. Semiquantitative RT-PCR revealed that the expression levels of PmSePM and keratinocyte-associated protein 2 significantly diminished throughout ovarian development, whereas Ser/Thrcheckpoint kinase 1 (Chk1), DNA replication licensing factor mcm2 and egalitarian were down-regulated in mature ovaries of wild P. monodon (p < 0.05). Accordingly, the expression profiles of PmSePM and keratinocyte-associated protein 2 could be used as biomarkers for evaluating the degree of reproductive maturation in domesticated P. monodon.

  5. Activity of mevalonate pathway inhibitors against breast and ovarian cancers in the ATP-based tumour chemosensitivity assay

    International Nuclear Information System (INIS)

    Knight, Louise A; Kurbacher, Christian M; Glaysher, Sharon; Fernando, Augusta; Reichelt, Ralf; Dexel, Susanne; Reinhold, Uwe; Cree, Ian A

    2009-01-01

    Previous data suggest that lipophilic statins such as fluvastatin and N-bisphosphonates such as zoledronic acid, both inhibitors of the mevalonate metabolic pathway, have anti-cancer effects in vitro and in patients. We have examined the effect of fluvastatin alone and in combination with zoledronic acid in the ATP-based tumour chemosensitivity assay (ATP-TCA) for effects on breast and ovarian cancer tumour-derived cells. Both zoledronic acid and fluvastatin showed activity in the ATP-TCA against breast and ovarian cancer, though fluvastatin alone was less active, particularly against breast cancer. The combination of zoledronic acid and fluvastatin was more active than either single agent in the ATP-TCA with some synergy against breast and ovarian cancer tumour-derived cells. Sequential drug experiments showed that pre-treatment of ovarian tumour cells with fluvastatin resulted in decreased sensitivity to zoledronic acid. Addition of mevalonate pathway components with zoledronic acid with or without fluvastatin showed little effect, while mevalonate did reduced inhibition due to fluvastatin. These data suggest that the combination of zoledronic acid and fluvastatin may have activity against breast and ovarian cancer based on direct anti-cancer cell effects. A clinical trial to test this is in preparation

  6. DC-CIK cells derived from ovarian cancer patient menstrual blood activate the TNFR1-ASK1-AIP1 pathway to kill autologous ovarian cancer stem cells.

    Science.gov (United States)

    Qin, Wenxing; Xiong, Ying; Chen, Juan; Huang, Yongyi; Liu, Te

    2018-03-22

    Ovarian cancer stem cells (OCSCs) are highly carcinogenic and have very strong resistance to traditional chemotherapeutic drugs; therefore, they are an important factor in ovarian cancer metastasis and recurrence. It has been reported that dendritic cell (DC)-cytokine-induced killer (CIK) cells have significant killing effects on all cancer cells across many systems including the blood, digestive, respiratory, urinary and reproductive systems. However, whether DC-CIK cells can selectively kill OCSCs is currently unclear. In this study, we collected ovarian cancer patient menstrual blood (OCPMB) samples to acquire mononuclear cells and isolated DC-CIK cells in vitro. In addition, autologous CD44+/CD133+ OCSCs were isolated and used as target cells. The experimental results showed that when DC-CIK cells and OCSCs were mixed and cultured in vitro at ratios of 5:1, 10:1 and 50:1, the DC-CIK cells killed significant amounts of OCSCs, inhibited their invasion in vitro and promoted their apoptosis. The qPCR and Western blot results showed that DC-CIK cells stimulated high expression levels and phosphorylation of TNFR1, ASK1, AIP1 and JNK in OCSCs through the release of TNF-α. After the endogenous TNFR1 gene was knocked out in OCSCs using the CRISPR/Cas9 technology, the killing function of DC-CIK cells on target OCSCs was significantly attenuated. The results of the analyses of clinical samples suggested that the TNFR1 expression level was negatively correlated with ovarian cancer stage and prognosis. Therefore, we innovatively confirmed that DC-CIK cells derived from OCPMB could secret TNF-α to activate the expression of the TNFR1-ASK1-AIP1-JNK pathway in OCSCs and kill autologous OCSCs. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  7. Immune-suppressive activity of punicalagin via inhibition of NFAT activation

    International Nuclear Information System (INIS)

    Lee, Sang-Ik; Kim, Byoung-Soo; Kim, Kyoung-Shin; Lee, Samkeun; Shin, Kwang-Soo; Lim, Jong-Soon

    2008-01-01

    Since T cell activation is central to the development of autoimmune diseases, we screened a natural product library comprising 1400 samples of medicinal herbal extracts, to identify compounds that suppress T cell activity. Punicalagin (PCG) isolated from the fruit of Punica granatum was identified as a potent immune suppressant, based on its inhibitory action on the activation of the nuclear factor of activated T cells (NFAT). PCG downregulated the mRNA and soluble protein expression of interleukin-2 from anti-CD3/anti-CD28-stimulated murine splenic CD4+ T cells and suppressed mixed leukocytes reaction (MLR) without exhibiting cytotoxicity to the cells. In vivo, the PCG treatment inhibited phorbol 12-myristate 13-acetate (PMA)-induced chronic ear edema in mice and decreased CD3+ T cell infiltration of the inflamed tissue. These results suggest that PCG could be a potential candidate for the therapeutics of various immune pathologies

  8. Post-partum ovarian activity in adult and first-calf dual purpose cows in Guatemala

    International Nuclear Information System (INIS)

    Ordonez, H.; Gatica, A.; Miranda, J.; Matamoros, R.

    1990-01-01

    Progesterone (P 4 ) levels in skin milk were determined in two groups of dual purpose cows from farms in the Department of Escuintla on the south coast of Guatemala. Fifteen adult cows (crosses of Criollo with Zebu and Brown Swiss) were selected on the first farm and ten first-calf heifers (crosses of Criollo with Zebu and Holstein) on the second; both groups were considered to be representative of dual purpose livestock (milk and meat producers) in the country. To study the resumption of ovarian activity post-partum, milk samples were taken once a week from 10 days after calving until the first natural service; thereafter, sampling continued twice-weekly for 60 more days when the animals were rectally palpated for pregnancy diagnosis. On farm 1, the mean interval from calving to first rise in P 4 levels indicative of ovarian function was 42±16.7 days; all the study cows were at third calving and resumed cyclicity. On farm 2, only 30% of the study heifers resumed cyclicity and these had an interval from calving to first rise in P 4 of 80±28.9 days; all were at first calving. On farm 1, 73% of cows were served during first oestrus, 13% at second oestrus and 13% at the third. On farm 2, only 30% (3/10) of cows were served at first oestrus; the other 70% did not show signs of ovarian activity during the trial period which lasted until day 129 post-partum. Palpation of the cows 60 days post-service showed that all cows had conceived on farm 1 but only 20% on farm 2. (author). 9 refs, 3 figs

  9. Ovarian activity, transuterine embryo migration and prenatal losses in Ethiopian highland ewes.

    Science.gov (United States)

    Regassa, F; Tamrat, H; Bekana, M

    2007-02-01

    A study was conducted on 1442 Ethiopian highland ewes to determine the seasonality of ovarian activity, intrauterine embryo migration and prenatal reproductive wastage. Assessment of ovarian follicular activity revealed that a higher (p < 0.01) proportion of ewes ovulated in the dry season than in the heavy and light rainy seasons. However, there was a tendency (p = 0.057) of decline in the mean number of ovulations per ewes during the light rains. The mean diameter of the largest follicle on the ipsilateral ovary was higher (p < 0.01) in both ewes with single and those with twin corpora lutea (CL) than on the contralateral ovary; and, compared to ewes with single CL, it was higher (p < 0.05) in those with twin CL. The right ovary was more active (p < 0.001) only in single-ovulating ewes. Similarly, a higher (p < 0.001) proportion of ewes were pregnant in the right horn. Embryos migrated to the opposite horn in single-, twin- and triple-ovulating ewes. There was a higher (p < 0.001) tendency for the left-to-right migration than the opposite. There was significant (p < 0.01) association between embryo loss and site and number of ovulations. Embryo loss was higher (p < 0.01) in ewes with twin ovulations on the right ovary. It is very likely that these results indicate a better chance of embryo survival in the right uterine horn.

  10. AT-406, an orally active antagonist of multiple inhibitor of apoptosis proteins, inhibits progression of human ovarian cancer.

    Science.gov (United States)

    Brunckhorst, Melissa K; Lerner, Dimitry; Wang, Shaomeng; Yu, Qin

    2012-07-01

    Ovarian carcinoma is the most deadly gynecological malignancy. Current chemotherapeutic drugs are only transiently effective and patients with advance disease often develop resistance despite significant initial responses. Mounting evidence suggests that anti-apoptotic proteins, including those of the inhibitor of apoptosis protein (IAP) family, play important roles in the chemoresistance. There has been a recent emergence of compounds that block the IAP functions. Here, we evaluated AT-406, a novel and orally active antagonist of multiple IAP proteins, in ovarian cancer cells as a single agent and in the combination with carboplatin for therapeutic efficacy and mechanism of action. We demonstrate that AT-406 has significant single agent activity in 60% of human ovarian cancer cell lines examined in vitro and inhibits ovarian cancer progression in vivo and that 3 out of 5 carboplatin-resistant cell lines are sensitive to AT-406, highlighting the therapeutic potential of AT-406 for patients with inherent or acquired platinum resistance. Additionally, our in vivo studies show that AT-406 enhances the carboplatin-induced ovarian cancer cell death and increases survival of the experimental mice, suggesting that AT-406 sensitizes the response of these cells to carboplatin. Mechanistically, we demonstrate that AT-406 induced apoptosis is correlated with its ability to down-regulate XIAP whereas AT-406 induces cIAP1 degradation in both AT-406 sensitive and resistance cell lines. Together, these results demonstrate, for the first time, the anti-ovarian cancer efficacy of AT-406 as a single agent and in the combination with carboplatin, suggesting that AT-406 has potential as a novel therapy for ovarian cancer patients, especially for patients exhibiting resistance to the platinum-based therapies.

  11. Covertly active and progressing neurochemical abnormalities in suppressed HIV infection.

    Science.gov (United States)

    Cysique, Lucette A; Jugé, Lauriane; Gates, Thomas; Tobia, Michael; Moffat, Kirsten; Brew, Bruce J; Rae, Caroline

    2018-01-01

    To assess whether HIV-related brain injury is progressive in persons with suppressed HIV infection. Seventy-three HIV+ virally suppressed men and 35 HIV- men, screened for psychiatric and alcohol/drug use disorders, underwent neuropsychological evaluation and proton magnetic resonance spectroscopy ( 1 H-MRS) at baseline and after and 23 ± 5 months. 1 H-MRS included brain regions known to be vulnerable to HIV and aging: frontal white matter (FWM), posterior cingulate cortex (PCC), and caudate area (CA). Major brain metabolites such as creatine (Cr: marker of cellular energy), N -acetyl aspartate (NAA: marker of neuronal integrity), choline (marker of cellular membrane turnover), glutamate/glutamine (excitatory/inhibitory neurotransmitter), and myo -Inositol (mI: marker of neuroinflammation) were calculated with reference to water signal. Neurocognitive decline was corrected for practice effect and baseline HIV-associated neurocognitive disorder (HAND) status. Across the study period, 44% had intact cognition, 42% stable HAND (including the single case that improved), 10% progressing HAND, and 4% incident HAND. When analyzing the neurochemical data per neurocognitive trajectories, we found decreasing PCC Cr in all subgroups compared with controls ( p < 0.002). In addition, relative to the HIV- group, stable HAND showed decreasing FWM Cr, incident HAND showed steep FWM Cr reduction, whereas progressing HAND had a sharply decreasing PCC NAA and reduced but stable CA NAA. When analyzing the neurochemical data at the group level (HIV+ vs HIV- groups), we found stable abnormal metabolite concentrations over the study period: decreased FWM and PCC Cr (both p < 0.001), decreased PCC NAA and CA NAA (both p < 0.05) and PCC mI increase ( p < 0.05). HIV duration and historical HAND had modest effects on metabolite changes. Our study reveals covertly active or progressing HIV-related brain injury in the majority of this virally suppressed cohort, reflecting ongoing

  12. Covertly active and progressing neurochemical abnormalities in suppressed HIV infection

    Science.gov (United States)

    Jugé, Lauriane; Gates, Thomas; Tobia, Michael; Moffat, Kirsten; Brew, Bruce J.; Rae, Caroline

    2018-01-01

    Objective To assess whether HIV-related brain injury is progressive in persons with suppressed HIV infection. Methods Seventy-three HIV+ virally suppressed men and 35 HIV− men, screened for psychiatric and alcohol/drug use disorders, underwent neuropsychological evaluation and proton magnetic resonance spectroscopy (1H-MRS) at baseline and after and 23 ± 5 months. 1H-MRS included brain regions known to be vulnerable to HIV and aging: frontal white matter (FWM), posterior cingulate cortex (PCC), and caudate area (CA). Major brain metabolites such as creatine (Cr: marker of cellular energy), N-acetyl aspartate (NAA: marker of neuronal integrity), choline (marker of cellular membrane turnover), glutamate/glutamine (excitatory/inhibitory neurotransmitter), and myo-Inositol (mI: marker of neuroinflammation) were calculated with reference to water signal. Neurocognitive decline was corrected for practice effect and baseline HIV-associated neurocognitive disorder (HAND) status. Results Across the study period, 44% had intact cognition, 42% stable HAND (including the single case that improved), 10% progressing HAND, and 4% incident HAND. When analyzing the neurochemical data per neurocognitive trajectories, we found decreasing PCC Cr in all subgroups compared with controls (p < 0.002). In addition, relative to the HIV− group, stable HAND showed decreasing FWM Cr, incident HAND showed steep FWM Cr reduction, whereas progressing HAND had a sharply decreasing PCC NAA and reduced but stable CA NAA. When analyzing the neurochemical data at the group level (HIV+ vs HIV− groups), we found stable abnormal metabolite concentrations over the study period: decreased FWM and PCC Cr (both p < 0.001), decreased PCC NAA and CA NAA (both p < 0.05) and PCC mI increase (p < 0.05). HIV duration and historical HAND had modest effects on metabolite changes. Conclusions Our study reveals covertly active or progressing HIV-related brain injury in the majority of this virally suppressed

  13. Monocyte activation, but not granulocyte activation, is inhibited in the presence of developing ovarian follicles

    NARCIS (Netherlands)

    Faas, MM; Moes, H; van der Schaaf, G; Heineman, MJ; de Vos, P

    This study was set up to evaluate the influence of ovarian factors on the acute phase of the endotoxin-induced glomerular inflammatory reaction. Six groups of rats with permanent jugular vein cannulas were used. This included three groups with increased progesterone and/or 17 beta-oestradiol

  14. Ovarian activity and estrus behavior in early postpartum cows grazing Leucaena leucocephala in the tropics.

    Science.gov (United States)

    Bottini-Luzardo, Maria; Aguilar-Perez, Carlos; Centurion-Castro, Fernando; Solorio-Sanchez, Francisco; Ayala-Burgos, Armin; Montes-Perez, Ruben; Muñoz-Rodriguez, David; Ku-Vera, Juan

    2015-12-01

    The legume Leucaena leucocephala (Leucaena) is widely used to supplement forage in silvopastoral livestock systems in Latin America. Little is known about its possible effects on the cow reproductive dynamic. The aim was to evaluate the effect of Leucaena foliage intake on re-establishment of ovarian activity and estrus behavior in early postpartum (7-90 days) cows. Twenty-four multiparous Bos taurus × Bos indicus cows were divided into two homogenous groups and assigned to one of two treatments: a silvopastoral system (SS, n = 12), consisting of an association of Cynodon nlemfuensis grass and L. leucocephala; and a control system (CS, n = 12), consisting of C. nlemfuensis alone. Intake of Leucaena in the SS ranged from 3.80 to 6.43 kg DM/cow/day. Plasma mimosine concentrations ranged from 1270 to 1530 μg/mL, and those for 2,3-dihydroxypyridine (DHP) from 147 to 729 μg/mL. No 3,4-DHP was detected in plasma. No difference (P > 0.05) between treatments was observed for the number of cows exhibiting small, medium, or dominant follicles, or estrus behavior. The number of cows which re-established ovarian cyclicity (n = 6) was lower (P < 0.05) in the SS than in the CS (n = 9). Corpus luteum lifespan was longer (P < 0.05) in the SS than in the CS. Intake of Leucaena affected the number of cows exhibiting ovarian cyclicity and extended corpus luteum life, but did not affect follicular development and estrus behavior.

  15. Active Suppression of Narrowband Noise by Multiple Secondary Sources

    Directory of Open Access Journals (Sweden)

    Seokhoon Ryu

    2016-01-01

    Full Text Available This study presents theoretical and experimental investigation on the active suppression of narrowband noise with C1, C1.5, and C2 components by using multichannel secondary sources in a duct. The quality manipulation in the duct was controlled by changing quality factors which were incorporated into a multichannel FxLMS algorithm. The algorithm is extensively investigated in both theory and real-time control experiment. After analysing the primary and secondary paths of the duct system, an acoustic narrowband signal was chosen as a primary noise and the impulse responses were implemented as the secondary path models. Control results show that the quality factors in the algorithm that was implemented in a dSPACE 1104 provide a stable and excellent response compared to before control. It is obvious that the lower quality factor cancels the more primary noise as defined in the theory although the attenuation levels are not exactly and inversely proportional to the quality factor. The results in this study can be used for practical active sound quality control systems.

  16. Reversible suppression of sexual activity in tomcats with deslorelin implant.

    Science.gov (United States)

    Novotny, R; Cizek, P; Vitasek, R; Bartoskova, A; Prinosilova, P; Janosovska, M

    2012-09-01

    The aim of the study was to assess the efficacy of using a Gn-RH agonist implant (deslorelin, 4.7 mg, Suprelorin) to control sexual activity of male cats and reestablishment of sexual function after the implant removal 4 mo after placement. Using a control group (Group 1, n = 5), 22 domestic tomcats were given the implant subcutaneously in the region of the right shoulder blade and were then divided into two treatment groups. Animals in Group 2 (n = 14) were observed from the date of implant surgery and the observation lasted for 4 mo. In Group 3 (n = 8) all animals were monitored from the date of implant surgery. Then, after 4 mo, all implants were removed and the toms were observed for a further 4 mo. In all animals during their first visit and then in 1-mo intervals, changes in testosterone concentrations were assessed before (T0) and 4 h after (T4) human chorionic gonadotropin (HCG) administration and testis size was measured. In all tomcats, semen collection was performed, using an electroejaculator, in the course of the first visit and then in 2-mo intervals or at the end of observation. Total sperm count was determined in each semen sample. Two to four animals were castrated at weeks 4, 8, 12, 16, 20, 24, 28 and 32 and histologic assessment of the testes was performed. By evaluation of 200 cross sections of seminiferous tubules, the degree of spermatogenic suppression was assessed and animals in Groups 2 and 3 were assigned into groups according to most tubules with the most developed germ cell observed: G1, spermatocytes; G2, round spermatids; G3, elongating spermatids and G4, elongated spermatids. The mean area of Leydig-cell nuclei was calculated. In animals in Group 2, suppression after implant insertion was monitored. T4 concentrations, testis size, and total sperm count gradually decreased (P < 0.01; P < 0.01; and P < 0.05, respectively) within 4 mo after implantation. Histologic evaluation showed a high individual variation in the degree of

  17. The milk-derived fusion peptide, ACFP, suppresses the growth of primary human ovarian cancer cells by regulating apoptotic gene expression and signaling pathways.

    Science.gov (United States)

    Zhou, Juan; Zhao, Mengjing; Tang, Yigui; Wang, Jing; Wei, Cai; Gu, Fang; Lei, Ting; Chen, Zhiwu; Qin, Yide

    2016-03-24

    ACFP is an anti-cancer fusion peptide derived from bovine milk protein. This study was to investigate the anti-cancer function and underlying mechanisms of ACFP in ovarian cancer. Fresh ovarian tumor tissues were collected from 53 patients who underwent initial debulking surgery, and primary cancer cells were cultured. Normal ovarian surface epithelium cells (NOSECs), isolated from 7 patients who underwent surgery for uterine fibromas, were used as normal control tissue. Anti-viabilities of ACFP were assessed by WST-1 (water-soluble tetrazolium 1), and apoptosis was measured using a flow cytometry-based assay. Gene expression profiles of ovarian cancer cells treated with ACFP were generated by cDNA microarray, and the expression of apoptotic-specific genes, such as bcl-xl, bax, akt, caspase-3, CDC25C and cyclinB1, was assessed by real time PCR and western blot analysis. Treatment with ACFP inhibited the viability and promoted apoptosis of primary ovarian cancer cells but exhibited little or no cytotoxicity toward normal primary ovarian cells. Mechanistically, the anti-cancer effects of ACFP in ovarian cells were shown to occur partially via changes in gene expression and related signal pathways. Gene expression profiling highlighted that ACFP treatment in ovarian cancer cells repressed the expression of bcl-xl, akt, CDC25C and cyclinB1 and promoted the expression of bax and caspase-3 in a time- and dose-dependent manner. Our results suggest that ACFP may represent a potential therapeutic agent for ovarian cancer that functions by altering the expression and signaling of cancer-related pathways in ovarian cancer cells.

  18. AKT activation drives the nuclear localization of CSE1L and a pro-oncogenic transcriptional activation in ovarian cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Lorenzato, Annalisa; Biolatti, Marta [Department of Oncology, University of Torino School of Medicine, Torino (Italy); Institute for Cancer Research at Candiolo, Candiolo, Torino (Italy); Delogu, Giuseppe [Department of Biomedical Sciences-Histology, University of Sassari, Sassari (Italy); Capobianco, Giampiero [Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, Sassari (Italy); Farace, Cristiano [Department of Biomedical Sciences-Histology, University of Sassari, Sassari (Italy); Dessole, Salvatore; Cossu, Antonio; Tanda, Francesco [Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, Sassari (Italy); Madeddu, Roberto [Department of Biomedical Sciences-Histology, University of Sassari, Sassari (Italy); National Institute of Biostructures and Biosystems, Rome (Italy); Olivero, Martina [Department of Oncology, University of Torino School of Medicine, Torino (Italy); Institute for Cancer Research at Candiolo, Candiolo, Torino (Italy); Di Renzo, Maria Flavia, E-mail: mariaflavia.direnzo@unito.it [Department of Oncology, University of Torino School of Medicine, Torino (Italy); Institute for Cancer Research at Candiolo, Candiolo, Torino (Italy)

    2013-10-15

    The human homolog of the yeast cse1 gene (CSE1L) is over-expressed in ovarian cancer. CSE1L forms complex with Ran and importin-α and has roles in nucleocytoplasmic traffic and gene expression. CSE1L accumulated in the nucleus of ovarian cancer cell lines, while it was localized also in the cytoplasm of other cancer cell lines. Nuclear localization depended on AKT, which was constitutively active in ovarian cancer cells, as the CSE1L protein translocated to the cytoplasm when AKT was inactivated. Moreover, the expression of a constitutively active AKT forced the translocation of CSE1L from the cytoplasm to the nucleus in other cancer cells. Nuclear accrual of CSE1L was associated to the nuclear accumulation of the phosphorylated Ran Binding protein 3 (RanBP3), which depended on AKT as well. Also in samples of human ovarian cancer, AKT activation was associated to nuclear accumulation of CSE1L and phosphorylation of RanBP3. Expression profiling of ovarian cancer cells after CSE1L silencing showed that CSE1L was required for the expression of genes promoting invasion and metastasis. In agreement, CSE1L silencing impaired motility and invasiveness of ovarian cancer cells. Altogether these data show that in ovarian cancer cells activated AKT by affecting RanBP3 phosphorylation determines the nuclear accumulation of CSE1L and likely the nuclear concentration of transcription factors conveying pro-oncogenic signals. - highlights: • CSE1L is a key player in nucleocytoplasmic traffic by forming complex with Ran. • AKT phosphorylates RanBP3 that regulates the nucleocytoplasmic gradient of Ran. • The activated oncogenic AKT drives the nuclear accumulation of CSE1L. • CSE1L in the nucleus up-regulates genes conveying pro-oncogenic signals. • CSE1L might contribute to tumor progression driven by the activated oncogenic AKT.

  19. The Suppression of Star Formation by Powerful Active Galactic Nuclei

    Science.gov (United States)

    Dwek, E.

    2012-01-01

    The old, red stars that constitute the bulges of galaxies, and the massive black holes at their centres, are the relics of a period in cosmic history when galaxies formed stars at remarkable rates and active galactic nuclei (AGN) shone brightly as a result of accretion onto black holes. It is widely suspected, but unproved, that the tight corre1ation between the mass of the black hole and the mas. of the stellar bulge results from the AGN quenching the surrounding star formation as it approaches its peak luminosity. X-rays trace emission from AGN unambiguously, whereas powerful star-forming ga1axies are usually dust-obscured and are brightest at infrared and submillimeter wavelengths. Here we report submillimetre and X-ray observations that show that rapid star formation was common in the host galaxies of AGN when the Universe was 2-6 billion years old, but that the most vigorous star formation is not observed around black holes above an X-ray luminosity of 10(exp 44) ergs per second. This suppression of star formation in the host galaxy of a powerful AGN is a key prediction of models in which the AGN drives an outflow, expe11ing the interstellar medium of its host and transforming the galaxy's properties in a brief period of cosmic time.

  20. The suppression of star formation by powerful active galactic nuclei.

    Science.gov (United States)

    Page, M J; Symeonidis, M; Vieira, J D; Altieri, B; Amblard, A; Arumugam, V; Aussel, H; Babbedge, T; Blain, A; Bock, J; Boselli, A; Buat, V; Castro-Rodríguez, N; Cava, A; Chanial, P; Clements, D L; Conley, A; Conversi, L; Cooray, A; Dowell, C D; Dubois, E N; Dunlop, J S; Dwek, E; Dye, S; Eales, S; Elbaz, D; Farrah, D; Fox, M; Franceschini, A; Gear, W; Glenn, J; Griffin, M; Halpern, M; Hatziminaoglou, E; Ibar, E; Isaak, K; Ivison, R J; Lagache, G; Levenson, L; Lu, N; Madden, S; Maffei, B; Mainetti, G; Marchetti, L; Nguyen, H T; O'Halloran, B; Oliver, S J; Omont, A; Panuzzo, P; Papageorgiou, A; Pearson, C P; Pérez-Fournon, I; Pohlen, M; Rawlings, J I; Rigopoulou, D; Riguccini, L; Rizzo, D; Rodighiero, G; Roseboom, I G; Rowan-Robinson, M; Sánchez Portal, M; Schulz, B; Scott, D; Seymour, N; Shupe, D L; Smith, A J; Stevens, J A; Trichas, M; Tugwell, K E; Vaccari, M; Valtchanov, I; Viero, M; Vigroux, L; Wang, L; Ward, R; Wright, G; Xu, C K; Zemcov, M

    2012-05-09

    The old, red stars that constitute the bulges of galaxies, and the massive black holes at their centres, are the relics of a period in cosmic history when galaxies formed stars at remarkable rates and active galactic nuclei (AGN) shone brightly as a result of accretion onto black holes. It is widely suspected, but unproved, that the tight correlation between the mass of the black hole and the mass of the stellar bulge results from the AGN quenching the surrounding star formation as it approaches its peak luminosity. X-rays trace emission from AGN unambiguously, whereas powerful star-forming galaxies are usually dust-obscured and are brightest at infrared and submillimetre wavelengths. Here we report submillimetre and X-ray observations that show that rapid star formation was common in the host galaxies of AGN when the Universe was 2-6 billion years old, but that the most vigorous star formation is not observed around black holes above an X-ray luminosity of 10(44) ergs per second. This suppression of star formation in the host galaxy of a powerful AGN is a key prediction of models in which the AGN drives an outflow, expelling the interstellar medium of its host and transforming the galaxy's properties in a brief period of cosmic time.

  1. Evodiamine from Evodia rutaecarpa induces apoptosis via activation of JNK and PERK in human ovarian cancer cells.

    Science.gov (United States)

    Chen, Tze-Chien; Chien, Chih-Chiang; Wu, Ming-Shun; Chen, Yen-Chou

    2016-01-15

    Evodiamine (EVO; 8,13,13b,14-tetrahydro-14-methylindolo[2'3'-3,4]pyrido[2,1-b]quinazolin-5-[7H]-one derived from the traditional herbal medicine Evodia rutaecarpa was reported to possess anticancer activity; however, the anticancer mechanism of EVO against the viability of human ovarian cancer cells is still unclear. A number of studies showed that chemotherapeutic benefits may result from targeting the endoplasmic reticular (ER) stress signaling pathway. The objective of the study is to investigate the mechanism by which ER stress protein PERK plays in EVO-induced apoptosis of human ovarian cancer cells. Cell death analysis was performed by MTT assay, DNA fragmentation assay, and Giemsa staining. DiOC6 staining was used for mitochondrial membrane potential measurement. Protein levels were analyzed by Western blotting. Pharmacological studies using MAPK inhibitors and PERK inhibitor GSK2606414 were involved. The viability of human ovarian cancer cells A2780, A2780CP, ES-2, and SKOV-3 was inhibited by EVO at various concentrations in accordance with increases in the percentage of apoptotic cells, DNA ladders, and cleavage of caspase 3 and poly(ADP ribose) polymerase (PARP) proteins. Decreased viability of cells was reversed by adding caspase inhibitors VAD and DEVD in SKOV-3 and A2780CP cells, and incubation of cells with JNK inhibitor SP600125 (SP) and JNKI, but not other MAPK and AKT inhibitors including PD98059, SB203580, significantly prevented the apoptosis elicited by EVO in human ovarian cancer cells. Furthermore, increased expression of phospho-eIF2α (peIF2α) and phospho-PERK (pPERK) proteins was detected in EVO-treated human ovarian cancer cells, and that was inhibited by adding JNK inhibitors SP600125 and JNKI. Application of a PERK inhibitor GSK2606414 showed a significant protection of human ovarian cancer cells A2780 and A2780CP from EVO-induced apoptosis. EVO disruption of mitochondrial membrane potential (MMP) was also inhibited by adding JNK or

  2. TLR4 activates NF-{kappa}B in human ovarian granulosa tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Woods, Dori C., E-mail: dwoods2@partners.org [Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114 (United States); White, Yvonne A.R. [Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114 (United States); Dau, Caroline [University of California, San Francisco, School of Dentistry, San Francisco, CA 94143 (United States); Johnson, A.L. [Center for Reproductive Biology and Health, The Pennsylvania State University, University Park, PA 16802 (United States)

    2011-06-17

    Highlights: {yields} TLR4 is expressed in human ovarian granulosa tumor cells. {yields} Acting through TLR4, LPS and HSP60 induce a NF{kappa}B signaling cascade in human ovarian granulosa tumor cells. {yields} NF{kappa}B activation or inhibition did not alter chemosensitivity to TRAIL or cisplatin. -- Abstract: Previous studies have demonstrated expression of Toll-like receptors (TLRs) in the surface epithelium of normal ovaries (OSE) and in epithelial ovarian tumors. Most notably, OSE-derived cancers express TLR4, which activates the nuclear factor-kappa B (NF-{kappa}B) signaling cascade as a mediator of inflammatory response. Currently, there is considerable interest in elucidating the role of TLR-mediated signaling in cancers. Nevertheless, the expression of TLRs in granulosa cell tumors (GCTs) of the ovary, and the extent to which GCT expression of TLRs may influence cell-signaling pathways and/or modulate the efficacy of chemotherapeutics, has yet to be determined. In the present study, human GCT lines (COV434 and KGN) were utilized to evaluate expression of functional TLR4. TLR4 is expressed in GCT cell lines and ligation of TLR4 with bacterial lipopolysaccharide (LPS) led to I{kappa}B degradation and activation of NF-{kappa}B. NF-{kappa}B activation was confirmed by nuclear localization of NF-{kappa}B p65 following treatment with LPS and the naturally occurring ligand, HSP60. Notably, immunoneutralization of TLR4 blocked nuclear localization, and inhibition of NF-{kappa}B signaling attenuated LPS-induced TNF{alpha} plus increased doubling time in both cell lines. Contradictory to reports using human OSE cell lines, inhibition of NF-{kappa}B signaling failed to sensitize GCT lines to TRAIL or cisplatin. In summary, findings herein are the first to demonstrate a functional TLR-signaling pathway specifically in GCTs, and indicate that in contrast to OSE-derived cancers, inhibition of NF-{kappa}B does not sensitize GCTs to TRAIL or cisplatin.

  3. HGF and BFGF Secretion by Human Adipose-Derived Stem Cells Improves Ovarian Function During Natural Aging via Activation of the SIRT1/FOXO1 Signaling Pathway.

    Science.gov (United States)

    Ding, Chenyue; Zou, Qinyan; Wang, Fuxin; Wu, Huihua; Wang, Wei; Li, Hong; Huang, Boxian

    2018-01-01

    Human adipose-derived stem cells (hADSCs) are a potential therapeutic option for clinical applications because of their ability to produce cytokines and their capacity for trilineage differentiation. To date, few researchers have investigated the effects of hADSCs on natural ovarian aging (NOA). An NOA mouse model and human ovarian granule cells (hGCs) collected from individuals with NOA were prepared to assess the therapeutic effects and illuminate the mechanism of hADSCs in curing NOA. Enzyme-linked immunosorbent assay was used to detect the serum levels of sex hormones and antioxidative enzymes. The proliferation rate and marker expression level of hGCs were measured by flow cytometry (FACS). Cytokines were measured by a protein antibody array methodology. Western blot assays were used to determine the protein expression levels of SIRT1 and FOXO1. Our results showed that hADSCs displayed therapeutic activity against ovarian function in an NOA mouse model, increasing the proliferation rate and marker expression level of hGCs. Furthermore, the yields of hADSC-secreted HGF and bFGF were higher than those of other growth factors. FACS showed that combination treatment with the growth factors HGF and bFGF more strongly promoted proliferation and inhibited apoptosis in hGCs than HGF or bFGF treatment alone. FACS and ELISA revealed that the combination treatment with both growth factors inhibited oxidative stress more forcefully than treatments with only one of these growth factors. In addition, protein assays demonstrated that combination treatment with both growth factors suppressed oxidative stress by up-regulating the expression of SIRT1 and FOXO1. These findings demonstrate for the first time the molecular cascade and related cell biology events involved in the mechanism by which HGF and bFGF derived from hADSCs improved ovarian function during natural aging via reduction of oxidative stress by activating the SIRT1/FOXO1 signaling pathway. © 2018 The Author

  4. Photodynamic action of LED-activated pyropheophorbide-α methyl ester in cisplatin-resistant human ovarian carcinoma cells

    Science.gov (United States)

    Tan, Y.; Xu, C. S.; Xia, X. S.; Yu, H. P.; Bai, D. Q.; He, Y.; Leung, A. W. N.

    2009-04-01

    Cisplatin-resistance is a major obstacle for the successful therapy to ovarian cancer, and exploring novel approach to deactivate cisplatin-resistant ovarian cells will improve the clinical outcomes. Our present study showed that there was no dark cytotoxicity of MPPa in the COC1/DDP cells at the dose of 0.25 - 4 μM, and LED-activated MPPa resulted in drug dose- and light-dependent cytotoxicity. Apoptotic rate 6 h after LED-activated MPPa (2 μM) increased to 16.71% under the light energy of 1 J/cm2. Confocal laser scanning microscopy showed that MPPa mainly localized in the intracellular membrane system, namely the endoplasmic reticulum, Golgi apparatus, lysosomes and mitochondria in the COC1/DDP cells. Mitochondrial membrane potential (ΔΨm) was collapsed when COC1/DDP cells were exposed to 2 μM MPPa for 20 h and then 1 J/cm2 irradiation of LED source. These data demonstrated that LED-activated MPPa significantly deactivated cisplatin-resistant ovarian cell line COC1/DDP cells and enhanced apoptosis and decreased ΔΨm, which suggests LED is an efficient light source for PDT and LED-activated MPPa can be developed as new modality for treating cisplatin-resistant ovarian.

  5. Mechanisms underlying p53 regulation of PIK3CA transcription in ovarian surface epithelium and in ovarian cancer.

    Science.gov (United States)

    Astanehe, Arezoo; Arenillas, David; Wasserman, Wyeth W; Leung, Peter C K; Dunn, Sandra E; Davies, Barry R; Mills, Gordon B; Auersperg, Nelly

    2008-03-01

    Inactivation of the transcription factor and tumor suppressor p53, and overexpression or mutational activation of PIK3CA, which encodes the p110alpha catalytic subunit of phosphatidylinositol-3-kinase (PI3K), are two of the most common deleterious genomic changes in cancer, including in ovarian carcinomas. We investigated molecular mechanisms underlying interactions between these two mediators and their possible roles in ovarian tumorigenesis. We identified two alternate PIK3CA promoters and showed direct binding of and transcriptional inhibition by p53 to one of these promoters. Conditional suppression of functional p53 increased p110alpha transcripts, protein levels and PI3K activity in immortalized, non-tumorigenic ovarian surface epithelial (OSE) cells, the precursors of ovarian carcinoma. Conversely, overexpression of p53 by adenoviral infection and activation of p53 by gamma-irradiation both diminished p110alpha protein levels in normal OSE and ovarian cancer cells. The demonstration that p53 binds directly to the PIK3CA promoter and inhibits its activity identifies a novel mechanism whereby these two mediators regulate cellular functions, and whereby inactivation of p53 and subsequent upregulation of PIK3CA might contribute to the pathophysiology of ovarian cancer.

  6. Ovarian activity and sexual behavior in the postpartum Swamp Buffalo (Bubalus bubalis

    Directory of Open Access Journals (Sweden)

    B. Colenbrander

    2010-02-01

    Full Text Available Early postpartum follicular activity and sexual behavior was evaluated in the swamp buffalo (Bubalus bubalis in a tropical climate. Sixteen multiparous postpartum swamp buffaloes, 4-12 years of age, (432 - 676 kg were studied starting between 5-29 days after parturition. Ovarian follicular activity was examined daily in the morning with a real-time B-mode linear array ultrasound scanner (Aloka SSD-500, Tokyo, Japan equipped with a 7.5 MHz transrectal transducer. Estrous detection was performed daily using a mature bull, via personal observation as well as via video registration. In addition, vaginal discharge around estrus was evaluated. Uterine involution took 28.74+1.21 days (mean +SEM, range 22-41 d, n=16. Follicular activity prior to the first ovulation was characterized by a wave like pattern. Follicular growth rates and maximum diameter of the follicle in the second, third and fourth cycle post partum did not differ while that of the first ovulation follicle was significantly lower (p<0.05. Short ovarian cycles were observed in 93.3% of the buffaloes in the first to second ovulation interval (10.14+40 d, and in 50.0% of the buffaloes in the second to third ovulation interval (12.00+1.53 d, while one buffalo cow then had a long estrus cycle (27 d. The behavioral characteristics of estrus around the first postpartum ovulation were not as obvious as around the second, third and fourth postpartum ovulation. It can be concluded that for optimal reproductive efficiency the swamp buffalo should be mated between 1- 2 months postpartum at the second ovulation.

  7. Inhibition of RUNX2 transcriptional activity blocks the proliferation, migration and invasion of epithelial ovarian carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Zhi-Qiang Wang

    Full Text Available Previously, we have identified the RUNX2 gene as hypomethylated and overexpressed in post-chemotherapy (CT primary cultures derived from serous epithelial ovarian cancer (EOC patients, when compared to primary cultures derived from matched primary (prior to CT tumors. However, we found no differences in the RUNX2 methylation in primary EOC tumors and EOC omental metastases, suggesting that DNA methylation-based epigenetic mechanisms have no impact on RUNX2 expression in advanced (metastatic stage of the disease. Moreover, RUNX2 displayed significantly higher expression not only in metastatic tissue, but also in high-grade primary tumors and even in low malignant potential tumors. Knockdown of the RUNX2 expression in EOC cells led to a sharp decrease of cell proliferation and significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as various genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon RUNX2 suppression, while a number of pro-apoptotic genes and some EOC tumor suppressor genes were induced. Taken together, our data are indicative for a strong oncogenic potential of the RUNX2 gene in serous EOC progression and suggest that RUNX2 might be a novel EOC therapeutic target. Further studies are needed to more completely elucidate the functional implications of RUNX2 and other members of the RUNX gene family in ovarian tumorigenesis.

  8. Public exposure and number of conspecifics have no influence on ovarian and adrenal activity in the cheetah (Acinonyx jubatus).

    Science.gov (United States)

    Koester, Diana C; Wildt, David E; Brown, Janine L; Meeks, Karen; Crosier, Adrienne E

    2017-03-01

    Cheetahs in managed zoological collections do not reproduce efficiently, a problem that may be related to environmental/management stressors. In this study, we examined 17 adult female cheetahs to determine the influence of two environmental factors, (1) being housed on- or off-exhibit and (2) number of adult conspecifics (males and/or females) in nearby enclosures, on profiles and concentrations of ovarian and adrenal hormones. Secondarily, we assessed a subset of group-housed siblings (n=5 females in groups of 2 or 3) for effects of long-term cohabitation. All of the females demonstrated waves of estrogen excretion (indicative of ovarian activity) as well as occasional periods of no estrogen production (anestrus). Glucocorticoid and estrogen concentrations were correlated within an individual (r s =0.53; P0.05) on estrogen or glucocorticoid metabolite excretory patterns. Although we recently reported that public exposure can negatively affect sperm production, ovarian steroidogenesis in females was unaffected. There also was no evidence of hyper-adrenal activity. Thus, different methods of ex situ management appear to have minimal influence on ovarian function or stress susceptibility of female cheetahs. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Methylseleninic acid sensitizes Notch3-activated OVCA429 ovarian cancer cells to carboplatin

    Science.gov (United States)

    Ovarian cancer, the deadliest of gynecologic cancers, is usually diagnosed at advanced stage due to invalidated screening test and non-specific symptoms presented. Although carboplatin has been popular for treating ovarian cancer for decades, patients eventually develop resistance to this platinum-c...

  10. The role of the addition of ovarian suppression to tamoxifen in young women with hormone-sensitive breast cancer who remain premenopausal or regain menstruation after chemotherapy (ASTRRA): study protocol for a randomized controlled trial and progress

    International Nuclear Information System (INIS)

    Kim, Hyun-Ah; Ahn, Sei Hyun; Nam, Seok Jin; Park, Seho; Ro, Jungsil

    2016-01-01

    Ovarian function suppression (OFS) has been shown to be effective as adjuvant endocrine therapy in premenopausal women with hormone receptor-positive breast cancer. However, it is currently unclear if addition of OFS to standard tamoxifen therapy after completion of adjuvant chemotherapy results in a survival benefit. In 2008, the Korean Breast Cancer Society Study Group initiated the ASTRRA randomized phase III trial to evaluate the efficacy of OFS in addition to standard tamoxifen treatment in hormone receptor-positive breast cancer patients who remain or regain premenopausal status after chemotherapy. Premenopausal women with estrogen receptor-positive breast cancer treated with definitive surgery were enrolled after completion of neoadjuvant or adjuvant chemotherapy. Ovarian function was assessed at the time of enrollment and every 6 months for 2 years by follicular-stimulating hormone levels and bleeding history. If ovarian function was confirmed as premenopausal status, the patient was randomized to receive 2 years of goserelin plus 5 years of tamoxifen treatment or 5 years of tamoxifen alone. The primary end point will be the comparison of the 5-year disease-free survival rates between the OFS and tamoxifen alone groups. Patient recruitment was finished on March 2014 with the inclusion of a total of 1483 patients. The interim analysis will be performed at the time of the observation of the 187th event. This study will provide evidence of the benefit of OFS plus tamoxifen compared with tamoxifen only in premenopausal patients with estrogen receptor-positive breast cancer treated with chemotherapy

  11. TGF-beta induces serous borderline ovarian tumor cell invasion by activating EMT but triggers apoptosis in low-grade serous ovarian carcinoma cells.

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    Jung-Chien Cheng

    Full Text Available Apoptosis in ovarian surface epithelial (OSE cells is induced by transforming growth factor-beta (TGF-β. However, high-grade serous ovarian carcinomas (HGC are refractory to the inhibitory functions of TGF-β; their invasiveness is up-regulated by TGF-β through epithelial-mesenchymal transition (EMT activation. Serous borderline ovarian tumors (SBOT have been recognized as distinct entities that give rise to invasive low-grade serous carcinomas (LGC, which have a relatively poor prognosis and are unrelated to HGC. While it is not fully understood how TGF-β plays disparate roles in OSE cells and its malignant derivative HGC, its role in SBOT and LGC remains unknown. Here we demonstrate the effects of TGF-β on cultured SBOT3.1 and LGC-derived MPSC1 cells, which express TGF-β type I and type II receptors. TGF-β treatment induced the invasiveness of SBOT3.1 cells but reduced the invasiveness of MPSC1 cells. The analysis of apoptosis, which was assessed by cleaved caspase-3 and trypan blue exclusion assay, revealed TGF-β-induced apoptosis in MPSC1, but not SBOT3.1 cells. The pro-apoptotic effect of TGF-β on LGC cells was confirmed in another immortalized LGC cell line ILGC. TGF-β treatment led to the activation of Smad3 but not Smad2. The specific TβRI inhibitor SB431542 and TβRI siRNA abolished the SBOT3.1 invasion induced by TGF-β, and it prevented TGF-β-induced apoptosis in MPSC1 cells. In SBOT3.1 cells, TGF-β down-regulated E-cadherin and concurrently up-regulated N-cadherin. TGF-β up-regulated the expression of the transcriptional repressors of E-cadherin, Snail, Slug, Twist and ZEB1. In contrast, co-treatment with SB431542 and TβRI depletion by siRNA abolished the effects of TGF-β on the relative cadherin expression levels and that of Snail, Slug, Twist and ZEB1 as well. This study demonstrates dual TGF-β functions: the induction of SBOT cell invasion by EMT activation and apoptosis promotion in LGC cells.

  12. Patterns of ovarian and oestrous activity and induction of cyclic activity during the post-partum period in Egyptian buffaloes

    International Nuclear Information System (INIS)

    Aboul-Ela, M.B.; Shafie, M.M.

    1988-01-01

    This report covers three studies. In the first study, ovarian and oestrous activity were monitored in 47 buffaloes for 90 days following parturition. Failure to resume ovarian cyclicity after calving was found to be the main reason for the delay in conception. High incidence of ovulatory anoestrus (64%) constitutes also a major problem in Egyptian buffaloes. In the second study, buffaloes with inactive ovaries were treated at 90 days post-partum with either GnRH or progesterone, given either intravaginally (PRID) or orally (CAP). Both GnRH and PRID were effective in inducing ovulation but GnRH administration was followed by a high incidence of silent ovulation. Within the 35 days following treatment, about 50% of the PRID treated animals got in calf vs. 44 and 22% for GnRH and CAP treated animals, respectively. In the third study, buffaloes were treated with either 6 or 12μg GnRH at either 7 or 15 days post-partum. GnRH treatment resulted in significant reductions in the intervals from calving to first ovulation, first detected oestrus and time to first rise in serum progesterone concentration (> 1 ng/mL). (author). 26 refs, 5 figs, 4 tabs

  13. Intermedin suppresses pressure overload cardiac hypertrophy through activation of autophagy.

    Science.gov (United States)

    Chen, Huali; Wang, Xue; Tong, Mingming; Wu, Dan; Wu, Sisi; Chen, Jiaxiang; Wang, Xiaoxiao; Wang, Xulei; Kang, Yu; Tang, Hong; Tang, Chaoshu; Jiang, Wei

    2013-01-01

    Left ventricular hypertrophy is a maladaptive response to pressure overload and an important risk factor for heart failure. Intermedin (IMD), a multi-functional peptide, plays important roles in cardiovascular protection. In this study, we revealed an autophagy-dependent mechanism involved in IMD's protection against cardiac remodeling and cardiomyocyte death in heart hypertrophy. We observed that transverse aortic contraction (TAC) induction, Ang II or ISO exposure induced remarkable increase in the expression of endogenous IMD and its receptor components, CRLR, RAMP1 and RAMP3, in mouse hearts and H9c2 cell cultures, respectively. Furthermore, the heart size, heart weight/body weight ratios, cardiomyocyte size and apoptosis, interstitial collagen, hypertrophic markers including ANP and BNP expression were also significantly increased, which were effectively suppressed by IMD supplementation. In addition, IMD induced capillary angiogenesis and improved functions in hypertrophic hearts. We further observed that IMD induced strong autophagy in hypertrophic hearts and cultured cells, which was paralleling with the decrease in cardiomyocyte size and apoptosis. Furthermore, an autophagy inhibitor, 3-MA, was used to block the IMD-augmented autophagy level, and then the protection of IMD on cardiomyocyte hypertrophy and apoptosis was almost abrogated. We also observed that IMD supplementation stirred intracellular cAMP production, and augmented the ERK1/2 phosphorylation induced by Ang II/ISO exposure in H9c2 cells. In addition, we inhibited PI3K, PKA and MAPK/ERK1/2 signaling pathways by using wortamannin, H89 and PD98059, respectively, in H9c2 cells co-incubating with both IMD and Ang II or ISO, and observed that these inhibitors effectively reduced IMD-augmented autophagy level, but only H89 and PD98059 pre-incubation abrogated the anti-apoptotic action of IMD. These results indicate that the endogenous IMD and its receptor complexes are induced in hypertrophic

  14. Intermedin suppresses pressure overload cardiac hypertrophy through activation of autophagy.

    Directory of Open Access Journals (Sweden)

    Huali Chen

    Full Text Available Left ventricular hypertrophy is a maladaptive response to pressure overload and an important risk factor for heart failure. Intermedin (IMD, a multi-functional peptide, plays important roles in cardiovascular protection. In this study, we revealed an autophagy-dependent mechanism involved in IMD's protection against cardiac remodeling and cardiomyocyte death in heart hypertrophy. We observed that transverse aortic contraction (TAC induction, Ang II or ISO exposure induced remarkable increase in the expression of endogenous IMD and its receptor components, CRLR, RAMP1 and RAMP3, in mouse hearts and H9c2 cell cultures, respectively. Furthermore, the heart size, heart weight/body weight ratios, cardiomyocyte size and apoptosis, interstitial collagen, hypertrophic markers including ANP and BNP expression were also significantly increased, which were effectively suppressed by IMD supplementation. In addition, IMD induced capillary angiogenesis and improved functions in hypertrophic hearts. We further observed that IMD induced strong autophagy in hypertrophic hearts and cultured cells, which was paralleling with the decrease in cardiomyocyte size and apoptosis. Furthermore, an autophagy inhibitor, 3-MA, was used to block the IMD-augmented autophagy level, and then the protection of IMD on cardiomyocyte hypertrophy and apoptosis was almost abrogated. We also observed that IMD supplementation stirred intracellular cAMP production, and augmented the ERK1/2 phosphorylation induced by Ang II/ISO exposure in H9c2 cells. In addition, we inhibited PI3K, PKA and MAPK/ERK1/2 signaling pathways by using wortamannin, H89 and PD98059, respectively, in H9c2 cells co-incubating with both IMD and Ang II or ISO, and observed that these inhibitors effectively reduced IMD-augmented autophagy level, but only H89 and PD98059 pre-incubation abrogated the anti-apoptotic action of IMD. These results indicate that the endogenous IMD and its receptor complexes are induced in

  15. Insulin resistance enhances the mitogen-activated protein kinase signaling pathway in ovarian granulosa cells.

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    Linghui Kong

    Full Text Available The ovary is the main regulator of female fertility. Granulosa cell dysfunction may be involved in various reproductive endocrine disorders. Here we investigated the effect of insulin resistance on the metabolism and function of ovarian granulosa cells, and dissected the functional status of the mitogen-activated protein kinase signaling pathway in these cells. Our data showed that dexamethasone-induced insulin resistance in mouse granulosa cells reduced insulin sensitivity, accompanied with an increase in phosphorylation of p44/42 mitogen-activated protein kinase. Furthermore, up-regulation of cytochrome P450 subfamily 17 and testosterone and down-regulation of progesterone were observed in insulin-resistant mouse granulosa cells. Inhibition of p44/42 mitogen-activated protein kinase after induction of insulin resistance in mouse granulosa cells decreased phosphorylation of p44/42 mitogen-activated protein kinase, downregulated cytochrome P450 subfamily 17 and lowered progesterone production. This insulin resistance cell model can successfully demonstrate certain mechanisms such as hyperandrogenism, which may inspire a new strategy for treating reproductive endocrine disorders by regulating cell signaling pathways.

  16. Oestrous behaviour and ovarian activity in D'man and Sardi breeds of Moroccan sheep under normal and experimental photoperiods

    International Nuclear Information System (INIS)

    Lahlou-Kassi, A.; Boukhliq, R.

    1988-01-01

    The effect of photoperiod on sexual activity was investigated in Sardi and D'man ewes. Twenty ewes from each breed were subjected to an experimental photoperiod corresponding to latitude 56 deg. N. Control ewes (12 per breed) were maintained under natural photoperiod (32 deg. N). Behavioural oestrus and ovarian activity were monitored using penis deviated rams and plasma progesterone levels. Preliminary results from this study show that an increase in amplitude of photoperiod variations causes a decrease in the expression of oestrous behaviour in D'man ewes during the period of decreasing daylight. Ovarian activity remained unchanged. Sardi ewes were not markedly affected by change in photoperiod. (author). 13 refs, 3 figs, 1 tab

  17. Polyunsaturated fatty acids induce ovarian cancer cell death through ROS-dependent MAP kinase activation.

    Science.gov (United States)

    Tanaka, Aiko; Yamamoto, Akane; Murota, Kaeko; Tsujiuchi, Toshifumi; Iwamori, Masao; Fukushima, Nobuyuki

    2017-11-04

    Free fatty acids not only play a role in cell membrane construction and energy production but also exert diverse cellular effects through receptor and non-receptor mechanisms. Moreover, epidemiological and clinical studies have so far suggested that polyunsaturated fatty acids (PUFAs) could have health benefits and the advantage as therapeutic use in cancer treatment. However, the underlying mechanisms of PUFA-induced cellular effects remained to be cleared. Here, we examined the effects of ω-3 and ω-6 PUFAs on cell death in ovarian cancer cell lines. ω-3 PUFA, docosahexaenoic acid (DHA) and ω-6 PUFA, γ-linolenic acid (γ-LNA) induced cell death in KF28 cells at the levels of physiological concentrations, but not HAC2 cells. Pharmacological and biochemical analyses demonstrated that cell death induced by DHA and γ-LNA was correlated with activation of JNK and p38 MAP kinases, and further an upstream MAP kinase kinase, apoptosis signal-regulating kinase 1, which is stimulated by reactive oxygen species (ROS). Furthermore, an antioxidant vitamin E attenuated PUFA-induced cell death and MAP kinase activation. These findings indicate that PUFA-induced cell death involves ROS-dependent MAP kinase activation and is a cell type-specific action. A further study of the underlying mechanisms for ROS-dependent cell death induced by PUFAs will lead to the discovery of a new target for cancer therapy or diagnosis. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms.

    Science.gov (United States)

    Mackenzie, Robertson; Kommoss, Stefan; Winterhoff, Boris J; Kipp, Benjamin R; Garcia, Joaquin J; Voss, Jesse; Halling, Kevin; Karnezis, Anthony; Senz, Janine; Yang, Winnie; Prigge, Elena-Sophie; Reuschenbach, Miriam; Doeberitz, Magnus Von Knebel; Gilks, Blake C; Huntsman, David G; Bakkum-Gamez, Jamie; McAlpine, Jessica N; Anglesio, Michael S

    2015-05-19

    Mucinous ovarian tumors represent a distinct histotype of epithelial ovarian cancer. The rarest (2-4 % of ovarian carcinomas) of the five major histotypes, their genomic landscape remains poorly described. We undertook hotspot sequencing of 50 genes commonly mutated in human cancer across 69 mucinous ovarian tumors. Our goals were to establish the overall frequency of cancer-hotspot mutations across a large cohort, especially those tumors previously thought to be "RAS-pathway alteration negative", using highly-sensitive next-generation sequencing as well as further explore a small number of cases with apparent heterogeneity in RAS-pathway activating alterations. Using the Ion Torrent PGM platform, we performed next generation sequencing analysis using the v2 Cancer Hotspot Panel. Regions of disparate ERBB2-amplification status were sequenced independently for two mucinous carcinoma (MC) cases, previously established as showing ERBB2 amplification/overexpression heterogeneity, to assess the hypothesis of subclonal populations containing either KRAS mutation or ERBB2 amplification independently or simultaneously. We detected mutations in KRAS, TP53, CDKN2A, PIK3CA, PTEN, BRAF, FGFR2, STK11, CTNNB1, SRC, SMAD4, GNA11 and ERBB2. KRAS mutations remain the most frequently observed alteration among MC (64.9 %) and mucinous borderline tumors (MBOT) (92.3 %). TP53 mutation occurred more frequently in carcinomas than borderline tumors (56.8 % and 11.5 %, respectively), and combined IHC and mutation data suggest alterations occur in approximately 68 % of MC and as many as 20 % of MBOT. Proven and potential RAS-pathway activating changes were observed in all but one MC. Concurrent ERBB2 amplification and KRAS mutation were observed in a substantial number of cases (7/63 total), as was co-occurrence of KRAS and BRAF mutations (one case). Microdissection of ERBB2-amplified regions of tumors harboring KRAS mutation suggests these alterations are occurring in the same cell

  19. Suppression of cancer stemness p21-regulating mRNA and microRNA signatures in recurrent ovarian cancer patient samples

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    Gallagher Michael F

    2012-01-01

    Full Text Available Abstract Background Malignant ovarian disease is characterised by high rates of mortality due to high rates of recurrent chemoresistant disease. Anecdotal evidence indicates this may be due to chemoresistant properties of cancer stem cells (CSCs. However, our understanding of the role of CSCs in recurrent ovarian disease remains sparse. In this study we used gene microarrays and meta-analysis of our previously published microRNA (miRNA data to assess the involvement of cancer stemness signatures in recurrent ovarian disease. Methods Microarray analysis was used to characterise early regulation events in an embryonal carcinoma (EC model of cancer stemness. This was then compared to our previously published microarray data from a study of primary versus recurrent ovarian disease. In parallel, meta-analysis was used to identify cancer stemness miRNA signatures in tumor patient samples. Results Microarray analysis demonstrated a 90% difference between gene expression events involved in early regulation of differentiation in murine EC (mEC and embryonic stem (mES cells. This contrasts the known parallels between mEC and mES cells in the undifferentiated and well-differentiated states. Genelist comparisons identified a cancer stemness signature set of genes in primary versus recurrent data, a subset of which are known p53-p21 regulators. This signature is present in primary and recurrent or in primary alone but essentially never in recurrent tumors specifically. Meta-analysis of miRNA expression showed a much stronger cancer stemness signature within tumor samples. This miRNA signature again related to p53-p21 regulation and was expressed prominently in recurrent tumors. Our data indicate that the regulation of p53-p21 in ovarian cancer involves, at least partially, a cancer stemness component. Conclusion We present a p53-p21 cancer stemness signature model for ovarian cancer. We propose that this may, at least partially, differentially regulate the p

  20. Suppression of Cancer Stemness p21-regulating mRNA and microRNA Signatures in Recurrent Ovarian Cancer Patient Samples

    LENUS (Irish Health Repository)

    Gallagher, Michael F

    2012-01-19

    Abstract Background Malignant ovarian disease is characterised by high rates of mortality due to high rates of recurrent chemoresistant disease. Anecdotal evidence indicates this may be due to chemoresistant properties of cancer stem cells (CSCs). However, our understanding of the role of CSCs in recurrent ovarian disease remains sparse. In this study we used gene microarrays and meta-analysis of our previously published microRNA (miRNA) data to assess the involvement of cancer stemness signatures in recurrent ovarian disease. Methods Microarray analysis was used to characterise early regulation events in an embryonal carcinoma (EC) model of cancer stemness. This was then compared to our previously published microarray data from a study of primary versus recurrent ovarian disease. In parallel, meta-analysis was used to identify cancer stemness miRNA signatures in tumor patient samples. Results Microarray analysis demonstrated a 90% difference between gene expression events involved in early regulation of differentiation in murine EC (mEC) and embryonic stem (mES) cells. This contrasts the known parallels between mEC and mES cells in the undifferentiated and well-differentiated states. Genelist comparisons identified a cancer stemness signature set of genes in primary versus recurrent data, a subset of which are known p53-p21 regulators. This signature is present in primary and recurrent or in primary alone but essentially never in recurrent tumors specifically. Meta-analysis of miRNA expression showed a much stronger cancer stemness signature within tumor samples. This miRNA signature again related to p53-p21 regulation and was expressed prominently in recurrent tumors. Our data indicate that the regulation of p53-p21 in ovarian cancer involves, at least partially, a cancer stemness component. Conclusion We present a p53-p21 cancer stemness signature model for ovarian cancer. We propose that this may, at least partially, differentially regulate the p53-p21

  1. Expression of activated PIK3CA in ovarian surface epithelium results in hyperplasia but not tumor formation.

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    Shun Liang

    Full Text Available The Phosphatidylinositol 3'-kinase is a key regulator in various cancer-associated signal transduction pathways. Genetic alterations of its catalytic subunit alpha, PIK3CA, have been identified in ovarian cancer. Our in vivo data suggests that PIK3CA activation is one of the early genetic events in ovarian cancer. However, its role in malignant transformation of ovarian surface epithelium (OSE is largely unclear.Using the Müllerian inhibiting substance type II receptor (MISIIR promoter, we generated transgenic mice that expressed activated PIK3CA in the Müllerian epithelium. Overexpression of PIK3CA in OSE induced remarkable hyperplasia, but was not able to malignantly transform OSE in vivo. The consistent result was also observed in primary cultured OSEs. Although enforced expression of PIK3CA could not induce OSE anchorage-independent growth, it significantly increased anchorage-independent growth of OSE transformed by mutant K-ras.While PIK3CA activation may not be able to initiate OSE transformation, we conclude that activation of PIK3CA may be an important molecular event contributing to the maintenance of OSE transformation initiated by oncogenes such as K-ras.

  2. HMGB1 enhances immune suppression by facilitating the differentiation and suppressive activity of myeloid-derived suppressor cells.

    Science.gov (United States)

    Parker, Katherine H; Sinha, Pratima; Horn, Lucas A; Clements, Virginia K; Yang, Huan; Li, Jianhua; Tracey, Kevin J; Ostrand-Rosenberg, Suzanne

    2014-10-15

    Chronic inflammation often precedes malignant transformation and later drives tumor progression. Likewise, subversion of the immune system plays a role in tumor progression, with tumoral immune escape now well recognized as a crucial hallmark of cancer. Myeloid-derived suppressor cells (MDSC) are elevated in most individuals with cancer, where their accumulation and suppressive activity are driven by inflammation. Thus, MDSCs may define an element of the pathogenic inflammatory processes that drives immune escape. The secreted alarmin HMGB1 is a proinflammatory partner, inducer, and chaperone for many proinflammatory molecules that MDSCs develop. Therefore, in this study, we examined HMGB1 as a potential regulator of MDSCs. In murine tumor systems, HMGB1 was ubiquitous in the tumor microenvironment, activating the NF-κB signal transduction pathway in MDSCs and regulating their quantity and quality. We found that HMGB1 promotes the development of MDSCs from bone marrow progenitor cells, contributing to their ability to suppress antigen-driven activation of CD4(+) and CD8(+) T cells. Furthermore, HMGB1 increased MDSC-mediated production of IL-10, enhanced crosstalk between MDSCs and macrophages, and facilitated the ability of MDSCs to downregulate expression of the T-cell homing receptor L-selectin. Overall, our results revealed a pivotal role for HMGB1 in the development and cancerous contributions of MDSCs. ©2014 American Association for Cancer Research.

  3. Quercetin suppresses DNA double-strand break repair and enhances the radiosensitivity of human ovarian cancer cells via p53-dependent endoplasmic reticulum stress pathway

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    Gong C

    2017-12-01

    Full Text Available Cheng Gong,1 Zongyuan Yang,1 Lingyun Zhang,2 Yuehua Wang,2 Wei Gong,2 Yi Liu3 1Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 2Department of Oncology, XiangYang Central Hospital, Hubei University of Arts and Science, XiangYang, 3Department of Medicinal Chemistry, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China Abstract: Quercetin is proven to have anticancer effects for many cancers. However, the role of tumor suppressor p53 on quercetin’s radiosensitization and regulation of endoplasmic reticulum (ER stress response in this process remains obscure. Here, quercetin exposure resulted in ER stress, prolonged DNA repair, and the expression of p53 protein; phosphorylation on serine 15 and 20 increased in combination with X-irradiation. Quercetin pretreatment could potentiate radiation-induced cell death. The combination of irradiation and quercetin treatment aggravated DNA damages and caused typical apoptotic cell death; as well the expression of Bax and p21 elevated and the expression of Bcl-2 decreased. Knocking down of p53 could reverse all the above effects under quercetin in combination with radiation. In addition, quercetin-induced radiosensitization was through stimulation of ATM phosphorylation. In human ovarian cancer xenograft model, combined treatment of quercetin and radiation significantly restrained the growth of tumors, accompanied with the activation of p53, CCAAT/enhancer-binding protein homologous protein, and γ-H2AX. Overall, these results indicated that quercetin acted as a promising radiosensitizer through p53-dependent ER stress signals. Keywords: quercetin, p53, endoplasmic reticulum stress, DNA double-strand breaks, eIF-2α (eukaryotic initiation factor 2α, ATM kinase

  4. Guanylate cyclase activator YC-1 potentiates apoptotic effect of licochalcone A on human epithelial ovarian carcinoma cells via activation of death receptor and mitochondrial pathways.

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    Lee, Chung Soo; Kwak, Sang Won; Kim, Yun Jeong; Lee, Seon Ae; Park, Eon Sob; Myung, Soon Chul; Kim, Wonyong; Lee, Min Sung; Lee, Jeong Jae

    2012-05-15

    Natural phenol licorice compounds have been shown to induce apoptosis in cancer cells. 3-(5'-Hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) may enhance the sensitivity of cancer cells to anticancer drugs. However, the combined effect of licochalcone A and YC-1 on cell death in ovarian cancer cells has not been studied. We assessed the combined effect of licochalcone A and YC-1 on apoptosis in human epithelial ovarian carcinoma cell lines in relation to the cell death process. In the OVCAR-3 and SK-OV-3 cell lines, licochalocone A induced a decrease in Bid, Bcl-2, Bcl-xL and survivin protein levels; an increase in Bax levels; loss of the mitochondrial transmembrane potential; cytochrome c release; activation of caspases (-8, -9 and -3); cleavage of PARP-1; and an increase in the tumor suppressor p53 levels. YC-1 enhanced licochalcone A-induced apoptosis-related protein activation, nuclear damage and cell death. These results suggest that YC-1 may potentiate the apoptotic effect of licochalcone A on ovarian carcinoma cell lines by increasing the activation of the caspase-8- and Bid-dependent pathway and the mitochondria-mediated apoptotic pathway, leading to caspase activation. The combination of licochalcone A and YC-1 may confer a benefit in the treatment of human epithelial ovarian adenocarcinoma. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Delphinidin inhibits BDNF-induced migration and invasion in SKOV3 ovarian cancer cells.

    Science.gov (United States)

    Lim, Won-Chul; Kim, Hyunhee; Kim, Young-Joo; Park, Seung-Ho; Song, Ji-Hye; Lee, Ki Heon; Lee, In Ho; Lee, Yoo-Kyung; So, Kyeong A; Choi, Kyung-Chul; Ko, Hyeonseok

    2017-12-01

    Brain-derived neurotrophic factor (BDNF), the TrkB ligand, is associated with aggressive malignant behavior, including migration and invasion, in tumor cells and a poor prognosis in patients with various types of cancer. Delphinidin is a diphenylpropane-based polyphenolic ring structure-harboring compound, which exhibits a wide range of pharmacological activities, anti-tumor, anti-oxidant, anti-inflammatory, anti-angiogenic and anti-mutagenic activity. However, the possible role of delphinidin in the cancer migration and invasion is unclear. We investigated the suppressive effect of delphinidin on the cancer migration and invasion. Thus, we found that BDNF enhanced cancer migration and invasion in SKOV3 ovarian cancer cell. To exam the inhibitory role of delphinidin in SKOV3 ovarian cancer migration and invasion, we investigated the use of delphinidin as inhibitors of BDNF-induced motility and invasiveness in SKOV3 ovarian cancer cells in vitro. Here, we found that delphinidin prominently inhibited the BDNF-induced increase in cell migration and invasion of SKOV3 ovarian cancer cells. Furthermore, delphinidin remarkably inhibited BDNF-stimulated expression of MMP-2 and MMP-9. Also, delphinidin antagonized the phosphorylation of Akt and nuclear translocation of NF-κB permitted by the BDNF in SKOV3 ovarian cancer cells. Taken together, our findings provide new evidence that delphinidin suppressed the BDNF-induced ovarian cancer migration and invasion through decreasing of Akt activation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. The anti-tumor effect and bioactive phytochemicals of Hedyotis diffusa willd on ovarian cancer cells.

    Science.gov (United States)

    Zhang, Lin; Zhang, Jing; Qi, Bing; Jiang, Guoqiang; Liu, Jia; Zhang, Pei; Ma, Yuan; Li, Weiling

    2016-11-04

    Hedyotis diffusa willd (HDW) is a widely used medicinal herb in China. It processed various medicinal properties including antioxidative, anti-inflamatory and anti-cancer effects. This study aimed to investigate the anti-tumor effects of HDW on ovarian cancer cells and the underlying mechanisms as well as identify the bioactive compounds. Effects of HDW on the viability of ovarian cancer A2780 cells were detected by MTT assay. Apoptosis was detected by cell morphologic observation through DAPI staining and flow cytometry analysis. The migration of ovarian cancer cells which exposed to HDW were detected by wound healing and transwell assays. The protein levels of caspase 3/9, Bcl-2 and MMP-2/9 in human ovarian cancer cells treated with HDW were assessed by western blotting analysis. The potential bioactive compounds were characterized by HPLC-Q-TOF-MS. HDW significantly inhibited the growth of A2780 ovarian cancer cells and induced apoptosis. The induction of apoptosis by HDW was associated with down-regulation of anti-apoptotic protein Bcl-2 and the activation of caspase 3/9. Wound healing and transwell chamber assays indicated HDW suppressed the migration of ovarian cancer cells. HDW dramatically decreased MMP-2/9 expression. A HPLC-Q-TOF-MS analysis of HDW indicated the presence of 13 flavonoids compounds and one anthraquinone compound, which may contribute to the anticancer activity of the HDW. HDW effectively restricted the growth of ovarian cancer cells and induced apoptosis through the mitochondria-associated apoptotic pathway. Furthermore, HDW suppressed the migration of ovarian cancer cells through down-regulation of MMP-2 and MMP-9 expression. These results showed that HDW hold potential therapeutic effect for ovarian cancer patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. Ovarian activity and embryo yield in relation to the postpartum period in superovulated dairy cows

    Directory of Open Access Journals (Sweden)

    Luděk Stádník

    2017-01-01

    Full Text Available The aim of this study was to evaluate superovulation response in cows at various postpartum periods (early postpartum period up to 3.5 months; middle postpartum period 3.7–7 months; later postpartum period above 7.5 months after calving. The data included observation of 55 Holstein cows superovulated at one farm in the Czech Republic during the years 2010 and 2013. Reproduction traits (dependent variable were represented as number of the corpora lutea, number of transferable embryos, morulae, blastocysts, total number of embryos and embryo recovery. For statistical evaluation we used the PROC GLM of SAS® with fixed effect - breeding value of milk production. The study results show significant differences (P < 0.05–0.01 in the three postpartum periods (early, middle, and later postpartum periods and the number of corpora lutea (4.6; 7.4; 10.8, number of total embryos (3.2; 2.9; 6.5 and transferable embryos (1.8; 1.7; 4.4. Effective timing of embryo transfer in the later postpartum period resulted in greater ovarian activity and embryo yield compared to early lactation periods.

  8. Platelet activating factor receptor binding plays a critical role in jet fuel-induced immune suppression

    International Nuclear Information System (INIS)

    Ramos, Gerardo; Kazimi, Nasser; Nghiem, Dat X.; Walterscheid, Jeffrey P.; Ullrich, Stephen E.

    2004-01-01

    Applying military jet fuel (JP-8) or commercial jet fuel (Jet-A) to the skin of mice suppresses the immune response in a dose-dependant manner. The release of biological response modifiers, particularly prostaglandin E 2 (PGE 2 ), is a critical step in activating immune suppression. Previous studies have shown that injecting selective cyclooxygenase-2 inhibitors into jet fuel-treated mice blocks immune suppression. Because the inflammatory phospholipid mediator, platelet-activating factor (PAF), up-regulates cyclooxygenase-2 production and PGE 2 synthesis by keratinocytes, we tested the hypothesis that PAF-receptor binding plays a role in jet fuel-induced immune suppression. Treating keratinocyte cultures with PAF and/or jet fuel (JP-8 and Jet-A) stimulates PGE 2 secretion. Jet fuel-induced PGE 2 production was suppressed by treating the keratinocytes with specific PAF-receptor antagonists. Injecting mice with PAF, or treating the skin of the mice with JP-8, or Jet-A, induced immune suppression. Jet fuel-induced immune suppression was blocked when the jet fuel-treated mice were injected with PAF-receptor antagonists before treatment. Jet fuel treatment has been reported to activate oxidative stress and treating the mice with anti-oxidants (Vitamins C, or E or beta-hydroxy toluene), before jet fuel application, interfered with immune suppression. These findings confirm previous studies showing that PAF-receptor binding can modulate immune function. Furthermore, they suggest that PAF-receptor binding may be an early event in the induction of immune suppression by immunotoxic environmental agents that target the skin

  9. Active Suppression of Drilling System Vibrations For Deep Drilling

    Energy Technology Data Exchange (ETDEWEB)

    Raymond, David W.; Blankenship, Douglas A.; Buerger, Stephen; Mesh, Mikhail; Radigan, William Thomas; Su, Jiann-Cherng

    2015-10-01

    The dynamic stability of deep drillstrings is challenged by an inability to impart controllability with ever-changing conditions introduced by geology, depth, structural dynamic properties and operating conditions. A multi-organizational LDRD project team at Sandia National Laboratories successfully demonstrated advanced technologies for mitigating drillstring vibrations to improve the reliability of drilling systems used for construction of deep, high-value wells. Using computational modeling and dynamic substructuring techniques, the benefit of controllable actuators at discrete locations in the drillstring is determined. Prototype downhole tools were developed and evaluated in laboratory test fixtures simulating the structural dynamic response of a deep drillstring. A laboratory-based drilling applicability demonstration was conducted to demonstrate the benefit available from deployment of an autonomous, downhole tool with self-actuation capabilities in response to the dynamic response of the host drillstring. A concept is presented for a prototype drilling tool based upon the technical advances. The technology described herein is the subject of U.S. Patent Application No. 62219481, entitled "DRILLING SYSTEM VIBRATION SUPPRESSION SYSTEMS AND METHODS", filed September 16, 2015.

  10. Active vertical tail buffeting suppression based on macro fiber composites

    Science.gov (United States)

    Zou, Chengzhe; Li, Bin; Liang, Li; Wang, Wei

    2016-04-01

    Aerodynamic buffet is unsteady airflow exerting forces onto a surface, which can lead to premature fatigue damage of aircraft vertical tail structures, especially for aircrafts with twin vertical tails at high angles of attack. In this work, Macro Fiber Composite (MFC), which can provide strain actuation, was used as the actuator for the buffet-induced vibration control, and the positioning of the MFC patches was led by the strain energy distribution on the vertical tail. Positive Position Feedback (PPF) control algorithm has been widely used for its robustness and simplicity in practice, and consequently it was developed to suppress the buffet responses of first bending and torsional mode of vertical tail. However, its performance is usually attenuated by the phase contributions from non-collocated sensor/actuator configuration and plants. The phase lag between the input and output signals of the control system was identified experimentally, and the phase compensation was considered in the PPF control algorithm. The simulation results of the amplitude frequency of the closed-loop system showed that the buffet response was alleviated notably around the concerned bandwidth. Then the wind tunnel experiment was conducted to verify the effectiveness of MFC actuators and compensated PPF, and the Root Mean Square (RMS) of the acceleration response was reduced 43.4%, 28.4% and 39.5%, respectively, under three different buffeting conditions.

  11. Preliminary studies on LED-activated pyropheophorbide-α methyl ester killing cisplatin-resistant ovarian carcinoma cells

    Science.gov (United States)

    Tan, Yong; Xu, Chuan Shan; Xia, Xin Shu; Yu, He Ping; Bai, Ding Qun; He, Yong; Xu, Jing; Wang, Ping; Wang, Xin Na; Leung, Albert Wing Nang

    2009-05-01

    In the present study, a novel LED source was applied for activating pyropheophorbids-a methyl ester (MPPa) in cisplatin-resistant ovarian cell line COC1/DDP cells. MPPa concentration was 2 μM and light energy from 0.125-8 J/cm2. Cytotoxicity was investigated 24 h using MTT reduction assay and light microscopy after treatment. Cellular ultrastructure was observed using transmission electron microscopy (TEM) and nuclear chromatin by fluorescent microscope with Hoechst33258 staining. MTT reduction assay showed that the cytotoxicity of LED-activated MPPa in the COC1/DDP cells increased along with the light dose of LED source and LED-activated MPPa resulted in light-dependent cytotoxicity. The observations from light microscopy reinforced the above results. TEM showed that necrotic cells with the disruption of karyotheca, karyorrhexis, and karyolysis of nucleus and apoptotic cells, especially the apoptotic body, can be seen post LED-activated MPPa. Hoechst33258 staining showed that condensation of chromatin and nuclear fragmentations could be found in many treated cells and some of them formed the structure of apoptotic bodies when COC1/DDP cells were exposed to 2 μM MPPa for 20 h and then 1 J/cm2 irradiation of LED source. The findings demonstrated that the novel LED source could efficiently activated MPPa and LED-activated MPPa could significantly kill cisplatin-resistant ovarian cell line COC1/DDP cells through two major pathways including necrosis and apoptosis, suggesting that LED is a novel and efficient light source and LED-activated MPPa might be potential therapeutic modality for treating cisplatin-resistant ovarian carcinoma.

  12. Protein phosphatase 2A associates with Rb2/p130 and mediates retinoic acid-induced growth suppression of ovarian carcinoma cells

    DEFF Research Database (Denmark)

    Vuocolo, Scott; Purev, Enkhtsetseg; Zhang, Dongmei

    2003-01-01

    following ATRA treatment. Finally, using both small interfering RNA specific to the catalytic subunit of PP2A and a variant of the SKOV3 cell line that overexpresses PP2A, we have shown that modulation of PP2A protein levels correlates with the ability of ATRA to inhibit growth of ovarian carcinoma cells......Levels of Rb2/p130 protein are increased 5-10-fold following all-trans-retinoic acid (ATRA) treatment of the retinoid-sensitive ovarian adenocarcinoma cell line CAOV3, but not the retinoid-resistant adenocarcinoma cell line SKOV3. We found that this increase in Rb2/p130 protein levels in ATRA...

  13. Withaferin a alone and in combination with cisplatin suppresses growth and metastasis of ovarian cancer by targeting putative cancer stem cells.

    Directory of Open Access Journals (Sweden)

    Sham S Kakar

    Full Text Available Currently, the treatment for ovarian cancer entails cytoreductive surgery followed by chemotherapy, mainly, carboplatin combined with paclitaxel. Although this regimen is initially effective in a high percentage of cases, unfortunately within few months of initial treatment, tumor relapse occurs because of platinum-resistance. This is attributed to chemo-resistance of cancer stem cells (CSCs. Herein we show for the first time that withaferin A (WFA, a bioactive compound isolated from the plant Withania somnifera, when used alone or in combination with cisplatin (CIS targets putative CSCs. Treatment of nude mice bearing orthotopic ovarian tumors generated by injecting human ovarian epithelial cancer cell line (A2780 with WFA and cisplatin (WFA alone or in combination resulted in a 70 to 80% reduction in tumor growth and complete inhibition of metastasis to other organs compared to untreated controls. Histochemical and Western blot analysis of the tumors revealed that inclusion of WFA (2 mg/kg resulted in a highly significant elimination of cells expressing CSC markers - CD44, CD24, CD34, CD117 and Oct4 and downregulation of Notch1, Hes1 and Hey1 genes. In contrast treatment of mice with CIS alone (6 mg/kg had opposite effect on those cells. Increase in cells expressing CSC markers and Notch1 signaling pathway in tumors exposed to CIS may explain recurrence of cancer in patients treated with carboplatin and paclitaxel. Since, WFA alone or in combination with CIS eliminates putative CSCs, we conclude that WFA in combination with CIS may present more efficacious therapy for ovarian cancer.

  14. p21 promotes oncolytic adenoviral activity in ovarian cancer and is a potential biomarker

    Directory of Open Access Journals (Sweden)

    Lockley Michelle

    2010-07-01

    Full Text Available Abstract The oncolytic adenovirus dl922-947 replicates selectively within and lyses cells with a dysregulated Rb pathway, a finding seen in > 90% human cancers. dl922-947 is more potent than wild type adenovirus and the E1B-deletion mutant dl1520 (Onyx-015. We wished to determine which host cell factors influence cytotoxicity. SV40 large T-transformed MRC5-VA cells are 3-logs more sensitive to dl922-947 than isogenic parental MRC5 cells, confirming that an abnormal G1/S checkpoint increases viral efficacy. The sensitivity of ovarian cancer cells to dl922-947 varied widely: IC50 values ranged from 51 (SKOV3ip1 to 0.03 pfu/cell (TOV21G. Cells sensitive to dl922-947 had higher S phase populations and supported earlier E1A expression. Cytotoxicity correlated poorly with both infectivity and replication, but well with expression of p21 by microarray and western blot analyses. Matched p21+/+ and -/- Hct116 cells confirmed that p21 influences dl922-947 activity in vitro and in vivo. siRNA-mediated p21 knockdown in sensitive TOV21G cells decreases E1A expression and viral cytotoxicity, whilst expression of p21 in resistant A2780CP cells increases virus activity in vitro and in intraperitoneal xenografts. These results highlight that host cell factors beyond simple infectivity can influence the efficacy of oncolytic adenoviruses. p21 expression may be an important biomarker of response in clinical trials.

  15. Extinction cross-section suppression and active acoustic invisibility cloaking

    Science.gov (United States)

    Mitri, F. G.

    2017-10-01

    Invisibility in its canonical form requires rendering a zero extinction cross-section (or energy efficiency) from an active or a passive object. This work demonstrates the successful theoretical realization of this physical effect for an active cylindrically radiating acoustic body, undergoing periodic axisymmetric harmonic vibrations near a flat rigid boundary. Radiating, amplification and extinction cross-sections of the active source are defined. Assuming monopole and dipole modal oscillations of the circular source, conditions are found where the extinction energy efficiency factor of the active source vanishes, achieving total invisibility with minimal influence of the source size. It also takes positive or negative values, depending on its size and distance from the boundary. Moreover, the amplification energy efficiency factor is negative for the acoustically-active source. These effects also occur for higher-order modal oscillations of the active source. The results find potential applications in the development of acoustic cloaking devices and invisibility.

  16. Optimizing outcomes from ovarian tissue cryopreservation and transplantation; activation versus preservation

    DEFF Research Database (Denmark)

    Meirow, Dror; Roness, Hadassa; Kristensen, Stine Gry

    2015-01-01

    Ovarian tissue cryopreservation and transplantation (OTCP) is gaining increasing traction in the field of fertility preservation as a result of accumulated successes. We now have a decade of experience with the technique, with tens of live births and greater than 90% return of ovarian function...... be generated in the immediate short term after transplantation. By contrast, conventional OTCP seeks to maintain dormancy and thus preserve the follicle reserve in the graft with the aim of maximizing graft lifespan. This opinion paper will compare the two methods of OTCP, highlighting their respective...

  17. Helminth induced suppression of macrophage activation is correlated with inhibition of calcium channel activity.

    Directory of Open Access Journals (Sweden)

    Arun Chauhan

    Full Text Available Helminth parasites cause persistent infections in humans and yet many infected individuals are asymptomatic. Neurocysticercosis (NCC, a disease of the central nervous system (CNS caused by the cestode Taenia solium, has a long asymptomatic phase correlated with an absence of brain inflammation. However, the mechanisms of immune suppression remain poorly understood. Here we report that murine NCC displays a lack of cell surface maturation markers in infiltrating myeloid cells. Furthermore, soluble parasite ligands (PL failed to induce maturation of macrophages, and inhibited TLR-induced inflammatory cytokine production. Importantly, PL treatment abolished both LPS and thapsigargin-induced store operated Ca2+ entry (SOCE. Moreover, electrophysiological recordings demonstrated PL-mediated inhibition of LPS or Tg-induced currents that were TRPC1-dependent. Concomitantly STIM1-TRPC1 complex was also impaired that was essential for SOCE and sustained Ca2+ entry. Likewise loss of SOCE due to PL further inhibited NFkB activation. Overall, our results indicate that the negative regulation of agonist induced Ca2+ signaling pathway by parasite ligands may be a novel immune suppressive mechanism to block the initiation of the inflammatory response associated with helminth infections.

  18. The interpretation of mu suppression as an index of mirror neuron activity: past, present and future

    Science.gov (United States)

    2017-01-01

    Mu suppression studies have been widely used to infer the activity of the human mirror neuron system (MNS) in a number of processes, ranging from action understanding, language, empathy and the development of autism spectrum disorders (ASDs). Although mu suppression is enjoying a resurgence of interest, it has a long history. This review aimed to revisit mu's past, and examine its recent use to investigate MNS involvement in language, social processes and ASDs. Mu suppression studies have largely failed to produce robust evidence for the role of the MNS in these domains. Several key potential shortcomings with the use and interpretation of mu suppression, documented in the older literature and highlighted by more recent reports, are explored here. PMID:28405354

  19. Osteoclast activated FoxP3+ CD8+ T-cells suppress bone resorption in vitro.

    Directory of Open Access Journals (Sweden)

    Zachary S Buchwald

    Full Text Available BACKGROUND: Osteoclasts are the body's sole bone resorbing cells. Cytokines produced by pro-inflammatory effector T-cells (T(EFF increase bone resorption by osteoclasts. Prolonged exposure to the T(EFF produced cytokines leads to bone erosion diseases such as osteoporosis and rheumatoid arthritis. The crosstalk between T-cells and osteoclasts has been termed osteoimmunology. We have previously shown that under non-inflammatory conditions, murine osteoclasts can recruit naïve CD8 T-cells and activate these T-cells to induce CD25 and FoxP3 (Tc(REG. The activation of CD8 T-cells by osteoclasts also induced the cytokines IL-2, IL-6, IL-10 and IFN-γ. Individually, these cytokines can activate or suppress osteoclast resorption. PRINCIPAL FINDINGS: To determine the net effect of Tc(REG on osteoclast activity we used a number of in vitro assays. We found that Tc(REG can potently and directly suppress bone resorption by osteoclasts. Tc(REG could suppress osteoclast differentiation and resorption by mature osteoclasts, but did not affect their survival. Additionally, we showed that Tc(REG suppress cytoskeletal reorganization in mature osteoclasts. Whereas induction of Tc(REG by osteoclasts is antigen-dependent, suppression of osteoclasts by Tc(REG does not require antigen or re-stimulation. We demonstrated that antibody blockade of IL-6, IL-10 or IFN-γ relieved suppression. The suppression did not require direct contact between the Tc(REG and osteoclasts. SIGNIFICANCE: We have determined that osteoclast-induced Tc(REG can suppress osteoclast activity, forming a negative feedback system. As the CD8 T-cells are activated in the absence of inflammatory signals, these observations suggest that this regulatory loop may play a role in regulating skeletal homeostasis. Our results provide the first documentation of suppression of osteoclast activity by CD8 regulatory T-cells and thus, extend the purview of osteoimmunology.

  20. Emergence of spatially heterogeneous burst suppression in a neural field model of electrocortical activity

    Directory of Open Access Journals (Sweden)

    Ingo eBojak

    2015-02-01

    Full Text Available Burst suppression in the electroencephalogram (EEG is a well described phenomenon that occurs during deep anaesthesia, as well as in a variety of congenital and acquired brain insults. Classically it is thought of as spatially synchronous, quasi-periodic bursts of high amplitude EEG separated by low amplitude activity. However, its characterisation as a ``global brain state'' has been challenged by recent results obtained with intracranial electrocortigraphy. Not only does it appear that burst suppression activity is highly asynchronous across cortex, but also that it may occur in isolated regions of circumscribed spatial extent. Here we outline a realistic neural field model for burst suppression by adding a slow process of synaptic resource depletion and recovery, which is able to reproduce qualitatively the empirically observed features during general anaesthesia at the whole cortex level. Simulations reveal heterogeneous bursting over the model cortex and complex spatiotemporal dynamics during simulated anaesthetic action, and provide forward predictions of neuroimaging signals for subsequent empirical comparisons and more detailed characterisation.Because burst suppression corresponds to a dynamical end-point of brain activity, theoretically accounting for its spatiotemporal emergence will vitally contribute to efforts aimed at clarifying whether a common physiological trajectory is induced by the actions of general anaesthetic agents. We have taken a first step in this direction by showing that a neural field model can qualitatively match recent experimental data that indicate spatial differentiation of burst suppression activity across cortex.

  1. Polyphenol derivatives inhibit human neutrophil activity by suppressing oxidative burst

    Czech Academy of Sciences Publication Activity Database

    Drábiková, K.; Perečko, T.; Nosáľ, R.; Harmatha, Juraj; Šmidrkal, J.; Jančinová, V.

    2012-01-01

    Roč. 5, Suppl.1 (2012), s. 31-31 ISSN 1337-6853. [Interdisciplinary Toxicological Conference & Advanced Toxicological Course /17./. 27.08.2012-31.08.2012, Stará Lesná] Institutional research plan: CEZ:AV0Z40550506 Keywords : polyphenol derivatives * neutrophil activity * pinosylvin Subject RIV: CC - Organic Chemistry

  2. Plasma progesterone profile and ovarian activity of forced-moult layers

    African Journals Online (AJOL)

    Owner

    2Department of Animal Science, University of Nigeria, Nsukka, Nigeria. Accepted 26 July.2005. Different techniques of ... associated with reduced levels of luteinizing hormone and sex steroids. The major changes ... population were slaughtered and their ovaries were removed and weighed. The ovarian weights were taken ...

  3. Ad-PUMA sensitizes ovarian cancer cells to chemotherapeutic agents.

    Science.gov (United States)

    Luan, Q-C; Sun, Y-R; Han, P; Chen, Y

    2015-12-01

    Ovarian cancer accounted for the first cause of death in female reproductive system tumor even with the operation and chemotherapy. We sought to evaluate the therapeutic potential of p53 up-regulated modulator of apoptosis (PUMA) in ovarian cancer. An adenovirus expressing PUMA (Ad-PUMA), alone or in combination with chemotherapeutic agents, was used to treat two different ovarian cancer cell lines. The mechanism of PUMA-mediated growth suppression and apoptosis was investigated by analysis of caspase-9 activation and the change of mitochondrial membrane potential (Δψm). The exogenous PUMA was expressed 6 h after Ad-PUMA infection, which increased the chemosensitivity of the cancer cells and decreased the IC50 of chemotherapeutic agents compared with uninfected cells. The apoptotic percentage of OVCAR-3 and SKOV3 increased greatly compared with Taxol or Cisplatin alone. There was shear zone in caspase-9 and Δψm decrease after Ad-PUMA infection which suggested apoptosis started in mitochondrial mediated pathway. PUMA plays a role in suppressing tumor growth and sensitizing ovarian cancer cells to anticancer drugs and may be a promising tool for cancer biotherapy.

  4. Active power filter equivalent to an infinite feeder for harmonic suppression in radial distribution systems

    DEFF Research Database (Denmark)

    Shen, Hong; Yang, Lili; Sun, Xiaofeng

    2016-01-01

    This study proposes to install a novel active power filter (IF-APF) mimicking the character of an infinitely long transmission line at the end of a radial feeder. The proposed IF-APF eliminates the reflected wave and realises the background harmonic voltage suppression capability throughout...... the feeder by mimicking the characteristic of an infinite feeder. The proposed IF-APF shows a better harmonic damping performance than the traditional resistive active power filter (R-APF). Moreover, the proposed IF-APF achieves a better harmonic suppression performance than the traditional R-APF, especially...

  5. Dopa therapy and action impulsivity: subthreshold error activation and suppression in Parkinson's disease.

    Science.gov (United States)

    Fluchère, Frédérique; Deveaux, Manon; Burle, Borís; Vidal, Franck; van den Wildenberg, Wery P M; Witjas, Tatiana; Eusebio, Alexandre; Azulay, Jean-Philippe; Hasbroucq, Thierry

    2015-05-01

    Impulsive actions entail (1) capture of the motor system by an action impulse, which is an urge to act and (2) failed suppression of that impulse in order to prevent a response error. Several studies indicate that dopaminergic treatment can induce action impulsivity in patients diagnosed with Parkinson's disease (PD). Whether this effect is due to increased impulse expression or to decreased impulse suppression remains to be deciphered. We used a novel approach based on electromyographic (EMG) analyses to decipher the effects of the patient's usual dopaminergic therapy on the expression and suppression of subliminal erroneous impulses. To this end, we used a within-subject design and took advantage of the Simon task, that elicits prepotent response tendencies. The patients (N = 15) performed the task on their usual dopaminergic medication and after complete medication withdrawal (for at least 12 h). The correction rate that measures the ability to suppress subthreshold impulsive muscle activity was lower when the patients were on medication as compared to their off medication state (p < 0.05). The incorrect activation rate that measures the capture of the motor system by action impulses was unaffected by medication. Dopa therapy affected action impulsivity. Although medication did not influence the incidence of fast action impulses, it significantly reduced patients' ability to abort and suppress muscle activation related to the incorrect response alternative.

  6. Phase II activity of belinostat (PXD-101), carboplatin, and paclitaxel in women with previously treated ovarian cancer

    DEFF Research Database (Denmark)

    Dizon, Don S; Damstrup, Lars; Finkler, Neil J

    2012-01-01

    BACKGROUND: Preclinical data show that belinostat (Bel) is synergistic with carboplatin and paclitaxel in ovarian cancer. To further evaluate the clinical activity of belinostat, carboplatin, and paclitaxel (BelCaP), a phase 1b/2 study was performed, with an exploratory phase 2 expansion planned...... end point was overall response rate (ORR), using a Simon 2 stage design. RESULTS: The median age was 60 years (range, 39-80 years), and patients had received a median of 3 prior regimens (range, 1-4). Fifty-four percent had received more than two prior platinum-based combinations, sixteen patients (46...

  7. Therapeutic Strategies Against Cyclin E1 Amplified Ovarian Cancers

    Science.gov (United States)

    2017-10-01

    hypothesize that HSP90-inhibitors may be effective against CCNE1-amplified ovarian tumors because they suppress HR, downregulate BRCA1, and...of FOXM1 and RB interaction is an effective approach for targeting CCNE1-amplified ovarian tumors . Specifically, suppression of FOXM1/RB...cells. In the third aim, we hypothesize that miR-1255b, miR-148b*, and miR-193b* may be effective against CCNE1- amplified ovarian tumors in

  8. Suppression of leukocyte inhibitory factor (LIF) production and [3H]thymidine incorporation by concanavalin A-activated mononuclear cells

    International Nuclear Information System (INIS)

    Lomnitzer, R.; Rabson, A.R.

    1979-01-01

    The capacity of human mononuclear (MN) cells pretreated with concanavalin A (Con A) to suppress the activity of fresh phytohemagglutinin (PHA)-pulsed mononuclear cells was assessed. Con A-pretreated MN cells suppressed leukocyte inhibitory factor (LIF) activity in supernatants of PHA-pulsed cell cultures and [ 3 H]thymidine incorporation by these cells. Suppression was obtained in both allogeneic and autologous systems with mitomycin-treated, irradiated, or untreated Con A-induced cells. Lymphocytes from two patients that, following treatment with Con A, did not suppress mitogen-induced proliferative response of normal cells also did not suppress LIF production

  9. Natural mixtures of persistent organic pollutants (POPs) suppress ovarian follicle development, liver vitellogenin immunostaining and hepatocyte proliferation in female zebrafish (Danio rerio)

    Energy Technology Data Exchange (ETDEWEB)

    Kraugerud, Marianne, E-mail: Marianne.Kraugerud@nvh.no [Dept. of Basic Sciences and Aquatic Medicine, Norwegian School of Veterinary Science, POB 8146 Dep., 0033 Oslo (Norway); Doughty, Richard William, E-mail: vetrwdoughty@yahoo.co.uk [Sundveien 22, 2015 Leirsund (Norway); Lyche, Jan L., E-mail: Jan.Lyche@nvh.no [Dept. of Food Safety and Infection Biology, Norwegian School of Veterinary Science, POB 8146 Dep., 0033 Oslo (Norway); Berg, Vidar, E-mail: Vidar.Berg@nvh.no [Dept. of Food Safety and Infection Biology, Norwegian School of Veterinary Science, POB 8146 Dep., 0033 Oslo (Norway); Tremoen, Nina H., E-mail: Nina.Hardnes@nvh.no [Dept. of Production Animal Clinical Sciences, Norwegian School of Veterinary Science, POB 8146 Dep., 0033 Oslo (Norway); Alestrom, Peter, E-mail: Peter.Alestrom@nvh.no [Dept. of Basic Sciences and Aquatic Medicine, Norwegian School of Veterinary Science, POB 8146 Dep., 0033 Oslo (Norway); Aleksandersen, Mona, E-mail: Mona.Aleksandersen@nvh.no [Dept. of Basic Sciences and Aquatic Medicine, Norwegian School of Veterinary Science, POB 8146 Dep., 0033 Oslo (Norway); Ropstad, Erik, E-mail: Erik.Ropstad@nvh.no [Dept. of Production Animal Clinical Sciences, Norwegian School of Veterinary Science, POB 8146 Dep., 0033 Oslo (Norway)

    2012-07-15

    Persistent organic pollutants such as polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and dichlorodiphenyltrichloroethane (DDT) are present in high concentrations in livers of burbot (Lota lota) in Lake Mjosa, Norway. In order to assess effects of such pollutants on fish gonadal morphology, female zebrafish were exposed in two generations by food to mixtures of pollutants extracted from livers of burbot from Lake Mjosa (high and low dose) and Lake Losna, which represents background pollution, and compared to a control group. Ovarian follicle counts detected a significant decrease in late vitellogenic follicle stages in fish exposed to the Losna and the high concentrations of Mjosa mixtures in fish from the first generation. In addition, proliferation of granulosa cells, visualized by immunohistochemistry against proliferating cell nuclear antigen (PCNA), was decreased in all exposure groups in either early or late vitellogenic follicle stages compared to control. This was accompanied by increased apoptosis of granulosa cells. There was a decrease in proliferation of liver hepatocytes with exposure to both Mjosa mixtures. In addition, immunopositivity for vitellogenin in the liver was significantly lower in the Mjosa high group than in the control group. When analysing effects of parental exposure, fish with parents exposed to Mjosa high mixture had significantly higher numbers of perinucleolar follicles than fish with control parents. We conclude that long-term exposure of a real-life mixture of pollutants containing high- and background levels of chemicals supress ovarian follicle development, liver vitellogenin immunostaining intensity and hepatocyte proliferation in the zebrafish model.

  10. Oral activated charcoal suppresses hyperphosphataemia in haemodialysis patients.

    Science.gov (United States)

    Wang, Zunsong; Cui, Meiyu; Tang, Lijun; Li, Wenbin; Wei, Yong; Zhu, Zhuxian; Jia, Xiaoyan; Kong, Xianglei; Xu, Dongmei

    2012-09-01

    Hyperphosphataemia is almost inevitable in end stage renal disease (ESRD) patients and is associated with increased morbidity and mortality. In this study we examined whether oral activated charcoal (oAC) reduces serum phosphate level in haemodialysis patients. This was an open-label, prospective, uncontrolled study. One hundred and thirty-five haemodialysis patients were included in this study, with cessation of treatment with any phosphate binders during a 2 week washout period. Patients with serum phosphate levels greater than 5.5 mg/dL during the washout period were included for treatment with oAC. oAC was started at a dose of 600 mg three times per day with meals and was administered for 24 weeks. oAC dose was titrated up during the 24 week period to achieve phosphate control (3.5-5.5 mg/dL). A second 2 week washout period followed the end of oAC treatment. In the 114 patients who successfully completed the trial, the mean dose of activated charcoal was 3190 ± 806 mg/day. oAC reduced mean phosphate levels to below 5.5 mg/dL, with mean decreases of 2.60 ± 0.11 mg/dL (P < 0.01) and 103 (90.4%) of the patients reached the phosphate target. After the second washout period the phosphate levels increased to 7.50 ± 1.03 mg/dL (P < 0.01). Serum intact parathyroid hormone (iPTH) levels declined from 338.75 ± 147.77 pg/mL to 276.51 ± 127.82 pg/mL (P < 0.05) during the study. oAC had no influence on serum prealbumin, total cholesterol, triglycerides, serum ferritin, haemoglobin or platelet levels and the levels of 1,25-dihydroxyvitamin D were stable during the study. In this open-label uncontrolled study, oAC effectively controls hyperphosphataemia and hyperparathyroidism in haemodialysis patients. The safety and efficacy of oAC needs to be assessed in a randomized controlled trial. © 2012 The Authors. Nephrology © 2012 Asian Pacific Society of Nephrology.

  11. Ovarian Cancer

    Science.gov (United States)

    ... contraceptives may have a reduced risk of ovarian cancer. But oral contraceptives do have risks, so discuss whether the benefits outweigh those risks based on your situation. Discuss your risk factors ... of breast and ovarian cancers, bring this up with your doctor. Your doctor ...

  12. Dietary supplementation of yucca (Yucca schidigera) affects ovine ovarian functions.

    Science.gov (United States)

    Vlčková, Radoslava; Sopková, Drahomíra; Andrejčáková, Zuzana; Valocký, Igor; Kádasi, Attila; Harrath, Abdel Halim; Petrilla, Vladimír; Sirotkin, Alexander V

    2017-01-15

    Yucca (Yucca schidigera) is a popular medicinal plant due to its many positive effects on animal and human physiology, including their reproductive systems. To examine the effect of supplemental yucca feeding on sheep reproduction, including ovarian functions and their hormonal regulators, ewes were fed (or not fed, control) yucca powder (1.5 g/head/day, 30 days). Macromorphometric indexes of the oviduct, ovary, and ovarian folliculogenesis were measured. Reproductive hormone levels in the blood were measured using a radioimmunoassay. Granulosa cells were aspirated from the ovary, and their proliferation and apoptosis were detected using immunocytochemistry. To assess secretory activity and its response to gonadotropin, ovarian fragments of treated and control ewes were cultured with and without follicle-stimulating hormone (FSH; 0, 0.1, 1, 10, or 100 IU/mL), and the release of reproductive hormones into the culture medium was evaluated. Finally, to examine the direct action of yucca on the ovary, ovarian fragments from control ewes were cultured with and without yucca extract (1, 10, or 100 μg/mL), and the release of reproductive hormones was measured. Yucca supplementation significantly decreased the size of small antral follicles (2 to yucca supplementation did not affect the size of larger follicles and number of follicles, volume and weight of ovaries, length and weight of oviducts, caspase 3 accumulation, cell proliferation, testosterone (T) or IGF-I serum levels, or T or E2 release by cultured ovarian fragments and their response to FSH. Yucca addition to culture medium inhibited P4 and IGF-I, but not T or E2 release at the lowest (1 μg/mL) dose, and stimulated P4, but not T, E2, or IGF-I release at the highest (100 μg/mL) dose. These data suggest that yucca supplementation can reduce small antral ovarian follicle development possibly via the stimulation of apoptosis of their granulosa cells, suppression of ovarian P4 and E2 release, and

  13. HGF-independent regulation of MET and GAB1 by nonreceptor tyrosine kinase FER potentiates metastasis in ovarian cancer.

    Science.gov (United States)

    Fan, Gaofeng; Zhang, Siwei; Gao, Yan; Greer, Peter A; Tonks, Nicholas K

    2016-07-01

    Ovarian cancer cells disseminate readily within the peritoneal cavity, which promotes metastasis, and are often resistant to chemotherapy. Ovarian cancer patients tend to present with advanced disease, which also limits treatment options; consequently, new therapies are required. The oncoprotein tyrosine kinase MET, which is the receptor for hepatocyte growth factor (HGF), has been implicated in ovarian tumorigenesis and has been the subject of extensive drug development efforts. Here, we report a novel ligand- and autophosphorylation-independent activation of MET through the nonreceptor tyrosine kinase feline sarcoma-related (FER). We demonstrated that the levels of FER were elevated in ovarian cancer cell lines relative to those in immortalized normal surface epithelial cells and that suppression of FER attenuated the motility and invasive properties of these cancer cells. Furthermore, loss of FER impaired the metastasis of ovarian cancer cells in vivo. Mechanistically, we demonstrated that FER phosphorylated a signaling site in MET: Tyr1349. This enhanced activation of RAC1/PAK1 and promoted a kinase-independent scaffolding function that led to recruitment and phosphorylation of GAB1 and the specific activation of the SHP2-ERK signaling pathway. Overall, this analysis provides new insights into signaling events that underlie metastasis in ovarian cancer cells, consistent with a prometastatic role of FER and highlighting its potential as a novel therapeutic target for metastatic ovarian cancer. © 2016 Fan et al.; Published by Cold Spring Harbor Laboratory Press.

  14. Salidroside Suppresses HUVECs Cell Injury Induced by Oxidative Stress through Activating the Nrf2 Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Yao Zhu

    2016-08-01

    Full Text Available Oxidative stress plays an important role in the pathogenesis of cardiovascular diseases. Salidroside (SAL, one of the main effective constituents of Rhodiola rosea, has been reported to suppress oxidative stress-induced cardiomyocyte injury and necrosis by promoting transcription of nuclear factor E2-related factor 2 (Nrf2-regulated genes such as heme oxygenase-1 (HO-1 and NAD(PH dehydrogenase (quinone1 (NQO1. However, it has not been indicated whether SAL might ameliorate endothelial injury induced by oxidative stress. Here, our study demonstrated that SAL might suppress HUVEC cell injury induced by oxidative stress through activating the Nrf2 signaling pathway. The results of our study indicated that SAL decreased the levels of intercellular reactive oxygen species (ROS and malondialdehyde (MDA, and improved the activities of superoxide dismutase (SOD and catalase (CAT, resulting in protective effects against oxidative stress-induced cell damage in HUVECs. It suppressed oxidative stress damage by inducing Nrf2 nuclear translocation and activating the expression of Nrf2-regulated antioxidant enzyme genes such as HO-1 and NQO1 in HUVECs. Knockdown of Nrf2 with siRNA abolished the cytoprotective effects against oxidative stress, decreased the expression of Nrf2, HO-1, and NQO1, and inhibited the nucleus translocation of Nrf2 in HUVECs. This study is the first to demonstrate that SAL suppresses HUVECs cell injury induced by oxidative stress through activating the Nrf2 signaling pathway.

  15. Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Notaridou, Maria; Quaye, Lydia; Dafou, Dimitra

    2011-01-01

    Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell-mediated chromosome transfer and expression microarray analysis identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines...

  16. Cyclin F suppresses B-Myb activity to promote cell cycle checkpoint control

    DEFF Research Database (Denmark)

    Klein, Ditte Kjærsgaard; Hoffmann, Saskia; Ahlskog, Johanna K

    2015-01-01

    an important role in checkpoint control following ionizing radiation. Cyclin F-depleted cells initiate checkpoint signalling after ionizing radiation, but fail to maintain G2 phase arrest and progress into mitosis prematurely. Importantly, cyclin F suppresses the B-Myb-driven transcriptional programme...... that promotes accumulation of crucial mitosis-promoting proteins. Cyclin F interacts with B-Myb via the cyclin box domain. This interaction is important to suppress cyclin A-mediated phosphorylation of B-Myb, a key step in B-Myb activation. In summary, we uncover a regulatory mechanism linking the F-box protein...

  17. Natural mixtures of persistent organic pollutants (POPs) suppress ovarian follicle development, liver vitellogenin immunostaining and hepatocyte proliferation in female zebrafish (Danio rerio)

    International Nuclear Information System (INIS)

    Kraugerud, Marianne; Doughty, Richard William; Lyche, Jan L.; Berg, Vidar; Tremoen, Nina H.; Alestrøm, Peter; Aleksandersen, Mona; Ropstad, Erik

    2012-01-01

    Persistent organic pollutants such as polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and dichlorodiphenyltrichloroethane (DDT) are present in high concentrations in livers of burbot (Lota lota) in Lake Mjøsa, Norway. In order to assess effects of such pollutants on fish gonadal morphology, female zebrafish were exposed in two generations by food to mixtures of pollutants extracted from livers of burbot from Lake Mjøsa (high and low dose) and Lake Losna, which represents background pollution, and compared to a control group. Ovarian follicle counts detected a significant decrease in late vitellogenic follicle stages in fish exposed to the Losna and the high concentrations of Mjøsa mixtures in fish from the first generation. In addition, proliferation of granulosa cells, visualized by immunohistochemistry against proliferating cell nuclear antigen (PCNA), was decreased in all exposure groups in either early or late vitellogenic follicle stages compared to control. This was accompanied by increased apoptosis of granulosa cells. There was a decrease in proliferation of liver hepatocytes with exposure to both Mjøsa mixtures. In addition, immunopositivity for vitellogenin in the liver was significantly lower in the Mjøsa high group than in the control group. When analysing effects of parental exposure, fish with parents exposed to Mjøsa high mixture had significantly higher numbers of perinucleolar follicles than fish with control parents. We conclude that long-term exposure of a real-life mixture of pollutants containing high- and background levels of chemicals supress ovarian follicle development, liver vitellogenin immunostaining intensity and hepatocyte proliferation in the zebrafish model.

  18. Suppression of SOS-inducing activity of chemical mutagens by metabolites from microbial transformation of (-)-isolongifolene.

    Science.gov (United States)

    Sakata, Kazuki; Oda, Yoshimitsu; Miyazawa, Mitsuo

    2010-02-24

    In this study, biotransformation of (-)-isolongifolene (1) by Glomerella cingulata and suppressive effect on umuC gene expression by chemical mutagens 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide (furylfuramide) and aflatoxin B(1) (AFB(1)) of the SOS response in Salmonella typhimurium TA1535/pSK1002 were investigated. Initially, 1 was carried out the microbial transformation by G. cingulata. The result found that 1 was converted into (-)-isolongifolen-9-one (2), (-)-(2S)-13-hydroxy-isolongifolen-9-one (3), and (-)-(4R)-4-hydroxy-isolongifolen-9-one (4) by G. cingulata, and their conversion rates were 60, 25, and 15%, respectively. The metabolites suppressed the SOS-inducing activity of furylfuramid and AFB(1) in the umu test. Comound 2 showed gene expression by chemical mutagens furylfuramide and AFB(1) was suppressed 54 and 50% at <0.5 mM, respectively. Compound 2 is the most effective compound in this experiment.

  19. MicroRNA-214 suppresses gluconeogenesis by targeting activating transcriptional factor 4.

    Science.gov (United States)

    Li, Kai; Zhang, Jin; Yu, Junjie; Liu, Bin; Guo, Yajie; Deng, Jiali; Chen, Shanghai; Wang, Chunxia; Guo, Feifan

    2015-03-27

    Although the gluconeogenesis pathway is already a target for the treatment of type 2 diabetes, the potential role of microRNAs (miRNAs) in gluconeogenesis remains unclear. Here, we investigated the physiological functions of miR-214 in gluconeogenesis. The expression of miR-214 was suppressed by glucagon via protein kinase A signaling in primary hepatocytes, and miR-214 was down-regulated in the livers of fasted, high fat diet-induced diabetic and leptin receptor-mutated (db/db) mice. The overexpression of miR-214 in primary hepatocytes suppressed glucose production, and silencing miR-214 reversed this effect. Gluconeogenesis was suppressed in the livers of mice injected with an adenovirus expressing miR-214 (Ad-miR-214). Additionally, Ad-miR-214 alleviated high fat diet-induced elevation of gluconeogenesis and hyperglycemia. Furthermore, we found that activating transcription factor 4 (ATF4), a reported target of miR-214, can reverse the suppressive effect of miR-214 on gluconeogenesis in primary hepatocytes, and this suppressive effect was blocked in liver-specific ATF4 knock-out mice. ATF4 regulated gluconeogenesis via affecting forkhead box protein O1 (FOXO1) transcriptional activity. Finally, liver-specific miR-214 transgenic mice exhibited suppressed gluconeogenesis and reduced expression of ATF4, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase in liver. Taken together, our results suggest that the miR-214-ATF4 axis is a novel pathway for the regulation of hepatic gluconeogenesis. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. MicroRNA-214 Suppresses Gluconeogenesis by Targeting Activating Transcriptional Factor 4*

    Science.gov (United States)

    Li, Kai; Zhang, Jin; Yu, Junjie; Liu, Bin; Guo, Yajie; Deng, Jiali; Chen, Shanghai; Wang, Chunxia; Guo, Feifan

    2015-01-01

    Although the gluconeogenesis pathway is already a target for the treatment of type 2 diabetes, the potential role of microRNAs (miRNAs) in gluconeogenesis remains unclear. Here, we investigated the physiological functions of miR-214 in gluconeogenesis. The expression of miR-214 was suppressed by glucagon via protein kinase A signaling in primary hepatocytes, and miR-214 was down-regulated in the livers of fasted, high fat diet-induced diabetic and leptin receptor-mutated (db/db) mice. The overexpression of miR-214 in primary hepatocytes suppressed glucose production, and silencing miR-214 reversed this effect. Gluconeogenesis was suppressed in the livers of mice injected with an adenovirus expressing miR-214 (Ad-miR-214). Additionally, Ad-miR-214 alleviated high fat diet-induced elevation of gluconeogenesis and hyperglycemia. Furthermore, we found that activating transcription factor 4 (ATF4), a reported target of miR-214, can reverse the suppressive effect of miR-214 on gluconeogenesis in primary hepatocytes, and this suppressive effect was blocked in liver-specific ATF4 knock-out mice. ATF4 regulated gluconeogenesis via affecting forkhead box protein O1 (FOXO1) transcriptional activity. Finally, liver-specific miR-214 transgenic mice exhibited suppressed gluconeogenesis and reduced expression of ATF4, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase in liver. Taken together, our results suggest that the miR-214-ATF4 axis is a novel pathway for the regulation of hepatic gluconeogenesis. PMID:25657009

  1. Ovarian cancer

    International Nuclear Information System (INIS)

    Wakabayashi, Yukari; Yachida, Meri; Akata, Soichi; Kawana, Koji; Kotake, Fumio; Kakizaki, Dai; Abe, Kimihiko; Negishi, Noriyuki; Akiya, Kiyoshi

    1988-01-01

    In 40 patients undergoing pre-treatment for an ovarian tumor, a CT scan of the pelvis and measurements of their CA 125, CA 19 - 9, IAP (immunosupressive acidic antigen), and TPA (tissue polypeptide antigen were performed. The specificity and sensitivity of the CT diagnosis was found to be better than any of other tumor markers measurements. Comparison of the 4 markers showed that the CA 125 testing had the greatest sensitivity in detecting an ovarian cancer. Moreover, the sensitivity of CA 125, was better than a combination of the 4 markers. Thus, a CT scan still remains necessary for the diagnosis of an ovarian cancer. (author)

  2. PG545 enhances anti-cancer activity of chemotherapy in ovarian models and increases surrogate biomarkers such as VEGF in preclinical and clinical plasma samples.

    Science.gov (United States)

    Winterhoff, Boris; Freyer, Luisa; Hammond, Edward; Giri, Shailendra; Mondal, Susmita; Roy, Debarshi; Teoman, Attila; Mullany, Sally A; Hoffmann, Robert; von Bismarck, Antonia; Chien, Jeremy; Block, Matthew S; Millward, Michael; Bampton, Darryn; Dredge, Keith; Shridhar, Viji

    2015-05-01

    Despite the utility of antiangiogenic drugs in ovarian cancer, efficacy remains limited due to resistance linked to alternate angiogenic pathways and metastasis. Therefore, we investigated PG545, an anti-angiogenic and anti-metastatic agent which is currently in Phase I clinical trials, using preclinical models of ovarian cancer. PG545's anti-cancer activity was investigated in vitro and in vivo as a single agent, and in combination with paclitaxel, cisplatin or carboplatin using various ovarian cancer cell lines and tumour models. PG545, alone, or in combination with chemotherapeutics, inhibited proliferation of ovarian cancer cells, demonstrating synergy with paclitaxel in A2780 cells. PG545 inhibited growth factor-mediated cell migration and reduced HB-EGF-induced phosphorylation of ERK, AKT and EGFR in vitro and significantly reduced tumour burden which was enhanced when combined with paclitaxel in an A2780 model or carboplatin in a SKOV-3 model. Moreover, in the immunocompetent ID8 model, PG545 also significantly reduced ascites in vivo. In the A2780 maintenance model, PG545 initiated with, and following paclitaxel and cisplatin treatment, significantly improved overall survival. PG545 increased plasma VEGF levels (and other targets) in preclinical models and in a small cohort of advanced cancer patients which might represent a potential biomarker of response. Our results support clinical testing of PG545, particularly in combination with paclitaxel, as a novel therapeutic strategy for ovarian cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Changes in O-Linked N-Acetylglucosamine (O-GlcNAc) Homeostasis Activate the p53 Pathway in Ovarian Cancer Cells.

    Science.gov (United States)

    de Queiroz, Rafaela Muniz; Madan, Rashna; Chien, Jeremy; Dias, Wagner Barbosa; Slawson, Chad

    2016-09-02

    O-GlcNAcylation is a dynamic post-translational modification consisting of the addition of a single N-acetylglucosamine sugar to serine and threonine residues in proteins by the enzyme O-linked β-N-acetylglucosamine transferase (OGT), whereas the enzyme O-GlcNAcase (OGA) removes the modification. In cancer, tumor samples present with altered O-GlcNAcylation; however, changes in O-GlcNAcylation are not consistent between tumor types. Interestingly, the tumor suppressor p53 is modified by O-GlcNAc, and most solid tumors contain mutations in p53 leading to the loss of p53 function. Because ovarian cancer has a high frequency of p53 mutation rates, we decided to investigate the relationship between O-GlcNAcylation and p53 function in ovarian cancer. We measured a significant decrease in O-GlcNAcylation of tumor tissue in an ovarian tumor microarray. Furthermore, O-GlcNAcylation was increased, and OGA protein and mRNA levels were decreased in ovarian tumor cell lines not expressing the protein p53. Treatment with the OGA inhibitor Thiamet-G (TMG), silencing of OGA, or overexpression of OGA and OGT led to p53 stabilization, increased nuclear localization, and increased protein and mRNA levels of p53 target genes. These data suggest that changes in O-GlcNAc homeostasis activate the p53 pathway. Combination treatment of the chemotherapeutic cisplatin with TMG decreased tumor cell growth and enhanced cell cycle arrest without impairing cytotoxicity. The effects of TMG on tumor cell growth were partially dependent on wild type p53 activation. In conclusion, changes in O-GlcNAc homeostasis activate the wild type p53 pathway in ovarian cancer cells, and OGA inhibition has the potential as an adjuvant treatment for ovarian carcinoma. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. Changes in O-Linked N-Acetylglucosamine (O-GlcNAc) Homeostasis Activate the p53 Pathway in Ovarian Cancer Cells*

    Science.gov (United States)

    de Queiroz, Rafaela Muniz; Madan, Rashna; Chien, Jeremy; Dias, Wagner Barbosa; Slawson, Chad

    2016-01-01

    O-GlcNAcylation is a dynamic post-translational modification consisting of the addition of a single N-acetylglucosamine sugar to serine and threonine residues in proteins by the enzyme O-linked β-N-acetylglucosamine transferase (OGT), whereas the enzyme O-GlcNAcase (OGA) removes the modification. In cancer, tumor samples present with altered O-GlcNAcylation; however, changes in O-GlcNAcylation are not consistent between tumor types. Interestingly, the tumor suppressor p53 is modified by O-GlcNAc, and most solid tumors contain mutations in p53 leading to the loss of p53 function. Because ovarian cancer has a high frequency of p53 mutation rates, we decided to investigate the relationship between O-GlcNAcylation and p53 function in ovarian cancer. We measured a significant decrease in O-GlcNAcylation of tumor tissue in an ovarian tumor microarray. Furthermore, O-GlcNAcylation was increased, and OGA protein and mRNA levels were decreased in ovarian tumor cell lines not expressing the protein p53. Treatment with the OGA inhibitor Thiamet-G (TMG), silencing of OGA, or overexpression of OGA and OGT led to p53 stabilization, increased nuclear localization, and increased protein and mRNA levels of p53 target genes. These data suggest that changes in O-GlcNAc homeostasis activate the p53 pathway. Combination treatment of the chemotherapeutic cisplatin with TMG decreased tumor cell growth and enhanced cell cycle arrest without impairing cytotoxicity. The effects of TMG on tumor cell growth were partially dependent on wild type p53 activation. In conclusion, changes in O-GlcNAc homeostasis activate the wild type p53 pathway in ovarian cancer cells, and OGA inhibition has the potential as an adjuvant treatment for ovarian carcinoma. PMID:27402830

  5. Experimental therapy of ovarian cancer with synthetic makaluvamine analog: in vitro and in vivo anticancer activity and molecular mechanisms of action.

    Directory of Open Access Journals (Sweden)

    Tao Chen

    Full Text Available The present study was designed to determine the biological effects of novel marine alkaloid analog 7-(4-fluorobenzylamino-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H-one (FBA-TPQ on human ovarian cancer cells for its anti-tumor potential and the underlying mechanisms as a novel chemotherapeutic agent. Human ovarian cancer cells (A2780 and OVCAR-3, and Immortalized non-tumorigenic human Ovarian Surface Epithelial cells (IOSE-144, were exposed to FBA-TPQ for initial cytotoxicity evaluation (via MTS assay kit, Promega. The detailed in-vitro (cell level and in-vivo (animal model studies on the antitumor effects and possible underlying mechanisms of action of the compounds were then performed. FBA-TPQ exerted potent cytotoxicity against human ovarian cancer A2780 and OVCAR-3 cells as an effective inhibitor of cell growth and proliferation, while exerting lesser effects on non-tumorigenic IOSE-144 cells. Further study in the more sensitive OVCAR-3 cell line showed that it could potently induce cell apoptosis (Annexin V-FITC assay, G2/M cell cycle arrest (PI staining analysis and also dose-dependently inhibit OVCAR-3 xenograft tumors' growth on female athymic nude mice (BALB/c, nu/nu. Mechanistic studies (both in vitro and in vivo revealed that FBA-TPQ might exert its activity through Reactive Oxygen Species (ROS-associated activation of the death receptor, p53-MDM2, and PI3K-Akt pathways in OVCAR-3 cells, which is in accordance with in vitro microarray (Human genome microarrays, Agilent data analysis (GEO accession number: GSE25317. In conclusion, FBA-TPQ exhibits significant anticancer activity against ovarian cancer cells, with minimal toxicity to non-tumorigenic human IOSE-144 cells, indicating that it may be a potential therapeutic agent for ovarian cancer.

  6. Suppression of superoxide anion generation catalyzed by xanthine oxidase with alkyl caffeates and the scavenging activity.

    Science.gov (United States)

    Masuoka, Noriyoshi; Kubo, Isao

    2016-01-01

    Alkyl caffeates are strong antioxidants and inhibitors of xanthine oxidase. However, it is unclear about the effect of caffeic acid and alkyl caffeates on superoxide anion (O2(-)) generation catalyzed by xanthine oxidase. Effects of caffeic acid and alkyl caffeates on the uric acid formation and O2(-) generation catalyzed by xanthine oxidase were analyzed. The scavenging activities of 1,1-diphenyl-2-picryhydrazyl (DPPH) radical and O2(-) generated with phenazine methosulfate (PMS) and NADH were examined. Caffeic acid derivatives equally suppressed O2(-) generation, and the suppression is stronger than inhibition of xanthine oxidase. Scavenging activity of O2(-) is low compared to the suppression of O2(-) generation. Suppression of O2(-) generation catalyzed by xanthine oxidase with caffeic acid derivatives was not due to enzyme inhibition or O2(-) scavenging but due to the reduction of xanthine oxidase molecules. Alkyl caffeates are effective inhibitors of uric acid and O2(-) catalyzed by xanthine oxidase as well as antioxidants for edible oil.

  7. Effects of carotenoids, immune activation and immune suppression on the intensity of chronic coccidiosis in greenfinches.

    Science.gov (United States)

    Sepp, Tuul; Karu, Ulvi; Sild, Elin; Männiste, Marju; Hõrak, Peeter

    2011-03-01

    Allocation trade-offs of carotenoids between their use in the immune system and production of integumentary colouration have been suggested as a proximate mechanism maintaining honesty of signal traits. We tested how dietary carotenoid supplementation, immune activation and immune suppression affect intensity of coccidian infection in captive greenfinches Carduelis chloris, a passerine with carotenoid-based plumage. Immune activation with phytohaemagglutinin (PHA) decreased body mass among birds not supplemented with lutein, while among the carotenoid-fed birds, PHA had no effect on mass dynamics. Immune suppression with dexamethasone (DEX) induced loss of body mass and reduced the swelling response to PHA. DEX and PHA increased the concentration of circulating heterophils. Lutein supplementation increased plasma carotenoid levels but had no effect on the swelling response induced by PHA. PHA and DEX treatments did not affect plasma carotenoids. Immune stimulation by PHA suppressed the infection, but only among carotenoid-supplemented birds. Priming of the immune system can thus aid in suppressing chronic infection but only when sufficient amount of carotenoids is available. Our experiment shows the importance of carotenoids in immune response, but also the complicated nature of this impact, which could be the reason for inconsistent results in studies investigating the immunomodulatory effects of carotenoids. The findings about involvement of carotenoids in modulation of an immune response against coccidiosis suggest that carotenoid-based ornaments may honestly signal individuals' ability to manage chronic infections. Copyright © 2010 Elsevier Inc. All rights reserved.

  8. The serotonin reuptake inhibitor citalopram suppresses activity in the neonatal rat barrel cortex in vivo.

    Science.gov (United States)

    Akhmetshina, Dinara; Zakharov, Andrei; Vinokurova, Daria; Nasretdinov, Azat; Valeeva, Guzel; Khazipov, Roustem

    2016-06-01

    Inhibition of serotonin uptake, which causes an increase in extracellular serotonin levels, disrupts the development of thalamocortical barrel maps in neonatal rodents. Previous in vitro studies have suggested that the disruptive effect of excessive serotonin on barrel map formation involves a depression at thalamocortical synapses. However, the effects of serotonin uptake inhibitors on the early thalamocortical activity patterns in the developing barrel cortex in vivo remain largely unknown. Here, using extracellular recordings of the local field potentials and multiple unit activity (MUA) we explored the effects of the selective serotonin reuptake inhibitor (SSRI) citalopram (10-20mg/kg, intraperitoneally) on sensory evoked activity in the barrel cortex of neonatal (postnatal days P2-5) rats in vivo. We show that administration of citalopram suppresses the amplitude and prolongs the delay of the sensory evoked potentials, reduces the power and frequency of the early gamma oscillations, and suppresses sensory evoked and spontaneous neuronal firing. In the adolescent P21-29 animals, citalopram affected neither sensory evoked nor spontaneous activity in barrel cortex. We suggest that suppression of the early thalamocortical activity patterns contributes to the disruption of the barrel map development caused by SSRIs and other conditions elevating extracellular serotonin levels. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Ovarian Cancer

    Science.gov (United States)

    ... I find more information about ovarian and other gynecologic cancers? Centers for Disease Control and Prevention: 800-CDC-INFO or www. cdc. gov/ cancer/ gynecologic National Cancer Institute: 800-4-CANCER or www. ...

  10. Use of [1,2-3 h] testosterone in 5 α- reductase enzymatic activity dosing in dermal fibroblast cultures from polycystic ovarian patients

    International Nuclear Information System (INIS)

    Matei, Lidia; Postolache, Cristian; Condac, Eduard

    2003-01-01

    Polycystic ovarian syndrome is an endocrine malady very frequent in women characterized by the presence of ovarian cysts, visible or not by ultrasonography, menstrual cycle deregulation and sometimes by high plasmatic concentrations of androgen hormones. Many cases of polycystic syndrome could not be easily diagnosed or had an erroneous diagnostic. Therefore, is useful to know the plasmatic androgen hormone profile. This profile could indicate the cause for observed clinical manifestations; this cause may be observed in ovarian, suprarenal glands or hypothalamo-hypophysis level. In vitro studies on dermal fibroblasts permit the detail determination of steroid hormones metabolism in target organs and offer important information regarding action mechanism. This study follows the identification of testosterone metabolites in fibroblasts and enzymatic activities of 5α-reductase using testosterone radioactively labeled with tritium. (authors)

  11. Studies on the post-partum ovarian activity of dairy cattle under different feeding regimes in Ecuador

    International Nuclear Information System (INIS)

    Jarrin, J.; Villalba, P.; Guerron, E.; Zurita, E.

    1990-01-01

    In order to monitor ovarian activity in post-partum dairy cows in the Cayambe Valley, Ecuador, 164 cows from three farms were studied. Milk progesterone concentrations (analysed by RIA) and additional data on livestock management, nutritional status and health were compiled. Farms were classified mainly according to nutritional and management status; the better the nutritional status of the cows the sooner they resumed oestrous activity (28.3-31.6 days post-partum). The duration of the first oestrous cycle was found to be variable, 18.0 to 20.4 days. Thirty-one per cent of the study cows did not conceive during the course of the trial and the mean calving interval of those that calved was 426 days. The high incidence of hypofunctional ovaries was a cause for concern on one farm. (author). 6 refs, 4 figs, 2 tabs

  12. IL-12 Expressing oncolytic herpes simplex virus promotes anti-tumor activity and immunologic control of metastatic ovarian cancer in mice.

    Science.gov (United States)

    Thomas, Eric D; Meza-Perez, Selene; Bevis, Kerri S; Randall, Troy D; Gillespie, G Yancey; Langford, Catherine; Alvarez, Ronald D

    2016-10-27

    Despite advances in surgical aggressiveness and conventional chemotherapy, ovarian cancer remains the most lethal cause of gynecologic cancer mortality; consequently there is a need for new therapeutic agents and innovative treatment paradigms for the treatment of ovarian cancer. Several studies have demonstrated that ovarian cancer is an immunogenic disease and immunotherapy represents a promising and novel approach that has not been completely evaluated in ovarian cancer. Our objective was to evaluate the anti-tumor activity of an oncolytic herpes simplex virus "armed" with murine interleukin-12 and its ability to elicit tumor-specific immune responses. We evaluated the ability of interleukin-12-expressing and control oncolytic herpes simplex virus to kill murine and human ovarian cancer cell lines in vitro. We also administered interleukin-12-expressing oncolytic herpes simplex virus to the peritoneal cavity of mice that had developed spontaneous, metastatic ovarian cancer and determined overall survival and tumor burden at 95 days. We used flow cytometry to quantify the tumor antigen-specific CD8 + T cell response in the omentum and peritoneal cavity. All ovarian cancer cell lines demonstrated susceptibility to oncolytic herpes simplex virus in vitro. Compared to controls, mice treated with interleukin-12-expressing oncolytic herpes simplex virus demonstrated a more robust tumor antigen-specific CD8 + T-cell immune response in the omentum (471.6 cells vs 33.1 cells; p = 0.02) and peritoneal cavity (962.3 cells vs 179.5 cells; p = 0.05). Compared to controls, mice treated with interleukin-12-expressing oncolytic herpes simplex virus were more likely to control ovarian cancer metastases (81.2 % vs 18.2 %; p = 0.008) and had a significantly longer overall survival (p = 0.02). Finally, five of 6 mice treated with interleukin-12-expressing oHSV had no evidence of metastatic tumor when euthanized at 6 months, compared to two of 4 mice treated with

  13. Omega-3 free fatty acids suppress macrophage inflammasome activation by inhibiting NF-κB activation and enhancing autophagy.

    Directory of Open Access Journals (Sweden)

    Yolanda Williams-Bey

    Full Text Available The omega-3 (ω3 fatty acid docosahexaenoic acid (DHA can suppress inflammation, specifically IL-1β production through poorly understood molecular mechanisms. Here, we show that DHA reduces macrophage IL-1β production by limiting inflammasome activation. Exposure to DHA reduced IL-1β production by ligands that stimulate the NLRP3, AIM2, and NAIP5/NLRC4 inflammasomes. The inhibition required Free Fatty Acid Receptor (FFAR 4 (also known as GPR120, a G-protein coupled receptor (GPR known to bind DHA. The exposure of cells to DHA recruited the adapter protein β-arrestin1/2 to FFAR4, but not to a related lipid receptor. DHA treatment reduced the initial inflammasome priming step by suppressing the nuclear translocation of NF-κB. DHA also reduced IL-1β levels by enhancing autophagy in the cells. As a consequence macrophages derived from mice lacking the essential autophagy protein ATG7 were partially resistant to suppressive effects of DHA. Thus, DHA suppresses inflammasome activation by two distinct mechanisms, inhibiting the initial priming step and by augmenting autophagy, which limits inflammasome activity.

  14. Deep brain stimulation suppresses pallidal low frequency activity in patients with phasic dystonic movements.

    Science.gov (United States)

    Barow, Ewgenia; Neumann, Wolf-Julian; Brücke, Christof; Huebl, Julius; Horn, Andreas; Brown, Peter; Krauss, Joachim K; Schneider, Gerd-Helge; Kühn, Andrea A

    2014-11-01

    Deep brain stimulation of the globus pallidus internus alleviates involuntary movements in patients with dystonia. However, the mechanism is still not entirely understood. One hypothesis is that deep brain stimulation suppresses abnormally enhanced synchronized oscillatory activity within the motor cortico-basal ganglia network. Here, we explore deep brain stimulation-induced modulation of pathological low frequency (4-12 Hz) pallidal activity that has been described in local field potential recordings in patients with dystonia. Therefore, local field potentials were recorded from 16 hemispheres in 12 patients undergoing deep brain stimulation for severe dystonia using a specially designed amplifier allowing simultaneous high frequency stimulation at therapeutic parameter settings and local field potential recordings. For coherence analysis electroencephalographic activity (EEG) over motor areas and electromyographic activity (EMG) from affected neck muscles were recorded before and immediately after cessation of high frequency stimulation. High frequency stimulation led to a significant reduction of mean power in the 4-12 Hz band by 24.8 ± 7.0% in patients with predominantly phasic dystonia. A significant decrease of coherence between cortical EEG and pallidal local field potential activity in the 4-12 Hz range was revealed for the time period of 30 s after switching off high frequency stimulation. Coherence between EMG activity and pallidal activity was mainly found in patients with phasic dystonic movements where it was suppressed after high frequency stimulation. Our findings suggest that high frequency stimulation may suppress pathologically enhanced low frequency activity in patients with phasic dystonia. These dystonic features are the quickest to respond to high frequency stimulation and may thus directly relate to modulation of pathological basal ganglia activity, whereas improvement in tonic features may depend on long-term plastic changes within the

  15. Cisplatin induced apoptosis of ovarian cancer A2780s cells by activation of ERK/p53/PUMA signals.

    Science.gov (United States)

    Song, Hao; Wei, Mei; Liu, Wenfen; Shen, Shulin; Li, Jiaqun; Wang, Liming

    2018-01-01

    Cisplatin (CDDP) is one of the most effective anticancer agents widely used in the treatment of solid tumors, including ovarian cancer. It is generally considered as a cytotoxic drug which kills cancer cells by causing DNA damage, and subsequently inducing apoptosis in cancer cells. However, the underlying mechanisms leading to cell apoptosis remain obscure. In this study, the signaling pathways involved in CDDP-induced apoptosis were examined using CDDP-sensitive ovarian cancer A2780s cells. A2780s cells were treated with CDDP (1.5-3 μg/ml) for 6h, 12h and 24h. Using siRNA targeting P53 and PUMA, and a selective MEK inhibitor, PD98059 to examine the relation between ERK1/2 activation, p53 and PUMA expression after exposure to CDDP, and the effect on CDDP-induced apoptosis. The results shown that treatment of A2780s cells with CDDP (3 μg/ml) for 6-24h induced apoptosis, resulting in the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and accumulation of p53 and PUMA (p53 upregulated modulator of apoptosis) protein. Knockdown of P53 or PUMA by siRNA transfection blocked CDDP-induced apoptosis. Inhibition of ERK1/2 using PD98059, a selective MEK inhibitor, blocked the apoptotic cell death but prevented CDDP-induced accumulation of p53 and PUMA. Knockdown of P53 by siRNA transfection also blocked CDDP-induced accumulation of PUMA. We therefore concluded that CDDP activated ERK1/2 and induced-p53-dependent PUMA upregulation, resulting in triggering apoptosis in A2780s cells. Our study clearly demonstrates that the ERK1/2/p53/PUMA axis is related to CDDP-induced cell death in A2780s cells.

  16. Targeting ILK and β4 integrin abrogates the invasive potential of ovarian cancer

    International Nuclear Information System (INIS)

    Choi, Yoon Pyo; Kim, Baek Gil; Gao, Ming-Qing; Kang, Suki; Cho, Nam Hoon

    2012-01-01

    Highlights: ► The potential of targeting ILK and integrins for highly aggressive ovarian cancer. ► Unanticipated synergistic effect for the combination of ILK/β4 integrin. ► Combination of ILK/β4 integrin effectively inhibited the PI3K/Akt/Rac1 cascade. ► Targeting of β4 integrin/ILK had potent inhibitory effects in ovarian cancer. -- Abstract: Integrins and integrin-linked kinase (ILK) are essential to cancerous invasion because they mediate physical interactions with the extracellular matrix, and regulate oncogenic signaling pathways. The purpose of our study is to determine whether deletion of β1 and β4 integrin and ILK, alone or in combination, has antitumoral effects in ovarian cancer. Expression of β1 and β4 integrin and ILK was analyzed by immunohistochemistry in 196 ovarian cancer tissue samples. We assessed the effects of depleting these molecules with shRNAs in ovarian cancer cells by Western blot, conventional RT-PCR, cell proliferation, migration, invasion, and in vitro Rac1 activity assays, and in vivo xenograft formation assays. Overexpression of β4 integrin and ILK in human ovarian cancer specimens was found to correlate with tumor aggressiveness. Depletion of these targets efficiently suppresses ovarian cancer cell proliferation, migration, and invasion in vitro and xenograft tumor formation in vivo. We also demonstrated that single depletion of ILK or combination depletion of β4 integrin/ILK inhibits phosphorylation of downstream signaling targets, p-Ser 473 Akt and p-Thr202/Tyr204 Erk1/2, and activation of Rac1, as well as reduce expression of MMP-2 and MMP-9 and increase expression of caspase-3 in vitro. In conclusion, targeting β4 integrin combined with ILK can instigate the latent tumorigenic potential and abrogate the invasive potential in ovarian cancer.

  17. Targeting ILK and {beta}4 integrin abrogates the invasive potential of ovarian cancer

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Yoon Pyo; Kim, Baek Gil [BK21 Project for Medical Science, Yonsei University College of Medicine, Seoul (Korea, Republic of); Department of Pathology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Gao, Ming-Qing; Kang, Suki [Department of Pathology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Cho, Nam Hoon, E-mail: cho1988@yuhs.ac [BK21 Project for Medical Science, Yonsei University College of Medicine, Seoul (Korea, Republic of); Department of Pathology, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer The potential of targeting ILK and integrins for highly aggressive ovarian cancer. Black-Right-Pointing-Pointer Unanticipated synergistic effect for the combination of ILK/{beta}4 integrin. Black-Right-Pointing-Pointer Combination of ILK/{beta}4 integrin effectively inhibited the PI3K/Akt/Rac1 cascade. Black-Right-Pointing-Pointer Targeting of {beta}4 integrin/ILK had potent inhibitory effects in ovarian cancer. -- Abstract: Integrins and integrin-linked kinase (ILK) are essential to cancerous invasion because they mediate physical interactions with the extracellular matrix, and regulate oncogenic signaling pathways. The purpose of our study is to determine whether deletion of {beta}1 and {beta}4 integrin and ILK, alone or in combination, has antitumoral effects in ovarian cancer. Expression of {beta}1 and {beta}4 integrin and ILK was analyzed by immunohistochemistry in 196 ovarian cancer tissue samples. We assessed the effects of depleting these molecules with shRNAs in ovarian cancer cells by Western blot, conventional RT-PCR, cell proliferation, migration, invasion, and in vitro Rac1 activity assays, and in vivo xenograft formation assays. Overexpression of {beta}4 integrin and ILK in human ovarian cancer specimens was found to correlate with tumor aggressiveness. Depletion of these targets efficiently suppresses ovarian cancer cell proliferation, migration, and invasion in vitro and xenograft tumor formation in vivo. We also demonstrated that single depletion of ILK or combination depletion of {beta}4 integrin/ILK inhibits phosphorylation of downstream signaling targets, p-Ser 473 Akt and p-Thr202/Tyr204 Erk1/2, and activation of Rac1, as well as reduce expression of MMP-2 and MMP-9 and increase expression of caspase-3 in vitro. In conclusion, targeting {beta}4 integrin combined with ILK can instigate the latent tumorigenic potential and abrogate the invasive potential in ovarian cancer.

  18. Troglitazone inhibits endothelial cell proliferation through suppression of casein kinase 2 activity

    International Nuclear Information System (INIS)

    Lee, Kuy-Sook; Park, Jin-Hee; Lee, Seahyoung; Lim, Hyun-Joung; Jang, Yangsoo; Park, Hyun-Young

    2006-01-01

    Troglitazone, an agonist of peroxisome proliferator activated receptorγ (PPARγ), has been reported to inhibit endothelial cell proliferation by suppressing Akt activation. Recently, it has been also proposed that phosphatase and tensin homolog deleted from chromosome 10 (PTEN) plays an important role in such effect of troglitazone. However, the mechanism of how troglitazone regulates PTEN remains to be elucidated. We therefore investigated the effects of troglitazone on casein kinase 2 (CK2), which is known to negatively regulate PTEN activity. Troglitazone significantly inhibited serum-induced proliferation of HUVEC in a concentration dependent manner. Serum-induced Akt and its downstream signaling pathway activation was attenuated by troglitazone (10 μM) pretreatment. The phosphorylation of PTEN, which was directly related to Akt activation, was decreased with troglitazone pretreatment and was inversely proportional to CK2 activity. DRB, a CK2 inhibitor, also showed effects similar to that of troglitazone on Akt and its downstream signaling molecules. In conclusion, our results suggest that troglitazone inhibits proliferation of HUVECs through suppression of CK2 activity rendering PTEN to remain activated, and this effect of troglitazone in HUVECs seems to be PPARγ independent

  19. Effect of 21-day and 24-day oral contraceptive regimens containing gestodene (60 microg) and ethinyl estradiol (15 microg) on ovarian activity.

    Science.gov (United States)

    Sullivan, H; Furniss, H; Spona, J; Elstein, M

    1999-07-01

    To compare ovulation inhibition and ovarian activity with 21-day and 24-day regimens of a low-dose combined oral contraceptive (COC) containing 60 microg of gestodene and 15 microg of ethinyl estradiol. Interventional observational study. Reproductive medicine unit. Fifty-eight healthy volunteers aged 18-35 years. Ovarian activity was monitored every other day with the use of ultrasound to measure the diameters of follicle-like structures and blood samples to measure serum concentrations of 17beta-E2 and progesterone. Subjects were observed for five cycles: pretreatment and posttreatment control cycles and three cycles in which the COC was administered for either 21 or 24 days of each cycle. Occurrence of ovulation and evidence of ovarian activity. The study was completed by 27 (90%) of the 30 subjects who received the 24-day regimen and by 24 (79%) of the 28 subjects who received the 21-day regimen. Ovulation was inhibited in all cycles in the 24-day group and in 74 of 75 cycles in the 21-day group. Luteinized unruptured follicles were seen in no cycles with the 24-day regimen and in 6 (8%) of 75 cycles with the 21-day regimen. Mean ovarian follicular development and serum 17beta-E2 and progesterone levels were lower in the 24-day group. The 24-day regimen is an innovative strategy for maintaining effective ovulation inhibition at ultra-low doses of contraceptive steroids.

  20. Mechanism of Ovarian Epithelial Tumor Predispostion in Individuals Carrying Germline BRCA1 Mutations

    National Research Council Canada - National Science Library

    Dubeau, Louis

    2005-01-01

    .... Given the strong link between menstrual activity and risk of ovarian cancer in the general population, we hypothesized that BRCA1 might predispose to ovarian cancer indirectly, by influencing ovarian...

  1. Mechanism of Ovarian Epithelial Tumor Predisposition in Individuals Carrying Germline BRCA1 Mutations

    National Research Council Canada - National Science Library

    Dubeau, Louis

    2006-01-01

    .... Given the strong link between menstrual activity and risk of ovarian cancer in the general population, we hypothesized that BRCA1 might predispose to ovarian cancer indirectly, by influencing ovarian...

  2. Apparent suppression of MMP-9 activity by GD1a as determined by gelatin zymography.

    Science.gov (United States)

    Hu, Dan; Tan, Xuan; Sato, Toshinori; Yamagata, Sadako; Yamagata, Tatsuya

    2006-10-13

    Gelatin zymography is widely used to detect and evaluate matrix metalloproteinase-9 (MMP-9) activity. MMP-9 transcription was previously shown to be negatively regulated by ganglioside GD1a [D. Hu, Z. Man, T. Xuan, P. Wang, T. Takaku, S. Hyuga, X.S. Yao, T. Sato, S. Yamagata, T. Yamagata, Ganglioside GD1a regulation of matrix metalloproteinase-9 (MMP-9) expression in mouse FBJ cell Lines: GD1a suppression of MMP-9 expression stimulated by PI3K-Akt and p38 though not by the Erk signaling pathway, 2006, submitted for publication.]. Zymography of MMP-9 of FBJ-M5 cells preincubated with GD1a indicated a greater decrease in activity than expected from mRNA suppression. Incubation of conditioned medium containing MMP-9 with GD1a caused MMP-9 activity to decrease. Examination was thus made to confirm that MMP-9 activity is actually suppressed and/or MMP-9 protein undergoes degradation by GD1a. GD1a was found to have no effect on MMP-9 activity and Western blots indicated GD1a not to diminish MMP-9 during electrophoresis under reducing conditions. GD1a appeared to mediate the binding of a portion of MMP-9 with certain molecules, with consequently greater molecular mass on the gel, to cause decrease in the activity of MMP-9 at the site where it would normally appear. Caution should be used in doing gelatin zymography since molecules other than GD1a may similarly work, causing decrease in MMP-9 activity in zymography.

  3. Suppressed sympathetic outflow to skeletal muscle, muscle thermogenesis, and activity energy expenditure with calorie restriction.

    Science.gov (United States)

    Almundarij, Tariq I; Gavini, Chaitanya K; Novak, Colleen M

    2017-02-01

    During weight loss, adaptive thermogenesis occurs where energy expenditure (EE) is suppressed beyond that predicted for the smaller body size. Here, we investigated the contributions of resting and nonresting EE to the reduced total EE seen after 3 weeks of 50% calorie restriction (CR) in rats, focusing on activity-associated EE, muscle thermogenesis, and sympathetic outflow. Prolonged food restriction resulted in a 42% reduction in daily EE, through a 40% decrease in resting EE, and a 48% decline in nonresting EE These decreases in EE were significant even when the reductions in body weight and lean mass were taken into account. Along with a decreased caloric need for low-to-moderate-intensity treadmill activity with 50% CR, baseline and activity-related muscle thermogenesis were also suppressed, though the ability to increase muscle thermogenesis above baseline levels was not compromised. When sympathetic drive was measured by assessing norepinephrine turnover (NETO), 50% CR was found to decrease NETO in three of the four muscle groups examined, whereas elevated NETO was found in white adipose tissue of food-restricted rats. Central activation of melanocortin 4 receptors in the ventromedial hypothalamus stimulated this pathway, enhancing activity EE; this was not compromised by 50% CR These data suggest that suppressed activity EE contributes to adaptive thermogenesis during energy restriction. This may stem from decreased sympathetic drive to skeletal muscle, increasing locomotor efficiency and reducing skeletal muscle thermogenesis. The capacity to increase activity EE in response to central stimuli is retained, however, presenting a potential target for preventing weight regain. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  4. Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways

    Directory of Open Access Journals (Sweden)

    Radhakrishnan Sridhar

    2010-05-01

    Full Text Available Abstract Background Obesity is a global phenomenon and is associated with various types of cancer, including colon cancer. There is a growing interest for safe and effective bioactive compounds that suppress the risk for obesity-promoted colon cancer. Resveratrol (trans-3, 4', 5,-trihydroxystilbene, a stilbenoid found in the skin of red grapes and peanuts suppresses many types of cancers by regulating cell proliferation and apoptosis through a variety of mechanisms, however, resveratrol effects on obesity-promoted colon cancer are not clearly established. Methods We investigated the anti-proliferative effects of resveratrol on HT-29 and SW480 human colon cancer cells in the presence and absence of insulin like growth factor-1 (IGF-1; elevated during obesity and elucidated the mechanisms of action using IGF-1R siRNA in HT-29 cells which represents advanced colon carcinogenesis. Results Resveratrol (100-150 μM exhibited anti-proliferative properties in HT-29 cells even after IGF-1 exposure by arresting G0/G1-S phase cell cycle progression through p27 stimulation and cyclin D1 suppression. Treatment with resveratrol suppressed IGF-1R protein levels and concurrently attenuated the downstream Akt/Wnt signaling pathways that play a critical role in cell proliferation. Targeted suppression of IGF-1R using IGF-1R siRNA also affected these signaling pathways in a similar manner. Resveratrol treatment induced apoptosis by activating tumor suppressor p53 protein, whereas IGF-1R siRNA treatment did not affect apoptosis. Our data suggests that resveratrol not only suppresses cell proliferation by inhibiting IGF-1R and its downstream signaling pathways similar to that of IGF-1R siRNA but also enhances apoptosis via activation of the p53 pathway. Conclusions For the first time, we report that resveratrol suppresses colon cancer cell proliferation and elevates apoptosis even in the presence of IGF-1 via suppression of IGF-1R/Akt/Wnt signaling pathways and

  5. Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways

    International Nuclear Information System (INIS)

    Vanamala, Jairam; Reddivari, Lavanya; Radhakrishnan, Sridhar; Tarver, Chris

    2010-01-01

    Obesity is a global phenomenon and is associated with various types of cancer, including colon cancer. There is a growing interest for safe and effective bioactive compounds that suppress the risk for obesity-promoted colon cancer. Resveratrol (trans-3, 4', 5,-trihydroxystilbene), a stilbenoid found in the skin of red grapes and peanuts suppresses many types of cancers by regulating cell proliferation and apoptosis through a variety of mechanisms, however, resveratrol effects on obesity-promoted colon cancer are not clearly established. We investigated the anti-proliferative effects of resveratrol on HT-29 and SW480 human colon cancer cells in the presence and absence of insulin like growth factor-1 (IGF-1; elevated during obesity) and elucidated the mechanisms of action using IGF-1R siRNA in HT-29 cells which represents advanced colon carcinogenesis. Resveratrol (100-150 μM) exhibited anti-proliferative properties in HT-29 cells even after IGF-1 exposure by arresting G 0 /G 1 -S phase cell cycle progression through p27 stimulation and cyclin D1 suppression. Treatment with resveratrol suppressed IGF-1R protein levels and concurrently attenuated the downstream Akt/Wnt signaling pathways that play a critical role in cell proliferation. Targeted suppression of IGF-1R using IGF-1R siRNA also affected these signaling pathways in a similar manner. Resveratrol treatment induced apoptosis by activating tumor suppressor p53 protein, whereas IGF-1R siRNA treatment did not affect apoptosis. Our data suggests that resveratrol not only suppresses cell proliferation by inhibiting IGF-1R and its downstream signaling pathways similar to that of IGF-1R siRNA but also enhances apoptosis via activation of the p53 pathway. For the first time, we report that resveratrol suppresses colon cancer cell proliferation and elevates apoptosis even in the presence of IGF-1 via suppression of IGF-1R/Akt/Wnt signaling pathways and activation of p53, suggesting its potential role as a

  6. Ovarian function and hormone secretion of gilts actively immunized against androstenedione.

    Science.gov (United States)

    McKinnie, M R; Britt, J H; Esbenshade, K L

    1988-12-01

    Fifty crossbred gilts immunized against bovine serum albumin (BSA) or androstenedione conjugated to BSA (AD) were used in three experiments. Primary immunizations were given at 120 d of age and boosters at 148 and 176 d. Gilts were moved to pens containing four to five animals each and exposed to boars beginning at 180 d of age. Immunization against AD did not affect age at puberty, percentage of gilts exhibiting estrus or duration of first estrous cycle. Over the three experiments, ovulation rate was 24% greater for AD-immunized gilts than for controls, and the number of corpora lutea was related positively (r = .82) to the log of the antibody titer. Number of ovulations decreased as interval from booster immunization to onset of estrus increased. During diestrus of the first estrous cycle, gilts immunized against AD had more follicles 5 to 10 mm in diameter, more total ovarian follicles and more total ovarian structures (corpora lutea plus follicles) than controls. Immunization against AD increased the frequency of LH pulses on d 16 but not on d 17 or 18, of the estrous cycle. However, average serum concentrations of LH, FSH and estradiol from 5 d before until 2 d after expected estrus were not different between treatment groups. Concentrations of AD in follicles 4 to 6 and greater than 7 mm in diameter were greater in gilts immunized against AD. Mean serum progesterone was higher on d 9 and 12 after mating in AD immunized gilts than in controls. Immunization against AD had no effect on maintenance of pregnancy or embryo survival rate.

  7. Radiosensitivity profiles from a panel of ovarian cancer cell lines exhibiting genetic alterations in p53 and disparate DNA-dependent protein kinase activities

    Energy Technology Data Exchange (ETDEWEB)

    Langland, Gregory T.; Yannone, Steven M.; Langland, Rachel A.; Nakao, Aki; Guan, Yinghui; Long, Sydney B.T.; Vonguyen, Lien; Chen, David J.; Gray, Joe W; Chen, Fanqing

    2009-09-07

    The variability of radiation responses in ovarian tumors and tumor-derived cell lines is poorly understood. Since both DNA repair capacity and p53 status can significantly alter radiation sensitivity, we evaluated these factors along with radiation sensitivity in a panel of sporadic human ovarian carcinoma cell lines. We observed a gradation of radiation sensitivity among these sixteen lines, with a five-fold difference in the LD50 between the most radiosensitive and the most radioresistant cells. The DNA-dependent protein kinase (DNA-PK) is essential for the repair of radiation induced DNA double-strand breaks in human somatic cells. Therefore, we measured gene copy number, expression levels, protein abundance, genomic copy and kinase activity for DNA-PK in all of our cell lines. While there were detectable differences in DNA-PK between the cell lines, there was no clear correlation with any of these differences and radiation sensitivity. In contrast, p53 function as determined by two independent methods, correlated well with radiation sensitivity, indicating p53 mutant ovarian cancer cells are typically radioresistant relative to p53 wild-type lines. These data suggest that the activity of regulatory molecules such as p53 may be better indicators of radiation sensitivity than DNA repair enzymes such as DNAPK in ovarian cancer.

  8. Isoliquiritigenin Induces Autophagy and Inhibits Ovarian Cancer Cell Growth

    Directory of Open Access Journals (Sweden)

    Hsin-Yuan Chen

    2017-09-01

    Full Text Available Ovarian cancer is one of the commonest gynecologic malignancies, which has a poor prognosis for patients at the advanced stage. Isoliquiritigenin (ISL, an active flavonoid component of the licorice plant, previously demonstrated antioxidant, anti-inflammatory, and tumor suppressive effects. In this study, we investigated the antitumor effect of ISL on human ovarian cancer in vitro using the human ovarian cancer cell lines, OVCAR5 and ES-2, as model systems. Our results show that ISL significantly inhibited the viability of cancer cells in a concentration- and time-dependent manner. Flow cytometry analysis indicated that ISL induced G2/M phase arrest. Furthermore, the expression of cleaved PARP, cleaved caspase-3, Bax/Bcl-2 ratio, LC3B-II, and Beclin-1 levels were increased in western blot analysis. To clarify the role of autophagy and apoptosis in the effect of ISL, we used the autophagy inhibitor—3-methyladenine (3-MA to attenuate the punctate fluorescence staining pattern of the p62/sequestosome 1 (SQSTM1, red fluorescence and LC3 (green fluorescence proteins after ISL treatment, and 3-MA inhibited the cytotoxicity of ISL. These findings provide new information about the link between ISL-induced autophagy and apoptosis and suggest that ISL is a candidate agent for the treatment of human ovarian cancer.

  9. Active Vibration Suppression of a 3-DOF Flexible Parallel Manipulator Using Efficient Modal Control

    Directory of Open Access Journals (Sweden)

    Quan Zhang

    2014-01-01

    Full Text Available This paper addresses the dynamic modeling and efficient modal control of a planar parallel manipulator (PPM with three flexible linkages actuated by linear ultrasonic motors (LUSM. To achieve active vibration control, multiple lead zirconate titanate (PZT transducers are mounted on the flexible links as vibration sensors and actuators. Based on Lagrange’s equations, the dynamic model of the flexible links is derived with the dynamics of PZT actuators incorporated. Using the assumed mode method (AMM, the elastic motion of the flexible links are discretized under the assumptions of pinned-free boundary conditions, and the assumed mode shapes are validated through experimental modal test. Efficient modal control (EMC, in which the feedback forces in different modes are determined according to the vibration amplitude or energy of their own, is employed to control the PZT actuators to realize active vibration suppression. Modal filters are developed to extract the modal displacements and velocities from the vibration sensors. Numerical simulation and vibration control experiments are conducted to verify the proposed dynamic model and controller. The results show that the EMC method has the capability of suppressing multimode vibration simultaneously, and both the structural and residual vibrations of the flexible links are effectively suppressed using EMC approach.

  10. Monocytes and the 38kDa-antigen of mycobacterium tuberculosis modulate natural killer cell activity and their cytolysis directed against ovarian cancer cell lines

    Directory of Open Access Journals (Sweden)

    Gottschalk Nina

    2012-10-01

    Full Text Available Abstract Background Despite strong efforts to improve clinical outcome of ovarian cancer patients by conventional and targeted immuno-based therapies, the prognosis of advanced ovarian cancer is still poor. Natural killer (NK cells mediate antibody-dependent cellular cytotoxicity (ADCC, release immunostimulatory cytokines and thus function as potent anti-tumour effector cells. However, tumour cells developed mechanisms to escape from an effective immune response. So highly immunogenic substances, like the 38 kDa-preparation of M. tuberculosis, PstS-1, are explored for their potential to enhance cancer-targeted immune responses. In this study we examined the modulation of different NK cell functions by accessory monocytes and PstS-1. We focussed on NK cell activation as well as natural and antibody-dependent cellular cytotoxicity directed against epidermal-growth-factor-receptor (EGFR-positive ovarian cancer cell lines. Methods Activation, cytokine release and cytotoxicity of NK cells stimulated by monocytes and PstS-1 were determined by FACS-analysis, ELISA, Bioplex assay and quantitative polymerase-chain reaction (qPCR. Transwell assays were used to discriminate cell-cell contact-dependent from contact-independent mechanisms. Five ovarian cancer cell lines (A2780, IGROV-1, OVCAR-3, OVCAR-4 and SKOV-3 with different EGFR-expression were used as target cells for natural and antibody-dependent cellular cytotoxicity assays. Cetuximab (anti-EGFR-antibody was used for ADCC studies. Results Our data show that monocytes effectively enhance activation as well natural and antibody-dependent cytolytic activity of NK cells. PstS-1 directly stimulated monocytes and further activated monocyte-NK-co-cultures. However, PstS-1 did not directly influence purified NK cells and did also not affect natural and antibody-dependent cellular cytotoxicity directed against EGFR-positive ovarian cancer cells, even in presence of monocytes. Direct cell-cell contact between

  11. TET1 Suppresses Cancer Invasion by Activating the Tissue Inhibitors of Metalloproteinases

    Directory of Open Access Journals (Sweden)

    Chih-Hung Hsu

    2012-09-01

    Full Text Available Tumor suppressor gene silencing through cytosine methylation contributes to cancer formation. Whether DNA demethylation enzymes counteract this oncogenic effect is unknown. Here, we show that TET1, a dioxygenase involved in cytosine demethylation, is downregulated in prostate and breast cancer tissues. TET1 depletion facilitates cell invasion, tumor growth, and cancer metastasis in prostate xenograft models and correlates with poor survival rates in breast cancer patients. Consistently, enforced expression of TET1 reduces cell invasion and breast xenograft tumor formation. Mechanistically, TET1 suppresses cell invasion through its dioxygenase and DNA binding activities. Furthermore, TET1 maintains the expression of tissue inhibitors of metalloproteinase (TIMP family proteins 2 and 3 by inhibiting their DNA methylation. Concurrent low expression of TET1 and TIMP2 or TIMP3 correlates with advanced node status in clinical samples. Together, these results illustrate a mechanism by which TET1 suppresses tumor development and invasion partly through downregulation of critical gene methylation.

  12. USP10 Antagonizes c-Myc Transcriptional Activation through SIRT6 Stabilization to Suppress Tumor Formation

    Directory of Open Access Journals (Sweden)

    Zhenghong Lin

    2013-12-01

    Full Text Available The reduced protein expression of SIRT6 tumor suppressor is involved in tumorigenesis. The molecular mechanisms underlying SIRT6 protein downregulation in human cancers remain unknown. Using a proteomic approach, we have identified the ubiquitin-specific peptidase USP10, another tumor suppressor, as one of the SIRT6-interacting proteins. USP10 suppresses SIRT6 ubiquitination to protect SIRT6 from proteasomal degradation. USP10 antagonizes the transcriptional activity of the c-Myc oncogene through SIRT6, as well as p53, to inhibit cell-cycle progression, cancer cell growth, and tumor formation. To support this conclusion, we detected significant reductions in both USP10 and SIRT6 protein expression in human colon cancers. Our study discovered crosstalk between two tumor-suppressive genes in regulating cell-cycle progression and proliferation and showed that dysregulated USP10 function promotes tumorigenesis through SIRT6 degradation.

  13. Analysis of Harmonics Suppression by Active Damping Control on Multi Slim DC-link Drives

    DEFF Research Database (Denmark)

    Yang, Feng; Máthé, Lászlo; Lu, Kaiyuan

    2016-01-01

    Compared with conventional dc-link drive, slim dc-link drive is expected to achieve lower cost and longer life time. However, harmonics distortion problem may occur in such drive systems. This paper proposes to use an active damping control method to suppress the harmonic distortion...... with the benefit of low cost and also low loss. A new analysis method, based on the frequency domain impedance model, is presented to explore the mechanism of harmonics suppression. Also, a general method is presented to build the impedance model of a PMSM drive system using Field Oriented Control (FOC) method....... Some design issues, including power levels, current control bandwidth and harmonic interaction, are discussed when the drive system is fed by a weak grid. Case studies on a two-drive system composed by two slim dc-link drive units are provided to verify the proposed analysis method....

  14. Study on Active Suppression Control of Drivetrain Oscillations in an Electric Vehicle

    Science.gov (United States)

    Huang, Lei; Cui, Ying

    2017-07-01

    Due to the low damping in a central driven electric vehicle and lack of passive damping mechanisms as compared with a conventional vehicle, the vehicle may endure torsional vibrations which may deteriorates the vehicle’s drivability. Thus active damping control strategy is required to reduce the undesirable oscillations in an EV. In this paper, the origin of the vibration and the design of a damping control method to suppress such oscillations to improve the drivability of an EV are studied. The traction motor torque that is given by the vehicle controller is adjusted according to the acceleration rate of the motor speed to attenuate the resonant frequency. Simulations and experiments are performed to validate the system. The results show that the proposed control system can effectively suppress oscillations and hence improve drivability.

  15. Actively approaching women with a history of ovarian cancer for genetic counselling by GP, desirable and feasible?

    NARCIS (Netherlands)

    Vliet, L.M. van; Helpser, C.W.; Velthuizen, M.E.; Dulmen, A.M. van; Zweemer, R.P.; Witteveen, P.O.; Butter, E.S.F.A.; Luijt, R.B. van der; Gent-Wagemakers, M.P.L. van; Beijaert, R.P.H.; Wit, N.J. de; Ausems, M.G.E.M.

    2017-01-01

    Background: According to recent guidelines, genetic counselling and DNA testing is recommended to all women with ovarian cancer to optimally customize follow-up for them and their kin. Since previous guidelines did not advise referral for most of these women, the majority of ovarian cancer survivors

  16. HPIP promotes epithelial-mesenchymal transition and cisplatin resistance in ovarian cancer cells through PI3K/AKT pathway activation.

    Science.gov (United States)

    Bugide, Suresh; Gonugunta, Vijay Kumar; Penugurti, Vasudevarao; Malisetty, Vijaya Lakshmi; Vadlamudi, Ratna K; Manavathi, Bramanandam

    2017-04-01

    Hematopoietic PBX interacting protein (HPIP), a scaffold protein, is known to regulate the proliferation, migration and invasion in different cancer cell types. The aim of this study was to assess the role of HPIP in ovarian cancer cell migration, invasion and epithelial-mesenchymal transition (EMT), and to unravel the mechanism by which it regulates these processes. HPIP expression was assessed by immunohistochemistry of tissue microarrays containing primary ovarian tumor samples of different grades. OAW42, an ovarian carcinoma-derived cell line exhibiting a high HPIP expression, was used to study the role of HPIP in cell migration, invasion and EMT. HPIP knockdown in these cells was achieved using a small hairpin RNA (shRNA) approach. Cell migration and invasion were assessed using scratch wound and transwell invasion assays, respectively. The extent of EMT was assessed by determining the expression levels of Snail, Vimentin and E-cadherin using Western blotting. The effect of HPIP expression on AKT and MAPK activation was also investigated by Western blotting. Cell viabilities in response to cisplatin treatment were assessed using a MTT assay, whereas apoptosis was assessed by determining caspase-3 and PARP cleavage in ovarian carcinoma-derived SKOV3 cells. We found that HPIP is highly expressed in high-grade primary ovarian tumors. In addition, we found that HPIP promotes the migration, invasion and EMT in OAW42 cells and induces EMT in these cells via activation of the PI3K/AKT pathway. The latter was found to lead to stabilization of the Snail protein and to repression of E-cadherin expression through inactivation of GSK-3β. We also found that HPIP expression confers cisplatin resistance to SKOV3 cells after prolonged exposure and that its subsequent knockdown decreases the viability of these cells and increases caspase-3 activation and PARP proteolysis in these cells following cisplatin treatment. From these results we conclude that HPIP expression is

  17. Chimaerin suppresses Rac1 activation at the apical membrane to maintain the cyst structure.

    Directory of Open Access Journals (Sweden)

    Shunsuke Yagi

    Full Text Available Epithelial organs are made of a well-polarized monolayer of epithelial cells, and their morphology is maintained strictly for their proper functions. Previously, we showed that Rac1 activation is suppressed at the apical membrane in the mature organoid, and that such spatially biased Rac1 activity is required for the polarity maintenance. Here we identify Chimaerin, a GTPase activating protein for Rac1, as a suppressor of Rac1 activity at the apical membrane. Depletion of Chimaerin causes over-activation of Rac1 at the apical membrane in the presence of hepatocyte growth factor (HGF, followed by luminal cell accumulation. Importantly, Chimaerin depletion did not inhibit extension formation at the basal membrane. These observations suggest that Chimaerin functions as the apical-specific Rac1 GAP to maintain epithelial morphology.

  18. Hybrid Active Filter with Variable Conductance for Harmonic Resonance Suppression in Industrial Power Systems

    DEFF Research Database (Denmark)

    Lee, Tzung-Lin; Wang, Yen-Ching; Li, Jian-Cheng

    2015-01-01

    Unintentional series and/or parallel resonances, due to the tuned passive filter and the line inductance, may result in severe harmonic distortion in the industrial power system. This paper presents a hybrid active filter to suppress harmonic resonance and reduce harmonic distortion as well......-tuned passive filter and an active filter in series connection, both dc voltage and kVA rating of the active filter are dramatically decreased compared with the pure shunt active filter. In real application, this feature is very attractive since the active power filter with fully power electronics is very....... The proposed hybrid filter is operated as variable harmonic conductance according to the voltage total harmonic distortion, so harmonic distortion can be reduced to an acceptable level in response to load change or parameter variation of power system. Since the hybrid filter is composed of a seventh...

  19. Endothelial cells suppress monocyte activation through secretion of extracellular vesicles containing antiinflammatory microRNAs.

    Science.gov (United States)

    Njock, Makon-Sébastien; Cheng, Henry S; Dang, Lan T; Nazari-Jahantigh, Maliheh; Lau, Andrew C; Boudreau, Emilie; Roufaiel, Mark; Cybulsky, Myron I; Schober, Andreas; Fish, Jason E

    2015-05-14

    The blood contains high concentrations of circulating extracellular vesicles (EVs), and their levels and contents are altered in several disease states, including cardiovascular disease. However, the function of circulating EVs, especially the microRNAs (miRNAs) that they contain, are poorly understood. We sought to determine the effect of secreted vesicles produced by quiescent endothelial cells (ECs) on monocyte inflammatory responses and to assess whether transfer of microRNAs occurs between these cells. We observed that monocytic cells cocultured (but not in contact) with ECs were refractory to inflammatory activation. Further characterization revealed that endothelium-derived EVs (EC-EVs) suppressed monocyte activation by enhancing immunomodulatory responses and diminishing proinflammatory responses. EVs isolated from mouse plasma also suppressed monocyte activation. Importantly, injection of EC-EVs in vivo repressed monocyte/macrophage activation, confirming our in vitro findings. We found that several antiinflammatory microRNAs were elevated in EC-EV-treated monocytes. In particular, miR-10a was transferred to monocytic cells from EC-EVs and could repress inflammatory signaling through the targeting of several components of the NF-κB pathway, including IRAK4. Our findings reveal that ECs secrete EVs that can modulate monocyte activation and suggest that altered EV secretion and/or microRNA content may affect vascular inflammation in the setting of cardiovascular disease. © 2015 by The American Society of Hematology.

  20. Antiosteoclastic Activity of Milk Thistle Extract after Ovariectomy to Suppress Estrogen Deficiency-Induced Osteoporosis

    Science.gov (United States)

    Kim, Jung-Lye; Kim, Yun-Ho; Kang, Min-Kyung; Gong, Ju-Hyun; Han, Seoung-Jun; Kang, Young-Hee

    2013-01-01

    Bone integrity abnormality and imbalance between bone formation by osteoblasts and bone resorption by osteoclasts are known to result in metabolic bone diseases such as osteoporosis. Silymarin-rich milk thistle extract (MTE) and its component silibinin enhanced alkaline phosphatase activity of osteoblasts but reduced tartrate-resistant acid phosphatase (TRAP) activity of osteoclasts. The osteoprotective effects of MTE were comparable to those of estrogenic isoflavone. Low-dose combination of MTE and isoflavone had a pharmacological synergy that may be useful for osteogenic activity. This study attempted to reveal the suppressive effects of MTE on bone loss. C57BL/6 female mice were ovariectomized (OVX) as a model for postmenopausal osteopenia and orally administered 10 mg/kg MTE or silibinin for 8 weeks. The sham-operated mice served as estrogen controls. The treatment of ovariectomized mice with nontoxic MTE and silibinin improved femoral bone mineral density and serum receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio, an index of osteoclastogenic stimulus. In addition, the administration of MTE or silibinin inhibited femoral bone loss induced by ovariectomy and suppressed femoral TRAP activity and cathepsin K induction responsible for osteoclastogenesis and bone resorption. Collectively, oral dosage of MTE containing silibinin in the preclinical setting is effective in preventing estrogen deficiency-induced bone loss. PMID:23781510

  1. Principle and Control Design of Active Ground-Fault Arc Suppression Device for Full Compensation of Ground Current

    DEFF Research Database (Denmark)

    Wang, Wen; Zeng, Xiangjun; Yan, Lingjie

    2017-01-01

    . The commonly-used large-capacity reactive component may bring about overvoltage because of possible resonance with the distributed phase-to-ground capacitance. To solve these problems, an active ground-fault arc suppression device is presented. It employs a topology based on single-phase inverter to inject...... suppression without capacitive current detection. Its time-based feature also brings the benefit of fast response on ground-fault arc suppression. The principle of full current compensation is analyzed, together with the controller design method of the proposed device. Experiment on a prototype was carried......Traditional ground-fault arc suppression devices mainly deal with capacitive component of ground current and have weak effect on the active and harmonic ones, which limits the arc suppression performance. The capacitive current detection needed in them suffers from low accuracy and robustness...

  2. Ovarian structure and oogenesis of the extremophile viviparous teleost Poecilia mexicana (Poeciliidae) from an active sulfur spring cave in Southern Mexico.

    Science.gov (United States)

    Torres-Martínez, Aarón; Hernández-Franyutti, Arlette; Uribe, Mari Carmen; Contreras-Sánchez, Wilfrido Miguel

    2017-12-01

    The structure of the ovary and oogenesis of Poecilia mexicana from an active sulfur spring cave is documented. Poecilia mexicana is the only poeciliid adapted to a subterranean environment with high hydrogen sulfide levels and extreme hypoxic conditions. Twenty females were captured throughout one year at Cueva del Azufre, located in the State of Tabasco in Southern Mexico. Ovaries were processed with histological techniques. P. mexicana has a single, ovoid ovary with ovigerous lamella that project to the ovarian lumen. The ovarian wall presents abundant loose connective tissue, numerous melanomacrophage centers and large blood vessels, possibly associated with hypoxic conditions. The germinal epithelium bordering the ovarian lumen contains somatic and germ cells forming cell nests projecting into the stroma. P. mexicana stores sperm in ovarian folds associated with follicles at different developmental phases. Oogenesis in P. mexicana consisted of the following stages: (i) oogonial proliferation, (ii) chromatin nucleolus, (iii) primary growth, subdivided into: (a) one nucleolus, (b) multiple nucleoli, (c) droplet oils-cortical alveoli steps; (iv) secondary growth, subdivided in: (a) early secondary growth, (b) late secondary growth, and (c) full grown. Follicular atresia was present in all stages of follicular development; it was characterized by oocyte degeneration, where follicle cells hypertrophy and differentiate in phagocytes. The ovary and oogenesis are similar to these seen in other poeciliids, but we found frequent atretic follicles, melanomacrophage centers, reduced fecundity and increased of offspring size. © 2017 Wiley Periodicals, Inc.

  3. Specific TP53 Mutants Overrepresented in Ovarian Cancer Impact CNV, TP53 Activity, Responses to Nutlin-3a, and Cell Survival

    Directory of Open Access Journals (Sweden)

    Lisa K. Mullany

    2015-10-01

    Full Text Available Evolutionary Action analyses of The Cancer Gene Atlas data sets show that many specific p53 missense and gain-of-function mutations are selectively overrepresented and functional in high-grade serous ovarian cancer (HGSC. As homozygous alleles, p53 mutants are differentially associated with specific loss of heterozygosity (R273; chromosome 17; copy number variation (R175H; chromosome 9; and up-stream, cancer-related regulatory pathways. The expression of immune-related cytokines was selectively related to p53 status, showing for the first time that specific p53 mutants impact, and are related to, the immune subtype of ovarian cancer. Although the majority (31% of HGSCs exhibit loss of heterozygosity, a significant number (24% maintain a wild-type (WT allele and represent another HGSC subtype that is not well defined. Using human and mouse cell lines, we show that specific p53 mutants differentially alter endogenous WT p53 activity; target gene expression; and responses to nutlin-3a, a small molecular that activates WT p53 leading to apoptosis, providing “proof of principle” that ovarian cancer cells expressing WT and mutant alleles represent a distinct ovarian cancer subtype. We also show that siRNA knock down of endogenous p53 in cells expressing homozygous mutant alleles causes apoptosis, whereas cells expressing WT p53 (or are heterozygous for WT and mutant p53 alleles are highly resistant. Therefore, despite different gene regulatory pathways associated with specific p53 mutants, silencing mutant p53 might be a suitable, powerful, global strategy for blocking ovarian cancer growth in those tumors that rely on mutant p53 functions for survival. Knowing p53 mutational status in HGSC should permit new strategies tailored to control this disease.

  4. The Activities and Impact of State Programs to Address Hereditary Breast and Ovarian Cancer, 2011–2014

    Directory of Open Access Journals (Sweden)

    Katrina F. Trivers

    2015-10-01

    Full Text Available In 2011, the Division of Cancer Prevention and Control (DCPC, at the United States Centers for Disease Control and Prevention (CDC, released a three-year funding opportunity announcement (FOA for a competitive, non-research cooperative agreement. The agreement enhanced the capacities of state health departments to promote the application of best practices for evidence-based breast cancer genomics through education, surveillance, and policy activities. The FOA required that applicants focus on activities related to hereditary breast and ovarian cancer (HBOC. The DCPC funded three states: Georgia, Michigan, and Oregon. Georgia was a first-time recipient of cancer genomics funding, whereas Michigan and Oregon had long standing activities in cancer genomics and had received CDC funding in the past. By the end of the funding period, each state had well-functioning and impactful state-based programs in breast cancer genomics. This article highlights the impact of a few key state activities by using CDC’s Science Impact Framework. There were challenges to implementing public health genomics programs, including the need to develop relevant partnerships, the highly technical nature of the subject matter, a lack of genetic services in certain areas, and the difficulty in funding genetic services. Georgia, Michigan, and Oregon have served as models for others interested in initiating or expanding cancer genomics programs, and they helped to determine what works well for promoting and integrating public health genomics into existing systems.

  5. Fear conditioning suppresses large-conductance calcium-activated potassium channels in lateral amygdala neurons.

    Science.gov (United States)

    Sun, P; Zhang, Q; Zhang, Y; Wang, F; Wang, L; Yamamoto, R; Sugai, T; Kato, N

    2015-01-01

    It was previously shown that depression-like behavior is accompanied with suppression of the large-conductance calcium activated potassium (BK) channel in cingulate cortex pyramidal cells. To test whether BK channels are also involved in fear conditioning, we studied neuronal properties of amygdala principal cells in fear conditioned mice. After behavior, we made brain slices containing the amygdala, the structure critically relevant to fear memory. The resting membrane potential in lateral amygdala (LA) neurons obtained from fear conditioned mice (FC group) was more depolarized than in neurons from naïve controls. The frequencies of spikes evoked by current injections were higher in neurons from FC mice, demonstrating that excitability of LA neurons was elevated by fear conditioning. The depolarization in neurons from FC mice was shown to depend on BK channels by using the BK channel blocker charybdotoxin. Suppression of BK channels in LA neurons from the FC group was further confirmed on the basis of the spike width, since BK channels affect the descending phase of spikes. Spikes were broader in the FC group than those in the naïve control in a manner dependent on BK channels. Consistently, quantitative real-time PCR revealed a decreased expression of BK channel mRNA. The present findings suggest that emotional disorder manifested in the forms of fear conditioning is accompanied with BK channel suppression in the amygdala, the brain structure critical to this emotional disorder. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. IKKα Activation of NOTCH LinksTumorigenesis via FOXA2 Suppression

    Science.gov (United States)

    Liu, Mo; Lee, Dung-Fang; Chen, Chun-Te; Yen, Chia-Jui; Li, Long-Yuan; Lee, Hong-Jen; Chang, Chun-Ju; Chang, Wei-Chao; Hsu, Jung-Mao; Kuo, Hsu-Ping; Xia, Weiya; Wei, Yongkun; Chiu, Pei-Chun; Chou, Chao-Kai; Du, Yi; Dhar, Debanjan; Karin, Michael; Chen, Chung-Hsuan; Hung, Mien-Chie

    2011-01-01

    SUMMARY Pro-inflammatory cytokine TNFα plays critical roles in promoting malignant cell proliferation, angiogenesis, and tumor metastasis in many cancers. However, the mechanism of TNFα-mediated tumor development remains unclear. Here, we show that IKKα, an important downstream kinase of TNFα, interacts with and phosphorylates FOXA2 at S107/ S111, thereby suppressing FOXA2 transactivation activity, leading to decreased NUMB expression and further activates the downstream NOTCH pathway and promotes cell proliferation and tumorigenesis. Moreover, we found that levels of IKKα, pFOXA2 (S107/111), and activated NOTCH1 were significantly higher in hepatocellular carcinoma tumors than in normal liver tissues and that pFOXA2 (S107/111) expression was positively correlated with IKKα and activated NOTCH1 expression in tumor tissues. Therefore, dysregulation of NUMB-mediated suppression of NOTCH1 by TNFα/IKKα-associated FOXA2 inhibition likely contributes to inflammation-mediated cancer pathogenesis. Here, we report TNFα/IKKα/FOXA2/NUMB/NOTCH1 pathway that is critical for inflammation-mediated tumorigenesis and may provide a target for clinical intervention in human cancer. PMID:22196886

  7. The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis.

    Science.gov (United States)

    Dominy, John E; Lee, Yoonjin; Jedrychowski, Mark P; Chim, Helen; Jurczak, Michael J; Camporez, Joao Paulo; Ruan, Hai-Bin; Feldman, Jessica; Pierce, Kerry; Mostoslavsky, Raul; Denu, John M; Clish, Clary B; Yang, Xiaoyong; Shulman, Gerald I; Gygi, Steven P; Puigserver, Pere

    2012-12-28

    Hepatic glucose production (HGP) maintains blood glucose levels during fasting but can also exacerbate diabetic hyperglycemia. HGP is dynamically controlled by a signaling/transcriptional network that regulates the expression/activity of gluconeogenic enzymes. A key mediator of gluconeogenic gene transcription is PGC-1α. PGC-1α's activation of gluconeogenic gene expression is dependent upon its acetylation state, which is controlled by the acetyltransferase GCN5 and the deacetylase Sirt1. Nevertheless, whether other chromatin modifiers-particularly other sirtuins-can modulate PGC-1α acetylation is currently unknown. Herein, we report that Sirt6 strongly controls PGC-1α acetylation. Surprisingly, Sirt6 induces PGC-1α acetylation and suppresses HGP. Sirt6 depletion decreases PGC-1α acetylation and promotes HGP. These acetylation effects are GCN5 dependent: Sirt6 interacts with and modifies GCN5, enhancing GCN5's activity. Lepr(db/db) mice, an obese/diabetic animal model, exhibit reduced Sirt6 levels; ectopic re-expression suppresses gluconeogenic genes and normalizes glycemia. Activation of hepatic Sirt6 may therefore be therapeutically useful for treating insulin-resistant diabetes. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Macrophage activation induced by Brucella DNA suppresses bacterial intracellular replication via enhancing NO production.

    Science.gov (United States)

    Liu, Ning; Wang, Lin; Sun, Changjiang; Yang, Li; Tang, Bin; Sun, Wanchun; Peng, Qisheng

    2015-12-01

    Brucella DNA can be sensed by TLR9 on endosomal membrane and by cytosolic AIM2-inflammasome to induce proinflammatory cytokine production that contributes to partially activate innate immunity. Additionally, Brucella DNA has been identified to be able to act as a major bacterial component to induce type I IFN. However, the role of Brucella DNA in Brucella intracellular growth remains unknown. Here, we showed that stimulation with Brucella DNA promote macrophage activation in TLR9-dependent manner. Activated macrophages can suppresses wild type Brucella intracellular replication at early stage of infection via enhancing NO production. We also reported that activated macrophage promotes bactericidal function of macrophages infected with VirB-deficient Brucella at the early or late stage of infection. This study uncovers a novel function of Brucella DNA, which can help us further elucidate the mechanism of Brucella intracellular survival. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. PCAF Improves Glucose Homeostasis by Suppressing the Gluconeogenic Activity of PGC-1α

    Directory of Open Access Journals (Sweden)

    Cheng Sun

    2014-12-01

    Full Text Available PGC-1α plays a central role in hepatic gluconeogenesis and has been implicated in the onset of type 2 diabetes. Acetylation is an important posttranslational modification for regulating the transcriptional activity of PGC-1α. Here, we show that PCAF is a pivotal acetyltransferase for acetylating PGC-1α in both fasted and diabetic states. PCAF acetylates two lysine residues K328 and K450 in PGC-1α, which subsequently triggers its proteasomal degradation and suppresses its transcriptional activity. Adenoviral-mediated expression of PCAF in the obese mouse liver greatly represses gluconeogenic enzyme activation and glucose production and improves glucose homeostasis and insulin sensitivity. Moreover, liver-specific knockdown of PCAF stimulates PGC-1α activity, resulting in an increase in blood glucose and hepatic glucose output. Our results suggest that PCAF might be a potential pharmacological target for developing agents against metabolic disorders associated with hyperglycemia, such as obesity and diabetes.

  10. Study of exteroceptive suppression of voluntary muscular activity in healthy volunteers and patients with paroxysmal neuropathic pain.

    Science.gov (United States)

    Gordeev, S A; Turbina, L G; Shtang, O M

    2014-07-01

    The exteroceptive suppression of voluntary electromyographic activity of the masseter and temporal muscles was studied in healthy volunteers and patients with paroxysmal neuropathic pain (trigeminal neuralgia). The latent period of the exteroceptive suppression was prolonged and the duration of its late fragment was shortened in the patients in comparison with normal subjects. A short exteroceptive suppression period in patients with trigeminal neuralgia reflected deficient activity of inhibitory interneurons of the reflector loop and excessive activity of the antinociceptive system of the brain stem, while prolongation of the latent period reflected prolongation of inhibitory interneurons activation. A direct correlation between the degree of changes in the exteroceptive suppression parameters and pain intensity, evaluated by the patients by the visual analog scale, was detected.

  11. Functional connectivity in raphé-pontomedullary circuits supports active suppression of breathing during hypocapnic apnea

    Science.gov (United States)

    Nuding, Sarah C.; Segers, Lauren S.; Iceman, Kimberly E.; O'Connor, Russell; Dean, Jay B.; Bolser, Donald C.; Baekey, David M.; Dick, Thomas E.; Shannon, Roger; Morris, Kendall F.

    2015-01-01

    Hyperventilation is a common feature of disordered breathing. Apnea ensues if CO2 drive is sufficiently reduced. We tested the hypothesis that medullary raphé, ventral respiratory column (VRC), and pontine neurons have functional connectivity and persistent or evoked activities appropriate for roles in the suppression of drive and rhythm during hyperventilation and apnea. Phrenic nerve activity, arterial blood pressure, end-tidal CO2, and other parameters were monitored in 10 decerebrate, vagotomized, neuromuscularly-blocked, and artificially ventilated cats. Multielectrode arrays recorded spiking activity of 649 neurons. Loss and return of rhythmic activity during passive hyperventilation to apnea were identified with the S-transform. Diverse fluctuating activity patterns were recorded in the raphé-pontomedullary respiratory network during the transition to hypocapnic apnea. The firing rates of 160 neurons increased during apnea; the rates of 241 others decreased or stopped. VRC inspiratory neurons were usually the last to cease firing or lose rhythmic activity during the transition to apnea. Mayer wave-related oscillations (0.04–0.1 Hz) in firing rate were also disrupted during apnea. Four-hundred neurons (62%) were elements of pairs with at least one hyperventilation-responsive neuron and a correlational signature of interaction identified by cross-correlation or gravitational clustering. Our results support a model with distinct groups of chemoresponsive raphé neurons contributing to hypocapnic apnea through parallel processes that incorporate disfacilitation and active inhibition of inspiratory motor drive by expiratory neurons. During apnea, carotid chemoreceptors can evoke rhythm reemergence and an inspiratory shift in the balance of reciprocal inhibition via suppression of ongoing tonic expiratory neuron activity. PMID:26203111

  12. Opiate-induced suppression of rat hypoglossal motoneuron activity and its reversal by ampakine therapy.

    Directory of Open Access Journals (Sweden)

    Amanda R Lorier

    2010-01-01

    Full Text Available Hypoglossal (XII motoneurons innervate tongue muscles and are vital for maintaining upper-airway patency during inspiration. Depression of XII nerve activity by opioid analgesics is a significant clinical problem, but underlying mechanisms are poorly understood. Currently there are no suitable pharmacological approaches to counter opiate-induced suppression of XII nerve activity while maintaining analgesia. Ampakines accentuate alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA receptor responses. The AMPA family of glutamate receptors mediate excitatory transmission to XII motoneurons. Therefore the objectives were to determine whether the depressant actions of mu-opioid receptor activation on inspiratory activity includes a direct inhibitory action at the inspiratory premotoneuron to XII motoneuron synapse, and to identify underlying mechanism(s. We then examined whether ampakines counteract opioid-induced depression of XII motoneuron activity.A medullary slice preparation from neonatal rat that produces inspiratory-related output in vitro was used. Measurements of inspiratory burst amplitude and frequency were made from XII nerve roots. Whole-cell patch recordings from XII motoneurons were used to measure membrane currents and synaptic events. Application of the mu-opioid receptor agonist, DAMGO, to the XII nucleus depressed the output of inspiratory XII motoneurons via presynaptic inhibition of excitatory glutamatergic transmission. Ampakines (CX614 and CX717 alleviated DAMGO-induced depression of XII MN activity through postsynaptic actions on XII motoneurons.The inspiratory-depressant actions of opioid analgesics include presynaptic inhibition of XII motoneuron output. Ampakines counteract mu-opioid receptor-mediated depression of XII motoneuron inspiratory activity. These results suggest that ampakines may be beneficial in countering opiate-induced suppression of XII motoneuron activity and resultant impairment of airway patency.

  13. Scutellarin Suppresses NLRP3 Inflammasome Activation in Macrophages and Protects Mice against Bacterial Sepsis.

    Science.gov (United States)

    Liu, Yi; Jing, Yan-Yun; Zeng, Chen-Ying; Li, Chen-Guang; Xu, Li-Hui; Yan, Liang; Bai, Wen-Jing; Zha, Qing-Bing; Ouyang, Dong-Yun; He, Xian-Hui

    2017-01-01

    The NLRP3 inflammasome plays a critical role in mediating the innate immune defense against pathogenic infections, but aberrant activation of NLRP3 inflammasome has been linked to a variety of inflammatory diseases. Thus targeting the NLRP3 inflammasome represents a promising therapeutic for the treatment of such diseases. Scutellarin is a flavonoid isolated from Erigeron breviscapus (Vant.) Hand.-Mazz. and has been reported to exhibit potent anti-inflammatory activities, but the underlying mechanism is only partly understood. In this study, we aimed to investigate whether scutellarin could affect the activation of NLRP3 inflammasome in macrophages. The results showed that scutellarin dose-dependently reduced caspase-1 activation and decreased mature interleukin-1β (IL-1β) release in lipopolysaccharide (LPS)-primed macrophages upon ATP or nigericin stimulation, indicating that scutellarin inhibited NLRP3 inflammasome activation in macrophages. Consistent with this, scutellarin also suppressed pyroptotic cell death in LPS-primed macrophages treated with ATP or nigericin. ATP or nigericin-induced ASC speck formation and its oligomerization were blocked by scutellarin pre-treatment. Intriguingly, scutellarin augmented PKA-specific phosphorylation of NLRP3 in LPS-primed macrophages, which was completely blocked by selective PKA inhibitor H89, suggesting that PKA signaling had been involved in the action of scutellarin to suppress NLRP3 inflammasome activation. Supporting this, the inhibitory effect of scutellarin on NLRP3 inflammasome activation was completely counteracted by H89 or adenyl cyclase inhibitor MDL12330A. As NLRP3-dependent release of IL-1β has a critical role in sepsis, the in vivo activity of scutellarin was assayed in a mouse model of bacterial sepsis, which was established by intraperitoneally injection of a lethal dose of viable Escherichia coli . Oral administration of scutellarin significantly improved the survival of mice with bacterial sepsis

  14. Scutellarin Suppresses NLRP3 Inflammasome Activation in Macrophages and Protects Mice against Bacterial Sepsis

    Directory of Open Access Journals (Sweden)

    Yi Liu

    2018-01-01

    Full Text Available The NLRP3 inflammasome plays a critical role in mediating the innate immune defense against pathogenic infections, but aberrant activation of NLRP3 inflammasome has been linked to a variety of inflammatory diseases. Thus targeting the NLRP3 inflammasome represents a promising therapeutic for the treatment of such diseases. Scutellarin is a flavonoid isolated from Erigeron breviscapus (Vant. Hand.-Mazz. and has been reported to exhibit potent anti-inflammatory activities, but the underlying mechanism is only partly understood. In this study, we aimed to investigate whether scutellarin could affect the activation of NLRP3 inflammasome in macrophages. The results showed that scutellarin dose-dependently reduced caspase-1 activation and decreased mature interleukin-1β (IL-1β release in lipopolysaccharide (LPS-primed macrophages upon ATP or nigericin stimulation, indicating that scutellarin inhibited NLRP3 inflammasome activation in macrophages. Consistent with this, scutellarin also suppressed pyroptotic cell death in LPS-primed macrophages treated with ATP or nigericin. ATP or nigericin-induced ASC speck formation and its oligomerization were blocked by scutellarin pre-treatment. Intriguingly, scutellarin augmented PKA-specific phosphorylation of NLRP3 in LPS-primed macrophages, which was completely blocked by selective PKA inhibitor H89, suggesting that PKA signaling had been involved in the action of scutellarin to suppress NLRP3 inflammasome activation. Supporting this, the inhibitory effect of scutellarin on NLRP3 inflammasome activation was completely counteracted by H89 or adenyl cyclase inhibitor MDL12330A. As NLRP3-dependent release of IL-1β has a critical role in sepsis, the in vivo activity of scutellarin was assayed in a mouse model of bacterial sepsis, which was established by intraperitoneally injection of a lethal dose of viable Escherichia coli. Oral administration of scutellarin significantly improved the survival of mice with

  15. Activation of peroxisome proliferator-activated receptor-α (PPARα) suppresses postprandial lipidemia through fatty acid oxidation in enterocytes

    International Nuclear Information System (INIS)

    Kimura, Rino; Takahashi, Nobuyuki; Murota, Kaeko; Yamada, Yuko; Niiya, Saori; Kanzaki, Noriyuki; Murakami, Yoko; Moriyama, Tatsuya; Goto, Tsuyoshi; Kawada, Teruo

    2011-01-01

    Highlights: → PPARα activation increased mRNA expression levels of fatty acid oxidation-related genes in human intestinal epithelial Caco-2 cells. → PPARα activation also increased oxygen consumption rate and CO 2 production and decreased secretion of triglyceride and ApoB from Caco-2 cells. → Orally administration of bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and CO 2 production in small intestinal epithelial cells. → Treatment with bezafibrate decreased postprandial serum concentration of triglyceride after oral injection of olive oil in mice. → It suggested that intestinal lipid metabolism regulated by PPARα activation suppresses postprandial lipidemia. -- Abstract: Activation of peroxisome proliferator-activated receptor (PPAR)-α which regulates lipid metabolism in peripheral tissues such as the liver and skeletal muscle, decreases circulating lipid levels, thus improving hyperlipidemia under fasting conditions. Recently, postprandial serum lipid levels have been found to correlate more closely to cardiovascular diseases than fasting levels, although fasting hyperlipidemia is considered an important risk of cardiovascular diseases. However, the effect of PPARα activation on postprandial lipidemia has not been clarified. In this study, we examined the effects of PPARα activation in enterocytes on lipid secretion and postprandial lipidemia. In Caco-2 enterocytes, bezafibrate, a potent PPARα agonist, increased mRNA expression levels of fatty acid oxidation-related genes, such as acyl-CoA oxidase, carnitine palmitoyl transferase, and acyl-CoA synthase, and oxygen consumption rate (OCR) and suppressed secretion levels of both triglycerides and apolipoprotein B into the basolateral side. In vivo experiments revealed that feeding high-fat-diet containing bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and production of CO 2 and acid soluble metabolites in enterocytes. Moreover

  16. Anticancer Activity of Toxins from Bee and Snake Venom—An Overview on Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Marius Alexandru Moga

    2018-03-01

    Full Text Available Cancer represents the disease of the millennium, a major problem in public health. The proliferation of tumor cells, angiogenesis, and the relationship between the cancer cells and the components of the extracellular matrix are important in the events of carcinogenesis, and these pathways are being used as targets for new anticancer treatments. Various venoms and their toxins have shown possible anticancer effects on human cancer cell lines, providing new perspectives in drug development. In this review, we observed the effects of natural toxins from bee and snake venom and the mechanisms through which they can inhibit the growth and proliferation of cancer cells. We also researched how several types of natural molecules from venom can sensitize ovarian cancer cells to conventional chemotherapy, with many toxins being helpful for developing new anticancer drugs. This approach could improve the efficiency of standard therapies and could allow the administration of decreased doses of chemotherapy. Natural toxins from bee and snake venom could become potential candidates for the future treatment of different types of cancer. It is important to continue these studies concerning therapeutic drugs from natural resource and, more importantly, to investigate their mechanism of action on cancer cells.

  17. Anticancer Activity of Toxins from Bee and Snake Venom-An Overview on Ovarian Cancer.

    Science.gov (United States)

    Moga, Marius Alexandru; Dimienescu, Oana Gabriela; Arvătescu, Cristian Andrei; Ifteni, Petru; Pleş, Liana

    2018-03-19

    Cancer represents the disease of the millennium, a major problem in public health. The proliferation of tumor cells, angiogenesis, and the relationship between the cancer cells and the components of the extracellular matrix are important in the events of carcinogenesis, and these pathways are being used as targets for new anticancer treatments. Various venoms and their toxins have shown possible anticancer effects on human cancer cell lines, providing new perspectives in drug development. In this review, we observed the effects of natural toxins from bee and snake venom and the mechanisms through which they can inhibit the growth and proliferation of cancer cells. We also researched how several types of natural molecules from venom can sensitize ovarian cancer cells to conventional chemotherapy, with many toxins being helpful for developing new anticancer drugs. This approach could improve the efficiency of standard therapies and could allow the administration of decreased doses of chemotherapy. Natural toxins from bee and snake venom could become potential candidates for the future treatment of different types of cancer. It is important to continue these studies concerning therapeutic drugs from natural resource and, more importantly, to investigate their mechanism of action on cancer cells.

  18. PAX8 activates a p53-p21-dependent pro-proliferative effect in high grade serous ovarian carcinoma.

    Science.gov (United States)

    Ghannam-Shahbari, Dima; Jacob, Eyal; Kakun, Reli Rachel; Wasserman, Tanya; Korsensky, Lina; Sternfeld, Ofir; Kagan, Juliana; Bublik, Debora Rosa; Aviel-Ronen, Sarit; Levanon, Keren; Sabo, Edmond; Larisch, Sarit; Oren, Moshe; Hershkovitz, Dov; Perets, Ruth

    2018-01-30

    High grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer and it is now widely accepted that this disease often originates from the fallopian tube epithelium. PAX8 is a fallopian tube lineage marker with an essential role in embryonal female genital tract development. In the adult fallopian tube, PAX8 is expressed in the fallopian tube secretory epithelial cell (FTSEC) and its expression is maintained through the process of FTSEC transformation to HGSC. We now report that PAX8 has a pro-proliferative and anti-apoptotic role in HGSC. The tumor suppressor gene TP53 is mutated in close to 100% of HGSC; in the majority of cases, these are missense mutations that endow the mutant p53 protein with potential gain of function (GOF) oncogenic activities. We show that PAX8 positively regulates the expression of TP53 in HGSC and the pro-proliferative role of PAX8 is mediated by the GOF activity of mutant p53. Surprisingly, mutant p53 transcriptionally activates the expression of p21, which localizes to the cytoplasm of HGSC cells where it plays a non-canonical, pro-proliferative role. Together, our findings illustrate how TP53 mutations in HGSC subvert a normal regulatory pathway into a driver of tumor progression.

  19. Multirate Flutter Suppression System Design for the Benchmark Active Controls Technology Wing. Part 2; Methodology Application Software Toolbox

    Science.gov (United States)

    Mason, Gregory S.; Berg, Martin C.; Mukhopadhyay, Vivek

    2002-01-01

    To study the effectiveness of various control system design methodologies, the NASA Langley Research Center initiated the Benchmark Active Controls Project. In this project, the various methodologies were applied to design a flutter suppression system for the Benchmark Active Controls Technology (BACT) Wing. This report describes the user's manual and software toolbox developed at the University of Washington to design a multirate flutter suppression control law for the BACT wing.

  20. Activation of the aryl hydrocarbon receptor suppresses sensitization in a mouse peanut allergy model.

    Science.gov (United States)

    Schulz, V J; Smit, J J; Willemsen, K J; Fiechter, D; Hassing, I; Bleumink, R; Boon, L; van den Berg, M; van Duursen, M B M; Pieters, R H H

    2011-10-01

    Food allergy is an increasing health problem in Western countries. Previously, it has been shown that the intensity of food allergic reactions can be regulated by regulatory T (T(reg)) cells. In addition, it has been shown that activation of the aryl hydrocarbon receptor (AhR) regulates T-cell responses by induction of T(reg) cells. Therefore, we hypothesized that activation of the AhR pathway can suppress development of food allergic responses through the induction of T(reg) cells. This was investigated by using a mouse model for peanut allergy. C3H/HeOuJ mice (AhR(b)(-2)) were sensitized to peanut by administering peanut extract (PE) by gavage in the presence of cholera toxin and were treated with the prototypical AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (0.6, 1.7, 5, and 15 μg/kg body weight) on days 3 and 11 orally. The functional role of CD4(+)CD25(+)Foxp3(+) T(reg) cells was investigated by depleting these cells with anti-CD25 mAb during sensitization to PE. TCDD treatment dose dependently suppressed sensitization to peanut (PE-specific IgE, IgG1, and IgG2a and PE-induced IL-5, IL-10, and IL-13, respectively). The percentage, but not the number, of CD4(+)CD25(+)Foxp3(+) T(reg) cells dose dependently increased by AhR activation in both spleen and mesenteric lymph nodes. Depletion of CD4(+)CD25(+)Foxp3(+) T(reg) cells markedly reversed the suppressive effect of TCDD on PE-specific antibody levels and PE-induced IL-5, IL-10, and IL-13 cytokine production. Present data demonstrate for the first time that activation of the AhR by TCDD suppressed the development of Th2-mediated food allergic responses. A functional shift within the CD4(+) cell population toward CD4(+)CD25(+)Foxp3(+) T(reg) cells appeared to underlie this effect. This suggests that the AhR pathway might provide potential therapeutic targets to treat food allergic diseases.

  1. Induction of anergy or active suppression following oral tolerance is determined by antigen dosage.

    OpenAIRE

    Friedman, A; Weiner, H L

    1994-01-01

    Oral tolerance was generated to hen egg white lysozyme in the mouse or to guinea pig myelin basic protein in the rat by a low-dose (1 mg) or a high-dose (5-20 mg) feeding regimen. High doses of antigen induced tolerance characterized by anergy with little or no active suppression and increased secretion of interleukin 4 (IL-4). Anergy was shown by an increase in frequency of IL-2-secreting cells following culture in recombinant IL-2. Low doses of antigen induced tolerance characterized by ant...

  2. Long non-coding RNA ZFAS1 interacts with miR-150-5p to regulate Sp1 expression and ovarian cancer cell malignancy.

    Science.gov (United States)

    Xia, Bairong; Hou, Yan; Chen, Hong; Yang, Shanshan; Liu, Tianbo; Lin, Mei; Lou, Ge

    2017-03-21

    We reported that long non-coding RNA ZFAS1 was upregulated in epithelial ovarian cancer tissues, and was negatively correlated to the overall survival rate of patients with epithelial ovarian cancer in this study. While depletion of ZFAS1 inhibited proliferation, migration, and development of chemoresistance, overexpression of ZFAS1 exhibited an even higher proliferation rate, migration activity, and chemoresistance in epithelial ovarian cancer cell lines. We further found miR-150-5p was a potential target of ZFAS1, which was downregulated in epithelial ovarian cancer tissue. MiR-150-5p subsequently inhibited expression of transcription factor Sp1, as evidence by luciferase assays. Inhibition of miR-150-5p rescued the suppressed proliferation and migration induced by depletion of ZFAS1 in epithelial ovarian cancer cells, at least in part. Taken together, our findings revealed a critical role of ZFAS1/miR-150-5p/Sp1 axis in promoting proliferation rate, migration activity, and development of chemoresistance in epithelial ovarian cancer. And ZFAS1/miR-150-5p may serve as novel markers and therapeutic targets of epithelial ovarian cancer.

  3. Cholesterol synthesis inhibitor RO 48-8071 suppresses transcriptional activity of human estrogen and androgen receptor.

    Science.gov (United States)

    Mafuvadze, Benford; Liang, Yayun; Hyder, Salman M

    2014-10-01

    Breast cancer cells express enzymes that convert cholesterol, the synthetic precursor of steroid hormones, into estrogens and androgens, which then drive breast cancer cell proliferation. In the present study, we sought to determine whether oxidosqualene cyclase (OSC), an enzyme in the cholesterol biosynthetic pathway, may be targeted to suppress progression of breast cancer cells. In previous studies, we showed that the OSC inhibitor RO 48-8071 (RO) may be a ligand which could potentially be used to control the progression of estrogen receptor-α (ERα)-positive breast cancer cells. Herein, we showed, by real-time PCR analysis of mRNA from human breast cancer biopsies, no significant differences in OSC expression at various stages of disease, or between tumor and normal mammary cells. Since the growth of hormone-responsive tumors is ERα-dependent, we conducted experiments to determine whether RO affects ERα. Using mammalian cells engineered to express human ERα or ERβ protein, together with an ER-responsive luciferase promoter, we found that RO dose-dependently inhibited 17β-estradiol (E2)-induced ERα responsive luciferase activity (IC50 value, ~10 µM), under conditions that were non-toxic to the cells. RO was less effective against ERβ-induced luciferase activity. Androgen receptor (AR) mediated transcriptional activity was also reduced by RO. Notably, while ERα activity was reduced by atorvastatin, the HMG-CoA reductase inhibitor did not influence AR activity, showing that RO possesses broader antitumor properties. Treatment of human BT-474 breast cancer cells with RO reduced levels of estrogen-induced PR protein, confirming that RO blocks ERα activity in tumor cells. Our findings demonstrate that an important means by which RO suppresses hormone-dependent growth of breast cancer cells is through its ability to arrest the biological activity of ERα. This warrants further investigation of RO as a potential therapeutic agent for use against hormone

  4. Cellulase activity as a mechanism for suppression of phytophthora root rot in mulches.

    Science.gov (United States)

    Richter, Brantlee Spakes; Ivors, Kelly; Shi, Wei; Benson, D M

    2011-02-01

    Wood-based mulches are used in avocado production and are being tested on Fraser fir for reduction of Phytophthora root rot, caused by Phytophthora cinnamomi. Research with avocado has suggested a role of microbial cellulase enzymes in pathogen suppression through effects on the cellulosic cell walls of Phytophthora. This work was conducted to determine whether cellulase activity could account for disease suppression in mulch systems. A standard curve was developed to correlate cellulase activity in mulches with concentrations of a cellulase product. Based on this curve, cellulase activity in mulch samples was equivalent to a cellulase enzyme concentration of 25 U ml(-1) or greater of product. Sustained exposure of P. cinnamomi to cellulase at 10 to 50 U ml(-1) significantly reduced sporangia production, but biomass was only reduced with concentrations over 100 U ml(-1). In a lupine bioassay, cellulase was applied to infested soil at 100 or 1,000 U ml(-1) with three timings. Cellulase activity diminished by 47% between 1 and 15 days after application. Cellulase applied at 100 U ml(-1) 2 weeks before planting yielded activity of 20.08 μmol glucose equivalents per gram of soil water (GE g(-1) aq) at planting, a level equivalent to mulch samples. Cellulase activity at planting ranged from 3.35 to 48.67 μmol GE g(-1) aq, but no treatment significantly affected disease progress. Based on in vitro assays, cellulase activity in mulch was sufficient to impair sporangia production of P. cinnamomi, but not always sufficient to impact vegetative biomass.

  5. Magnetic suppression of turbulence and the star formation activity of molecular clouds

    Science.gov (United States)

    Zamora-Avilés, Manuel; Vázquez-Semadeni, Enrique; Körtgen, Bastian; Banerjee, Robi; Hartmann, Lee

    2018-03-01

    We present magnetohydrodynamic simulations aimed at studying the effect of the magnetic suppression of turbulence (generated through various instabilities during the formation of molecular clouds by converging) on the subsequent star formation (SF) activity. We study four magnetically supercritical models with magnetic field strengths B = 0, 1, 2, and 3 μG (corresponding to mass-to-flux ratios of ∞, 4.76, 2.38, and 1.59 times the critical value), with the magnetic field, initially being aligned with the flows. We find that, for increasing magnetic field strength, the clouds formed tend to be more massive, denser, less turbulent, and with higher SF activity. This causes the onset of SF activity in the non-magnetic or more weakly magnetized cases to be delayed by a few Myr in comparison to the more strongly magnetized cases. We attribute this behaviour to the suppression of the non-linear thin shell instability (NTSI) by the magnetic field, previously found by Heitsch and coworkers. This result is contrary to the standard notion that the magnetic field provides support to the clouds, thus reducing their star formation rate. However, our result is a completely non-linear one, and could not be foreseen from simple linear considerations.

  6. Folliculin contributes to VHL tumor suppressing activity in renal cancer through regulation of autophagy.

    Directory of Open Access Journals (Sweden)

    Prabhat Bastola

    Full Text Available Von Hippel-Lindau tumor suppressor (VHL is lost in the majority of clear cell renal cell carcinomas (ccRCC. Folliculin (FLCN is a tumor suppressor whose function is lost in Birt-Hogg-Dubé syndrome (BHD, a disorder characterized by renal cancer of multiple histological types including clear cell carcinoma, cutaneous fibrofolliculoma, and pneumothorax. Here we explored whether there is connection between VHL and FLCN in clear cell renal carcinoma cell lines and tumors. We demonstrate that VHL regulates expression of FLCN at the mRNA and protein levels in RCC cell lines, and that FLCN protein expression is decreased in human ccRCC tumors with VHL loss, as compared with matched normal kidney tissue. Knockdown of FLCN results in increased formation of tumors by RCC cells with wild-type VHL in orthotopic xenografts in nude mice, an indication that FLCN plays a role in the tumor-suppressing activity of VHL. Interestingly, FLCN, similarly to VHL, is necessary for the activity of LC3C-mediated autophagic program that we have previously characterized as contributing to the tumor suppressing activity of VHL. The results show the existence of functional crosstalk between two major tumor suppressors in renal cancer, VHL and FLCN, converging on regulation of autophagy.

  7. Suppression of human immunodeficiency virus type 1 activity in vitro by oligonucleotides which form intramolecular tetrads.

    Science.gov (United States)

    Rando, R F; Ojwang, J; Elbaggari, A; Reyes, G R; Tinder, R; McGrath, M S; Hogan, M E

    1995-01-27

    An oligonucleotide (I100-15) composed of only deoxyguanosine and thymidine was able to inhibit human immunodeficiency virus type-1 (HIV-1) in culture assay systems. I100-15 did not block virus entry into cells but did reduce viral-specific transcripts. As assessed by NMR and polyacrylamide gel methods, I100-15 appears to form a structure in which two stacked guanosine tetrads are connected by three two-base long loops. Structure/activity experiments indicated that formation of intramolecular guanosine tetrads was necessary to achieve maximum antiviral activity. The single deoxyguanosine nucleotide present in each loop was found to be extremely important for the overall antiviral activity. The toxicity of I100-15 was determined to be well above the 50% effective dose (ED50) in culture which yielded a high therapeutic index (> 100). The addition of a cholesterol moiety to the 3' terminus of I100-15 (I100-23) reduced the ED50 value to less than 50 nM (from 0.12 microM for I100-15) and increased the duration of viral suppression to greater than 21 days (versus 7-10 days for I100-15) after removal of the drug from infected cell cultures. The favorable therapeutic index of such molecules coupled with the prolonged suppression of HIV-1, suggest that such compounds further warrant investigation as potential therapeutic agents.

  8. Paracrine stimulation of P2X7 receptor by ATP activates a proliferative pathway in ovarian carcinoma cells.

    Science.gov (United States)

    Vázquez-Cuevas, Francisco G; Martínez-Ramírez, Angélica S; Robles-Martínez, Leticia; Garay, Edith; García-Carrancá, Alejandro; Pérez-Montiel, Delia; Castañeda-García, Carolina; Arellano, Rogelio O

    2014-11-01

    P2X7 is a purinergic receptor-channel; its activation by ATP elicits a broad set of cellular actions, from apoptosis to signals for survival. Here, P2X7 expression and function was studied in human ovarian carcinoma (OCA) cells, and biopsies from non-cancerous and cancer patients were analyzed by immunohistochemistry. Ovarian surface epithelium in healthy tissue expressed P2X7 at a high level that was maintained throughout the cancer. The cell lines SKOV-3 and CAOV-3 were used to investigate P2X7 functions in OCA. In SKOV-3 cells, selective stimulation of P2X7 by 2'(3')-O-(4-benzoylbenzoyl) adenosine-5'-triphosphate (BzATP) induced a dose-dependent increase of intracellular Ca(2+) concentration ([Ca(2+)](i)) but not cell death. Instead, BzATP increased the levels of phosphorylated ERK and AKT (pERK and pAKT), with an EC(50) of 44 ± 2 and 1.27 ± 0.5 μM, respectively; 10 μM BzATP evoked a maximum effect within 15 min that lasted for 120 min. Interestingly, basal levels of pERK and pAKT were decreased in the presence of apyrase in the medium, strongly suggesting an endogenous, ATP-mediated phenomenon. Accordingly: (i) mechanically stimulated cells generated a [Ca(2+)](i) increase that was abolished by apyrase; (ii) apyrase induced a decrease in culture viability, as measured by the MTS assay for mitochondrial activity; and (iii) incubation with 10 μM AZ10606120, a specific P2X7 antagonist and transfection with the dominant negative P2X7 mutant E496A, both reduced cell viability to 70.1 ± 8.9% and to 76.5 ± 5%, respectively, of control cultures. These observations suggested that P2X7 activity was auto-induced through ATP efflux; this increased pERK and pAKT levels that generated a positive feedback on cell viability. © 2014 Wiley Periodicals, Inc.

  9. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Anastasiou, Dimitrios; Yu, Yimin; Israelsen, William J.; Jiang, Jian-Kang; Boxer, Matthew B.; Hong, Bum Soo; Tempel, Wolfram; Dimov, Svetoslav; Shen, Min; Jha, Abhishek; Yang, Hua; Mattaini, Katherine R.; Metallo, Christian M.; Fiske, Brian P.; Courtney, Kevin D.; Malstrom, Scott; Khan, Tahsin M.; Kung, Charles; Skoumbourdis, Amanda P.; Veith, Henrike; Southall, Noel; Walsh, Martin J.; Brimacombe, Kyle R.; Leister, William; Lunt, Sophia Y.; Johnson, Zachary R.; Yen, Katharine E.; Kunii, Kaiko; Davidson, Shawn M.; Christofk, Heather R.; Austin, Christopher P.; Inglese, James; Harris, Marian H.; Asara, John M.; Stephanopoulos, Gregory; Salituro, Francesco G.; Jin, Shengfang; Dang, Lenny; Auld, Douglas S.; Park, Hee-Won; Cantley, Lewis C.; Thomas, Craig J.; Vander Heiden, Matthew G.

    2012-08-26

    Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. This data supports the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.

  10. Activated Charcoal Suppresses Breeding of the House Dust Mite, Dermatophagoides Pteronyssinus, in Culture

    Science.gov (United States)

    Nam, Hae-Seon; Lee, Sun-Hwa; Kim, Sung-Ho; Lee, Sang-Han; Crane, Julian

    2007-01-01

    House dust mite sensitized asthmatics are advised to practice allergen avoidance. Charcoal pillows are used in Korea with unsubstantiated claims regarding their efficacy in alleviating asthma symptoms. We tested the effects of activated charcoal on breeding of house dust mites in culture. Twenty live adult house dust mites (Dermatophagoides pteronyssinus) were inoculated, 10 replicates, on culture media containing 0%, 1%, 3%, 5%, 10%, and 20% activated charcoal and incubated at 25℃ and a relative humidity of 75%. After four weeks, the mean numbers of live house dust mites were 286, 176, 46, 16, 7, and 0 for the 0%, 1%, 3%, 5%, 10%, and 20% charcoal-containing culture media, respectively. Thus, activated charcoal suppresses breeding of house dust mites and offers a new promising method for house dust mite control. PMID:17449957

  11. RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Bignone, P A; Lee, K Y; Liu, Y

    2007-01-01

    -activated protein kinase pathway. It is expressed in normal ovarian epithelium, whereas reduced or absent in tumours or cell lines. We show that RPS6KA2 is monoallelically expressed in the ovary suggesting that loss of a single expressed allele is sufficient to cause complete loss of expression in cancer cells....... Further, we have identified two new isoforms of RPS6KA2 with an alternative start codon. Homozygous deletions were identified within the RPS6KA2 gene in two cell lines. Re-expression of RPS6KA2 in ovarian cancer cell lines suppressed colony formation. In UCI101 cells, the expression of RPS6KA2 reduced...

  12. In vitro effects of diethylstilbestrol, genistein, 4-tert-butylphenol, and 4-tert-octylphenol on steroidogenic activity of isolated immature rat ovarian follicles

    International Nuclear Information System (INIS)

    Myllymaeki, Sari; Haavisto, Tapio; Vainio, Minna; Toppari, Jorma; Paranko, Jorma

    2005-01-01

    Isolated rat ovarian follicles grow and produce steroid hormones in vitro and so provide a good model for studying the effects of hormonally active compounds on follicular steroidogenesis. We have evaluated the effects of diethylstilbestrol (DES), genistein (GEN) and two alkylphenols, 4-tert-butylphenol (BP) and 4-tert-octylphenol (OP) on the growth, survival, and steroid hormone and cAMP production by isolated 14-day-old rat (Sprague-Dawley) ovarian follicles. During a 5-day culture, FSH was obligatory for follicle growth and increased estradiol and testosterone secretion in a dose-dependent manner. DES (10 -6 M) caused the strongest decline in estradiol and testosterone levels but did not have detectable effects on either cAMP production or aromatase enzyme activity. GEN caused a prominent decrease in cAMP and testosterone levels without significant changes in secreted estradiol. The latter, apparently, was due to a dose-dependent stimulation of aromatase enzyme activity in the presence of genistein. Both BP and OP decreased estradiol and testosterone secretion in a dose-dependent manner while no effect on aromatase activity was observed. OP, unlike BP, decreased forskolin-induced cAMP levels. Xenoestrogens at the used concentrations did not interfere with the growth and survival of the follicles. The results indicate that isolated ovarian follicles representing intact morphological and functional units offer a sensitive model system for elucidating the female-specific reproductive effects of environmental chemicals

  13. Treadmill exercise ameliorates symptoms of Alzheimer disease through suppressing microglial activation-induced apoptosis in rats.

    Science.gov (United States)

    Baek, Seung-Soo; Kim, Sang-Hoon

    2016-12-01

    Alzheimer disease (AD) is a most common form of dementia and eventually causes impairments of learning ability and memory function. In the present study, we investigated the effects of treadmill exercise on the symptoms of AD focusing on the microglial activation-induced apoptosis. AD was made by bilateral intracerebroventricular injection of streptozotocin. The rats in the exercise groups were made to run on a treadmill once a day for 30 min during 4 weeks. The distance and latency in the Morris water maze task and the latency in the step-down avoidance task were increased in the AD rats, in contrast, treadmill exercise shortened these parameters. The numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive and caspase-3-positive cells in the hippocampal dentate gyrus were decreased in the AD rats, in contrast, treadmill exercise suppressed these numbers. Expressions of glial fibrillary acidic protein (GFAP) and cluster of differentiation molecule 11B (CD11b) in the hippocampal dentate gyrus were increased in the AD rats, in contrast, treadmill exercise suppressed GFAP and CD11b expressions. Bax expression was increased and Bcl-2 expression was decreased in the hippocampus of AD rats, in contrast, treadmill exercise decreased Bax expression and increased Bcl-2 expression. The present results demonstrated that treadmill exercise ameliorated AD-induced impairments of spatial learning ability and short-term memory through suppressing apoptosis. The antiapoptotic effect of treadmill exercise might be ascribed to the inhibitory effect of treadmill exercise on microglial activation.

  14. TGF-β suppresses β-catenin-dependent tolerogenic activation program in dendritic cells.

    Directory of Open Access Journals (Sweden)

    Bryan Vander Lugt

    Full Text Available The mechanisms that underlie the critical dendritic cell (DC function in maintainance of peripheral immune tolerance are incompletely understood, although the β-catenin signaling pathway is critical for this role. The molecular details by which β-catenin signaling is regulated in DCs are unknown. Mechanical disruption of murine bone marrow-derived DC (BMDC clusters activates DCs while maintaining their tolerogenic potential and this activation is associated with β-catenin signaling, providing a useful model with which to explore tolerance-associated β-catenin signaling in DCs. In this report, we demonstrate novel molecular features of the signaling events that control DC activation in response to mechanical stimulation. Non-canonical β-catenin signaling is an essential component of this tolerogenic activation and is modulated by adhesion molecules, including integrins. This unique β-catenin-dependent signaling pathway is constitutively active at low levels, suggesting that mechanical stimulation is not necessarily required for induction of this unique activation program. We additionally find that the immunomodulatory cytokine TGF-β antagonizes β-catenin in DCs, thereby selectively suppressing signaling associated with tolerogenic DC activation while having no impact on LPS-induced, β-catenin-independent immunogenic activation. These findings provide new molecular insight into the regulation of a critical signaling pathway for DC function in peripheral immune tolerance.

  15. A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis.

    Directory of Open Access Journals (Sweden)

    Claude Jourdan Le Saux

    Full Text Available The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L, a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.

  16. Suppression of adenosine-activated chloride transport by ethanol in airway epithelia.

    Directory of Open Access Journals (Sweden)

    Sammeta V Raju

    Full Text Available Alcohol abuse is associated with increased lung infections. Molecular understanding of the underlying mechanisms is not complete. Airway epithelial ion transport regulates the homeostasis of airway surface liquid, essential for airway mucosal immunity and lung host defense. Here, air-liquid interface cultures of Calu-3 epithelial cells were basolaterally exposed to physiologically relevant concentrations of ethanol (0, 25, 50 and 100 mM for 24 hours and adenosine-stimulated ion transport was measured by Ussing chamber. The ethanol exposure reduced the epithelial short-circuit currents (I(SC in a dose-dependent manner. The ion currents activated by adenosine were chloride conductance mediated by cystic fibrosis transmembrane conductance regulator (CFTR, a cAMP-activated chloride channel. Alloxazine, a specific inhibitor for A(2B adenosine receptor (A(2BAR, largely abolished the adenosine-stimulated chloride transport, suggesting that A(2BAR is a major receptor responsible for regulating the chloride transport of the cells. Ethanol significantly reduced intracellular cAMP production upon adenosine stimulation. Moreover, ethanol-suppression of the chloride secretion was able to be restored by cAMP analogs or by inhibitors to block cAMP degradation. These results imply that ethanol exposure dysregulates CFTR-mediated chloride transport in airways by suppression of adenosine-A(2BAR-cAMP signaling pathway, which might contribute to alcohol-associated lung infections.

  17. Drosera rotundifolia and Drosera tokaiensis suppress the activation of HMC-1 human mast cells.

    Science.gov (United States)

    Fukushima, Kenji; Nagai, Kanji; Hoshi, Yoshikazu; Masumoto, Saeko; Mikami, Ichiho; Takahashi, Yumiko; Oike, Hideaki; Kobori, Masuko

    2009-08-17

    Several Northern Hemisphere Drosera species have been used in the therapy of respiratory tract infections as the traditional medicine Droserae Herba. To determine the anti-inflammatory effects of Drosera species and to investigate a substitute material for Droserae Herba, we examined the effect of extracts of Drosera rotundifolia, Drosera tokaiensis and Drosera spatulata on activated T cell membrane (aTc-m)-induced inflammatory gene expression in HMC-1 human mast cells. Drosera rotundifolia, Drosera spatulata and Drosera tokaiensis were collected in Japan. Herbs were extracted with 80% EtOH, and subsequently applied to OASIS HLB column. HMC-1 cells were treated with each Drosera column-adsorbed fraction for 15min, and subsequently added to aTc-m and incubated for 16h. Inflammatory gene and protein expressions were determined by DNA microarray, RT-PCR and Western blotting. Drosera rotundifolia and Drosera tokaiensis fractions, but not the Drosera spatulata fraction, suppressed inflammatory gene expression induced by aTc-m in HMC-1 cells. Drosera rotundifolia and Drosera tokaiensis suppressed activation of HMC-1 cells induced by aTc-m. Since the Drosera tokaiensis fraction was more effective than the traditionally used Drosera rotundifolia, Drosera tokaiensis is a likely substitute as a source of Droserae Herba.

  18. Dormancy of cancer cells with suppression of AKT activity contributes to survival in chronic hypoxia.

    Directory of Open Access Journals (Sweden)

    Hiroko Endo

    Full Text Available A hypoxic microenvironment in tumors has been recognized as a cause of malignancy or resistance to various cancer therapies. In contrast to recent progress in understanding the acute response of cancer cells to hypoxia, the characteristics of tumor cells in chronic hypoxia remain elusive. We have identified a pancreatic cancer cell line, AsPC-1, that is exceptionally able to survive for weeks under 1% oxygen conditions while most tested cancer cell lines die after only some days under these conditions. In chronic hypoxia, AsPC-1 cells entered a state of dormancy characterized by no proliferation, no death, and metabolic suppression. They reversibly switched to active status after being placed again in optimal culture conditions. ATP turnover, an indicator of energy demand, was markedly decreased and accompanied by reduced AKT phosphorylation. Forced activation of AKT resulted in increased ATP turnover and massive cell death in vitro and a decreased number of dormant cells in vivo. In contrast to most cancer cell lines, primary-cultured colorectal cancer cells easily entered the dormant status with AKT suppression under hypoxia combined with growth factor-depleted conditions. Primary colorectal cancer cells in dormancy were resistant to chemotherapy. Thus, the ability to survive in a deteriorated microenvironment by entering into dormancy under chronic hypoxia might be a common property among cancer cells. Targeting the regulatory mechanism inducing this dormant status could provide a new strategy for treating cancer.

  19. Rhodiola crenulata extract suppresses hepatic gluconeogenesis via activation of the AMPK pathway.

    Science.gov (United States)

    Lee, Shih-Yu; Lai, Feng-Yi; Shi, Li-Shian; Chou, Yu-Ching; Yen, I-Chuan; Chang, Tsu-Chung

    2015-04-15

    Rhodiola, a popular herb, has been used for treating high altitude sicknesses, depression, fatigue, and diabetes. However, the detailed mechanisms by which Rhodiola crenulata functions in the liver need further clarification. The current study was designed to examine the effects of Rhodiola crenulata root extract (RCE) on hepatic glucose production. Human hepatoma HepG2 cells were treated with RCE for 6 h. Glucose production, the expression level of p-AMPK, and the expression of key gluconeogenic genes were measured. The effects of RCE were also studied in Sprague-Dawley (SD) rats. The efficacy and underlying mechanism of RCE in the liver were examined. RCE significantly suppressed glucose production and gluconeogenic gene expression in HepG2 cells while activating the AMPK signaling pathway. Interestingly, RCE-suppressed hepatic gluconeogenesis was eliminated by an AMPK-specific inhibitor, but not by the PI3K/AKT-specific inhibitor. In addition, oral administration of RCE significantly increased phosphorylated AMPK levels and inhibited gluconeogenic gene expression in the rat liver. Furthermore, RCE treatment also decreased plasma glucose concentration in rats. We present in vitro and in vivo evidence that RCE might exert the glucose-lowering effect partly by inhibiting hepatic gluconeogenesis through activating the AMPK signaling pathway. These findings provide evidence that Rhodiola crenulata may be helpful for the management of type II diabetes. Copyright © 2015 Elsevier GmbH. All rights reserved.

  20. Secondary immunity to Legionella pneumophila and Th1 activity are suppressed by delta-9-tetrahydrocannabinol injection.

    Science.gov (United States)

    Newton, C A; Klein, T W; Friedman, H

    1994-01-01

    Resistance to infection with Legionella pneumophila is primarily dependent upon cell-mediated immunity rather than humoral immunity. Recent evidence suggests that activation of cell-mediated immunity depends on Th1 cells and activation of humoral immunity depends on Th2 cells. In this report, delta 9-tetrahydrocannabinol (THC), the major psychoactive cannabinoid of marijuana and an immunomodulator, suppressed development of secondary immunity to L. pneumophila, which correlated with a reduction in Th1 activity. BALB/c mice, infected with a primary sublethal dose of L. pneumophila, developed resistance to a larger challenge infection 3 to 4 weeks later. However, intravenous injection of THC (4 mg/kg of body weight) 1 day prior to primary infection resulted in increased mortality after the challenge infection. The level of anti-L. pneumophila antibodies in serum increased in both THC-treated and control mice; however, in the THC group IgG1 antibodies which are stimulated by Th2 cells were elevated while Th1-regulated, IgG2a antibodies were depressed. Furthermore, cultured splenocytes from THC-treated mice had less L. pneumophila-specific lymphoproliferation, indicating a deficiency in cell-mediated immunity. Normal mouse splenocytes treated in vitro with THC and pokeweed mitogen showed suppressed production of gamma interferon, a cytokine associated with Th1 cells, but increased production of interleukin 4, a cytokine produced by Th2 cells. Splenocytes from THC-treated mice, stimulated in vitro with either pokeweed mitogen or anti-CD3 antibodies, also produced less gamma interferon, indicating less Th1 activity in these mice. These results suggest that THC decreases the development of anti-L. pneumophila immunity by causing a change in the balance of Th1 and Th2 activities. PMID:8063421

  1. miR-191 suppresses angiogenesis by activation of NF-κB signaling.

    Science.gov (United States)

    Gu, Yuan; Ampofo, Emmanuel; Menger, Michael D; Laschke, Matthias W

    2017-08-01

    MicroRNAs (miRNAs) are powerful regulators of diverse biologic processes. However, the function of most miRNAs in angiogenesis remains elusive. In this study, we identified miR-191-5p (miR-191) as a potent inhibitor of blood vessel development. Transfection of human dermal microvascular endothelial cells with miR-191 mimic (miR-191m) inhibited their proliferation, migration, and tube formation. Moreover, vascular sprouting of miR-191m-transfected mouse aortic rings was significantly reduced when compared with controls. Transfection with miR-191 inhibitor (miR-191i) induced proangiogenic effects. The anti- and proangiogenic activities of miR-191m and -191i were further demonstrated in vivo Additional molecular biologic analyses revealed that miR-191m activates NF-κB signaling by up-regulating the mRNA expression of p65. miR-191 also increased the mRNA levels of the antiangiogenic factors p21 and tissue inhibitor of metalloproteinase-1 and reduced the expression of the proangiogenic factors eNOS and matrix metalloproteinase-1 and -9. Blockade of NF-κB activation with Bay 11-7082 reversed the antiangiogenic effects of miR-191m. These findings indicate that miR-191 effectively suppresses angiogenesis by activation of the NF-κB signaling pathway.-Gu, Y., Ampofo, E., Menger, M. D., Laschke, M. W. miR-191 suppresses angiogenesis by activation of NF-κB signaling. © FASEB.

  2. Knockdown of Pokemon protein expression inhibits hepatocellular carcinoma cell proliferation by suppression of AKT activity.

    Science.gov (United States)

    Zhu, Xiaosan; Dai, Yichen; Chen, Zhangxin; Xie, Junpei; Zeng, Wei; Lin, Yuanyuan

    2013-01-01

    Overexpression of Pokemon, which is an erythroid myeloid ontogenic factor protein, occurs in different cancers, including hepatocellular carcinoma (HCC). Pokemon is also reported to have an oncogenic activity in various human cancers. This study investigated the effect of Pokemon knockdown on the regulation of HCC growth. POK shRNA suppressed the expression of Pokemon protein in HepG2 cells compared to the negative control vector-transfected HCC cells. Pokemon knockdown also reduced HCC cell viability and enhanced cisplatin-induced apoptosis in HCC cells. AKT activation and the expression of various cell cycle-related genes were inhibited following Pokemon knockdown. These data demonstrate that Pokemon may play a role in HCC progression, suggesting that inhibition of Pokemon expression using Pokemon shRNA should be further evaluated as a novel target for the control of HCC.

  3. Dihydromyricetin Protects against Bone Loss in Ovariectomized Mice by Suppressing Osteoclast Activity

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    Libo Zhao

    2017-12-01

    Full Text Available Dihydromyricetin (DMY, the main flavonoid component of Ampelopsis grossedentata, possesses pharmacological activities useful for treatment of diseases associated with inflammation and oxidative damage. Because osteoclasts are often involved in chronic low-grade systemic inflammation and oxidative damage, we hypothesized that DMY may be an effective treatment for osteoclast-related diseases. The effects of DMY on osteoclast formation and activity were examined in vitro. Female C57BL/6 mice were ovariectomized to mimic menopause-induced bone loss and treated with DMY, and femur samples were subjected to bone structure and histological analysis, serum biochemical indicators were also measured. DMY suppressed the activation of nuclear factor-κB, c-Fos and mitogen-activated protein kinase, and prevented production of reactive oxygen species. DMY decreased expression of osteoclast-specific genes, including Trap, Mmp-9, Cathepsin K, C-Fos, Nfatc1, and Rank. In addition, DMY prevented bone loss and decreased serum levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6, and with a decrease in the ratio between receptor activator of nuclear factor-κB (RANK ligand (RANKL and osteoprotegerin (OPG in vivo. These findings demonstrate that DMY attenuates bone loss and inhibits osteoclast formation and activity through modulation of multiple pathways both upstream and downstream of RANKL signaling. DMY may thus be a useful option for treatment of osteoclast-related diseases such as rheumatoid arthritis and osteoporosis.

  4. Anti-Müllerian hormone inhibits activation and growth of bovine ovarian follicles in vitro and is localized to growing follicles.

    Science.gov (United States)

    Yang, M Y; Cushman, R A; Fortune, J E

    2017-05-01

    Does anti-Müllerian hormone (AMH) inhibit activation (initiation of growth) of primordial follicles and attenuate the growth of primary follicles in cattle, an excellent animal model for human ovarian follicular development? AMH inhibited activation of bovine primordial follicles and attenuated the growth of activated follicles in vitro. In mice null mutant for AMH, the pool of primordial follicles is depleted prematurely and AMH inhibits follicle activation in vitro. Results of studies with human ovarian tissue in vitro were inconsistent. Our previous work provided indirect evidence that AMH inhibits follicle activation in bovine ovaries. Pieces of fetal bovine ovarian cortex (2 pieces/culture well), obtained during mid or late pregnancy, were cultured in control medium or with graded doses of AMH for 2, 10 or 12 days. Effects of treatment on follicle activation and growth were determined by histological morphometry; follicles in every 20th histological section were staged (primordial or primary), counted, and measured. In addition, AMH was immunolocalized in bovine ovaries obtained at various times during pregnancy (n = 20 ovaries). Bovine fetal ovaries at mid or late gestation were obtained at a commercial abattoir. Pieces of ovarian cortex were cultured without or with AMH and fixed for histological morphometry on Day 0 and at the end of culture. Treatments were applied to duplicate cultures from each of two or three fetuses. In 12-day cultures, addition of AMH was delayed until the third day. Histological analysis provided information about the types, numbers and sizes of follicles in cortical pieces before and after treatments. Ovaries obtained during the second and third trimesters were assessed for the presence of AMH by immunohistochemistry. AMH (100-500 ng/ml) inhibited follicle activation in response to an activator (insulin) in ovarian cortical pieces from fetal ovaries in late gestation. Dose-dependent inhibitory effects on the diameters of primary

  5. Inhibitory role of prohibitin in human ovarian epithelial cancer

    Science.gov (United States)

    Jia, Lin; Ren, Jian-Min; Wang, Yi-Ying; Zheng, Yu; Zhang, Hui; Zhang, Qing; Kong, Bei-Hua; Zheng, Wen-Xin

    2014-01-01

    Objectives: To characterize the exact individual roles of gonadotropins on ovarian epithelial carcinogenesis, an earlier study showed that prohibitin was significantly up-regulated by luteinizing hormone (LH). To further clarify the role of prohibitin in ovarian carcinogenesis and its association with LH, herein we studied the expression of prohibitin in various ovarian tissues including different developmental stages of ovarian epithelial tumors. Methods: A total of 135 samples were studied by immunohistochemistry. These included benign ovarian cases with follicles, ovarian surface epithelia and ovarian epithelial inclusions (OEI) (n=30), serous cystadenoma (n=14), serous borderline tumor (n=12), serous carcinoma (n=20), mucinous cystadenoma (n=10), mucinous borderline tumor (n=10), mucinous carcinomas (n=10), endometrioid carcinomas (n=12), poorly/undifferentiated carcinomas (n=5), and fallopian tube (n=12). Results: Strong and diffuse staining of prohibitin was detected in luteinized ovarian stromal cells, follicular cells, fallopian tube, and OEI with serous differentiation. A significantly higher prohibitin expression in luteinized stromal cells than in non-luteinized stromal cells was observed (POEI. However, compared to the level of prohibitin expression in OEI, it showed a trend of gradual loss from benign ovarian tumors, to borderline tumors and to carcinomas (POEI. Conclusions: These data further suggest that prohibitin plays a tumor suppressing role, which is probably associated with LH mediated protection role against ovarian epithelial carcinoma. In addition to the tumor suppressive role of prohibitin, it also plays a role in cellular differentiation, which may be helpful to differentiate ovarian mucinous tumors from the tumors with serous differentiation in clinical settings. More importantly, our findings are supportive that the ovarian epithelial cancers, particularly the serous cancers including those precursors with serous differentiation are

  6. Reverse feeding suppresses the activity of the GH axis in rats and induces a preobesogenic state.

    Science.gov (United States)

    Glad, Camilla A-M; Kitchen, Edward E J; Russ, Gemma C; Harris, Sophie M; Davies, Jeffrey S; Gevers, Evelien F; Gabrielsson, Britt G; Wells, Timothy

    2011-03-01

    Reversed feeding (RF) is known to disrupt hormone rhythmicity and metabolism. Although these effects may be mediated in part by phase inversion of glucocorticoid secretion, the precise mechanism is incompletely characterized. In this study, we demonstrate that acute nocturnal food deprivation in male rats suppressed the amplitude of spontaneous GH secretion during the dark phase by 62% (P inversion of core clock gene expression in liver, abdominal white adipose tissue (WAT) and skeletal muscle, without affecting their expression patterns in the suprachiasmatic nucleus. In addition, RF resulted in phase inversion of hepatic peroxisome proliferator-activated receptor γ2 mRNA expression, a 3- to 5-fold elevation in fatty acid synthase mRNA in WAT in both light- and dark-phase samples (P < 0.01) and an elevation in muscle uncoupling protein 3 mRNA expression at the beginning of the light phase (P < 0.01). Consumption of a high-fat diet increased inguinal (by 36%; P < 0.05) and retroperitoneal WAT weight (by 72%; P < 0.01) only in RF-maintained rats, doubling the efficiency of lipid accumulation (P < 0.05). Thus, RF not only desynchronizes central and peripheral circadian clocks, and suppresses nocturnal GH secretion, but induces a preobesogenic state.

  7. The Ustilago maydis effector Pep1 suppresses plant immunity by inhibition of host peroxidase activity.

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    Christoph Hemetsberger

    Full Text Available The corn smut Ustilago maydis establishes a biotrophic interaction with its host plant maize. This interaction requires efficient suppression of plant immune responses, which is attributed to secreted effector proteins. Previously we identified Pep1 (Protein essential during penetration-1 as a secreted effector with an essential role for U. maydis virulence. pep1 deletion mutants induce strong defense responses leading to an early block in pathogenic development of the fungus. Using cytological and functional assays we show that Pep1 functions as an inhibitor of plant peroxidases. At sites of Δpep1 mutant penetrations, H₂O₂ strongly accumulated in the cell walls, coinciding with a transcriptional induction of the secreted maize peroxidase POX12. Pep1 protein effectively inhibited the peroxidase driven oxidative burst and thereby suppresses the early immune responses of maize. Moreover, Pep1 directly inhibits peroxidases in vitro in a concentration-dependent manner. Using fluorescence complementation assays, we observed a direct interaction of Pep1 and the maize peroxidase POX12 in vivo. Functional relevance of this interaction was demonstrated by partial complementation of the Δpep1 mutant defect by virus induced gene silencing of maize POX12. We conclude that Pep1 acts as a potent suppressor of early plant defenses by inhibition of peroxidase activity. Thus, it represents a novel strategy for establishing a biotrophic interaction.

  8. H-reflex suppression and autonomic activation during lucid REM sleep: a case study.

    Science.gov (United States)

    Brylowski, A; Levitan, L; LaBerge, S

    1989-08-01

    A single subject, a proficient lucid dreamer experienced with signaling the onset of lucidity (reflective consciousness of dreaming) by means of voluntary eye movements, spent 4 nonconsecutive nights in the sleep laboratory. The subject reported becoming lucid and signaling in 8 of the 18 rapid-eye movement (REM) periods recorded. Ten lucid dream reports were verified by polygraphic examination of signals, providing a total of 12.5 min of signal-verified lucid REM. H-Reflex amplitude was recorded every 5 s, along with continuous recording of electroencephalogram, electrooculogram, electromyogram, electrocardiogram, finger pulse, and respiration. Significant findings included greater mean H-reflex suppression during lucid REM sleep than during nonlucid REM and correlations of H-reflex suppression with increased eye movement density, heart rate, and respiration rate. These results support previous studies reporting that lucid REM is not, as might be supposed, a state closer to awakening than ordinary, or nonlucid, REM; rather, lucid dreaming occurs during unequivocal REM sleep and is characteristically associated with phasic REM activation.

  9. Effect of Melatonin Implants during the Non-Breeding Season on the Onset of Ovarian Activity and the Plasma Prolactin in Dromedary Camel

    Directory of Open Access Journals (Sweden)

    Khalid El Allali

    2018-03-01

    Full Text Available To examine a possible control of reproductive seasonality by melatonin, continual-release subcutaneous melatonin implants were inserted 4.5 months before the natural breeding season (October–April into female camels (Melatonin-treated group. The animals were exposed to an artificial long photoperiod (16L:8D for 41 days prior to implant placement to facilitate receptivity to the short-day signal that is expected with melatonin implants. The treated and control groups (untreated females were maintained separately under outdoor natural conditions. Ovarian follicular development was monitored in both groups by transrectal ultrasonography and by plasma estradiol-17β concentrations performed weekly for 8 weeks and then for 14 weeks following implant insertion. Plasma prolactin concentrations were determined at 45 and 15 days before and 0, 14, 28, 56, and 98 days after implant insertion. Plasma melatonin concentration was determined to validate response to the artificial long photoperiod and to verify the pattern of release from the implants. Results showed that the artificial long photoperiod induced a melatonin secretion peak of significantly (P < 0.05 shorter duration (about 2.5 h. Melatonin release from the implants resulted in higher circulating plasma melatonin levels during daytime and nighttime which persisted for more than 12 weeks following implants insertion. Treatment with melatonin implants advanced the onset of follicular growth activity by 3.5 months compared to untreated animals. Plasma estradiol-17β increased gradually from the second week after the beginning of treatment to reach significantly (P < 0.01 higher concentrations (39.2 ± 6.2 to 46.4 ± 4.5 pg/ml between the third and the fifth week post insertion of melatonin implants. Treatment with melatonin implants also induced a moderate, but significant (P < 0.05 suppressive effect on plasma prolactin concentration on the 28th day. These

  10. Mevalonate Pathway Antagonist Inhibits Proliferation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models

    Science.gov (United States)

    Kobayashi, Yusuke; Kashima, Hiroyasu; Wu, Ren-Chin; Jung, Jin- Gyoung; Kuan, Jen-Chun; Gu, Jinghua; Xuan, Jianhua; Sokoll, Lori; Visvanathan, Kala; Shih, Ie-Ming; Wang, Tian-Li

    2015-01-01

    Purpose Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with TP53 mutations. Since TP53 mutations occur in almost all of the ovarian high-grade serous carcinoma, we determined if statins suppressed tumor growth in animal models of ovarian cancer. Experimental Design Two ovarian cancer mouse models were employed. The first one was a genetically engineered model, mogp-TAg, in which the promoter of oviduct glycoprotein-1 was used to drive the expression of SV40 T-antigen in gynecologic tissues. These mice spontaneously develop serous tubal intraepithelial carcinomas (STICs), which are known as ovarian cancer precursor lesions. The second model was a xenograft tumor model in which human ovarian cancer cells were inoculated into immunocompromised mice. Mice in both models were treated with lovastatin, and effects on tumor growth were monitored. The molecular mechanisms underlying the anti-tumor effects of lovastatin were also investigated. Results Lovastatin significantly reduced the development of STICs in mogp-TAg mice and inhibited ovarian tumor growth in the mouse xenograft model. Knockdown of prenylation enzymes in the mevalonate pathway recapitulated the lovastatin-induced anti-proliferative phenotype. Transcriptome analysis indicated that lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways, suggesting that statins have pleiotropic effects on tumor cells. Conclusion The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease. PMID:26109099

  11. Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis.

    Science.gov (United States)

    Li, Jinpeng; Bhattacharya, Sudin; Zhou, Jiajun; Phadnis-Moghe, Ashwini S; Crawford, Robert B; Kaminski, Norbert E

    2017-11-15

    Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates biological responses to endogenous and environmental chemical cues. Increasing evidence shows that the AHR plays physiological roles in regulating development, homeostasis, and function of a variety of cell lineages in the immune system. However, the role of AHR in human B cell development has not been investigated. Toward this end, an in vitro feeder-free human B cell developmental model system was employed using human cord blood CD34 + hematopoietic stem/progenitor cells. Using this model, we found that AHR activation by the high-affinity ligand 2,3,7,8-tetrachlorodibenzo- p -dioxin significantly suppressed the generation of early B cells and pro-B cells from hematopoietic stem/progenitor cells, indicating the impairment of B cell lineage specification and commitment. Addition of an AHR antagonist reversed 2,3,7,8-tetrachlorodibenzo- p -dioxin-elicited suppression of early B and pro-B cells, suggesting a role of AHR in regulating B lymphopoiesis. Gene expression analysis revealed a significant decrease in the messenger RNA level of early B cell factor 1 (EBF1) and paired box 5, two critical transcription factors directing B cell lineage specification and commitment. Additionally, binding of the ligand-activated AHR to the putative dioxin response elements in the EBF1 promoter was demonstrated by EMSAs and chromatin immunoprecipitation analysis, suggesting transcriptional regulation of EBF1 by AHR. Taken together, this study demonstrates a role for the AHR in regulating human B cell development, and it suggests that transcriptional alterations of EBF1 by the AHR are involved in the underlying mechanism. Copyright © 2017 by The American Association of Immunologists, Inc.

  12. Sodium salicylate suppresses GABAergic inhibitory activity in neurons of rodent dorsal raphe nucleus.

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    Yan Jin

    Full Text Available Sodium salicylate (NaSal, a tinnitus inducing agent, can activate serotonergic (5-HTergic neurons in the dorsal raphe nucleus (DRN and can increase serotonin (5-HT level in the inferior colliculus and the auditory cortex in rodents. To explore the underlying neural mechanisms, we first examined effects of NaSal on neuronal intrinsic properties and the inhibitory synaptic transmissions in DRN slices of rats by using whole-cell patch-clamp technique. We found that NaSal hyperpolarized the resting membrane potential, decreased the input resistance, and suppressed spontaneous and current-evoked firing in GABAergic neurons, but not in 5-HTergic neurons. In addition, NaSal reduced GABAergic spontaneous and miniature inhibitory postsynaptic currents in 5-HTergic neurons. We next examined whether the observed depression of GABAergic activity would cause an increase in the excitability of 5-HTergic neurons using optogenetic technique in DRN slices of the transgenic mouse with channelrhodopsin-2 expressed in GABAergic neurons. When the GABAergic inhibition was enhanced by optical stimulation to GABAergic neurons in mouse DRN, NaSal significantly depolarized the resting membrane potential, increased the input resistance and increased current-evoked firing of 5-HTergic neurons. However, NaSal would fail to increase the excitability of 5-HTergic neurons when the GABAergic synaptic transmission was blocked by picrotoxin, a GABA receptor antagonist. Our results indicate that NaSal suppresses the GABAergic activities to raise the excitability of local 5-HTergic neural circuits in the DRN, which may contribute to the elevated 5-HT level by NaSal in the brain.

  13. Sodium salicylate suppresses GABAergic inhibitory activity in neurons of rodent dorsal raphe nucleus.

    Science.gov (United States)

    Jin, Yan; Luo, Bin; Su, Yan-Yan; Wang, Xin-Xing; Chen, Liang; Wang, Ming; Wang, Wei-Wen; Chen, Lin

    2015-01-01

    Sodium salicylate (NaSal), a tinnitus inducing agent, can activate serotonergic (5-HTergic) neurons in the dorsal raphe nucleus (DRN) and can increase serotonin (5-HT) level in the inferior colliculus and the auditory cortex in rodents. To explore the underlying neural mechanisms, we first examined effects of NaSal on neuronal intrinsic properties and the inhibitory synaptic transmissions in DRN slices of rats by using whole-cell patch-clamp technique. We found that NaSal hyperpolarized the resting membrane potential, decreased the input resistance, and suppressed spontaneous and current-evoked firing in GABAergic neurons, but not in 5-HTergic neurons. In addition, NaSal reduced GABAergic spontaneous and miniature inhibitory postsynaptic currents in 5-HTergic neurons. We next examined whether the observed depression of GABAergic activity would cause an increase in the excitability of 5-HTergic neurons using optogenetic technique in DRN slices of the transgenic mouse with channelrhodopsin-2 expressed in GABAergic neurons. When the GABAergic inhibition was enhanced by optical stimulation to GABAergic neurons in mouse DRN, NaSal significantly depolarized the resting membrane potential, increased the input resistance and increased current-evoked firing of 5-HTergic neurons. However, NaSal would fail to increase the excitability of 5-HTergic neurons when the GABAergic synaptic transmission was blocked by picrotoxin, a GABA receptor antagonist. Our results indicate that NaSal suppresses the GABAergic activities to raise the excitability of local 5-HTergic neural circuits in the DRN, which may contribute to the elevated 5-HT level by NaSal in the brain.

  14. Targeted p53 activation by saRNA suppresses human bladder cancer cells growth and metastasis.

    Science.gov (United States)

    Wang, Chenghe; Ge, Qiangqiang; Zhang, Qingsong; Chen, Zhong; Hu, Jia; Li, Fan; Ye, Zhangqun

    2016-03-25

    Previous study showed that dsP53-285 has the capacity to induce tumor suppressor gene p53 expression by targeting promoter in non-human primates' cells. And it is well known that TP53 gene is frequently mutant or inactivated in human bladder cancer. Hereby, whether this small RNA can activate the expression of wild-type p53 and inhibit human bladder cancer cells remains to be elucidated. Oligonucleotide and lentivirus were used to overexpress dsP53-285 and dsControl. Real-time PCR and western blot were used to detect genes' mRNA and protein expression, respectively. Cell proliferation assay, colony formation, flow cytometry, transwell assay and wound healing assay were performed to determine the effects on bladder cancer cells proliferation and migration/invasion in vitro. Animal models were carried out to analyze the effects on cells growth and metastasis in vivo. Transfection of dsP53-285 into human bladder cancer cell lines T24 and EJ readily activate wild-type p53 expression by targeting promoter. Moreover, dsP53-285 exhibited robust capacity to inhibit cells proliferation and colony formation, induce cells G0/G1 arrest, suppress migration and invasion. Besides, the Cyclin-CDK genes (Cyclin D1 and CDK4/6) were down-regulated and the EMT-associated genes (E-cadherin, β-catenin, ZEB1 and Vimentin) were also expressed inversely after dsP53-285 treatment. In addition, dsP53-285 could also significantly suppress the growth of bladder cancer xenografts and metastasis in nude mice. Most importantly, the anti-tumor effects mediated by dsP53-285 were mainly achieved by manipulating wild-type p53 expression. Our findings indicate that the dsP53-285 can upregulate wild-type p53 expression in human bladder cancer cells through RNA activation, and suppresses cells proliferation and metastasis in vitro and in vivo.

  15. Simvastatin suppresses dexamethasone-induced secretion of plasminogen activator inhibitor-1 in human bone marrow adipocytes

    Directory of Open Access Journals (Sweden)

    Baba Hideo

    2011-04-01

    Full Text Available Abstract Background Osteonecrosis of the femoral head is a common complication of high-dose glucocorticoid treatment. Intravascular thrombosis is thought to be associated with the ischemic state of the femoral head. Plasminogen activator inhibitor-1 (PAI-1 is an adipokine, which are physiologically active substances secreted from visceral and subcutaneous adipocytes. PAI-1 suppresses fibrinolysis by binding tissue-type plasminogen activator. Several reports have described the relationship between PAI-1 and steroid-induced osteonecrosis of the femoral head, and the preventive effects of lipid-lowering agents (statins against steroid-induced osteonecrosis of the femoral head. We previously reported that adipokines and dexamethasone induced PAI-1 secretion from bone marrow adipocytes. The purpose of the present study is to examine the effects of simvastatin on PAI-1 secretion from human bone marrow adipocytes in vitro. Methods Primary bone marrow adipocytes were extracted from collagenase-treated bone marrow fluid obtained from the femoral necks of 40 patients (6 men, 34 women; age range, 52-81 years undergoing hip joint replacement surgery. After suspended culture with or without dexamethasone or simvastatin, PAI-1 mRNA expression was assessed by real-time RT-PCR. Total PAI-1 protein secretion in culture medium was assessed by enzyme-linked immunosorbent assay. Results PAI-1 mRNA expression was up-regulated by 388% (P = 0.002 with dexamethasone, and down-regulated by 45% (P = 0.002 with simvastatin, as compared to control levels. Dexamethasone increased total PAI-1 secretion by 166% (P = 0.001 and simvastatin decreased total PAI-1 secretion by 64% (P = 0.002. No significant changes were observed in adiponectin mRNA expression and secretion by dexamethasone and simvastatin, while pre-treatment with simvastatin reversed dexamethasone induced PAI-1 secretion by 89%, as compared to control levels. Conclusion The present study confirmed the suppressive

  16. Curcumin-induced apoptosis in ovarian carcinoma cells is p53-independent and involves p38 mitogen-activated protein kinase activation and downregulation of Bcl-2 and survivin expression and Akt signaling.

    Science.gov (United States)

    Watson, Jane L; Greenshields, Anna; Hill, Richard; Hilchie, Ashley; Lee, Patrick W; Giacomantonio, Carman A; Hoskin, David W

    2010-01-01

    New cytotoxic agents are urgently needed for the treatment of advanced ovarian cancer because of the poor long-term response of this disease to conventional chemotherapy. Curcumin, obtained from the rhizome of Curcuma longa, has potent anticancer activity; however, the mechanism of curcumin-induced cytotoxicity in ovarian cancer cells remains a mystery. In this study we show that curcumin exhibited time- and dose-dependent cytotoxicity against monolayer cultures of ovarian carcinoma cell lines with differing p53 status (wild-type p53: HEY, OVCA429; mutant p53: OCC1; null p53: SKOV3). In addition, p53 knockdown or p53 inhibition did not diminish curcumin killing of HEY cells, confirming p53-independent cytotoxicity. Curcumin also killed OVCA429, and SKOV3 cells grown as multicellular spheroids. Nuclear condensation and fragmentation, as well as DNA fragmentation and poly (ADP-ribose) polymerase-1 cleavage in curcumin-treated HEY cells, indicated cell death by apoptosis. Procaspase-3, procaspase-8, and procaspase-9 cleavage, in addition to cytochrome c release and Bid cleavage into truncated Bid, revealed that curcumin activated both the extrinsic and intrinsic pathways of apoptosis. Bax expression was unchanged but Bcl-2, survivin, phosphorylated Akt (on serine 473), and total Akt were downregulated in curcumin-treated HEY cells. Curcumin also activated p38 mitogen-activated protein kinase (MAPK) without altering extracellular signal-regulated kinase 1/2 activity. We conclude that p53-independent curcumin-induced apoptosis in ovarian carcinoma cells involves p38 MAPK activation, ablation of prosurvival Akt signaling, and reduced expression of the antiapoptotic proteins Bcl-2 and survivin. These data provide a mechanistic rationale for the potential use of curcumin in the treatment of ovarian cancer. 2009 Wiley-Liss, Inc.

  17. Isolated ovarian tuberculosis mimicking ovarian carcinoma: Case ...

    African Journals Online (AJOL)

    Although genitourinary tuberculosis is common, reports of isolated ovarian tuberculosis are rare. However, its presentation can mimick that of an ovarian tumour, leading to diagnostic difficulties. A woman of 17 years presented with chronic pelvic pain, weight loss, a right ovarian mass on ultrasound, and a significantly ...

  18. Inhibition of Hedgehog signaling antagonizes serous ovarian cancer growth in a primary xenograft model.

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    Christopher K McCann

    Full Text Available Recent evidence links aberrant activation of Hedgehog (Hh signaling with the pathogenesis of several cancers including medulloblastoma, basal cell, small cell lung, pancreatic, prostate and ovarian. This investigation was designed to determine if inhibition of this pathway could inhibit serous ovarian cancer growth.We utilized an in vivo pre-clinical model of serous ovarian cancer to characterize the anti-tumor activity of Hh pathway inhibitors cyclopamine and a clinically applicable derivative, IPI-926. Primary human serous ovarian tumor tissue was used to generate tumor xenografts in mice that were subsequently treated with cyclopamine or IPI-926.Both compounds demonstrated significant anti-tumor activity as single agents. When IPI-926 was used in combination with paclitaxel and carboplatinum (T/C, no synergistic effect was observed, though sustained treatment with IPI-926 after cessation of T/C continued to suppress tumor growth. Hh pathway activity was analyzed by RT-PCR to assess changes in Gli1 transcript levels. A single dose of IPI-926 inhibited mouse stromal Gli1 transcript levels at 24 hours with unchanged human intra-tumor Gli1 levels. Chronic IPI-926 therapy for 21 days, however, inhibited Hh signaling in both mouse stromal and human tumor cells. Expression data from the micro-dissected stroma in human serous ovarian tumors confirmed the presence of Gli1 transcript and a significant association between elevated Gli1 transcript levels and worsened survival.IPI-926 treatment inhibits serous tumor growth suggesting the Hh signaling pathway contributes to the pathogenesis of ovarian cancer and may hold promise as a novel therapeutic target, especially in the maintenance setting.

  19. Predictive and therapeutic markers in ovarian cancer

    Science.gov (United States)

    Gray, Joe W.; Guan, Yinghui; Kuo, Wen-Lin; Fridlyand, Jane; Mills, Gordon B.

    2013-03-26

    Cancer markers may be developed to detect diseases characterized by increased expression of apoptosis-suppressing genes, such as aggressive cancers. Genes in the human chromosomal regions, 8q24, 11q13, 20q11-q13, were found to be amplified indicating in vivo drug resistance in diseases such as ovarian cancer. Diagnosis and assessment of amplification levels certain genes shown to be amplified, including PVT1, can be useful in prediction of poor outcome of patient's response and drug resistance in ovarian cancer patients with low survival rates. Certain genes were found to be high priority therapeutic targets by the identification of recurrent aberrations involving genome sequence, copy number and/or gene expression are associated with reduced survival duration in certain diseases and cancers, specifically ovarian cancer. Therapeutics to inhibit amplification and inhibitors of one of these genes, PVT1, target drug resistance in ovarian cancer patients with low survival rates is described.

  20. Control of immune ligands by members of a cytomegalovirus gene expansion suppresses natural killer cell activation.

    Science.gov (United States)

    Fielding, Ceri A; Weekes, Michael P; Nobre, Luis V; Ruckova, Eva; Wilkie, Gavin S; Paulo, Joao A; Chang, Chiwen; Suárez, Nicolás M; Davies, James A; Antrobus, Robin; Stanton, Richard J; Aicheler, Rebecca J; Nichols, Hester; Vojtesek, Borek; Trowsdale, John; Davison, Andrew J; Gygi, Steven P; Tomasec, Peter; Lehner, Paul J; Wilkinson, Gavin W G

    2017-02-10

    The human cytomegalovirus (HCMV) US12 family consists of ten sequentially arranged genes (US12-21) with poorly characterized function. We now identify novel natural killer (NK) cell evasion functions for four members: US12, US14, US18 and US20. Using a systematic multiplexed proteomics approach to quantify ~1300 cell surface and ~7200 whole cell proteins, we demonstrate that the US12 family selectively targets plasma membrane proteins and plays key roles in regulating NK ligands, adhesion molecules and cytokine receptors. US18 and US20 work in concert to suppress cell surface expression of the critical NKp30 ligand B7-H6 thus inhibiting NK cell activation. The US12 family is therefore identified as a major new hub of immune regulation.

  1. Inverse agonistic activity of antihistamines and suppression of histamine H1 receptor gene expression.

    Science.gov (United States)

    Mizuguchi, Hiroyuki; Ono, Shohei; Hattori, Masashi; Fukui, Hiroyuki

    2012-01-01

    Histamine H(1) receptor (H1R) expression influences the severity of allergy symptoms. We examined the effect of inverse agonists on H1R gene expression. Two inverse agonists (carebastine and mepyramine), but not the neutral antagonist oxatomide, decreased inositol phosphate accumulation. The inverse agonists also decreased H1R gene expression and down-regulated H1R mRNA below basal expression, while basal H1R mRNA expression was maintained after oxatomide treatment. These results suggest that inverse agonists more potently alleviate allergy symptoms by not only inhibiting stimulus-induced up-regulation of H1R gene expression but also by suppressing basal histamine signaling through their inverse agonistic activity.

  2. Sodium azide suppresses LPS-induced expression MCP-1 through regulating IκBζ and STAT1 activities in macrophages.

    Science.gov (United States)

    Park, Cho-Yi; Heo, Jae-Nyoung; Suk, Kyoungho; Lee, Won-Ha

    2017-05-01

    Sodium azide (NaN 3 ) is a chemical compound with multiple toxic effects on vascular and neuronal systems, causing hypotension and neurotoxicity, respectively. In order to test its effects on the immune system, human and mouse macrophage-like cell lines were treated with nontoxic doses of NaN 3 and the changes in LPS-induced inflammatory activation was measured. Interestingly, the LPS-induced expression of monocyte chemoattractant protein (MCP)-1 was suppressed by NaN 3 without affecting the expression of IL-8 and TNF-α. Further analysis of cellular signaling mediators involved in the expression of these cytokines revealed that NaN 3 suppressed the LPS-induced activation of signal transducers and activator of transcription (STAT)1 and inhibitor of κB (IκB) ς, which are involved in the LPS-induced expression of MCP-1, while the LPS-induced activation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) was not affected. The LPS-induced expression of MCP-2 and CXCL10, which are also regulated by STAT1, was suppressed by NaN 3 . Similarly, the LPS-induced expression of IL-6, which is regulated by IκBζ, was suppressed by NaN 3 . These results demonstrate that NaN 3 selectively suppresses the LPS-induced expression of pro-inflammatory mediators through the suppression of STAT1 and IκBζ activation. These new findings about the activity of NaN 3 may contribute to the development of specific regulators of macrophage activity during acute and chronic inflammation. Copyright © 2017. Published by Elsevier Inc.

  3. Effects of calcium channel on ovarian cancer cells

    OpenAIRE

    Zhang, Chunyun; Li, Hailing

    2017-01-01

    The aim of the present study was to examine the effects of calcium channel protein on ovarian cancer cells. The expression of calcium channel protein in normal ovarian cells and ovarian cancer cells was detected by fluorescence quantitative PCR. Subsequently, the ovarian cancer cells were added to calcium channel protein activator media at various concentrations of 0, 1, 4, 8, 12, 16 and 20 mmol/l. The concentration of calcium ion in different samples was produced, and using an MTT assay, ova...

  4. Novel direct AMPK activator suppresses non-small cell lung cancer through inhibition of lipid metabolism

    Science.gov (United States)

    Chen, Xi; Xie, Chun; Fan, Xing-Xing; Jiang, Ze-Bo; Wong, Vincent Kam-Wai; Xu, Jia-Hui; Yao, Xiao-Jun; Liu, Liang; Leung, Elaine Lai-Han

    2017-01-01

    Drug resistance is becoming an obstacle in anti-cancer therapies. For target-based therapy of lung cancer, gefitinib, as the first generation of tyrosine kinase inhibitors (TKIs), demonstrated good initial response to the non-small cell lung cancer (NSCLC) patients whom harbors epidermal growth factor receptor (EGFR) mutation. However, within one year, additional EGFR mutation occurred, leading to eventual gefitinib-resistance. Therefore, it is urgently to discover novel effective small molecule inhibitors for those patients. Abnormal energy metabolism is accepted as new cancer hallmark. Recently, a metabolism rate-limiting enzyme 5’-adenosine menophosphate-activated protein kinase (AMPK) has become a promising anti-cancer target. In this study, we have identified a novel direct AMPK agonist, D561-0775 from a compound library by using molecular docking screening technique. We demonstrated that D561-0775 exhibited significant inhibitory effect on gefitinib-resistant NSCLC cell lines but less cytotoxicity on normal cells. Furthermore, D561-0775 demonstrated a remarkable in vitro AMPK enzyme activation effect. Taken together, D561-0775 showed potential anti-cancer activity via inducing apoptosis, cell cycle arrest, suppressing glycolysis and cholesterol synthesis after activation of AMPK in gefitinib-resistant H1975 cells. D561-0775 has provided a new chemical structure that could be developed as cancer drug for gefitinib-resistant NSCLC patients through inhibition lipid metabolism by directly targeting at AMPK directly. PMID:29221189

  5. Chicoric acid suppresses BAFF expression in B lymphocytes by inhibiting NF-κB activity.

    Science.gov (United States)

    Chen, Lingxi; Huang, Gang; Gao, Min; Shen, Xiaodong; Gong, Wei; Xu, Zhizhen; Zeng, Yijun; He, Fengtian

    2017-03-01

    B cell activating factor belonging to the TNF family (BAFF) plays a critical role in the pathogenesis of autoimmune diseases. The inhibition of BAFF expression is an emerging therapeutic approach for these disorders. Chicoric acid (CA), a bioactive phytochemical found in several widely used traditional medicinal plants, has significant anti-inflammatory activity and anti-arthritic effects. However, the role of CA in modulation of BAFF expression remains unknown. In this study, we demonstrated that CA reduced BAFF expression in human B lymphocyte cell lines and decreased the DNA-binding activity of nuclear factor-κB (NF-κB) in the BAFF promoter region. Furthermore, CA inhibited both the nuclear translocation of p65 (the subunit of NF-κB) and the phosphorylation of IκBα (inhibitor of NF-κB). These results suggest that CA suppresses BAFF expression by inhibiting NF-κB activity, and CA may serve as a novel therapeutic agent to down-regulate excessive BAFF expression in autoimmune diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Effects of melatonin supplementation prior to Ovsynch protocol on ovarian activity and conception rates in anestrous Murrah buffalo heifers during out of breeding season.

    Science.gov (United States)

    Kavita; Phogat, Jagat Bir; Pandey, Anand Kumar; Balhara, Ashok Kumar; Ghuman, Sarvpreet Singh; Gunwant, Pankaj

    2018-03-27

    Buffalo heifers have tendency to show anestrus during summer season. Melatonin has been used for correcting summer dependent anestrous via inducing resumption of ovarian activity. Therefore, the investigation was conducted to compare efficacy of melatonin for induction of estrus and conception rate with Ovsynch protocol in summer anestrous Murrah buffalo heifers. Thirty, summer anestrous Murrah buffalo heifers were selected and divided into two groups- treatment (n = 20; 12 melatonin implants) and control (n = 10; no treatment). On day 28 post-implant insertion, animals of both the groups were subjected to Ovsynch protocol. Blood sampling and ovarian ultrasonography were conducted to measure plasma melatonin, progesterone concentration and ovarian dynamics, respectively. No animal in either group showed estrus during first 28 days post-implant insertion. However, estrus induction rate was 100% after Ovsynch protocol in both groups. As compared to controls, treatment group exhibited higher (p AI, subsequently developed larger (p AI as compared to the control group. The overall conception rate was 50 and 20% in treatment and control groups, respectively. In conclusion, melatonin treatment along with Ovsynch protocol improved the luteal profiles as well as the conception rate in buffalo heifers when compared with animals treated with Ovsynch protocol alone during summer season. Copyright © 2018 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier B.V. All rights reserved.

  7. A randomized trial of diet and physical activity in women treated for stage II—IV ovarian cancer: Rationale and design of the Lifestyle Intervention for Ovarian Cancer Enhanced Survival (LIVES): An NRG Oncology/Gynecologic Oncology Group (GOG-225) Study☆,☆☆

    Science.gov (United States)

    Thomson, Cynthia A.; Crane, Tracy E.; Miller, Austin; Garcia, David O.; Basen-Engquist, Karen; Alberts, David S.

    2016-01-01

    Ovarian cancer is the most common cause of gynecological cancer death in United States women. Efforts to improve progression free survival (PFS) and quality of life (QoL) after treatment for ovarian cancer are necessary. Observational studies suggest that lifestyle behaviors, including diet and physical activity, are associated with lower mortality in this population. The Lifestyle Intervention for Ovarian Cancer Enhanced Survival (LIVES) NRG 0225 study is a randomized, controlled trial designed to test the hypothesis that a 24 month lifestyle intervention will significantly increase PFS after oncological therapy for stage II-IV ovarian cancer. Women are randomized 1:1 to a high vegetable and fiber, low-fat diet with daily physical activity goals or an attention control group. Secondary outcomes to be evaluated include QoL and gastrointestinal health. Moreover an a priori lifestyle adherence score will be used to evaluate relationships between adoption of the diet and activity goals and PFS. Blood specimens are collected at baseline, 6, 12 and 24 months for analysis of dietary adherence (carotenoids) in addition to mechanistic biomarkers (lipids, insulin, telomere length). Women are enrolled at NRG clinic sites nationally and the telephone based lifestyle intervention is delivered from The University of Arizona call center by trained health coaches. A study specific multi-modal telephone, email, and SMS behavior change software platform is utilized for information delivery, coaching and data capture. When completed, LIVES will be the largest behavior-based lifestyle intervention trial conducted among ovarian cancer survivors. PMID:27394382

  8. Inhibiting aerobic glycolysis suppresses renal interstitial fibroblast activation and renal fibrosis.

    Science.gov (United States)

    Ding, Hao; Jiang, Lei; Xu, Jing; Bai, Feng; Zhou, Yang; Yuan, Qi; Luo, Jing; Zen, Ke; Yang, Junwei

    2017-09-01

    Chronic kidney diseases generally lead to renal fibrosis. Despite great progress having been made in identifying molecular mediators of fibrosis, the mechanism that governs renal fibrosis remains unclear, and so far no effective therapeutic antifibrosis strategy is available. Here we demonstrated that a switch of metabolism from oxidative phosphorylation to aerobic glycolysis (Warburg effect) in renal fibroblasts was the primary feature of fibroblast activation during renal fibrosis and that suppressing renal fibroblast aerobic glycolysis could significantly reduce renal fibrosis. Both gene and protein assay showed that the expression of glycolysis enzymes was upregulated in mouse kidneys with unilateral ureter obstruction (UUO) surgery or in transforming growth factor-β1 (TGF-β1)-treated renal interstitial fibroblasts. Aerobic glycolysis flux, indicated by glucose uptake and lactate production, was increased in mouse kidney with UUO nephropathy or TGF-β1-treated renal interstitial fibroblasts and positively correlated with fibrosis process. In line with this, we found that increasing aerobic glycolysis can remarkably induce myofibroblast activation while aerobic glycolysis inhibitors shikonin and 2-deoxyglucose attenuate UUO-induced mouse renal fibrosis and TGF-β1-stimulated myofibroblast activation. Furthermore, mechanistic study indicated that shikonin inhibits renal aerobic glycolysis via reducing phosphorylation of pyruvate kinase type M2, a rate-limiting glycolytic enzyme associated with cell reliance on aerobic glycolysis. In conclusion, our findings demonstrate the critical role of aerobic glycolysis in renal fibrosis and support treatment with aerobic glycolysis inhibitors as a potential antifibrotic strategy. Copyright © 2017 the American Physiological Society.

  9. Profiling of Sox4-dependent transcriptome in skin links tumour suppression and adult stem cell activation

    Directory of Open Access Journals (Sweden)

    Miguel Foronda

    2015-12-01

    Full Text Available Adult stem cells (ASCs reside in specific niches in a quiescent state in adult mammals. Upon specific cues they become activated and respond by self-renewing and differentiating into newly generated specialised cells that ensure appropriate tissue fitness. ASC quiescence also serves as a tumour suppression mechanism by hampering cellular transformation and expansion (White AC et al., 2014. Some genes restricted to early embryonic development and adult stem cell niches are often potent modulators of stem cell quiescence, and derailed expression of these is commonly associated to cancer (Vervoort SJ et al., 2013. Among them, it has been shown that recommissioned Sox4 expression facilitates proliferation, survival and migration of malignant cells. By generating a conditional Knockout mouse model in stratified epithelia (Sox4cKO mice, we demonstrated a delayed plucking-induced Anagen in the absence of Sox4. Skin global transcriptome analysis revealed a prominent defect in the induction of transcriptional networks that control hair follicle stem cell (HFSC activation such as those regulated by Wnt/Ctnnb1, Shh, Myc or Sox9, cell cycle and DNA damage response-associated pathways. Besides, Sox4cKO mice are resistant to skin carcinogenesis, thus linking Sox4 to both normal and pathological HFSC activation (Foronda M et al., 2014. Here we provide additional details on the analysis of Sox4-regulated transcriptome in Telogen and Anagen skin. The raw and processed microarray data is deposited in GEO under GSE58155.

  10. Constitutively Active Parathyroid Hormone Receptor Signaling in Cells in Osteoblastic Lineage Suppresses Mechanical Unloading-induced Bone Resorption*

    Science.gov (United States)

    Ono, Noriaki; Nakashima, Kazuhisa; Schipani, Ernestina; Hayata, Tadayoshi; Ezura, Yoichi; Soma, Kunimichi; Kronenberg, Henry M.; Noda, Masaki

    2013-01-01

    Multiple signaling pathways participate in the regulation of bone remodeling, and pathological negative balance in the regulation results in osteoporosis. However, interactions of signaling pathways that act comprehensively in concert to maintain bone mass are not fully understood. We investigated roles of parathyroid hormone receptor (PTH/PTHrP receptor) signaling in osteoblasts in unloading-induced bone loss using transgenic mice. Hind limb unloading by tail suspension reduced bone mass in wild-type mice. In contrast, signaling by constitutively active PTH/PTHrP receptor (caPPR), whose expression was regulated by the osteoblast-specific Col1a1 promoter (Col1a1-caPPR), suppressed unloading-induced reduction in bone mass in these transgenic mice. In Col1a1-caPPR transgenic (Tg) mice, hind limb unloading suppressed bone formation parameters in vivo and mineralized nodule formation in vitro similarly to those observed in wild-type mice. In addition, serum osteocalcin levels and mRNA expression levels of type I collagen, Runx2 and Osterix in bone were suppressed by unloading in both wild-type mice and Tg mice. However, in contrast to unloading-induced enhancement of bone resorption parameters in wild-type mice, Col1a1-caPPR signaling suppressed, rather than enhanced, osteoclast number and osteoclast surface as well as urinary deoxypyridinoline excretion upon unloading. Col1a1-caPPR signaling also suppressed mRNA expression levels of RANK and c-fms in bone upon unloading. Although the M-CSF and monocyte chemoattractant protein 1 (MCP-1) mRNA levels were enhanced in control Tg mice, these levels were suppressed in unloaded Tg mice. These results indicated that constitutive activation of PTH/PTHrP receptor signaling in osteoblastic cells suppresses unloading-induced bone loss specifically through the regulation of osteoclastic activity. PMID:17500070

  11. Organic amendments to avocado crops induce suppressiveness and influence the composition and activity of soil microbial communities.

    Science.gov (United States)

    Bonilla, Nuria; Vida, Carmen; Martínez-Alonso, Maira; Landa, Blanca B; Gaju, Nuria; Cazorla, Francisco M; de Vicente, Antonio

    2015-05-15

    One of the main avocado diseases in southern Spain is white root rot caused by the fungus Rosellinia necatrix Prill. The use of organic soil amendments to enhance the suppressiveness of natural soil is an inviting approach that has successfully controlled other soilborne pathogens. This study tested the suppressive capacity of different organic amendments against R. necatrix and analyzed their effects on soil microbial communities and enzymatic activities. Two-year-old avocado trees were grown in soil treated with composted organic amendments and then used for inoculation assays. All of the organic treatments reduced disease development in comparison to unamended control soil, especially yard waste (YW) and almond shells (AS). The YW had a strong effect on microbial communities in bulk soil and produced larger population levels and diversity, higher hydrolytic activity and strong changes in the bacterial community composition of bulk soil, suggesting a mechanism of general suppression. Amendment with AS induced more subtle changes in bacterial community composition and specific enzymatic activities, with the strongest effects observed in the rhizosphere. Even if the effect was not strong, the changes caused by AS in bulk soil microbiota were related to the direct inhibition of R. necatrix by this amendment, most likely being connected to specific populations able to recolonize conducive soil after pasteurization. All of the organic amendments assayed in this study were able to suppress white root rot, although their suppressiveness appears to be mediated differentially. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  12. Suppressed PHA activation of T lymphocytes in simulated microgravity is restored by direct activation of protein kinase C

    Science.gov (United States)

    Cooper, D.; Pellis, N. R.; McIntire, L. V. (Principal Investigator)

    1998-01-01

    Utilizing clinostatic rotating wall vessel (RWV) bioreactors that simulate aspects of microgravity, we found phytohemagglutinin (PHA) responsiveness to be almost completely diminished. Activation marker expression was significantly reduced in RWV cultures. Furthermore, cytokine secretion profiles suggested that monocytes are not as adversely affected by simulated microgravity as T cells. Reduced cell-cell and cell-substratum interactions may play a role in the loss of PHA responsiveness because placing peripheral blood mononuclear cells (PBMC) within small collagen beads did partially restore PHA responsiveness. However, activation of purified T cells with cross-linked CD2/CD28 and CD3/CD28 antibody pairs was completely suppressed in the RWV, suggesting a defect in signal transduction. Activation of purified T cells with PMA and ionomycin was unaffected by RWV culture. Furthermore, sub-mitogenic doses of PMA alone but not ionomycin alone restored PHA responsiveness of PBMC in RWV culture. Thus our data indicate that during polyclonal activation the signaling pathways upstream of PKC activation are sensitive to simulated microgravity.

  13. Restoration of microRNA-708 sensitizes ovarian cancer cells to cisplatin via IGF2BP1/Akt pathway.

    Science.gov (United States)

    Qin, Xuying; Sun, Linlin; Wang, Jing

    2017-10-01

    A previous study has shown that microRNA-708 (miR-708) functions as a metastasis suppressor in ovarian cancer. In this study, we aimed to explore its implication in regulating cisplatin sensitivity in ovarian cancer cells. To this end, ovarian cancer cells were transfected with miR-708-expressing plasmids or vector before treatment with different concentrations of cisplatin for 48 h. The 50% inhibitory concentration (IC 50 ) value was calculated. Apoptosis was analyzed by measuring caspase-3 activity. The target gene mediating the function of miR-708 was identified. Ectopic expression of miR-708 sensitized SKOV3 and A2780 cells to cisplatin, decreasing the IC 50 value by two- to threefold. miR-708 overexpression significantly augmented cisplatin-induced apoptosis in ovarian cancer cells, which was coupled with increased caspase-3 activity by two- to fourfold. Similarly, overexpression of miR-708 increased the sensitivity of cisplatin-resistant SKOV3/DDP and A2780/DDP cells to cisplatin-induced toxicity, reducing the IC 50 by three- and fivefold, respectively. Delivery of miR-708 enhanced cisplatin-induced elevation in caspase-3 activity in both cisplatin-resistant and parental ovarian cancer cells. Mechanistically, miR-708 downregulated the expression of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and suppressed Akt phosphorylation. Silencing of IGF2BP1 markedly blocked the phosphorylation of Akt. Overexpression of IGF2BP1 restored cisplatin resistance and Akt phosphorylation in miR-708-overexpressing ovarian cancer cells. Collectively, miR-708 increases the susceptibility of ovarian cancer cells to cisplatin by targeting IGF2BP1 and inhibiting Akt signaling. Delivery of miR-708 may represent a promising strategy for improving cisplatin chemotherapy. © 2017 International Federation for Cell Biology.

  14. Metformin prevents aggressive ovarian cancer growth driven by high-energy diet: similarity with calorie restriction.

    Science.gov (United States)

    Al-Wahab, Zaid; Mert, Ismail; Tebbe, Calvin; Chhina, Jasdeep; Hijaz, Miriana; Morris, Robert T; Ali-Fehmi, Rouba; Giri, Shailendra; Munkarah, Adnan R; Rattan, Ramandeep

    2015-05-10

    Caloric restriction (CR) was recently demonstrated by us to restrict ovarian cancer growth in vivo. CR resulted in activation of energy regulating enzymes adenosine monophosphate activated kinase (AMPK) and sirtuin 1 (SIRT1) followed by downstream inhibition of Akt-mTOR. In the present study, we investigated the effects of metformin on ovarian cancer growth in mice fed a high energy diet (HED) and regular diet (RD) and compared them to those seen with CR in an immunocompetent isogeneic mouse model of ovarian cancer. Mice either on RD or HED diet bearing ovarian tumors were treated with 200 mg/kg metformin in drinking water. Metformin treatment in RD and HED mice resulted in a significant reduction in tumor burden in the peritoneum, liver, kidney, spleen and bowel accompanied by decreased levels of growth factors (IGF-1, insulin and leptin), inflammatory cytokines (MCP-1, IL-6) and VEGF in plasma and ascitic fluid, akin to the CR diet mice. Metformin resulted in activation of AMPK and SIRT1 and inhibition of pAkt and pmTOR, similar to CR. Thus metformin can closely mimic CR's tumor suppressing effects by inducing similar metabolic changes, providing further evidence of its potential not only as a therapeutic drug but also as a preventive agent.

  15. Malignancy-Associated Regions of Transcriptional Activation: Gene Expression Profiling Identifies Common Chromosomal Regions of a Recurrent Transcriptional Activation in Human Prostate, Breast, Ovarian, and Colon Cancers

    Directory of Open Access Journals (Sweden)

    Gennadi V. Glinsky

    2003-05-01

    Full Text Available Despite remarkable advances in our understanding of a genetic basis of cancer, the precise molecular definition of the phenotypically relevant genetic features associated with human epithelial malignancies remains a significant and highly relevant challenge. Here we performed a systematic analysis of the chromosomal positions of cancer-associated transcripts for prostate, breast, ovarian, and colon tumors, and identified short segments of human chromosomes that appear to represent a common target for transcriptional activation in major epithelial malignancies in human. These cancer-associated transcriptomeres correspond well to the regions of transient transcriptional activity on chromosomes 1q21-q23 (144-160 Mbp, 12q13 (52-63 Mbp, 17q21 (38-50 Mbp, 17q23-q25 (72-82 Mbp, 19p13 (1-16 Mbp, and Xq28 (132-142 Mbp during human cell cycle, suggesting a common epigenetic mechanism of transcriptional activation. Consistent with this idea, two of these transcriptomeres (12q13 and 17q21 seemed to be related to the p53regulated transcriptional clusters, and some of the cancer-associated transcriptomeres appeared to correspond well to the recently identified regions of increased gene expression on human chromosomes.

  16. Livers with constitutive mTORC1 activity resist steatosis independent of feedback suppression of Akt.

    Directory of Open Access Journals (Sweden)

    Heidi L Kenerson

    Full Text Available Insulin resistance is an important contributing factor in non-alcoholic fatty liver disease. AKT and mTORC1 are key components of the insulin pathway, and play a role in promoting de novo lipogenesis. However, mTORC1 hyperactivity per se does not induce steatosis in mouse livers, but instead, protects against high-fat diet induced steatosis. Here, we investigate the in vivo mechanism of steatosis-resistance secondary to mTORC1 activation, with emphasis on the role of S6K1-mediated feedback inhibition of AKT. Mice with single or double deletion of Tsc1 and/or S6k1 in a liver-specific or whole-body manner were generated to study glucose and hepatic lipid metabolism between the ages of 6-14 weeks. Following 8 weeks of high-fat diet, the Tsc1-/-;S6k1-/- mice had lower body weights but higher liver TG levels compared to that of the Tsc1-/- mice. However, the loss of S6k1 did not relieve feedback inhibition of Akt activity in the Tsc1-/- livers. To overcome Akt suppression, Pten was deleted in Tsc1-/- livers, and the resultant mice showed improved glucose tolerance compared with the Tsc1-/- mice. However, liver TG levels were significantly reduced in the Tsc1-/-;Pten-/- mice compared to the Pten-/- mice, which was restored with rapamycin. We found no correlation between liver TG and serum NEFA levels. Expression of lipogenic genes (Srebp1c, Fasn were elevated in the Tsc1-/-;Pten-/- livers, but this was counter-balanced by an up-regulation of Cpt1a involved in fatty acid oxidation and the anti-oxidant protein, Nrf2. In summary, our in vivo models showed that mTORC1-induced resistance to steatosis was dependent on S6K1 activity, but not secondary to AKT suppression. These findings confirm that AKT and mTORC1 have opposing effects on hepatic lipid metabolism in vivo.

  17. KPNA2 promotes migration and invasion in epithelial ovarian cancer cells by inducing epithelial-mesenchymal transition via Akt/GSK-3β/Snail activation.

    Science.gov (United States)

    Huang, Long; Zhou, Yun; Cao, Xin-Ping; Lin, Jia-Xin; Zhang, Lan; Huang, Shu-Ting; Zheng, Min

    2018-01-01

    Background : Increased karyopherin alpha 2 (KPNA2) expression has been demonstrated in epithelial ovarian carcinoma (EOC) tissue. However, its role in the disease is not clear. Here, we investigate the mechanism of involvement of KPNA2 in EOC. Methods : Stable cell lines expressing KPNA2, or KPNA2 shRNAs, were constructed. The effects of KPNA2 overexpression and knockdown on EOC cell migration, invasion, and epithelial-to-mesenchymal transition (EMT) were evaluated using relevant assays and western blot analysis. Key components of the Akt/GSK-3β/Snail signaling pathway were detected using western blotting and immunofluorescence. Results: KPNA2 overexpression increased the migration and invasion of EOC cells (EFO-21 and SK-OV3); these cells also exhibited characteristics of EMT. Key proteins in the Akt/GSK-3β/Snail signaling pathway were also upregulated in cells overexpressing KPNA2. In contrast, knockdown of KPNA2 effectively suppressed migration and invasion of these EOC cells. Conclusions: KPNA2 may reduce the migration and invasion of EOC by inhibiting the Akt/GSK-3β/Snail signaling pathway and suppressing EMT.

  18. [Stable isotopes of Mg2+ as activators of the suppressed ATP-generating function of mitochondria].

    Science.gov (United States)

    Kuznetsov, D A; Arkhantel'skiĭ, S E; Berdieva, A G; Markarian, A A; Khasigov, P Z; Gatagonova, T M; Ktsova, S A; Orlova, M A

    2005-01-01

    The ATP-generating activity of rat myocardial mitochondria and intramitochondrial creatine kinase was examined as a function of the isotopy of the incubation medium magnesium pool. The study was performed using in vitro systems prepared from the hearts of animals injected with 1-methylnicotine amide, which suppresses the NAD (NADP)-dependent reactions in vivo. It was shown that the presence of the 25Mg paramagnetic cations essential by compensates for the intramitochondrial ATP deficiency caused by the 1-methyl-nicotine amide-induced blockade of oxidative phosphorylation. This effect is hardey achievable in systems where the magnesium pool consists of isotopes with a zero nuclear spin (24Mg, 26Mg). The restoration of mitochondrial ATP synthesis involves the participation of creatine kinase since the activity of the latter does not depend on 1-methyl-nicotine amide. In this case, the high efficiency of this restaration seems to be a spin-selective phenomenon which requires predominantly 25Mg2+ cations. A possible meaning of the data for further studies on the mechanisms of enzymatic catalysis regulation is discussed.

  19. MST2 phosphorylation at serine 385 in mitosis inhibits its tumor suppressing activity.

    Science.gov (United States)

    Chen, Xingcheng; Chen, Yuanhong; Dong, Jixin

    2016-12-01

    Mammalian sterile 20-like kinase 1/2 (MST1/2) are core tumor suppressors in the Hippo signaling pathway. MST1/2 have been shown to regulate mitotic progression. Here, we report a novel mechanism for phospho-regulation of MST2 in mitosis and its biological significance in cancer. We found that the mitotic kinase cyclin-dependent kinase 1 (CDK1) phosphorylates MST2 in vitro and in vivo at serine 385 during antimitotic drug-induced G2/M phase arrest. This phosphorylation occurs transiently during unperturbed mitosis. Mitotic phosphorylation of MST2 does not affect its kinase activity or Hippo-YAP signaling. We further showed that mitotic phosphorylation-deficient mutant MST2-S385A possesses higher activity in suppressing cell proliferation and anchorage-independent growth in vitro and tumorigenesis in vivo. Together, our findings reveal a novel layer of regulation for MST2 in mitosis and its role in tumorigenesis. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Blocking Myristoylation of Src Inhibits Its Kinase Activity and Suppresses Prostate Cancer Progression.

    Science.gov (United States)

    Kim, Sungjin; Alsaidan, Omar Awad; Goodwin, Octavia; Li, Qianjin; Sulejmani, Essilvo; Han, Zhen; Bai, Aiping; Albers, Thomas; Beharry, Zanna; Zheng, Y George; Norris, James S; Szulc, Zdzislaw M; Bielawska, Alicja; Lebedyeva, Iryna; Pegan, Scott D; Cai, Houjian

    2017-12-15

    Protein N -myristoylation enables localization to membranes and helps maintain protein conformation and function. N -myristoyltransferases (NMT) catalyze co- or posttranslational myristoylation of Src family kinases and other oncogenic proteins, thereby regulating their function. In this study, we provide genetic and pharmacologic evidence that inhibiting the N -myristoyltransferase NMT1 suppresses cell-cycle progression, proliferation, and malignant growth of prostate cancer cells. Loss of myristoylation abolished the tumorigenic potential of Src and its synergy with androgen receptor in mediating tumor invasion. We identified the myristoyl-CoA analogue B13 as a small-molecule inhibitor of NMT1 enzymatic activity. B13 exposure blocked Src myristoylation and Src localization to the cytoplasmic membrane, attenuating Src-mediated oncogenic signaling. B13 exerted its anti-invasive and antitumor effects against prostate cancer cells, with minimal toxic side-effects in vivo Structural optimization based on structure-activity relationships enabled the chemical synthesis of LCL204, with enhanced inhibitory potency against NMT1. Collectively, our results offer a preclinical proof of concept for the use of protein myristoylation inhibitors as a strategy to block prostate cancer progression. Cancer Res; 77(24); 6950-62. ©2017 AACR . ©2017 American Association for Cancer Research.

  1. RAG-induced DNA lesions activate proapoptotic BIM to suppress lymphomagenesis in p53-deficient mice

    Science.gov (United States)

    Herold, Marco J.

    2016-01-01

    Neoplastic transformation is driven by oncogenic lesions that facilitate unrestrained cell expansion and resistance to antiproliferative signals. These oncogenic DNA lesions, acquired through errors in DNA replication, gene recombination, or extrinsically imposed damage, are thought to activate multiple tumor suppressive pathways, particularly apoptotic cell death. DNA damage induces apoptosis through well-described p53-mediated induction of PUMA and NOXA. However, loss of both these mediators (even together with defects in p53-mediated induction of cell cycle arrest and cell senescence) does not recapitulate the tumor susceptibility observed in p53−/− mice. Thus, potentially oncogenic DNA lesions are likely to also trigger apoptosis through additional, p53-independent processes. We found that loss of the BH3-only protein BIM accelerated lymphoma development in p53-deficient mice. This process was negated by concomitant loss of RAG1/2-mediated antigen receptor gene rearrangement. This demonstrates that BIM is critical for the induction of apoptosis caused by potentially oncogenic DNA lesions elicited by RAG1/2-induced gene rearrangement. Furthermore, this highlights the role of a BIM-mediated tumor suppressor pathway that acts in parallel to the p53 pathway and remains active even in the absence of wild-type p53 function, suggesting this may be exploited in the treatment of p53-deficient cancers. PMID:27621418

  2. Fem1b promotes ubiquitylation and suppresses transcriptional activity of Gli1.

    Science.gov (United States)

    Gilder, Andrew S; Chen, Yong-Bin; Jackson, Ramon J; Jiang, Jin; Maher, Joseph F

    2013-10-25

    The mammalian Fem1b gene encodes a homolog of FEM-1, a protein in the sex-determination pathway of the nematode Caenorhabditis elegans. Fem1b and FEM-1 proteins each contain a VHL-box motif that mediates their interaction with certain E3 ubiquitin ligase complexes. In C. elegans, FEM-1 negatively regulates the transcription factor TRA-1, and functions as an E3 ubiquitin ligase substrate recognition subunit to target TRA-1 for ubiquitylation. TRA-1 is homologous to the mammalian Gli1 protein, a transcription factor that mediates Hedgehog signaling as well as having Hedgehog-independent functions. Whether the interaction between nematode FEM-1 and TRA-1 proteins is conserved, between corresponding mammalian homologs, has not been reported. Herein, we show that Fem1b interacts with Gli1 within cells, and directly binds Gli1. Fem1b also promotes ubiquitylation of Gli1, suppresses transcriptional activation by Gli1, and attenuates an oncogenic Gli1 autoregulatory loop in cancer cells, all dependent on the VHL-box of Fem1b. These findings have implications for understanding the cellular functions of Fem1b, and the regulation of Gli1 oncoprotein activity. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Evodia alkaloids suppress gluconeogenesis and lipogenesis by activating the constitutive androstane receptor.

    Science.gov (United States)

    Yu, Lushan; Wang, Zhangting; Huang, Minmin; Li, Yingying; Zeng, Kui; Lei, Jinxiu; Hu, Haihong; Chen, Baian; Lu, Jing; Xie, Wen; Zeng, Su

    2016-09-01

    The constitutive androstane receptor (CAR) is a key sensor in xenobiotic detoxification and endobiotic metabolism. Increasing evidence suggests that CAR also plays a role in energy metabolism by suppressing the hepatic gluconeogenesis and lipogenesis. In this study, we investigated the effects of two evodia alkaloids, rutaecarpine (Rut) and evodiamine (Evo), on gluconeogenesis and lipogenesis through their activation of the human CAR (hCAR). We found that both Rut and Evo exhibited anti-lipogenic and anti-gluconeogenic effects in the hyperlipidemic HepG2 cells. Both compounds can potently activate hCAR, and treatment of cells with hCAR antagonists reversed the anti-lipogenic and anti-gluconeogenic effects of Rut and Evo. The anti-gluconeogenic effect of Rut and Evo was due to the CAR-mediated inhibition of the recruitment of forkhead box O1 (FoxO1) and hepatocyte nuclear factor 4α (HNF4α) onto the phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) gene promoters. In vivo, we showed that treatment of mice with Rut improved glucose tolerance in a CAR-dependent manner. Our results suggest that the evodia alkaloids Rut and Evo may have a therapeutic potential for the treatment of hyperglycemia and type 2 diabetes. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity

    International Nuclear Information System (INIS)

    Pols, Thijs W.H.; Ottenhoff, Roelof; Vos, Mariska; Levels, Johannes H.M.; Quax, Paul H.A.; Meijers, Joost C.M.; Pannekoek, Hans; Groen, Albert K.; Vries, Carlie J.M. de

    2008-01-01

    NR4A nuclear receptors are induced in the liver upon fasting and regulate hepatic gluconeogenesis. Here, we studied the role of nuclear receptor Nur77 (NR4A1) in hepatic lipid metabolism. We generated mice expressing hepatic Nur77 using adenoviral vectors, and demonstrate that these mice exhibit a modulation of the plasma lipid profile and a reduction in hepatic triglyceride. Expression analysis of >25 key genes involved in lipid metabolism revealed that Nur77 inhibits SREBP1c expression. This results in decreased SREBP1c activity as is illustrated by reduced expression of its target genes stearoyl-coA desaturase-1, mitochondrial glycerol-3-phosphate acyltransferase, fatty acid synthase and the LDL receptor, and provides a mechanism for the physiological changes observed in response to Nur77. Expression of LXR target genes Abcg5 and Abcg8 is reduced by Nur77, and may suggest involvement of LXR in the inhibitory action of Nur77 on SREBP1c expression. Taken together, our study demonstrates that Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity

  5. Chronic recordings reveal tactile stimuli can suppress spontaneous activity of neurons in somatosensory cortex of awake and anesthetized primates.

    Science.gov (United States)

    Qi, Hui-Xin; Reed, Jamie L; Franca, Joao G; Jain, Neeraj; Kajikawa, Yoshinao; Kaas, Jon H

    2016-04-01

    In somatosensory cortex, tactile stimulation within the neuronal receptive field (RF) typically evokes a transient excitatory response with or without postexcitatory inhibition. Here, we describe neuronal responses in which stimulation on the hand is followed by suppression of the ongoing discharge. With the use of 16-channel microelectrode arrays implanted in the hand representation of primary somatosensory cortex of New World monkeys and prosimian galagos, we recorded neuronal responses from single units and neuron clusters. In 66% of our sample, neuron activity tended to display suppression of firing when regions of skin outside of the excitatory RF were stimulated. In a small proportion of neurons, single-site indentations suppressed firing without initial increases in response to any of the tested sites on the hand. Latencies of suppressive responses to skin indentation (usually 12-34 ms) were similar to excitatory response latencies. The duration of inhibition varied across neurons. Although most observations were from anesthetized animals, we also found similar neuron response properties in one awake galago. Notably, suppression of ongoing neuronal activity did not require conditioning stimuli or multi-site stimulation. The suppressive effects were generally seen following single-site skin indentations outside of the neuron's minimal RF and typically on different digits and palm pads, which have not often been studied in this context. Overall, the characteristics of widespread suppressive or inhibitory response properties with and without initial facilitative or excitatory responses add to the growing evidence that neurons in primary somatosensory cortex provide essential processing for integrating sensory stimulation from across the hand. Copyright © 2016 the American Physiological Society.

  6. Inhibitory effect of putranjivain A on allergic inflammation through suppression of mast cell activation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hui-Hun; Park, Seung-Bin; Lee, Soyoung [CMRI, Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422 (Korea, Republic of); Kwon, Taeg Kyu [Department of Immunology, School of Medicine, Keimyung University, Daegu 704-701 (Korea, Republic of); Shin, Tae-Yong [College of Pharmacy, Woosuk University, Jeonju 565-701 (Korea, Republic of); Park, Pil-Hoon; Lee, Seung-Ho [College of Pharmacy, Youngnam University, Kyungsan 712-749 (Korea, Republic of); Kim, Sang-Hyun, E-mail: shkim72@knu.ac.kr [CMRI, Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422 (Korea, Republic of)

    2014-02-01

    A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. Putranjivain A (PJA), member of ellagitannin, is known to possess beneficial effects including anti-cancer and anti-viral activities. The aim of the present study was to elucidate whether PJA modulates the allergic inflammatory reaction and to study its possible mechanisms of action using mast cell-based in vitro and in vivo models. The study was performed in anaphylaxis mouse model and cultured mast cells. PJA inhibited the expression of pro-inflammatory cytokines in immunoglobulin E-stimulated mast cells. PJA reduced this expression by inhibiting nuclear factor (NF)-κB and nuclear factor of activated T cell. The oral administration of PJA reduced systemic and cutaneous anaphylaxis, the release of serum histamine, and the expression of the histamine H{sub 1} receptor. In addition, PJA attenuated the activation of mast cells. PJA inhibited the release of histamine from various types of mast cells by the suppression of intracellular calcium. The inhibitory activity of PJA on the allergic reaction was similar to that of disodium cromoglycate, a known anti-allergic drug. These results suggest that PJA can facilitate the prevention or treatment of allergic inflammatory diseases mediated by mast cells. - Highlights: • PJA reduced the degranulation of mast cells. • PJA inhibited the production of inflammatory cytokines. • The effect of PJA on allergic reaction was comparable to the DSCG. • PJA might be a candidate for the treatment of allergic inflammatory diseases.

  7. Antiplatelet Aggregation Activity of Walnut Hull Extract via Suppression of Reactive Oxygen Species Generation and Caspase Activation.

    Science.gov (United States)

    Meshkini, Azadeh; Tahmasbi, Masoumeh

    2017-06-01

    Walnut hull (wal hull) is an agricultural by-product that is widely used in traditional medicine for alleviating pain and treating skin diseases, however, recently it has gained much attention in modern pharmacology due to its antioxidant properties. The current study was aimed to determine the total phenolic, flavonoid, and tannin content of Persian wal hull extract and evaluate its biological effects on platelet function. Experimental data showed that acetone extract of wal hulls has a high content of polyphenolic compounds and antioxidant properties. The analytical study of crude extract by gas chromatography-mass spectrometry demonstrated different types of high- and low-molecular-weight compounds that are basically and biologically important. Moreover, an in vitro study revealed that wal hull extract at a concentration of 50 μg/mL inhibited thrombin-induced platelet aggregation and protein secretion by 50%, without any cytotoxic effects on platelets. The examined extract suppressed reactive oxygen species generation and also caspase activation in thrombin-stimulated platelets. Identically, N-acetylcysteine inhibited the increase of reactive oxygen species level induced by thrombin in platelets, and supported a link between cellular redox status and caspase activation in activated platelets. Presumably, the antiplatelet activity of wal hull extract is related to its polyphenolic compounds and their antioxidant properties. Therefore, wal hulls can be considered as a candidate for thrombotic disorders. Copyright © 2017. Published by Elsevier B.V.

  8. Antiplatelet Aggregation Activity of Walnut Hull Extract via Suppression of Reactive Oxygen Species Generation and Caspase Activation

    Directory of Open Access Journals (Sweden)

    Azadeh Meshkini

    2017-06-01

    Full Text Available Walnut hull (wal hull is an agricultural by-product that is widely used in traditional medicine for alleviating pain and treating skin diseases, however, recently it has gained much attention in modern pharmacology due to its antioxidant properties. The current study was aimed to determine the total phenolic, flavonoid, and tannin content of Persian wal hull extract and evaluate its biological effects on platelet function. Experimental data showed that acetone extract of wal hulls has a high content of polyphenolic compounds and antioxidant properties. The analytical study of crude extract by gas chromatography–mass spectrometry demonstrated different types of high- and low-molecular-weight compounds that are basically and biologically important. Moreover, an in vitro study revealed that wal hull extract at a concentration of 50 μg/mL inhibited thrombin-induced platelet aggregation and protein secretion by 50%, without any cytotoxic effects on platelets. The examined extract suppressed reactive oxygen species generation and also caspase activation in thrombin-stimulated platelets. Identically, N-acetylcysteine inhibited the increase of reactive oxygen species level induced by thrombin in platelets, and supported a link between cellular redox status and caspase activation in activated platelets. Presumably, the antiplatelet activity of wal hull extract is related to its polyphenolic compounds and their antioxidant properties. Therefore, wal hulls can be considered as a candidate for thrombotic disorders.

  9. Wnt signaling in ovarian development inhibits Sf1 activation of Sox9 via the Tesco enhancer.

    Science.gov (United States)

    Bernard, Pascal; Ryan, Janelle; Sim, Helena; Czech, Daniel P; Sinclair, Andrew H; Koopman, Peter; Harley, Vincent R

    2012-02-01

    Genome analysis of patients with disorders of sex development, and gain- and loss-of-function studies in mice indicate that gonadal development is regulated by opposing signals. In females, the Wnt/β-catenin canonical pathway blocks testicular differentiation by repressing the expression of the Sertoli cell-specific gene Sox9 by an unknown mechanism. Using cell and embryonic gonad culture models, we show that activation of the Wnt/β-catenin pathway inhibits the expression of Sox9 and Amh, whereas mRNA and protein levels of Sry and steroidogenic factor 1 (Sf1), two key transcriptional regulators of Sox9, are not altered. Ectopic activation of Wnt/β-catenin signaling in male gonads led to a loss of Sf1 binding to the Tesco enhancer and absent Sox9 expression that we also observed in wild-type ovaries. Moreover, ectopic Wnt/β-catenin signaling induced the expression of the female somatic cell markers, Bmp2 and Rspo1, as a likely consequence of Sox9 loss. Wnt/β-catenin signaling in XY gonads did not, however, affect gene expression of the steroidogenic Leydig cell Sf1 target gene, Cyp11a1, or Sf1 binding to the Cyp11a1 promoter. Our data support a model in ovary development whereby activation of β-catenin prevents Sf1 binding to the Sox9 enhancer, thereby inhibiting Sox9 expression and Sertoli cell differentiation.

  10. Targeting of p38 mitogen-activated protein kinases to early growth response gene 1 (EGR-1) in the human paclitaxel-resistance ovarian carcinoma cells.

    Science.gov (United States)

    Lu, Meisong; Xiao, Lan; Hu, Jianli; Deng, Suo; Xu, Yan

    2008-08-01

    To investigate the relationship between the expression of early growth response gene 1 (EGR-1) and p38MAPK pathway in the paclitaxel resistance of ovarian carcinoma cells, the effect of p38MAPK inhibitor SB203580 on cell apoptosis was examined by using Hoechst 33258 staining. The intracellular Rh123 (Rhodamine 123) accumulation was detected by the flow cytometry (FCM). The 50% inhibition concentration (IC50) of paclitaxel for A2780/Taxol cells was determined by MTT method. Electrophoretic motility shift assay (EMSA) was employed to examine the EGR-1DNA binding activity. MDR1 and EGR-1 mRNA were assessed by RT-PCR. The expressed of p-gp, phosphorylated p53 and p38 were detected by Western blotting. SB203580 could remarkably promote the apoptosis of A2780/Taxol cells, and the cell apoptosis was in a time-dependent manner. Cellular Rh123 accumulation was increased, and the IC50 of paclitaxel for A2780/Taxol cells was decreased significantly. A2780/Taxol cell line after SB203580 treatment was shown to have a significantly higher level of EGR-1 DNA binding activity. SB203580 down-regulated the activity of p38MAPK pathway, but up-regulated EGR-1 expression. SB203580 significantly increased the level of cellular phosphorylated p53 protein, but decreased the p-gp protein level and MDR1 mRNA level in A2780/Taxol cells. There existed a close relationship between p38MAPK pathway and the paclitaxel resistance of ovarian carcinoma cells. The expression of EGR-1 mediated by p38MAPK pathway plays a critical role in paclitaxel resistance of ovarian carcinoma cells.

  11. Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Takeshi Fukumoto

    2018-03-01

    Full Text Available Summary: ARID1A, a subunit of the SWI/SNF complex, is among the most frequently mutated genes across cancer types. ARID1A is mutated in more than 50% of ovarian clear cell carcinomas (OCCCs, diseases that have no effective therapy. Here, we show that ARID1A mutation confers sensitivity to pan-HDAC inhibitors such as SAHA in ovarian cancers. This correlated with enhanced growth suppression induced by the inhibition of HDAC2 activity in ARID1A-mutated cells. HDAC2 interacts with EZH2 in an ARID1A status-dependent manner. HDAC2 functions as a co-repressor of EZH2 to suppress the expression of EZH2/ARID1A target tumor suppressor genes such as PIK3IP1 to inhibit proliferation and promote apoptosis. SAHA reduced the growth and ascites of the ARID1A-inactivated OCCCs in both orthotopic and genetic mouse models. This correlated with a significant improvement of survival of mice bearing ARID1A-mutated OCCCs. These findings provided preclinical rationales for repurposing FDA-approved pan-HDAC inhibitors for treating ARID1A-mutated cancers. : Fukumoto et al. show that ARID1A mutation confers sensitivity to pan-HDAC inhibitors such as SAHA in ovarian cancers. This correlated with enhanced growth suppression induced by the inhibition of HDAC2 activity in ARID1A-mutated cells. These findings provided preclinical rationales for repurposing FDA-approved pan-HDAC inhibitors for treating ARID1A-mutated cancers. Keywords: ovarian cancer, ARID1A, HDAC2, pan-HDAC inhibitor, SAHA, SWI/SNF, chromatin remodeling

  12. Downregulation of LRRC8A protects human ovarian and alveolar carcinoma cells against Cisplatin-induced expression of p53, MDM2, p21Waf1/Cip1 and Caspase-9/-3 activation

    DEFF Research Database (Denmark)

    Sørensen, Belinda Halling; Nielsen, Dorthe; Thorsteinsdottir, Unnur Arna

    2016-01-01

    ovarian (A2780) and alveolar (A549) carcinoma cells. In Cisplatin-sensitive cells Cisplatin treatment increases p53-protein level as well as downstream signaling, e.g., expression of p21(Waf1/Cip1), Bax, Noxa, MDM2, and activation of caspase-9/-3. In contrast, Cisplatin-resistant cells do not enter....../-3 activation, expression of p21(Waf1/Cip1) and MDM2 and (ii) that down-regulation of LRRC8A-dependent osmolyte transporters contributes to acquirement of Cisplatin resistance in ovarian and lung carcinoma cells. Activation of LRRC8A containing channels is upstream to apoptotic volume decrease as hypertonic...

  13. Copper suppresses abscisic acid catabolism and catalase activity, and inhibits seed germination of rice.

    Science.gov (United States)

    Ye, Nenghui; Li, Haoxuan; Zhu, Guohui; Liu, Yinggao; Liu, Rui; Xu, Weifeng; Jing, Yu; Peng, Xinxiang; Zhang, Jianhua

    2014-11-01

    Although copper (Cu) is an essential micronutrient for plants, a slight excess of Cu in soil can be harmful to plants. Unfortunately, Cu contamination is a growing problem all over the world due to human activities, and poses a soil stress to plant development. As one of the most important biological processes, seed germination is sensitive to Cu stress. However, little is known about the mechanism of Cu-induced inhibition of seed germination. In the present study, we investigated the relationship between Cu and ABA which is the predominant regulator of seed germination. Cu at a concentration of 30 µM effectively inhibited germination of rice caryopsis. ABA content in germinating seeds under copper stress was also higher than that under control conditions. Quantitative real-time PCR (qRT-PCR) revealed that Cu treatment reduced the expression of OsABA8ox2, a key gene of ABA catabolism in rice seeds. In addition, both malondialdehyde (MDA) and H2O2 contents were increased by Cu stress in the germinating seeds. Antioxidant enzyme assays revealed that only catalase activity was reduced by excess Cu, which was consistent with the mRNA profile of OsCATa during seed germination under Cu stress. Together, our results demonstrate that suppression of ABA catabolism and catalase (CAT) activity by excess Cu leads to the inhibition of seed germination of rice. © The Author 2014. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  14. Binding properties of a blood group Le(a+) active sialoglycoprotein, purified from human ovarian cyst, with applied lectins.

    Science.gov (United States)

    Wu, A M; WU, J H; Watkins, W M; Chen, C P; Tsai, M C

    1996-06-07

    Studies on the structures and binding properties of the glycoproteins, purified from human ovarian cyst fluids, will aid the understanding of the carbohydrate alterations occurring during the biosynthesis of blood group antigens and neoplasm formation. These glycoproteins can also serve as important biological materials to study blood group A, B, H, Le(a), Le(b), Le(x), Le(y), T and Tn determinants, precursor type I and II sequences and cold agglutinin I and i epitopes. In this study, the binding property of a cyst glycoprotein from a human blood group Le(a+) nonsecretor individual, that contains an unusually high amount (18%) of sialic acid (HOC 350) was characterized by quantitative precipitin assay with a panel of lectins exhibiting a broad range of carbohydrate-binding specificities. Native HOC 350 reacted well only with three out of nineteen lectins tested. It precipitated about 80% of Ricinus communis (RCA1), 50% of Triticum vulgaris (WGA) and 37% of Bauhinia purpurea aba (BPA) agglutinins, respectively. However, its asialo product had dramatically enhanced reactivity and reacted well with many I/II (Gal beta1 --> 3/4GcNAc), T(Gal beta1 --> 3GalNAc) and Tn(GaNIAc alphaI --> Ser/Thr) active lectins. It bound best to Jacalin, BPA, and abrin-a and completely precipitated all the lectins added. Asialo-HOC 350 also reacted strongly with Wistaria floribunda, Abrus precatorius agglutinin, ricin and RCA1 and precipitated over 75% of the lectin nitrogen added, and moderately with Arachis hypogaea, Maclura pomifera, WGA, Vicia viosa-B4, Codium fragile tomentosoides and Ulex europaeus-II. But native HOC 350 and its asialo product reacted not at all or poorly with Dolichos biflorus, Helix pomatia, Lotus tetra-gonolobus, Ulex europaeus-I, Lens culinaris lectins and Con A. The lectin-glycoform interactions through bioactive sugars were confirmed by precipitin inhibition assay. Mapping the precipitation profiles of the interactions have led to the conclusion that HOC 350

  15. The effects of buserelin microparticles on ovarian function in healthy ...

    African Journals Online (AJOL)

    Design. Asingle-blind, randomised, parallel-group design was used to investigate the duration of suppression of ovarian function associated with doses of 1,8, 3,6 and 7,2 mg buserelin administered subcutaneously as ... In another study gonadorelin microcapsules suppressed the pituitary testicular axis for at least 50 days.

  16. Asiatic acid attenuates malignancy of human metastatic ovarian ...

    African Journals Online (AJOL)

    vimetin, N-cad and. ZEB1/2) were suppressed, indicating the EMT process was significantly suppressed by AA treatment at the concentration of 10 μM. DISCUSSION. As a highly metastatic disease, patients with a stage III/IV ovarian cancer ...

  17. The effects of buserelin microparticles on ovarian function in healthy ...

    African Journals Online (AJOL)

    Apart from minor side-effects such as hot flushes, vaginal spotting and acne, the compound was tolerated well. We conclude that a good relationship exists between dose and duration of suppression of ovarian function. Doses of 3,6 - 7,2 mg buserelin should suppress oestrogen production for approximately 6 - 9 weeks and ...

  18. An Update on Ovarian Aging and Ovarian Reserve Tests

    Directory of Open Access Journals (Sweden)

    Migraci Tosun

    2016-12-01

    Full Text Available Ovaries are the female organs that age more quickly than other tissues such as the uterus, the pituitary gland or pancreas. Different from males, an interesting question is why and how the females lose fertility so rapidly. During the aging process, both the number and quality of the oocytes in the ovaries decrease and reach to a point beyond that no more viable offspring may be produced and the associated cyclic endocrinological activities cease, entering the menopause in females at an average age of 50 years. Females who delayed childbearing with or without their willing until their 30 years or 40 years constitute the largest portion of the total infertility population. Ovarian reserve tests (ORTs provide an indirect estimate of a female�s diminishing ovarian reserve or remaining follicular pool. This article briefly reviews recent progresses in relation to ovarian aging and ORTs.

  19. Cystatin E/M suppresses legumain activity and invasion of human melanoma

    Directory of Open Access Journals (Sweden)

    Fodstad Øystein

    2010-01-01

    Full Text Available Abstract Background High activity of cysteine proteases such as legumain and the cathepsins have been shown to facilitate growth and invasion of a variety of tumor types. In breast cancer, several recent studies have indicated that loss of the cysteine protease inhibitor cystatin E/M leads to increased growth and metastasis. Although cystatin E/M is normally expressed in the skin, its role in cysteine protease regulation and progression of malignant melanoma has not been studied. Methods A panel of various non-melanoma and melanoma cell lines was used. Cystatin E/M and C were analyzed in cell media by immunoblotting and ELISA. Legumain, cathepsin B and L were analyzed in cell lysates by immunoblotting and their enzymatic activities were analyzed by peptide substrates. Two melanoma cell lines lacking detectable secretion of cystatin E/M were transfected with a cystatin E/M expression plasmid (pCST6, and migration and invasiveness were studied by a Matrigel invasion assay. Results Cystatin E/M was undetectable in media from all established melanoma cell lines examined, whereas strong immunobands were detected in two of five primary melanoma lines and in two of six lines derived from patients with metastatic disease. Among the four melanoma lines secreting cystatin E/M, the glycosylated form (17 kD was predominant compared to the non-glycosylated form (14 kD. Legumain, cathepsin B and L were expressed and active in most of the cell lines, although at low levels in the melanomas expressing cystatin E/M. In the melanoma lines where cystatin E/M was secreted, cystatin C was generally absent or expressed at a very low level. When melanoma cells lacking secretion of cystatin E/M were transfected with pCST6, their intracellular legumain activity was significantly inhibited. In contrast, cathepsin B activity was not affected. Furthermore, invasion was suppressed in cystatin E/M over-expressing melanoma cell lines as measured by the transwell Matrigel

  20. LPV Modeling and Control for Active Flutter Suppression of a Smart Airfoil

    Science.gov (United States)

    Al-Hajjar, Ali M. H.; Al-Jiboory, Ali Khudhair; Swei, Sean Shan-Min; Zhu, Guoming

    2018-01-01

    In this paper, a novel technique of linear parameter varying (LPV) modeling and control of a smart airfoil for active flutter suppression is proposed, where the smart airfoil has a groove along its chord and contains a moving mass that is used to control the airfoil pitching and plunging motions. The new LPV modeling technique is proposed that uses mass position as a scheduling parameter to describe the physical constraint of the moving mass, in addition the hard constraint at the boundaries is realized by proper selection of the parameter varying function. Therefore, the position of the moving mass and the free stream airspeed are considered the scheduling parameters in the study. A state-feedback based LPV gain-scheduling controller with guaranteed H infinity performance is presented by utilizing the dynamics of the moving mass as scheduling parameter at a given airspeed. The numerical simulations demonstrate the effectiveness of the proposed LPV control architecture by significantly improving the performance while reducing the control effort.

  1. Entada phaseoloides extract suppresses hepatic gluconeogenesis via activation of the AMPK signaling pathway.

    Science.gov (United States)

    Zheng, Tao; Hao, Xincai; Wang, Qibin; Chen, Li; Jin, Si; Bian, Fang

    2016-12-04

    The seed of Entada phaseoloides (L.) Merr. (Entada phaseoloides) has been long used as a folk medicine for the treatment of Diabetes mellitus by Chinese ethnic minorities. Recent reports have demonstrated that total saponins from Entada phaseoloides (TSEP) could reduce fasting blood glucose in type 2 diabetic rats. However, the mechanism has not been fully elucidated. The aim of this study was to explore the underlying mechanisms of TSEP on type 2 Diabetes mellitus (T2DM). Primary mouse hepatocytes and HepG2 cells were used to investigate the effects of TSEP on gluconeogenesis. After treatment with TSEP, glucose production, genes expression levels of Glucose-6-phosphatase (G6pase) and Phosphoenoylpyruvate carboxykinase (Pepck) were detected. The efficacy and underlying mechanism of TSEP on AMP-activated protein kinase (AMPK) signaling pathway were determinated. TSEP significantly inhibited glucose production and the gluconeogenic gene expression. Treatment with TSEP elevated the phosphorylation of AMPK, which in turn promoted the phosphorylation of acetyl coenzyme A (ACC) and Akt/glycogen synthase kinase 3β (GSK3β), respectively. Furthermore, TSEP reduced lipid accumulation and improved insulin sensitivity in hepatocytes. These findings provide evidence that TSEP exerts an antidiabetic effect by suppressing hepatic gluconeogenesis via the AMPK signaling pathway. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. Neuropeptide Y acts in the paraventricular nucleus to suppress sympathetic nerve activity and its baroreflex regulation

    Science.gov (United States)

    Cassaglia, Priscila A; Shi, Zhigang; Li, Baoxin; Reis, Wagner L; Clute-Reinig, Nicholas M; Stern, Javier E; Brooks, Virginia L

    2014-01-01

    Neuropeptide Y (NPY), a brain neuromodulator that has been strongly implicated in the regulation of energy balance, also acts centrally to inhibit sympathetic nerve activity (SNA); however, the site and mechanism of action are unknown. In chloralose-anaesthetized female rats, nanoinjection of NPY into the paraventricular nucleus of the hypothalamus (PVN) dose-dependently suppressed lumbar SNA (LSNA) and its baroreflex regulation, and these effects were blocked by prior inhibition of NPY Y1 or Y5 receptors. Moreover, PVN injection of Y1 and Y5 receptor antagonists in otherwise untreated rats increased basal and baroreflex control of LSNA, indicating that endogenous NPY tonically inhibits PVN presympathetic neurons. The sympathoexcitation following blockade of PVN NPY inhibition was eliminated by prior PVN nanoinjection of the melanocortin 3/4 receptor inhibitor SHU9119. Moreover, presympathetic neurons, identified immunohistochemically using cholera toxin b neuronal tract tracing from the rostral ventrolateral medulla (RVLM), express NPY Y1 receptor immunoreactivity, and patch-clamp recordings revealed that both NPY and α–melanocyte-stimulating hormone (α-MSH) inhibit and stimulate, respectively, PVN–RVLM neurons. Collectively, these data suggest that PVN NPY inputs converge with α-MSH to influence presympathetic neurons. Together these results identify endogenous NPY as a novel and potent inhibitory neuromodulator within the PVN that may contribute to changes in SNA that occur in states associated with altered energy balance, such as obesity and pregnancy. PMID:24535439

  3. Monitoring of chemotherapy successfulness of Platina/Taxol chemotherapy protocol by using determination of serum urokinase plasminogen activator (uPA and soluble urokinase plasminogen activator receptor (suPAR in patients with ovarian carcinoma FIGO II

    Directory of Open Access Journals (Sweden)

    Dženita Ljuca

    2007-05-01

    Full Text Available In about 70% of cases, ovarian carcinoma has been diagnosed at an advanced stage. Invasion and metastasis of solid tumors request protease activity resulting in basal membrane destruction and surrounding matrix. In that process, urokinase plasminogen activator (uPA and its receptor, urokinase plasminogen activator receptor (suPAR play a key role, that via plasmin activation lead to basal membrane and matrix degradation in surrounding of the tumor, enable to its invasion and metastasis. Determination of serum concentration of those tumor markers can be useful in preoperative as well as in postoperative period. Their serum concentrations in ovarian cancer patients may help in good monitoring of remission or progression during chemotherapy treatment. In late 1950s and eariy 1960s, when it was found out that malignant ovarian tumors were chemosensitive, their chemotherapy treatment has begun. In the beginning it was used only mono-therapy, and by discovering new cytostatics it was replaced by poly-chemotherapy. Now days, in the therapy of advanced stages of ovarian carcinoma combination of cisplatine or carboplatine with paclitaxel is considering as standard treatment. Aim of this study was to determine serum uPA, suPAR and CEA in FIGO II and III patients with different histo-logical type (serous, mucinous, clear cell tumor before and after PT chemotherapy protocol during following three cycles. In this prospective study we have analyzed 17 patients with ovarian carcinoma, those have been after surgery treated by chemotherapy. Serum levels of uPA and suPAR have been determined by ELISA-test (Imubind uPA, Imubind uPAR, American Diagnostica, and CEA by OPUS Imunoassay method. Results of this study have shown that uPA, suPAR and CEA met criteria for prognostic markers for monitoring of successful-ness of platina/taxol chemotherapy protocol for serous, mucinous and clear cell tumor FIGO II and III stage of ovarian carcinoma. In case of PT chemotherapy

  4. Jasmonate inhibits COP1 activity to suppress hypocotyl elongation and promote cotyledon opening in etiolated Arabidopsis seedlings.

    Science.gov (United States)

    Zheng, Yuyu; Cui, Xuefei; Su, Liang; Fang, Shuang; Chu, Jinfang; Gong, Qingqiu; Yang, Jianping; Zhu, Ziqiang

    2017-06-01

    A germinating seedling undergoes skotomorphogenesis to emerge from the soil and reach for light. During this phase, the cotyledons are closed, and the hypocotyl elongates. Upon exposure to light, the seedling rapidly switches to photomorphogenesis by opening its cotyledons and suppressing hypocotyl elongation. The E3 ubiquitin ligase CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) is critical for maintaining skotomorphogenesis. Here, we report that jasmonate (JA) suppresses hypocotyl elongation and stimulates cotyledon opening in etiolated seedlings, partially phenocopying cop1 mutants in the dark. We also find that JA stabilizes several COP1-targeted transcription factors in a COP1-dependent manner. RNA-seq analysis further defines a JA-light co-modulated and cop1-dependent transcriptome, which is enriched for auxin-responsive genes and genes participating in cell wall modification. JA suppresses COP1 activity through at least two distinct mechanisms: decreasing COP1 protein accumulation in the nucleus; and reducing the physical interaction between COP1 and its activator, SUPPRESSOR OF PHYTOCHROME A-105 1 (SPA1). Our work reveals that JA suppresses COP1 activity to stabilize COP1 targets, thereby inhibiting hypocotyl elongation and stimulating cotyledon unfolding in etiolated Arabidopsis seedlings. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

  5. Suppression and excitation of MHD activity with an electrically polarized electrode at the TCABR tokamak plasma edge

    International Nuclear Information System (INIS)

    Nascimento, I.C.; Kuznetsov, Yu.K.; Guimaraes-Filho, Z.O.; Chamaa-Neto, I. El; Usuriaga, O.; Fonseca, A.M.M.; Galvao, R.M.O.; Caldas, I.L.; Severo, J.H.F.; Semenov, I.B.; Ribeiro, C.; Heller, M.V.P.; Bellintani, V.; Elizondo, J.I.; Sanada, E.

    2007-01-01

    Two reproducible regimes of tokamak operation, with excitation or suppression of MHD activity can be obtained using a voltage-biased electrode inside the edge of the TCABR tokamak. The experiment was carried out adjusting the tokamak parameters to obtain two types of discharges: with strong or weak MHD activity, without biasing in both cases. The plasma current was adjusted to cover a range of safety factor from 2.9 up to 3.5, so that when biasing was applied the magnetic island (3,1) could interact with the edge barrier. The application of biasing in subsequent discharges of each type resulted in excitation or suppression of the MHD activity. The results show that the dominant modes are m = 2, n = 1 and m = 3, n = 1 for excitation and partial suppression, respectively. In both regimes a strong decrease in the radial electric field is detected with destruction of the transport barrier and of the improved confinement caused by different mechanisms. The measurements include temporal behaviour of edge transport, turbulence, poloidal electric and magnetic fields, edge density, radial electric fields and radial profile of H α line intensity. The explanation of the excitation and suppression processes is discussed in the paper

  6. Auricular Acupuncture May Suppress Epileptic Seizures via Activating the Parasympathetic Nervous System: A Hypothesis Based on Innovative Methods

    Directory of Open Access Journals (Sweden)

    Wei He

    2012-01-01

    Full Text Available Auricular acupuncture is a diagnostic and treatment system based on normalizing the body's dysfunction. An increasing number of studies have demonstrated that auricular acupuncture has a significant effect on inducing parasympathetic tone. Epilepsy is a neurological disorder consisting of recurrent seizures resulting from excessive, uncontrolled electrical activity in the brain. Autonomic imbalance demonstrating an increased sympathetic activity and a reduced parasympathetic activation is involved in the development and progress of epileptic seizures. Activation of the parasympathetic nervous system such as vagus nerve stimulation has been used for the treatment of intractable epilepsy. Here, we propose that auricular acupuncture may suppress epileptic seizures via activating the parasympathetic nervous system.

  7. Auricular Acupuncture May Suppress Epileptic Seizures via Activating the Parasympathetic Nervous System: A Hypothesis Based on Innovative Methods.

    Science.gov (United States)

    He, Wei; Rong, Pei-Jing; Li, Liang; Ben, Hui; Zhu, Bing; Litscher, Gerhard

    2012-01-01

    Auricular acupuncture is a diagnostic and treatment system based on normalizing the body's dysfunction. An increasing number of studies have demonstrated that auricular acupuncture has a significant effect on inducing parasympathetic tone. Epilepsy is a neurological disorder consisting of recurrent seizures resulting from excessive, uncontrolled electrical activity in the brain. Autonomic imbalance demonstrating an increased sympathetic activity and a reduced parasympathetic activation is involved in the development and progress of epileptic seizures. Activation of the parasympathetic nervous system such as vagus nerve stimulation has been used for the treatment of intractable epilepsy. Here, we propose that auricular acupuncture may suppress epileptic seizures via activating the parasympathetic nervous system.

  8. An in-beam Compton-suppressed Ge spectrometer for nondestructive neutron activation analysis

    International Nuclear Information System (INIS)

    Zaghloul, R.; Abd El-Haleam, A.; Mostafa, M.; Gantner, E.; Ache, H.J.

    1993-04-01

    A high-efficiency compton background suppressed gamma-ray spectrometer by anti-coincidence counting with a NaI(Tl)-shield around a central HPGe-detector for in-beam prompt gamma-ray neutron activation analysis (AC-PGNAA) using a Cf-252 neutron source has been designed and built to provide simultaneous anti-coincidence spectrometry of natural, industrial and environmental samples. The spectrometer consists of a high-purity germanium detector as the main detector and a large volume cylindrical NaI(Tl) detector as a guard detector. The assembly has the ability to measure instantaneously, simultaneously and nondestructively bulk samples up to about 50 cm 3 . Major constituent elements in several rocks and minerals such as H, B, N, Na, Mg, Al, Si, Cl, K, Ca, P, S, Ti, Fe, Sm, Nd, Mn and Gd can be determined, while oxygen cannot be measured due to its small capture cross section (0.27 mb). Several important minor and trace elements such as B, Cd and Hg beside the low residual activity, rare earths and short-lived isotopes could be detected. The sensitivity of the AC-PGNAA technique is limited by the available neutron flux at the target matrix and the neutron absorption cross section of the elements of interest. PGNAA has the advantage to estimate the constituent elements which are difficult to be measured through the delayed gamm-ray measurements such as B, Bi, C, H, P, Tl, Be, Cl and S in industrial and reference materials and those elements which are transformed into other stable isotopes when undergoing neutron capture. The design of the spectrometer assembly, its properties and performance are described

  9. Coriandrum sativum Suppresses Aβ42-Induced ROS Increases, Glial Cell Proliferation, and ERK Activation.

    Science.gov (United States)

    Liu, Quan Feng; Jeong, Haemin; Lee, Jang Ho; Hong, Yoon Ki; Oh, Youngje; Kim, Young-Mi; Suh, Yoon Seok; Bang, Semin; Yun, Hye Sup; Lee, Kyungho; Cho, Sung Man; Lee, Sung Bae; Jeon, Songhee; Chin, Young-Won; Koo, Byung-Soo; Cho, Kyoung Sang

    2016-01-01

    Alzheimer's disease (AD), the most common neurodegenerative disease, has a complex and widespread pathology that is characterized by the accumulation of amyloid [Formula: see text]-peptide (A[Formula: see text]) in the brain and various cellular abnormalities, including increased oxidative damage, an amplified inflammatory response, and altered mitogen-activated protein kinase signaling. Based on the complex etiology of AD, traditional medicinal plants with multiple effective components are alternative treatments for patients with AD. In the present study, we investigated the neuroprotective effects of an ethanol extract of Coriandrum sativum (C. sativum) leaves on A[Formula: see text] cytotoxicity and examined the molecular mechanisms underlying the beneficial effects. Although recent studies have shown the benefits of the inhalation of C. sativum oil in an animal model of AD, the detailed molecular mechanisms by which C. sativum exerts its neuroprotective effects are unclear. Here, we found that treatment with C. sativum extract increased the survival of both A[Formula: see text]-treated mammalian cells and [Formula: see text]42-expressing flies. Moreover, C. sativum extract intake suppressed [Formula: see text]-induced cell death in the larval imaginal disc and brain without affecting A[Formula: see text]42 expression and accumulation. Interestingly, the increases in reactive oxygen species levels and glial cell number in AD model flies were reduced by C. sativum extract intake. Additionally, C. sativum extract inhibited the epidermal growth factor receptor- and A[Formula: see text]-induced phosphorylation of extracellular signal-regulated kinase (ERK). The constitutively active form of ERK abolished the protective function of C. sativum extract against the [Formula: see text]-induced eye defect phenotype in Drosophila. Taken together, these results suggest that C. sativum leaves have antioxidant, anti-inflammatory, and ERK signaling inhibitory properties that

  10. Midazolam more effectively suppresses sympathetic activations and reduces stress feelings during mental arithmetic task than propofol.

    Science.gov (United States)

    Tsugayasu, Rie; Handa, Toshiyuki; Kaneko, Yuzuru; Ichinohe, Tatsuya

    2010-03-01

    The aim of the present study was to examine the effect of intravenous midazolam and propofol sedation on autonomic nervous activities during psychological stress, and whether these results are associated with changes in subjective stress feelings. Seven healthy male volunteers were included in a randomized crossover manner. The heart rate (HR), HR variability, arterial oxygen saturation, and bispectral index value were continuously monitored. A mental arithmetic task for 7 minutes was given with or without intravenous sedation with midazolam or propofol. A bispectral index value of 75 to 85 and an Observer's Assessment of Alertness/Sedation score of 4 were the targeted sedation level in both groups. HR variability was assessed using the power spectral analysis (low-frequency [LF] and high-frequency [HF] components and LF/HF ratio). The faces anxiety scale was used to grade their stress feelings after each mental arithmetic task. During the mental arithmetic task with intravenous sedation, no differences were found in the bispectral index values, arterial oxygen saturation, or the results of the mental arithmetic task between the 2 groups. The HR, LF/HF ratio, and normalized unit LF increased, and the normalized unit HF decreased in both groups. However, the percentage of changes in LF/HF ratio, normalized unit LF, and normalized unit HF were smaller in the midazolam group. In addition, the reduction in faces anxiety scale was greater in the midazolam group. These results suggest that midazolam more effectively suppresses sympathetic nervous activation and reduces subjective stress feelings during a mental arithmetic task than propofol. Copyright (c) 2010 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  11. FOXD1 is targeted by miR-30a-5p and miR-200a-5p and suppresses the proliferation of human ovarian carcinoma cells by promoting p21 expression in a p53-independent manner.

    Science.gov (United States)

    Wang, Yu; Qiu, Chunping; Lu, Nan; Liu, Zhaojian; Jin, Chengjuan; Sun, Chenggong; Bu, Hualei; Yu, Hongfeng; Dongol, Samina; Kong, Beihua

    2018-04-04

    High-grade serous ovarian carcinoma (HGSOC) accounts for the highest number of deaths among patients with epithelial ovarian cancer. However, the molecular mechanisms underlying HGSOC tumorigenesis are currently unclear. In the present study, a lentiviral expression system was employed to manipulate forkhead box D1 (FOXD1) expression in ovarian cancer cells. Immunohistochemical staining was used to examine the expression of FOXD1 in tissue samples. Clonogenic and MTT assays were employed to evaluate cell proliferation, and flow cytometry was applied for cell cycle analysis. Dual-luciferase reporter and chromatin immunoprecipitation assays were used to determine the role of FOXD1 in regulating p21 expression. The results demonstrated that FOXD1 expression was downregulated in HGSOC, and high expression levels of FOXD1 were found to be a predictor of good prognosis. FOXD1 significantly inhibited the proliferation of human ovarian cancer cells and induced cell cycle arrest at G1 phase in vitro. In addition, exogenous FOXD1 expression inhibited ovarian cancer cell growth in vivo. Furthermore, microRNA (miR)-30a-5p and miR-200a-5p were observed to be upregulated in HGSOC, and function as direct negative regulators of FOXD1 by targeting its 3'-untranslated region. The present study also revealed that FOXD1 promotes p21 expression in a p53-independent manner. In conclusion, the results of the present study indicate a direct association between FOXD1 and p21 that may be mediated by miR-30a-5p and miR-200a-5p. The authors hypothesize that FOXD1 may serve as a biomarker or therapeutic target in HGSOC.

  12. Human steroidogenic factor-1 (hSF-1) regulates progesterone biosynthesis and growth of ovarian surface epithelial cancer cells.

    Science.gov (United States)

    Ramayya, M S; Sheng, M; Moroz, K; Hill, S M; Rowan, B G

    2010-03-01

    The majority of cancers derived from ovarian surface epithelial (OSE) cells are lethal. Estrogens promote proliferation of OSE cells, whereas progesterone inhibits proliferation and promotes apoptosis of OSE cells. Human steroidogenic factor-1 (hSF-1) induction of the steroidogenic acute regulatory protein (StAR) gene, and the steroidogenic enzymes CYP11A1 and HSD3B2 is central to progesterone biosynthesis. Whereas hSF-1 and StAR are expressed in human ovarian surface epithelial (HOSE) cells, hSF-1 and StAR protein were not expressed in a panel of malignant ovarian cancer cell lines (SKOV-3, BG-1, and Caov-3), and in human OSE cells immortalized by SV40 large T antigen (IOSE-121). Transient expression of hSF-1 in SKOV-3 cells activated the expression of StAR, p450scc and 3betaHSD-II mRNAs, and induced progesterone biosynthesis. Additionally, hSF-1 suppressed proliferation and promoted apoptosis of SKOV-3 cells and suppressed SKOV-3 cell growth induced by ERalpha and estradiol. These findings suggest that hSF-1 is central to progesterone biosynthesis in OSE cells. Human SF-1 may decrease OSE cancer cell numbers directly by apoptosis, and indirectly by opposing estradiol-induced proliferation. These findings are consistent with the hypothesis, that down-regulation of hSF-1 contributes to progression of ovarian epithelial cancers. Copyright 2009 Elsevier Ltd. All rights reserved.

  13. Analysis of the Mitogen-activated protein kinase kinase 4 (MAP2K4) tumor suppressor gene in ovarian cancer

    International Nuclear Information System (INIS)

    Davis, Sally J; Choong, David YH; Ramakrishna, Manasa; Ryland, Georgina L; Campbell, Ian G; Gorringe, Kylie L

    2011-01-01

    MAP2K4 is a putative tumor and metastasis suppressor gene frequently found to be deleted in various cancer types. We aimed to conduct a comprehensive analysis of this gene to assess its involvement in ovarian cancer. We screened for mutations in MAP2K4 using High Resolution Melt analysis of 149 primary ovarian tumors and methylation at the promoter using Methylation-Specific Single-Stranded Conformation Polymorphism analysis of 39 tumors. We also considered the clinical impact of changes in MAP2K4 using publicly available expression and copy number array data. Finally, we used siRNA to measure the effect of reducing MAP2K4 expression in cell lines. In addition to 4 previously detected homozygous deletions, we identified a homozygous 16 bp truncating deletion and a heterozygous 4 bp deletion, each in one ovarian tumor. No promoter methylation was detected. The frequency of MAP2K4 homozygous inactivation was 5.6% overall, and 9.8% in high-grade serous cases. Hemizygous deletion of MAP2K4 was observed in 38% of samples. There were significant correlations of copy number and expression in three microarray data sets. There was a significant correlation between MAP2K4 expression and overall survival in one expression array data set, but this was not confirmed in an independent set. Treatment of JAM and HOSE6.3 cell lines with MAP2K4 siRNA showed some reduction in proliferation. MAP2K4 is targeted by genetic inactivation in ovarian cancer and restricted to high grade serous and endometrioid carcinomas in our cohort

  14. A phase 2, randomized, double-blind, placebo-controlled trial of clinical activity and safety of subcutaneous Å6 in women with asymptomatic CA125 progression after first-line chemotherapy of epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Ghamande, Sharad A.; Silverman, Michael H.; Huh, Warner

    2008-01-01

    OBJECTIVES: A6 is a novel peptide that interferes with single-chain urokinase plasminogen activator activity and has shown anti-angiogenic, anti-migratory, and anti-invasive properties. We evaluated clinical efficacy and safety of subcutaneously administered A6 in women with epithelial ovarian ca...

  15. Ovarian activity and oocyte quality associated with the biochemical profile of serum and follicular fluid from Girolando dairy cows postpartum.

    Science.gov (United States)

    Alves, Benner G; Alves, Kele A; Lúcio, Aline C; Martins, Muller C; Silva, Thiago H; Alves, Bruna G; Braga, Lucas S; Silva, Thiago V; Viu, Marco A O; Beletti, Marcelo E; Jacomini, José O; Santos, Ricarda M; Gambarini, Maria L

    2014-05-01

    This study was designed to evaluate the influence of heat stress (HS) on the metabolic profile of serum and follicular fluid (FF), ovarian follicle development, and oocyte quality of Girolando dairy cows. Oocytes, blood, and FF (follicles ≥9mm) samples were obtained at 30, 45, 60, 75, and 90 days postpartum in the summer and winter seasons. During transvaginal follicular aspiration, rectal temperature (RT), body condition score (BCS), number of ovarian follicles, and quality of oocytes were recorded. The ambient air temperature (AT) and relative humidity (RH) were also recorded to calculate the temperature humidity index (THI). Glucose, total cholesterol (TC), triglycerides (TG), urea, sodium (Na), potassium (K), and calcium (Ca) concentrations were determined using serum and FF samples. The RT, THI, and BCS loss were greater (P<0.01) in the summer; however, glucose, Na, and K serum concentrations decreased in the same season (P<0.05). Degenerated oocytes were positively associated (P<0.05) with THI (r=0.14) and AT (r=0.13), and negatively associated with glucose (r=-0.12) and K (r=-0.11) serum concentrations. HS induces metabolic changes, which compromise the number of ovarian follicles and the follicular environment, thus resulting in morphologically damaged oocytes. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Anticancer effect and mechanism of polymer micelle-encapsulated quercetin on ovarian cancer

    Science.gov (United States)

    Gao, Xiang; Wang, Bilan; Wei, Xiawei; Men, Ke; Zheng, Fengjin; Zhou, Yingfeng; Zheng, Yu; Gou, Maling; Huang, Meijuan; Guo, Gang; Huang, Ning; Qian, Zhiyong; Wei, Yuquan

    2012-10-01

    Encapsulation of hydrophobic agents in polymer micelles can improve the water solubility of cargos, contributing to develop novel drugs. Quercetin (QU) is a hydrophobic agent with potential anticancer activity. In this work, we encapsulated QU into biodegradable monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles and tried to provide proof-of-principle for treating ovarian cancer with this nano-formulation of quercetin. These QU loaded MPEG-PCL (QU/MPEG-PCL) micelles with drug loading of 6.9% had a mean particle size of 36 nm, rendering the complete dispersion of quercetin in water. QU inhibited the growth of A2780S ovarian cancer cells on a dose dependent manner in vitro. Intravenous administration of QU/MPEG-PCL micelles significantly suppressed the growth of established xenograft A2780S ovarian tumors through causing cancer cell apoptosis and inhibiting angiogenesis in vivo. Furthermore, the anticancer activity of quercetin on ovarian cancer cells was studied in vitro. Quercetin treatment induced the apoptosis of A2780S cells associated with activating caspase-3 and caspase-9. MCL-1 downregulation, Bcl-2 downregulation, Bax upregulation and mitochondrial transmembrane potential change were observed, suggesting that quercetin may induce apoptosis of A2780S cells through the mitochondrial apoptotic pathway. Otherwise, quercetin treatment decreased phosphorylated p44/42 mitogen-activated protein kinase and phosphorylated Akt, contributing to inhibition of A2780S cell proliferation. Our data suggested that QU/MPEG-PCL micelles were a novel nano-formulation of quercetin with a potential clinical application in ovarian cancer therapy.

  17. Comparative Proteomics of Ovarian Cancer Aggregate Formation Reveals an Increased Expression of Calcium-activated Chloride Channel Regulator 1 (CLCA1).

    Science.gov (United States)

    Musrap, Natasha; Tuccitto, Alessandra; Karagiannis, George S; Saraon, Punit; Batruch, Ihor; Diamandis, Eleftherios P

    2015-07-10

    Ovarian cancer is a lethal gynecological disease that is characterized by peritoneal metastasis and increased resistance to conventional chemotherapies. This increased resistance and the ability to spread is often attributed to the formation of multicellular aggregates or spheroids in the peritoneal cavity, which seed abdominal surfaces and organs. Given that the presence of metastatic implants is a predictor of poor survival, a better understanding of how spheroids form is critical to improving patient outcome, and may result in the identification of novel therapeutic targets. Thus, we attempted to gain insight into the proteomic changes that occur during anchorage-independent cancer cell aggregation. As such, an ovarian cancer cell line, OV-90, was cultured in adherent and non-adherent conditions using stable isotope labeling with amino acids in cell culture (SILAC). Anchorage-dependent cells (OV-90AD) were grown in tissue culture flasks, whereas anchorage-independent cells (OV-90AI) were grown in suspension using the hanging-drop method. Cellular proteins from both conditions were then identified using LC-MS/MS, which resulted in the quantification of 1533 proteins. Of these, 13 and 6 proteins were up-regulated and down-regulated, respectively, in aggregate-forming cells compared with cells grown as monolayers. Relative gene expression and protein expression of candidates were examined in other cell line models of aggregate formation (TOV-112D and ES-2), which revealed an increased expression of calcium-activated chloride channel regulator 1 (CLCA1). Moreover, inhibitor and siRNA transfection studies demonstrated an apparent effect of CLCA1 on cancer cell aggregation. Further elucidation of the role of CLCA1 in the pathogenesis of ovarian cancer is warranted. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Effect of Calcium Soap of Fatty Acids Supplementation on Serum Biochemical Parameters and Ovarian Activity during Out-of-the-Breeding Season in Crossbred Ewes

    Science.gov (United States)

    El-Nour, Hayat H. M.; Nasr, Soad M.; Hassan, Walid R.

    2012-01-01

    This experiment aimed to evaluate the effect of calcium soap of fatty acid (CSFA) supplementation on serum biochemical and hormones and ovarian activity during out-of-the-breeding season in ewes. Twelve crossbred ewes, 2-3 years of age and weighting 45–55 kg, were allocated into two equal groups. The first group was control and the other was treated with 50 g/head of CSFA. All ewes were fed basal diet and treated with 60 mg of medroxy progesterone acetate intravaginal sponge for 12 day. At the third day of sponge removal, the CSFA-treated group was given 50 g/head of CSFA daily for two estrous cycles. During the estrus phase, ovarian activity was detected using ultrasonography in both groups. All ewes were then subjected to natural breeding and conception rate. Blood samples were collected from all ewes during treatment period. Results revealed significant (P < 0.05) increases in serum cholesterol, triglycerides, low-density lipoprotein cholesterol, glucose, and progesterone levels with decrease in calcium and phosphorous levels in treated group. In treated group, normal-size ovaries and more than one follicle on the ovaries were detected and pregnancy rate increased. In conclusion, CSFA supplementation was effective to maintain the reproductive performance when ewes were out of the breeding season. PMID:22629155

  19. Targeting influenza virosomes to ovarian carcinoma cells

    NARCIS (Netherlands)

    Mastrobattista, E; Schoen, P; Wilschut, J; Crommelin, DJA; Storm, G

    2001-01-01

    Reconstituted influenza virus envelopes (virosomes) containing the viral hemagglutinin (HA) have attracted attention as delivery vesicles for cytosolic drug delivery as they possess membrane fusion activity. Here, we show that influenza virosomes can be targeted towards ovarian carcinoma cells

  20. Dihydroartemisinin potentiates the anticancer effect of cisplatin via mTOR inhibition in cisplatin-resistant ovarian cancer cells: involvement of apoptosis and autophagy

    Energy Technology Data Exchange (ETDEWEB)

    Feng, Xue [Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001 (China); Li, Ling [Department of Brain Cognition Computing Lab, University of Kent, Kent CT2 7NZ (United Kingdom); Jiang, Hong; Jiang, Keping; Jin, Ye [Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001 (China); Zheng, Jianhua, E-mail: zhengjianhua1115@126.com [Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001 (China)

    2014-02-14

    Highlights: • Phosphorylation of mTOR is abnormal activation in SKOV3/DDP ovarian cancer cells. • Downregulation of mTOR by DHA helps to sensitize the SKOV3/DDP cells to chemotherapy. • DHA has the potential of induce autophagy in cancer cells. - Abstract: Dihydroartemisinin (DHA) exhibits anticancer activity in tumor cells but its mechanism of action is unclear. Cisplatin (DDP) is currently the best known chemotherapeutic available for ovarian cancer. However, tumors return de novo with acquired resistance over time. Mammalian target of rapamycin (mTOR) is an important kinase that regulates cell apoptosis and autophagy, and its dysregulation has been observed in chemoresistant human cancers. Here, we show that compared with control ovarian cancer cells (SKOV3), mTOR phosphorylation was abnormally activated in cisplatin-resistant ovarian cancer cells (SKOV3/DDP) following cisplatin monotherapy. Treatment with cisplatin combined with DHA could enhance cisplatin-induced proliferation inhibition in SKOV3/DDP cells. This mechanism is at least partially due to DHA deactivation of mTOR kinase and promotion of apoptosis. Although autophagy was also induced by DHA, the reduced cell death was not found by suppressing autophagic flux by Bafilomycin A1 (BAF). Taken together, we conclude that inhibition of cisplatin-induced mTOR activation is one of the main mechanisms by which DHA dramatically promotes its anticancer effect in cisplatin-resistant ovarian cancer cells.

  1. Dihydroartemisinin potentiates the anticancer effect of cisplatin via mTOR inhibition in cisplatin-resistant ovarian cancer cells: involvement of apoptosis and autophagy

    International Nuclear Information System (INIS)

    Feng, Xue; Li, Ling; Jiang, Hong; Jiang, Keping; Jin, Ye; Zheng, Jianhua

    2014-01-01

    Highlights: • Phosphorylation of mTOR is abnormal activation in SKOV3/DDP ovarian cancer cells. • Downregulation of mTOR by DHA helps to sensitize the SKOV3/DDP cells to chemotherapy. • DHA has the potential of induce autophagy in cancer cells. - Abstract: Dihydroartemisinin (DHA) exhibits anticancer activity in tumor cells but its mechanism of action is unclear. Cisplatin (DDP) is currently the best known chemotherapeutic available for ovarian cancer. However, tumors return de novo with acquired resistance over time. Mammalian target of rapamycin (mTOR) is an important kinase that regulates cell apoptosis and autophagy, and its dysregulation has been observed in chemoresistant human cancers. Here, we show that compared with control ovarian cancer cells (SKOV3), mTOR phosphorylation was abnormally activated in cisplatin-resistant ovarian cancer cells (SKOV3/DDP) following cisplatin monotherapy. Treatment with cisplatin combined with DHA could enhance cisplatin-induced proliferation inhibition in SKOV3/DDP cells. This mechanism is at least partially due to DHA deactivation of mTOR kinase and promotion of apoptosis. Although autophagy was also induced by DHA, the reduced cell death was not found by suppressing autophagic flux by Bafilomycin A1 (BAF). Taken together, we conclude that inhibition of cisplatin-induced mTOR activation is one of the main mechanisms by which DHA dramatically promotes its anticancer effect in cisplatin-resistant ovarian cancer cells

  2. Ovarian cancer and smoking

    DEFF Research Database (Denmark)

    Beral, V; Gaitskell, K; Hermon, C

    2012-01-01

    Smoking has been linked to mucinous ovarian cancer, but its effects on other ovarian cancer subtypes and on overall ovarian cancer risk are unclear, and the findings from most studies with relevant data are unpublished. To assess these associations, we review the published and unpublished evidence....

  3. New ways enhancing the vital activity of plants in order to increase crop yields and to suppress radionuclide accumulation

    International Nuclear Information System (INIS)

    Goncharova, N. V; Zebrakova, I. V.; Matsko, V. P.; Kislushko, P. M.

    1994-01-01

    After Chernobyl nuclear accident it has become very important to seek new ways of enhancing the vital activity of plants in order to increase crop yields and to suppress radionuclide accumulation. It is found that by optimizing the vital activity processes in plants, is possible to reduce radionuclide uptake. A great number of biologically active compounds have been tested, which increased the disease resistance of plants and simultaneously activated the physiological and biochemical processes that control the transport of micro- and macroelements (radionuclide included) and their 'soil-root-stem-leaf' redistribution. (author)

  4. Kurarinol induces hepatocellular carcinoma cell apoptosis through suppressing cellular signal transducer and activator of transcription 3 signaling

    Energy Technology Data Exchange (ETDEWEB)

    Shu, Guangwen; Yang, Jing; Zhao, Wenhao; Xu, Chan; Hong, Zongguo; Mei, Zhinan; Yang, Xinzhou, E-mail: xinzhou_yang@hotmail.com

    2014-12-01

    Kurarinol is a flavonoid isolated from roots of the medical plant Sophora flavescens. However, its cytotoxic activity against hepatocellular carcinoma (HCC) cells and toxic effects on mammalians remain largely unexplored. Here, the pro-apoptotic activities of kurarinol on HCC cells and its toxic impacts on tumor-bearing mice were evaluated. The molecular mechanisms underlying kurarinol-induced HCC cell apoptosis were also investigated. We found that kurarinol dose-dependently provoked HepG2, Huh-7 and H22 HCC cell apoptosis. In addition, kurarinol gave rise to a considerable decrease in the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) in HCC cells. Suppression of STAT3 signaling is involved in kurarinol-induced HCC cell apoptosis. In vivo studies showed that kurarinol injection substantially induced transplanted H22 cell apoptosis with low toxic impacts on tumor-bearing mice. Similarly, the transcriptional activity of STAT3 in transplanted tumor tissues was significantly suppressed after kurarinol treatment. Collectively, our current research demonstrated that kurarinol has the capacity of inducing HCC cell apoptosis both in vitro and in vivo with undetectable toxic impacts on the host. Suppressing STAT3 signaling is implicated in kurarinol-mediated HCC cell apoptosis. - Highlights: • Kurarinol induces hepatocellular carcinoma (HCC) cell apoptosis. • Kurarinol induces HCC cell apoptosis via inhibiting STAT3. • Kurarinol exhibits low toxic effects on tumor-bearing animals.

  5. Kurarinol induces hepatocellular carcinoma cell apoptosis through suppressing cellular signal transducer and activator of transcription 3 signaling

    International Nuclear Information System (INIS)

    Shu, Guangwen; Yang, Jing; Zhao, Wenhao; Xu, Chan; Hong, Zongguo; Mei, Zhinan; Yang, Xinzhou

    2014-01-01

    Kurarinol is a flavonoid isolated from roots of the medical plant Sophora flavescens. However, its cytotoxic activity against hepatocellular carcinoma (HCC) cells and toxic effects on mammalians remain largely unexplored. Here, the pro-apoptotic activities of kurarinol on HCC cells and its toxic impacts on tumor-bearing mice were evaluated. The molecular mechanisms underlying kurarinol-induced HCC cell apoptosis were also investigated. We found that kurarinol dose-dependently provoked HepG2, Huh-7 and H22 HCC cell apoptosis. In addition, kurarinol gave rise to a considerable decrease in the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) in HCC cells. Suppression of STAT3 signaling is involved in kurarinol-induced HCC cell apoptosis. In vivo studies showed that kurarinol injection substantially induced transplanted H22 cell apoptosis with low toxic impacts on tumor-bearing mice. Similarly, the transcriptional activity of STAT3 in transplanted tumor tissues was significantly suppressed after kurarinol treatment. Collectively, our current research demonstrated that kurarinol has the capacity of inducing HCC cell apoptosis both in vitro and in vivo with undetectable toxic impacts on the host. Suppressing STAT3 signaling is implicated in kurarinol-mediated HCC cell apoptosis. - Highlights: • Kurarinol induces hepatocellular carcinoma (HCC) cell apoptosis. • Kurarinol induces HCC cell apoptosis via inhibiting STAT3. • Kurarinol exhibits low toxic effects on tumor-bearing animals

  6. Suppression of Natural Killer Cell Activity by Regulatory NKT10 Cells Aggravates Alcoholic Hepatosteatosis

    Directory of Open Access Journals (Sweden)

    Kele Cui

    2017-10-01

    Full Text Available We and others have found that the functions of hepatic natural killer (NK cells are inhibited but invariant NKT (iNKT cells become activated after alcohol drinking, leaving a possibility that there exists interplay between NK cells and iNKT cells during alcoholic liver disease. Here, in a chronic plus single-binge ethanol consumption mouse model, we observed that NK cells and interferon-γ (IFN-γ protected against ethanol-induced liver steatosis, as both wild-type (WT mice treated with anti-asialo GM1 antibody and IFN-γ-deficient GKO mice developed more severe alcoholic fatty livers. As expected, IFN-γ could directly downregulate lipogenesis in primary hepatocytes in vitro. On the contrary, iNKT cell-deficient Jα18−/− or interleukin-10 (IL-10−/− mice showed fewer alcoholic steatosis, along with the recovered number and IFN-γ release of hepatic NK cells, and exogenous IL-10 injection was sufficient to compensate for iNKT cell deficiency. Furthermore, NK cell depletion in Jα18−/− or IL-10−/− mice caused more severe hepatosteatosis, implying NK cells are the direct effector cells to inhibit liver steatosis. Importantly, adoptive transfer of iNKT cells purified from normal but not IL-10−/− mice resulted in suppression of the number and functions of NK cells and aggravated alcoholic liver injury in Jα18−/− mice, indicating that IL-10-producing iNKT (NKT10 cells are the regulators on NK cells. Conclusion: Ethanol exposure-triggered NKT10 cells antagonize the protective roles of NK cells in alcoholic hepatosteatosis.

  7. Vorinostat Modulates the Imbalance of T Cell Subsets, Suppresses Macrophage Activity, and Ameliorates Experimental Autoimmune Uveoretinitis.

    Science.gov (United States)

    Fang, Sijie; Meng, Xiangda; Zhang, Zhuhong; Wang, Yang; Liu, Yuanyuan; You, Caiyun; Yan, Hua

    2016-03-01

    The purpose of the study was to investigate the anti-inflammatory efficiency of vorinostat, a histone deacetylase inhibitor, in experimental autoimmune uveitis (EAU). EAU was induced in female C57BL/6J mice immunized with interphotoreceptor retinoid-binding protein peptide. Vorinostat or the control treatment, phosphate-buffered saline, was administrated orally from 3 days before immunization until euthanasia at day 21 after immunization. The clinical and histopathological scores of mice were graded, and the integrity of the blood-retinal barrier was examined by Evans blue staining. T helper cell subsets were measured by flow cytometry, and the macrophage functions were evaluated with immunohistochemistry staining and immunofluorescence assays. The mRNA levels of tight junction proteins were measured by qRT-PCR. The expression levels of intraocular cytokines and transcription factors were examined by western blotting. Vorinostat relieved both clinical and histopathological manifestations of EAU in our mouse model, and the BRB integrity was maintained in vorinostat-treated mice, which had less vasculature leakage and higher mRNA and protein expressions of tight junction proteins than controls. Moreover, vorinostat repressed Th1 and Th17 cells and increased Th0 and Treg cells. Additionally, the INF-γ and IL-17A expression levels were significantly decreased, while the IL-10 level was increased by vorinostat treatment. Furthermore, due to the reduced TNF-α level, the macrophage activity was considerably inhibited in EAU mice. Finally, transcription factors, including STAT1, STAT3, and p65, were greatly suppressed by vorinostat treatment. Our data suggest that vorinostat might be a potential anti-inflammatory agent in the management of uveitis and other autoimmune inflammatory diseases.

  8. The effects on ovarian activity of ulipristal acetate when 'quickstarting' a combined oral contraceptive pill: a prospective, randomized, double-blind parallel-arm, placebo-controlled study.

    Science.gov (United States)

    Cameron, S T; Berger, C; Michie, L; Klipping, C; Gemzell-Danielsson, K

    2015-07-01

    What is the effect on ovarian activity of a preceding intake of ulipristal acetate (UPA) when starting a combined oral contraceptive (COC) in the mid- to late-follicular phase of the cycle? This study shows that UPA does not affect the ability of the COC to induce ovarian quiescence. UPA is a progesterone receptor modulator that is available for emergency contraception (EC). In theory, UPA could alter the effectiveness of hormonal contraception started immediately following it and vice versa. Current guidelines regarding quick starting a COC following UPA are based on expert opinion only. A double-blind, randomized, placebo-controlled trial was conducted at three separate sites, Edinburgh (Scotland), Stockholm (Sweden) and Groningen (the Netherlands), over a 5-month period in 2012. Healthy female volunteers were randomized to take either UPA or an identically packaged placebo, at mid-cycle (once a lead ovarian follicle was determined to be >13 mm on transvaginal ultrasound imaging). Participants were randomized by a computer-generated randomization schedule, allocated by sequential, sealed envelopes. All women then started 21 days of the same COC the following day. The study was designed to show non-inferiority of UPA compared with placebo in terms of the proportion of women attaining ovarian quiescence, as measured by the Hoogland scoring system, while taking COC. A total of 76 women were recruited over the three sites, Edinburgh (n = 18), Stockholm (n = 13), Groningen (n = 45) and received either UPA (n = 39) or placebo (n = 37). There were no significant differences in demographic characteristics of women in the UPA and placebo groups. Among the 76 participants treated, 47 (61.8%) reached quiescence and 25 (32.9%) ovulated. There were no significant differences between the groups in the odds ratio (OR) of reaching ovarian quiescence or not; OR 0.97 (95% CI: 0.39-2.46). All women who reached quiescence had done so after taking COCs for 14 days. The main

  9. Suppressive effect of AMP-activated protein kinase on the epithelial-mesenchymal transition in retinal pigment epithelial cells.

    Directory of Open Access Journals (Sweden)

    Ryo Matoba

    Full Text Available The epithelial-mesenchymal transition (EMT in retinal pigment epithelial (RPE cells plays a central role in the development of proliferative vitreoretinopathy (PVR. The purpose of this study was to investigate the effect of AMP-activated protein kinase (AMPK, a key regulator of energy homeostasis, on the EMT in RPE cells. In this study, EMT-associated formation of cellular aggregates was induced by co-stimulation of cultured ARPE-19 cells with tumor necrosis factor (TNF-α (10 ng/ml and transforming growth factor (TGF-β2 (5 ng/ml. 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR, a potent activator of AMPK, significantly suppressed TNF-α and TGF-β2-induced cellular aggregate formation (p < 0.01. Dipyridamole almost completely reversed the suppressive effect of AICAR, whereas 5'-amino-5'-deoxyadenosine restored aggregate formation by approximately 50%. AICAR suppressed the downregulation of E-cadherin and the upregulation of fibronectin and α-smooth muscle actin by TNF-α and TGF-β2. The levels of matrix metalloproteinase (MMP-2, MMP-9, interleukin-6, and vascular endothelial growth factor were significantly decreased by AICAR. Activation of the mitogen-activated protein kinase and mammalian target of rapamycin pathways, but not the Smad pathway, was inhibited by AICAR. These findings indicate that AICAR suppresses the EMT in RPE cells at least partially via activation of AMPK. AMPK is a potential target molecule for the prevention and treatment of PVR, so AICAR may be a promising candidate for PVR therapy.

  10. Adenovirus-mediated truncated Bid overexpression induced by the Cre/LoxP system promotes the cell apoptosis of CD133+ ovarian cancer stem cells.

    Science.gov (United States)

    Long, Qifang; Yang, Ru; Lu, Weixian; Zhu, Weipei; Zhou, Jundong; Zheng, Cui; Zhou, Dongmei; Yu, Ling; Wu, Jinchang

    2017-01-01

    Cancer stem cells are a small subset of cancer cells that contribute to cancer progression, metastasis, chemoresistance and recurrence. CD133-positive (CD133+) ovarian cancer cells have been identified as ovarian cancer stem cells. Adenovirus-mediated gene therapy is an innovative therapeutic method for cancer treatment. In the present study, we aimed to develop a new gene therapy to specifically eliminate CD133+ ovarian cancer stem cells by targeting CD133. We used the Cre/LoxP system to augment the selective expression of the truncated Bid (tBid) gene as suicide gene therapy in CD133+ ovarian cancer stem cells. The adenovirus (Ad)-CD133-Cre expressing Cre recombinase under the control of the CD133 promoter and Ad-CMV-LoxP-Neo-LoxP-tBid expressing tBid under the control of the CMV promoter were successfully constructed using the Cre/LoxP switching system. The co-infection of Ad-CMV-LoxP-Neo-LoxP-tBid and Ad-CD133-Cre selectively induced tBid overexpression, which inhibited cell growth and triggered the cell apoptosis of CD133+ ovarian cancer stem cells. The Cre/LoxP system-mediated tBid overexpression activated the pro-apoptotic signaling pathway and augmented the cytotoxic effect of cisplatin in CD133+ ovarian cancer stem cells. Furthermore, in xenograft experiments, co-infection with the two recombinant adenoviruses markedly suppressed tumor growth in vivo and promoted cell apoptosis in tumor tissues. Taken together, the present study provides evidence that the adenovirus-mediated tBid overexpression induced by the Cre/LoxP system can effectively eliminate CD133+ ovarian cancer stem cells, representing a novel therapeutic strategy for the treatment of ovarian cancer.

  11. Heat treatment enhances the NO-suppressing and peroxynitrite-intercepting activities of kumquat (Fortunella margarita Swingle) peel.

    Science.gov (United States)

    Lin, Chih-Cheng; Hung, Pi-Fang; Ho, Su-Chen

    2008-07-01

    In Taiwan, folk remedies containing dried kumquats (Fortunella margarita Swingle) are used to cure inflammatory respiratory disorders. The induction of inducible nitric oxide (NO) synthase in inflammatory cells and increased airway production of NO and peroxynitrite, its derivative, are key events in such disorders. Although heat is known to affect the antioxidant activity of citrus peels, the effects of dehydration and heating on NO suppression and on the interception of peroxynitrite are unclear. We determined the NO-suppressing activities of freeze-dried, oven-dried, and heat-treated kumquat extracts by measuring their inhibition of NO production in lipopolysaccharide-activated RAW 264.7 macrophages. Furthermore, we evaluated the attenuation of peroxynitrite-mediated nitrotyrosine formation in albumin. Heating, but not oven drying, enhanced the ability of kumquat peels to suppress NO and intercept peroxynitrite, as compared with freeze drying. However, heat treatment and oven drying of kumquat flesh attenuated these activities; these effects were at least partially attributed to heat-susceptible ascorbate. Copyright © 2007 Elsevier Ltd. All rights reserved.

  12. Carvacrol, a component of thyme oil, activates PPARα and γ and suppresses COX-2 expression[S

    Science.gov (United States)

    Hotta, Mariko; Nakata, Rieko; Katsukawa, Michiko; Hori, Kazuyuki; Takahashi, Saori; Inoue, Hiroyasu

    2010-01-01

    Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostaglandin biosynthesis, plays a key role in inflammation and circulatory homeostasis. Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors belonging to the nuclear receptor superfamily and are involved in the control of COX-2 expression, and vice versa. Here, we show that COX-2 promoter activity was suppressed by essential oils derived from thyme, clove, rose, eucalyptus, fennel, and bergamot in cell-based transfection assays using bovine arterial endothelial cells. Moreover, from thyme oil, we identified carvacrol as a major component of the suppressor of COX-2 expression and an activator of PPARα and γ. PPARγ-dependent suppression of COX-2 promoter activity was observed in response to carvacrol treatment. In human macrophage-like U937 cells, carvacrol suppressed lipopolysaccharide-induced COX-2 mRNA and protein expression, suggesting that carvacrol regulates COX-2 expression through its agonistic effect on PPARγ. These results may be important in understanding the antiinflammatory and antilifestyle-related disease properties of carvacrol. PMID:19578162

  13. Ovarian volume throughout life

    DEFF Research Database (Denmark)

    Kelsey, Thomas W; Dodwell, Sarah K; Wilkinson, A Graham

    2013-01-01

    cancer. To date there is no normative model of ovarian volume throughout life. By searching the published literature for ovarian volume in healthy females, and using our own data from multiple sources (combined n=59,994) we have generated and robustly validated the first model of ovarian volume from...... to about 2.8 mL (95% CI 2.7-2.9 mL) at the menopause and smaller volumes thereafter. Our model allows us to generate normal values and ranges for ovarian volume throughout life. This is the first validated normative model of ovarian volume from conception to old age; it will be of use in the diagnosis...

  14. Cis-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT2A receptor

    Science.gov (United States)

    Walterscheid, Jeffrey P.; Nghiem, Dat X.; Kazimi, Nasser; Nutt, Leta K.; McConkey, David J.; Norval, Mary; Ullrich, Stephen E.

    2006-01-01

    Exposure to UV radiation induces skin cancer and suppresses the immune response. To induce immune suppression, the electromagnetic energy of UV radiation must be absorbed by an epidermal photoreceptor and converted into a biologically recognizable signal. Two photoreceptors have been recognized: DNA and trans-urocanic acid (UCA). Trans-UCA is normally found in the outermost layer of skin and isomerizes to the cis isomer upon exposure to UV radiation. Although UCA was identified as a UV photoreceptor years ago, and many have documented its ability to induce immune suppression, its exact mode of action remains elusive. Particularly vexing has been the identity of the molecular pathway by which cis-UCA mediates immune suppression. Here we provide evidence that cis-UCA binds to the serotonin [5-hydroxytryptamine (5-HT)] receptor with relatively high affinity (Kd = 4.6 nM). Anti-cis-UCA antibody precipitates radiolabeled 5-HT, and the binding is inhibited by excess 5-HT and/or excess cis-UCA. Similarly, anti-5-HT antibody precipitates radiolabeled cis-UCA, and the binding is inhibited by excess 5-HT or excess cis-UCA. Calcium mobilization was activated when a mouse fibroblast line, stably transfected with the human 5-HT2A receptor, was treated with cis-UCA. Cis-UCA-induced calcium mobilization was blocked with a selective 5-HT2A receptor antagonist. UV- and cis-UCA-induced immune suppression was blocked by antiserotonin antibodies or by treating the mice with 5-HT2A receptor antagonists. Our findings identify cis-UCA as a serotonin receptor ligand and indicate that the immunosuppressive effects of cis-UCA and UV radiation are mediated by activation of the 5-HT2A receptor. PMID:17085585

  15. ASH1L Suppresses Matrix Metalloproteinase through Mitogen-activated Protein Kinase Signaling Pathway in Pulpitis.

    Science.gov (United States)

    Bei, Yin; Tianqian, Hui; Fanyuan, Yu; Haiyun, Luo; Xueyang, Liao; Jing, Yang; Chenglin, Wang; Ling, Ye

    2017-02-01

    with in vitro results, ASH1L was found in increased quantities in experimental dental pulpitis tissue. ASH1L knockdown markedly up-regulated the occurrence of MMP-1, MMP-2, and MMP-13. It also exercised an impact on the enzymatic activity of MMP-2 in HDPCs that had been stimulated with TNF-α. ASH1L knockdown activated the MAPK signal pathway in TNF-α-triggered HDPCs, the inhibition of which reversed the induction of MMPs. Our research identifies a mechanism by which ASH1L suppresses the occurrence and operation of MMPs during pulpitis. It does this through the MAPK pathway. Copyright © 2016 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  16. Arabidopsis cryptochrome 1 interacts with SPA1 to suppress COP1 activity in response to blue light

    Science.gov (United States)

    Liu, Bin; Zuo, Zecheng; Liu, Hongtao; Liu, Xuanming; Lin, Chentao

    2011-01-01

    Plant photoreceptors mediate light suppression of the E3 ubiquitin ligase COP1 (CONSTITUTIVE PHOTOMORPHOGENIC 1) to affect gene expression and photomorphogenesis. However, how photoreceptors mediate light regulation of COP1 activity remains unknown. We report here that Arabidopsis blue-light receptor cryptochrome 1 (CRY1) undergoes blue-light-dependent interaction with the COP1-interacting protein SPA1 (SUPPRESSOR OF PHYTOCHROME A). We further show that the CRY1–SPA1 interaction suppresses the SPA1–COP1 interaction and COP1-dependent degradation of the transcription factor HY5. These results are consistent with a hypothesis that photoexcited CRY1 interacts with SPA1 to modulate COP1 activity and plant development. PMID:21511871

  17. Influence of c-Src on hypoxic resistance to paclitaxel in human ovarian cancer cells and reversal of FV-429.

    Science.gov (United States)

    Guo, Qinglong; Lu, Lu; Liao, Yan; Wang, Xiaoping; Zhang, Yi; Liu, Yicheng; Huang, Shaoliang; Sun, Haopeng; Li, Zhiyu; Zhao, Li

    2018-01-11

    SRC family kinase was documented to have vital roles in adjusting cancer cell malignant behaviors. To date, the role of c-Src, a member of SRC family kinase, in resistance to paclitaxel in human ovarian cancer cells under hypoxia has not been investigated. In the present study, we discovered that hypoxic environment suppressed paclitaxel-induced G2/M phase arrest and blockade of c-Src improved ovarian cancer cells' sensitivity to paclitaxel. FV-429, a derivative of natural flavonoid wogonin, could suppress gene expression and activation of c-Src, followed by deteriorated Stat3 nuclear translocation and its binding to HIF-1α, resulting in paclitaxel resistance reversal through G2/M arrest potentiation. Our study demonstrated that c-Src contributed to hypoxic microenvironment-rendered paclitaxel resistance in human epithelial ovarian cancer cells by G2/M phase arrest deterioration, and through c-Src suppression, FV-429 was capable of reversing the resistance by blocking c-Src/Stat3/HIF-1α pathway.

  18. Genomic activation of the EGFR and HER2-neu genes in a significant proportion of invasive epithelial ovarian cancers

    Directory of Open Access Journals (Sweden)

    Ghislain Vanessa

    2008-01-01

    Full Text Available Abstract Background The status of the EGFR and HER2-neu genes has not been fully defined in ovarian cancer. An integrated analysis of both genes could help define the proportion of patients that would potentially benefit from targeted therapies. Methods We determined the tumour mutation status of the entire tyrosine kinase (TK domain of the EGFR and HER2-neu genes in a cohort of 52 patients with invasive epithelial ovarian cancer as well as the gene copy number and protein expression of both genes in 31 of these patients by DGGE and direct sequecing, immunohistochemistry and Fluorescent in Situ Hybridisation (FISH. Results The EGFR was expressed in 59% of the cases, with a 2+/3+ staining intensity in 38%. HER2-neu expression was found in 35%, with a 2/3+ staining in 18%. No mutations were found in exons 18–24 of the TK domains of EGFR and HER2-neu. High polysomy of the EGFR gene was observed in 13% of the invasive epthelial cancers and amplification of the HER2-neu gene was found in 10% and correlated with a high expression level by immunohistochemistry. Mutations within the tyrosine kinase domain were not found in the entire TK domain of both genes, but have been found in very rare cases by others. Conclusion Genomic alteration of the HER2-neu and EGFR genes is frequent (25% in ovarian cancer. EGFR/HER2-neu targeted therapies should be investigated prospectively and specifically in that subset of patients.

  19. The involvement of noradrenergic mechanisms in the suppressive effects of diazepam on the hypothalamicpituitary- adrenal axis activity in female rats

    OpenAIRE

    Švob Štrac, Dubravka; Muck-Šeler, Dorotea

    2012-01-01

    Aim To elucidate the involvement of noradrenergic system in the mechanism by which diazepam suppresses basal hypothalamic-pituitary-adrenal (HPA) axis activity. Methods Plasma corticosterone and adrenocorticotropic hormone (ACTH) levels were determined in female rats treated with diazepam alone, as well as with diazepam in combination with clonidine (α2-adrenoreceptor agonist), yohimbine (α2-adrenoreceptor antagonist), alpha-methylp- tyrosine (α-MPT, an inhibitor of ca...

  20. Activation of glucocorticoid receptors in Müller glia is protective to retinal neurons and suppresses microglial reactivity

    OpenAIRE

    Gallina, Donika; Zelinka, Christopher Paul; Cebulla, Colleen; Fischer, Andy J.

    2015-01-01

    Reactive microglia and macrophages are prevalent in damaged retinas. Glucocorticoid signaling is known to suppress inflammation and the reactivity of microglia and macrophages. In the vertebrate retina, the glucocorticoid receptor (GCR) is known to be activated and localized to the nuclei of Müller glia (Gallina et al., 2014). Accordingly, we investigated how signaling through GCR influences the survival of neurons using the chick retina in vivo as a model system. We applied intraocular injec...

  1. Design of a Ge-NaI(Tl) Compton suppression spectrometer and its use in neutron activation analysis

    International Nuclear Information System (INIS)

    Petra, M.; Swift, G.; Landsberger, S.

    1990-01-01

    A Compton suppression spectrometer consisting of a germanium detector surrounded by a NaI(Tl) shield and its performance are described. The system reduces the Compton continuum, thus making possible the identification of low-intensity peaks. This allows the determination of small amounts of various elements in biological and environmental materials following neutron activation. Representative results for arsenic in biological materials are presented. (orig.)

  2. Evaluation of the ovarian reserve in women transplanted with frozen and thawed ovarian cortical tissue

    DEFF Research Database (Denmark)

    Greve, Tine; Schmidt, Kirsten Tryde; Kristensen, Stine Gry

    2012-01-01

    To investigate ovarian reserve and ovarian function in women transplanted with frozen/thawed ovarian tissue.......To investigate ovarian reserve and ovarian function in women transplanted with frozen/thawed ovarian tissue....

  3. Dopa therapy and action impulsivity: subthreshold error activation and suppression in Parkinson's disease

    NARCIS (Netherlands)

    Fluchère, F.; Deveaux, M.; Burle, B.; Vidal, F.; van den Wildenberg, W.P.M.; Witjas, T.; Eusebio, A.; Azulay, J.-P.; Hasbroucq, T.

    2015-01-01

    Rationale: Impulsive actions entail (1) capture of the motor system by an action impulse, which is an urge to act and (2) failed suppression of that impulse in order to prevent a response error. Several studies indicate that dopaminergic treatment can induce action impulsivity in patients diagnosed

  4. Multi-walled carbon nanotubes suppress potassium channel activities in PC12 cells

    Science.gov (United States)

    Xu, Haifei; Bai, Juan; Meng, Jie; Hao, Wei; Xu, Haiyan; Cao, Ji-Min

    2009-07-01

    The advancement in nanotechnology has produced technological and conceptual breakthroughs but the effects nanomaterials have on organisms at the cellular level are poorly understood. Here we report that carboxyl-terminated multi-walled carbon nanotubes (MWCNTs) act as antagonists of three types of potassium channels as assessed by whole-cell patch clamp electrophysiology on undifferentiated pheochromocytoma (PC12) cells. Our results showed that carboxyl-terminated MWCNTs suppress the current densities of Ito, IK and IK1 in a time-dependent and irreversible manner. The suppressions were most distinct 24 h after incubation with MWCNTs. However, MWCNTs did not significantly change the expression levels of reactive oxygen species (ROS) or intracellular free calcium and also did not alter the mitochondrial membrane potential (ΔΨm) in PC12 cells. These results suggest that oxidative stress was not involved in the MWCNTs suppression of Ito, IK and IK1 current densities. Nonetheless, the suppression of potassium currents by MWCNTs will impact on electrical signaling of excitable cells such as neurons and muscles.

  5. Broccoli and watercress suppress matrix metalloproteinase-9 activity and invasiveness of human MDA-MB-231 breast cancer cells

    International Nuclear Information System (INIS)

    Rose, Peter; Huang, Qing; Ong, Choon Nam; Whiteman, Matt

    2005-01-01

    A high dietary intake of cruciferous vegetables has been associated with a reduction in numerous human pathologies particularly cancer. In the current study, we examined the inhibitory effects of broccoli (Brassica oleracea var. italica) and watercress (Rorripa nasturtium aquaticum) extracts on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cancer cell invasion and matrix metalloproteinase-9 activity using human MDA-MB-231 breast cancer cells. Aberrant overexpression of matrix metalloproteinases, including metalloproteinase-9, is associated with increased invasive potential in cancer cell lines. Our results demonstrate that extracts of broccoli and Rorripa suppressed TPA-induced MMP-9 activity and invasiveness in a concentration dependant manner as determined by zymographic analysis. Furthermore, fractionation of individual extracts followed by liquid chromatography mass spectroscopy analysis (LC-MS) revealed that the inhibitory effects of each vegetable were associated with the presence of 4-methysulfinylbutyl (sulforaphane) and 7-methylsulphinylheptyl isothiocyanates. Taken together, our data indicate that isothiocyanates derived form broccoli and Rorripa inhibit metalloproteinase 9 activities and also suppress the invasive potential of human MDA-MB-231 breast cancer cells in vitro. The inhibitory effects observed in the current study may contribute to the suppression of carcinogenesis by diets high in cruciferous vegetables

  6. Suppressing epileptic activity in a neural mass model using a closed-loop proportional-integral controller

    Science.gov (United States)

    Wang, Junsong; Niebur, Ernst; Hu, Jinyu; Li, Xiaoli

    2016-01-01

    Closed-loop control is a promising deep brain stimulation (DBS) strategy that could be used to suppress high-amplitude epileptic activity. However, there are currently no analytical approaches to determine the stimulation parameters for effective and safe treatment protocols. Proportional-integral (PI) control is the most extensively used closed-loop control scheme in the field of control engineering because of its simple implementation and perfect performance. In this study, we took Jansen’s neural mass model (NMM) as a test bed to develop a PI-type closed-loop controller for suppressing epileptic activity. A graphical stability analysis method was employed to determine the stabilizing region of the PI controller in the control parameter space, which provided a theoretical guideline for the choice of the PI control parameters. Furthermore, we established the relationship between the parameters of the PI controller and the parameters of the NMM in the form of a stabilizing region, which provided insights into the mechanisms that may suppress epileptic activity in the NMM. The simulation results demonstrated the validity and effectiveness of the proposed closed-loop PI control scheme. PMID:27273563

  7. Aloin Suppresses Lipopolysaccharide-Induced Inflammatory Response and Apoptosis by Inhibiting the Activation of NF-κB

    Directory of Open Access Journals (Sweden)

    Xuan Luo

    2018-02-01

    Full Text Available Numerous herbal-derived natural products are excellent anti-inflammatory agents. Several studies have reported that aloin, the major anthraquinone glycoside obtained from the Aloe species, exhibits anti-inflammatory activity. However, the molecular mechanism of this activity is not well understood. In this report, we found that aloin suppresses lipopolysaccharide-induced pro-inflammatory cytokine secretion and nitric oxide production, and downregulates the expression of tumor necrosis factor alpha (TNF-α, interleukin 6 (IL-6, inducible nitric oxide synthase (iNOS, and cyclooxygenase-2 (COX-2. Aloin inhibits the phosphorylation and acetylation of the NF-κB p65 subunit by suppressing the upstream kinases p38 and Msk1, preventing LPS-induced p65 translocation to the nucleus. We have also shown that aloin inhibits LPS-induced caspase-3 activation and apoptotic cell death. Collectively, these findings suggest that aloin effectively suppresses the inflammatory response, primarily through the inhibition of NF-κB signaling.

  8. Aloin Suppresses Lipopolysaccharide-Induced Inflammatory Response and Apoptosis by Inhibiting the Activation of NF-κB.

    Science.gov (United States)

    Luo, Xuan; Zhang, Haowei; Wei, Xiduan; Shi, Mengjuan; Fan, Ping; Xie, Weidong; Zhang, Yaou; Xu, Naihan

    2018-02-26

    Numerous herbal-derived natural products are excellent anti-inflammatory agents. Several studies have reported that aloin, the major anthraquinone glycoside obtained from the Aloe species, exhibits anti-inflammatory activity. However, the molecular mechanism of this activity is not well understood. In this report, we found that aloin suppresses lipopolysaccharide-induced pro-inflammatory cytokine secretion and nitric oxide production, and downregulates the expression of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Aloin inhibits the phosphorylation and acetylation of the NF-κB p65 subunit by suppressing the upstream kinases p38 and Msk1, preventing LPS-induced p65 translocation to the nucleus. We have also shown that aloin inhibits LPS-induced caspase-3 activation and apoptotic cell death. Collectively, these findings suggest that aloin effectively suppresses the inflammatory response, primarily through the inhibition of NF-κB signaling.

  9. Activated MEK Suppresses Activation of PKR and Enables Efficient Replication and In Vivo Oncolysis by Δγ134.5 Mutants of Herpes Simplex Virus 1

    Science.gov (United States)

    Smith, Kerrington D.; Mezhir, James J.; Bickenbach, Kai; Veerapong, Jula; Charron, Jean; Posner, Mitchell C.; Roizman, Bernard; Weichselbaum, Ralph R.

    2006-01-01

    Herpes simplex virus mutants lacking the γ134.5 gene are not destructive to normal tissues but are potent cytolytic agents in human tumor cells in which the activation of double-stranded RNA-dependent protein kinase (PKR) is suppressed. Thus, replication of a Δγ134.5 mutant (R3616) in 12 genetically defined cancer cell lines correlates with suppression of PKR but not with the genotype of RAS. Extensive analyses of two cell lines transduced with either dominant negative MEK (dnMEK) or constitutively active MEK (caMEK) indicated that in R3616 mutant-infected cells dnMEK enabled PKR activation and decreased virus yields, whereas caMEK suppressed PKR and enabled better viral replication and cell destruction in transduced cells in vitro or in mouse xenografts. The results indicate that activated MEK mediates the suppression of PKR and that the status of MEK predicts the ability of Δγ134.5 mutant viruses to replicate in and destroy tumor cells. PMID:16414988

  10. Coalition of Oct4A and β1 integrins in facilitating metastasis in ovarian cancer

    International Nuclear Information System (INIS)

    Samardzija, Chantel; Luwor, Rodney B.; Quinn, Michael A.; Kannourakis, George; Findlay, Jock K.; Ahmed, Nuzhat

    2016-01-01

    Ovarian cancer is a metastatic disease and one of the leading causes of gynaecology malignancy-related deaths in women. Cancer stem cells (CSCs) are key contributors of cancer metastasis and relapse. Integrins are a family of cell surface receptors which allow interactions between cells and their surrounding microenvironment and play a fundamental role in promoting metastasis. This study investigates the molecular mechanism which associates CSCs and integrins in ovarian cancer metastasis. The expression of Oct4A in high-grade serous ovarian tumors and normal ovaries was determined by immunofluorescence analysis. The functional role of Oct4A was evaluated by generating stable knockdown (KD) of Oct4A clones in an established ovarian cancer cell line HEY using shRNA-mediated silencing. The expression of integrins in cell lines was evaluated by flow cytometry. Spheroid forming ability, adhesion and the activities of matrix metalloproteinases 9/2 (MMP-9/2) was measured by in vitro functional assays and gelatin zymography. These observations were further validated in in vivo mouse models using Balb/c nu/nu mice. We report significantly elevated expression of Oct4A in high-grade serous ovarian tumors compared to normal ovarian tissues. The expression of Oct4A in ovarian cancer cell lines correlated with their CSC-related sphere forming abilities. The suppression of Oct4A in HEY cells resulted in a significant diminution of integrin β1 expression and associated α5 and α2 subunits compared to vector control cells. This was associated with a reduced adhesive ability on collagen and fibronectin and decreased secretion of pro-MMP2 in Oct4A KD cells compared to vector control cells. In vivo, Oct4A knock down (KD) cells produced tumors which were significantly smaller in size and weight compared to tumors derived from vector control cells. Immunohistochemical analyses of Oct4A KD tumor xenografts demonstrated a significant loss of cytokeratin 7 (CK7), Glut-1 as well as CD34

  11. The intact strontium ranelate complex stimulates osteoblastogenesis and suppresses osteoclastogenesis by antagonizing NF-κB activation.

    Science.gov (United States)

    Yamaguchi, Masayoshi; Weitzmann, M Neale

    2012-01-01

    Strontium ranelate, a pharmaceutical agent shown in clinical trials to be effective in managing osteoporosis and reducing fracture risk in postmenopausal women, is relatively unique in its ability to both blunt bone resorption and stimulate bone formation. However, its mechanisms of action are largely unknown. As the nuclear factor-kappa B (NF-κB) activation antagonists both stimulate osteoblastic bone formation and repress osteoclastic bone resorption, we hypothesized that strontium ranelate may achieve its anabolic and anti-catabolic activities by modulating NF-κB activation in bone cells. In this study, osteoclast and osteoblast precursors were treated with intact strontium ranelate or its individual components sodium ranelate and/or strontium chloride, and its effect on in vitro osteoclastogenesis and osteoblastogenesis and on NF-κB activation quantified. Although the activity of strontium ranelate has been attributed to the release of strontium ions, low dose intact strontium ranelate complex, but not sodium ranelate and/or strontium chloride, potently antagonized NF-κB activation in osteoclasts and osteoblasts in vitro, and promoted osteoblast differentiation while suppressing osteoclast formation. Taken together, our data suggest a novel centralized mechanism by which strontium ranelate promotes osteoblast activity and suppresses osteoclastogenesis, based on suppression of NF-κB signal transduction. We further demonstrate that the biological actions of strontium ranelate may be related to low dose of the intact molecule rather than dissociation and release of strontium ions, as previously thought. These data may facilitate the development of additional novel pharmacological agents for the amelioration of osteoporosis, based on NF-κB blockade.

  12. A MAPK-Driven Feedback Loop Suppresses Rac Activity to Promote RhoA-Driven Cancer Cell Invasion.

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    Joseph H R Hetmanski

    2016-05-01

    Full Text Available Cell migration in 3D microenvironments is fundamental to development, homeostasis and the pathobiology of diseases such as cancer. Rab-coupling protein (RCP dependent co-trafficking of α5β1 and EGFR1 promotes cancer cell invasion into fibronectin (FN containing extracellular matrix (ECM, by potentiating EGFR1 signalling at the front of invasive cells. This promotes a switch in RhoGTPase signalling to inhibit Rac1 and activate a RhoA-ROCK-Formin homology domain-containing 3 (FHOD3 pathway and generate filopodial actin-spike protrusions which drive invasion. To further understand the signalling network that drives RCP-driven invasive migration, we generated a Boolean logical model based on existing network pathways/models, where each node can be interrogated by computational simulation. The model predicted an unanticipated feedback loop, whereby Raf/MEK/ERK signalling maintains suppression of Rac1 by inhibiting the Rac-activating Sos1-Eps8-Abi1 complex, allowing RhoA activity to predominate in invasive protrusions. MEK inhibition was sufficient to promote lamellipodia formation and oppose filopodial actin-spike formation, and led to activation of Rac and inactivation of RhoA at the leading edge of cells moving in 3D matrix. Furthermore, MEK inhibition abrogated RCP/α5β1/EGFR1-driven invasive migration. However, upon knockdown of Eps8 (to suppress the Sos1-Abi1-Eps8 complex, MEK inhibition had no effect on RhoGTPase activity and did not oppose invasive migration, suggesting that MEK-ERK signalling suppresses the Rac-activating Sos1-Abi1-Eps8 complex to maintain RhoA activity and promote filopodial actin-spike formation and invasive migration. Our study highlights the predictive potential of mathematical modelling approaches, and demonstrates that a simple intervention (MEK-inhibition could be of therapeutic benefit in preventing invasive migration and metastasis.

  13. Δ9-tetrahydrocannabinol suppresses cytotoxic T lymphocyte function independent of CB1 and CB 2, disrupting early activation events.

    Science.gov (United States)

    Karmaus, Peer W F; Chen, Weimin; Kaplan, Barbara L F; Kaminski, Norbert E

    2012-12-01

    Previously, CD8(+) T cells were found to be a sensitive target for suppression by Δ(9)-tetrahydrocannabinol (Δ(9)-THC) in a murine model of influenza infection. To study the effect of Δ(9)-THC on CD8(+) cytotoxic T lymphocytes (CTL), an allogeneic model of MHC I mismatch was used to elicit CTL. In addition, to determine the requirement for the cannabinoid receptors 1 (CB(1)) and 2 (CB(2)) in Δ(9)-THC-mediated CTL response modulation, mice null for both receptors were used (CB(1) (-/-)CB(2) (-/-)). Δ(9)-THC suppressed CTL function independent of CB(1) and CB(2) as evidenced by reduction of (51)Cr release by CTL generated from CB(1) (-/-)CB(2) (-/-) mice. Furthermore, viability in CD4(+) and CD8(+) cells was reduced in a concentration-dependent manner with Δ(9)-THC, independent of CB(1) and CB(2), but no effect of Δ(9)-THC on proliferation was observed, suggesting that Δ(9)-THC decreases the number of T cells initially activated. Δ(9)-THC increased expression of the activation markers, CD69 in CD8(+) cells and CD25 in CD4(+) cells in a concentration-dependent manner in cells derived from WT and CB(1) (-/-)CB(2) (-/-) mice. Furthermore, Δ(9)-THC synergized with the calcium ionophore, ionomycin, to increase CD69 expression on both CD4(+) and CD8(+) cells. In addition, without stimulation, Δ(9)-THC increased CD69 expression in CD8(+) cells from CB(1) (-/-)CB(2) (-/-) and WT mice. Overall, these results suggest that CB(1) and CB(2) are dispensable for Δ(9)-THC-mediated suppression and that perturbation of Ca(2+) signals during T cell activation plays an important role in the mechanism by which Δ(9)-THC suppresses CTL function.

  14. Effects of calcium channel on ovarian cancer cells.

    Science.gov (United States)

    Zhang, Chunyun; Li, Hailing

    2017-12-01

    The aim of the present study was to examine the effects of calcium channel protein on ovarian cancer cells. The expression of calcium channel protein in normal ovarian cells and ovarian cancer cells was detected by fluorescence quantitative PCR. Subsequently, the ovarian cancer cells were added to calcium channel protein activator media at various concentrations of 0, 1, 4, 8, 12, 16 and 20 mmol/l. The concentration of calcium ion in different samples was produced, and using an MTT assay, ovarian cancer cell activity in various samples was detected. Finally, a flow cytometer was used to explore the apoptosis rate. It was found that there was a significant difference between the expression of calcium channel protein in normal ovarian tissue and ovarian cancer cells (Pcancer cells to a certain extent, in a dose-dependent manner, especially when the concentration was at 12 mmol/l at which the intracellular calcium concentration was similar to that in normal ovarian cells. In conclusion, calcium ions play an important role in promoting cell proliferation of ovarian cancer cells, and they were involved in apoptosis of ovarian cancer cells to some extent, which regulates apoptosis by controlling the content of intracellular calcium.

  15. 4-Acetylantroquinonol B suppresses autophagic flux and improves cisplatin sensitivity in highly aggressive epithelial cancer through the PI3K/Akt/mTOR/p70S6K signaling pathway.

    Science.gov (United States)

    Liu, Mingche; Bamodu, Oluwaseun Adebayo; Huang, Wen-Chien; Zucha, Muhammad Ary; Lin, Yen-Kuang; Wu, Alexander T H; Huang, Chun-Chih; Lee, Wei-Hwa; Yuan, Chiou-Chung; Hsiao, M; Deng, Li; Tzeng, Yew-Min; Yeh, Chi-Tai

    2017-06-15

    Targeting residual self-renewing, chemoresistant cancerous cells may represent the key to overcoming therapy resistance. The entry of these quiescent cells into an activated state is associated with high metabolic demand and autophagic flux. Therefore, modulating the autophagy pathway in aggressive carcinomas may be beneficial as a therapeutic modality. In this study, we evaluated the anti-tumor activities of 4-acetylantroquinonol B (4-AAQB) in chemoresistant ovarian cancer cells, particularly its ability to modulate autophagy through autophagy-related genes (Atg). Atg-5 was overexpressed in invasive ovarian cancer cell lines and tissue (OR: 5.133; P=0.027) and depleting Atg-5 in ES-2 cell lines significantly induced apoptosis. 4-AAQB effectively suppressed viability of various subtypes of ovarian cancer. Cells with higher cisplatin-resistance were more responsive to 4-AAQB. For the first time, we demonstrate that 4-AAQB significantly suppress Atg-5 and Atg-7 expression with decreased autophagic flux in ovarian cancer cells via inhibition of the PI3K/Akt/mTOR/p70S6K signaling pathway. Similar to Atg-5 silencing, 4-AAQB-induced autophagy inhibition significantly enhanced cell death in vitro. These results are comparable to those of hydroxychloroquine (HCQ). In addition, 4-AAQB/cisplatin synergistically induced apoptosis in ovarian cancer cells. In vivo, 4-AAQB/cisplatin also significantly induced apoptosis and autophagy in an ES-2 mouse xenografts model. This is the first report demonstrating the efficacy of 4-AAQB alone or in combination with cisplatin on the suppression of ovarian cancer via Atg-5-dependent autophagy. We believe these findings will be beneficial in the development of a novel anti-ovarian cancer therapeutic strategy. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. A retrospective evaluation of activity of gemcitabine/platinum regimens in the treatment of recurrent ovarian cancer

    Directory of Open Access Journals (Sweden)

    Tran N. Le

    2017-11-01

    Full Text Available Abstract Background While many of these agents have been compared in prospective clinical trials, the gemcitabine/platinumbased regimens have not been compared in a prospective, randomized clinical trial. While bothgemcitabine/carboplatin and gemcitabine/cisplatin have a similar ORR in separate clinical trials, the tworegimens have never been directly been compared. With overlapping dose-limiting toxicity of thrombocytopenia, the gemcitabine/carboplatin regimen has been challenging to employ in the clinical setting in previously treated ovarian cancer patients and is often associated with treatment delays and/or dose reductions. Gemcitabine/cisplatin can also be a challenge due to its dose limiting neuropathy and renal toxicity, especially in previously treated patients. In the absence of any prospective, head to head comparison this retrospective study was embarked upon to compare the response rate and toxicity profiles of gemcitabine/cisplatin verses gemcitabine/carboplatin for the treatment of platinum-sensitive verses platinum-resistant recurrent ovarian cancer. Methods This was a retrospective chart review study that identified patients that had received either gemcitabine/cisplatin or gemcitabine/carboplatin for treatment of recurrent ovarian cancer and compared documented hematological and non-hematological toxicity and response based on RECIST (v1.1. Data was evaluated based upon platinum sensitivity/resistance as well. Results A total of 93 patients were identified that had received a gemcitabine/platinum regimen with 48 with recurrent ovarian cancer that were included in the study. There were 21 patients in the gemcitabine/cisplatin arm and 27 patients identified in the gemcitabine/carboplatin arm. Objective response rate (ORR was greater in platinum-sensitive patients that received gemcitabine/carboplatin compared to gemcitabine/cisplatin (8 (67% vs 2 (25%, p < 0.05. Conversely, ORR was greater in platinum-resistant patients treated

  17. Lipoic acid decreases Mcl-1, Bcl-xL and up regulates Bim on ovarian carcinoma cells leading to cell death.

    Science.gov (United States)

    Kafara, Perrine; Icard, Philippe; Guillamin, Marilyne; Schwartz, Laurent; Lincet, Hubert

    2015-06-12

    Ovarian carcinoma is the leading cause of death from gynecological cancer because there is risk of chemoresistance. As previously demonstrated in our laboratory, Alpha-lipoic acid (LA), a co-factor for metabolic enzymes, suppresses the tumor growth. In this study, we have researched the mechanisms that are responsible for the activity of LA. We have studied the mechanisms of LA in two ovarian cancer cell lines, a cisplatin sensitive one, IGROV1 and its resistant counterpart, IGROV1-R10. These cells have been exposed to lipoic acid at various concentrations. Cell proliferation, cell cycle repartition and nuclear staining with DAPI were recorded. Western blot analyses were performed to detect various proteins implied in apoptotic cell death pathways. To investigate the formation of ROS, the oxidation of CM-DCFH2-DA were also determined. LA suppressed growth proliferation and induced apoptosis in both ovarian cell lines. Moreover, LA provoked a down regulation of two anti-apoptotic proteins, Mcl-1 and Bcl-xL protein and a strong induction of the BH3-only protein Bim. Furthermore, LA induced ROS generation which could be involved in the CHOP induction which is known to activate the Bim translation. Our results reveal novel actions of LA which could explain the anti-tumoral effects of the LA. Therefore, LA seems to be a promising compound for ovarian cancer treatment.

  18. Eclalbasaponin II induces autophagic and apoptotic cell death in human ovarian cancer cells

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    Yoon Jin Cho

    2016-09-01

    Full Text Available Triterpenoids echinocystic acid and its glycosides, isolated from several Eclipta prostrata, have been reported to possess various biological activities such as anti-inflammatory, anti-bacterial, and anti-diabetic activity. However, the cytotoxicity of the triterpenoids in human cancer cells and their molecular mechanism of action are poorly understood. In the present study, we found that eclalbasaponin II with one glucose moiety has potent cytotoxicity in three ovarian cancer cells and two endometrial cancer cells compared to an aglycone echinocystic acid and eclalbasaponin I with two glucose moiety. Eclalbasaponin II treatment dose-dependently increased sub G1 population. Annexin V staining revealed that eclalbasaponin II induced apoptosis in SKOV3 and A2780 ovarian cancer cells. In addition, eclalbasaponin II-induced cell death was associated with characteristics of autophagy; an increase in acidic vesicular organelle content and elevation of the levels of LC3-II. Interestingly, autophagy inhibitor BaF1 suppressed the eclalbasaponin II-induced apoptosis. Moreover, eclalbasaponin II activated JNK and p38 signaling and inhibited the mTOR signaling. We further demonstrated that pre-treatment with a JNK and p38 inhibitor and mTOR activator attenuated the eclalbasaponin II-induced autophagy. This suggests that eclalbasaponin II induces apoptotic and autophagic cell death through the regulation of JNK, p38, and mTOR signaling in human ovarian cancer cells.

  19. Homocysteine restricts copper availability leading to suppression of cytochrome C oxidase activity in phenylephrine-treated cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Xiao Zuo

    Full Text Available Cardiomyocyte hypertrophy induced by phenylephrine (PE is accompanied by suppression of cytochrome c oxidase (CCO activity, and copper (Cu supplementation restores CCO activity and reverses the hypertrophy. The present study was aimed to understand the mechanism of PE-induced decrease in CCO activity. Primary cultures of neonatal rat cardiomyocytes were treated with PE at a final concentration of l00 µM in cultures for 72 h to induce cell hypertrophy. The CCO activity was determined by enzymatic assay and changes in CCO subunit COX-IV as well as copper chaperones for CCO (COX17, SCO2, and COX11 were determined by Western blotting. PE treatment increased both intracellular and extracellular homocysteine concentrations and decreased intracellular Cu concentrations. Studies in vitro found that homocysteine and Cu form complexes. Inhibition of the intracellular homocysteine synthesis in the PE-treated cardiomyocytes prevented the increase in the extracellular homocysteine concentration, retained the intracellular Cu concentration, and preserved the CCO activity. PE treatment decreased protein concentrations of the COX-IV, and the Cu chaperones COX17, COX11, and SCO2. These PE effects were prevented by either inhibition of the intracellular homocysteine synthesis or Cu supplementation. Therefore, PE-induced elevation of homocysteine restricts Cu availability through its interaction with Cu and suppression of Cu chaperones, leading to the decrease in CCO enzyme activity.

  20. Consideration of Spillover Effect in Active Vibration Suppression of a Smart Composite Plate Using Piezoelectric Elements

    Directory of Open Access Journals (Sweden)

    Eman Eshraqi

    Full Text Available Abstract In this paper, the problem of vibration suppression of a smart composite plate with bonded piezoelectric patches is considered. A higher order plate model is used for finite element modeling of the plate and the PID controller is used to generate control voltage command to the piezo actuators from the piezo sensors data. Derived formulation and the control algorithm is implemented in a finite element (FE code and the FE modeling results are verified using available results of previous studies. The effect of control gain on the vibration suppression characteristics is studied. Furthermore, since FE modeling reduces the order of the real problem, the problem of un-modeled residual modes on the so-called spillover effect is investigated.

  1. The activity of satellite cells and myonuclei following 8 weeks of strength training in young men with suppressed testosterone levels

    DEFF Research Database (Denmark)

    Kvorning, T; Kadi, F; Schjerling, P.

    2015-01-01

    AIM: To investigate how suppression of endogenous testosterone during an 8-week strength training period influences the activity of satellite cells and myonuclei. METHODS: Twenty-two moderately trained young men participated in this randomized, placebo-controlled, and double-blinded intervention...... study. The participants were randomized to treatment with a GnRH analogue, goserelin (n = 12), which suppresses testosterone or placebo (n = 10) for 12 weeks. The strength training period of 8 weeks started after 4 weeks of treatment and included exercises for all major muscles. Biopsies were obtained......% in placebo and by 52% in goserelin (P changes in satellite cells and myonuclei were seen in type I fibres in either group. Data from the microarray analysis...

  2. Prenylated Flavonoids from Cudrania tricuspidata Suppress Lipopolysaccharide-Induced Neuroinflammatory Activities in BV2 Microglial Cells

    Science.gov (United States)

    Kim, Dong-Cheol; Yoon, Chi-Su; Quang, Tran Hong; Ko, Wonmin; Kim, Jong-Su; Oh, Hyuncheol; Kim, Youn-Chul

    2016-01-01

    In Korea and China, Cudrania tricuspidata Bureau (Moraceae) is an important traditional medicinal plant used to treat lumbago, hemoptysis, and contusions. The C. tricuspidata methanol extract suppressed both production of NO and PGE2 in BV2 microglial cells. Cudraflavanone D (1), isolated from this extract, remarkably suppressed the protein expression of inducible NO synthase and cyclooxygenase-2, and decreased the levels of NO and PGE2 in BV2 microglial cells exposed to lipopolysaccharide. Cudraflavanone D (1) also decreased IL-6, TNF-α, IL-12, and IL-1β production, blocked nuclear translocation of NF-κB heterodimers (p50 and p65) by interrupting the degradation and phosphorylation of inhibitor of IκB-α, and inhibited NF-κB binding. In addition, cudraflavanone D (1) suppressed the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK pathways. This study indicated that cudraflavanone D (1) can be a potential drug candidate for the cure of neuroinflammation. PMID:26907256

  3. SIRT7 Represses Myc Activity to Suppress ER Stress and Prevent Fatty Liver Disease

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    Jiyung Shin

    2013-11-01

    Full Text Available Nonalcoholic fatty liver disease is the most common chronic liver disorder in developed countries. Its pathogenesis is poorly understood, and therapeutic options are limited. Here, we show that SIRT7, an NAD+-dependent H3K18Ac deacetylase, functions at chromatin to suppress ER stress and prevent the development of fatty liver disease. SIRT7 is induced upon ER stress and is stabilized at the promoters of ribosomal proteins through its interaction with the transcription factor Myc to silence gene expression and to relieve ER stress. SIRT7-deficient mice develop chronic hepatosteatosis resembling human fatty liver disease. Myc inactivation or pharmacological suppression of ER stress alleviates fatty liver caused by SIRT7 deficiency. Importantly, SIRT7 suppresses ER stress and reverts the fatty liver disease in diet-induced obese mice. Our study identifies SIRT7 as a cofactor of Myc for transcriptional repression and delineates a druggable regulatory branch of the ER stress response that prevents and reverts fatty liver disease.

  4. Suppression of NRF2–ARE activity sensitizes chemotherapeutic agent-induced cytotoxicity in human acute monocytic leukemia cells

    International Nuclear Information System (INIS)

    Peng, Hui; Wang, Huihui; Xue, Peng; Hou, Yongyong; Dong, Jian; Zhou, Tong; Qu, Weidong; Peng, Shuangqing; Li, Jin; Carmichael, Paul L.; Nelson, Bud; Clewell, Rebecca; Zhang, Qiang; Andersen, Melvin E.; Pi, Jingbo

    2016-01-01

    Nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of the antioxidant response element (ARE)-dependent transcription, plays a pivotal role in chemical detoxification in normal and tumor cells. Consistent with previous findings that NRF2–ARE contributes to chemotherapeutic resistance of cancer cells, we found that stable knockdown of NRF2 by lentiviral shRNA in human acute monocytic leukemia (AML) THP-1 cells enhanced the cytotoxicity of several chemotherapeutic agents, including arsenic trioxide (As 2 O 3 ), etoposide and doxorubicin. Using an ARE-luciferase reporter expressed in several human and mouse cells, we identified a set of compounds, including isonicotinic acid amides, isoniazid and ethionamide, that inhibited NRF2–ARE activity. Treatment of THP-1 cells with ethionamide, for instance, significantly reduced mRNA expression of multiple ARE-driven genes under either basal or As 2 O 3 -challenged conditions. As determined by cell viability and cell cycle, suppression of NRF2–ARE by ethionamide also significantly enhanced susceptibility of THP-1 and U937 cells to As 2 O 3 -induced cytotoxicity. In THP-1 cells, the sensitizing effect of ethionamide on As 2 O 3 -induced cytotoxicity was highly dependent on NRF2. To our knowledge, the present study is the first to demonstrate that ethionamide suppresses NRF2–ARE signaling and disrupts the transcriptional network of the antioxidant response in AML cells, leading to sensitization to chemotherapeutic agents. - Highlights: • Identification of novel inhibitors of ARE-dependent transcription • Suppression of NRF2–ARE sensitizes THP-1 cells to chemotherapy. • Ethionamide suppresses ARE-dependent transcriptional activity. • Ethionamide and isoniazid increase the cytotoxicity of As 2 O 3 in AML cells. • Sensitization of THP-1 cells to As 2 O 3 toxicity by ethionamide is NRF2-dependent.

  5. Hotair mediates hepatocarcinogenesis through suppressing miRNA-218 expression and activating P14 and P16 signaling.

    Science.gov (United States)

    Fu, Wei-Ming; Zhu, Xiao; Wang, Wei-Mao; Lu, Ying-Fei; Hu, Bao-Guang; Wang, Hua; Liang, Wei-Cheng; Wang, Shan-Shan; Ko, Chun-Hay; Waye, Mary Miu-Yee; Kung, Hsiang-Fu; Li, Gang; Zhang, Jin-Fang

    2015-10-01

    Long non-coding RNA Hotair has been considered as a pro-oncogene in multiple cancers. Although there is emerging evidence that reveals its biological function and the association with clinical prognosis, the precise mechanism remains largely elusive. We investigated the function and mechanism of Hotair in hepatocellular carcinoma (HCC) cell models and a xenograft mouse model. The regulatory network between miR-218 and Hotair was elucidated by RNA immunoprecipitation and luciferase reporter assays. Finally, the correlation between Hotair, miR-218 and the target gene Bmi-1 were evaluated in 52 paired HCC specimens. In this study, we reported that Hotair negatively regulated miR-218 expression in HCC, which might be mediated through an EZH2-targeting-miR-218-2 promoter regulatory axis. Further investigation revealed that Hotair knockdown dramatically inhibited cell viability and induced G1-phase arrest in vitro and suppressed tumorigenicity in vivo by promoting miR-218 expression. Oncogene Bmi-1 was shown to be a functional target of miR-218, and the main downstream targets signaling, P16(Ink4a) and P14(ARF), were activated in Hotair-suppressed tumorigenesis. In primary human HCC specimens, Hotair and Bmi-1 were concordantly upregulated whereas miR-218 was downregulated in these tissues. Furthermore, Hotair was inversely associated with miR-218 expression and positively correlated with Bmi-1 expression in these clinical tissues. Hotair silence activates P16(Ink4a) and P14(ARF) signaling by enhancing miR-218 expression and suppressing Bmi-1 expression, resulting in the suppression of tumorigenesis in HCC. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  6. Wogonin Suppresses the Activity of Matrix Metalloproteinase-9 and Inhibits Migration and Invasion in Human Hepatocellular Carcinoma

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    Ming Hong

    2018-02-01

    Full Text Available As one of the major active ingredients in Radix Scutellariae, wogonin has been shown to be associated with various pharmacological activities on cancer cell growth, apoptosis, and cell invasion and migration. Here, we demonstrated that wogonin may harbor potential anti-metastatic activities in hepatocarcinoma (HCC. The anti-metastasis potential of wogonin and its underlying mechanisms were evaluated by ligand–protein docking approach, surface plasmon resonance assay, and in vitro gelatin zymography studies. Our results showed that wogonin (100 μM, 50 μM suppressed MHCC97L and PLC/PRF/5 cells migration and invasion in vitro. The docking approach and surface plasmon resonance assay indicated that the potential binding affinity between wogonin and matrix metalloproteinase-9 (MMP-9 may lead to inhibition of MMP-9 activity and further leads to suppression of tumor metastasis. This conclusion was further verified by Western blot results and gelatin zymography analysis. Wogonin might be a potent treatment option for disrupting the tumor metastasis that favors HCC development. The potential active targets from computational screening integrated with biomedical study may help us to explore the molecular mechanism of herbal medicines.

  7. Iguratimod prevents ovariectomy‑induced bone loss and suppresses osteoclastogenesis via inhibition of peroxisome proliferator‑activated receptor‑γ.

    Science.gov (United States)

    Wu, Ying-Xing; Sun, Yue; Ye, Ya-Ping; Zhang, Peng; Guo, Jia-Chao; Huang, Jun-Ming; Jing, Xing-Zhi; Xiang, Wei; Yu, Shi-Ying; Guo, Feng-Jing

    2017-12-01

    Iguratimod is known for its anti‑inflammatory activities and therapeutic effects in patients with rheumatoid arthritis. It has previously been demonstrated that iguratimod attenuates bone destruction and osteoclast formation in the Walker 256 rat mammary gland carcinoma cell‑induced bone cancer pain model. Therefore, it was hypothesized that iguratimod may additionally exhibit therapeutic effects on benign osteoclast‑associated diseases including postmenopausal osteoporosis. In the present study, ovariectomized mice were used to investigate the effects of iguratimod in vivo. Bone marrow mononuclear cells were cultured to detect the effects of iguratimod on receptor activator of nuclear factor‑κB ligand (RANKL)‑induced osteoclastogenesis in vitro and the molecular mechanisms involved. It was demonstrated that iguratimod may prevent ovariectomy‑induced bone loss by suppressing osteoclast activity in vivo. Consistently, iguratimod may inhibit RANKL‑induced osteoclastogenesis and bone resorption in primary bone marrow mononuclear cells. At the molecular level, peroxisome proliferator‑activated receptor‑γ (PPAR‑γ)/c‑Fos pathway, which is essential in RANKL‑induced osteoclast differentiation, was suppressed by iguratimod. Subsequently, iguratimod decreased the expression of nuclear factor of activated T cells c1 and downstream osteoclast marker genes. The results of the present study demonstrated that iguratimod may inhibit ovariectomy‑induced bone loss and osteoclastogenesis by modulating RANKL signaling. Therefore, iguratimod may act as a novel therapeutic to prevent postmenopausal osteoporosis.

  8. A practical dexamethasone suppression test to evaluate hirsute women

    International Nuclear Information System (INIS)

    Wu, C.H.

    1982-01-01

    Fifty-five hirsute women were subjected to a 2-week dexamethasone (DXM) suppression test. The pre- and post-DXM plasma dehydroepiandrosteronesulfate (DS) and testosterone (T) were measured by radioimmunoassay to define the source of androgen excess in hirsute women. Four patients (7%) failed to have adequate adrenal suppression due to failure in medication. Among the 51 patients with adequate adrenal suppression, the source of androgen excess was clearly defined in 48 patients (94%). Seventeen patients (33%) showed ovarian source, 13 patients (26%) had adrenal source, while 18 patients (35%) revealed a mixed adrenal and ovarian source. Normal baseline DS and T levels were noted in 22% of hirsute women and more than half (55%) of them had ovarian androgen excess. Even in 17 patients with normal DS and elevated T, 6 patients (36%) suggested adrenal androgen excess. The source of androgen excess in hirsute women seems evenly distributed among the ovarian, the adrenal, and the mixed group. (author)

  9. Association of apoptosis with the inhibition of extracellular signal-regulated protein kinase activity in the tumor necrosis factor alpha-resistant ovarian carcinoma cell line UCI 101.

    Science.gov (United States)

    Yazlovitskaya, E M; Pelling, J C; Persons, D L

    1999-05-01

    Tumor necrosis factor-alpha (TNF alpha) can function as both an autocrine and a paracrine growth factor and may therefore play a role in ovarian tumor progression. TNF alpha initiates multiple cellular responses, many of which are mediated through the mitogen-activated protein kinase pathways, which transduce signals from the TNF alpha receptors through the cytoplasm to the nucleus, resulting in regulation of gene expression. We examined the role of c-jun N-terminal kinase 1 (JNK1) and extracellular signal-regulated protein kinase (ERK) 1 and 2 in the cellular growth response to TNF alpha in the ovarian carcinoma cell line UCI 101. JNK1 activity was increased to a maximum level ninefold above the basal level after 10-20 min of treatment with 10 ng/mL TNF alpha. A maximum threefold induction of ERK1/2 activity was observed after 1 min of treatment. At concentrations up to 100 ng/mL, TNF alpha had neither a stimulatory nor an inhibitory effect on growth of UCI 101 cells. However, inhibition of TNF alpha-induced ERK1/2 activity by the MAP/ERK kinase 1 inhibitor PD 98059 resulted in 60% inhibition of cell growth in TNF alpha-treated UCI 101 cells. This decrease in cell growth was accompanied by apoptosis, as demonstrated by the presence of a 180-bp DNA ladder. Thus, the inhibition of TNF alpha-induced ERK1/2 activity was associated with induction of apoptosis in the TNF alpha-resistant cell line UCI 101. Inhibition of TNF alpha-induced ERK1/2 activity was accompanied by a subsequent transient increase in TNF alpha-induced JNK1 activity. The significance of this increase with respect to apoptosis induction remains to be determined. These findings demonstrated that ERK1/2 activity can modulate cellular sensitivity to TNF alpha and suggested that the balance between the levels of ERK1/2 and JNK1 activation may be critical in the cellular growth response to TNF alpha.

  10. Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor

    Directory of Open Access Journals (Sweden)

    d'Avila Joana C

    2012-02-01

    Full Text Available Abstract Background Traumatic brain injury (TBI induces activation of microglia. Activated microglia can in turn increase secondary injury and impair recovery. This innate immune response requires hours to days to become fully manifest, thus providing a clinically relevant window of opportunity for therapeutic intervention. Microglial activation is regulated in part by poly(ADP-ribose polymerase-1 (PARP-1. Inhibition of PARP-1 activity suppresses NF-kB-dependent gene transcription and thereby blocks several aspects of microglial activation. Here we evaluated the efficacy of a PARP inhibitor, INO-1001, in suppressing microglial activation after cortical impact in the rat. Methods Rats were subjected to controlled cortical impact and subsequently treated with 10 mg/kg of INO-1001 (or vehicle alone beginning 20 - 24 hours after the TBI. Brains were harvested at several time points for histological evaluation of inflammation and neuronal survival, using markers for microglial activation (morphology and CD11b expression, astrocyte activation (GFAP, and neuronal survival (NeuN. Rats were also evaluated at 8 weeks after TBI using measures of forelimb dexterity: the sticky tape test, cylinder test, and vermicelli test. Results Peak microglial and astrocyte activation was observed 5 to 7 days after this injury. INO-1001 significantly reduced microglial activation in the peri-lesion cortex and ipsilateral hippocampus. No rebound inflammation was observed in rats that were treated with INO-1001 or vehicle for 12 days followed by 4 days without drug. The reduced inflammation was associated with increased neuronal survival in the peri-lesion cortex and improved performance on tests of forelimb dexterity conducted 8 weeks after TBI. Conclusions Treatment with a PARP inhibitor for 12 days after TBI, with the first dose given as long as 20 hours after injury, can reduce inflammation and improve histological and functional outcomes.

  11. Super p53 for Treatment of Ovarian Cancer

    Science.gov (United States)

    2016-07-01

    killing ovarian cancer cells in vitro. This is unreported, novel finding paves the way for using super p53 for ovarian cancer treatment. Main...This is unreported, novel finding paves the way for using super p53 for ovarian cancer treatment. Main activities and objectives completed to date...What do you plan to do during the next reporting period to accomplish the goals?  Now that the basic groundwork for the experimental assays has

  12. Activation of glucocorticoid receptors in Müller glia is protective to retinal neurons and suppresses microglial reactivity.

    Science.gov (United States)

    Gallina, Donika; Zelinka, Christopher Paul; Cebulla, Colleen M; Fischer, Andy J

    2015-11-01

    Reactive microglia and macrophages are prevalent in damaged retinas. Glucocorticoid signaling is known to suppress inflammation and the reactivity of microglia and macrophages. In the vertebrate retina, the glucocorticoid receptor (GCR) is known to be activated and localized to the nuclei of Müller glia (Gallina et al., 2014). Accordingly, we investigated how signaling through GCR influences the survival of neurons using the chick retina in vivo as a model system. We applied intraocular injections of GCR agonist or antagonist, assessed microglial reactivity, and the survival of retinal neurons following different damage paradigms. Microglial reactivity was increased in retinas from eyes that were injected with vehicle, and this reactivity was decreased by GCR-agonist dexamethasone (Dex) and increased by GCR-antagonist RU486. We found that activation of GCR suppresses the reactivity of microglia and inhibited the loss of retinal neurons resulting from excitotoxicity. We provide evidence that the protection-promoting effects of Dex were maintained when the microglia were selectively ablated. Similarly, intraocular injections of Dex protected ganglion cells from colchicine-treatment and protected photoreceptors from damage caused by retinal detachment. We conclude that activation of GCR promotes the survival of ganglion cells in colchicine-damaged retinas, promotes the survival of amacrine and bipolar cells in excitotoxin-damaged retinas, and promotes the survival of photoreceptors in detached retinas. We propose that suppression of microglial reactivity is secondary to activation of GCR in Müller glia, and this mode of signaling is an effective means to lessen the damage and vision loss resulting from different types of retinal damage. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. The effect of yucca on proliferation, apoptosis, and steroidogenesis of porcine ovarian granulosa cells

    Directory of Open Access Journals (Sweden)

    Aneta Štochmaľová

    2014-02-01

    Full Text Available Yucca shidigera is a medicinal plant native to Mexico. Is a plant widely used in folk medicine to treat a variety of ailmentary disorders, but its action on reproductive processes and possible mechanisms of such action remains unknown. Yucca schidigera extract contains a number of steroidal saponins that, because of their biological activity, have attracted attention from the food industry for many years. Yucca extract is used as a natural feed additive with positive effect to microflora, digestion, metabolism and to improve animal muscle growth. Its extract has been used as a foodstuff and folk medicine to treat a wide variety of diseases for many years. Nevertheless, it remaines unknown, whether consumption of yucca can affect reproductive system. The aim of this study was to examine the effects of yucca on basic ovarian cell functions - proliferation, apoptosis and steroidogenesis. Porcine ovarian granulosa cells were cultured with and without yucca extract (added at doses 0; 1; 10 and 100 μg.mL-1 of medium. Markers of proliferation (% of PCNA-positive cells and apoptosis (% cells containing bax were analysed by immunocytochemistry. Release of steroid hormones (progesterone and testosterone was measured by EIA. It was observed, that addition of yucca inhibited proliferation (expression of PCNA, increased apoptosis (expression of bax, stimulated progesterone and inhibited testosterone release. The ability of yucca to reduce ovarian cell proliferation, to promote ovarian cell apoptosis and affect steroidogenesis demonstrates the direct influence of yucca on female gonads. Furthermore, our observations suggest the multiple sites of action (proliferation, apoptosis, steroidogenesis of yucca on porcine ovarian cell functions. It is not to be excluded, that consumption of yucca can suppress female reproductive functions.

  14. Plasma-activated medium suppresses choroidal neovascularization in mice: a new therapeutic concept for age-related macular degeneration.

    Science.gov (United States)

    Ye, Fuxiang; Kaneko, Hiroki; Nagasaka, Yosuke; Ijima, Ryo; Nakamura, Kae; Nagaya, Masatoshi; Takayama, Kei; Kajiyama, Hiroaki; Senga, Takeshi; Tanaka, Hiromasa; Mizuno, Masaaki; Kikkawa, Fumitaka; Hori, Masaru; Terasaki, Hiroko

    2015-01-09

    Choroidal neovascularization (CNV) is the main pathogenesis of age-related macular degeneration (AMD), which leads to severe vision loss in many aged patients in most advanced country. CNV compromises vision via hemorrhage and retinal detachment on account of pathological neovascularization penetrating the retina. Plasma medicine represents the medical application of ionized gas "plasma" that is typically studied in the field of physical science. Here we examined the therapeutic ability of plasma-activated medium (PAM) to suppress CNV. The effect of PAM on vascularization was assessed on the basis of human retinal endothelial cell (HREC) tube formation. In mice, laser photocoagulation was performed to induce CNV (laser-CNV), followed by intravitreal injection of PAM. N-Acetylcysteine was used to examine the role of reactive oxygen species in PAM-induced CNV suppression. Fundus imaging, retinal histology examination, and electroretinography (ERG) were also performed to evaluate PAM-induced retinal toxicity. Interestingly, HREC tube formation and laser-CNV were both reduced by treatment with PAM. N-acetylcysteine only partly neutralized the PAM-induced reduction in laser-CNV. In addition, PAM injection had no effect on regular retinal vessels, nor did it show retinal toxicity in vivo. Our findings indicate the potential of PAM as a novel therapeutic agent for suppressing CNV.

  15. Spermidine Suppresses Age-Associated Memory Impairment by Preventing Adverse Increase of Presynaptic Active Zone Size and Release.

    Directory of Open Access Journals (Sweden)

    Varun K Gupta

    2016-09-01

    Full Text Available Memories are assumed to be formed by sets of synapses changing their structural or functional performance. The efficacy of forming new memories declines with advancing age, but the synaptic changes underlying age-induced memory impairment remain poorly understood. Recently, we found spermidine feeding to specifically suppress age-dependent impairments in forming olfactory memories, providing a mean to search for synaptic changes involved in age-dependent memory impairment. Here, we show that a specific synaptic compartment, the presynaptic active zone (AZ, increases the size of its ultrastructural elaboration and releases significantly more synaptic vesicles with advancing age. These age-induced AZ changes, however, were fully suppressed by spermidine feeding. A genetically enforced enlargement of AZ scaffolds (four gene-copies of BRP impaired memory formation in young animals. Thus, in the Drosophila nervous system, aging AZs seem to steer towards the upper limit of their operational range, limiting synaptic plasticity and contributing to impairment of memory formation. Spermidine feeding suppresses age-dependent memory impairment by counteracting these age-dependent changes directly at the synapse.

  16. Premature ovarian failure

    Directory of Open Access Journals (Sweden)

    Persani Luca

    2006-04-01

    Full Text Available Abstract Premature ovarian failure (POF is a primary ovarian defect characterized by absent menarche (primary amenorrhea or premature depletion of ovarian follicles before the age of 40 years (secondary amenorrhea. It is a heterogeneous disorder affecting approximately 1% of women e.g. Turner syndrome represent the major cause of primary amenorrhea associated with ovarian dysgenesis. Despite the description of several candidate genes, the cause of POF remains undetermined in the vast majority of the cases. Management includes substitution of the hormone defect by estrogen/progestin preparations. The only solution presently available for the fertility defect in women with absent follicular reserve is ovum donation.

  17. Methane Suppresses Microglial Activation Related to Oxidative, Inflammatory, and Apoptotic Injury during Spinal Cord Injury in Rats

    Directory of Open Access Journals (Sweden)

    WeiHeng Wang

    2017-01-01

    Full Text Available Objective. We investigated the hypothesis that methane-rich saline (MS can be used to repair spinal cord injury (SCI in a rat model through suppressing microglial activation related to oxidative, inflammatory, and apoptotic injury. Methods. MS was injected intraperitoneally in rats after SCI. Hematoxylin-eosin (HE staining, oxidative stress, inflammatory parameters, and cell apoptosis were detected 72 h after SCI to determine the optimal dose. Then, we investigated the protective mechanisms and the long-term effects of MS on SCI. HE and microglial activation were observed. Neurological function was evaluated by the Basso, Beattie, and Bresnahan (BBB scale. Results. MS can significantly decrease infarct area and inhibit oxidative stress, inflammation, and cell apoptosis 72 h following SCI. The MS protective effect at a dose of 20 ml/kg was better. Moreover, MS can significantly suppress microglial activation related to oxidative and inflammatory injury after SCI and improve hind limb neurological function. Conclusion. MS could repair SCI and reduce the release of oxidative stress, inflammatory cytokines, and cell apoptosis produced by activated microglia. MS provides a novel and promising strategy for the treatment of SCI.

  18. Inhibition of KDM4A activity as a strategy to suppress interleukin-6 production and attenuate colitis induction.

    Science.gov (United States)

    Ishiguro, Kazuhiro; Watanabe, Osamu; Nakamura, Masanao; Yamamura, Takeshi; Matsushita, Masanobu; Goto, Hidemi; Hirooka, Yoshiki

    2017-07-01

    4-Chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) functions as a hapten and fluoresces upon binding to proteins. Therefore, fluorescence visualization of hapten-proteins is a feature of the colitis induced by NBD-Cl. Using this colitis model, we located activated fibroblasts in the vicinity of hapten-proteins upon colitis induction and observed interleukin (IL)-6 production in the activated fibroblasts. We screened herbal ingredients using primary fibroblasts stimulated with tumor necrosis factor α (TNF-α) and found the suppressive action of Atractylodin on IL-6 production. Under TNF-α stimulation, Atractylodin induced the tri-methylation of histone H3 at lysine residue 9, which impaired the binding between NF-κB and the IL-6 promoter on the genomic DNA. Atractylodin inhibited KDM4A but not KDM6A activity. Atractylodin administration attenuated colitis induction. The KDM4A inhibitor ML324 showed similar actions on IL-6 production and colitis induction. We propose the inhibition of KDM4A activity as a strategy to suppress IL-6 production and attenuate colitis induction. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Morusin induces apoptosis and suppresses NF-κB activity in human colorectal cancer HT-29 cells

    International Nuclear Information System (INIS)

    Lee, J.-C.; Won, S.-J.; Chao, C.-L.; Wu, F.-L.; Liu, H.-S.; Ling Pin; Lin, C.-N.; Su, C.-L.

    2008-01-01

    Morusin is a pure compound isolated from root bark of Morusaustralis (Moraceae). In this study, we demonstrated that morusin significantly inhibited the growth and clonogenicity of human colorectal cancer HT-29 cells. Apoptosis induced by morusin was characterized by accumulation of cells at the sub-G 1 phase, fragmentation of DNA, and condensation of chromatin. Morusin also inhibited the phosphorylation of IKK-α, IKK-β and IκB-α, increased expression of IκB-α, and suppressed nuclear translocation of NF-κB and its DNA binding activity. Dephosphorylation of NF-κB upstream regulators PI3K, Akt and PDK1 was also displayed. In addition, activation of caspase-8, change of mitochondrial membrane potential, release of cytochrome c and Smac/DIABLO, and activation of caspase-9 and -3 were observed at the early time point. Downregulation in the expression of Ku70 and XIAP was exhibited afterward. Caspase-8 or wide-ranging caspase inhibitor suppressed morusin-induced apoptosis. Therefore, the antitumor mechanism of morusin in HT-29 cells may be via activation of caspases and inhibition of NF-κB

  20. Butyrate enhances antibacterial effects while suppressing other features of alternative activation in IL-4-induced macrophages.

    Science.gov (United States)

    Fernando, Maria R; Saxena, Alpana; Reyes, José-Luis; McKay, Derek M

    2016-05-15

    The short-chain fatty acid butyrate is produced by fermentation of dietary fiber by the intestinal microbiota; butyrate is the primary energy source of colonocytes and has immunomodulatory effects. Having shown that macrophages differentiated with IL-4 [M(IL-4)s] can suppress colitis, we hypothesized that butyrate would reinforce an M(IL-4) phenotype. Here, we show that in the presence of butyrate M(IL-4)s display reduced expression of their hallmark markers Arg1 and Ym1 and significantly suppressed LPS-induced nitric oxide, IL-12p40, and IL-10 production. Butyrate treatment likely altered the M(IL-4) phenotype via inhibition of histone deacetylation. Functionally, M(IL-4)s treated with butyrate showed increased phagocytosis and killing of bacteria, compared with M(IL-4) and this was not accompanied by enhanced proinflammatory cytokine production. Culture of regulatory T cells with M(IL-4)s and M(IL-4 + butyrate)s revealed that both macrophage subsets suppressed expression of the regulatory T-cell marker Foxp3. However, Tregs cocultured with M(IL-4 + butyrate) produced less IL-17A than Tregs cocultured with M(IL-4). These data illustrate the importance of butyrate, a microbial-derived metabolite, in the regulation of gut immunity: the demonstration that butyrate promotes phagocytosis in M(IL-4)s that can limit T-cell production of IL-17A reveals novel aspects of bacterial-host interaction in the regulation of intestinal homeostasis. Copyright © 2016 the American Physiological Society.

  1. New approach to the defibrillation problem: Suppression of the spiral wave activity of cardiac tissue

    Science.gov (United States)

    Loskutov, A. Yu.; Vysotskiĭ, S. A.

    2007-01-01

    A model of an excitable medium is considered for describing the development of fibrillation (i.e., spatiotemporal chaos) in cardiac tissue through the generation of a set of coexisting spiral waves. It is shown that a weak external point action on such a medium leads to the suppression of all spiral waves and, correspondingly, to the stabilization of the system dynamics. After reaching the regular regime, only the external source exists in the medium. The frequencies and amplitudes at which such stabilization occurs are determined. The case of the action of several point sources is considered. Analysis is performed using the Bray method to identify the number of spiral waves.

  2. Chimyl Alcohol Suppresses PGE2Synthesis by Human Epidermal Keratinocytes through the Activation of PPAR-γ.

    Science.gov (United States)

    Yokota, Mariko; Yahagi, Shoichi; Tokudome, Yoshihiro; Masaki, Hitoshi

    2018-03-09

    Alkyl glyceryl ethers (AKGs) are widely used as emulsion stabilizers, and their anti-inflammatory effects are well known. Daily exposure to environmental stresses, such as chemicals, low humidity and ultraviolet light (UV), can initiate and promote the development of various skin problems. Among those stresses, it has been established that UV induces skin pigmentation and accelerates premature skin aging due to the inflammation that results. Here, we investigated whether chimyl alcohol (CA), which is an AKG, suppresses the inflammatory process. The suppression of cell damage and the reduction of intracellular levels of reactive oxygen species (ROS) in normal human epidermal keratinocytes (NHEKs) after UVB exposure was evaluated using the Neutral red (NR) and the 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) assays, respectively. Moreover, the expression levels of mRNAs and proteins related to inflammation were evaluated by Realtime RT-PCR and ELISA assays, respectively. CA suppressed prostaglandin E 2 (PGE 2 ) production in UVB-exposed NHEKs according to the down-regulated expression level of cyclooxygenase-2 (COX-2) mRNA. Furthermore, CA up-regulated the mRNA expression levels of peroxisome proliferator-activated receptor (PPAR)-γ, nuclear factor E2-related factor 2 (Nrf2) and γ-glutamyl cysteine synthase (γ-GCS) in NHEKs. Finally, we examined the effects of CA on siPPAR-γtransfected NHEKs. siPPAR-γ transfection of NHEKs abolished the mRNA expression levels of Nrf2 and UVB-stimulated PGE 2 secretion that were regulated by CA. Hence, CA suppresses the UVB-induced COX-2 mRNA expression and PGE 2 production through PPAR-γ as an agonist. We conclude that CA provides useful protection and/or alleviation against UV damage.

  3. Erlotinib Plus Carboplatin and Paclitaxel in Ovarian Carcinoma

    Science.gov (United States)

    2015-10-29

    Brenner Tumor; Fallopian Tube Cancer; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

  4. Respective roles and interactions of T-lymphocyte and PGE2-mediated monocyte suppressive activities in human newborns and mothers at the time of delivery

    International Nuclear Information System (INIS)

    Durandy, A.; Fischer, A.; Mamas, S.; Dray, F.; Griscelli, C.

    1982-01-01

    Recently the concept of a poorly functional humoral immune response in the newborn was proposed. Data have been presented indicating that the impaired newborn B cell maturation, as shown in vitro in a pokeweed mitogen-induced B cell maturation system, is due both to an immaturity of lymphocyte subsets and to an increased suppressive T activity. In the present work, we present evidence that there exists a predominance of a naturally occurring T lymphocyte suppressive activity in the cord blood in that the removal of the suppressive activity by irradiation allows a normal maturation of newborn B cells. Such normal maturation of newborn B cells can also be obtained using mixed cultures of adult T cells and newborn B cells. Newborn suppressor T cells belong to both EA gamma (+) and EA gamma (-) fractions, and it is not known whether these two groups do or do not belong to different subsets. The PGE2-dependent monocyte suppressive activity does not play any role in the suppression observed in newborns since newborn monocytes are poorly suppressive and since they produce a smaller amount of PGE2 than adult monocytes. Some observations suggest, on the contrary, that the suppressive T lymphocytes can regulate the level of the PGE2-dependent monocyte suppressive activity. It should be noticed that similar observations about T lymphocyte and PGE2-dependent monocyte suppressive activities have been made at the same time using mothers' cells. These observations suggest the possibility that such changes in B cell immune regulation may result from an interaction between maternal and fetal lymphoid cells

  5. γ-Glutamyl cyclotransferase contributes to tumor progression in high grade serous ovarian cancer by regulating epithelial-mesenchymal transition via activating PI3K/AKT/mTOR pathway.

    Science.gov (United States)

    Li, Yanli; Wu, Tingting; Wang, Yanan; Yang, Liu; Hu, Chengcheng; Chen, Limo; Wu, Sufang

    2018-02-08

    High grade serous ovarian cancer (HGSC) remains one of the most lethal malignancies in females. We previously reported that γ-glutamyl cyclotransferase (GGCT) was significantly upregulated in serous ovarian cancer. The current study was aimed to explore the function and underlying mechanism of GGCT in HGSC. GGCT expression was assessed by immunohistochemistry in 128 HGSC patients. Stable cell lines with GGCT gene overexpression or knockdown were established to investigate the function of GGCT in HGSC in vitro and in vivo. GGCT is highly upregulated in HGSC tissues and associated with FIGO stage, lymph node metastasis and ascitic fluid volume. High expression of GGCT is associated with poor survival in HGSC patients. The Harrell's c-indexes of the prognostic models for overall survival and progression-free survival prediction were 0.758 and 0.726, respectively. GGCT knockdown suppresses proliferation, clone formation, migration, and invasion of tumor cells in vitro while forced GGCT overexpression presents opposite results. Furthermore, GGCT silencing inhibits tumor growth and spread in vivo. Epithelial-mesenchymal transition (EMT) and PI3K/AKT/mTOR signaling pathway are suppressed in GGCT silenced cells and enhanced in GGCT overexpressed cells. Inactivation of PI3K/AKT/mTOR signaling pathway in GGCT overexpressed cells induces EMT inhibition. Our data reveals an important role of GGCT in regulating EMT and progression of HGSC, providing a valuable prognostic marker and potential target for treatment of HGSC patients. Published by Elsevier Inc.

  6. Gonadotropin-dependent oocyte maturational competence requires activation of the protein kinase A pathway and synthesis of RNA and protein in ovarian follicles of Nibe, Nibea mitsukurii (Teleostei, Sciaenidae)

    Science.gov (United States)

    Yoshizaki, G.; Shusa, M.; Takeuchi, T.; Patino, R.

    2002-01-01

    Luteinizing hormone- (LH)-dependent ovarian follicle maturation has been recently described in two stages for teleost fishes. The oocyte's ability to respond to the steroidal maturation-inducing hormone (MIH), also known as oocyte maturational competence (OMC), is acquired during the first stage; whereas the MIH-dependent resumption of meiosis occurs during the second stage. However, studies directly addressing OMC have been performed with a limited number of species and therefore the general relevance of the two-stage model and its mechanisms remain uncertain. In this study, we examined the hormonal regulation of OMC and its basic transduction mechanisms in ovarian follicles of the sciaenid teleost, Nibe (Nibea mitsukurii). Exposure to MIH [17,20??-dihydroxy-4-pregnen-3-one or 17,20??,21-trihydroxy-4-pregnen-3-one] stimulated germinal vesicle breakdown (index of meiotic resumption) in full-grown follicles primed with human chorionic gonadotropin (HCG, an LH-like gonadotropin) but not in those pre-cultured in plain incubation medium. The induction of OMC by HCG was mimicked by protein kinase A (PKA) activators (forskolin and dibutyryl cyclic AMP), and blocked by specific inhibitors of PKA (H89 and H8) as well as inhibitors of RNA (actinomycin D) and protein (cycloheximide) synthesis. Forskolin-induced OMC was also inhibited by actinomycin D and cycloheximide. A strong activator of protein kinase C, PMA, inhibited HCG-dependent OMC. In conclusion, OMC in Nibe ovarian follicles is gonadotropin-dependent and requires activation of the PKA pathway followed by gene transcription and translation events. These observations are consistent with the two-stage model of ovarian follicle maturation proposed for other teleosts, and suggest that Nibe can be used as new model species for mechanistic studies of ovarian follicle differentiation and maturation in fishes.

  7. The aryl hydrocarbon receptor suppresses osteoblast proliferation and differentiation through the activation of the ERK signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Haitao; Du, Yuxuan; Zhang, Xulong; Sun, Ying; Li, Shentao; Dou, Yunpeng [Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069 (China); Li, Zhanguo [Department of Rheumatology and Immunology, Clinical Immunology Center, Peking University People' s Hospital, No. 11 Xizhimen South Street, Beijing 100044 (China); Yuan, Huihui, E-mail: huihui_yuan@163.com [Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069 (China); Zhao, Wenming, E-mail: zhao-wenming@163.com [Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069 (China)

    2014-11-01

    Ahr activation is known to be associated with synovitis and exacerbated rheumatoid arthritis (RA), but its contributions to bone loss have not been completely elucidated. Osteoblast proliferation and differentiation are abnormal at the erosion site in RA. Here, we reported that the expression of Ahr was increased in the hind paws' bone upon collagen-induced arthritis (CIA) in mice, and the levels of Ahr were negatively correlated with bone mineral density (BMD). In addition, immunofluorescent staining showed that the high expression of Ahr was mainly localized in osteoblasts from the CIA mice compared to normal controls. Moreover, the luciferase intensity of Ahr in the nucleus increased by 12.5% in CIA osteoblasts compared to that in normal controls. In addition, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activation of the Ahr inhibited pre-osteoblast MC3T3-E1 cellular proliferation and differentiation in a dose-dependent manner. Interestingly, the levels of alkaline phosphatase (ALP) mRNA expression in the osteoblasts of CIA mice were reduced compared to normal controls. In contrast, decreased ALP expression by activated Ahr was completely reversed after pretreatment with an Ahr inhibitor (CH-223191) in MC3T3-E1 cell lines and primary osteoblasts on day 5. Our data further showed that activation of Ahr promoted the phosphorylation of ERK after 5 days. Moreover, Ahr-dependent activation of the ERK signaling pathway decreased the levels of proliferation cells and inhibited ALP activity in MC3T3-E1 cells. These results demonstrated that the high expression of Ahr may suppress osteoblast proliferation and differentiation through activation of the ERK signaling pathway, further enabling bone erosion in CIA mice. - Highlights: • The upregulation of Ahr was localized in osteoblasts of CIA mice. • The overexpression of Ahr suppressed osteoblast development. • The Ahr activated ERK signaling pathway to exacerbate bone erosion.

  8. Fbxw5 suppresses nuclear c-Myb activity via DDB1-Cul4-Rbx1 ligase-mediated sumoylation

    Energy Technology Data Exchange (ETDEWEB)

    Kanei-Ishii, Chie; Nomura, Teruaki; Egoh, Ayako [Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074 (Japan); Ishii, Shunsuke, E-mail: sishii@rtc.riken.jp [Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074 (Japan)

    2012-09-14

    Highlights: Black-Right-Pointing-Pointer Fbxw5 enhances sumoylation of c-Myb. Black-Right-Pointing-Pointer The DDB1-Cul4A-Rbx1 complex mediates c-Myb sumoylation. Black-Right-Pointing-Pointer The Fbxw5-DDB1-Cul4A-Rdx1 complex is a dual SUMO/ubiquitin ligase. Black-Right-Pointing-Pointer Fbxw5 suppresses the c-Myb trans-activating capacity. -- Abstract: The c-myb proto-oncogene product (c-Myb) is degraded in response to Wnt-1 signaling. In this process, Fbxw7{alpha}, the F-box protein of the SCF complex, binds to c-Myb via its C-terminal WD40 domain, and induces the ubiquitination of c-Myb. Here, we report that Fbxw5, another F-box protein, enhances sumoylation of nuclear c-Myb. Fbxw5 enhanced c-Myb sumoylation via the DDB1-Cul4A-Rbx1 complex. Since the Fbxw5-DDB1-Cul4A-Rbx1 complex was shown to act as a ubiquitin ligase for tumor suppressor TSC2, our results suggest that this complex can function as a dual SUMO/ubiquitin ligase. Fbxw5, which is localized to both nucleus and cytosol, enhanced sumoylation of nuclear c-Myb and induced the localization of c-Myb to nuclear dot-like domains. Co-expression of Fbxw5 suppressed the trans-activation of c-myc promoter by wild-type c-Myb, but not by v-Myb, which lacks the sumoylation sites. These results suggest that multiple E3 ligases suppress c-Myb activity through sumoylation or ubiquitination, and that v-Myb is no longer subject to these negative regulations.

  9. Expression of protease-activated receptor-2 (PAR-2) is related to advanced clinical stage and adverse prognosis in ovarian clear cell carcinoma.

    Science.gov (United States)

    Aman, Murasaki; Ohishi, Yoshihiro; Imamura, Hiroko; Shinozaki, Tomoko; Yasutake, Nobuko; Kato, Kiyoko; Oda, Yoshinao

    2017-06-01

    Recent studies demonstrated that protease-activated receptor-2 (PAR-2) correlates with tumor progression in various tissues. On the other hand, oxidative stress arising from endometriosis has been considered a cause of carcinogenesis in ovarian clear cell carcinoma (OCCC). We previously demonstrated that oxidative stress up-regulates PAR-2 expression, and we conducted the present study to investigate the PAR-2 expression and its relation to clinicopathological factors and oxidative stress in OCCC. We performed an immunohistochemical evaluation in 95 cases of OCCC. For the evaluation of oxidative stress markers, 31 cases of ovarian endometrioid carcinoma (OEC) were also examined. No significant differences in the expression of cyclooxygenase-2 and inducible nitric oxide synthase were observed between OCCC and OEC. Sixty-two percent of the OCCC cases showed high 8-hydroxydeoxyguanosine expression, whereas all of the OEC cases showed almost negative immunoreactivities. The presence of endometriosis did not affect the expression of these oxidative stress markers or prognosis. High PAR-2 expression was observed in 20% (14/71) of the early International Federation of Gynecology and Obstetrics (FIGO) stage cases and 58% (14/24) of the advanced FIGO stage cases. High PAR-2 expression was significantly correlated with advanced FIGO stage and shorter overall survival. We found no correlations between PAR-2 expression and oxidative stress in OCCC. Our results suggest that PAR-2 plays an important role in the progression of OCCC. The expression of 8-hydroxydeoxyguanosine is a characteristic finding of OCCC, indicating that the injury of DNA by oxidative stress may be involved in the carcinogenesis of OCCC. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. PI3K/Akt-independent NOS/HO activation accounts for the facilitatory effect of nicotine on acetylcholine renal vasodilations: modulation by ovarian hormones.

    Directory of Open Access Journals (Sweden)

    Eman Y Gohar

    Full Text Available We investigated the effect of chronic nicotine on cholinergically-mediated renal vasodilations in female rats and its modulation by the nitric oxide synthase (NOS/heme oxygenase (HO pathways. Dose-vasodilatory response curves of acetylcholine (0.01-2.43 nmol were established in isolated phenylephrine-preconstricted perfused kidneys obtained from rats treated with or without nicotine (0.5-4.0 mg/kg/day, 2 weeks. Acetylcholine vasodilations were potentiated by low nicotine doses (0.5 and 1 mg/kg/day in contrast to no effect for higher doses (2 and 4 mg/kg/day. The facilitatory effect of nicotine was acetylcholine specific because it was not observed with other vasodilators such as 5'-N-ethylcarboxamidoadenosine (NECA, adenosine receptor agonist or papaverine. Increases in NOS and HO-1 activities appear to mediate the nicotine-evoked enhancement of acetylcholine vasodilation because the latter was compromised after pharmacologic inhibition of NOS (L-NAME or HO-1 (zinc protoporphyrin, ZnPP. The renal protein expression of phosphorylated Akt was not affected by nicotine. We also show that the presence of the two ovarian hormones is necessary for the nicotine augmentation of acetylcholine vasodilations to manifest because nicotine facilitation was lost in kidneys of ovariectomized (OVX and restored after combined, but not individual, supplementation with medroxyprogesterone acetate (MPA and estrogen (E2. Together, the data suggests that chronic nicotine potentiates acetylcholine renal vasodilation in female rats via, at least partly, Akt-independent HO-1 upregulation. The facilitatory effect of nicotine is dose dependent and requires the presence of the two ovarian hormones.

  11. Pyrrolidinium fullerene induces apoptosis by activation of procaspase-9 via suppression of Akt in primary effusion lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Watanabe, Tadashi [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan); Nakamura, Shigeo [Department of Chemistry, Nippon Medical School, 1-7-1 Kyonan-cho, Musashino, Tokyo 180-0023 (Japan); Ono, Toshiya; Ui, Sadaharu [Department of Biotechnology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Kofu 400-8511 (Japan); Yagi, Syota; Kagawa, Hiroki [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan); Watanabe, Hisami [Center of Molecular Biosciences, Tropical Biosphere Research Center, University of the Ryukyus, 1 Senbaru, Nishihara-cho, Okinawa 903-0213 (Japan); Ohe, Tomoyuki; Mashino, Tadahiko [Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512 (Japan); Fujimuro, Masahiro, E-mail: fuji2@mb.kyoto-phu.ac.jp [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan)

    2014-08-15

    Highlights: • Seven fullerenes were evaluated in terms of their cytotoxic effects on B-lymphomas. • Pyrrolidinium fullerene induced apoptosis of KSHV-infected B-lymphoma PEL cells. • The activation of Akt is essential for PEL cell survival. • Pyrrolidinium fullerene activated caspase-9 by inactivating Akt in PEL cells. • Pyrrolidinium fullerene have potential as novel drugs for the treatment of PEL. - Abstract: Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin’s B-cell lymphoma and is an aggressive neoplasm caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients. In general, PEL cells are derived from post-germinal center B-cells and are infected with KSHV. To evaluate potential novel anti-tumor compounds against KSHV-associated PEL, seven water-soluble fullerene derivatives were evaluated as potential drug candidates for the treatment of PEL. Herein, we discovered a pyrrolidinium fullerene derivative, 1,1,1′,1′-tetramethyl [60]fullerenodipyrrolidinium diiodide, which induced apoptosis of PEL cells via a novel mechanism, the caspase-9 activation by suppressing the caspase-9 phosphorylation, causing caspase-9 inactivation. Pyrrolidinium fullerene treatment reduced significantly the viability of PEL cells compared with KSHV-uninfected lymphoma cells, and induced the apoptosis of PEL cells by activating caspase-9 via procaspase-9 cleavage. Pyrrolidinium fullerene additionally reduced the Ser473 phosphorylation of Akt and Ser196 of procaspase-9. Ser473-phosphorylated Akt (i.e., activated Akt) phosphorylates Ser196 in procaspase-9, causing inactivation of procaspase-9. We also demonstrated that Akt inhibitors suppressed the proliferation of PEL cells compared with KSHV-uninfected cells. Our data therefore suggest that Akt activation is essential for cell survival in PEL and a pyrrolidinium fullerene derivative induced apoptosis by activating caspase-9 via suppression of Akt in PEL cells. In addition, we evaluated

  12. Curcumin Modulates the Radiosensitivity of Colorectal Cancer Cells by Suppressing Constitutive and Inducible NF-κB Activity

    International Nuclear Information System (INIS)

    Sandur, Santosh K.; Deorukhkar, Amit; Pandey, Manoj K.; Pabon, Ana Maria B.S.; Shentu, Shujun; Guha, Sushovan; Aggarwal, Bharat B.; Krishnan, Sunil

    2009-01-01

    Purpose: Radiation therapy is an integral part of the preoperative treatment of rectal cancers. However, only a minority of patients achieve a complete pathologic response to therapy because of resistance of these tumors to radiation therapy. This resistance may be mediated by constitutively active pro-survival signaling pathways or by inducible/acquired mechanisms in response to radiation therapy. Simultaneous inhibition of these pathways can sensitize these tumors to radiation therapy. Methods and Materials: Human colorectal cancer cells were exposed to clinically relevant doses of gamma rays, and the mechanism of their radioresistance was investigated. We characterized the transcription factor nuclear factor-κB (NF-κB) activation as a mechanism of inducible radioresistance in colorectal cancer and used curcumin, the active ingredient in the yellow spice turmeric, to overcome this resistance. Results: Curcumin inhibited the proliferation and the post-irradiation clonogenic survival of multiple colorectal cancer cell lines. Radiation stimulated NF-κB activity in a dose- and time-dependent manner, whereas curcumin suppressed this radiation-induced NF-κB activation via inhibition of radiation-induced phosphorylation and degradation of inhibitor of κB alpha, inhibition of inhibitor of κB kinase activity, and inhibition of Akt phosphorylation. Curcumin also suppressed NF-κB-regulated gene products (Bcl-2, Bcl-x L , inhibitor of apoptosis protein-2, cyclooxygenase-2, and cyclin D1). Conclusions: Our results suggest that transient inducible NF-κB activation provides a prosurvival response to radiation that may account for development of radioresistance. Curcumin blocks this signaling pathway and potentiates the antitumor effects of radiation therapy.

  13. Ubiquitin carboxyl terminal hydrolase L1 negatively regulates TNFα-mediated vascular smooth muscle cell proliferation via suppressing ERK activation

    International Nuclear Information System (INIS)

    Ichikawa, Tomonaga; Li, Jinqing; Dong, Xiaoyu; Potts, Jay D.; Tang, Dong-Qi; Li, Dong-Sheng; Cui, Taixing

    2010-01-01

    Deubiquitinating enzymes (DUBs) appear to be critical regulators of a multitude of processes such as proliferation, apoptosis, differentiation, and inflammation. We have recently demonstrated that a DUB of ubiquitin carboxyl terminal hydrolase L1 (UCH-L1) inhibits vascular lesion formation via suppressing inflammatory responses in vasculature. However, the precise underlying mechanism remains to be defined. Herein, we report that a posttranscriptional up-regulation of UCH-L1 provides a negative feedback to tumor necrosis factor alpha (TNFα)-mediated activation of extracellular signal-regulated kinases (ERK) and proliferation in vascular smooth muscle cells (VSMCs). In rat adult VSMCs, adenoviral over-expression of UCH-L1 inhibited TNFα-induced activation of ERK and DNA synthesis. In contrast, over-expression of UCH-L1 did not affect platelet derived growth factor (PDGF)-induced VSMC proliferation and activation of growth stimulating cascades including ERK. TNFα hardly altered UCH-L1 mRNA expression and stability; however, up-regulated UCH-L1 protein expression via increasing UCH-L1 translation. These results uncover a novel mechanism by which UCH-L1 suppresses vascular inflammation.

  14. Colchicine therapy in acute coronary syndrome patients acts on caspase-1 to suppress NLRP3 inflammasome monocyte activation.

    Science.gov (United States)

    Robertson, Stacy; Martínez, Gonzalo J; Payet, Cloe A; Barraclough, Jennifer Y; Celermajer, David S; Bursill, Christina; Patel, Sanjay

    2016-07-01

    Inflammasome activation, with subsequent release of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, has recently been implicated in atherosclerosis-associated inflammation. This study aims to assess in acute coronary syndrome (ACS) patients (1) inflammasome activation in circulating monocytes and (2) whether short-term oral colchicine, a recognized anti-inflammatory agent that has been shown to be cardio-protective in clinical studies, might acutely suppress inflammasome-dependent inflammation. ACS patients (n=21) were randomized to oral colchicine (1 mg followed by 0.5 mg 1 h later) or no treatment, and compared with untreated healthy controls (n=9). Peripheral venous blood was sampled pre- (day 1) and 24 h post- (day 2) treatment. Monocytes were cultured and stimulated with ATP. Analysis of key inflammasome markers was performed by ELISA. IL-1β secretion increased by 580.4% (PColchicine treatment in ACS patients markedly reduced intracellular and secreted levels of IL-1β compared with pre-treatment levels (Pcolchicine acutely and markedly suppresses monocyte caspase-1 activity, thereby reducing monocyte secretion of IL-1β. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  15. Cancer/testis antigen PIWIL2 suppresses circadian rhythms by regulating the stability and activity of BMAL1 and CLOCK.

    Science.gov (United States)

    Lu, Yilu; Zheng, Xulei; Hu, Wei; Bian, Shasha; Zhang, Zhiwei; Tao, Dachang; Liu, Yunqiang; Ma, Yongxin

    2017-08-15

    Circadian rhythms are regulated by transcriptional and post-translational feedback loops generated by appropriate functions of clock proteins. Rhythmic degradation of the circadian clock proteins is critical for maintenance of the circadian oscillations. Notably, circadian clock does not work during spermatogenesis and can be disrupted in tumors. However, the underlying mechanism that suppresses circadian rhythms in germ cells and cancer cells remains largely unknown. Here we report that the cancer/testis antigen PIWIL2 can repress circadian rhythms both in the testis and cancer cells. By facilitating SRC binding with PI3K, PIWIL2 activates the PI3K-AKT pathway to phosphorylate and deactivate GSK3β, suppressing GSK3β-induced phosphorylation and degradation of circadian protein BMAL1 and CLOCK. Meanwhile, PIWIL2 can bind with E-Box sequences associated with the BMAL1/CLOCK complex to negatively regulate the transcriptional activation activity of promoters of clock-controlled genes. Taken together, our results first described a function for the germline-specific protein PIWIL2 in regulation of the circadian clock, providing a molecular link between spermatogenesis as well as tumorigenesis to the dysfunction of circadian rhythms.

  16. Proteasome Inhibitor Bortezomib Suppresses Nuclear Factor-Kappa B Activation and Ameliorates Eye Inflammation in Experimental Autoimmune Uveitis

    Directory of Open Access Journals (Sweden)

    Sheng-Min Hsu

    2015-01-01

    Full Text Available Bortezomib is a proteasome inhibitor used for hematologic cancer treatment. Since it can suppress NF-κB activation, which is critical for the inflammatory process, bortezomib has been found to possess anti-inflammatory activity. In this study, we evaluated the effect of bortezomib on experimental autoimmune uveitis (EAU in mice and investigated the potential mechanisms related to NF-κB inactivation. High-dose bortezomib (0.75 mg/kg, low-dose bortezomib (0.15 mg/kg, or phosphate buffered saline was given after EAU induction. We found that the EAU is ameliorated by high-dose bortezomib treatment when compared with low-dose bortezomib or PBS treatment. The DNA-binding activity of NF-κB was suppressed and expression of several key inflammatory mediators including TNF-α, IL-1α, IL-1β, IL-12, IL-17, and MCP-1 was lowered in the high-dose bortezomib-treated group. These results suggest that proteasome inhibition is a promising treatment strategy for autoimmune uveitis.

  17. Suppression of Tumor Growth in Mice by Rationally Designed Pseudopeptide Inhibitors of Fibroblast Activation Protein and Prolyl Oligopeptidase

    Directory of Open Access Journals (Sweden)

    Kenneth W. Jackson

    2015-01-01

    Full Text Available Tumor microenvironments (TMEs are composed of cancer cells, fibroblasts, extracellular matrix, microvessels, and endothelial cells. Two prolyl endopeptidases, fibroblast activation protein (FAP and prolyl oligopeptidase (POP, are commonly overexpressed by epithelial-derived malignancies, with the specificity of FAP expression by cancer stromal fibroblasts suggesting FAP as a possible therapeutic target. Despite overexpression in most cancers and having a role in angiogenesis, inhibition of POP activity has received little attention as an approach to quench tumor growth. We developed two specific and highly effective pseudopeptide inhibitors, M83, which inhibits FAP and POP proteinase activities, and J94, which inhibits only POP. Both suppressed human colon cancer xenograft growth >90% in mice. By immunohistochemical stains, M83- and J94-treated tumors had fewer microvessels, and apoptotic areas were apparent in both. In response to M83, but not J94, disordered collagen accumulations were observed. Neither M83- nor J94-treated mice manifested changes in behavior, weight, or gastrointestinal function. Tumor growth suppression was more extensive than noted with recently reported efforts by others to inhibit FAP proteinase function or reduce FAP expression. Diminished angiogenesis and the accompanying profound reduction in tumor growth suggest that inhibition of either FAP or POP may offer new therapeutic approaches that directly target TMEs.

  18. Arctigenin promotes apoptosis in ovarian cancer cells via the iNOS/NO/STAT3/survivin signalling.

    Science.gov (United States)

    Huang, Ke; Li, Li-an; Meng, Yuan-guang; You, Yan-qin; Fu, Xiao-yu; Song, Lei

    2014-12-01

    Arctigenin is a biologically active lignan extracted from the seeds of Arctium lappa and shows anticancer activity against a variety of human cancers. The aim of this study was to determine the effects of arctigenin on ovarian cancer cell proliferation and survival and associated molecular mechanisms. Human ovarian cancer OVCAR3 and SKOV3 cells were treated with arctigenin, and cell proliferation and apoptosis were assessed. Western blot analysis was used to examine signal transducer and activator of transcription-3 (STAT3) phosphorylation and survivin and inducible nitric oxide synthase (iNOS) expression. The involvement of STAT3/survivin/iNOS/NO signalling in arctigenin action was checked. Arctigenin treatment resulted in a significant and dose-dependent inhibition of cell proliferation. Arctigenin-treated cells showed a 4-6 times increase in the percentage of apoptosis, compared with control cells. Pre-treatment with Ac-DEVD-CHO, a specific inhibitor of caspase-3, counteracted the induction of apoptosis by arctigenin. Arctigenin treatment significantly inhibited STAT3 phosphorylation and survivin and iNOS expression. Arctigenin-induced apoptosis was impaired by pre-transfection with survivin-expressing plasmid or addition of chemical nitric oxide (NO) donors. Additionally, exogenous NO prevented the suppression of STAT3 phosphorylation and survivin expression by arctigenin. Arctigenin treatment inhibits the proliferation and induces caspase-3-dependent apoptosis of ovarian cancer cells. Suppression of iNOS/NO/STAT3/survivin signalling is causally linked to the anticancer activity of arctigenin. Therefore, arctigenin may be applicable to anticancer therapy for ovarian cancer. © 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  19. Dieckol, isolated from the edible brown algae Ecklonia cava, induces apoptosis of ovarian cancer cells and inhibits tumor xenograft growth.

    Science.gov (United States)

    Ahn, Ji-Hye; Yang, Yeong-In; Lee, Kyung-Tae; Choi, Jung-Hye

    2015-02-01

    Ecklonia cava is an abundant brown alga and has been reported to possess various bioactive compounds having anti-inflammatory effect. However, the anticancer effects of dieckol, a major active compound in E. cava, are poorly understood. In the present study, we investigated the anti-tumor activity of dieckol and its molecular mechanism in ovarian cancer cells and in a xenograft mouse model . MTT assay, PI staining, and PI and Annexin double staining were performed to study cell cytotoxicity, cell cycle distribution, and apoptosis. We also investigated reactive oxygen species (ROS) production and protein expression using flow cytometry and Western blot analysis, respectively. Anti-tumor effects of dieckol were evaluated in SKOV3 tumor xenograft model. We found that the E. cava extract and its phlorotannins have cytotoxic effects on A2780 and SKOV3 ovarian cancer cells. Dieckol induced the apoptosis of SKOV3 cells and suppressed tumor growth without any significant adverse effect in the SKOV3-bearing mouse model. Dieckol triggered the activation of caspase-8, caspase-9, and caspase-3, and pretreatment with caspase inhibitors neutralized the pro-apoptotic activity of dieckol. Furthermore, treatment with dieckol caused mitochondrial dysfunction and suppressed the levels of anti-apoptotic proteins. We further demonstrated that dieckol induced an increase in intracellular ROS, and the antioxidant N-acetyl-L-cysteine (NAC) significantly reversed the caspase activation, cytochrome c release, Bcl-2 downregulation, and apoptosis that were caused by dieckol. Moreover, dieckol inhibited the activity of AKT and p38, and overexpression of AKT and p38, at least in part, reversed dieckol-induced apoptosis in SKOV3 cells. These data suggest that dieckol suppresses ovarian cancer cell growth by inducing caspase-dependent apoptosis via ROS production and the regulation of AKT and p38 signaling.

  20. Development of A Mouse Model of Menopausal Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Elizabeth R. Smith

    2014-02-01

    Full Text Available Despite significant understanding of the genetic mutations involved in ovarian epithelial cancer and advances in genomic approaches for expression and mutation profiling of tumor tissues, several key questions in ovarian cancer biology remain enigmatic: the mechanism for the well-established impact of reproductive factors on ovarian cancer risk remains obscure; questions of the cell of origin of ovarian cancer continue to be debated; and the precursor lesion, sequence, or events in progression remain to be defined. Suitable mouse models should complement the analysis of human tumor tissues and may provide clues to these questions currently perplexing ovarian cancer biology.A potentially useful model is the germ cell-deficient Wv (white spotting variant mutant mouse line, which may be used to study the impact of menopausal physiology on the increased risk of ovarian cancer. The Wv mice harbor a point mutation in c-Kit that reduces the receptor tyrosine kinase activity to about 1-5% (it is not a null mutation. Homozygous Wv mutant females have a reduced ovarian germ cell reservoir at birth and the follicles are rapidly depleted upon reaching reproductive maturity, but other biological phenotypes are minimal and the mice have a normal life span. The loss of ovarian function precipitates changes in hormonal and metabolic activity that model features of menopause in humans. As a consequence of follicle depletion, the Wv ovaries develop ovarian tubular adenomas, a benign epithelial tumor corresponding to surface epithelial invaginations and papillomatosis that mark human ovarian aging. Ongoing work will test the possibility of converting the benign epithelial tubular adenomas into neoplastic tumors by addition of an oncogenic mutation, such as of Tp53, to model the genotype and biology of serous ovarian cancer.Model based on the Wv mice may have the potential to gain biological and etiological insights into ovarian cancer development and prevention.

  1. Kaempferol modulates pro-inflammatory NF-κB activation by suppressing advanced glycation endproducts-induced NADPH oxidase

    Science.gov (United States)

    Kim, Ji Min; Lee, Eun Kyeong; Kim, Dae Hyun; Yu, Byung Pal

    2010-01-01

    Advanced glycation endproducts (AGE) are oxidative products formed from the reaction between carbohydrates and a free amino group of proteins that are provoked by reactive species (RS). It is also known that AGE enhance the generation of RS and that the binding of AGE to a specific AGE receptor (RAGE) induces the activation of the redox-sensitive, pro-inflammatory transcription factor, nuclear factor-kappa B (NF-ĸB). In this current study, we investigated the anti-oxidative effects of short-term kaempferol supplementation on the age-related formation of AGE and the binding activity of RAGE in aged rat kidney. We further investigated the suppressive action of kaempferol against AGE's ability to stimulate activation of pro-inflammatory NF-ĸB and its molecular mechanisms. For this study, we utilized young (6 months old), old (24 months old), and kaempferol-fed (2 and 4 mg/kg/day for 10 days) old rats. In addition, for the molecular work, the rat endothelial cell line, YPEN-1 was used. The results show that AGE and RAGE were increased during aging and that these increases were blunted by kaempferol. In addition, dietary kaempferol reduced age-related increases in NF-κB activity and NF-ĸB-dependant pro-inflammatory gene activity. The most significant new finding from this study is that kaempferol supplementation prevented age-related NF-κB activation by suppressing AGE-induced nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase). Taken together, our results demonstrated that dietary kaempferol exerts its anti-oxidative and anti-inflammatory actions by modulating the age-related NF-κB signaling cascade and its pro-inflammatory genes by suppressing AGE-induced NADPH oxidase activation. Based on these data, dietary kaempferol is proposed as a possible anti-AGE agent that may have the potential for use in anti-inflammation therapies. PMID:20431987

  2. Suppression of neurotoxic lesion-induced seizure activity: evidence for a permanent role for the hippocampus in contextual memory.

    Directory of Open Access Journals (Sweden)

    Fraser T Sparks

    Full Text Available Damage to the hippocampus (HPC using the excitotoxin N-methyl-D-aspartate (NMDA can cause retrograde amnesia for contextual fear memory. This amnesia is typically attributed to loss of cells in the HPC. However, NMDA is also known to cause intense neuronal discharge (seizure activity during the hours that follow its injection. These seizures may have detrimental effects on retrieval of memories. Here we evaluate the possibility that retrograde amnesia is due to NMDA-induced seizure activity or cell damage per se. To assess the effects of NMDA induced activity on contextual memory, we developed a lesion technique that utilizes the neurotoxic effects of NMDA while at the same time suppressing possible associated seizure activity. NMDA and tetrodotoxin (TTX, a sodium channel blocker, are simultaneously infused into the rat HPC, resulting in extensive bilateral damage to the HPC. TTX, co-infused with NMDA, suppresses propagation of seizure activity. Rats received pairings of a novel context with foot shock, after which they received NMDA-induced, TTX+NMDA-induced, or no damage to the HPC at a recent (24 hours or remote (5 weeks time point. After recovery, the rats were placed into the shock context and freezing was scored as an index of fear memory. Rats with an intact HPC exhibited robust memory for the aversive context at both time points, whereas rats that received NMDA or NMDA+TTX lesions showed a significant reduction in learned fear of equal magnitude at both the recent and remote time points. Therefore, it is unlikely that observed retrograde amnesia in contextual fear conditioning are due to disruption of non-HPC networks by propagated seizure activity. Moreover, the memory deficit observed at both time points offers additional evidence supporting the proposition that the HPC has a continuing role in maintaining contextual memories.

  3. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP.

    Science.gov (United States)

    Liu-Chittenden, Yi; Huang, Bo; Shim, Joong Sup; Chen, Qian; Lee, Se-Jin; Anders, Robert A; Liu, Jun O; Pan, Duojia

    2012-06-15

    The Drosophila TEAD ortholog Scalloped is required for Yki-mediated overgrowth but is largely dispensable for normal tissue growth, suggesting that its mammalian counterpart may be exploited for selective inhibition of oncogenic growth driven by YAP hyperactivation. Here we test this hypothesis genetically and pharmacologically. We show that a dominant-negative TEAD molecule does not perturb normal liver growth but potently suppresses hepatomegaly/tumorigenesis resulting from YAP overexpression or Neurofibromin 2 (NF2)/Merlin inactivation. We further identify verteporfin as a small molecule that inhibits TEAD-YAP association and YAP-induced liver overgrowth. These findings provide proof of principle that inhibiting TEAD-YAP interactions is a pharmacologically viable strategy against the YAP oncoprotein.

  4. Bitter Melon (Momordica charantia) Extract Inhibits Tumorigenicity and Overcomes Cisplatin-Resistance in Ovarian Cancer Cells Through Targeting AMPK Signaling Cascade.

    Science.gov (United States)

    Yung, Mingo M H; Ross, Fiona A; Hardie, D Grahame; Leung, Thomas H Y; Zhan, Jinbiao; Ngan, Hextan Y S; Chan, David W

    2016-09-01

    Objective Acquired chemoresistance is a major obstacle in the clinical management of ovarian cancer. Therefore, searching for alternative therapeutic modalities is urgently needed. Bitter melon (Momordica charantia) is a traditional dietary fruit, but its extract also shows potential medicinal values in human diabetes and cancers. Here, we sought to investigate the extract of bitter melon (BME) in antitumorigenic and cisplatin-induced cytotoxicity in ovarian cancer cells. Three varieties of bitter melon were used to prepare the BME. Ovarian cancer cell lines, human immortalized epithelial ovarian cells (HOSEs), and nude mice were used to evaluate the cell cytotoxicity, cisplatin resistance, and tumor inhibitory effect of BME. The molecular mechanism of BME was examined by Western blotting. Cotreatment with BME and cisplatin markedly attenuated tumor growth in vitro and in vivo in a mouse xenograft model, whereas there was no observable toxicity in HOSEs or in nude mice in vivo Interestingly, the antitumorigenic effects of BME varied with different varieties of bitter melon, suggesting that the amount of antitumorigenic substances may vary. Studies of the molecular mechanism demonstrated that BME activates AMP-activated protein kinase (AMPK) in an AMP-independent but CaMKK (Ca(2+)/calmodulin-dependent protein kinase)-dependent manner, exerting anticancer effects through activation of AMPK and suppression of the mTOR/p70S6K and/or the AKT/ERK/FOXM1 (Forkhead Box M1) signaling cascade. BME functions as a natural AMPK activator in the inhibition of ovarian cancer cell growth and might be useful as a supplement to improve the efficacy of cisplatin-based chemotherapy in ovarian cancer. © The Author(s) 2015.

  5. Nightshift work and risk of ovarian cancer.

    Science.gov (United States)

    Bhatti, Parveen; Cushing-Haugen, Kara L; Wicklund, Kristine G; Doherty, Jennifer A; Rossing, Mary Anne

    2013-04-01

    Animal evidence suggests that circadian disruption may be associated with ovarian cancer, though very little epidemiological work has been done to assess this potential association. We evaluated the association between self-reported nightshift work, a known circadian disruptor, and ovarian cancer in a population-based case-control study. The study included 1101 women with invasive epithelial ovarian cancer, 389 women with borderline epithelial ovarian tumours and 1832 controls and was conducted in western Washington state. Shift work data were collected as part of inperson interviews. Working the nightshift was associated with an increased risk of invasive (OR=1.24, 95% CI 1.04 to 1.49) and borderline (OR=1.48, 95% CI 1.15 to 1.90) tumours; however, we observed little evidence that risks increased with increasing cumulative duration of nightshift work, and risks were not elevated in the highest duration category (>7 nightshift work-years). Increased risks were restricted to women who were 50 years of age and older and to serous and mucinous histologies of invasive and borderline tumours. There was suggestive evidence of a decreased risk of ovarian cancer among women reporting a preference for activity during evenings rather than mornings. We found evidence suggesting an association between shift work and ovarian cancer. This observation should be followed up in future studies incorporating detailed assessments of diurnal preference (ie, chronotype) in addition to detailed data on shift schedules.

  6. Molecular determinants of resistance activation and suppression by Phytophthora infestans effector IPI-O.

    Science.gov (United States)

    Chen, Yu; Liu, Zhenyu; Halterman, Dennis A

    2012-01-01

    Despite intensive breeding efforts, potato late blight, caused by the oomycete pathogen Phytophthora infestans, remains a threat to potato production worldwide because newly evolved pathogen strains have consistently overcome major resistance genes. The potato RB gene, derived from the wild species Solanum bulbocastanum, confers resistance to most P. infestans strains through recognition of members of the pathogen effector family IPI-O. While the majority of IPI-O proteins are recognized by RB to elicit resistance (e.g. IPI-O1, IPI-O2), some family members are able to elude detection (e.g. IPI-O4). In addition, IPI-O4 blocks recognition of IPI-O1, leading to inactivation of RB-mediated programmed cell death. Here, we report results that elucidate molecular mechanisms governing resistance elicitation or suppression of RB by IPI-O. Our data indicate self-association of the RB coiled coil (CC) domain as well as a physical interaction between this domain and the effectors IPI-O4 and IPI-O1. We identified four amino acids within IPI-O that are critical for interaction with the RB CC domain and one of these amino acids, at position 129, determines hypersensitive response (HR) elicitation in planta. IPI-O1 mutant L129P fails to induce HR in presence of RB while IPI-O4 P129L gains the ability to induce an HR. Like IPI-O4, IPI-O1 L129P is also able to suppress the HR mediated by RB, indicating a critical step in the evolution of this gene family. Our results point to a model in which IPI-O effectors can affect RB function through interaction with the RB CC domain.

  7. Nutrient-Induced Inflammation in Polycystic Ovary Syndrome: Role in the Development of Metabolic Aberration and Ovarian Dysfunction.

    Science.gov (United States)

    González, Frank

    2015-07-01

    A pathophysiology paradigm shift has emerged with the discovery that polycystic ovary syndrome (PCOS) is a proinflammatory state. Despite the dogma that the compensatory hyperinsulinemia of insulin resistance is the promoter of hyperandrogenism, physiological insulin infusion has no effect on androgen levels in PCOS. The dogma also does not explain the cause of hyperandrogenism and ovarian dysfunction in the 30 to 50% of women with PCOS who are of normal weight and lack insulin resistance. Inflammation is the underpinning of insulin resistance in obesity and type 2 diabetes, and may also be the cause of insulin resistance when present in PCOS. The origin of inflammation in PCOS has been ascribed to excess abdominal adiposity or frank obesity. However, nutrients such as glucose and saturated fat can incite inflammation from circulating mononuclear cells (MNC) of women with PCOS independent of excess adiposity and insulin resistance, and can also promote atherogenesis. Hyperandrogenism activates MNC in the fasting state to increase MNC sensitivity to nutrients, and is a potential mechanism for initiating inflammation in PCOS. However, chronic ovarian androgen suppression does not reduce inflammation in normal-weight women with PCOS. Direct exposure of ovarian theca cells to proinflammatory stimuli in vitro increases androgen production. These findings may be corroborated in vivo with anti-inflammatory therapy to normal-weight insulin-sensitive women with PCOS without abdominal adiposity to observe for amelioration of ovarian dysfunction. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  8. Ovarian Cancer FAQ

    Science.gov (United States)

    ... cancer, ovarian cancer, colon cancer, or endometrial cancer (cancer of the lining of the uterus ) Personal history of breast cancer Mutations in BRCA1 ... If a woman is thought to have ovarian cancer, surgery usually is recommended to remove the uterus, ovaries, and fallopian tubes . Lymph nodes and tissues ...

  9. Ectopic ovarian pregnancy

    International Nuclear Information System (INIS)

    Sachdev, P.S.; Jatoi, N.; Memon, R.A.; Sachdev, C.S.

    2003-01-01

    A case of ectopic ovarian pregnancy is presented occurring in a 24 years old woman after natural conception. The clinical diagnosis was ruptured tubal pregnancy. Gross findings were suggestive of ruptured corpus luteum cyst on exploration. The histopathological examination of specimen brought forward the diagnosis of ovarian pregnancy. (author)

  10. Candidate Tumor-Suppressor Gene DLEC1 Is Frequently Downregulated by Promoter Hypermethylation and Histone Hypoacetylation in Human Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Joseph Kwong

    2006-04-01

    Full Text Available Suppression of ovarian tumor growth by chromosome 3p was demonstrated in a previous study. Deleted in Lung and Esophageal Cancer 1 (DLEC1 on 3p22.3 is a candidate tumor suppressor in lung, esophageal, and renal cancers. The potential involvement of DLEC1 in epithelial ovarian cancer remains unknown. In the present study, DLEC1 downregulation was found in ovarian cancer cell lines and primary ovarian tumors. Focus-expressed DLEC1 in two ovarian cancer cell lines resulted in 41% to 52% inhibition of colony formation. No chromosomal loss of chromosome 3p22.3 in any ovarian cancer cell line or tissue was found. Promoter hypermethylation of DLEC1 was detected in ovarian cancer cell lines with reduced DLEC1 transcripts, whereas methylation was not detected in normal ovarian epithelium and DLEC1-expressing ovarian cancer cell lines. Treatment with demethylating agent enhanced DLEC1 expression in 90% (9 of 10 of ovarian cancer cell lines. DLEC1 promoter methylation was examined in 13 high-grade ovarian tumor tissues with DLEC1 downregulation, in which 54% of the tumors showed DLEC1 methylation. In addition, 80% of ovarian cancer cell lines significantly upregulated DLEC1 transcripts after histone deacetylase inhibitor treatment. Therefore, our results suggested that DLEC1 suppressed the growth of ovarian cancer cells and that its downregulation was closely associated with promoter hypermethylation and histone hypoacetylation.

  11. Health-related quality of life and pelvic floor dysfunction in advanced-stage ovarian cancer survivors: associations with objective activity behaviors and physiological characteristics.

    Science.gov (United States)

    Schofield, Christelle; Newton, Robert U; Cohen, Paul A; Galvão, Daniel A; McVeigh, Joanne A; Mohan, Ganendra R; Tan, Jason; Salfinger, Stuart G; Straker, Leon M; Peddle-McIntyre, Carolyn J

    2018-02-01

    Little is known about the relationship between health-related quality of life (HRQoL), pelvic floor dysfunction (PFD), and modifiable lifestyle and physiological factors for ovarian cancer survivors (OCS). The primary aim of the study was to compare post-treatment advanced-stage OCS with age-matched controls on measures of HRQoL and PFD. The secondary aim was to examine associations between HRQoL, PFD, objective activity behaviors, physical function, and body composition in OCS. Twenty advanced-stage OCS and 20 controls completed questionnaires assessing HRQoL (SF-36) and PFD (Australian Pelvic Floor Questionnaire), and underwent objective assessments of activity behavior (7-day accelerometry), physical function (400-m walk, repeated chair rise, 6-m usual-pace walk, one-repetition maximum chest press, and single-leg extension), and body composition (dual-energy x-ray absorptiometry). Compared to controls, OCS had worse physical HRQoL (- 4.3 median difference, p = 0.013), but equivalent self-reported PFD, indicated by combined bladder, bowel, and pelvic organ prolapse symptoms (0.89 mean difference, p = 0.277). In OCS, physical HRQoL was significantly negatively associated with PFD (r = 0.468, p = 0.043). Decreased physical HRQoL and increased PFD were significantly associated with less moderate-to-vigorous physical activity in ≥ 10-min bouts (ρ = 0.627, p = 0.003; ρ = - 0.457, p = 0.049), more sedentary time (r = - 0.449, p = 0.047; r = 0.479, p = 0.038), and slower 400-m walk time (ρ = - 0.565, p = 0.022; ρ = 0.504, p = 0.028). Post-treatment advanced-stage OCS have decreased physical HRQoL, which is associated with modifiable factors such as worse PFD, less moderate-to-vigorous physical activity, more sedentary time, and decreased objective physical function. This highlights the need for ongoing supportive care and multidisciplinary interventions after first-line ovarian cancer

  12. Autoimmune premature ovarian failure

    Directory of Open Access Journals (Sweden)

    Beata Komorowska

    2017-02-01

    Full Text Available Premature ovarian failure (POF, also termed as primary ovarian insufficiency (POI, is a highly heterogenous condition affecting 0.5-3.0% of women in childbearing age. These young women comprise quite a formidable group with unique physical and psychological needs that require special attention. Premature ovarian senescence (POS in all of its forms evolves insidiously as a basically asymptomatic process, leading to complete loss of ovarian function, and POI/POF diagnoses are currently made at relatively late stages. Well-known and well-documented risk factors exist, and the presence or suspicion of autoimmune disorder should be regarded as an important one. Premature ovarian failure is to some degree predictable in its occurrence and should be considered while encountering young women with loss of menstrual regularity, especially when there is a concomitant dysfunction in the immune system.

  13. Ovarian reserve parameters

    DEFF Research Database (Denmark)

    Bentzen, J G; Forman, Julie Lyng; Pinborg, Anja

    2012-01-01

    2-5 of the menstrual cycle or during withdrawal bleeding, blood sampling and transvaginal sonography was performed. After adjusting for age, ovarian reserve parameters were lower among users than among non-users of hormonal contraception: serum AMH concentration by 29.8% (95% CI 19.9 to 38...... was observed between duration of hormonal-contraception use and ovarian reserve parameters. No dose-response relation was found between the dose of ethinyloestradiol and AMH or AFC. This study indicates that ovarian reserve markers are lower in women using sex steroids for contraception. Thus, AMH...... concentration and AFC may not retain their accuracy as predictors of ovarian reserve in women using hormonal contraception. Serum anti-Müllerian hormone (AMH) concentration is an indirect marker of the number of small follicles in the ovary and thereby the ovarian reserve. The AMH concentration is now widely...

  14. Multiple metastases from ovarian cancer

    African Journals Online (AJOL)

    Epithelial ovarian cancer is one of the most common ovarian tumours. Ovarian cancer affects women in the age group >60 years much more frequently than younger women. At the time of diagnosis, cancer will already have spread beyond the ovaries in approximately 75% of cases. We report a case of epithelial ovarian ...

  15. Premature ovarian failure

    Directory of Open Access Journals (Sweden)

    Vujović Svetlana

    2012-01-01

    Full Text Available Premature ovarian failure (POF is the occurrence of hypergonadotropic hypoestrogenic amenorrhea in women under the age of forty years. It is idiopathic in 74-90% patients. Known cases can be divided into primary and secondary POF. In primary POF genetic aberrations can involve the X chromosome (monosomy, trisomy, translocations, deletions or autosomes. Genetic mechanisms include reduced gene dosage and non-specific chromosome effects impairing meiosis, decreasing the pool of primordial follicles and increasing atresia due to apoptosis or failure of follicle maturation. Autoimmune ovarian damage is caused by alteration of T-cell subsets and T-cell mediated injury, increase of autoantibody producing B-cells, a low number of effector/cytotoxic lymphocyte, which decreases the number and activity of natural killer cells. Bilateral oophorectomy, chemotherapy, radiotherapy and infections cause the secondary POF. Symptoms of POF include irritability, nervousness, loss of libido, depression, lack of concentration, hot flushes, weight gaining, dry skin, vaginal dryness, frequent infections etc. The diagnosis is confirmed by the level of FSH of over 40 IU/L and estradiol below 50 pmol/L in women aged below 40 years. Biochemical and other hormonal analysis (free thyroxin, TSH, prolactin, testosterone, karyotype (<30 years of age, ultrasound of the breasts and pelvis are advisable. Optimal therapy is combined estrogen progestagen therapy given in a sequential rhythm, after excluding absolute contraindications. Testosterone can be added to adnexectomized women and those with a low libido. Sequential estrogen progestagen replacement therapy is the first line therapy for ovulation induction in those looking for pregnancy and after that oocyte donation will be advised. Appropriate estro-progestagen therapy improves the quality of life and prevents complications such as cardiovascular diseases, osteoporosis, stroke etc.

  16. Characterization of the Chicken Ovarian Cancer Model

    National Research Council Canada - National Science Library

    Rodriquez, Gustavo

    2001-01-01

    .... Unlike other ovarian cancer models, which require experimental induction of ovarian tumors, chickens develop ovarian adenocarcinoma spontaneously, with an incidence ranging from 13 to 40 percent...

  17. Characterization of the Chicken Ovarian Cancer Model

    National Research Council Canada - National Science Library

    Rodriguez, Gustavo C

    2004-01-01

    .... Unlike other ovarian cancer models, which require experimental induction of ovarian tumors, chickens develop ovarian adenocarcinoma spontaneously, with an incidence ranging from 13 to 40 percent...

  18. Characterization of the Chicken Ovarian Cancer Model

    National Research Council Canada - National Science Library

    Rodriguez, Gustavo

    2002-01-01

    .... Unlike other ovarian cancer models, which require experimental induction of ovarian tumors, chickens develop ovarian adenocarcinoma spontaneously, with an incidence ranging from 13 to 40 percent...

  19. Characterization of the Chicken Ovarian Cancer Model

    National Research Council Canada - National Science Library

    Rodriguez, Gustavo C

    2005-01-01

    .... Unlike other ovarian cancer models, which require experimental induction of ovarian tumors, chickens develop ovarian adenocarcinoma spontaneously, with an incidence ranging from 13 to 40 percent...

  20. Characterization of the Chicken Ovarian Cancer Model

    National Research Council Canada - National Science Library

    Rodriguez, Gustavo

    2003-01-01

    .... Unlike other ovarian cancer models, which require experimental induction of ovarian tumors, chickens develop ovarian adenocarcinoma spontaneously, with an incidence ranging from 13 to 40 percent...

  1. Ginsenoside Compound K suppresses the hepatic gluconeogenesis via activating adenosine-5'monophosphate kinase: A study in vitro and in vivo.

    Science.gov (United States)

    Wei, Shengnan; Li, Wei; Yu, Yang; Yao, Fan; A, Lixiang; Lan, Xiaoxin; Guan, Fengying; Zhang, Ming; Chen, Li

    2015-10-15

    Compound K (CK) is a final intestinal metabolite of protopanaxadiol-type ginsenoside. We have reported that CK presented anti-diabetic effect via diminishing the expressions of hepatic gluconeogenesis key enzyme. Here, we further explore the possible mechanism of CK on suppression hepatic gluconeogenesis via activation of adenosine-5'monophosphate kinase (AMPK) on type 2 diabetes mice in vivo and in HepG2 cells. Type 2 diabetes mice model was developed by high fat diet combined with STZ injection. 30mg/kg/d CK was orally administrated for 4weeks, the fasting blood glucose level and 2h OGTT were conducted, and the protein expression of AMPK, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase) were examined. The mechanism of Compound K on hepatic gluconeogenesis was further explored in HepG2 hepatocytes. Glucose production, the protein expression of AMPK, PEPCK, G6pase and PGC-1α, hepatic nuclear factor 4α (HNF-4α) and forkhead transcription factor O1 (FOXO1) were determined after Compound K treatment at the presence of AMPK inhibitor Compound C. We observed that CK inhibited the expression of PEPCK and G6Pase in the liver and in HepG2 hepatocytes. Meanwhile, CK treatment remarkably increased the activation of AMPK, while decreasing the expressions of PGC-1α, HNF-4α and FOXO1. However, AMPK inhibitor Compound C could reverse these effects of CK on gluconeogenesis in part. The results indicated that the effect of CK on suppression hepatic gluconeogenesis might be via the activation the AMPK activity. Copyright © 2015. Published by Elsevier Inc.

  2. Activation of peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) suppresses postprandial lipidemia through fatty acid oxidation in enterocytes

    Energy Technology Data Exchange (ETDEWEB)

    Kimura, Rino [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Takahashi, Nobuyuki, E-mail: nobu@kais.kyoto-u.ac.jp [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Murota, Kaeko [Department of Life Science, School of Science and Engineering, Kinki University, Osaka 770-8503 (Japan); Yamada, Yuko [Laboratory of Physiological Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Niiya, Saori; Kanzaki, Noriyuki; Murakami, Yoko [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Moriyama, Tatsuya [Department of Applied Cell Biology, Graduate School of Agriculture, Kinki University, Nara 631-8505 (Japan); Goto, Tsuyoshi; Kawada, Teruo [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan)

    2011-06-24

    Highlights: {yields} PPAR{alpha} activation increased mRNA expression levels of fatty acid oxidation-related genes in human intestinal epithelial Caco-2 cells. {yields} PPAR{alpha} activation also increased oxygen consumption rate and CO{sub 2} production and decreased secretion of triglyceride and ApoB from Caco-2 cells. {yields} Orally administration of bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and CO{sub 2} production in small intestinal epithelial cells. {yields} Treatment with bezafibrate decreased postprandial serum concentration of triglyceride after oral injection of olive oil in mice. {yields} It suggested that intestinal lipid metabolism regulated by PPAR{alpha} activation suppresses postprandial lipidemia. -- Abstract: Activation of peroxisome proliferator-activated receptor (PPAR)-{alpha} which regulates lipid metabolism in peripheral tissues such as the liver and skeletal muscle, decreases circulating lipid levels, thus improving hyperlipidemia under fasting conditions. Recently, postprandial serum lipid levels have been found to correlate more closely to cardiovascular diseases than fasting levels, although fasting hyperlipidemia is considered an important risk of cardiovascular diseases. However, the effect of PPAR{alpha} activation on postprandial lipidemia has not been clarified. In this study, we examined the effects of PPAR{alpha} activation in enterocytes on lipid secretion and postprandial lipidemia. In Caco-2 enterocytes, bezafibrate, a potent PPAR{alpha} agonist, increased mRNA expression levels of fatty acid oxidation-related genes, such as acyl-CoA oxidase, carnitine palmitoyl transferase, and acyl-CoA synthase, and oxygen consumption rate (OCR) and suppressed secretion levels of both triglycerides and apolipoprotein B into the basolateral side. In vivo experiments revealed that feeding high-fat-diet containing bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and

  3. Observations on ovarian structure and development of the southern ...

    African Journals Online (AJOL)

    The occurrence of vesicular follicles and corpora lutea (CL), without evidence of ovulation, in late fetuses and during prepubertal life was confirmed in the southern giraffe. In this, and other respects, the pattern of ovarian development is similar in the southern giraffe to the northern subspecies. This early ovarian activity ...

  4. IKKε coordinates invasion and metastasis of ovarian cancer

    Science.gov (United States)

    Hsu, Sarah; Kim, Marianne; Hernandez, Lidia; Grajales, Valentina; Noonan, Anne; Anver, Miriam; Davidson, Ben; Annunziata, Christina M.

    2012-01-01

    I-κB kinases (IKKs) are key regulators of NF-κB signaling. Three IKK isoforms – α, β and ε – have been linked to oncogenesis, yet the precise components of NF-κB signaling in ovarian cancer have not yet been dissected. We surveyed 120 ovarian cancer specimens for IKKε expression. Notably, cytoplasmic expression was elevated in metastatic lesions relative to primary tumors (p=0.03). Therefore, we hypothesized that IKKε drives ovarian cancer metastasis. IKKε was identified previously as a breast cancer oncogene and was associated with poor clinical outcome in ovarian cancer. We now define an ov