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Sample records for bisbibenzyls induce growth

  1. Abscisic acid induces biosynthesis of bisbibenzyls and tolerance to UV-C in the liverwort Marchantia polymorpha.

    PubMed

    Kageyama, Akito; Ishizaki, Kimitsune; Kohchi, Takayuki; Matsuura, Hideyuki; Takahashi, Kosaku

    2015-09-01

    Environmental stresses are effective triggers for the biosynthesis of various secondary metabolites in plants, and phytohormones such as jasmonic acid and abscisic acid are known to mediate such responses in flowering plants. However, the detailed mechanism underlying the regulation of secondary metabolism in bryophytes remains unclear. In this study, the induction mechanism of secondary metabolites in the model liverwort Marchantia polymorpha was investigated. Abscisic acid (ABA) and ultraviolet irradiation (UV-C) were found to induce the biosynthesis of isoriccardin C, marchantin C, and riccardin F, which are categorized as bisbibenzyls, characteristic metabolites of liverworts. UV-C led to the significant accumulation of ABA. Overexpression of MpABI1, which encodes protein phosphatase 2C (PP2C) as a negative regulator of ABA signaling, suppressed accumulation of bisbibenzyls in response to ABA and UV-C irradiation and conferred susceptibility to UV-C irradiation. These data show that ABA plays a significant role in the induction of bisbibenzyl biosynthesis, which might confer tolerance against UV-C irradiation in M. polymorpha. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Bis(bibenzyls) from liverworts inhibit lipopolysaccharide-induced inducible NOS in RAW 264.7 cells: a study of structure-activity relationships and molecular mechanism.

    PubMed

    Harinantenaina, Liva; Quang, Dang Ngoc; Takeshi, Nishizawa; Hashimoto, Toshihiro; Kohchi, Chie; Soma, Gen-Ichiro; Asakawa, Yoshinori

    2005-12-01

    The inhibition of lipopolysaccharide-induced NOS by 19 bis(bibenzyls) isolated from liverworts in RAW 264.7 macrophages was evaluated. The presence of phenolic hydroxyls and saturation at 7,8 and/or 7'/8' are required for inhibition of NO production. Among the compounds tested, marchantin A was the most potent, and its inhibitory activity was consistent with the inhibition of LPS-induced iNOS mRNA.

  3. Marchantin A, a cyclic bis(bibenzyl ether), isolated from the liverwort Marchantia emarginata subsp. tosana induces apoptosis in human MCF-7 breast cancer cells.

    PubMed

    Huang, Wei-Jan; Wu, Chia-Li; Lin, Chia-Wei; Chi, Li-Ling; Chen, Pen-Yuan; Chiu, Chun-Jung; Huang, Chung-Yang; Chen, Chia-Nan

    2010-05-01

    Liverwort constituents have been reported to exert a broad spectrum of biological activities. In this study, we used a bioactivity-guided separation of an extract from the liverwort species Marchantia emarginata subsp. tosana to determine its anticancer activity. A high level of the active ingredient was isolated from this liverwort and its chemical structure was identified and characterized by various spectra. It was found to be identical to a well-known compound, marchantin A, a cyclic bisbibenzyl ether. However, no anticancer activities of this compound have previously been reported. We found that marchantin A efficiently induced cell growth inhibition in human MCF-7 breast cancer cells, with an IC(50) of 4.0microg/mL. Fluorescence microscopy and a Western blot analysis indicated that marchantin A actively induced apoptosis of MCF-7 cells. The levels of cleaved caspase-8, cleaved caspase-3, cleaved caspase-9, and cleaved poly (ADP ribose) polymerase (PARP) increased. However, the level of Bid markedly decreased in a dose- and time-dependent manner. We also evaluated the anticancer activities of marchantin A on the regulation of cell cycle regulators such as p21, p27, cyclin B1, and cyclin D1. The p21 and p27 gene expressions increased markedly while cyclin B1 and D1 gene expression decreased markedly by treatment with marchantin A. Many report demonstrated that liverwort was suggested to possess potent antioxidant activity. Our results indicate that marchantin A possesses free radical-scavenging activity (EC(50)=20microg/mL). Taken together, for the first time, the compound marchantin A from liverworts demonstrated to be a potent inducer of apoptosis in MCF-7 cells.

  4. Marchantin A, a macrocyclic bisbibenzyl ether, isolated from the liverwort Marchantia polymorpha, inhibits protozoal growth in vitro.

    PubMed

    Jensen, Sophie; Omarsdottir, Sesselja; Bwalya, Angela Gono; Nielsen, Morten Agertoug; Tasdemir, Deniz; Olafsdottir, Elin Soffia

    2012-10-15

    In vitro anti-plasmodial activity-guided fractionation of a diethyl ether extract of the liverwort species Marchantia polymorpha, collected in Iceland, led to isolation of the bisbibenzyl ether, marchantin A. The structure of marchantin A (1) was confirmed by NMR and HREIMS. Marchantin A inhibited proliferation of the Plasmodium falciparum strains, NF54 (IC(50)=3.41μM) and K1 (IC(50)=2.02μM) and showed activity against other protozoan species Trypanosoma brucei rhodesiense, T. cruzi and Leishmania donovani with IC(50) values 2.09, 14.90 and 1.59μM, respectively. Marchantin A was tested against three recombinant enzymes (PfFabI, PfFabG and PfFabZ) of the PfFAS-II pathway of P. falciparum for malaria prophylactic potential and showed moderate inhibitory activity against PfFabZ (IC(50)=18.18μM). In addition the cytotoxic effect of marchantin A was evaluated. This is the first report describing the inhibitory effects of the liverwort metabolite marchantin A against these parasites in vitro. Copyright © 2012 Elsevier GmbH. All rights reserved.

  5. Dihydroptychantol A, a macrocyclic bisbibenzyl derivative, induces autophagy and following apoptosis associated with p53 pathway in human osteosarcoma U2OS cells

    SciTech Connect

    Li Xia; Wu, William K.K.; Sun Bin; Cui Min; Liu Shanshan; Gao Jian; Lou Hongxiang

    2011-03-01

    Dihydroptychantol A (DHA), a novel macrocyclic bisbibenzyl compound extracted from liverwort Asterella angusta, has antifungal and multi-drug resistance reversal properties. Here, the chemically synthesized DHA was employed to test its anti-cancer activities in human osteosarcoma U2OS cells. Our results demonstrated that DHA induced autophagy followed by apoptotic cell death accompanied with G{sub 2}/M-phase cell cycle arrest in U2OS cells. DHA-induced autophagy was morphologically characterized by the formation of double membrane-bound autophagic vacuoles recognizable at the ultrastructural level. DHA also increased the levels of LC3-II, a marker of autophagy. Surprisingly, DHA-mediated apoptotic cell death was potentiated by the autophagy inhibitor 3-methyladenine, suggesting that autophagy may play a protective role that impedes the eventual cell death. Furthermore, p53 was shown to be involved in DHA-meditated autophagy and apoptosis. In this connection, DHA increased nuclear expression of p53, induced p53 phosphorylation, and upregulated p53 target gene p21{sup Waf1/Cip1}. In contrast, cytoplasmic p53 was reduced by DHA, which contributed to the stimulation of autophagy. In relation to the cell cycle, DHA decreased the expression of cyclin B{sub 1}, a cyclin required for progression through the G{sub 2}/M phase. Taken together, DHA induces G{sub 2}/M-phase cell cycle arrest and apoptosis in U2OS cells. DHA-induced apoptosis was preceded by the induction of protective autophagy. DHA-mediated autophagy and apoptosis are associated with the cytoplasmic and nuclear functions of p53.

  6. Vasorelaxant effects of macrocyclic bis(bibenzyls) from liverworts.

    PubMed

    Morita, Hiroshi; Zaima, Kazumasa; Koga, Ikumi; Saito, Aiko; Tamamoto, Haruka; Okazaki, Hiroki; Kaneda, Toshio; Hashimoto, Toshihiro; Asakawa, Yoshinori

    2011-07-01

    Vasorelaxant effects of a series of bis(bibenzyls) from liverworts such as Marchantia polymorpha and Marchantia paleacea on rat aorta demonstrated that they relaxed phenylephrine (PE)-induced contractions, which may be mediated through the increased release of NO from endothelial cells as well as opening of K(+) channels, and inhibition of Ca(2+) influx through voltage-dependent Ca(2+) channels (VDCs) and/or receptor-operated Ca(2+) channels (ROCs). Structure-activity relationship based on their structures was discussed. The presence of two aromatic rings which can be connected through two atoms bridge spacer may play an important role for vasorelaxant effect.

  7. Overcoming of P-glycoprotein-mediated multidrug resistance in K562/A02 cells using riccardin F and pakyonol, bisbibenzyl derivatives from liverworts.

    PubMed

    Ji, Mei; Shi, Yanquiu; Lou, Hongxiang

    2011-01-01

    Riccardin F and pakyonol, macrocyclic bisbibenzyls from Plagiochasm intermedium, have been confirmed to possess antifungic activities against Candida albicans. Herein, we evaluated their anti-tumor activity in vitro by employing K562 and K562/A02 cells, the well-known adriamycin (ADR)-induced multidrug resistance (MDR) tumor cell lines over-expressing P-glycoprotein (P-gp). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assays showed that riccardin F and pakyonol ranging from 0 to 6 μg/mL exhibited no inhibitory effects on the growth of the two cell lines. However, in the presence of 3 μg/mL riccardin F or pakyonol (non-cytotoxic concentration), the IC50 of ADR against K562/A02 cells decreased by 2.51- and 4.78-fold, respectively. Flow cytometry showed that riccardin F and pakyonol significantly enhanced the accumulation of ADR in K562/A02 cells. Furthermore, fluorescence intensity detection revealed that the two natural products remarkably increased the retention of rhodamine-123 in K562/A02 cells rather than in K562 cells, indicating that the major cause for riccardin F and pakyonol to reverse P-gp-mediated MDR in K562/A02 cells is probably due to the constrained transport activity of P-gp. This study explores the potential application of bisbibenzyl type compounds as modulators of P-gp-mediated MDR in tumor cells.

  8. Activity-guided isolation of cytotoxic bis-bibenzyl constituents from Dumortiera hirsuta.

    PubMed

    Toyota, Masao; Ikeda, Risa; Kenmoku, Hiromichi; Asakawa, Yoshinori

    2013-01-01

    Activity-guided fractionation of the ether extract of Dumortiera hirsute (Japanese liverwort), using cytotoxicity testing with cultured HL 60 and KB cells, resulted in the isolation of a new cytotoxic bis-bibenzyl compound, along with the two known bis-bibenzyls: isomarchantin C and isoriccardin C. The structural determination of the new bis-bibenzyl through extensive NMR spectral data indicated a derivative of marchantin A, which has been isolated from the liverwort Marchantia polymorpha. The cytotoxicity of the bis-bibenzyls was evaluated by the MTT (3-(4,5-di-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay using cultured HL 60 and KB cells.

  9. Bi- and bisbibenzyls from the roots of Dichapetalum heudelotii and their antiproliferative activities.

    PubMed

    Osei-Safo, Dorcas; Dziwornu, Godwin Akpeko; Salgado, Antonio; Sunassee, Suthananda Naidu; Chama, Mary Anti

    2017-10-01

    Two new bisbibenzyls, heudelotol A (1) and B (2), along with the known bibenzyls, (E)-combretastatin A-1 (3) and combretastatin B-1 (4) have been isolated from the ethyl acetate extract of the roots of Dichapetalum heudelotii. Structure elucidation of all four isolated compounds was achieved using UV, IR, 1D and 2D NMR spectroscopy and HR-Mass Spectrometry. The compounds exhibited varying antiproliferative activity against six cancer cell lines using the CellTiter-Glo® Luminiscent Cell Viability Assay. Compound 3 was found to be the most active with sub-micromolar growth inhibition concentrations against all the cell lines (GI50 0.03-0.72μM). However, it was about ten-fold less active than the positive control, taxol. The new bisbibenzyls heudelotol A and B exhibited good activity against human pancreatic adenocarcinoma (GI50 9.04μM) and Burkitt's lymphoma (GI50 4.67μM) respectively, and average activity against the other cancer cell lines. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Stereochemistry of isoplagiochin C, a macrocyclic bisbibenzyl from liverworts.

    PubMed

    Bringmann, Gerhard; Mühlbacher, Jörg; Reichert, Matthias; Dreyer, Michael; Kolz, Jürgen; Speicher, Andreas

    2004-08-04

    Cyclic bisbibenzyls, like isoplagiochins C (1) and D (2), are stereochemically intriguing molecules: Although not equipped with any of the traditional stereogenic elements that render molecules conformationally stable per se, they are sometimes isolated in an optically active form and are thus chiral at room temperature. The paper describes quantum chemical calculations, in particular investigations of the conformational space and molecular dynamics simulations, showing that the helicity is a property of the entire molecule, whose ring strain makes the molecule configurationally stable overall, with (formally) three stereogenic elements (two biaryl axes and one helical stilbene unit). Only one of the biaryl axes (the 'upper' one, joining C-12' and C-14) has a stable configuration, leading to a population of four interconverting diastereomers, yet without racemization at room temperature. On the basis of these conformational and dynamic calculations, the circular dichroism spectrum of isoplagiochin C (1) was calculated, leading to the first assignment of the absolute configuration of a cyclic bisbibenzyl. Accordingly, 1 has the P-configuration at the stereochemically stable biaryl axis and constitutes a mixture of diastereomers with respect to the other biaryl axis and the helical stilbene unit. From the temperature dependence of the racemization rates, an enantiomerization barrier of 101.6 kJ/mol was determined. Likewise, for the first time for cyclic bisbibenzyls, the enantiomeric ratio of this natural product was determined, by chromatography on a chiral phase with CD-coupling. Accordingly, 1 from Plagiochila deflexa is not enantiomerically pure, but occurs in a 85:15 ratio in favor of the enantiomer that has the P-configuration at the stereochemically stable axis.

  11. Structure-anti-MRSA activity relationship of macrocyclic bis(bibenzyl) derivatives.

    PubMed

    Sawada, Hiromi; Onoda, Kenji; Morita, Daichi; Ishitsubo, Erika; Matsuno, Kenji; Tokiwa, Hiroaki; Kuroda, Teruo; Miyachi, Hiroyuki

    2013-12-15

    We synthesized a series of macrocyclic bis(bibenzyl) derivatives, including riccardin-, isoplagiochin- and marchantin-class structures, and evaluated their antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity). The structure-activity relationships and the results of molecular dynamics simulations indicated that bis(bibenzyl)s with potent anti-MRSA activity commonly have a 4-hydroxyl group at the D-benzene ring and a 2-hydroxyl group at the C-benzene ring in the hydrophilic part of the molecule, and an unsubstituted phenoxyphenyl group in the hydrophobic part of the molecule containing the A-B-benzene rings. Pharmacological characterization of the bis(bibenzyl) derivatives and 2-phenoxyphenol fragment 25, previously proposed as the minimum structure of riccardin C 1 for anti-MRSA activity, indicated that they have different action mechanisms: the bis(bibenzyl)s are bactericidal, while 25 is bacteriostatic, showing only weak bactericidal activity. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Anti-influenza activity of marchantins, macrocyclic bisbibenzyls contained in liverworts.

    PubMed

    Iwai, Yuma; Murakami, Kouki; Gomi, Yasuyuki; Hashimoto, Toshihiro; Asakawa, Yoshinori; Okuno, Yoshinobu; Ishikawa, Toyokazu; Hatakeyama, Dai; Echigo, Noriko; Kuzuhara, Takashi

    2011-01-01

    The H1N1 influenza A virus of swine-origin caused pandemics throughout the world in 2009 and the highly pathogenic H5N1 avian influenza virus has also caused epidemics in Southeast Asia in recent years. The threat of influenza A thus remains a serious global health issue and novel drugs that target these viruses are highly desirable. Influenza A possesses an endonuclease within its RNA polymerase which comprises PA, PB1 and PB2 subunits. To identify potential new anti-influenza compounds in our current study, we screened 33 different types of phytochemicals using a PA endonuclease inhibition assay in vitro and an anti-influenza A virus assay. The marchantins are macrocyclic bisbibenzyls found in liverworts, and plagiochin A and perrottetin F are marchantin-related phytochemicals. We found from our screen that marchantin A, B, E, plagiochin A and perrottetin F inhibit influenza PA endonuclease activity in vitro. These compounds have a 3,4-dihydroxyphenethyl group in common, indicating the importance of this moiety for the inhibition of PA endonuclease. Docking simulations of marchantin E with PA endonuclease suggest a putative "fitting and chelating model" as the mechanism underlying PA endonuclease inhibition. The docking amino acids are well conserved between influenza A and B. In a cultured cell system, marchantin E was further found to inhibit the growth of both H3N2 and H1N1 influenza A viruses, and marchantin A, E and perrotein F showed inhibitory properties towards the growth of influenza B. These marchantins also decreased the viral infectivity titer, with marchantin E showing the strongest activity in this assay. We additionally identified a chemical group that is conserved among different anti-influenza chemicals including marchantins, green tea catechins and dihydroxy phenethylphenylphthalimides. Our present results indicate that marchantins are candidate anti-influenza drugs and demonstrate the utility of the PA endonuclease assay in the screening of

  13. Design, synthesis and biological evaluation of nitrogen-containing macrocyclic bisbibenzyl derivatives as potent anticancer agents by targeting the lysosome.

    PubMed

    Sun, Bin; Liu, Jun; Gao, Yun; Zheng, Hong-Bo; Li, Lin; Hu, Qing-Wen; Yuan, Hui-Qing; Lou, Hong-Xiang

    2017-08-18

    A series of novel nitrogen-containing macrocyclic bisbibenzyl derivatives was designed, synthesized, and evaluated for antiproliferative activity against three anthropic cancer cell lines. Among these novel molecules, the tri-O-alkylated compound 18a displayed the most potent anticancer activity against the A549, MCF-7, and k562 cancer cell lines, with IC50 values of 0.51, 0.23, and 0.19 μM, respectively, which were obviously superior to those of the parent compound riccardin D, and were 3-10-fold better than those of the clinical used drug ADR. The bis-Mannich derivative 11b also exhibited significantly enhanced antiproliferative potency, with submicromolar IC50 values. Structure-activity relationship analyses of these newly synthesized compounds were also performed. Mechanistic studies indicated that these compounds could target the lysosome to induce lysosomal membrane permeabilization, and could also induce cell death that displayed features characteristic of both apoptosis and necrosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  14. Study of bis(bibenzyls) in bryophytes using electron ionization time-of-flight and electrospray ionization triple-quadrupole mass spectrometry.

    PubMed

    Guo, Huaifang; Xing, Jie; Xie, Chunfeng; Qu, Jianbo; Gao, Yanhui; Lou, Hongxiang

    2007-01-01

    A detailed analysis of mass spectra generated from bis(bibenzyl) compounds in bryophytes under electron ionization time-of-flight (EI-TOF) and electrospray ionization triple-quadrupole (ESI-TQ) mass spectrometry conditions is reported. Proposed structures of the fragment ions were obtained by tracking the functional groups of 15 bis(bibenzyls), the structures of which are similar except for some alkoxyl substituents and linkage sites of biphenyl ether bonds. The elucidation was aided by the use of accurate mass measurements. Attempts have been made to provide rational pathways for the formation of these fragment ions, and a generalized fragmentation mechanism is proposed. The bis(bibenzyls) mentioned in this study include three types according to their structure characteristics, i.e. one biphenyl ether bond (A-type), two biphenyl ether bonds (B-type), one biphenyl ether and one biphenyl bond (C-type). The three types display different EI-MS and ESI-MS/MS product profiles, by which the bis(bibenzyl) type and the number of alkoxyl substituents can be identified. Isomers of bis(bibenzyls) can be differentiated to some extent, while the linkage sites of biphenyl ether bonds are difficult to identify. The structure-fragmentation relationships will facilitate the characterization of other bis(bibenzyls) and this will be of value for the high-throughput screening of novel bis(bibenzyls) in bryophytes.

  15. Anti-MRSA activity of isoplagiochin-type macrocyclic bis(bibenzyl)s is mediated through cell membrane damage.

    PubMed

    Onoda, Kenji; Sawada, Hiromi; Morita, Daichi; Fujii, Kana; Tokiwa, Hiroaki; Kuroda, Teruo; Miyachi, Hiroyuki

    2015-07-01

    We synthesized three geometrical isomers of a macrocyclic bis(bibenzyl) based on isoplagiochin, a natural product isolated from bryophytes, and evaluated their antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity). The isomer containing a 1,4-linked ring (5) showed only weak activity, whereas the isomers containing a 1,3-linked (6) or 1,2-linked (7) C ring showed potent anti-MRSA activity. Molecular dynamics calculations indicated that these differences are probably due to differences in the conformational flexibility of the macrocyclic ring; the active compounds 6 and 7 were more rigid than 5. In order to understand the action mechanism of anti-MRSA activity, we investigated the cellular flux of a fluorescent DNA-binder, ethidium bromide (EtBr), in the presence and absence of these macrocycles. The active compound 6 increased the levels of EtBr inflow and outflow in S. aureus cells, as did our potent anti-MRSA riccardin derivative (4), indicating that these compounds increased the permeability of the cytoplasmic membrane. Inactive 5 had no effect on EtBr inflow or outflow. Furthermore, compound 6 abrogated the normal intracellular concentration gradients of Na(+) and K(+) in S. aureus cells, increasing the intracellular Na(+) concentration and decreasing the K(+) concentration, while 5 had no such effect. These results indicate that anti-MRSA-active macrocyclic bis(bibenzyl) derivatives directly damage the gram-positive bacterial membrane, resulting in increased permeability. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Growth factor involvement in tension-induced skeletal muscle growth

    NASA Technical Reports Server (NTRS)

    Vandenburgh, Herman W.

    1987-01-01

    New muscle tissue culture techniques were developed to grow embryonic skeletal myofibers which are able to differentiate into more adultlike myofibers. Studies on mechanical simulation of cultured muscle cell growth will now be more directly applicable to mechanically-induced growth in adult muscle, and lead to better models for understanding muscle tissue atrophy caused by disuse in the microgravity of space.

  17. Growth factor involvement in tension-induced skeletal muscle growth

    NASA Technical Reports Server (NTRS)

    Vandenburgh, Herman H.

    1993-01-01

    Long-term manned space travel will require a better understanding of skeletal muscle atrophy which results from microgravity. Astronaut strength and dexterity must be maintained for normal mission operations and for emergency situations. Although exercise in space slows the rate of muscle loss, it does not prevent it. A biochemical understanding of how gravity/tension/exercise help to maintain muscle size by altering protein synthesis and/or degradation rate should ultimately allow pharmacological intervention to prevent muscle atrophy in microgravity. The overall objective is to examine some of the basic biochemical processes involved in tension-induced muscle growth. With an experimental in vitro system, the role of exogenous and endogenous muscle growth factors in mechanically stimulated muscle growth are examined. Differentiated avian skeletal myofibers can be 'exercised' in tissue culture using a newly developed dynamic mechanical cell stimulator device which simulates different muscle activity patterns. Patterns of mechanical activity which significantly affect muscle growth and metabolic characteristics were found. Both exogenous and endogenous growth factors are essential for tension-induced muscle growth. Exogenous growth factors found in serum, such as insulin, insulin-like growth factors, and steroids, are important regulators of muscle protein turnover rates and mechanically-induced muscle growth. Endogenous growth factors are synthesized and released into the culture medium when muscle cells are mechanically stimulated. At least one family of mechanically induced endogenous factors, the prostaglandins, help to regulate the rates of protein turnover in muscle cells. Endogenously synthesized IGF-1 is another. The interaction of muscle mechanical activity and these growth factors in the regulation of muscle protein turnover rates with our in vitro model system is studied.

  18. Growth factor involvement in tension-induced skeletal muscle growth

    NASA Technical Reports Server (NTRS)

    Vandenburgh, H. H.

    1987-01-01

    Muscle tissue culture techniques were developed to grow skeletal myofibers which differentiate into more adult-like myofibers. Mechanical simulation studies of these muscle cells in a newly developed mechanical cell simulator can now be performed to study growth processes in skeletal muscle. Conditions in the mechanical cell simulator were defined where mechanical activity can either prevent muscle wasting or stimulate muscle growth. The role of endogenous and exogenous growth factors in tension-induced muscle growth is being investigated under the defined conditions of tissue culture.

  19. Electron beam induced growth of tin whiskers

    SciTech Connect

    Vasko, A. C.; Karpov, V. G.; Warrell, G. R.; Parsai, E. I.; Shvydka, Diana

    2015-09-28

    We have investigated the influence of electron irradiation on tin whisker growth. Sputtered tin samples exposed to electron beam of 6 MeV energy exhibited fast whisker growth, while control samples did not grow any whiskers. The statistics of e-beam induced whiskers was found to follow the log-normal distribution. The observed accelerated whisker growth is attributed to electrostatic effects due to charges trapped in an insulating substrate. These results offer promise for establishing whisker-related accelerated life testing protocols.

  20. Growth Factors and Tension-Induced Skeletal Muscle Growth

    NASA Technical Reports Server (NTRS)

    Vandenburgh, Herman H.

    1994-01-01

    The project investigated biochemical mechanisms to enhance skeletal muscle growth, and developed a computer based mechanical cell stimulator system. The biochemicals investigated in this study were insulin/(Insulin like Growth Factor) IGF-1 and Steroids. In order to analyze which growth factors are essential for stretch-induced muscle growth in vitro, we developed a defined, serum-free medium in which the differentiated, cultured avian muscle fibers could be maintained for extended periods of time. The defined medium (muscle maintenance medium, MM medium) maintains the nitrogen balance of the myofibers for 3 to 7 days, based on myofiber diameter measurements and myosin heavy chain content. Insulin and IGF-1, but not IGF-2, induced pronounced myofiber hypertrophy when added to this medium. In 5 to 7 days, muscle fiber diameters increase by 71 % to 98% compared to untreated controls. Mechanical stimulation of the avian muscle fibers in MM medium increased the sensitivity of the cells to insulin and IGF-1, based on a leftward shift of the insulin dose/response curve for protein synthesis rates. (54). We developed a ligand binding assay for IGF-1 binding proteins and found that the avian skeletal muscle cultures produced three major species of 31, 36 and 43 kD molecular weight (54) Stretch of the myofibers was found to have no significant effect on the efflux of IGF-1 binding proteins, but addition of exogenous collagen stimulated IGF-1 binding protein production 1.5 to 5 fold. Steroid hormones have a profound effect on muscle protein turnover rates in vivo, with the stress-related glucocorticoids inducing rapid skeletal muscle atrophy while androgenic steroids induce skeletal muscle growth. Exercise in humans and animals reduces the catabolic effects of glucocorticoids and may enhance the anabolic effects of androgenic steroids on skeletal muscle. In our continuing work on the involvement of exogenrus growth factors in stretch-induced avian skeletal muscle growth, we

  1. Laser-induced crystallization and crystal growth.

    PubMed

    Sugiyama, Teruki; Masuhara, Hiroshi

    2011-11-04

    Recent streams of laser studies on crystallization and crystal growth are summarized and reviewed. Femtosecond multiphoton excitation of solutions leads to their ablation at the focal point, inducing local bubble formation, shockwave propagation, and convection flow. This phenomenon, called "laser micro tsunami" makes it possible to trigger crystallization of molecules and proteins from their supersaturated solutions. Femtosecond laser ablation of a urea crystal in solution triggers the additional growth of a single daughter crystal. Intense continuous wave (CW) near infrared laser irradiation at the air/solution interface of heavy-water amino acid solutions results in trapping of the clusters and evolves to crystallization. A single crystal is always prepared in a spatially and temporally controlled manner, and the crystal polymorph of glycine depends on laser power, polarization, and solution concentration. Upon irradiation at the glass/solution interface, a millimeter-sized droplet is formed, and a single crystal is formed by shifting the irradiation position to the surface. Directional and selective crystal growth is also possible with laser trapping. Finally, characteristics of laser-induced crystallization and crystal growth are summarized.

  2. Origin of growth-induced water potential

    SciTech Connect

    Nonami, H.; Boyer, J.S.

    1987-03-01

    The authors developed a new method to measure the solute concentration in the apoplast of stem tissue involving pressurizing the roots of intact seedlings (Glycine max (L.) Merr. or Pisum sativum L.), collecting a small amount of exudate from the surface of the stem under saturating humidities, and determining the osmotic potential of the solution with a micro-osmometer capable of measuring small volumes (0.5 microliter). In the elongating region, the apoplast concentrations were very low (equivalent to osmotic potentials of -0.03 to -0.04 megapascal) and negligible compared to the water potential of the apoplast (-0.15 to -0.30 megapascal) measured directly by isopiestic psychrometry in intact plants. Most of the apoplast water potential consisted of a negative pressure that could be measured with a pressure chamber (-0.15 to -0.28 megapascal). Tests showed that earlier methods involving infiltration of intercellular spaces or pressurizing cut segments caused solute to be released to the apoplast and resulted in spuriously high concentrations. These results indicate that, although a small amount of solute is present in the apoplast, the major component is a tension that is part of a growth-induced gradient in water potential in the enlarging tissue. The gradient originates from the extension of the cell walls, which prevents turgor from reaching its maximum and creates a growth-induced water potential that causes water to move from the xylem at a rate that satisfies the rate of enlargement. The magnitude of the gradient implies that growing tissue contains a large resistance to water movement.

  3. Nutritionally-Induced Catch-Up Growth

    PubMed Central

    Gat-Yablonski, Galia; Phillip, Moshe

    2015-01-01

    Malnutrition is considered a leading cause of growth attenuation in children. When food is replenished, spontaneous catch-up (CU) growth usually occurs, bringing the child back to its original growth trajectory. However, in some cases, the CU growth is not complete, leading to a permanent growth deficit. This review summarizes our current knowledge regarding the mechanism regulating nutrition and growth, including systemic factors, such as insulin, growth hormone, insulin- like growth factor-1, vitamin D, fibroblast growth factor-21, etc., and local mechanisms, including autophagy, as well as regulators of transcription, protein synthesis, miRNAs and epigenetics. Studying the molecular mechanisms regulating CU growth may lead to the establishment of better nutritional and therapeutic regimens for more effective CU growth in children with malnutrition and growth abnormalities. It will be fascinating to follow this research in the coming years and to translate the knowledge gained to clinical benefit. PMID:25594438

  4. Neurohumoral mediation of exercise-induced growth.

    PubMed

    Borer, K T

    1994-06-01

    To assess exercise effects on growth, other variables modulating growth need to be taken into account. Endogenous control of growth proceeds from local actions of growth factors and dependence on nutrition abundance through guidance by growth hormone (GH) and other anabolic hormones to neuroendocrine suppression of growth. Nutrient abundance controls the reparative growth of lean body mass in adulthood by coupling it to anabolic endocrine reflexes. Growth is blocked when catabolic endocrine reflexes govern energy expenditure. The relationship between exercise intensity and growth is nonlinear. Growth is an intermittent process. Its expression and stimulation are dependent on ultradian and circadian rhythms of energy metabolism and neurohumoral release. High-resistance exercise selectively stimulates growth of the musculoskeletal system through expression of growth factor genes in the challenged tissues and without the GH guidance or abundant nutritional support. Habitual endurance exercise stimulates reparative growth of lean body mass through the neuroendocrine adaptations including increased pulsatile GH secretion. These also facilitate oxidative utilization of storage lipids thereby contributing to the regulation of body composition in adulthood. In the absence of sufficient high-resistance and endurance exercise regulation of adult body mass is impaired: excess LBM is lost during energy deficit, and excess fat accumulates during energy surplus.

  5. CSR-induced emittance growth in achromats: Linear formalism revisited

    NASA Astrophysics Data System (ADS)

    Venturini, M.

    2015-09-01

    We review the R-matrix formalism used to describe Coherent Synchrotron Radiation (CSR)-induced projected emittance growth in electron beam transport lines and establish the connection with a description in terms of the dispersion-invariant function.

  6. Decreased growth-induced water potential: A primary cause of growth inhibition at low water potentials

    SciTech Connect

    Nonami, Hiroshi; Wu, Yajun; Boyer, J.S.

    1997-06-01

    Cell enlargement depends on a growth-induced difference in water potential to move water into the cells. Water deficits decrease this potential difference and inhibit growth. To investigate whether the decrease causes the growth inhibition, pressure was applied to the roots of soybean seedlings and the growth and potential difference were monitored in the stems. In water-limited plants, the inhibited stem growth increased when the roots were pressurized and it reverted to the previous rate when the pressure was released. The pressure around the roots was perceived as an increased turgor in the stem in small cells next to the xylem, but not in outlying cortical cells. This local effect implied that water transport was impeded by the small cells. The diffusivity for water was much less in the small cells than in the outlying cells. The small cells thus were a barrier that caused the growth-induced potential difference to be large during rapid growth, but to reverse locally during the early part of a water deficit. Such a barrier may be a frequent property of meristems. Because stem growth responded to the pressure-induced recovery of the potential difference across this barrier, we conclude that a decrease in the growth-induced potential difference was a primary cause of the inhibition.

  7. Selective fishing induces density-dependent growth

    PubMed Central

    Svedäng, Henrik; Hornborg, Sara

    2014-01-01

    Over the last decades, views on fisheries management have oscillated between alarm and trust in management progress. The predominant policy for remedying the world fishing crisis aims at maximum sustainable yield (MSY) by adjusting gear selectivity and fishing effort. Here we report a case study on how striving for higher yields from the Eastern Baltic cod stock by increasing selectivity has become exceedingly detrimental for its productivity. Although there is a successive increase in numbers of undersized fish, growth potential is severely reduced, and fishing mortality in fishable size has increased. Once density-dependent growth is introduced, the process is self-enforcing as long as the recruitment remains stable. Our findings suggest that policies focusing on maximum yield while targeting greater sizes are risky and should instead prioritize catch rates over yield. Disregarding the underlying population structure may jeopardize stock productivity, with dire consequences for the fishing industry and ecosystem structure and function. PMID:24920387

  8. Selective fishing induces density-dependent growth.

    PubMed

    Svedäng, Henrik; Hornborg, Sara

    2014-06-12

    Over the last decades, views on fisheries management have oscillated between alarm and trust in management progress. The predominant policy for remedying the world fishing crisis aims at maximum sustainable yield (MSY) by adjusting gear selectivity and fishing effort. Here we report a case study on how striving for higher yields from the Eastern Baltic cod stock by increasing selectivity has become exceedingly detrimental for its productivity. Although there is a successive increase in numbers of undersized fish, growth potential is severely reduced, and fishing mortality in fishable size has increased. Once density-dependent growth is introduced, the process is self-enforcing as long as the recruitment remains stable. Our findings suggest that policies focusing on maximum yield while targeting greater sizes are risky and should instead prioritize catch rates over yield. Disregarding the underlying population structure may jeopardize stock productivity, with dire consequences for the fishing industry and ecosystem structure and function.

  9. Growth-Induced Instability in Metabolic Networks

    SciTech Connect

    Goyal, Sidhartha; Wingreen, Ned S.

    2007-03-30

    Product-feedback inhibition is a ubiquitous regulatory scheme for maintaining homeostasis in living cells. Individual metabolic pathways with product-feedback inhibition are stable as long as one pathway step is rate limiting. However, pathways are often coupled both by the use of a common substrate and by stoichiometric utilization of their products for cell growth. We show that such a coupled network with product-feedback inhibition may exhibit limit-cycle oscillations which arise via a Hopf bifurcation. Our results highlight novel evolutionary constraints on the architecture of metabolism.

  10. Autophagy contributes to gefitinib-induced glioma cell growth inhibition

    SciTech Connect

    Chang, Cheng-Yi; Kuan, Yu-Hsiang; Ou, Yen-Chuan; Li, Jian-Ri; Wu, Chih-Cheng; Pan, Pin-Ho; Chen, Wen-Ying; Huang, Hsuan-Yi; Chen, Chun-Jung

    2014-09-10

    Epidermal growth factor receptor tyrosine kinase inhibitors, including gefitinib, have been evaluated in patients with malignant gliomas. However, the molecular mechanisms involved in gefitinib-mediated anticancer effects against glioma are incompletely understood. In the present study, the cytostatic potential of gefitinib was demonstrated by the inhibition of glioma cell growth, long-term clonogenic survival, and xenograft tumor growth. The cytostatic consequences were accompanied by autophagy, as evidenced by monodansylcadaverine staining of acidic vesicle formation, conversion of microtubule-associated protein-1 light chain 3-II (LC3-II), degradation of p62, punctate pattern of GFP-LC3, and conversion of GFP-LC3 to cleaved-GFP. Autophagy inhibitor 3-methyladenosine and chloroquine and genetic silencing of LC3 or Beclin 1 attenuated gefitinib-induced growth inhibition. Gefitinib-induced autophagy was not accompanied by the disruption of the Akt/mammalian target of rapamycin signaling. Instead, the activation of liver kinase-B1/AMP-activated protein kinase (AMPK) signaling correlated well with the induction of autophagy and growth inhibition caused by gefitinib. Silencing of AMPK suppressed gefitinib-induced autophagy and growth inhibition. The crucial role of AMPK activation in inducing glioma autophagy and growth inhibition was further supported by the actions of AMP mimetic AICAR. Gefitinib was shown to be capable of reducing the proliferation of glioma cells, presumably by autophagic mechanisms involving AMPK activation. - Highlights: • Gefitinib causes cytotoxic and cytostatic effect on glioma. • Gefitinib induces autophagy. • Gefitinib causes cytostatic effect through autophagy. • Gefitinib induces autophagy involving AMPK.

  11. Computational aspects of growth-induced instabilities through eigenvalue analysis

    NASA Astrophysics Data System (ADS)

    Javili, A.; Dortdivanlioglu, B.; Kuhl, E.; Linder, C.

    2015-09-01

    The objective of this contribution is to establish a computational framework to study growth-induced instabilities. The common approach towards growth-induced instabilities is to decompose the deformation multiplicatively into its growth and elastic part. Recently, this concept has been employed in computations of growing continua and has proven to be extremely useful to better understand the material behavior under growth. While finite element simulations seem to be capable of predicting the behavior of growing continua, they often cannot naturally capture the instabilities caused by growth. The accepted strategy to provoke growth-induced instabilities is therefore to perturb the solution of the problem, which indeed results in geometric instabilities in the form of wrinkles and folds. However, this strategy is intrinsically subjective as the user is prescribing the perturbations and the simulations are often highly perturbation-dependent. We propose a different strategy that is inherently suitable for this problem, namely eigenvalue analysis. The main advantages of eigenvalue analysis are that first, no arbitrary, artificial perturbations are needed and second, it is, in general, independent of the time step size. Therefore, the solution obtained by this methodology is not subjective and thus, is generic and reproducible. Equipped with eigenvalue analysis, we are able to compute precisely the critical growth to initiate instabilities. Furthermore, this strategy allows us to compare different finite elements for this family of problems. Our results demonstrate that linear elements perform strikingly poorly, as compared to quadratic elements.

  12. Mechanically induced alterations in cultured skeletal muscle growth

    NASA Technical Reports Server (NTRS)

    Vandenburgh, H. H.; Hatfaludy, S.; Karlisch, P.; Shansky, J.

    1991-01-01

    Model systems are available for mechanically stimulating cultured skeletal muscle cells by passive tensile forces which simulate those found in vivo. When applied to embryonic muscle cells in vitro these forces induce tissue organogenesis, metabolic adaptations, and muscle cell growth. The mechanical stimulation of muscle cell growth correlates with stretch-induced increases in the efflux of prostaglandins PGE2 and PGF2(alpha) in a time and frequency dependent manner. These prostaglandins act as mechanical 'second messengers' regulating skeletal muscle protein turnover rates. Since they also effect bone remodelling in response to tissue loading and unloading, secreted prostaglandins may serve as paracrine growth factors, coordinating the growth rates of muscle and bone in response to external mechanical forces. Cell culture model systems will supplement other models in understanding mechanical transduction processes at the molecular level.

  13. Mechanically induced alterations in cultured skeletal muscle growth

    NASA Technical Reports Server (NTRS)

    Vandenburgh, H. H.; Hatfaludy, S.; Karlisch, P.; Shansky, J.

    1991-01-01

    Model systems are available for mechanically stimulating cultured skeletal muscle cells by passive tensile forces which simulate those found in vivo. When applied to embryonic muscle cells in vitro these forces induce tissue organogenesis, metabolic adaptations, and muscle cell growth. The mechanical stimulation of muscle cell growth correlates with stretch-induced increases in the efflux of prostaglandins PGE2 and PGF2(alpha) in a time and frequency dependent manner. These prostaglandins act as mechanical 'second messengers' regulating skeletal muscle protein turnover rates. Since they also effect bone remodelling in response to tissue loading and unloading, secreted prostaglandins may serve as paracrine growth factors, coordinating the growth rates of muscle and bone in response to external mechanical forces. Cell culture model systems will supplement other models in understanding mechanical transduction processes at the molecular level.

  14. Different growth rates for catalyst-induced and self-induced GaN nanowires

    NASA Astrophysics Data System (ADS)

    Chèze, C.; Geelhaar, L.; Jenichen, B.; Riechert, H.

    2010-10-01

    The catalyst- and self-induced pathways of GaN nanowire growth by molecular beam epitaxy are compared. The catalyst-induced nanowires elongate faster than the self-induced ones and their growth rate is fully determined by the impinging N rate. The self-induced nanowire growth rate is identical on both Si(111) and Si(001) and approaches the impinging N rate only for the few longest nanowires. This difference is attributed to the presence of the Ni-catalyst which enhances the incorporation of Ga at the nanowire tip while for the self-induced nanowires, growth is limited by the different incorporation rates on the nanowire tip and sidewall facets.

  15. Growth Hormone Improves Growth Retardation Induced by Rapamycin without Blocking Its Antiproliferative and Antiangiogenic Effects on Rat Growth Plate

    PubMed Central

    Álvarez-García, Óscar; García-López, Enrique; Loredo, Vanessa; Gil-Peña, Helena; Mejía-Gaviria, Natalia; Rodríguez-Suárez, Julián; Ordóñez, Flor Á.; Santos, Fernando

    2012-01-01

    Rapamycin, an immunosuppressant agent used in renal transplantation with antitumoral properties, has been reported to impair longitudinal growth in young individuals. As growth hormone (GH) can be used to treat growth retardation in transplanted children, we aimed this study to find out the effect of GH therapy in a model of young rat with growth retardation induced by rapamycin administration. Three groups of 4-week-old rats treated with vehicle (C), daily injections of rapamycin alone (RAPA) or in combination with GH (RGH) at pharmacological doses for 1 week were compared. GH treatment caused a 20% increase in both growth velocity and body length in RGH animals when compared with RAPA group. GH treatment did not increase circulating levels of insulin-like growth factor I, a systemic mediator of GH actions. Instead, GH promoted the maturation and hypertrophy of growth plate chondrocytes, an effect likely related to AKT and ERK1/2 mediated inactivation of GSK3β, increase of glycogen deposits and stabilization of β-catenin. Interestingly, GH did not interfere with the antiproliferative and antiangiogenic activities of rapamycin in the growth plate and did not cause changes in chondrocyte autophagy markers. In summary, these findings indicate that GH administration improves longitudinal growth in rapamycin-treated rats by specifically acting on the process of growth plate chondrocyte hypertrophy but not by counteracting the effects of rapamycin on proliferation and angiogenesis. PMID:22493717

  16. Growth hormone improves growth retardation induced by rapamycin without blocking its antiproliferative and antiangiogenic effects on rat growth plate.

    PubMed

    Álvarez-García, Óscar; García-López, Enrique; Loredo, Vanessa; Gil-Peña, Helena; Mejía-Gaviria, Natalia; Rodríguez-Suárez, Julián; Ordóñez, Flor Á; Santos, Fernando

    2012-01-01

    Rapamycin, an immunosuppressant agent used in renal transplantation with antitumoral properties, has been reported to impair longitudinal growth in young individuals. As growth hormone (GH) can be used to treat growth retardation in transplanted children, we aimed this study to find out the effect of GH therapy in a model of young rat with growth retardation induced by rapamycin administration. Three groups of 4-week-old rats treated with vehicle (C), daily injections of rapamycin alone (RAPA) or in combination with GH (RGH) at pharmacological doses for 1 week were compared. GH treatment caused a 20% increase in both growth velocity and body length in RGH animals when compared with RAPA group. GH treatment did not increase circulating levels of insulin-like growth factor I, a systemic mediator of GH actions. Instead, GH promoted the maturation and hypertrophy of growth plate chondrocytes, an effect likely related to AKT and ERK1/2 mediated inactivation of GSK3β, increase of glycogen deposits and stabilization of β-catenin. Interestingly, GH did not interfere with the antiproliferative and antiangiogenic activities of rapamycin in the growth plate and did not cause changes in chondrocyte autophagy markers. In summary, these findings indicate that GH administration improves longitudinal growth in rapamycin-treated rats by specifically acting on the process of growth plate chondrocyte hypertrophy but not by counteracting the effects of rapamycin on proliferation and angiogenesis.

  17. Ion beam-induced interfacial growth in Si and silicides

    NASA Astrophysics Data System (ADS)

    Fortuna, F.; Nédellec, P.; Ruault, M. O.; Bernas, H.; Lin, X. W.; Boucaud, P.

    1995-12-01

    We review the mechanisms and consequences of ion beam-induced epitaxial crystallization (IBIEC) in the transition metal- or rare earth-implanted {aSi}/{cSi} systems, as determined from in situ transmission electron microscopy (TEM) during irradiation, combined with channeling, high resolution TEM and optical measurements. IBIEC experiments on nm-size crystals confirm previously measured low values of interface roughness in IBIEC. We have performed interfacial growth simulations which indicate that the IBIEC process is, in fact, interface roughness-limited. They also suggest that interfacial growth processes are similar in several respects to surface growth processes, and that they largely determine (i) the growth habit of silicide precipitation, which is dominated by the interfacial energy, (ii) the possibility of trapping a large fraction of the impurities in non-equilibrium sites, leading to significant supersaturation. A consequence of this effect is to allow incorporation of large (over 300-fold supersaturation) Er concentrations in the substitutional sites of the Si lattice, leading to room-temperature photoluminescence (without any oxygen co-implantation). Evidence of a new, thermally induced instability in interfacial growth is presented: it displays both intermittency and very high growth rates, and is strongly affected by ion irradiation.

  18. Nutrition-induced catch-up growth increases hypoxia inducible factor 1alpha RNA levels in the growth plate.

    PubMed

    Even-Zohar, N; Jacob, J; Amariglio, N; Rechavi, G; Potievsky, O; Phillip, M; Gat-Yablonski, G

    2008-03-01

    Although catch-up growth is a well-known phenomenon, the local pathways at the epiphyseal growth plate that govern this process remain poorly understood. To study the mechanisms governing catch-up growth in the growth plate, we subjected prepubertal rats to 10 days of 40% food restriction, followed by a renewal of the regular food supply to induce catch-up growth. The animals were weighed daily, and their humeral length was measured at sacrifice. The proximal tibial epiphyseal growth plates (EGPs) were studied, and findings were compared with EGPs from animals fed ad libitum and animals under food restriction. The gene expression profile in the growth plates was examined using DNA microarrays, and the expression levels of selected genes were validated by real-time polymerase chain reaction. To localize gene expression in different growth plate zones, microdissection was used. Protein levels and localization were examined using immunohistochemistry. We showed that the expression level of 550 genes decreased during food restriction and increased during catch-up growth, starting already one day after refeeding. HIF-1alpha, as well as several of its downstream targets, was found among these genes. Immunohistochemistry showed a similar pattern for HIF-1alpha protein abundance. Additionally, HIF-1alpha mRNA and protein levels were higher in the proliferating than in the hypertrophic zone, and this distribution was unaffected by nutritional status. These findings indicate that nutrition has a profound effect on gene expression level during growth plate growth, and suggest an important role for HIF-1alpha in the growth plate and its response to nutritional manipulation.

  19. Differential gene expression induced by growth hormone treatment in the uremic rat growth plate.

    PubMed

    Gil, Helena; Lozano, Juan J; Alvarez-García, Oscar; Secades-Vázquez, Pablo; Rodríguez-Suárez, Julián; García-López, Enrique; Carbajo-Pérez, Eduardo; Santos, Fernando

    2008-08-01

    Treatment with growth hormone (GH) improves growth retardation of chronic renal failure. cDNA microarrays were used to investigate GH-induced modifications in gene expression in the tibial growth plate of young rats. RNA was extracted from the tibial growth plate from two groups, untreated and treated with GH, of young rats made uremic by subtotal nephrectomy (n=10). To validate changes shown by the Agilent oligo microarrays, some modulated genes known to play a physiological role in growth plate metabolism were analyzed by real-time quantitative polymerase chain reaction (qPCR). The microarrays showed that GH modified the expression of 224 genes, 195 being upregulated and 29 downregulated. qPCR results confirmed the sense of expression change found in the arrays for insulin-like growth factor I, insulin-like growth factor II, collagen V alpha 1, bone morphogenetic protein 3 and proteoglycan type II. This study shows for the first time the profile of growth plate gene expression modifications caused by GH treatment in experimental uremia and provides a basis to further investigate selected individual genes with potential implication in the stimulating effect on the growth of GH treatment in chronic renal failure.

  20. Transpiration- and growth-induced water potentials in maize

    SciTech Connect

    Westgate, M.E.; Boyer, J.S.

    1984-01-01

    Recent evidence from leaves and stems indicates that gradients in water potential (psi/sub w/) necessary for water movement through growing tissues are larger than previously assumed. Because growth is sensitive to tissue psi/sub w/ and the behavior of these gradients has not been investigated in transpiring plants, the authors examined the water status of all the growing and mature vegetative tissues of maize (Zea mays L.) during high and low rates of transpiration. The psi/sub w/ measured in the mature regions of the plant responded primarily to transpiration, while the psi/sub w/ in the growing regions was affected both by transpiration and growth. The transpiration-induced potentials of the mature tissue formed a gradient of decreasing psi/sub w/ along the transpiration stream while the growth-induced potentials formed a gradient of decreasing psi/sub w/ from the transpiration stream to the expanding cells in the growing tissue. The growth-induced gradient in psi/sub w/ within the leaf remained fairly constant as the xylem psi/sub w/ decreased during the day and was associated with a decreased osmotic potential (psi/sub s/) of the growing region (osmotic adjustment). The growth-induced gradient in psi/sub w/ was not caused by excision of the tissue because intact maize stems exhibited a similar psi/sub w/. These observations support the concept that large gradients in psi/sub w/ are required to maintain water flow to expanding cells within all the vegetative tissues and suggest that the maintenance of a favorable gradient in psi/sub w/ for cell enlargement may be an important role for osmotic adjustment. 33 references, 7 figures, 1 table.

  1. Delaying cluster growth of ionotropic induced alginate gelation by oligoguluronate.

    PubMed

    Padoł, Anna Maria; Maurstad, Gjertrud; Draget, Kurt Ingar; Stokke, Bjørn Torger

    2015-11-20

    Alginates form gels in the presence of various divalent ions, such as Ca(2+) that mediate lateral association of chain segments. Various procedures exist that introduce Ca(2+) to yield alginate hydrogels with overall homogeneous or controlled gradients in the concentration profiles. In the present study, the effect of adding oligomers of α-l-guluronic acid (oligoGs) to gelling solutions of alginate was investigated by determination of the cluster growth stimulated by in situ release of Ca(2+). Three different alginate samples varying in fraction of α-l-guluronic acid and molecular weights were employed. The cluster growth was determined for both pure alginates and alginates with two different concentrations of the oligoGs employing dynamic light scattering. The results show that addition of oligoG slows down the cluster growth, the more efficient for the alginates with higher fraction of α-l-guluronic acid, and the higher molecular weight. The efficiency in delaying and slowing the cluster growth induced by added oligoG were discussed in view of the molecular parameters of the alginates. These results show that oligoG can be added to alginate solutions to control the cluster growth and eventually also transition to the gel state. Quantitative relation between the concentration of added oligoG, type and molecular weight of the alginate, and concentration, can be employed as guidelines in tuning alginate cluster growth with specific properties.

  2. Placental Growth Factor Administration Abolishes Placental Ischemia-Induced Hypertension.

    PubMed

    Spradley, Frank T; Tan, Adelene Y; Joo, Woo S; Daniels, Garrett; Kussie, Paul; Karumanchi, S Ananth; Granger, Joey P

    2016-04-01

    Preeclampsia is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Placental ischemia appears central to the pathogenesis of preeclampsia because placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in humans stimulates release of hypertensive placental factors into the maternal circulation. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), which antagonizes and reduces bioavailable vascular endothelial growth factor and placental growth factor (PlGF), is elevated in RUPP rats and preeclampsia. Although PlGF and vascular endothelial growth factor are both natural ligands for sFlt-1, vascular endothelial growth factor also has high affinity to VEGFR2 (Flk-1) causing side effects like edema. PlGF is specific for sFlt-1. We tested the hypothesis that PlGF treatment reduces placental ischemia-induced hypertension by antagonizing sFlt-1 without adverse consequences to the mother or fetus. On gestational day 14, rats were randomized to 4 groups: normal pregnant or RUPP±infusion of recombinant human PlGF (180 μg/kg per day; AG31, a purified, recombinant human form of PlGF) for 5 days via intraperitoneal osmotic minipumps. On day 19, mean arterial blood pressure and plasma sFlt-1 were higher and glomerular filtration rate lower in RUPP than normal pregnant rats. Infusion of recombinant human PlGF abolished these changes seen with RUPP along with reducing oxidative stress. These data indicate that the increased sFlt-1 and reduced PlGF resulting from placental ischemia contribute to maternal hypertension. Our novel finding that recombinant human PlGF abolishes placental ischemia-induced hypertension, without major adverse consequences, suggests a strong therapeutic potential for this growth factor in preeclampsia. © 2016 American Heart Association, Inc.

  3. Growth Induced Magnetic Anisotropy in Crystalline and Amorphous Thin Films

    SciTech Connect

    Hellman, Frances

    1998-10-03

    OAK B204 Growth Induced Magnetic Anisotropy in Crystalline and Amorphous Thin Films. The work in the past 6 months has involved three areas of magnetic thin films: (1) amorphous rare earth-transition metal alloys, (2) epitaxial Co-Pt and hTi-Pt alloy thin films, and (3) collaborative work on heat capacity measurements of magnetic thin films, including nanoparticles and CMR materials.

  4. Leptin-Induced JAK/STAT Signaling and Cancer Growth

    PubMed Central

    Mullen, McKay; Gonzalez-Perez, Ruben Rene

    2016-01-01

    Growth factor and cytokine signaling can influence the development of several cancer types. One of the key players in the development of cancer is the Janus kinas (JAK) signal transducer of activators of transcription (STAT) signaling pathway. The majority of growth factors and cytokine interactions with their membrane-bound receptors trigger JAK-STAT activation. The influential relationship between obesity and cancer is a fact. However, there is a complex sequence of events contributing to the regulation of this mechanism to promote tumor growth, yet to be fully elucidated. The JAK-STAT pathway is influenced by obesity-associated changes that have been shown to impact cancer growth and progression. This intricate process is highly regulated by a vast array of adipokines and cytokines that exert their pleiotropic effects on cancer cells to enhance metastasis to distant target sites. Leptin is a cytokine, or more precise, an adipokine secreted mainly by adipose tissue that requires JAK-STAT activation to exert its biological functions. Leptin is the central regulator of energy balance and appetite. Leptin binding to its receptor OB-R in turn activates JAK-STAT, which induces proliferation, angiogenesis, and anti-apoptotic events in normal cells and malignant cells expressing the receptor. Leptin also induces crosstalk with Notch and IL-1 (NILCO), which involves other angiogenic factors promoting tumor growth. Therefore, the existence of multiple novel classes of therapeutics that target the JAK/STAT pathway has significant clinical implications. Then, the identification of the signaling networks and factors that regulate the obesity-cancer link to which potential pharmacologic interventions can be implemented to inhibit tumor growth and metastasis. In this review, we will discuss the specific relationship between leptin-JAK-STAT signaling and cancer. PMID:27472371

  5. Tumor-Induced Hyperlipidemia Contributes to Tumor Growth

    PubMed Central

    Huang, Jianfeng; Li, Lena; Lian, Jihong; Schauer, Silvia; Vesely, Paul W.; Kratky, Dagmar; Hoefler, Gerald; Lehner, Richard

    2016-01-01

    Summary The known link between obesity and cancer suggests an important interaction between the host lipid metabolism and tumorigenesis. Here, we used a syngeneic tumor graft model to demonstrate that tumor development influences the host lipid metabolism. BCR-Abl-transformed precursor B cell tumors induced hyperlipidemia by stimulating very low-density lipoprotein (VLDL) production and blunting VLDL and low-density lipoprotein (LDL) turnover. To assess whether tumor progression was dependent on tumor-induced hyperlipidemia, we utilized the VLDL production-deficient mouse model, carboxylesterase3/triacylglycerol hydrolase (Ces3/TGH) knockout mice. In Ces3/Tgh–/– tumor-bearing mice, plasma triglyceride and cholesterol levels were attenuated. Importantly tumor weight was reduced in Ces3/Tgh–/– mice. Mechanistically, reduced tumor growth in Ces3/Tgh–/– mice was attributed to reversal of tumor-induced PCSK9-mediated degradation of hepatic LDLR and decrease of LDL turnover. Our data demonstrate that tumor-induced hyperlipidemia encompasses a feed-forward loop that reprograms hepatic lipoprotein homeostasis in part by providing LDL cholesterol to support tumor growth. PMID:27050512

  6. Retinoic acid induces TGFbeta-dependent autocrine fibroblast growth.

    PubMed

    Fadloun, A; Kobi, D; Delacroix, L; Dembélé, D; Michel, I; Lardenois, A; Tisserand, J; Losson, R; Mengus, G; Davidson, I

    2008-01-17

    To evaluate the role of murine TFIID subunit TAF4 in activation of cellular genes by all-trans retinoic acid (T-RA), we have characterized the T-RA response of taf4(lox/-) and taf4(-/-) embryonic fibroblasts. T-RA regulates almost 1000 genes in taf4(lox/-) cells, but less than 300 in taf4(-/-) cells showing that TAF4 is required for T-RA regulation of most, but not all cellular genes. We further show that T-RA-treated taf4(lox/-) cells exhibit transforming growth factor (TGF)beta-dependent autocrine growth and identify a set of genes regulated by loss of TAF4 and by T-RA corresponding to key mediators of the TGFbeta signalling pathway. T-RA rapidly and potently induces expression of connective tissue growth factor (CTGF) via a conserved DR2 type response element in its proximal promoter leading to serum-free autocrine growth. These results highlight the role of TAF4 as a cofactor in the cellular response to T-RA and identify the genetic programme of a novel cross talk between the T-RA and TGFbeta pathways that leads to deregulated cell growth.

  7. CREB-Induced Inflammation Is Important for Malignant Mesothelioma Growth

    PubMed Central

    Westbom, Catherine M.; Shukla, Anurag; MacPherson, Maximilian B.; Yasewicz, Elizabeth C.; Miller, Jill M.; Beuschel, Stacie L.; Steele, Chad; Pass, Harvey I.; Vacek, Pamela M.; Shukla, Arti

    2015-01-01

    Malignant mesothelioma (MM) is an aggressive tumor with no treatment regimen. Previously we have demonstrated that cyclic AMP response element binding protein (CREB) is constitutively activated in MM tumor cells and tissues and plays an important role in MM pathogenesis. To understand the role of CREB in MM tumor growth, we generated CREB-inhibited MM cell lines and performed in vitro and in vivo experiments. In vitro experiments demonstrated that CREB inhibition results in significant attenuation of proliferation and drug resistance of MM cells. CREB-silenced MM cells were then injected into severe combined immunodeficiency mice, and tumor growth in s.c. and i.p. models of MM was followed. We observed significant inhibition in MM tumor growth in both s.c. and i.p. models and the presence of a chemotherapeutic drug, doxorubicin, further inhibited MM tumor growth in the i.p. model. Peritoneal lavage fluids from CREB-inhibited tumor-bearing mice showed a significantly reduced total cell number, differential cell counts, and pro-inflammatory cytokines and chemokines (IL-6, IL-8, regulated on activation normal T cell expressed and secreted, monocyte chemotactic protein-1, and vascular endothelial growth factor). In vitro studies showed that asbestos-induced inflammasome/inflammation activation in mesothelial cells was CREB dependent, further supporting the role of CREB in inflammation-induced MM pathogenesis. In conclusion, our data demonstrate the involvement of CREB in the regulation of MM pathogenesis by regulation of inflammation. PMID:25111229

  8. Total triterpenoids from Ganoderma Lucidum suppresses prostate cancer cell growth by inducing growth arrest and apoptosis.

    PubMed

    Wang, Tao; Xie, Zi-ping; Huang, Zhan-sen; Li, Hao; Wei, An-yang; Di, Jin-ming; Xiao, Heng-jun; Zhang, Zhi-gang; Cai, Liu-hong; Tao, Xin; Qi, Tao; Chen, Di-ling; Chen, Jun

    2015-10-01

    In this study, one immortalized human normal prostatic epithelial cell line (BPH) and four human prostate cancer cell lines (LNCaP, 22Rv1, PC-3, and DU-145) were treated with Ganoderma Lucidum triterpenoids (GLT) at different doses and for different time periods. Cell viability, apoptosis, and cell cycle were analyzed using flow cytometry and chemical assays. Gene expression and binding to DNA were assessed using real-time PCR and Western blotting. It was found that GLT dose-dependently inhibited prostate cancer cell growth through induction of apoptosis and cell cycle arrest at G1 phase. GLT-induced apoptosis was due to activation of Caspases-9 and -3 and turning on the downstream apoptotic events. GLT-induced cell cycle arrest (mainly G1 arrest) was due to up-regulation of p21 expression at the early time and down-regulation of cyclin-dependent kinase 4 (CDK4) and E2F1 expression at the late time. These findings demonstrate that GLT suppresses prostate cancer cell growth by inducing growth arrest and apoptosis, which might suggest that GLT or Ganoderma Lucidum could be used as a potential therapeutic drug for prostate cancer.

  9. Endothelin-1 induces connective tissue growth factor expression in cardiomyocytes.

    PubMed

    Recchia, Anna Grazia; Filice, Elisabetta; Pellegrino, Daniela; Dobrina, Aldo; Cerra, Maria Carmela; Maggiolini, Marcello

    2009-03-01

    Endothelin (ET)-1 is a vasoconstrictor involved in cardiovascular diseases. Connective tissue growth factor/CCN2 (CTGF) is a fibrotic mediator overexpressed in human atherosclerotic lesions, myocardial infarction, and hypertension. In different cell types CTGF regulates cell proliferation/apoptosis, migration, and extracellular matrix (ECM) accumulation and plays important roles in angiogenesis, chondrogenesis, osteogenesis, tissue repair, cancer and fibrosis. In the present study, we investigated the ET-1 signaling which triggers CTGF expression in cultured adult mouse atrial-muscle HL-1 cells used as a model system. ET-1 activated the CTGF promoter and induced CTGF expression at both mRNA and protein levels. Real-time PCR analysis revealed CTGF induction also in isolated rat heart preparations perfused with ET-1. Several intracellular signals elicited by ET-1 via ET receptors and even Epidermal Growth Factor Receptor (EGFR) contributed to the up-regulation of CTGF, including ERK activation and induction of the AP-1 components c-fos and c-jun, as also evaluated by ChIP analysis. Moreover, in cells treated with ET-1 the expression of ECM component decorin was abolished by CTGF silencing, indicating that CTGF is involved in ET-1 induced ECM accumulation not only in a direct manner but also through downstream effectors. Collectively, our data indicate that CTGF could be a mediator of the profibrotic effects of ET-1 in cardiomyocytes. CTGF inhibitors should be considered in setting a comprehensive pharmacological approach towards ET-1 induced cardiovascular diseases.

  10. Elastase induces lung epithelial cell autophagy through placental growth factor

    PubMed Central

    Hou, Hsin-Han; Cheng, Shih-Lung; Chung, Kuei-Pin; Kuo, Mark Yen-Ping; Yeh, Cheng-Chang; Chang, Bei-En; Lu, Hsuan-Hsuan; Wang, Hao-Chien; Yu, Chong-Jen

    2014-01-01

    Chronic obstructive pulmonary disease (COPD) is a devastating disease, which is associated with increasing mortality and morbidity. Therefore, there is a need to clearly define the COPD pathogenic mechanism and to explore effective therapies. Previous studies indicated that cigarette smoke (CS) induces autophagy and apoptosis in lung epithelial (LE) cells. Excessive ELANE/HNE (elastase, neutrophil elastase), a factor involved in protease-antiprotease imbalance and the pathogenesis of COPD, causes LE cell apoptosis and upregulates the expression of several stimulus-responsive genes. However, whether or not elastase induces autophagy in LE cell remains unknown. The level of PGF (placental growth factor) is higher in COPD patients than non-COPD controls. We hypothesize that elastase induces PGF expression and causes autophagy in LE cells. In this study, we demonstrated that porcine pancreatic elastase (PPE) induced PGF expression and secretion in LE cells in vitro and in vivo. The activation of MAPK8/JNK1 (mitogen-activated protein kinase 8) and MAPK14/p38alpha MAPK signaling pathways was involved in the PGF mediated regulation of the TSC (tuberous sclerosis complex) pathway and autophagy in LE cells. Notably, PGF-induced MAPK8 and MAPK14 signaling pathways mediated the inactivation of MTOR (mechanistic target of rapamycin), the upregulation of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β) and the increase of autophagosome formation in mice. Furthermore, the PPE-induced autophagy promotes further apoptosis in vitro and in vivo. In summary, elastase-induced autophagy promotes LE cell apoptosis and pulmonary emphysema through the upregulation of PGF. PGF and its downstream MAPK8 and MAPK14 signaling pathways are potential therapeutic targets for the treatment of emphysema and COPD. PMID:24988221

  11. The molecular dynamics simulation of ion-induced ripple growth

    NASA Astrophysics Data System (ADS)

    Süle, P.; Heinig, K.-H.

    2009-11-01

    The wavelength-dependence of ion-sputtering induced growth of repetitive nanostructures, such as ripples has been studied by molecular dynamics (MD) simulations in Si. The early stage of the ion erosion driven development of ripples has been simulated on prepatterned Si stripes with a wavy surface. The time evolution of the height function and amplitude of the sinusoidal surface profile has been followed by simulated ion-sputtering. According to Bradley-Harper (BH) theory, we expect correlation between the wavelength of ripples and the stability of them. However, we find that in the small ripple wavelength (λ) regime BH theory fails to reproduce the results obtained by molecular dynamics. We find that at short wavelengths (λ <35 nm) the adatom yield drops hence no surface diffusion takes place which is sufficient for ripple growth. The MD simulations predict that the growth of ripples with λ >35 nm is stabilized in accordance with the available experimental results. According to the simulations, few hundreds of ion impacts in λ long and few nanometers wide Si ripples are sufficient for reaching saturation in surface growth for for λ >35 nm ripples. In another words, ripples in the long wavelength limit seems to be stable against ion-sputtering. A qualitative comparison of our simulation results with recent experimental data on nanopatterning under irradiation is attempted.

  12. Repeated seizures induce prefrontal growth disturbance in frontal lobe epilepsy.

    PubMed

    Kanemura, Hideaki; Sano, Fumikazu; Tando, Tomoko; Sugita, Kanji; Aihara, Masao

    2012-03-01

    The possible consequences of seizures in the immature brain have been the subject of much conjecture. We prospectively measured frontal and prefrontal lobe volumes using three-dimensional (3D) magnetic resonance imaging (MRI)-based volumetry in patients with frontal lobe epilepsy (FLE) presenting with the same seizure semiology. The pathogenesis of repeated seizure-induced brain damage is discussed herein. Serial changes in regional cerebral volumes were measured in two patients with FLE presenting with intractable clinical courses and cognitive impairments/behavioral problems (FLE(+)) and four FLE patients without cognitive impairments/behavioral problems (FLE(-)). Eleven normal subjects (4-13 years old) served as controls. Volumes of the frontal and prefrontal lobes were determined using a workstation, and the prefrontal-to-frontal lobe volume ratio was calculated. Frontal and prefrontal lobe volumes revealed growth disturbance in FLE(+) compared with those of FLE(-) and control subjects. In addition, prefrontal-to-frontal lobe volume ratio increased serially in FLE(-) similarly to controls, but was stagnant or decreased in FLE(+). Prefrontal growth also revealed more rapid recovery in a FLE(+) patient with shorter active seizure period. These findings suggest that repeated seizures may lead to prefrontal growth disturbance. The occurrence of frequent seizures in patients with FLE may be associated with prefrontal lobe growth retardation, which relates to neuropsychological problems and ultimate neuropsychological outcome. Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  13. Sulodexide induces hepatocyte growth factor release in humans.

    PubMed

    Borawski, Jacek; Dubowski, Miroslaw; Pawlak, Krystyna; Mysliwiec, Michal

    2007-03-08

    Heparin influences numerous pleiotropic growth factors, including hepatocyte growth factor (HGF), partially by their release from endothelial and extracellular matrix stores. The effects of sulodexide, a heparin-like glycosaminoglycan medication of growing importance in medicine, on HGF liberation are not known. We performed a 2-week open-label sulodexide trial in healthy male volunteers. The drug was initially administered intravenously (i.v.) in a single dose of 1200 Lipoprotein Lipase Releasing Units (LRU), then -- orally for 12 days (500 LRU twice a day), and -- again by i.v. route (1200 LRU) on day 14. Intravenous sulodexide injections were repeatedly found to induce marked and reproducible increases in immunoreactive plasma HGF levels (more than 3500% vs baseline after 10 min, and more than 1200% after 120 min), and remained unchanged when measured 120 min following oral sulodexide administration. The percentage increments in plasma HGF evoked by i.v. sulodexide at both time points and on both days inversely correlated with baseline levels of the growth factor. On day 14, the HGF levels after 120 min and their percentage increase vs baseline were strongly and directly dependent on i.v. sulodexide dose per kg of body weight. This study shows that sulodexide has a novel, remarkable and plausibly biologically important stimulating effect on the release of pleiotropic hepatocyte growth factor in humans.

  14. Interferon alpha-inducible protein 6 regulates NRASQ61K-induced melanomagenesis and growth

    PubMed Central

    Gupta, Romi; Forloni, Matteo; Bisserier, Malik; Dogra, Shaillay Kumar; Yang, Qiaohong; Wajapeyee, Narendra

    2016-01-01

    Mutations in the NRAS oncogene are present in up to 20% of melanoma. Here, we show that interferon alpha-inducible protein 6 (IFI6) is necessary for NRASQ61K-induced transformation and melanoma growth. IFI6 was transcriptionally upregulated by NRASQ61K, and knockdown of IFI6 resulted in DNA replication stress due to dysregulated DNA replication via E2F2. This stress consequentially inhibited cellular transformation and melanoma growth via senescence or apoptosis induction depending on the RB and p53 pathway status of the cells. NRAS-mutant melanoma were significantly more resistant to the cytotoxic effects of DNA replication stress-inducing drugs, and knockdown of IFI6 increased sensitivity to these drugs. Pharmacological inhibition of IFI6 expression by the MEK inhibitor trametinib, when combined with DNA replication stress-inducing drugs, blocked NRAS-mutant melanoma growth. Collectively, we demonstrate that IFI6, via E2F2 regulates DNA replication and melanoma development and growth, and this pathway can be pharmacologically targeted to inhibit NRAS-mutant melanoma. DOI: http://dx.doi.org/10.7554/eLife.16432.001 PMID:27608486

  15. PLACENTAL GROWTH FACTOR ADMINISTRATION ABOLISHES PLACENTAL ISCHEMIA-INDUCED HYPERTENSION

    PubMed Central

    Spradley, Frank T.; Tan, Adelene Y.; Joo, Woo S.; Daniels, Garrett; Kussie, Paul; Karumanchi, S. Ananth; Granger, Joey P.

    2016-01-01

    Preeclampsia is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Placental ischemia appears central to the pathogenesis of preeclampsia as placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in humans stimulates release of hypertensive placental factors into the maternal circulation. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), which antagonizes and reduces bioavailable vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), is elevated in RUPP rats and preeclampsia. Although PlGF and VEGF are both natural ligands for sFlt-1, VEGF also has high affinity to VEGFR2 (Flk-1) causing side effects like edema. PlGF is specific for sFlt-1. We tested the hypothesis that PlGF treatment reduces placental ischemia-induced hypertension by antagonizing sFlt-1 without adverse consequences to the mother or fetus. On gestational day 14, rats were randomized to four groups: normal pregnant (NP) or RUPP ± infusion of rhPlGF (180 μg/kg/day; AG31, a purified, recombinant human form of PlGF) for 5 days via intraperitoneal osmotic minipumps. On day 19, mean arterial blood pressure and plasma sFlt-1 were higher and glomerular filtration rate lower in RUPP than NP rats. Infusion of rhPlGF abolished these changes seen with RUPP along with reducing oxidative stress. These data indicate that the increased sFlt-1 and reduced PlGF resulting from placental ischemia contribute to maternal hypertension. Our novel finding that rhPlGF abolishes placental ischemia-induced hypertension, without major adverse consequences, suggests a strong therapeutic potential for this growth factor in preeclampsia. PMID:26831193

  16. Sphingosine kinase-1 mediates androgen-induced osteoblast cell growth

    SciTech Connect

    Martin, Claire; Lafosse, Jean-Michel; Malavaud, Bernard; Cuvillier, Olivier

    2010-01-01

    Herein we report that the lipid kinase sphingosine kinase-1 (SphK1) is instrumental in mediating androgen-induced cell proliferation in osteoblasts. Dihydrotestosterone (DHT) triggered cell growth in steroid-deprived MC3T3 cells, which was associated with a rapid stimulation of SphK1 and activation of both Akt and ERK signaling pathways. This mechanism relied on functional androgen receptor/PI3K/Akt nongenotropic signaling as pharmacological antagonists could block SphK1 stimulation by DHT and its consequences. Finally, SphK1 inhibition not only abrogated DHT-induced ERK activation but also blocked cell proliferation, while ERK inhibition had no impact, suggesting that SphK1 was critical for DHT signaling yet independently of the ERK.

  17. Transforming growth factor-{beta}-inducible phosphorylation of Smad3.

    PubMed

    Wang, Guannan; Matsuura, Isao; He, Dongming; Liu, Fang

    2009-04-10

    Smad proteins transduce the transforming growth factor-beta (TGF-beta) signal at the cell surface into gene regulation in the nucleus. Upon TGF-beta treatment, the highly homologous Smad2 and Smad3 are phosphorylated by the TGF-beta receptor at the SSXS motif in the C-terminal tail. Here we show that in addition to the C-tail, three (S/T)-P sites in the Smad3 linker region, Ser(208), Ser(204), and Thr(179) are phosphorylated in response to TGF-beta. The linker phosphorylation peaks at 1 h after TGF-beta treatment, behind the peak of the C-tail phosphorylation. We provide evidence suggesting that the C-tail phosphorylation by the TGF-beta receptor is necessary for the TGF-beta-induced linker phosphorylation. Although the TGF-beta receptor is necessary for the linker phosphorylation, the receptor itself does not phosphorylate these sites. We further show that ERK is not responsible for TGF-beta-dependent phosphorylation of these three sites. We show that GSK3 accounts for TGF-beta-inducible Ser(204) phosphorylation. Flavopiridol, a pan-CDK inhibitor, abolishes TGF-beta-induced phosphorylation of Thr(179) and Ser(208), suggesting that the CDK family is responsible for phosphorylation of Thr(179) and Ser(208) in response to TGF-beta. Mutation of the linker phosphorylation sites to nonphosphorylatable residues increases the ability of Smad3 to activate a TGF-beta/Smad-target gene as well as the growth-inhibitory function of Smad3. Thus, these observations suggest that TGF-beta-induced phosphorylation of Smad3 linker sites inhibits its antiproliferative activity.

  18. Growth Hormone Induces Transforming Growth Factor-Beta-Induced Protein in Podocytes: Implications for Podocyte Depletion and Proteinuria.

    PubMed

    Chitra, P Swathi; Swathi, T; Sahay, Rakesh; Reddy, G Bhanuprakash; Menon, Ram K; Kumar, P Anil

    2015-09-01

    The glomerular podocytes form a major size selective barrier for the filtration of serum proteins and reduced podocyte number is a critical event in the pathogenesis of proteinuria during diabetic nephropathy (DN). An elevated level of growth hormone (GH) is implicated as a causative factor in the development of nephropathy in patients with type 1 diabetes mellitus. We have previously shown that podocytes express GH receptor and are a target for GH action. To elucidate the molecular basis for the effects of GH on podocyte depletion, we conducted PCR-array analyses for extracellular matrix and adhesion molecules in podocytes. Our studies reveal that GH increases expression of a gene that encodes transforming growth factor-beta-induced protein (TGFBIp) expression. Similarly, microarray data retrieved from the Nephromine database revealed elevation of TGFBIp in patients with DN. Treatment with GH results in increased secretion of extracellular TGFBIp by podocytes. Both GH and TGFBIp induced apoptosis and epithelial mesenchymal transition (EMT) of podocytes. Exposure of podocytes to GH and TGFBIp resulted in increased migration of cells and altered podocyte permeability to albumin across podocyte monolayer. Administration of GH to rats induced EMT and apoptosis in the glomerular fraction of the kidney. Therefore, we conclude that the GH-dependent increase in TGFBIp in the podocyte is one of the mechanisms responsible for podocyte depletion in DN.

  19. Mycobacterium massiliense Induces Macrophage Extracellular Traps with Facilitating Bacterial Growth

    PubMed Central

    Yoon, Yina; Na, Yirang; Kim, Bum-Joon; Seok, Seung Hyeok

    2016-01-01

    Human neutrophils have been known to release neutrophil extracellular traps (NETs), antimicrobial DNA structures capable of capturing and killing microbes. Recently, a similar phenomenon has been reported in macrophages infected with various pathogens. However, a role for macrophages extracellular traps (METs) in host defense responses against Mycobacterium massiliense (M. mass) has yet to be described. In this study, we show that M. mass, a rapid growing mycobacterium (RGM), also induces the release of METs from PMA-differentiated THP-1 cells. Intriguingly, this process is not dependent on NADPH oxidase activity, which regulates NET formation. Instead, M. mass-induced MET formation partially depends on calcium influx and requires phagocytosis of high bacterial load. The METs consist of a DNA backbone embedded with microbicidal proteins such as histone, MPO and elastase. Released METs entrap M. mass and prevent their dissemination, but do not have bactericidal activity. Instead, they result in enhanced bacterial growth. In this regard, METs were considered to provide interaction of M. mass with cells and an environment for bacterial aggregation, which may facilitate mycobacterial survival and growth. In conclusion, our results demonstrate METs as an innate defense response against M. mass infection, and suggest that extracellular traps play a multifaceted role in the interplay between host and bacteria. PMID:27191593

  20. Mycobacterium massiliense Induces Macrophage Extracellular Traps with Facilitating Bacterial Growth.

    PubMed

    Je, Sungmo; Quan, Hailian; Yoon, Yina; Na, Yirang; Kim, Bum-Joon; Seok, Seung Hyeok

    2016-01-01

    Human neutrophils have been known to release neutrophil extracellular traps (NETs), antimicrobial DNA structures capable of capturing and killing microbes. Recently, a similar phenomenon has been reported in macrophages infected with various pathogens. However, a role for macrophages extracellular traps (METs) in host defense responses against Mycobacterium massiliense (M. mass) has yet to be described. In this study, we show that M. mass, a rapid growing mycobacterium (RGM), also induces the release of METs from PMA-differentiated THP-1 cells. Intriguingly, this process is not dependent on NADPH oxidase activity, which regulates NET formation. Instead, M. mass-induced MET formation partially depends on calcium influx and requires phagocytosis of high bacterial load. The METs consist of a DNA backbone embedded with microbicidal proteins such as histone, MPO and elastase. Released METs entrap M. mass and prevent their dissemination, but do not have bactericidal activity. Instead, they result in enhanced bacterial growth. In this regard, METs were considered to provide interaction of M. mass with cells and an environment for bacterial aggregation, which may facilitate mycobacterial survival and growth. In conclusion, our results demonstrate METs as an innate defense response against M. mass infection, and suggest that extracellular traps play a multifaceted role in the interplay between host and bacteria.

  1. Growth factor deprivation induces cytosolic translocation of SIRT1

    NASA Astrophysics Data System (ADS)

    Meng, Chengbo; Xing, Da; Wu, Shengnan; Huang, Lei

    2010-02-01

    Sirtuin type 1 (SIRT1), a NAD+-dependent histone deacetylases, plays a critical role in cellular senescence, aging and longevity. In general, SIRT1 is localized in nucleus and is believed as a nuclear protein. Though overexpression of SIRT1 delays senescence, SIRT1-protein levels decline naturally in thymus and heart during aging. In the present studies, we investigated the subcellular localization of SIRT1 in response to growth factor deprivation in African green monkey SV40-transformed kidney fibroblast cells (COS-7). Using SIRT1-EGFP fluorescence reporter, we found that SIRT1 localized to nucleus in physiological conditions. We devised a model enabling cell senescence via growth factor deprivation, and we found that SIRT1 partially translocated to cytosol under the treatment, suggesting a reduced level of SIRT1's activity. We found PI3K/Akt pathway was involved in the inhibition of SIRT1's cytosolic translocation, because inhibition of these kinases significantly decreased the amount of SIRT1 maintained in nucleus. Taken together, we demonstrated that growth factor deprivation induces cytosolic translocation of SIRT1, which suggesting a possible connection between cytoplasm-localized SIRT1 and the aging process.

  2. X-ray-induced changes in growth of Mozambique tilapia

    SciTech Connect

    Jana, B.B.; Basu, M.

    1995-01-01

    Early fry (30 d postfertilization) and 7-8-week-old Mozambique tilapias (Tilapia mossambica) were exposed to X rays in dosages of 50, 100, 200, 300, 400 or 500 roentgens and reared in outdoor culture tanks between May 1981 and October 1988. Fish of either sex that were irradiated as fry grew faster than controls at all test X-ray doses. Among fish irradiated at 7-8 weeks, males grew significantly faster, but females grew significantly slower, than controls at all test doses. X-ray-induced changes in growth were dose-dependent: growth rates of fry (both sexes) and of juvenile males rose relative to those of controls with increased radiation dose. The growth increase per unit of radiation dose was higher for fry than for older juveniles. The length-weight regression was steeper for irradiated males than for controls. The average weights of F{sub 1} offspring of irradiated fish were greatly reduced as compared with controls, which suggests the transfer of the detrimental effects of X rays from irradiated parents to their offspring. 39 refs., 3 figs., 3 tabs.

  3. Biofilm Growth Induced Transformation of Porous Media Dynamics

    NASA Astrophysics Data System (ADS)

    Gage, J. P.; Seymour, J. D.; Codd, S. L.; Gerlach, R.

    2004-12-01

    Magnetic resonance microscopy (MRM) has been applied to study hydrodynamic dispersion in porous media impacted by biofilms growth. MRM measures the averaged propagator of motion which provides the probability of displacements to occur over experimentally controlled times. The transition from pre-asymptotic to asymptotic hydrodynamic dispersion in a homogeneous porous medium constructed from monodisperse spheres is clearly visualized by the time evolution of the propagator to a Gaussian distribution. The growth of biofilms in the porous media induces a transition in the hydrodynamic dispersion from normal to anomalous transport which is visualized by the propagator transition from Gaussian to that modeled by a subdiffusive fractal kinetics model based on continuous time random walks (CTRW's). This transition is consistent with the porous media structure changing from homogeneous to nonhomogeneous and connections to fractal dimensions are discussed. The MRM data can be analyzed in the q-space domain, i.e. the wavelength space reciprocal to displacement, and provides information on the dynamics on scales above and below a single pore. Fractional kinetics models for subdiffusive processes predict stretched exponential Gaussian behavior and the q-space data fits to strectched exponentials exhibit a transition from Gaussian to subdiffusion due to biofilm growth.

  4. Cortical bone growth and maturational changes in dwarf rats induced by recombinant human growth hormone

    NASA Technical Reports Server (NTRS)

    Martinez, D. A.; Orth, M. W.; Carr, K. E.; Vanderby, R. Jr; Vailas, A. C.

    1996-01-01

    The growth hormone (GH)-deficient dwarf rat was used to investigate recombinant human (rh) GH-induced bone formation and to determine whether rhGH facilitates simultaneous increases in bone formation and bone maturation during rapid growth. Twenty dwarf rats, 37 days of age, were randomly assigned to dwarf plus rhGH (GH; n = 10) and dwarf plus vehicle (n = 10) groups. The GH group received 1.25 mg rhGH/kg body wt two times daily for 14 days. Biochemical, morphological, and X-ray diffraction measurements were performed on the femur middiaphysis. rhGH stimulated new bone growth in the GH group, as demonstrated by significant increases (P < 0.05) in longitudinal bone length (6%), middiaphyseal cross-sectional area (20%), and the amount of newly accreted bone collagen (28%) in the total pool of middiaphyseal bone collagen. Cortical bone density, mean hydroxyapatite crystal size, and the calcium and collagen contents (microgram/mm3) were significantly smaller in the GH group (P < 0.05). Our findings suggest that the processes regulating new collagen accretion, bone collagen maturation, and mean hydroxyapatite crystal size may be independently regulated during rapid growth.

  5. Cortical bone growth and maturational changes in dwarf rats induced by recombinant human growth hormone

    NASA Technical Reports Server (NTRS)

    Martinez, D. A.; Orth, M. W.; Carr, K. E.; Vanderby, R. Jr; Vailas, A. C.

    1996-01-01

    The growth hormone (GH)-deficient dwarf rat was used to investigate recombinant human (rh) GH-induced bone formation and to determine whether rhGH facilitates simultaneous increases in bone formation and bone maturation during rapid growth. Twenty dwarf rats, 37 days of age, were randomly assigned to dwarf plus rhGH (GH; n = 10) and dwarf plus vehicle (n = 10) groups. The GH group received 1.25 mg rhGH/kg body wt two times daily for 14 days. Biochemical, morphological, and X-ray diffraction measurements were performed on the femur middiaphysis. rhGH stimulated new bone growth in the GH group, as demonstrated by significant increases (P < 0.05) in longitudinal bone length (6%), middiaphyseal cross-sectional area (20%), and the amount of newly accreted bone collagen (28%) in the total pool of middiaphyseal bone collagen. Cortical bone density, mean hydroxyapatite crystal size, and the calcium and collagen contents (microgram/mm3) were significantly smaller in the GH group (P < 0.05). Our findings suggest that the processes regulating new collagen accretion, bone collagen maturation, and mean hydroxyapatite crystal size may be independently regulated during rapid growth.

  6. Osteocalcin induces growth hormone/insulin-like growth factor-1 system by promoting testosterone synthesis in male mice.

    PubMed

    Li, Y; Li, K

    2014-10-01

    Osteocalcin has been shown to enhance testosterone production in men. In the present study, we investigated the effects of osteocalcin on testosterone and on induction of the growth hormone/insulin-like growth factor-1 axis. Osteocalcin injection stimulated growth, which could be inhibited by castration. In addition, osteocalcin induced testosterone secretion in testes both in vivo and in vitro. Using real-time polymerase chain reaction and Western blotting, we showed that growth hormone expression was significantly increased in the pituitary after osteocalcin injection (p<0.05). Growth hormone expression in CLU401 mouse pituitary cells was also significantly stimulated (p<0.05) by osteocalcin-induced MA-10 cells. Osteocalcin injection also promoted hepatic expression of growth hormone receptor and insulin-like growth factor-1 (p<0.05), as demonstrated by real-time polymerase chain reaction and Western blotting. Similarly, osteocalcin-induced MA-10 cells promoted growth hormone receptor and insulin-like growth factor-1 expression in NCTC1469 cells. These results suggest that the growth-stimulating activities of osteocalcin are mediated by testicular testosterone secretion, and thus provide valuable information regarding the regulatory effects of osteocalcin expression on the growth hormone/insulin-like growth factor-1 axis via reproductive activities.

  7. Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis

    PubMed Central

    Parajuli, Keshab R; Zhang, Qiuyang; Liu, Sen; Patel, Neil K; Lu, Hua; Zeng, Shelya X; Wang, Guangdi; Zhang, Changde; You, Zongbing

    2014-01-01

    Methoxyacetic acid (MAA) is a primary metabolite of ester phthalates that are used in production of consumer products and pharmaceutical products. MAA causes embryo malformation and spermatocyte death through inhibition of histone deacetylases (HDACs). Little is known about MAA’s effects on cancer cells. In this study, two immortalized human normal prostatic epithelial cell lines (RWPE-1 and pRNS-1-1) and four human prostate cancer cell lines (LNCaP, C4-2B, PC-3, and DU-145) were treated with MAA at different doses and for different time periods. Cell viability, apoptosis, and cell cycle analysis were performed using flow cytometry and chemical assays. Gene expression and binding to DNA were assessed using real-time PCR, Western blot, and chromatin immunoprecipitation analyses. We found that MAA dose-dependently inhibited prostate cancer cell growth through induction of apoptosis and cell cycle arrest at G1 phase. MAA-induced apoptosis was due to down-regulation of the anti-apoptotic gene baculoviral inhibitor of apoptosis protein repeat containing 2 (BIRC2, also named cIAP1), leading to activation of caspases 7 and 3 and turning on the downstream apoptotic events. MAA-induced cell cycle arrest (mainly G1 arrest) was due to up-regulation of p21 expression at the early time and down-regulation of cyclin-dependent kinase 4 (CDK4) and CDK2 expression at the late time. MAA up-regulated p21 expression through inhibition of HDAC activities, independently of p53/p63/p73. These findings demonstrate that MAA suppresses prostate cancer cell growth by inducing growth arrest and apoptosis, which suggests that MAA could be used as a potential therapeutic drug for prostate cancer. PMID:25606576

  8. Chronic intermittent hypoxia induces lung growth in adult mice

    PubMed Central

    Bevans-Fonti, Shannon; Grigoryev, Dmitry N.; Drager, Luciano F.; Myers, Allen C.; Wise, Robert A.; Schwartz, Alan R.; Mitzner, Wayne; Polotsky, Vsevolod Y.

    2011-01-01

    Obstructive sleep apnea (OSA) increases cardiovascular morbidity and mortality, which have been attributed to intermittent hypoxia (IH). The effects of IH on lung structure and function are unknown. We used a mouse model of chronic IH, which mimics the O2 profile in patients with OSA. We exposed adult C57BL/6J mice to 3 mo of IH with a fraction of inspired oxygen (FiO2) nadir of 5% 60 times/h during the 12-h light phase. Control mice were exposed to room air. Lung volumes were measured by quasistatic pressure-volume (PV) curves under anesthesia and by water displacement postmortem. Lungs were processed for morphometry, and the mean airspace chord length (Lm) and alveolar surface area were determined. Lung tissue was stained for markers of proliferation (proliferating cell nuclear antigen), apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling), and type II alveolar epithelial cells (surfactant protein C). Gene microarrays were performed, and results were validated by real-time PCR. IH increased lung volumes by both PV curves (air vs. IH, 1.16 vs. 1.44 ml, P < 0.0001) and water displacement (P < 0.01) without changes in Lm, suggesting that IH increased the alveolar surface area. IH induced a 60% increase in cellular proliferation, but the number of proliferating type II alveolocytes tripled. There was no increase in apoptosis. IH upregulated pathways of cellular movement and cellular growth and development, including key developmental genes vascular endothelial growth factor A and platelet-derived growth factor B. We conclude that IH increases alveolar surface area by stimulating lung growth in adult mice. PMID:21131398

  9. Fracture flow due to hydrothermally induced quartz growth

    NASA Astrophysics Data System (ADS)

    Kling, Tobias; Schwarz, Jens-Oliver; Wendler, Frank; Enzmann, Frieder; Blum, Philipp

    2017-09-01

    Mineral precipitations are a common feature and limitation of initially open, permeable rock fractures by forming sealing structures or secondary roughness in open voids. Hence, the objective of this numerical study is the evaluation of hydraulic properties of fractures sealed by hydrothermally induced needle and compact quartz growth. Phase-field models of progressive syntaxial and idiomorphic quartz growth are implemented into a fluid flow simulation solving the Navier-Stokes equation. Flow simulations for both quartz types indicate an obvious correlation between changes in permeability, fracture properties (e.g. aperture, relative roughness and porosity) and crystal growth behavior, which also forms distinct flow paths. Thus, at lower sealing stages initial fracture permeability significantly drops down for the 'needle fracture' forming highly tortuous flow paths, while the 'compact fracture' records a considerably smaller loss. Fluid flow in both sealing fractures most widely is governed by a ;parallel plate;-like cubic law behavior. However, the 'needle fracture' also reveals flow characteristics of a porous media. A semi-theoretical equation is introduced that links geometrical (am) with hydraulically effective apertures (ah) and the relative fracture roughness. For this purpose, a geometry factor α is introduced being α = 2.5 for needle quartz and α = 1.0 for compact quartz growth. In contrast to most common ah-am-relationships this novel formulation not only reveals more precise predictions for the needle (RMSE = 1.5) and the compact fractures (RMSE = 3.2), but also exhibit a larger range of validity concerning the roughness of the 'needle' (σ/am = 0-2.4) and the 'compact fractures' (σ/am = 0-1.8).

  10. Exercise-Induced growth hormone during acute sleep deprivation.

    PubMed

    Ritsche, Kevin; Nindl, Bradly C; Wideman, Laurie

    2014-10-01

    The effect of acute (24-h) sleep deprivation on exercise-induced growth hormone (GH) and insulin-like growth factor-1 (IGF-1) was examined. Ten men (20.6 ± 1.4 years) completed two randomized 24-h sessions including a brief, high-intensity exercise bout following either a night of sleep (SLEEP) or (24-h) sleep deprivation (SLD). Anaerobic performance (mean power [MP], peak power [PP], minimum power [MinP], time to peak power [TTPP], fatigue index, [FI]) and total work per sprint [TWPS]) was determined from four maximal 30-sec Wingate sprints on a cycle ergometer. Self-reported sleep 7 days prior to each session was similar between SLEEP and SLD sessions (7.92 ± 0.33 vs. 7.98 ± 0.39 h, P = 0.656, respectively) and during the actual SLEEP session in the lab, the total amount of sleep was similar to the 7 days leading up to the lab session (7.72 ± 0.14 h vs. 7.92 ± 0.33 h, respectively) (P = 0.166). No differences existed in MP, PP, MinP, TTPP, FI, TWPS, resting GH concentrations, time to reach exercise-induced peak GH concentration (TTP), or free IGF-1 between sessions. GH area under the curve (AUC) (825.0 ± 199.8 vs. 2212.9 ± 441.9 μg/L*min, P < 0.01), exercise-induced peak GH concentration (17.8 ± 3.7 vs. 39.6 ± 7.1 μg/L, P < 0.01) and ΔGH (peak GH - resting GH) (17.2 ± 3.7 vs. 38.2 ± 7.3 μg/L, P < 0.01) were significantly lower during the SLEEP versus SLD session. Our results indicate that the exercise-induced GH response was significantly augmented in sleep-deprived individuals.

  11. Exercise‐Induced growth hormone during acute sleep deprivation

    PubMed Central

    Ritsche, Kevin; Nindl, Bradly C.; Wideman, Laurie

    2014-01-01

    Abstract The effect of acute (24‐h) sleep deprivation on exercise‐induced growth hormone (GH) and insulin‐like growth factor‐1 (IGF‐1) was examined. Ten men (20.6 ± 1.4 years) completed two randomized 24‐h sessions including a brief, high‐intensity exercise bout following either a night of sleep (SLEEP) or (24‐h) sleep deprivation (SLD). Anaerobic performance (mean power [MP], peak power [PP], minimum power [MinP], time to peak power [TTPP], fatigue index, [FI]) and total work per sprint [TWPS]) was determined from four maximal 30‐sec Wingate sprints on a cycle ergometer. Self‐reported sleep 7 days prior to each session was similar between SLEEP and SLD sessions (7.92 ± 0.33 vs. 7.98 ± 0.39 h, P =0.656, respectively) and during the actual SLEEP session in the lab, the total amount of sleep was similar to the 7 days leading up to the lab session (7.72 ± 0.14 h vs. 7.92 ± 0.33 h, respectively) (P =0.166). No differences existed in MP, PP, MinP, TTPP, FI, TWPS, resting GH concentrations, time to reach exercise‐induced peak GH concentration (TTP), or free IGF‐1 between sessions. GH area under the curve (AUC) (825.0 ± 199.8 vs. 2212.9 ± 441.9 μg/L*min, P <0.01), exercise‐induced peak GH concentration (17.8 ± 3.7 vs. 39.6 ± 7.1 μg/L, P <0.01) and ΔGH (peak GH – resting GH) (17.2 ± 3.7 vs. 38.2 ± 7.3 μg/L, P <0.01) were significantly lower during the SLEEP versus SLD session. Our results indicate that the exercise‐induced GH response was significantly augmented in sleep‐deprived individuals. PMID:25281616

  12. Basic Fibroblast Growth Factor Induces Angiogenesis in vitro

    NASA Astrophysics Data System (ADS)

    Montesano, R.; Vassalli, J.-D.; Baird, A.; Guillemin, R.; Orci, L.

    1986-10-01

    Fibroblast growth factors (FGFs) are potent mitogens for vascular and capillary endothelial cells in vitro and can stimulate the formation of blood capillaries (angiogenesis) in vivo. A crucial event in this process is the invasion of the perivascular extracellular matrix by sprouting endothelial cells. Using a recently developed in vitro model of angiogenesis, we show here that highly purified basic pituitary FGF can induce capillary endothelial cells to invade a three-dimensional collagen matrix and to organize themselves to form characteristic tubules that resemble blood capillaries. We also show that basic FGF concomitantly stimulates endothelial cells to produce a urokinase-type plasminogen activator, a protease that has been implicated in the neovascular response. The results demonstrate that basic FGF can stimulate processes that are characteristic of angiogenesis in vivo, including endothelial cell migration, invasion, and production of plasminogen activator.

  13. Salt-induced aggregation of lysozyme: Implications for crystal growth

    NASA Astrophysics Data System (ADS)

    Wilson, Lori J.

    1994-10-01

    Crystallization of proteins is a prerequisite for structural analysis by x-ray crystallography. While improvements in protein crystals have been obtained in microgravity onboard the U.S. Space Shuttle, attempts to improve the crystal growth process both on the ground and in space have been limited by our lack of understanding of the mechanisms involved. Almost all proteins are crystallized with the aid of a precipitating agent. Many of the common precipitating agents are inorganic salts. An understanding of the role of salts on the aggregation of protein monomers is the key to the elucidation of the mechanisms involved in protein crystallization. In order for crystallization to occur individual molecules must self-associate into aggregates. Detection and characterization of aggregates in supersaturated protein solutions is the first step in understanding salt-induced crystallization.

  14. Keratinocyte growth factor induces pancreatic ductal epithelial proliferation.

    PubMed

    Yi, E S; Yin, S; Harclerode, D L; Bedoya, A; Bikhazi, N B; Housley, R M; Aukerman, S L; Morris, C F; Pierce, G F; Ulich, T R

    1994-07-01

    Keratinocyte growth factor (KGF) causes a proliferation of pancreatic ductal epithelial cells in adult rats after daily systemic administration for 1 to 2 weeks. Even before the proliferation of intralobular ducts is histologically evident, KGF also induces proliferating cell nuclear antigen expression within the ductal epithelium of intercalated, intralobular, and interlobular ducts. KGF also causes incorporation of 5-bromodeoxyuridine in ductal epithelial cells. Epithelial cell proliferation is histologically most prominent at the level of the intralobular ducts adjacent to and within the islets of Langerhans. Pancreatic ductal proliferation is not histologically apparent in rats sacrificed 7 to 10 days after the cessation of KGF administration. The pancreatic hormones insulin, glucagon, somatostatin, and pancreatic polypeptide are normally distributed within islets that demonstrate intrainsular ductal proliferation. The proliferating ductal epithelium does not show endocrine differentiation as evidenced by the lack of immunoreactivity for pancreatic hormones. KGF is a potent in vivo mitogen for pancreatic ductal epithelial cells.

  15. Metal Induced Growth of Transition Metal Dichalcogenides at Controlled Locations

    PubMed Central

    Wang, Zhendong; Huang, Qi; Chen, Peng; Guo, Shouhui; Liu, Xiaoqing; Liang, Xuelei; Wang, Li

    2016-01-01

    Metal induced nucleation is adopted to achieve the growth of transition metal dichalcogenides at controlled locations. Ordered arrays of MoS2 and WS2 have successfully been fabricated on SiO2 substrates by using the patterned Pt/Ti dots as the nucleation sites. Uniform MoS2 monolayers with the adjustable size up to 50 μm are grown surrounding these metal patterns and the mobility of such layer is about 0.86 cm2/V·s. The crystalline flakes of WS2 are also fabricated extending from the metal patterns and the electron mobility of these flakes is up to 11.36 cm2/V·s. PMID:27910917

  16. Proteasome Inhibition by Fellutamide B Induces Nerve Growth Factor Synthesis

    PubMed Central

    Hines, John; Groll, Michael; Fahnestock, Margaret; Crews, Craig M.

    2008-01-01

    SUMMARY Neurotrophic small molecules have the potential to aid in the treatment of neuronal injury and neurodegenerative diseases. The natural product fellutamide B, originally isolated from Penicillium fellutanum, potently induces nerve growth factor (NGF) release from fibroblasts and glial-derived cells, although the mechanism for this neurotrophic activity has not been elucidated. Here, we report that fellutamide B potently inhibits proteasome catalytic activity. High resolution structural information obtained from co-crystallization of the 20S proteasome reveals novel aspects regarding β-subunit binding and adduct formation by fellutamide B to inhibit their hydrolytic activity. We demonstrate that fellutamide B and other proteasome inhibitors increased NGF gene transcription via a cis-acting element (or elements) in the promoter. These results demonstrate an unrecognized connection between proteasome inhibition and NGF production, suggesting a possible new strategy in the development of neurotrophic agents. PMID:18482702

  17. Salt-induced aggregation of lysozyme: Implications for crystal growth

    NASA Technical Reports Server (NTRS)

    Wilson, Lori J.

    1994-01-01

    Crystallization of proteins is a prerequisite for structural analysis by x-ray crystallography. While improvements in protein crystals have been obtained in microgravity onboard the U.S. Space Shuttle, attempts to improve the crystal growth process both on the ground and in space have been limited by our lack of understanding of the mechanisms involved. Almost all proteins are crystallized with the aid of a precipitating agent. Many of the common precipitating agents are inorganic salts. An understanding of the role of salts on the aggregation of protein monomers is the key to the elucidation of the mechanisms involved in protein crystallization. In order for crystallization to occur individual molecules must self-associate into aggregates. Detection and characterization of aggregates in supersaturated protein solutions is the first step in understanding salt-induced crystallization.

  18. Isoproterenol inhibits fibroblast growth factor-2-induced growth of renal epithelial cells.

    PubMed

    Izevbigie, E B; Gutkind, J S; Ray, P E

    2000-08-01

    The signal transduction pathways modulating bFGF effects in renal tubular epithelial cells (RTEc) are not completely understood. Since the cAMP and the mitogen-activated protein kinase (MAPK) pathways can modulate the growth of RTEc, we studied whether two cAMP elevating agents, isoproterenol and 8-bromo-cAMP, would modulate basic fibroblast growth factor (bFGF) induction of MAPK activity (ERK-2) and cell proliferation in human renal proximal tubular epithelial cells (RPTEc) and Madin-Darby canine kidney cells (MDCK clone EI1). Isoproterenol, but not bFGF, stimulated cAMP production in RPTEc and MDCKEI1 cells. bFGF, isoproterenol, and 8-bromo-cAMP alone increased ERK-2 activity in both cell types. However, isoproterenol and 8-bromo-cAMP partially inhibited the bFGF induction of ERK-2 activity, but only isoproterenol inhibited the proliferation of both cell types. PD098059 (25 microM), an inhibitor of MAPK kinase (MEK 1/2), blocked the bFGF mitogenic effects, but did not affect the 8-bromo-cAMP-induced mitogenic effects in MDCKEI1 cells. These findings suggest that activation of ERK-2 is required but not sufficient for mitogenesis in RTEc. We conclude that isoproterenol inhibits the growth-promoting effects of bFGF in RTEc via MEK-dependent and -independent pathways.

  19. Laser-induced growth of nanocrystals embedded in porous materials

    NASA Astrophysics Data System (ADS)

    Capoen, Bruno; Chahadih, Abdallah; El Hamzaoui, Hicham; Cristini, Odile; Bouazaoui, Mohamed

    2013-06-01

    Space localization of the linear and nonlinear optical properties in a transparent medium at the submicron scale is still a challenge to yield the future generation of photonic devices. Laser irradiation techniques have always been thought to structure the matter at the nanometer scale, but combining them with doping methods made it possible to generate local growth of several types of nanocrystals in different kinds of silicate matrices. This paper summarizes the most recent works developed in our group, where the investigated nanoparticles are either made of metal (gold) or chalcogenide semiconductors (CdS, PbS), grown in precursor-impregnated porous xerogels under different laser irradiations. This review is associated to new results on silver nanocrystals in the same kind of matrices. It is shown that, depending on the employed laser, the particles can be formed near the sample surface or deep inside the silica matrix. Photothermal and/or photochemical mechanisms may be invoked to explain the nanoparticle growth, depending on the laser, precursor, and matrix. One striking result is that metal salt reduction, necessary to the production of the corresponding nanoparticles, can efficiently occur due to the thermal wrenching of electrons from the matrix itself or due to multiphoton absorption of the laser light by a reducer additive in femtosecond regime. Very localized semiconductor quantum dots could also be generated using ultrashort pulses, but while PbS nanoparticles grow faster than CdS particles due to one-photon absorption, this better efficiency is counterbalanced by a sensitivity to oxidation. In most cases where the reaction efficiency is high, particles larger than the pores have been obtained, showing that a fast diffusion of the species through the interconnected porosity can modify the matrix itself. Based on our experience in these techniques, we compare several examples of laser-induced nanocrystal growth in porous silica xerogels, which allows

  20. Laser-induced growth of nanocrystals embedded in porous materials.

    PubMed

    Capoen, Bruno; Chahadih, Abdallah; El Hamzaoui, Hicham; Cristini, Odile; Bouazaoui, Mohamed

    2013-06-06

    Space localization of the linear and nonlinear optical properties in a transparent medium at the submicron scale is still a challenge to yield the future generation of photonic devices. Laser irradiation techniques have always been thought to structure the matter at the nanometer scale, but combining them with doping methods made it possible to generate local growth of several types of nanocrystals in different kinds of silicate matrices. This paper summarizes the most recent works developed in our group, where the investigated nanoparticles are either made of metal (gold) or chalcogenide semiconductors (CdS, PbS), grown in precursor-impregnated porous xerogels under different laser irradiations. This review is associated to new results on silver nanocrystals in the same kind of matrices. It is shown that, depending on the employed laser, the particles can be formed near the sample surface or deep inside the silica matrix. Photothermal and/or photochemical mechanisms may be invoked to explain the nanoparticle growth, depending on the laser, precursor, and matrix. One striking result is that metal salt reduction, necessary to the production of the corresponding nanoparticles, can efficiently occur due to the thermal wrenching of electrons from the matrix itself or due to multiphoton absorption of the laser light by a reducer additive in femtosecond regime. Very localized semiconductor quantum dots could also be generated using ultrashort pulses, but while PbS nanoparticles grow faster than CdS particles due to one-photon absorption, this better efficiency is counterbalanced by a sensitivity to oxidation. In most cases where the reaction efficiency is high, particles larger than the pores have been obtained, showing that a fast diffusion of the species through the interconnected porosity can modify the matrix itself. Based on our experience in these techniques, we compare several examples of laser-induced nanocrystal growth in porous silica xerogels, which allows

  1. Laser-induced growth of nanocrystals embedded in porous materials

    PubMed Central

    2013-01-01

    Space localization of the linear and nonlinear optical properties in a transparent medium at the submicron scale is still a challenge to yield the future generation of photonic devices. Laser irradiation techniques have always been thought to structure the matter at the nanometer scale, but combining them with doping methods made it possible to generate local growth of several types of nanocrystals in different kinds of silicate matrices. This paper summarizes the most recent works developed in our group, where the investigated nanoparticles are either made of metal (gold) or chalcogenide semiconductors (CdS, PbS), grown in precursor-impregnated porous xerogels under different laser irradiations. This review is associated to new results on silver nanocrystals in the same kind of matrices. It is shown that, depending on the employed laser, the particles can be formed near the sample surface or deep inside the silica matrix. Photothermal and/or photochemical mechanisms may be invoked to explain the nanoparticle growth, depending on the laser, precursor, and matrix. One striking result is that metal salt reduction, necessary to the production of the corresponding nanoparticles, can efficiently occur due to the thermal wrenching of electrons from the matrix itself or due to multiphoton absorption of the laser light by a reducer additive in femtosecond regime. Very localized semiconductor quantum dots could also be generated using ultrashort pulses, but while PbS nanoparticles grow faster than CdS particles due to one-photon absorption, this better efficiency is counterbalanced by a sensitivity to oxidation. In most cases where the reaction efficiency is high, particles larger than the pores have been obtained, showing that a fast diffusion of the species through the interconnected porosity can modify the matrix itself. Based on our experience in these techniques, we compare several examples of laser-induced nanocrystal growth in porous silica xerogels, which allows

  2. Aerosol-nutrient-induced picoplankton growth in Lake Tahoe

    NASA Astrophysics Data System (ADS)

    Mackey, Katherine R. M.; Hunter, Deborah; Fischer, Emily V.; Jiang, Yilun; Allen, Brant; Chen, Ying; Liston, Anne; Reuter, John; Schladow, Geoff; Paytan, Adina

    2013-07-01

    Tahoe is an oligotrophic lake appreciated for its transparent waters, yet the Lake's clarity has been declining for several decades due in part to eutrophication. At the same time, a shift from nitrogen (N) toward phosphorus (P) limitation of phytoplankton has occurred that could be due to atmospheric deposition of nutrients with high N:P ratios. Atmospheric particle samples collected during 2005-2006 had a mean soluble N:P ratio of 192:1, well above the Redfield ratio of 16:1 typically required by phytoplankton. Samples collected during the Angora Fire that occurred in 2007 were particularly enriched in N relative to P, with a mean ratio >2800:1. A bioassay incubation experiment was conducted using locally collected atmospheric total suspended particulate (TSP) matter. TSP samples with high ammonium (NH4+) and low P content favored the growth of picoplankton (cells <3 µm) and opportunistic filamentous cyanobacteria, whereas larger nanophytoplankton (cells 3-20 µm) were better competitors when more P was available. Picoplankton growth can increase primary productivity without causing a large increase in chlorophyll (chl a) or biomass. Aerosol-nutrient-induced picoplankton growth (together with shifts in grazing dynamics and stratification trends) may contribute to the uncoupling between primary productivity, chl a, and biomass that has been observed in Lake Tahoe in the last several decades and, in particular, following the Wheeler and Angora Fires. The chemical composition of aerosols has a marked impact on ecosystem dynamics in Lake Tahoe with potential consequences to lake productivity and microbial community dynamics.

  3. Placental Induced Growth Factor (PIGf) in Coronary Artery Disease

    NASA Technical Reports Server (NTRS)

    Sundaresan, Alamelu; Carabello, Blaise; Mehta, Satish; Schlegel, Todd; Pellis, Neal; Ott, Mark; Pierson, Duane

    2010-01-01

    Our previous studies on normal human lymphocytes have shown a five-fold increase (p less than 0.001) in angiogenic inducers such as Placental Induced Growth Factor (PIGf) in physiologically stressful environments such as modeled microgravity, a space analog. This suggests de-regulation of cardiovascular signalling pathways indicated by upregulation of PIGf. In the current study, we measured PIGf in the plasma of 33 patients with and without coronary artery disease (CAD) to investigate whether such disease is associated with increased levels of PIGf. A control consisting of 31 sex matched apparently healthy subjects was also included in the study. We observed that the levels of PIGf in CAD patients were significantly increased compared to those in healthy control subjects (p less than 0.001) and usually increased beyond the clinical threshold level (greater than 27ng/L). The mechanisms leading to up-regulation of angiogenic factors and the adaptation of organisms to stressful environments such as isolation, high altitude, hypoxia, ischemia, microgravity, increased radiation, etc are presently unknown and require further investigation in spaceflight and these other physiologically stressed environments.

  4. Placental Induced Growth Factor (PIGf) in Coronary Artery Disease

    NASA Technical Reports Server (NTRS)

    Sundaresan, Alamelu; Carabello, Blaise; Mehta, Satish; Schlegel, Todd; Pellis, Neal; Ott, Mark; Pierson, Duane

    2010-01-01

    Our previous studies on normal human lymphocytes have shown a five-fold increase (p less than 0.001) in angiogenic inducers such as Placental Induced Growth Factor (PIGf) in physiologically stressful environments such as modeled microgravity, a space analog. This suggests de-regulation of cardiovascular signalling pathways indicated by upregulation of PIGf. In the current study, we measured PIGf in the plasma of 33 patients with and without coronary artery disease (CAD) to investigate whether such disease is associated with increased levels of PIGf. A control consisting of 31 sex matched apparently healthy subjects was also included in the study. We observed that the levels of PIGf in CAD patients were significantly increased compared to those in healthy control subjects (p less than 0.001) and usually increased beyond the clinical threshold level (greater than 27ng/L). The mechanisms leading to up-regulation of angiogenic factors and the adaptation of organisms to stressful environments such as isolation, high altitude, hypoxia, ischemia, microgravity, increased radiation, etc are presently unknown and require further investigation in spaceflight and these other physiologically stressed environments.

  5. Mesenteric Neovascularization with Distraction-Induced Intestinal Growth: Enterogenesis

    PubMed Central

    Ralls, Matthew W.; Sueyoshi, Ryo; Herman, Richard S.; Utter, Brent; Czarnocki, Isabel; Si, Nancy; Luntz, Jonathan; Brei, Diann; Teitelbaum, Daniel H.

    2012-01-01

    Background Distraction-induced enterogenesis, whereby the intestine lengthens with application of linear forces, is an emerging area which may provide a unique treatment for short bowel syndrome (SBS). With an increase in overall tissue mass, there is an increase in oxygen and nutrient demand. We hypothesized that a neovascularization within the mesentery is necessary to support the growing small bowel. Methods A curvilinear hydraulic device was used to induce growth within the small bowel of Yorkshire pigs, and the intestine was harvested after 14 days. High-resolution, gross pictures were recorded of the mesentery at implantation and at harvest, and CT imaging of the bowel and mesentery was performed at harvest after dye injection. Results After 2 weeks of distraction, an average of 72.5% (8.7cm) bowel lengthening was achieved. Gross images of the mesentery between major vessels showed a blossoming of the microvasculature and this was confirmed by CT imaging with 3D reconstruction. Mesenteric sample taken from the distracted segment had a 4-fold increase in the volume of microvasculature versus controls. Conclusion Enterogenesis results not only in increased bowel length, but significant increase in the mesenteric microvascularity. Presumably, this sustains the lengthened segment after application of longitudinal forces. PMID:23229341

  6. Epidermal Growth Factor-induced Vacuolar (H+)-ATPase Assembly

    PubMed Central

    Xu, Yanqing; Parmar, Amanda; Roux, Emmanuelle; Balbis, Alejandro; Dumas, Victor; Chevalier, Stephanie; Posner, Barry I.

    2012-01-01

    Using proteomics and immunofluorescence, we demonstrated epidermal growth factor (EGF) induced recruitment of extrinsic V1 subunits of the vacuolar (H+)-ATPase (V-ATPase) to rat liver endosomes. This was accompanied by reduced vacuolar pH. Bafilomycin, an inhibitor of V-ATPase, inhibited EGF-stimulated DNA synthesis and mammalian target of rapamycin complex 1 (mTORC1) activation as indicated by a decrease in eukaryotic initiation factor 4E-binding 1 (4E-BP1) phosphorylation and p70 ribosomal S6 protein kinase (p70S6K) phosphorylation and kinase activity. There was no corresponding inhibition of EGF-induced Akt and extracellular signal-regulated kinase (Erk) activation. Chloroquine, a neutralizer of vacuolar pH, mimicked bafilomycin effects. Bafilomycin did not inhibit the association of mTORC1 with Raptor nor did it affect AMP-activated protein kinase activity. Rather, the intracellular concentrations of essential but not non-essential amino acids were decreased by bafilomycin in EGF-treated primary rat hepatocytes. Cycloheximide, a translation elongation inhibitor known to augment intracellular amino acid levels, prevented the effect of bafilomycin on amino acids levels and completely reversed its inhibition of EGF-induced mTORC1 activation. In vivo administration of EGF stimulated the recruitment of Ras homologue enriched in brain (Rheb) but not mammalian target of rapamycin (mTOR) to endosomes and lysosomes. This was inhibited by chloroquine treatment. Our results suggest a role for vacuolar acidification in EGF signaling to mTORC1. PMID:22689575

  7. Enhancing the growth of natural eyelashes: the mechanism of bimatoprost-induced eyelash growth.

    PubMed

    Cohen, Joel L

    2010-09-01

    Many women desire prominent eyelashes. In December 2008, bimatoprost ophthalmic solution 0.03% was approved for the treatment of hypotrichosis of the eyelashes in the United States. To review eyelash physiology and the proposed mechanisms by which the topical pros-tamide product bimatoprost enhances eyelash growth. Clinical and preclinical studies pertaining to the efficacy, safety, and mechanisms of action of bimatoprost are presented. Treatment with bimatoprost increases the percentage of eyelash follicles in anagen at any one time. This probably accounts for its ability to lengthen lashes. Bimatoprost-induced stimulation of melanogenesis appears to result in darker lashes and, at the same time, appears to increase the size of the dermal papilla and hair bulb, affecting lash thickness and fullness. Such effects, largely demonstrated in animal studies, are consistent with the results of a recent Food and Drug Administration phase III clinical trial. The favorable safety profile of bimatoprost in human subjects is probably secondary to the limited exposure of ocular tissues resulting from topical application at the base of the upper lashes. By influencing the eyelash hair cycle and follicles, bimatoprost ophthalmic solution 0.03% is a safe and effective means of enhancing eyelash growth. Dr. Cohen has served as a consultant and clinical trial participant for Allergan, Inc. © 2010 by the American Society for Dermatologic Surgery, Inc.

  8. Modeling photothermal and acoustical induced microbubble generation and growth.

    PubMed

    Krasovitski, Boris; Kislev, Hanoch; Kimmel, Eitan

    2007-12-01

    Previous experimental studies showed that powerful heating of nanoparticles by a laser pulse using energy density greater than 100 mJ/cm(2), could induce vaporization and generate microbubbles. When ultrasound is introduced at the same time as the laser pulse, much less laser power is required. For therapeutic applications, generation of microbubbles on demand at target locations, e.g. cells or bacteria can be used to induce hyperthermia or to facilitate drug delivery. The objective of this work is to develop a method capable of predicting photothermal and acoustic parameters in terms of laser power and acoustic pressure amplitude that are needed to produce stable microbubbles; and investigate the influence of bubble coalescence on the thresholds when the microbubbles are generated around nanoparticles that appear in clusters. We develop and solve here a combined problem of momentum, heat and mass transfer which is associated with generation and growth of a microbubble, filled with a mixture of non-vaporized gas (air) and water vapor. The microbubble's size and gas content vary as a result of three mechanisms: gas expansion or compression, evaporation or condensation on the bubble boundary, and diffusion of dissolved air in the surrounding water. The simulations predict that when ultrasound is applied relatively low threshold values of laser and ultrasound power are required to obtain a stable microbubble from a single nanoparticle. Even lower power is required when microbubbles are formed by coalescence around a cluster of 10 nanoparticles. Laser pulse energy density of 21 mJ/cm(2) is predicted for instance together with acoustic pressure of 0.1 MPa for a cluster of 10 or 62 mJ/cm(2) for a single nanoparticle. Those values are well within the safety limits, and as such are most appealing for targeted therapeutic purposes.

  9. Branching geometry induced by lung self-regulated growth

    NASA Astrophysics Data System (ADS)

    Clément, Raphaël; Douady, Stéphane; Mauroy, Benjamin

    2012-12-01

    Branching morphogenesis is a widely spread phenomenon in nature. In organogenesis, it results from the inhomogeneous growth of the epithelial sheet, leading to its repeated branching into surrounding mesoderm. Lung morphogenesis is an emblematic example of tree-like organogenesis common to most mammals. The core signalling network is well identified, notably the Fgf10/Shh couple, required to initiate and maintain branching. In a previous study, we showed that the restriction by SHH of Fgf10 expression domain to distal mesenchyme spontaneously induces differential epithelial proliferation leading to branching. A simple Laplacian model qualitatively reproduced FGF10 dynamics in the mesenchyme and the spontaneous self-avoiding branching morphogenesis. However, early lung geometry has several striking features that remain to be addressed. In this paper, we investigate, through simulations and data analysis, if the FGF10-diffusion scenario accounts for the following aspects of lung morphology: size dispersion, asymmetry of branching events, and distal epithelium-mesothelium equilibrium. We report that they emerge spontaneously in the model, and that most of the underlying mechanisms can be understood as dynamical interactions between gradients and shape. This suggests that specific regulation may not be required for the emergence of these striking geometrical features.

  10. Connective tissue growth factor induces cardiac hypertrophy through Akt signaling

    SciTech Connect

    Hayata, Nozomi; Fujio, Yasushi; Yamamoto, Yasuhiro; Iwakura, Tomohiko; Obana, Masanori; Takai, Mika; Mohri, Tomomi; Nonen, Shinpei; Maeda, Makiko; Azuma, Junichi

    2008-05-30

    In the process of cardiac remodeling, connective tissue growth factor (CTGF/CCN2) is secreted from cardiac myocytes. Though CTGF is well known to promote fibroblast proliferation, its pathophysiological effects in cardiac myocytes remain to be elucidated. In this study, we examined the biological effects of CTGF in rat neonatal cardiomyocytes. Cardiac myocytes stimulated with full length CTGF and its C-terminal region peptide showed the increase in cell surface area. Similar to hypertrophic ligands for G-protein coupled receptors, such as endothelin-1, CTGF activated amino acid uptake; however, CTGF-induced hypertrophy is not associated with the increased expression of skeletal actin or BNP, analyzed by Northern-blotting. CTGF treatment activated ERK1/2, p38 MAPK, JNK and Akt. The inhibition of Akt by transducing dominant-negative Akt abrogated CTGF-mediated increase in cell size, while the inhibition of MAP kinases did not affect the cardiac hypertrophy. These findings indicate that CTGF is a novel hypertrophic factor in cardiac myocytes.

  11. Intrapulmonary growth of Staphylococcus aureus in rats during induced atelectasis.

    PubMed

    Frederick, D; Pesanti, E L

    1987-11-01

    Intrinsic pulmonary antibacterial defenses are mediated by alveolar macrophages and by noncellular factors. Mechanical ventilation in the resting tidal volume range leads to alterations in the physical characteristics of alveolar surfactant, alveolar instability, regional hypoxia, and systemic hypoxemia. While a number of experimental manipulations diminish the activity of the intrinsic antibacterial defense system, the effects of mechanical ventilation per se have not been systematically evaluated previously. We found that normal rats ventilated without sighing (periodic large breaths) manifested severe defects in pulmonary clearance of Staphylococcus aureus during 6-h experiments, such that growth of the inoculum occurred. Addition of a timer-controlled mechanism to cause the animals to sigh every 2 min, without other modifications in the experimental conditions, caused significant improvement in clearance. Analysis of cellular response, compartmentalization of viable bacteria, surfactant quantities and sedimentation characteristics, and protein influx indicated that the defect in clearance paralleled alterations in the physical state of surfactant and alveolar stability but was not strongly correlated with alterations in the other parameters we measured. The data show that defective pulmonary bacterial clearance is rapidly induced by measures which alter alveolar stability and suggest that intrinsic pulmonary defenses require maintenance of normal air-liquid interfaces for optimal function.

  12. Mifepristone inhibits MPA-and FGF2-induced mammary tumor growth but not FGF2-induced mammary hyperplasia.

    PubMed

    Cerliani, Juan P; Giulianelli, Sebastián; Sahores, Ana; Wargon, Victoria; Gongora, Adrian; Baldi, Alberto; Molinolo, Alfredo; Lamb, Caroline E; Lanari, Claudia

    2010-01-01

    We have previously demonstrated a crosstalk between fibroblast growth factor 2 (FGF2) and progestins inducing experimental breast cancer growth. The aim of the present study was to compare the effects of FGF2 and of medroxyprogesterone acetate (MPA) on the mouse mammary glands and to investigate whether the antiprogestin RU486 was able to reverse the MPA- or FGF2-induced effects on both, mammary gland and tumor growth. We demonstrate that FGF2 administered locally induced an intraductal hyperplasia that was not reverted by RU486, suggesting that FGF2-induced effects are progesterone receptor (PR)-independent. However, MPA-induced paraductal hyperplasia was reverted by RU486 and a partial agonistic effect was observed in RU486-treated glands. Using C4-HD tumors which only grow in the presence of MPA, we showed that FGF2 administered intratumorally was able to stimulate tumor growth as MPA. The histology of FGF2-treated tumors showed different degrees of gland differentiation. RU486 inhibited both, MPA or FGF2 induced tumor growth. However, only complete regression was observed in MPA-treated tumors. Our results support the hypothesis that stromal FGF2 activates PR inducing hormone independent tumor growth.

  13. A chemical pollen suppressant inhibits auxin-induced growth in maize coleoptile sections

    SciTech Connect

    Vesper, M.J. ); Cross, J.W. )

    1990-05-01

    Chemical inhibitors of pollen development having a phenylcinnoline carboxylate structure were found to inhibit IAA- and 1-NAA-induced growth in maize coleoptile sections. The inhibitor (100 {mu}M) used in these experiments caused approx. 35% reduction in auxin-induced growth over the auxin concentration range of 0.3 to 100 {mu}M. Growth inhibition was noted as a lengthening of the latent period and a decrease in the rate of an auxin-induced growth response. An acid growth response to pH 5 buffer in abraded sections was not impaired. The velocity of basipetal transport of ({sup 3}H)IAA through the coleoptile sections also was not inhibited by the compound, nor was uptake of ({sup 3}H)IAA. Similarly, the inhibitor does not appear to alter auxin-induced H{sup +} secretion. We suggest that the agent targets some other process necessary for auxin-dependent growth.

  14. Arctigenin induced gallbladder cancer senescence through modulating epidermal growth factor receptor pathway.

    PubMed

    Zhang, Mingdi; Cai, Shizhong; Zuo, Bin; Gong, Wei; Tang, Zhaohui; Zhou, Di; Weng, Mingzhe; Qin, Yiyu; Wang, Shouhua; Liu, Jun; Ma, Fei; Quan, Zhiwei

    2017-05-01

    Gallbladder cancer has poor prognosis and limited therapeutic options. Arctigenin, a representative dibenzylbutyrolactone lignan, occurs in a variety of plants. However, the molecular mechanisms involved in the antitumor effect of arctigenin on gallbladder cancer have not been fully elucidated. The expression levels of epidermal growth factor receptor were examined in 100 matched pairs of gallbladder cancer tissues. A positive correlation between high epidermal growth factor receptor expression levels and poor prognosis was observed in gallbladder cancer tissues. Pharmacological inhibition or inhibition via RNA interference of epidermal growth factor receptor induced cellular senescence in gallbladder cancer cells. The antitumor effect of arctigenin on gallbladder cancer cells was primarily achieved by inducing cellular senescence. In gallbladder cancer cells treated with arctigenin, the expression level of epidermal growth factor receptor significantly decreased. The analysis of the activity of the kinases downstream of epidermal growth factor receptor revealed that the RAF-MEK-ERK signaling pathway was significantly inhibited. Furthermore, the cellular senescence induced by arctigenin could be reverted by pcDNA-epidermal growth factor receptor. Arctigenin also potently inhibited the growth of tumor xenografts, which was accompanied by the downregulation of epidermal growth factor receptor and induction of senescence. This study demonstrates arctigenin could induce cellular senescence in gallbladder cancer through the modulation of epidermal growth factor receptor pathway. These data identify epidermal growth factor receptor as a key regulator in arctigenin-induced gallbladder cancer senescence.

  15. Role of chloride ions in the promotion of auxin-induced growth of maize coleoptile segments

    PubMed Central

    Burdach, Zbigniew; Kurtyka, Renata; Siemieniuk, Agnieszka; Karcz, Waldemar

    2014-01-01

    Background and Aims The mechanism of auxin action on ion transport in growing cells has not been determined in detail. In particular, little is known about the role of chloride in the auxin-induced growth of coleoptile cells. Moreover, the data that do exist in the literature are controversial. This study describes experiments that were carried out with maize (Zea mays) coleoptile segments, this being a classical model system for studies of plant cell elongation growth. Methods Growth kinetics or growth and pH changes were recorded in maize coleoptiles using two independent measuring systems. The growth rate of the segments was measured simultaneously with medium pH changes. Membrane potential changes in parenchymal cells of the segments were also determined for chosen variants. The question of whether anion transport is involved in auxin-induced growth of maize coleoptile segments was primarily studied using anion channel blockers [anthracene-9-carboxylic acid (A-9-C) and 4,4′-diisothiocyanatostilbene-2,2′-disulphonic acid (DIDS)]. In addition, experiments in which KCl was replaced by KNO3 were also performed. Key Results Both anion channel blockers, added at 0·1 mm, diminished indole-3-acetic acid (IAA)-induced elongation growth by ∼30 %. Medium pH changes measured simultaneously with growth indicated that while DIDS stopped IAA-induced proton extrusion, A-9-C diminished it by only 50 %. Addition of A-9-C to medium containing 1 mm KCl did not affect the characteristic kinetics of IAA-induced membrane potential changes, while in the presence of 10 mm KCl the channel blocker stopped IAA-induced membrane hyperpolarization. Replacement of KCl with KNO3 significantly decreased IAA-induced growth and inhibited proton extrusion. In contrast to the KCl concentration, the concentration of KNO3 did not affect the growth-stimulatory effect of IAA. For comparison, the effects of the cation channel blocker tetraethylammonium chloride (TEA-Cl) on IAA-induced growth and

  16. Thiazolidinediones enhance vascular endothelial growth factor expression and induce cell growth inhibition in non-small-cell lung cancer cells

    PubMed Central

    2010-01-01

    Background It is known that thiazolidinediones are involved in regulating the expression of various genes, including the vascular endothelial growth factor (VEGF) gene via peroxisome proliferator-activated receptor γ (PPARγ); VEGF is a prognostic biomarker for non-small-cell lung cancer (NSCLC). Methods In this study, we investigated the effects of troglitazone and ciglitazone on the mRNA expression of VEGF and its receptors in human NSCLC cell lines, RERF-LC-AI, SK-MES-1, PC-14, and A549. These mRNA expressions were evaluated by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. We also studied the effect of Je-11, a VEGF inhibitor, on the growth of these cells. Results In NSCLC cells, thiazolidinediones increased the mRNA expression of VEGF and neuropilin-1, but not that of other receptors such as fms-like tyrosine kinase and kinase insert domain receptor-1. Furthermore, the PPARγ antagonist GW9662 completely reversed this thiazolidinedione-induced increase in VEGF expression. Furthermore, the addition of VEGF inhibitors into the culture medium resulted in the reversal of thiazolidinedione-induced growth inhibition. Conclusions Our results indicated that thiazolidinediones enhance VEGF and neuropilin-1 expression and induce the inhibition of cell growth. We propose the existence of a pathway for arresting cell growth that involves the interaction of thiazolidinedione-induced VEGF and neuropilin-1 in NSCLC. PMID:20214829

  17. Lichen growth responses to stress induced by automobile exhaust pollution.

    PubMed

    Lawrey, J D; Hale, M E

    1979-04-27

    Growth rates were significantly suppressed in juvenile thalli (less than 0.1 square millimeter in initial size) of the saxicolous lichen Pseudoparmelia baltimorensis from a Potomac River island with high atmospheric lead burden as compared to the case for a similar island with a lower lead burden. However, larger thalli showed no significant changes in growth response as a result of atmospheric pollution stress. Disruptions in lichen growth thus appear to affect life stages when growth is most rapid andfood reserves are low. Once a minimnum thallus size is attained, the stress tolerance of the lichen increases.

  18. Transforming growth factor-beta induces endothelin-1 expression through activation of the Smad signaling pathway.

    PubMed

    Rodríguez-Pascual, Fernando; Reimunde, Francisco Manuel; Redondo-Horcajo, Mariano; Lamas, Santiago

    2004-11-01

    Expression of the endothelin-1 gene is subject to complex regulation by different factors, among which transforming growth factor-beta is one of the most important. We have analyzed the mechanism by which transforming growth factor-beta increases endothelin-1 expression in vascular endothelial cells. Transcriptional activation of the endothelin-1 promoter accounted for the transforming growth factor-beta-induced increase in endothelin-1 mRNA levels. Two DNA elements within the promoter are responsible for this effect: a Smad binding element and a proximal activator protein-1 site. Mutation of both elements abolished transforming growth factor-beta responsiveness. Overexpression of the Smad3 isoform strongly potentiates transforming growth factor-beta- induced endothelin-1 promoter activity in a phosphorylation-dependent manner. These results demonstrate that transforming growth factor-beta induces endothelin-1 expression by a functional cooperation between Smads and activator protein-1 through activation of the Smad signaling pathway.

  19. The plant growth-promoting fungus Aspergillus ustus promotes growth and induces resistance against different lifestyle pathogens in Arabidopsis thaliana.

    PubMed

    Salas-Marina, Miguel Angel; Silva-Flores, Miguel Angel; Cervantes-Badillo, Mayte Guadalupe; Rosales-Saavedra, Maria Teresa; Islas-Osuna, Maria Auxiliadora; Casas-Flores, Sergio

    2011-07-01

    To deal with pathogens, plants have evolved sophisticated mechanisms including constitutive and induced defense mechanisms. Phytohormones play important roles in plant growth and development, as well as in the systemic response induced by beneficial and pathogen microorganisms. In this work, we identified an Aspergillus ustus isolate that promotes growth and induces developmental changes in Solanum tuberosum and Arabidopsis thaliana. A. ustus inoculation on A. thaliana and S. tuberosum roots induced an increase in shoot and root growth, and lateral root and root hair numbers. Assays performed on Arabidopsis lines to measure reporter gene expression of auxin-induced/ repressed or cell cycle controlled genes (DR5 and CycB1, respectively) showed enhanced GUS activity, when compared with mock-inoculated seedlings. To determine the contribution of phytohormone signaling pathways in the effect elicited by A. ustus, we evaluated the response of a collection of hormone mutants of Arabidopsis defective in auxin, ethylene, cytokinin, or abscisic acid signaling to the inoculation with this fungus. All mutant lines inoculated with A. ustus showed increased biomass production, suggesting that these genes are not required to respond to this fungus. Moreover, we demonstrated that A. ustus synthesizes auxins and gibberellins in liquid cultures. In addition, A. ustus induced systemic resistance against the necrotrophic fungus Botrytis cinerea and the hemibiotrophic bacterium Pseudomonas syringae DC3000, probably through the induction of the expression of salicylic acid, jasmonic acid/ethylene, and camalexin defense-related genes in Arabidopsis.

  20. Proportionality of ELF electric field-induced growth inhibition to induced membrane potential in Zea mays and Vicia faba roots.

    PubMed

    Brayman, A A; Megumi, T; Miller, M W

    1990-01-01

    The postulate that 60-Hz electric field-induced bioeffect severity is proportional to induced transmembrane potential [Vmi] magnitude was tested and supported using a plant root model cell system. Statistically significant correlations were obtained upon regression of the relative rates of exposed Vicia faba and Zea mays root segment growth on the average Vmi (calculated) arising in those segments under specified 60 Hz field exposure conditions. The Vmi associated with the apparent threshold for growth inhibition was similar in Zea and Vicia roots (2.5 vs 2.4 mV, respectively). At Vmi greater than this threshold, Zea root growth declined by about 9% per mV, and Vicia root growth by about 19% per mV induced potential.

  1. Disseminated thrombosis-induced growth plate necrosis in rat: a unique model for growth plate arrest.

    PubMed

    Nyska, Meir; Shabat, Shay; Long, Philip H; Howard, Charles; Ezov, Nathan; Levin-Harrus, Tal; Mittelman, Moshe; Redlich, Meir; Yedgar, Saul; Nyska, Abraham

    2005-01-01

    Exposure of rats to 2-butoxyethanol (BE) produces early hemolytic anemia and disseminated thrombosis. This leads to infarctions in multiple organs, including bones and cartilage. BE, administered for different durations of exposure in two separate experiments, produced metaphyseal vascular thrombosis, growth plate infarction, and partial or complete physeal growth arrest. This reproducible model may serve as a useful tool in the study of some conditions that manifest growth plate damage. The suitability of this model for investigating the pathogenesis of growth plate necrosis and as a model for potential therapy for various human growth plate disorders are discussed.

  2. Tamoxifen induces permanent growth arrest through selective induction of apoptosis in growth plate chondrocytes in cultured rat metatarsal bones.

    PubMed

    Chagin, Andrei S; Karimian, Elham; Zaman, Farasat; Takigawa, Masaharu; Chrysis, Dionisios; Sävendahl, Lars

    2007-05-01

    Estrogen affects skeletal growth and promotes growth plate fusion in humans. High doses of estrogen have been used to limit growth in girls with predicted extreme tall stature; a treatment which has been associated with severe side effects. Selective estrogen receptor modulators (SERMs) could potentially be used as an alternative treatment. We chose to study the effects of Tamoxifen (Tam), a first generation SERM that has been used in the treatment of pubertal gynecomastia or McCune-Albright syndrome. Cultured fetal rat metatarsal bones were used to study the effects of Tam on longitudinal bone growth. In sectioned bones, chondrocyte apoptosis and proliferation were analyzed by TUNEL assay and BrdU incorporation, respectively. We also used a human chondrocytic cell line, HSC-2/8, to study the effects of Tam on apoptosis (FACS analysis and Cell Death detection ELISA) and caspase activation (caspase substrate cleavage and Western immunoblotting). Tam caused a dose-dependent growth retardation of cultured metatarsal bones. No catch-up growth was observed after Tam was removed from the culture medium. Detailed analysis of sectioned growth plate cartilage revealed increased apoptosis of chondrocytes within the resting and hypertrophic zones. HCS-2/8 cells also underwent apoptosis upon Tam treatment. Tam-induced apoptosis was caspase-dependent and completely abrogated by either caspase-8 or -9 inhibitors. A substrate assay revealed that caspase-8 is first activated followed by caspase-9 and -3. Finally, FasL secretion was stimulated by Tam and blocking of either FasL or Fas decreased Tam-induced apoptosis in chondrocytes. We here describe a novel mechanism of tamoxifen-induced apoptosis in chondrocytes, involving the activation of caspases and the FasL/Fas pathway, which diminishes the potential for bone growth.

  3. Surface-diffusion induced growth of ZnO nanowires

    NASA Astrophysics Data System (ADS)

    Kim, D. S.; Gösele, U.; Zacharias, M.

    2009-05-01

    The growth rate of ZnO nanowires grown epitaxially on GaN/sapphire substrates is studied. An inverse proportional relation between diameter and length of the nanowires is observed, i.e., nanowires with smaller diameters grow faster than larger ones. This unexpected result is attributed to surface diffusion of ZnO admolecules along the sidewalls of the nanowires. In addition, the unique c-axis growth of ZnO nanowires, which does not require a catalytic particle at the tip of the growing nanowires is discussed by taking into account polarity, surface free energy, and ionicity. Activation energies of the nanowire growth are determined as well.

  4. Galactose inhibits auxin-induced growth of Avena coleoptiles by two mechanisms

    NASA Technical Reports Server (NTRS)

    Cheung, S. P.; Cleland, R. E.

    1991-01-01

    Galactose inhibits auxin-induced growth of Avena coleoptiles by at least two mechanisms. First, it inhibits auxin-induced H(+)-excretion needed for the initiation of rapid elongation. Galactose cannot be doing so by directly interfering with the ATPase since fusicoccin-induced H(+)-excretion is not affected. Secondly, galactose inhibits long-term auxin-induced growth, even in an acidic (pH 4.5) solution. This may be due to an inhibition of cell wall synthesis. However, galactose does not reduce the capacity of walls to be loosened by H+, given exogenously or excreted in response to fusicoccin.

  5. Galactose inhibits auxin-induced growth of Avena coleoptiles by two mechanisms

    NASA Technical Reports Server (NTRS)

    Cheung, S. P.; Cleland, R. E.

    1991-01-01

    Galactose inhibits auxin-induced growth of Avena coleoptiles by at least two mechanisms. First, it inhibits auxin-induced H(+)-excretion needed for the initiation of rapid elongation. Galactose cannot be doing so by directly interfering with the ATPase since fusicoccin-induced H(+)-excretion is not affected. Secondly, galactose inhibits long-term auxin-induced growth, even in an acidic (pH 4.5) solution. This may be due to an inhibition of cell wall synthesis. However, galactose does not reduce the capacity of walls to be loosened by H+, given exogenously or excreted in response to fusicoccin.

  6. Effects of growth hormone plus a hyperproteic diet on methotrexate-induced injury in rat intestines.

    PubMed

    Ortega, M; Gomez-de-Segura, I A; Vázquez, I; López, J M; de Guevara, C L; De-Miguel, E

    2001-01-01

    The aim of this study was to determine whether growth hormone treatment reduces injury to the intestinal mucosa induced by methotrexate (MTX). Wistar rats with intestinal injury induced by methotrexate were treated with daily growth hormone, beginning 3 days before MTX treatment until 3 or 4 days after MTX administration. The rats were killed at 3 or 7 days post-MTX administration. The rats were fed with either a normoproteic diet or a hyperproteic diet. Body weight, mortality, bacterial translocation, intestinal morphometry, proliferation and apoptosis and blood somatostatin and IGF-1 were determined. Combined administration of growth hormone and a hyperproteic diet reduces MTX-induced mortality. This effect was accompanied by increased cell proliferation and decreased apoptosis within the crypt. Morphometric data showed complete recovery of the mucosa by day 7 post-MTX administration. These results indicate a synergistic protective action of growth hormone combined with a hyperproteic diet to MTX-induced injury.

  7. Initiation, Growth and Mitigation of UV Laser Induced Damage in Fused Silica

    SciTech Connect

    Rubenchik, A M; Feit, M D

    2003-06-10

    Laser damage of large fused silica optics initiates at imperfections. Possible initiation mechanisms are considered. We demonstrate that a model based on nanoparticle explosions is consistent with the observed initiation craters. Possible mechanisms for growth upon subsequent laser irradiation, including material modification and laser intensification, are discussed. Large aperture experiments indicate an exponential increase in damage size with number of laser shots. Physical processes associated with this growth and a qualitative explanation of self-accelerated growth is presented. Rapid growth necessitates damage growth mitigation techniques. Several possible mitigation techniques are mentioned, with special emphasis on CO{sub 2} processing. Analysis of material evaporation, crack healing, and thermally induced stress are presented.

  8. Initiation, Growth and Mitigation of UV Laser Induced Damage in Fused Silica

    SciTech Connect

    Rubenchik, A M; Feit, M D

    2001-12-21

    Laser damage of large fused silica optics initiates at imperfections. Possible initiation mechanisms are considered. We demonstrate that a model based on nanoparticle explosions is consistent with the observed initiation craters. Possible mechanisms for growth upon subsequent laser irradiation, including material modification and laser intensification, are discussed. Large aperture experiments indicate an exponential increase in damage size with number of laser shots. Physical processes associated with this growth and a qualitative explanation of self-accelerated growth is presented. Rapid growth necessitates damage growth mitigation techniques. Several possible mitigation techniques are mentioned, with special emphasis on CO{sub 2} processing. Analysis of material evaporation, crack healing, and thermally induced stress are presented.

  9. Inhibition of Estrogen-Induced Growth of Breast Cancer by Targeting Mitochondria Oxidants

    DTIC Science & Technology

    2010-04-01

    breast cancer cells and other cell types. Low levels of ROS have been reported to induce proliferation, growth and metastasis of breast cancer cells...cells and other cell types which at a chronic sublethal levelhave been shown to induce proliferation,growth, and metastasis to cause therapeutic...cooperates with E2F targeted gene expression of human bone osteosarcoma and mammary gland adenocarcinoma to down-regulates proliferation [78;79

  10. Evidence that auxin-induced growth of soybean hypocotyls involves proton excretion

    SciTech Connect

    Rayle, D.L.; Cleland, R.E.

    1980-09-01

    The role of H/sup +/ excretion in auxin-induced growth of soybean hypocotyl tissues has been investigated, using tissues whose cuticle was rendered permeable to protons or buffers by scarification (scrubbing). Indoleacetic acid induces both elongation and H/sup +/ excretion after a lag of 10 to 12 minutes. Cycloheximide inhibits growth and causes the tissues to remove protons from the medium. Neutral buffers (pH 7.0) inhibit auxin-induced growth of scrubbed but not intact sections; the inhibition increases as the buffers strength is increased. Both live and frozen-thawed sections, in the absence of auxin, extend in response to exogenously supplied protons. Fusicoccin induces both elongation and H/sup +/ excretion at rates greater than does auxin. These results indicate that H/sup +/ excretion is involved in the initiation of auxin-induced elongation in soybean hypocotyl tissue.

  11. Characteristics and implications of prolonged fusicoccin-induced growth of Avena coleoptile sections

    NASA Technical Reports Server (NTRS)

    Cleland, R. E.

    1994-01-01

    A study has been made of the prolonged growth of Avena coleoptile sections in response to fusicoccin (FC), a phytotoxin that promotes apoplastic acidification. The final amount of FC-induced growth is a function of the FC concentration. Removal of the epidermis speeds up the initial rate of elongation and shortens the duration of the response, without affecting the total amount of extension. A suboptimal FC concentration (7 x 10(-8) M) which induces the same rate of proton excretion as does optimal indoleacetic acid (IAA) (1 x 10(-5) M), causes elongation which is 60-75% of that induced by IAA in 4 h or 50-65% in 7 h. This suggests that acid-induced extension could make a major contribution to auxin-induced growth for at least 7 h.

  12. Characteristics and implications of prolonged fusicoccin-induced growth of Avena coleoptile sections

    NASA Technical Reports Server (NTRS)

    Cleland, R. E.

    1994-01-01

    A study has been made of the prolonged growth of Avena coleoptile sections in response to fusicoccin (FC), a phytotoxin that promotes apoplastic acidification. The final amount of FC-induced growth is a function of the FC concentration. Removal of the epidermis speeds up the initial rate of elongation and shortens the duration of the response, without affecting the total amount of extension. A suboptimal FC concentration (7 x 10(-8) M) which induces the same rate of proton excretion as does optimal indoleacetic acid (IAA) (1 x 10(-5) M), causes elongation which is 60-75% of that induced by IAA in 4 h or 50-65% in 7 h. This suggests that acid-induced extension could make a major contribution to auxin-induced growth for at least 7 h.

  13. Auxin-induced growth of Avena coleoptiles involves two mechanisms with different pH optima

    NASA Technical Reports Server (NTRS)

    Cleland, R. E.

    1992-01-01

    Although rapid auxin-induced growth of coleoptile sections can persist for at least 18 hours, acid-induced growth lasts for a much shorter period of time. Three theories have been proposed to explain this difference in persistence. To distinguish between these theories, the pH dependence for auxin-induced growth of oat (Avena sativa L.) coleoptiles has been determined early and late in the elongation process. Coleoptile sections from which the outer epidermis was removed to facilitate buffer entry were incubated, with or without 10 micromolar indoleacetic acid, in 20 millimolar buffers at pH 4.5 to 7.0 to maintain a fixed wall pH. During the first 1 to 2 hours after addition of auxin, elongation occurs by acid-induced extension (i.e. the pH optimum is <5 and the elongation varies inversely with the solution pH). Auxin causes no additional elongation because the buffers prevent further changes in wall pH. After 60 to 90 minutes, a second mechanism of auxin-induced growth, whose pH optimum is 5.5 to 6.0, predominates. It is proposed that rapid growth responses to changes in auxin concentration are mediated by auxin-induced changes in wall pH, whereas the prolonged, steady-state growth rate is controlled by a second, auxin-mediated process whose pH optimum is less acidic.

  14. Rapid auxin-induced root growth inhibition requires the TIR and AFB auxin receptors.

    PubMed

    Scheitz, Katharina; Lüthen, Hartwig; Schenck, Daniel

    2013-12-01

    We investigated the relation between auxin-induced gene expression and the rapid auxin-induced growth inhibition in Arabidopsis thaliana roots. The natural auxin indole-3-acetic acid (IAA) induced a strong activation of gene expression as visualized by the DR5rev::GFP reporter gene technique. This effect was specific for active auxins and was abolished in knockout mutants of the F-box auxin receptors. We measured the IAA-induced growth inhibition at high time resolution and show that the F-box auxin receptor mutants failed to display this effect. We conclude that the F-box auxin receptors are needed for the response. In hypocotyls, auxin induces an increase in elongation growth, and this effect has been earlier shown to be independent of the F-box receptors. Based on these findings, we discuss differences in the growth control modes in roots and shoots. We demonstrate that the rapid auxin-induced root growth inhibition, unlike the induction of growth in hypocotyls, requires the presence of the F-box auxin receptors.

  15. Auxin-induced growth of Avena coleoptiles involves two mechanisms with different pH optima

    NASA Technical Reports Server (NTRS)

    Cleland, R. E.

    1992-01-01

    Although rapid auxin-induced growth of coleoptile sections can persist for at least 18 hours, acid-induced growth lasts for a much shorter period of time. Three theories have been proposed to explain this difference in persistence. To distinguish between these theories, the pH dependence for auxin-induced growth of oat (Avena sativa L.) coleoptiles has been determined early and late in the elongation process. Coleoptile sections from which the outer epidermis was removed to facilitate buffer entry were incubated, with or without 10 micromolar indoleacetic acid, in 20 millimolar buffers at pH 4.5 to 7.0 to maintain a fixed wall pH. During the first 1 to 2 hours after addition of auxin, elongation occurs by acid-induced extension (i.e. the pH optimum is <5 and the elongation varies inversely with the solution pH). Auxin causes no additional elongation because the buffers prevent further changes in wall pH. After 60 to 90 minutes, a second mechanism of auxin-induced growth, whose pH optimum is 5.5 to 6.0, predominates. It is proposed that rapid growth responses to changes in auxin concentration are mediated by auxin-induced changes in wall pH, whereas the prolonged, steady-state growth rate is controlled by a second, auxin-mediated process whose pH optimum is less acidic.

  16. Auxin-induced growth of Avena coleoptiles involves two mechanisms with different pH optima.

    PubMed Central

    Cleland, R E

    1992-01-01

    Although rapid auxin-induced growth of coleoptile sections can persist for at least 18 hours, acid-induced growth lasts for a much shorter period of time. Three theories have been proposed to explain this difference in persistence. To distinguish between these theories, the pH dependence for auxin-induced growth of oat (Avena sativa L.) coleoptiles has been determined early and late in the elongation process. Coleoptile sections from which the outer epidermis was removed to facilitate buffer entry were incubated, with or without 10 micromolar indoleacetic acid, in 20 millimolar buffers at pH 4.5 to 7.0 to maintain a fixed wall pH. During the first 1 to 2 hours after addition of auxin, elongation occurs by acid-induced extension (i.e. the pH optimum is <5 and the elongation varies inversely with the solution pH). Auxin causes no additional elongation because the buffers prevent further changes in wall pH. After 60 to 90 minutes, a second mechanism of auxin-induced growth, whose pH optimum is 5.5 to 6.0, predominates. It is proposed that rapid growth responses to changes in auxin concentration are mediated by auxin-induced changes in wall pH, whereas the prolonged, steady-state growth rate is controlled by a second, auxin-mediated process whose pH optimum is less acidic. PMID:11537888

  17. Quantitative description for the growth rate of self-induced GaN nanowires

    NASA Astrophysics Data System (ADS)

    Consonni, V.; Dubrovskii, V. G.; Trampert, A.; Geelhaar, L.; Riechert, H.

    2012-04-01

    We determine with high precision the growth rate of self-induced GaN nanowires grown by molecular beam epitaxy under various conditions from scanning electron micrographs by taking into account in situ measurements of the initial incubation time, which is needed before the nanowire growth starts. In order to quantitatively describe the dependence of the growth rate on growth time, gallium flux, and growth temperature, we develop a detailed theoretical model of diffusion-induced nanowire growth specifically for the self-induced approach, i.e., without any droplet at the nanowire top. The theoretical fits are in excellent agreement with the experimental data and allow us to deduce important kinetic parameters of the self-induced GaN nanowire growth. The gallium adatom effective diffusion length on the nanowire sidewalls composed of m-plane facets is only 45 nm, which is consistent with our experimental finding that the growth rate initially decreases drastically as the contribution from the adatoms on the planar substrate surface rapidly vanishes. In contrast, the gallium adatom effective diffusion length on the amorphous silicon nitride substrate surface reaches about 100 nm. Furthermore, the nucleation energy on the nanowire sidewalls is found to be 5.44 eV and is larger than on their top facet accounting for the nanowire elongation.

  18. Lenvatinib in combination with golvatinib overcomes hepatocyte growth factor pathway-induced resistance to vascular endothelial growth factor receptor inhibitor

    PubMed Central

    Nakagawa, Takayuki; Matsushima, Tomohiro; Kawano, Satoshi; Nakazawa, Youya; Kato, Yu; Adachi, Yusuke; Abe, Takanori; Semba, Taro; Yokoi, Akira; Matsui, Junji; Tsuruoka, Akihiko; Funahashi, Yasuhiro

    2014-01-01

    Vascular endothelial growth factor receptor (VEGFR) inhibitors are approved for the treatment of several tumor types; however, some tumors show intrinsic resistance to VEGFR inhibitors, and some patients develop acquired resistance to these inhibitors. Therefore, a strategy to overcome VEGFR inhibitor resistance is urgently required. Recent reports suggest that activation of the hepatocyte growth factor (HGF) pathway through its cognate receptor, Met, contributes to VEGFR inhibitor resistance. Here, we explored the effect of the HGF/Met signaling pathway and its inhibitors on resistance to lenvatinib, a VEGFR inhibitor. In in vitro experiments, addition of VEGF plus HGF enhanced cell growth and tube formation of HUVECs when compared with stimulation by either factor alone. Lenvatinib potently inhibited the growth of HUVECs induced by VEGF alone, but cells induced by VEGF plus HGF showed lenvatinib resistance. This HGF-induced resistance was cancelled when the Met inhibitor, golvatinib, was added with lenvatinib. Conditioned medium from tumor cells producing high amounts of HGF also conferred resistance to inhibition by lenvatinib. In s.c. xenograft models based on various tumor cell lines with high HGF expression, treatment with lenvatinib alone showed weak antitumor effects, but treatment with lenvatinib plus golvatinib showed synergistic antitumor effects, accompanied by decreased tumor vessel density. These results suggest that HGF from tumor cells confers resistance to tumor endothelial cells against VEGFR inhibitors, and that combination therapy using VEGFR inhibitors with Met inhibitors may be effective for overcoming resistance to VEGFR inhibitors. Further evaluation in clinical trials is warranted. PMID:24689876

  19. Lenvatinib in combination with golvatinib overcomes hepatocyte growth factor pathway-induced resistance to vascular endothelial growth factor receptor inhibitor.

    PubMed

    Nakagawa, Takayuki; Matsushima, Tomohiro; Kawano, Satoshi; Nakazawa, Youya; Kato, Yu; Adachi, Yusuke; Abe, Takanori; Semba, Taro; Yokoi, Akira; Matsui, Junji; Tsuruoka, Akihiko; Funahashi, Yasuhiro

    2014-06-01

    Vascular endothelial growth factor receptor (VEGFR) inhibitors are approved for the treatment of several tumor types; however, some tumors show intrinsic resistance to VEGFR inhibitors, and some patients develop acquired resistance to these inhibitors. Therefore, a strategy to overcome VEGFR inhibitor resistance is urgently required. Recent reports suggest that activation of the hepatocyte growth factor (HGF) pathway through its cognate receptor, Met, contributes to VEGFR inhibitor resistance. Here, we explored the effect of the HGF/Met signaling pathway and its inhibitors on resistance to lenvatinib, a VEGFR inhibitor. In in vitro experiments, addition of VEGF plus HGF enhanced cell growth and tube formation of HUVECs when compared with stimulation by either factor alone. Lenvatinib potently inhibited the growth of HUVECs induced by VEGF alone, but cells induced by VEGF plus HGF showed lenvatinib resistance. This HGF-induced resistance was cancelled when the Met inhibitor, golvatinib, was added with lenvatinib. Conditioned medium from tumor cells producing high amounts of HGF also conferred resistance to inhibition by lenvatinib. In s.c. xenograft models based on various tumor cell lines with high HGF expression, treatment with lenvatinib alone showed weak antitumor effects, but treatment with lenvatinib plus golvatinib showed synergistic antitumor effects, accompanied by decreased tumor vessel density. These results suggest that HGF from tumor cells confers resistance to tumor endothelial cells against VEGFR inhibitors, and that combination therapy using VEGFR inhibitors with Met inhibitors may be effective for overcoming resistance to VEGFR inhibitors. Further evaluation in clinical trials is warranted.

  20. Strain-induced tissue growth laws: applications to embryonic cardiovascular development.

    PubMed

    Rugonyi, Sandra

    2013-02-28

    Hemodynamic conditions play an essential role in the cardiovascular system, with abnormal blood flow conditions leading to growth and remodeling of cardiovascular walls. During embryonic development, altered hemodynamic conditions lead to congenital heart disease, which affects about 1% of newborn babies in developed countries. However, the mechanisms by which hemodynamic conditions affect cardiovascular development have not been fully elucidated. In this paper, we propose a model of cardiac growth in response to hemodynamic conditions, in which growth is modulated by a combination of wall strains and wall shear stresses. This is in contrast to previous models that proposed stress-induced growth laws. Because during embryonic development blood pressure increases over time, and this increase in blood pressure produces an increase in wall stresses, stress-induced growth laws would require time-dependent parameters. While blood pressure increases during development, cardiovascular walls become stiffer and thicker, and thus we postulate that instead strains experienced by cells remain approximately the same during development. This assumption motivated our cardioavascular model of strain-induced growth in response to hemodynamic conditions, which we implemented using finite element methods. Model simulations show that the proposed model results in tissue growth that is physiologically reasonable. Further, our analyses demonstrate that mechanical coupling - that results from residual stresses originating from differential tissue growth - may play a more important role in the modulation of cardiovascular tissue growth and remodeling than currently acknowledged.

  1. Plant growth promotion induced by phosphate solubilizing endophytic Pseudomonas isolates

    PubMed Central

    Oteino, Nicholas; Lally, Richard D.; Kiwanuka, Samuel; Lloyd, Andrew; Ryan, David; Germaine, Kieran J.; Dowling, David N.

    2015-01-01

    The use of plant growth promoting bacterial inoculants as live microbial biofertilizers provides a promising alternative to chemical fertilizers and pesticides. Inorganic phosphate solubilization is one of the major mechanisms of plant growth promotion by plant associated bacteria. This involves bacteria releasing organic acids into the soil which solubilize the phosphate complexes converting them into ortho-phosphate which is available for plant up-take and utilization. The study presented here describes the ability of endophytic bacteria to produce gluconic acid (GA), solubilize insoluble phosphate, and stimulate the growth of Pisum sativum L. plants. This study also describes the genetic systems within three of these endophyte strains thought to be responsible for their effective phosphate solubilizing abilities. The results showed that many of the endophytic strains produced GA (14–169 mM) and have moderate to high phosphate solubilization capacities (~400–1300 mg L−1). When inoculated into P. sativum L. plants grown in soil under soluble phosphate limiting conditions, the endophytes that produced medium-high levels of GA displayed beneficial plant growth promotion effects. PMID:26257721

  2. Antisomatostatin-induced growth acceleration in chinook salmon (Oncorhynchus tshawytscha).

    PubMed

    Mayer, I; McLean, E; Kieffer, T J; Souza, L M; Donaldson, E M

    1994-10-01

    Since somatostatin (SRIF) inhibits the release of growth hormone (GH), its immunoneutralization may provide an alternative to GH therapy as a means of enhancing somatic growth in fish. The present study examined the feasibility of accelerating growth in juvenile chinook salmon by means of antiSRIF administration. Yearling salmon of Nicola River stock (BC, Canada) were injected intraperitoneally every 5 days, for a total of 40 days, with either SRIF (1 μg g-1 body wt.), antiSRIF (SOMA-10, 1 μg g(-1)), recombinant bovine GH (rbGH, 2.5 μg g(-1)), recombinant porcine GH (rpGH, 2.5 μg g(-1)) or saline (controls). No significant differences were observed in length, weight or final condition factor (k) between the SRIF-treated and control fish over the experimental period. However, the fish treated with the antiSRIF were significantly (p ≤ 0.05) longer and heavier than the control salmon after 25 and 30 days respectively. Furthermore, antiSRIF treatment caused a lowering in k when compared to the control salmon. Fish injected with rbGH or rpGH were significantly longer and heavier than all other groups (p ≤ 0.05), after only 5 days. GH treated groups also returned higher k when compared against all other treatments (p ≤ 0.05). No differences were observed in growth between the two rGH treatments over the experimental period.

  3. Cyclic stretching of soft substrates induces spreading and growth

    NASA Astrophysics Data System (ADS)

    Cui, Yidan; Hameed, Feroz M.; Yang, Bo; Lee, Kyunghee; Pan, Catherine Qiurong; Park, Sungsu; Sheetz, Michael

    2015-02-01

    In the body, soft tissues often undergo cycles of stretching and relaxation that may affect cell behaviour without changing matrix rigidity. To determine whether transient forces can substitute for a rigid matrix, we stretched soft pillar arrays. Surprisingly, 1-5% cyclic stretching over a frequency range of 0.01-10 Hz caused spreading and stress fibre formation (optimum 0.1 Hz) that persisted after 4 h of stretching. Similarly, stretching increased cell growth rates on soft pillars comparative to rigid substrates. Of possible factors linked to fibroblast growth, MRTF-A (myocardin-related transcription factor-A) moved to the nucleus in 2 h of cyclic stretching and reversed on cessation; but YAP (Yes-associated protein) moved much later. Knockdown of either MRTF-A or YAP blocked stretch-dependent growth. Thus, we suggest that the repeated pulling from a soft matrix can substitute for a stiff matrix in stimulating spreading, stress fibre formation and growth.

  4. Cyclic stretching of soft substrates induces spreading and growth

    PubMed Central

    Cui, Yidan; Hameed, Feroz M.; Yang, Bo; Lee, Kyunghee; Pan, Catherine Qiurong; Park, Sungsu; Sheetz, Michael

    2015-01-01

    In the body, soft tissues often undergo cycles of stretching and relaxation that may affect cell behaviour without changing matrix rigidity. To determine whether transient forces can substitute for a rigid matrix, we stretched soft pillar arrays. Surprisingly, 1–5% cyclic stretching over a frequency range of 0.01–10 Hz caused spreading and stress fibre formation (optimum 0.1 Hz) that persisted after 4 h of stretching. Similarly, stretching increased cell growth rates on soft pillars comparative to rigid substrates. Of possible factors linked to fibroblast growth, MRTF-A (myocardin-related transcription factor-A) moved to the nucleus in 2 h of cyclic stretching and reversed on cessation; but YAP (Yes-associated protein) moved much later. Knockdown of either MRTF-A or YAP blocked stretch-dependent growth. Thus, we suggest that the repeated pulling from a soft matrix can substitute for a stiff matrix in stimulating spreading, stress fibre formation and growth. PMID:25704457

  5. Laser Induced Chemical Vapor Epitaxial Growth of Gallium Arsenide Films.

    DTIC Science & Technology

    1988-05-23

    heteroepitaxial growth of GaAs. The important process parameters are: the substrate surface cleanliness , substrate temperature, composition and flow rate of the...hydrogen was used as the diluent and win.dw purging gas [9]. The important process parameters are: the substrate surface cleanliness , substrate temperature

  6. Fufang Kushen injection inhibits sarcoma growth and tumor-induced hyperalgesia via TRPV1 signaling pathways

    PubMed Central

    Zhao, Zhizheng; Fan, Huiting; Higgins, Tim; Qi, Jia; Haines, Diana; Trivett, Anna; Oppenheim, Joost J.; Wei, Hou; Li, Jie; Lin, Hongsheng; Howard, O.M. Zack

    2014-01-01

    Cancer pain is a deleterious consequence of tumor growth and related inflammation. Opioids and antiinflammatory drugs provide first line treatment for cancer pain, but both are limited by side effects. Fufang Kushen injection (FKI) is GMP produced, traditional Chinese medicine used alone or with chemotherapy to reduce cancer-associated pain. FKI limited mouse sarcoma growth both in vivo and in vitro, in part, by reducing the phosphorylation of ERK and AKT kinases and BAD. FKI inhibited TRPV1 mediated capsaicin-induced ERK phosphorylation and reduced tumor-induced proinflammatory cytokine production. Thus, FKI limited cancer pain both directly by blocking TRPV1 signaling and indirectly by reducing tumor growth. PMID:25242356

  7. Heparin Inhibits Hepatocyte Growth Factor Induced Motility and Invasion of Hepatocellular Carcinoma Cells through Early Growth Response Protein 1

    PubMed Central

    Ozen, Evin; Gozukizil, Aysim; Erdal, Esra; Uren, Aykut; Bottaro, Donald P.; Atabey, Nese

    2012-01-01

    The Hepatocyte Growth Factor (HGF)/c-Met signaling pathway regulates hepatocyte proliferation, and pathway aberrations are implicated in the invasive and metastatic behaviors of hepatocellular carcinoma (HCC). In addition to c-Met, heparin acts as a co-receptor to modulate pathway activity. Recently, anti-metastatic and anti-cancer effects of heparin have been reported. However, the role of heparin in the regulation of HGF signaling remains controversial and the effects of heparin on HGF-induced biological responses during hepatocarcinogenesis is not yet defined. In this study we determined the effects of heparin on HGF-induced activities of HCC cells and the underlying molecular mechanisms. Here, we report for the first time that heparin inhibits HGF-induced adhesion, motility and invasion of HCC cells. In addition, heparin reduced HGF-induced activation of c-Met and MAPK in a dose-dependent manner, as well as decreased transcriptional activation and expression of Early growth response factor 1 (Egr1). HGF-induced MMP-2 and MMP-9 activation, and MT1-MMP expression, also were inhibited by heparin. Stable knockdown of Egr1 caused a significant decrease in HGF-induced invasion, as well as the activation and expression of MMPs. Parallel to these findings, the overexpression of Egr1 increased the invasiveness of HCC cells. Our results suggest that Egr1 activates HGF-induced cell invasion through the regulation of MMPs in HCC cells and heparin inhibits HGF-induced cellular invasion via the downregulation of Egr1. Therefore, heparin treatment might be a therapeutic approach to inhibit invasion and metastasis of HCC, especially for patients with active HGF/c-Met signaling. PMID:22912725

  8. The role of EGF receptor transmodulation in embryonal carcinoma-derived growth factor-induced mitogenesis.

    PubMed Central

    Heath, J K; Mahadevan, L; Foulkes, J G

    1986-01-01

    Exposure of quiescent 10T1/2 fibroblast cells to embryonal carcinoma-derived growth factor (ECDGF) results in a rapid temperature and ECDGF concentration-dependent inhibition of [125I]EGF binding to the epidermal growth factor (EGF) receptor (transmodulation). ECDGF predominantly inhibits the association of [125I]EGF with a high affinity subclass of EGF receptors, and induces increased phosphorylation of the EGF receptor on serine and threonine residues. No mitogenic effect of EGF can be detected in the presence of ECDGF concentrations which induce maximal EGF receptor transmodulation. ECDGF-induced EGF receptor transmodulation is sensitive to phorbol ester-induced desensitization whereas ECDGF-induced DNA synthesis is unaffected by prolonged pre-treatment with biologically active phorbol ester. These findings suggest that EGF receptor transmodulation is not essential for ECDGF mitogenicity but may inhibit EGF-induced DNA synthesis. Images Fig. 5. PMID:3489616

  9. Cancer drug troglitazone stimulates the growth and response of renal cells to hypoxia inducible factors

    SciTech Connect

    Taub, Mary

    2016-03-11

    Troglitazone has been used to suppress the growth of a number of tumors through apoptosis and autophagy. However, previous in vitro studies have employed very high concentrations of troglitazone (≥10{sup −5} M) in order to elicit growth inhibitory effects. In this report, when employing lower concentrations of troglitazone in defined medium, troglitazone was observed to stimulate the growth of primary renal proximal tubule (RPT) cells. Rosiglitazone, like troglitazone, is a thiazolidinedione (TZD) that is known to activate Peroxisome Proliferator Activated Receptor Υ (PPARΥ). Notably, rosiglitazone also stimulates RPT cell growth, as does Υ-linolenic acids, another PPARΥ agonist. The PPARΥ antagonist GW9662 inhibited the growth stimulatory effect of troglitazone. In addition, troglitazone stimulated transcription by a PPAR Response Element/Luciferase construct. These results are consistent with the involvement of PPARΥ as a mediator of the growth stimulatory effect of troglitazone. In a number of tumor cells, the expression of hypoxia inducible factor (HIF) is increased, promoting the expression of HIF inducible genes, and vascularization. Troglitazone was observed to stimulate transcription by a HIF/luciferase construct. These observations indicate that troglitazone not only promotes growth, also the survival of RPT cells under conditions of hypoxia. - Highlights: • Troglitazone and rosiglitazone stimulate renal proximal tubule cell growth. • Troglitazone and linolenic acid stimulate growth via PPARϒ. • Linolenic acid stimulates growth in the presence of fatty acid free serum albumin. • Rosiglitazone stimulates transcription by a HRE luciferase construct.

  10. A novel strategy to identify the critical conditions for growth-induced instabilities.

    PubMed

    Javili, A; Steinmann, P; Kuhl, E

    2014-01-01

    Geometric instabilities in living structures can be critical for healthy biological function, and abnormal buckling, folding, or wrinkling patterns are often important indicators of disease. Mathematical models typically attribute these instabilities to differential growth, and characterize them using the concept of fictitious configurations. This kinematic approach toward growth-induced instabilities is based on the multiplicative decomposition of the total deformation gradient into a reversible elastic part and an irreversible growth part. While this generic concept is generally accepted and well established today, the critical conditions for the formation of growth-induced instabilities remain elusive and poorly understood. Here we propose a novel strategy for the stability analysis of growing structures motivated by the idea of replacing growth by prestress. Conceptually speaking, we kinematically map the stress-free grown configuration onto a prestressed initial configuration. This allows us to adopt a classical infinitesimal stability analysis to identify critical material parameter ranges beyond which growth-induced instabilities may occur. We illustrate the proposed concept by a series of numerical examples using the finite element method. Understanding the critical conditions for growth-induced instabilities may have immediate applications in plastic and reconstructive surgery, asthma, obstructive sleep apnoea, and brain development. © 2013 Elsevier Ltd. All rights reserved.

  11. Growth hormone used to control intractable bleeding caused by radiation-induced gastritis.

    PubMed

    Zhang, Liang; Xia, Wen-Jie; Zhang, Zheng-Sen; Lu, Xin-Liang

    2015-08-21

    Intractable bleeding caused by radiation-induced gastritis is rare. We describe a 69-year-old man with intractable hemorrhagic gastritis induced by postoperative radiotherapy for the treatment of esophageal carcinoma. Although anti-secretory therapy with or without octreotide was initiated for hemostasis over three months, melena still occurred off and on, and the patient required blood transfusions to maintain stable hemoglobin. Finally growth hormone was used in the treatment of hemorrhage for two weeks, and hemostasis was successfully achieved. This is the first report that growth hormone has been used to control intractable bleeding caused by radiation-induced gastritis.

  12. Growth hormone used to control intractable bleeding caused by radiation-induced gastritis

    PubMed Central

    Zhang, Liang; Xia, Wen-Jie; Zhang, Zheng-Sen; Lu, Xin-Liang

    2015-01-01

    Intractable bleeding caused by radiation-induced gastritis is rare. We describe a 69-year-old man with intractable hemorrhagic gastritis induced by postoperative radiotherapy for the treatment of esophageal carcinoma. Although anti-secretory therapy with or without octreotide was initiated for hemostasis over three months, melena still occurred off and on, and the patient required blood transfusions to maintain stable hemoglobin. Finally growth hormone was used in the treatment of hemorrhage for two weeks, and hemostasis was successfully achieved. This is the first report that growth hormone has been used to control intractable bleeding caused by radiation-induced gastritis. PMID:26309374

  13. Protein synthesis dependence of growth cone collapse induced by different Nogo-A-domains.

    PubMed

    Manns, Richard; Schmandke, Andre; Schmandke, Antonio; Jareonsettasin, Prem; Cook, Geoffrey; Schwab, Martin E; Holt, Christine; Keynes, Roger

    2014-01-01

    The protein Nogo-A regulates axon growth in the developing and mature nervous system, and this is carried out by two distinct domains in the protein, Nogo-A-Δ20 and Nogo-66. The differences in the signalling pathways engaged in axon growth cones by these domains are not well characterized, and have been investigated in this study. We analyzed growth cone collapse induced by the Nogo-A domains Nogo-A-Δ20 and Nogo-66 using explanted chick dorsal root ganglion neurons growing on laminin/poly-lysine substratum. Collapse induced by purified Nogo-A-Δ20 peptide is dependent on protein synthesis whereas that induced by Nogo-66 peptide is not. Nogo-A-Δ20-induced collapse is accompanied by a protein synthesis-dependent rise in RhoA expression in the growth cone, but is unaffected by proteasomal catalytic site inhibition. Conversely Nogo-66-induced collapse is inhibited ∼ 50% by proteasomal catalytic site inhibition. Growth cone collapse induced by the Nogo-A domains Nogo-A-Δ20 and Nogo-66 is mediated by signalling pathways with distinguishable characteristics concerning their dependence on protein synthesis and proteasomal function.

  14. Temperature extremes reduce seagrass growth and induce mortality.

    PubMed

    Collier, C J; Waycott, M

    2014-06-30

    Extreme heating (up to 43 °C measured from five-year temperature records) occurs in shallow coastal seagrass meadows of the Great Barrier Reef at low tide. We measured effective quantum yield (ϕPSII), growth, senescence and mortality in four tropical seagrasses to experimental short-duration (2.5h) spikes in water temperature to 35 °C, 40 °C and 43 °C, for 6 days followed by one day at ambient temperature. Increasing temperature to 35 °C had positive effects on ϕPSII (the magnitude varied between days and was highly correlated with PPFD), with no effects on growth or mortality. 40 °C represented a critical threshold as there were strong species differences and there was a large impact on growth and mortality. At 43 °C there was complete mortality after 2-3 days. These findings indicate that increasing duration (more days in a row) of thermal events above 40 °C is likely to affect the ecological function of tropical seagrass meadows. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Cortical Folding Pattern and its Consistency Induced by Biological Growth

    PubMed Central

    Jalil Razavi, Mir; Zhang, Tuo; Liu, Tianming; Wang, Xianqiao

    2015-01-01

    Cortical folding, characterized by convex gyri and concave sulci, has an intrinsic relationship to the brain’s functional organization. Understanding the mechanism of the brain’s convoluted patterns can provide useful clues into normal and pathological brain function. In this paper, the cortical folding phenomenon is interpreted both analytically and computationally, and, in some cases, the findings are validated with experimental observations. The living human brain is modeled as a soft structure with a growing outer cortex and inner core to investigate its developmental mechanism. Analytical interpretations of differential growth of the brain model provide preliminary insight into critical growth ratios for instability and crease formation of the developing brain. Since the analytical approach cannot predict the evolution of cortical complex convolution after instability, non-linear finite element models are employed to study the crease formation and secondary morphological folds of the developing brain. Results demonstrate that the growth ratio of the cortex to core of the brain, the initial thickness, and material properties of both cortex and core have great impacts on the morphological patterns of the developing brain. Lastly, we discuss why cortical folding is highly correlated and consistent by presenting an intriguing gyri-sulci formation comparison. PMID:26404042

  16. Cortical Folding Pattern and its Consistency Induced by Biological Growth

    NASA Astrophysics Data System (ADS)

    Jalil Razavi, Mir; Zhang, Tuo; Liu, Tianming; Wang, Xianqiao

    2015-09-01

    Cortical folding, characterized by convex gyri and concave sulci, has an intrinsic relationship to the brain’s functional organization. Understanding the mechanism of the brain’s convoluted patterns can provide useful clues into normal and pathological brain function. In this paper, the cortical folding phenomenon is interpreted both analytically and computationally, and, in some cases, the findings are validated with experimental observations. The living human brain is modeled as a soft structure with a growing outer cortex and inner core to investigate its developmental mechanism. Analytical interpretations of differential growth of the brain model provide preliminary insight into critical growth ratios for instability and crease formation of the developing brain. Since the analytical approach cannot predict the evolution of cortical complex convolution after instability, non-linear finite element models are employed to study the crease formation and secondary morphological folds of the developing brain. Results demonstrate that the growth ratio of the cortex to core of the brain, the initial thickness, and material properties of both cortex and core have great impacts on the morphological patterns of the developing brain. Lastly, we discuss why cortical folding is highly correlated and consistent by presenting an intriguing gyri-sulci formation comparison.

  17. Variation of antioxidative activity and growth enhancement of Brassicaceae induced by low-pressure oxygen plasma

    NASA Astrophysics Data System (ADS)

    Ono, Reoto; Hayashi, Nobuya

    2015-06-01

    The mechanism of growth enhancement induced by active oxygen species generated in an oxygen plasma is investigated. The plant growth enhancement induced by the active oxygen species would relate to an antioxidative activity, which is one of the biological responses. The amount of generated active oxygen species is varied by the oxygen gas pressure in a low-pressure RF glow discharge plasma. The antioxidative activity of sprouts of Brassicaceae induced by the oxygen plasma is maximized at pressures between 30 and 40 Pa, whereas the antioxidative activity becomes small at around 60 and 80 Pa. The pressure dependence of the antioxidative activity of sprout stems is opposite to that of the stem length of the sprouts. The growth enhancement would be induced by the increase in the concentration of active oxygen species in plants owing to the decrease in the amount of antioxidative substances.

  18. CO2-induced growth enhancements of co-occurring tree species decline at different rates.

    PubMed

    Bazzaz, F A; Miao, S L; Wayne, P M

    1993-12-01

    To elucidate how enriched CO2 atmospheres, soil fertility, and light availability interact to influence the long-term growth of tree seedlings, six co-occurring members of temperate forest communities including ash (Fraxinus americana L.), gray birch (Betula populifolia), red maple (Acer rubrum), yellow birch (Betula alleghaniensis), striped maple (Acer pensylvanicum), and red oak (Quercus rubra L.) were raised in a glasshouse for three years in a complete factorial design. After three years of growth, plants growing in elevated CO2 atmospheres were generally larger than those in ambient CO2 atmospheres, however, magnitudes of CO2-induced growth enhancements were contingent on the availability of nitrogen and light, as well as species identity. For all species, magnitudes of CO2-induced growth enhancements after one year of growth were greater than after three years of growth, though species' growth enhancements over the three years declined at different rates. These results suggest that CO2-induced enhancements in forest productivity may not be sustained for long periods of time. Additionally, species' differential growth responses to elevated CO2 may indirectly influence forest productivity via long-term species compositional changes in forests.

  19. The epidermis coordinates auxin-induced stem growth in response to shade

    PubMed Central

    Procko, Carl; Burko, Yogev; Long, Jeff A.; Chory, Joanne

    2016-01-01

    Growth of a complex multicellular organism requires coordinated changes in diverse cell types. These cellular changes generate organs of the correct size, shape, and functionality. In plants, the growth hormone auxin induces stem elongation in response to shade; however, which cell types of the stem perceive the auxin signal and contribute to organ growth is poorly understood. Here, we blocked the transcriptional response to auxin within specific tissues to show that auxin signaling is required in many cell types for correct hypocotyl growth in shade, with a key role for the epidermis. Combining genetic manipulations in Arabidopsis thaliana with transcriptional profiling of the hypocotyl epidermis from Brassica rapa, we show that auxin acts in the epidermis in part by inducing activity of the locally acting, growth-promoting brassinosteroid pathway. Our findings clarify cell-specific auxin function in the hypocotyl and highlight the complexity of cell type interactions within a growing organ. PMID:27401556

  20. Antioxidative activity and growth regulation of Brassicaceae induced by oxygen radical irradiation

    NASA Astrophysics Data System (ADS)

    Hayashi, Nobuya; Ono, Reoto; Shiratani, Masaharu; Yonesu, Akira

    2015-06-01

    The growth regulation characteristics of plants are investigated when plant seeds are irradiated with atmospheric discharge plasma. Enhancement of the germination and lengths of the stem and root of plants are observed after seeding. The total length of the stem and root increases approximately 1.6 times after a cultivation period of 72 h. The growth regulation effect is found to be maintained for 80 h of cultivation after seeding. The growth regulation originates from the change in the antioxidative activity of plant cells induced by active oxygen species generated in the oxygen plasma, which leads to the production of growth factor in plants.

  1. Mo polyoxometalate nanoparticles inhibit tumor growth and vascular endothelial growth factor induced angiogenesis

    NASA Astrophysics Data System (ADS)

    Zheng, Wenjing; Yang, Licong; Liu, Ying; Qin, Xiuying; Zhou, Yanhui; Zhou, Yunshan; Liu, Jie

    2014-06-01

    Tumor growth depends on angiogenesis, which can furnish the oxygen and nutrients that proliferate tumor cells. Thus, blocking angiogenesis can be an effective strategy to inhibit tumor growth. In this work, three typical nanoparticles based on polyoxometalates (POMs) have been prepared; we investigated their capability as antitumor and anti-angiogenesis agents. We found that Mo POM nanoparticles, especially complex 3, inhibited the growth of human hepatocellular liver carcinoma cells (HepG2) through cellular reactive oxygen species levels’ elevation and mitochondrial membrane potential damage. Complex 3 also suppressed the proliferation, migration, and tube formation of endothelial cells in vitro and chicken chorioallantoic membrane development ex vivo. Furthermore, western blot analysis of cell signaling molecules indicated that Mo POMs blocked the vascular endothelial growth factor receptor 2-mediated ERK1/2 and AKT signaling pathways in endothelial cells. Using transmission electron microscopy, we demonstrated their cellular uptake and localization within the cytoplasm of HepG2 cells. These results indicate that, owing to the extraordinary physical and chemical properties, Mo POM nanoparticles can significantly inhibit tumor growth and angiogenesis, which makes them potential drug candidates in anticancer and anti-angiogenesis therapies.

  2. Heparin-binding epidermal growth factor-like growth factor, a v-Jun target gene, induces oncogenic transformation

    PubMed Central

    Fu, Shu-ling; Bottoli, Ivan; Goller, Martin; Vogt, Peter K.

    1999-01-01

    Jun is a transcription factor belonging to the activator protein 1 family. A mutated version of Jun (v-Jun) transduced by the avian retrovirus ASV17 induces oncogenic transformation in avian cell cultures and sarcomas in young galliform birds. The oncogenicity of Jun probably results from transcriptional deregulation of v-Jun-responsive target genes. Here we describe the identification and characterization of a growth-related v-Jun target, a homolog of heparin-binding epidermal growth factor-like growth factor (HB-EGF). HB-EGF is strongly expressed in chicken embryo fibroblasts (CEF) transformed by v-Jun. HB-EGF expression is not detectable or is marginal in nontransformed CEF. Using a hormone-inducible Jun-estrogen receptor chimera, we found that HB-EGF expression is correlated with v-Jun activity. In this system, induction of v-Jun is followed within 1 hr by elevated levels of HB-EGF. In CEF infected with various Jun mutants, HB-EGF expression is correlated with the oncogenic potency of the mutant. Constitutive expression of HB-EGF conveys to CEF the ability to grow in soft agar and to form multilayered foci of transformed cells on a solid substrate. These observations suggest that HB-EGF is an effector of Jun-induced oncogenic transformation. PMID:10318950

  3. Gravity-induced asymmetric distribution of a plant growth hormone

    NASA Technical Reports Server (NTRS)

    Bandurski, R. S.; Schulze, A.; Momonoki, Y.

    1984-01-01

    Dolk (1936) demonstrated that gravistimulation induced an asymmetric distribution of auxin in a horizontally-placed shoot. An attempt is made to determine where and how that asymmetry arises, and to demonstrate that the endogenous auxin, indole-3-acetic acid, becomes asymmetrically distributed in the cortical cells of the Zea mays mesocotyl during 3 min of geostimulation. Further, indole-3-acetic acid derived by hydrolysis of an applied transport form of the hormone, indole-3-acetyl-myo-inositol, becomes asymmetrically distributed within 15 min of geostimulus time. From these and prior data is developed a working theory that the gravitational stimulus induces a selective leakage, or secretion, of the hormone from the vascular tissue to the cortical cells of the mesocotyl.

  4. Gravity-induced asymmetric distribution of a plant growth hormone

    NASA Technical Reports Server (NTRS)

    Bandurski, R. S.; Schulze, A.; Momonoki, Y.

    1984-01-01

    Dolk (1936) demonstrated that gravistimulation induced an asymmetric distribution of auxin in a horizontally-placed shoot. An attempt is made to determine where and how that asymmetry arises, and to demonstrate that the endogenous auxin, indole-3-acetic acid, becomes asymmetrically distributed in the cortical cells of the Zea mays mesocotyl during 3 min of geostimulation. Further, indole-3-acetic acid derived by hydrolysis of an applied transport form of the hormone, indole-3-acetyl-myo-inositol, becomes asymmetrically distributed within 15 min of geostimulus time. From these and prior data is developed a working theory that the gravitational stimulus induces a selective leakage, or secretion, of the hormone from the vascular tissue to the cortical cells of the mesocotyl.

  5. Plant Growth Biophysics: the Basis for Growth Asymmetry Induced by Gravity

    NASA Technical Reports Server (NTRS)

    Cosgrove, D.

    1985-01-01

    The identification and quantification of the physical properties altered by gravity when plant stems grow upward was studied. Growth of the stem in vertical and horizontal positions was recorded by time lapse photography. A computer program that uses a cubic spline fitting algorithm was used to calculate the growth rate and curvature of the stem as a function of time. Plant stems were tested to ascertain whether cell osmotic pressure was altered by gravity. A technique for measuring the yielding properties of the cell wall was developed.

  6. Chloroplasts Are Central Players in Sugar-Induced Leaf Growth.

    PubMed

    Van Dingenen, Judith; De Milde, Liesbeth; Vermeersch, Mattias; Maleux, Katrien; De Rycke, Riet; De Bruyne, Michiel; Storme, Véronique; Gonzalez, Nathalie; Dhondt, Stijn; Inzé, Dirk

    2016-05-01

    Leaves are the plant's powerhouses, providing energy for all organs through sugar production during photosynthesis. However, sugars serve not only as a metabolic energy source for sink tissues but also as signaling molecules, affecting gene expression through conserved signaling pathways to regulate plant growth and development. Here, we describe an in vitro experimental assay, allowing one to alter the sucrose (Suc) availability during early Arabidopsis (Arabidopsis thaliana) leaf development, with the aim to identify the affected cellular and molecular processes. The transfer of seedlings to Suc-containing medium showed a profound effect on leaf growth by stimulating cell proliferation and postponing the transition to cell expansion. Furthermore, rapidly after transfer to Suc, mesophyll cells contained fewer and smaller plastids, which are irregular in shape and contain fewer starch granules compared with control mesophyll cells. Short-term transcriptional responses after transfer to Suc revealed the repression of well-known sugar-responsive genes and multiple genes encoded by the plastid, on the one hand, and up-regulation of a GLUCOSE-6-PHOSPHATE TRANSPORTER (GPT2), on the other hand. Mutant gpt2 seedlings showed no stimulation of cell proliferation and no repression of chloroplast-encoded transcripts when transferred to Suc, suggesting that GPT2 plays a critical role in the Suc-mediated effects on early leaf growth. Our findings, therefore, suggest that induction of GPT2 expression by Suc increases the import of glucose-6-phosphate into the plastids that would repress chloroplast-encoded transcripts, restricting chloroplast differentiation. Retrograde signaling from the plastids would then delay the transition to cell expansion and stimulate cell proliferation. © 2016 American Society of Plant Biologists. All Rights Reserved.

  7. Mucosal wrinkling in animal antra induced by volumetric growth

    NASA Astrophysics Data System (ADS)

    Li, Bo; Cao, Yan-Ping; Feng, Xi-Qiao; Yu, Shou-Wen

    2011-04-01

    Surface wrinkling of animal mucosas is crucial for the biological functions of some tissues, and the change in their surface patterns is a phenotypic characteristic of certain diseases. Here we develop a biomechanical model to study the relationship between morphogenesis and volumetric growth, either physiological or pathological, of mucosas. Theoretical analysis and numerical simulations are performed to unravel the critical characteristics of mucosal wrinkling in a spherical antrum. It is shown that the thicknesses and elastic moduli of mucosal and submucosal layers dictate the surface buckling morphology. The results hold clinical relevance for such diseases as inflammation and gastritis.

  8. Proteasome dysfunction induces muscle growth defects and protein aggregation

    PubMed Central

    Kitajima, Yasuo; Tashiro, Yoshitaka; Suzuki, Naoki; Warita, Hitoshi; Kato, Masaaki; Tateyama, Maki; Ando, Risa; Izumi, Rumiko; Yamazaki, Maya; Abe, Manabu; Sakimura, Kenji; Ito, Hidefumi; Urushitani, Makoto; Nagatomi, Ryoichi; Takahashi, Ryosuke; Aoki, Masashi

    2014-01-01

    ABSTRACT The ubiquitin–proteasome and autophagy–lysosome pathways are the two major routes of protein and organelle clearance. The role of the proteasome pathway in mammalian muscle has not been examined in vivo. In this study, we report that the muscle-specific deletion of a crucial proteasomal gene, Rpt3 (also known as Psmc4), resulted in profound muscle growth defects and a decrease in force production in mice. Specifically, developing muscles in conditional Rpt3-knockout animals showed dysregulated proteasomal activity. The autophagy pathway was upregulated, but the process of autophagosome formation was impaired. A microscopic analysis revealed the accumulation of basophilic inclusions and disorganization of the sarcomeres in young adult mice. Our results suggest that appropriate proteasomal activity is important for muscle growth and for maintaining myofiber integrity in collaboration with autophagy pathways. The deletion of a component of the proteasome complex contributed to myofiber degeneration and weakness in muscle disorders that are characterized by the accumulation of abnormal inclusions. PMID:25380823

  9. Aerosol-induced mechanisms for cumulus congestus growth

    NASA Astrophysics Data System (ADS)

    Sheffield, Amanda M.; Saleeby, Stephen M.; Heever, Susan C.

    2015-09-01

    Tropical convection has been observed to contain three cloud modes, the middle of which is cumulus congestus clouds. Congestus clouds act to moisten the tropical atmosphere, may be mixed-phase, and on occasion surpass the freezing level inversion from where they may develop into deeper convection. This study investigates the impacts of enhanced aerosol concentrations on the growth of congestus clouds produced in idealized cloud-resolving model simulations run under a state of radiative convective equilibrium (RCE). High-resolution, long-duration simulations were completed using the Regional Atmospheric Modeling System (RAMS). Aerosol concentrations between 2 and 4 km above ground level were varied from clean to polluted conditions in order to represent the advection of Saharan dust over the Atlantic Ocean. The congestus populations within each aerosol simulation are statistically analyzed using 10 days of model output after the simulation reaches RCE. Results indicate that congestus in more polluted conditions produce greater amounts of cloud water and ice mass, enhanced updraft strengths, and an increase in the number of congestus cloud tops that extend above the freezing level. Enhanced vapor depositional growth on the populations of more numerous, smaller cloud droplets in the polluted conditions, and the subsequent increase in latent heat release in the warm phase regions of the cloud, is found to be important factors in convective invigoration of these cloud systems. Aerosol feedbacks associated with cold pools and condensate loading also influence the updraft strength and act in opposition to the warm phase invigoration processes.

  10. Cbl competitively inhibits epidermal growth factor-induced activation of phospholipase C-gamma1.

    PubMed

    Choi, Jang Hyun; Bae, Sun Sik; Park, Jong Bae; Ha, Sang Hoon; Song, Hebok; Kim, Jae-Ho; Cocco, Lucio; Ryu, Sung Ho; Suh, Pann-Ghill

    2003-04-30

    Phospholipase C-gamma1 (PLC-gamma1) plays pivotal roles in cellular growth and proliferation through its two Src homology (SH) 2 domains and its single SH3 domain, which interact with signaling molecules in response to various growth factors and hormones. However, the role of the SH domains in the growth factor-induced regulation of PLC-gamma1 is unclear. By peptide-mass fingerprinting analysis we have identified Cbl as a binding protein for the SH3 domain of PLC-gamma1 from rat pheochromatocyte PC12 cells. Association of Cbl with PLC-gamma1 was induced by epidermal growth factor (EGF) but not by nerve growth factor (NGF). Upon EGF stimulation, both Cbl and PLC-gamma1 were recruited to the activated EGF receptor through their SH2 domains. Mutation of the SH2 domains of either Cbl or PLC-gamma1 abrogated the EGF-induced interaction of PLC-gamma1 with Cbl, indicating that SH2-mediated translocation is essential for the association of PLC-gamma1 and Cbl. Overexpression of Cbl attenuated EGF-induced tyrosine phosphorylation and the subsequent activation of PLC-gamma1 by interfering competitively with the interaction between PLC-gamma1 and EGFR. Taken together, these results provide the first indications that Cbl may be a negative regulator of intracellular signaling following EGF-induced PLC-gamma1 activation.

  11. Inflammatory cytokines promote growth of intestinal smooth muscle cells by induced expression of PDGF-Rβ.

    PubMed

    Nair, Dileep G; Miller, Kurtis G; Lourenssen, Sandra R; Blennerhassett, Michael G

    2014-03-01

    Thickening of the inflamed intestinal wall involves growth of smooth muscle cells (SMC), which contributes to stricture formation. Earlier, the growth factor platelet-derived growth factor (PDGF)-BB was identified as a key mitogen for SMC from the rat colon (CSMC), and CSMC growth in colitis was associated with both appearance of its receptor, PDGF-Rβ and modulation of phenotype. Here, we examined the role of inflammatory cytokines in inducing and modulating the growth response to PDGF-BB. CSMC were enzymatically isolated from Sprague-Dawley rats, and the effect of tumour necrosis factor (TNF)-α, interleukin (IL)-1β, transforming growth factor (TGF), IL-17A and IL-2 on CSMC growth and responsiveness to PDGF-BB were assessed using proliferation assays, PCR and western blotting. Conditioned medium (CM) was obtained at 48 hrs of trinitrobenzene sulphonic acid-induced colitis. Neither CM alone nor cytokines caused proliferation of early-passage CSMC. However, CM from inflamed, but not control colon significantly promoted the effect of PDGF-BB. IL-1β, TNF-α and IL-17A, but not other cytokines, increased the effect of PDGF-BB because of up-regulation of mRNA and protein for PDGF-Rβ without change in receptor phosphorylation. PDGF-BB was identified in adult rat serum (RS) and RS-induced CSMC proliferation was inhibited by imatinib, suggesting that blood-derived PDGF-BB is a local mitogen in vivo. In freshly isolated CSMC, CM from the inflamed colon as well as IL-1β and TNF-α induced the early expression of PDGF-Rβ, while imatinib blocked subsequent RS-induced cell proliferation. Thus, pro-inflammatory cytokines both initiate and maintain a growth response in CSMC via PDGF-Rβ and serum-derived PDGF-BB, and control of PDGF-Rβ expression may be beneficial in chronic intestinal inflammation.

  12. Warming-Induced Decline of Picea crassifolia Growth in the Qilian Mountains in Recent Decades.

    PubMed

    Yu, Li; Huang, Lei; Shao, Xuemei; Xiao, Fengjing; Wilmking, Martin; Zhang, Yongxiang

    2015-01-01

    Warming-induced drought has widely affected forest dynamics in most places of the northern hemisphere. In this study, we assessed how climate warming has affected Picea crassifolia (Qinghai spruce) forests using tree growth-climate relationships and the normalized difference vegetation index (NDVI) along the Qilian Mountains, northeastern Tibet Plateau (the main range of Picea crassifolia). Based on the analysis on trees radial growth data from the upper tree line and the regional NDVI data, we identified a pervasive growth decline in recent decades, most likely caused by warming-induced droughts. The drought stress on Picea crassifolia radial growth were expanding from northeast to southwest and the favorable moisture conditions for tree growth were retreating along the identical direction in the study area over the last half century. Compared to the historical drought stress on tree radial growth in the 1920s, recent warming-induced droughts display a longer-lasting stress with a broader spatial distribution on regional forest growth. If the recent warming continues without the effective moisture increasing, then a notable challenge is developed for Picea crassifolia in the Qilian Mountains. Elaborate forest management is necessary to counteract the future risk of climate change effects in this region.

  13. Endogenous abscisic acid promotes hypocotyl growth and affects endoreduplication during dark-induced growth in tomato (Solanum lycopersicum L.).

    PubMed

    Humplík, Jan F; Bergougnoux, Véronique; Jandová, Michaela; Šimura, Jan; Pěnčík, Aleš; Tomanec, Ondřej; Rolčík, Jakub; Novák, Ondřej; Fellner, Martin

    2015-01-01

    Dark-induced growth (skotomorphogenesis) is primarily characterized by rapid elongation of the hypocotyl. We have studied the role of abscisic acid (ABA) during the development of young tomato (Solanum lycopersicum L.) seedlings. We observed that ABA deficiency caused a reduction in hypocotyl growth at the level of cell elongation and that the growth in ABA-deficient plants could be improved by treatment with exogenous ABA, through which the plants show a concentration dependent response. In addition, ABA accumulated in dark-grown tomato seedlings that grew rapidly, whereas seedlings grown under blue light exhibited low growth rates and accumulated less ABA. We demonstrated that ABA promotes DNA endoreduplication by enhancing the expression of the genes encoding inhibitors of cyclin-dependent kinases SlKRP1 and SlKRP3 and by reducing cytokinin levels. These data were supported by the expression analysis of the genes which encode enzymes involved in ABA and CK metabolism. Our results show that ABA is essential for the process of hypocotyl elongation and that appropriate control of the endogenous level of ABA is required in order to drive the growth of etiolated seedlings.

  14. Endogenous Abscisic Acid Promotes Hypocotyl Growth and Affects Endoreduplication during Dark-Induced Growth in Tomato (Solanum lycopersicum L.)

    PubMed Central

    Humplík, Jan F.; Bergougnoux, Véronique; Jandová, Michaela; Šimura, Jan; Pěnčík, Aleš; Tomanec, Ondřej; Rolčík, Jakub; Novák, Ondřej; Fellner, Martin

    2015-01-01

    Dark-induced growth (skotomorphogenesis) is primarily characterized by rapid elongation of the hypocotyl. We have studied the role of abscisic acid (ABA) during the development of young tomato (Solanum lycopersicum L.) seedlings. We observed that ABA deficiency caused a reduction in hypocotyl growth at the level of cell elongation and that the growth in ABA-deficient plants could be improved by treatment with exogenous ABA, through which the plants show a concentration dependent response. In addition, ABA accumulated in dark-grown tomato seedlings that grew rapidly, whereas seedlings grown under blue light exhibited low growth rates and accumulated less ABA. We demonstrated that ABA promotes DNA endoreduplication by enhancing the expression of the genes encoding inhibitors of cyclin-dependent kinases SlKRP1 and SlKRP3 and by reducing cytokinin levels. These data were supported by the expression analysis of the genes which encode enzymes involved in ABA and CK metabolism. Our results show that ABA is essential for the process of hypocotyl elongation and that appropriate control of the endogenous level of ABA is required in order to drive the growth of etiolated seedlings. PMID:25695830

  15. Bone morphogenetic protein-4 strongly potentiates growth factor-induced proliferation of mammary epithelial cells

    SciTech Connect

    Montesano, Roberto Sarkoezi, Rita; Schramek, Herbert

    2008-09-12

    Bone morphogenetic proteins (BMPs) are multifunctional cytokines that elicit pleiotropic effects on biological processes such as cell proliferation, cell differentiation and tissue morphogenesis. With respect to cell proliferation, BMPs can exert either mitogenic or anti-mitogenic activities, depending on the target cells and their context. Here, we report that in low-density cultures of immortalized mammary epithelial cells, BMP-4 did not stimulate cell proliferation by itself. However, when added in combination with suboptimal concentrations of fibroblast growth factor (FGF)-2, FGF-7, FGF-10, epidermal growth factor (EGF) or hepatocyte growth factor (HGF), BMP-4 potently enhanced growth factor-induced cell proliferation. These results reveal a hitherto unsuspected interplay between BMP-4 and growth factors in the regulation of mammary epithelial cell proliferation. We suggest that the ability of BMP-4 to potentiate the mitogenic activity of multiple growth factors may contribute to mammary gland ductal morphogenesis as well as to breast cancer progression.

  16. NOR-1 is involved in VEGF-induced endothelial cell growth.

    PubMed

    Rius, Jordi; Martínez-González, José; Crespo, Javier; Badimon, Lina

    2006-02-01

    Neuron-derived orphan receptor-1 (NOR-1) is a transcription factor over-expressed in human atherosclerotic plaques that is involved in vascular smooth muscle cell proliferation. The aim of this study was to analyze whether NOR-1 plays a role in vascular endothelial growth factor (VEGF) induced endothelial cell growth. VEGF induced an early and transient up-regulation of NOR-1 in human umbilical vein endothelial cells (HUVEC). NOR-1 up-regulation by VEGF is processed through VEGF receptor-2 (VEGFR-2) and involves different signaling pathways including increase in cytosolic Ca(2+), activation of protein kinase C and mitogen-activated protein kinase (MAPK) pathways (both extracellular-signaling regulated kinase [ERK] and p38 MAPK). VEGF induced CREB activation (phosphorylation in Ser(133)). In transfection assays, a dominant-negative of CREB inhibited NOR-1 promoter activity, while mutation of the three CRE sites in the NOR-1 promoter abolished VEGF-induced NOR-1 promoter activity. Antisense oligonucleotides against NOR-1 inhibited VEGF-induced endothelial cell growth (reduced DNA synthesis, and inhibited cell cycle progression and endothelial cell wound repair after mechanical injury). These results indicate that NOR-1 could be a key transcription factor regulating endothelial cell growth induced by VEGF.

  17. P53-dependent upregulation of neutral sphingomyelinase-2: role in doxorubicin-induced growth arrest

    PubMed Central

    Shamseddine, A A; Clarke, C J; Carroll, B; Airola, M V; Mohammed, S; Rella, A; Obeid, L M; Hannun, Y A

    2015-01-01

    Neutral sphingomyelinase-2 (nSMase2) is a ceramide-generating enzyme that has been implicated in growth arrest, apoptosis and exosome secretion. Although previous studies have reported transcriptional upregulation of nSMase2 in response to daunorubicin, through Sp1 and Sp3 transcription factors, the role of the DNA damage pathway in regulating nSMase2 remains unclear. In this study, we show that doxorubicin induces a dose-dependent induction of nSMase2 mRNA and protein with concomitant increases in nSMase activity and ceramide levels. Upregulation of nSMase2 was dependent on ATR, Chk1 and p53, thus placing it downstream of the DNA damage pathway. Moreover, overexpression of p53 was sufficient to transcriptionally induce nSMase2, without the need for DNA damage. DNA-binding mutants as well as acetylation mutants of p53 were unable to induce nSMase2, suggesting a role of nSMase2 in growth arrest. Moreover, knockdown of nSMase2 prevented doxorubicin-induced growth arrest. Finally, p53-induced nSMase2 upregulation appears to occur via a novel transcription start site upstream of exon 3. These results identify nSMase2 as a novel p53 target gene, regulated by the DNA damage pathway to induce cell growth arrest. PMID:26512957

  18. Cancer growth dynamics: stochastic models and noise induced effects

    NASA Astrophysics Data System (ADS)

    Spagnolo, B.; Fiasconaro, A.; Pizzolato, N.; Valenti, D.; Adorno, D. Persano; Caldara, P.; Ochab-Marcinek, A.; Gudowska-Nowak, E.

    2009-04-01

    In the framework of the Michaelis-Menten (MM) reaction kinetics, we analyze the cancer growth dynamics in the presence of the immune response. We found the coexistence of noise enhanced stability (NES) and resonant activation (RA) phenomena which act in an opposite way with respect to the extinction of the tumor. The role of the stochastic resonance (SR) in the case of weak cancer therapy has been analyzed. The evolutionary dynamics of a system of cancerous cells in a model of chronic myeloid leukemia (CML) is investigated by a Monte Carlo approach. We analyzed the effects of a targeted therapy on the evolutionary dynamics of normal, first-mutant and cancerous cell populations. We show how the patient response to the therapy changes when an high value of the mutation rate from healthy to cancerous cells is present. Our results are in agreement with clinical observations.

  19. Nanowire growth by an electron beam induced massive phase transformation

    SciTech Connect

    Sood, Shantanu; Kisslinger, Kim; Gouma, Perena

    2014-11-15

    Tungsten trioxide nanowires of a high aspect ratio have been synthesized in-situ in a TEM under an electron beam of current density 14A/cm² due to a massive polymorphic reaction. Sol-gel processed pseudocubic phase nanocrystals of tungsten trioxide were seen to rapidly transform to one dimensional monoclinic phase configurations, and this reaction was independent of the substrate on which the material was deposited. The mechanism of the self-catalyzed polymorphic transition and accompanying radical shape change is a typical characteristic of metastable to stable phase transformations in nanostructured polymorphic metal oxides. A heuristic model is used to confirm the metastable to stable growth mechanism. The findings are important to the control electron beam deposition of nanowires for functional applications starting from colloidal precursors.

  20. Nanowire growth by an electron beam induced massive phase transformation

    DOE PAGES

    Sood, Shantanu; Kisslinger, Kim; Gouma, Perena

    2014-11-15

    Tungsten trioxide nanowires of a high aspect ratio have been synthesized in-situ in a TEM under an electron beam of current density 14A/cm² due to a massive polymorphic reaction. Sol-gel processed pseudocubic phase nanocrystals of tungsten trioxide were seen to rapidly transform to one dimensional monoclinic phase configurations, and this reaction was independent of the substrate on which the material was deposited. The mechanism of the self-catalyzed polymorphic transition and accompanying radical shape change is a typical characteristic of metastable to stable phase transformations in nanostructured polymorphic metal oxides. A heuristic model is used to confirm the metastable to stablemore » growth mechanism. The findings are important to the control electron beam deposition of nanowires for functional applications starting from colloidal precursors.« less

  1. Growth hormone resistance exacerbates cholestasis-induced murine liver fibrosis

    PubMed Central

    Stiedl, Patricia; McMahon, Robert; Blaas, Leander; Stanek, Victoria; Svinka, Jasmin; Grabner, Beatrice; Zollner, Gernot; Kessler, Sonja M.; Claudel, Thierry; Müller, Mathias; Mikulits, Wolfgang; Bilban, Martin; Esterbauer, Harald; Eferl, Robert; Haybaeck, Johannes; Trauner, Michael; Casanova, Emilio

    2016-01-01

    Growth hormone (GH) resistance has been associated with liver cirrhosis in humans but its contribution to the disease remains controversial. In order to elucidate whether GH resistance plays a causal role in the establishment and development of liver fibrosis, or rather represents a major consequence thereof, we challenged mice lacking the Growth hormone receptor gene (Ghr-/-, a model for GH resistance) by crossing them with Mdr2 knockout mice (Mdr2-/-), a mouse model of inflammatory cholestasis and liver fibrosis. Ghr-/-;Mdr2-/- mice showed elevated serum markers associated with liver damage and cholestasis, extensive bile duct proliferation and increased collagen deposition relative to Mdr2 -/- mice, thus suggesting a more severe liver fibrosis phenotype. Additionally, Ghr-/-;Mdr2-/- mice had a pronounced down-regulation of hepato-protective genes Hnf6, Egfr and Igf-1, and significantly increased levels of ROS and apoptosis in hepatocytes, compared to control mice. Moreover, single knockout mice (Ghr-/-) fed with a diet containing 1% cholic acid displayed an increase in hepatocyte ROS production, hepatocyte apoptosis and bile infarcts compared to their wildtype littermates, indicating that loss of Ghr renders hepatocytes more susceptible to toxic bile acid accumulation. Surprisingly, and despite their severe fibrotic phenotype, Ghr-/-;Mdr2-/- mice displayed a significant decrease in tumour incidence compared to Mdr2-/- mice, indicating that loss of Ghr signaling may slow the progression from fibrosis/cirrhosis to cancer in the liver. Conclusion Our findings suggest that GH resistance dramatically exacerbates liver fibrosis in a mouse model of inflammatory cholestasis, therefore suggesting that GH resistance plays a causal role in the disease and provides a novel target for the development of liver fibrosis treatments. PMID:25179284

  2. Atrial natriuretic factor inhibits mitogen-induced growth in aortic smooth muscle cells.

    PubMed

    Baldini, P M; De Vito, P; Fraziano, M; Mattioli, P; Luly, P; Di Nardo, P

    2002-10-01

    Atrial natriuretic factor (ANF) is a polypeptide able to affect cardiovascular homeostasis exhibiting diuretic, natriuretic, and vasorelaxant activities. ANF shows antimitogenic effects in different cell types acting through R(2) receptor. Excessive proliferation of smooth muscle cells is a common phenomenon in diseases such as atherosclerosis, but the role of growth factors in the mechanism which modulate this process has yet to be clarified. The potential antimitogenic role of ANF on the cell growth induced by growth factors appears very intriguing. Aim of the present study was to investigate the possible involvement of ANF on rat aortic smooth muscle (RASM) cells proliferation induced by known mitogens and the mechanism involved. Our data show that ANF, at physiological concentration range, inhibits RASM cell proliferation induced by known mitogens such as PDGF and insulin, and the effect seems to be elicited through the modulation of phosphatidic acid (PA) production and MAP kinases involvement. Copyright 2002 Wiley-Liss, Inc.

  3. Growth hormone induces multiplication of the slowly cycling germinal cells of the rat tibial growth plate.

    PubMed

    Ohlsson, C; Nilsson, A; Isaksson, O; Lindahl, A

    1992-10-15

    To study the effect of locally infused growth hormone (GH) or insulin-like growth factor I(IGF-I) on slowly cycling cells in the germinal cell layer of the tibial growth plate, osmotic minipumps delivering 14.3 microCi of [3H]thymidine per day were implanted s.c. into hypophysectomized rats, and GH (1 microgram) or IGF-I (10 micrograms) was injected daily through a cannula implanted in the proximal tibia. The opposite leg served as a control. After 12 days of treatment, the osmotic minipumps were removed, and three rats in each group were given GH (20 micrograms/day, s.c.) for an additional 14 days to chase the labeled cells out of the proliferative layers. Labeled cells remained in the germinal layer, in the perichondrial ring, and on the surface of the articular cartilage close to the epiphyseal plate. GH administered together with labeled thymidine significantly increased the number of labeled cells in the germinal cell layer compared to that in the control leg (ratio = 1.95 +/- 0.13), whereas IGF-I showed no stimulatory effect (ratio = 0.96 +/- 0.04). Therefore GH but not IGF-I stimulates the multiplication of the slowly cycling (label-retaining) cells in the germinal layer of the epiphyseal plate. IGF-I acts only on the proliferation of the resulting chondrocytes.

  4. Modified growth kinetics of ion induced yttrium--silicide layers during subsequent thermal annealing

    SciTech Connect

    Alford, T.L.; Mayer, J.W. )

    1991-12-02

    Yttrium and amorphous silicon bilayers were irradiated with 600-keV inert ions between {minus}190 and 265 {degree}C. Ion-induced YSi{sub 1.7} layers occurred in those samples irradiated above {ge} (R18)205 {degree}C. These ion-mixed samples were thermally annealed at temperatures between 325 and 380 {degree}C. The diffusion-limited growth was observed only in those samples which had an ion-induced YSi{sub 1.7} layer present prior to thermal annealing. This type of growth is distinctly different from the interface limited, nonuniform, and irreproducible growth seen during typical thermal annealing of yttrium and silicon bilayers. This type of growth still occurred in those samples annealed after ion irradiations at {le}190 {degree}C.

  5. Catalyst-induced growth of carbon nanotubes on tips of cantilevers and nanowires

    DOEpatents

    Lee, James Weifu; Lowndes, Douglas H.; Merkulov, Vladimir I.; Eres, Gyula; Wei, Yayi; Greenbaum, Elias; Lee, Ida

    2004-06-29

    A method is described for catalyst-induced growth of carbon nanotubes, nanofibers, and other nanostructures on the tips of nanowires, cantilevers, conductive micro/nanometer structures, wafers and the like. The method can be used for production of carbon nanotube-anchored cantilevers that can significantly improve the performance of scaning probe microscopy (AFM, EFM etc). The invention can also be used in many other processes of micro and/or nanofabrication with carbon nanotubes/fibers. Key elements of this invention include: (1) Proper selection of a metal catalyst and programmable pulsed electrolytic deposition of the desired specific catalyst precisely at the tip of a substrate, (2) Catalyst-induced growth of carbon nanotubes/fibers at the catalyst-deposited tips, (3) Control of carbon nanotube/fiber growth pattern by manipulation of tip shape and growth conditions, and (4) Automation for mass production.

  6. A statistical mechanics model to predict electromigration induced damage and void growth in solder interconnects

    NASA Astrophysics Data System (ADS)

    Wang, Yuexing; Yao, Yao; Keer, Leon M.

    2017-02-01

    Electromigration is an irreversible mass diffusion process with damage accumulation in microelectronic materials and components under high current density. Based on experimental observations, cotton type voids dominate the electromigration damage accumulation prior to cracking in the solder interconnect. To clarify the damage evolution process corresponding to cotton type void growth, a statistical model is proposed to predict the stochastic characteristic of void growth under high current density. An analytical solution of the cotton type void volume growth over time is obtained. The synchronous electromigration induced damage accumulation is predicted by combining the statistical void growth and the entropy increment. The electromigration induced damage evolution in solder joints is developed and applied to verify the tensile strength deterioration of solder joints due to electromigration. The predictions agree well with the experimental results.

  7. Calcium influences sensitivity to growth inhibition induced by a cell surface sialoglycopeptide

    NASA Technical Reports Server (NTRS)

    Betz, N. A.; Fattaey, H. K.; Johnson, T. C.; Spooner, B. S. (Principal Investigator)

    1994-01-01

    While studies concerning mitogenic factors have been an important area of research for many years, much less is understood about the mechanisms of action of cell surface growth inhibitors. We have purified an 18 kDa cell surface sialoglycopeptide growth inhibitor (CeReS-18) which can reversibly inhibit the proliferation of diverse cell types. The studies discussed in this article show that three mouse keratinocyte cell lines exhibit sixty-fold greater sensitivity than other fibroblasts and epithelial-like cells to CeReS-18-induced growth inhibition. Growth inhibition induced by CeReS-18 treatment is a reversible process, and the three mouse keratinocyte cell lines exhibited either single or multiple cell cycle arrest points, although a predominantly G0/G1 cell cycle arrest point was exhibited in Swiss 3T3 fibroblasts. The sensitivity of the mouse keratinocyte cell lines to CeReS-18-induced growth inhibition was not affected by the degree of tumorigenic progression in the cell lines and was not due to differences in CeReS-18 binding affinity or number of cell surface receptors per cell. However, the sensitivity of both murine fibroblasts and keratinocytes could be altered by changing the extracellular calcium concentration, such that increased extracellular calcium concentrations resulted in decreased sensitivity to CeReS-18-induced proliferation inhibition. Thus the increased sensitivity of the murine keratinocyte cell lines to CeReS-18 could be ascribed to the low calcium concentration used in their propagation. Studies are currently under way investigating the role of calcium in CeReS-18-induced growth arrest. The CeReS-18 may serve as a very useful tool to study negative growth control and the signal transduction events associated with cell cycling.

  8. Calcium influences sensitivity to growth inhibition induced by a cell surface sialoglycopeptide

    NASA Technical Reports Server (NTRS)

    Betz, N. A.; Fattaey, H. K.; Johnson, T. C.; Spooner, B. S. (Principal Investigator)

    1994-01-01

    While studies concerning mitogenic factors have been an important area of research for many years, much less is understood about the mechanisms of action of cell surface growth inhibitors. We have purified an 18 kDa cell surface sialoglycopeptide growth inhibitor (CeReS-18) which can reversibly inhibit the proliferation of diverse cell types. The studies discussed in this article show that three mouse keratinocyte cell lines exhibit sixty-fold greater sensitivity than other fibroblasts and epithelial-like cells to CeReS-18-induced growth inhibition. Growth inhibition induced by CeReS-18 treatment is a reversible process, and the three mouse keratinocyte cell lines exhibited either single or multiple cell cycle arrest points, although a predominantly G0/G1 cell cycle arrest point was exhibited in Swiss 3T3 fibroblasts. The sensitivity of the mouse keratinocyte cell lines to CeReS-18-induced growth inhibition was not affected by the degree of tumorigenic progression in the cell lines and was not due to differences in CeReS-18 binding affinity or number of cell surface receptors per cell. However, the sensitivity of both murine fibroblasts and keratinocytes could be altered by changing the extracellular calcium concentration, such that increased extracellular calcium concentrations resulted in decreased sensitivity to CeReS-18-induced proliferation inhibition. Thus the increased sensitivity of the murine keratinocyte cell lines to CeReS-18 could be ascribed to the low calcium concentration used in their propagation. Studies are currently under way investigating the role of calcium in CeReS-18-induced growth arrest. The CeReS-18 may serve as a very useful tool to study negative growth control and the signal transduction events associated with cell cycling.

  9. Jasmonic Acid Enhances Al-Induced Root Growth Inhibition1[OPEN

    PubMed Central

    Yang, Zhong-Bao; Ma, Yanqi

    2017-01-01

    Phytohormones such as ethylene and auxin are involved in the regulation of the aluminum (Al)-induced root growth inhibition. Although jasmonate (JA) has been reported to play a crucial role in the regulation of root growth and development in response to environmental stresses through interplay with ethylene and auxin, its role in the regulation of root growth response to Al stress is not yet known. In an attempt to elucidate the role of JA, we found that exogenous application of JA enhanced the Al-induced root growth inhibition. Furthermore, phenotype analysis with mutants defective in either JA biosynthesis or signaling suggests that JA is involved in the regulation of Al-induced root growth inhibition. The expression of the JA receptor CORONATINE INSENSITIVE1 (COI1) and the key JA signaling regulator MYC2 was up-regulated in response to Al stress in the root tips. This process together with COI1-mediated Al-induced root growth inhibition under Al stress was controlled by ethylene but not auxin. Transcriptomic analysis revealed that many responsive genes under Al stress were regulated by JA signaling. The differential responsive of microtubule organization-related genes between the wild-type and coi1-2 mutant is consistent with the changed depolymerization of cortical microtubules in coi1 under Al stress. In addition, ALMT-mediated malate exudation and thus Al exclusion from roots in response to Al stress was also regulated by COI1-mediated JA signaling. Together, this study suggests that root growth inhibition is regulated by COI1-mediated JA signaling independent from auxin signaling and provides novel insights into the phytohormone-mediated root growth inhibition in response to Al stress. PMID:27932419

  10. Growth Enhancement of Radish Sprouts Induced by Low Pressure O2 Radio Frequency Discharge Plasma Irradiation

    NASA Astrophysics Data System (ADS)

    Kitazaki, Satoshi; Koga, Kazunori; Shiratani, Masaharu; Hayashi, Nobuya

    2012-01-01

    We studied growth enhancement of radish sprouts (Raphanus sativus L.) induced by low pressure O2 radio frequency (RF) discharge plasma irradiation. The average length of radish sprouts cultivated for 7 days after O2 plasma irradiation is 30-60% greater than that without irradiation. O2 plasma irradiation does not affect seed germination. The experimental results reveal that oxygen related radicals strongly enhance growth, whereas ions and photons do not.

  11. Growth hormone induces hepatic production of fibroblast growth factor 21 through a mechanism dependent on lipolysis in adipocytes.

    PubMed

    Chen, Wei; Hoo, Ruby Lai-chong; Konishi, Morichika; Itoh, Nobuyuki; Lee, Pui-Chi; Ye, Hong-ying; Lam, Karen Siu-ling; Xu, Aimin

    2011-10-07

    Fibroblast growth factor (FGF) 21 and growth hormone (GH) are metabolic hormones that play important roles in regulating glucose and lipid metabolism. Both hormones are induced in response to fasting and exert their actions on adipocytes to regulate lipolysis. However, the molecular interaction between these two hormones remains unclear. Here we demonstrate the existence of a feedback loop between GH and FGF21 on the regulation of lipolysis in adipocytes. A single bolus injection of GH into C57 mice acutely increases both mRNA and protein expression of FGF21 in the liver, thereby leading to a marked elevation of serum FGF21 concentrations. Such a stimulatory effect of GH on hepatic FGF21 production is abrogated by pretreatment of mice with the lipolysis inhibitor niacin. Direct incubation of either liver explants or human HepG2 hepatocytes with GH has no effect on FGF21 expression. On the other hand, FGF21 production in HepG2 cells is significantly induced by incubation with the conditioned medium harvested from GH-treated adipose tissue explants, which contains high concentrations of free fatty acids (FFA). Further analysis shows that FFA released by GH-induced lipolysis stimulates hepatic FGF21 expression by activation of the transcription factor PPARα. In FGF21-null mice, both the magnitude and duration of GH-induced lipolysis are significantly higher than those in their wild type littermates. Taken together, these findings suggest that GH-induced hepatic FGF21 production is mediated by FFA released from adipose tissues, and elevated FGF21 in turn acts as a negative feedback signal to terminate GH-stimulated lipolysis in adipocytes.

  12. Exposure to Nerve Growth Factor Worsens Nephrotoxic Effect Induced by Cyclosporine A in HK-2 Cells

    PubMed Central

    Lofaro, Danilo; Toteda, Giuseppina; Lupinacci, Simona; Leone, Francesca; Gigliotti, Paolo; Papalia, Teresa; Bonofiglio, Renzo

    2013-01-01

    Nerve growth factor is a neurotrophin that promotes cell growth, differentiation, survival and death through two different receptors: TrkANTR and p75NTR. Nerve growth factor serum concentrations increase during many inflammatory and autoimmune diseases, glomerulonephritis, chronic kidney disease, end-stage renal disease and, particularly, in renal transplant. Considering that nerve growth factor exerts beneficial effects in the treatment of major central and peripheral neurodegenerative diseases, skin and corneal ulcers, we asked whether nerve growth factor could also exert a role in Cyclosporine A-induced graft nephrotoxicity. Our hypothesis was raised from basic evidence indicating that Cyclosporine A-inhibition of calcineurin-NFAT pathway increases nerve growth factor expression levels. Therefore, we investigated the involvement of nerve growth factor and its receptors in the damage exerted by Cyclosporine A in tubular renal cells, HK-2. Our results showed that in HK-2 cells combined treatment with Cyclosporine A + nerve growth factor induced a significant reduction in cell vitality concomitant with a down-regulation of Cyclin D1 and up-regulation of p21 levels respect to cells treated with Cyclosporine A alone. Moreover functional experiments showed that the co-treatment significantly up-regulated human p21promoter activity by involvement of the Sp1 transcription factor, whose nuclear content was negatively regulated by activated NFATc1. In addition we observed that the combined exposure to Cyclosporine A + nerve growth factor promoted an up-regulation of p75 NTR and its target genes, p53 and BAD leading to the activation of intrinsic apoptosis. Finally, the chemical inhibition of p75NTR down-regulated the intrinsic apoptotic signal. We describe two new mechanisms by which nerve growth factor promotes growth arrest and apoptosis in tubular renal cells exposed to Cyclosporine A. PMID:24244623

  13. Ion beam-induced hydroxylation controls molybdenum disulfide growth

    NASA Astrophysics Data System (ADS)

    Bartolucci, Stephen F.; Kaplan, Daniel; Maurer, Joshua A.

    2017-06-01

    2D materials, such as graphene and transition metal dichalcogenides, are a promising class of nanomaterials for next generation electronics, photovoltaics, electrocatalysts, sensors, and optoelectronic devices. Molybdenum disulfide (MoS2) is of particular interest due to its direct bandgap in the visible spectrum, high electron mobility, and chemical stability. Here, we demonstrate that alterations in the density of surface hydroxyl groups on silicon dioxide substrates can control nucleation and growth in molybdenum disulfide thin films produced by atmospheric-pressure chemical vapor deposition. The extent of MoS2 nucleation is linearly correlated to the density of surface hydroxyl groups. Controlling the density of surface hydroxyl groups on the initial substrate provides a method of growing patterned molybdenum disulfide. Furthermore, we establish that the surface density of hydroxyl groups on silicon dioxide (SiO2) is altered using conventional gallium focused ion beam (FIB) patterning. Upon gallium-ion beam exposure, the number of hydroxyl groups generated on the surface is directly proportional to the ion dosage. This work establishes a means of patterning large-area monolayer MoS2 on silicon dioxide substrates, which is a critical step for realizing applications in imaging, catalysis, biosensing, chemical detection, electronics and optoelectronics.

  14. Ultrasmooth growth of amorphous silicon films through ion-induced long-range surface correlations

    SciTech Connect

    Redondo-Cubero, A.; Gago, R.; Vazquez, L.

    2011-01-03

    Ultrasmooth amorphous silicon films with a constant roughness below 0.2 nm were produced for film thickness up to {approx}1 {mu}m by magnetron sputtering under negative voltage substrate biasing (100-400 V). In contrast, under unbiased conditions the roughness of the resulting mounded films increased linearly with growth time due to shadowing effects. A detailed analysis of the amorphous film growth dynamics proves that the bias-induced ultrasmoothness is produced by a downhill mass transport process that leads to an extreme surface leveling inducing surface height correlations up to lateral distances close to 0.5 {mu}m.

  15. Growth suppressing activity for endothelial cells induced from macrophages by carboxymethylated curdlan.

    PubMed

    Usui, S; Matsunaga, T; Ukai, S; Kiho, T

    1997-11-01

    A carboxymethylated derivative of a linear (1-->3)-beta-D-glucan (CMCD) from Alcaligenes faecalis var. myxogenes acted directly on mouse peritoneal macrophages and mouse lymphoma P388D1 cells, and induced a growth suppressing activity for bovine artery endothelial cells (BAEs) from themselves at a concentration of 100 micrograms/ml. The suppressing activity was also detected in the mouse serum administered as an i.p. injection of CMCD at a dose of 100 mg/kg, suggesting that the growth suppressing activity was induced from macrophages potentiated by CMCD in vivo.

  16. Irradiation-induced grain growth and defect evolution in nanocrystalline zirconia with doped grain boundaries.

    PubMed

    Dey, Sanchita; Mardinly, John; Wang, Yongqiang; Valdez, James A; Holesinger, Terry G; Uberuaga, Blas P; Ditto, Jeff J; Drazin, John W; Castro, Ricardo H R

    2016-06-22

    Grain boundaries are effective sinks for radiation-induced defects, ultimately impacting the radiation tolerance of nanocrystalline materials (dense materials with nanosized grains) against net defect accumulation. However, irradiation-induced grain growth leads to grain boundary area decrease, shortening potential benefits of nanostructures. A possible approach to mitigate this is the introduction of dopants to target a decrease in grain boundary mobility or a reduction in grain boundary energy to eliminate driving forces for grain growth (using similar strategies as to control thermal growth). Here we tested this concept in nanocrystalline zirconia doped with lanthanum. Although the dopant is observed to segregate to the grain boundaries, causing grain boundary energy decrease and promoting dragging forces for thermally activated boundary movement, irradiation induced grain growth could not be avoided under heavy ion irradiation, suggesting a different growth mechanism as compared to thermal growth. Furthermore, it is apparent that reducing the grain boundary energy reduced the effectiveness of the grain boundary as sinks, and the number of defects in the doped material is higher than in undoped (La-free) YSZ.

  17. Dietary polyamines promote the growth of azoxymethane-induced aberrant crypt foci in rat colon.

    PubMed

    Paulsen, J E; Reistad, R; Eliassen, K A; Sjaastad, O V; Alexander, J

    1997-10-01

    We have examined whether dietary polyamines influence the formation and initial growth of azoxymethane (AOM)-induced aberrant crypt foci (ACF) in rat colon. Effects of a combination of dietary polyamines at three dose levels (putrescine: 50, 280, 740 nmol/g; spermidine: 10, 261, 763 nmol/g; spermine: 1, 31, 91 nmol/g) in the polyamine-poor AIN-76A diet were studied in animals in two different experimental situations: animals treated with AOM alone and animals treated with AOM + difluoromethylornithine (DFMO), a specific inhibitor of endogenous polyamine synthesis. In both experimental situations, dietary polyamines enhanced the growth of ACF, expressed as the number of large ACF (foci with three or more aberrant crypts, ACF > or = 3), whereas the formation of ACF, expressed as the number of ACF, was apparently not altered. In animals treated with AOM alone, maximal growth enhancing effect on ACF was nearly obtained with the median level of dietary polyamine. In rats fed a low polyamine diet, basic AIN-76A, DFMO reduced the growth of AOM-induced ACF by 83%. This inhibitory effect of DFMO was counteracted by dietary polyamines in a dose-dependent manner, and it was abolished at the highest level of polyamines. In conclusion, it was demonstrated that dietary polyamines are able to enhance the growth of AOM-induced ACF. Further, dietary polyamines reversed the DFMO-caused inhibition of ACF growth, probably by compensating for the DFMO-reduced endogenous polyamine synthesis.

  18. Irradiation-induced grain growth and defect evolution in nanocrystalline zirconia with doped grain boundaries

    SciTech Connect

    Dey, Sanchita; Mardinly, John; Wang, Yongqiang; Valdez, James Anthony; Holesinger, Terry George; Uberuaga, Blas P.; Ditto, Jeff J.; Drazin, John W.; Castro, Ricardo H. R.

    2016-05-27

    Grain boundaries are effective sinks for radiation-induced defects, ultimately impacting the radiation tolerance of nanocrystalline materials (dense materials with nanosized grains) against net defect accumulation. However, irradiation-induced grain growth leads to grain boundary area decrease, shortening potential benefits of nanostructures. A possible approach to mitigate this is the introduction of dopants to target a decrease in grain boundary mobility or a reduction in grain boundary energy to eliminate driving forces for grain growth (using similar strategies as to control thermal growth). Here, in this study, we tested this concept in nanocrystalline zirconia doped with lanthanum. Although the dopant is observed to segregate to the grain boundaries, causing grain boundary energy decrease and promoting dragging forces for thermally activated boundary movement, irradiation induced grain growth could not be avoided under heavy ion irradiation, suggesting a different growth mechanism as compared to thermal growth. Furthermore, it is apparent that reducing the grain boundary energy reduced the effectiveness of the grain boundary as sinks, and the number of defects in the doped material is higher than in undoped (La-free) YSZ.

  19. Irradiation-induced grain growth and defect evolution in nanocrystalline zirconia with doped grain boundaries

    SciTech Connect

    Dey, Sanchita; Mardinly, John; Wang, Yongqiang; Valdez, James Anthony; Holesinger, Terry George; Uberuaga, Blas P.; Ditto, Jeff J.; Drazin, John W.; Castro, Ricardo H. R.

    2016-05-27

    Grain boundaries are effective sinks for radiation-induced defects, ultimately impacting the radiation tolerance of nanocrystalline materials (dense materials with nanosized grains) against net defect accumulation. However, irradiation-induced grain growth leads to grain boundary area decrease, shortening potential benefits of nanostructures. A possible approach to mitigate this is the introduction of dopants to target a decrease in grain boundary mobility or a reduction in grain boundary energy to eliminate driving forces for grain growth (using similar strategies as to control thermal growth). Here, in this study, we tested this concept in nanocrystalline zirconia doped with lanthanum. Although the dopant is observed to segregate to the grain boundaries, causing grain boundary energy decrease and promoting dragging forces for thermally activated boundary movement, irradiation induced grain growth could not be avoided under heavy ion irradiation, suggesting a different growth mechanism as compared to thermal growth. Furthermore, it is apparent that reducing the grain boundary energy reduced the effectiveness of the grain boundary as sinks, and the number of defects in the doped material is higher than in undoped (La-free) YSZ.

  20. Irradiation-induced grain growth and defect evolution in nanocrystalline zirconia with doped grain boundaries

    DOE PAGES

    Dey, Sanchita; Mardinly, John; Wang, Yongqiang; ...

    2016-05-27

    Grain boundaries are effective sinks for radiation-induced defects, ultimately impacting the radiation tolerance of nanocrystalline materials (dense materials with nanosized grains) against net defect accumulation. However, irradiation-induced grain growth leads to grain boundary area decrease, shortening potential benefits of nanostructures. A possible approach to mitigate this is the introduction of dopants to target a decrease in grain boundary mobility or a reduction in grain boundary energy to eliminate driving forces for grain growth (using similar strategies as to control thermal growth). Here, in this study, we tested this concept in nanocrystalline zirconia doped with lanthanum. Although the dopant is observedmore » to segregate to the grain boundaries, causing grain boundary energy decrease and promoting dragging forces for thermally activated boundary movement, irradiation induced grain growth could not be avoided under heavy ion irradiation, suggesting a different growth mechanism as compared to thermal growth. Furthermore, it is apparent that reducing the grain boundary energy reduced the effectiveness of the grain boundary as sinks, and the number of defects in the doped material is higher than in undoped (La-free) YSZ.« less

  1. Dauricine inhibits insulin-like growth factor-I-induced hypoxia inducible factor 1α protein accumulation and vascular endothelial growth factor expression in human breast cancer cells

    PubMed Central

    Tang, Xu-dong; Zhou, Xin; Zhou, Ke-yuan

    2009-01-01

    Aim: To investigate the effects of dauricine (Dau) on insulin-like growth factor-I (IGF-I)-induced hypoxia inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression in human breast cancer cells (MCF-7). Methods: Serum-starved MCF-7 cells were pretreated for 1 h with different concentrations of Dau, followed by incubation with IGF-I for 6 h. HIF-1α and VEGF protein expression levels were analyzed by Western blotting and ELISA, respectively. HIF-1α and VEGF mRNA levels were determined by real-time PCR. In vitro angiogenesis was observed via the human umbilical vein endothelial cell (HUVEC) tube formation assay. An in vitro invasion assay on HUVECs was performed. Results: Dau significantly inhibited IGF-I-induced HIF-1α protein expression but had no effect on HIF-1α mRNA expression. However, Dau remarkably suppressed VEGF expression at both protein and mRNA levels in response to IGF-I. Mechanistically, Dau suppressed IGF-I-induced HIF-1α and VEGF protein expression mainly by blocking the activation of PI-3K/AKT/mTOR signaling pathway. In addition, Dau reduced IGF-I-induced HIF-1α protein accumulation by inhibiting its synthesis as well as by promoting its degradation. Functionally, Dau inhibited angiogenesis in vitro. Moreover, Dau had a direct effect on IGF-I-induced invasion of HUVECs. Conclusion: Dau inhibits human breast cancer angiogenesis by suppressing HIF-1α protein accumulation and VEGF expression, which may provide a novel potential mechanism for the anticancer activities of Dau in human breast cancer. PMID:19349962

  2. Transforming growth factor beta-induced (TGFBI) is an anti-adhesive protein regulating the invasive growth of melanoma cells.

    PubMed

    Nummela, Pirjo; Lammi, Johanna; Soikkeli, Johanna; Saksela, Olli; Laakkonen, Pirjo; Hölttä, Erkki

    2012-04-01

    Melanoma is a malignancy characterized by high invasive/metastatic potential, with no efficient therapy after metastasis. Understanding the molecular mechanisms underlying the invasive/metastatic tendency is therefore important. Our genome-wide gene expression analyses revealed that human melanoma cell lines WM793 and especially WM239 (vertical growth phase and metastatic cells, respectively) overexpress the extracellular matrix (ECM) protein transforming growth factor β induced (TGFBI). In adhesion assays, recombinant TGFBI was strongly anti-adhesive for both melanoma cells and skin fibroblasts. TGFBI further impaired the adhesion of melanoma cells to the adhesive ECM proteins fibronectin, collagen-I, and laminin, known to interact with it. Unexpectedly, WM239 cells migrated/invaded more effectively in three-dimensional collagen-I and Matrigel cultures after knockdown of TGFBI by shRNA expression. However, in the physiological subcutaneous microenvironment in nude mice, after TGFBI knockdown, these cells showed markedly impaired tumor growth and invasive capability; the initially formed small tumors later underwent myxoid degeneration and completely regressed. By contrast, the expanding control tumors showed intense TGFBI staining at the tumor edges, co-localizing with the fibrillar fibronectin/tenascin-C/periostin structures that characteristically surround melanoma cells at invasion fronts. Furthermore, TGFBI was found in similar fibrillar structures in clinical human melanoma metastases as well, co-localizing with fibronectin. These data imply an important role for TGFBI in the ECM deposition and invasive growth of melanoma cells, rendering TGFBI a potential target for therapeutic interventions.

  3. Tumor Growth Suppression Induced by Biomimetic Silk Fibroin Hydrogels

    PubMed Central

    Yan, Le-Ping; Silva-Correia, Joana; Ribeiro, Viviana P.; Miranda-Gonçalves, Vera; Correia, Cristina; da Silva Morais, Alain; Sousa, Rui A.; Reis, Rui M.; Oliveira, Ana L.; Oliveira, Joaquim M.; Reis, Rui L.

    2016-01-01

    Protein-based hydrogels with distinct conformations which enable encapsulation or differentiation of cells are of great interest in 3D cancer research models. Conformational changes may cause macroscopic shifts in the hydrogels, allowing for its use as biosensors and drug carriers. In depth knowledge on how 3D conformational changes in proteins may affect cell fate and tumor formation is required. Thus, this study reports an enzymatically crosslinked silk fibroin (SF) hydrogel system that can undergo intrinsic conformation changes from random coil to β-sheet conformation. In random coil status, the SF hydrogels are transparent, elastic, and present ionic strength and pH stimuli-responses. The random coil hydrogels become β-sheet conformation after 10 days in vitro incubation and 14 days in vivo subcutaneous implantation in rat. When encapsulated with ATDC-5 cells, the random coil SF hydrogel promotes cell survival up to 7 days, whereas the subsequent β-sheet transition induces cell apoptosis in vitro. HeLa cells are further incorporated in SF hydrogels and the constructs are investigated in vitro and in an in vivo chick chorioallantoic membrane model for tumor formation. In vivo, Angiogenesis and tumor formation are suppressed in SF hydrogels. Therefore, these hydrogels provide new insights for cancer research and uses of biomaterials. PMID:27485515

  4. Tumor Growth Suppression Induced by Biomimetic Silk Fibroin Hydrogels

    NASA Astrophysics Data System (ADS)

    Yan, Le-Ping; Silva-Correia, Joana; Ribeiro, Viviana P.; Miranda-Gonçalves, Vera; Correia, Cristina; da Silva Morais, Alain; Sousa, Rui A.; Reis, Rui M.; Oliveira, Ana L.; Oliveira, Joaquim M.; Reis, Rui L.

    2016-08-01

    Protein-based hydrogels with distinct conformations which enable encapsulation or differentiation of cells are of great interest in 3D cancer research models. Conformational changes may cause macroscopic shifts in the hydrogels, allowing for its use as biosensors and drug carriers. In depth knowledge on how 3D conformational changes in proteins may affect cell fate and tumor formation is required. Thus, this study reports an enzymatically crosslinked silk fibroin (SF) hydrogel system that can undergo intrinsic conformation changes from random coil to β-sheet conformation. In random coil status, the SF hydrogels are transparent, elastic, and present ionic strength and pH stimuli-responses. The random coil hydrogels become β-sheet conformation after 10 days in vitro incubation and 14 days in vivo subcutaneous implantation in rat. When encapsulated with ATDC-5 cells, the random coil SF hydrogel promotes cell survival up to 7 days, whereas the subsequent β-sheet transition induces cell apoptosis in vitro. HeLa cells are further incorporated in SF hydrogels and the constructs are investigated in vitro and in an in vivo chick chorioallantoic membrane model for tumor formation. In vivo, Angiogenesis and tumor formation are suppressed in SF hydrogels. Therefore, these hydrogels provide new insights for cancer research and uses of biomaterials.

  5. Glyphosate induces human breast cancer cells growth via estrogen receptors.

    PubMed

    Thongprakaisang, Siriporn; Thiantanawat, Apinya; Rangkadilok, Nuchanart; Suriyo, Tawit; Satayavivad, Jutamaad

    2013-09-01

    Glyphosate is an active ingredient of the most widely used herbicide and it is believed to be less toxic than other pesticides. However, several recent studies showed its potential adverse health effects to humans as it may be an endocrine disruptor. This study focuses on the effects of pure glyphosate on estrogen receptors (ERs) mediated transcriptional activity and their expressions. Glyphosate exerted proliferative effects only in human hormone-dependent breast cancer, T47D cells, but not in hormone-independent breast cancer, MDA-MB231 cells, at 10⁻¹² to 10⁻⁶M in estrogen withdrawal condition. The proliferative concentrations of glyphosate that induced the activation of estrogen response element (ERE) transcription activity were 5-13 fold of control in T47D-KBluc cells and this activation was inhibited by an estrogen antagonist, ICI 182780, indicating that the estrogenic activity of glyphosate was mediated via ERs. Furthermore, glyphosate also altered both ERα and β expression. These results indicated that low and environmentally relevant concentrations of glyphosate possessed estrogenic activity. Glyphosate-based herbicides are widely used for soybean cultivation, and our results also found that there was an additive estrogenic effect between glyphosate and genistein, a phytoestrogen in soybeans. However, these additive effects of glyphosate contamination in soybeans need further animal study. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. Inhibition of Estrogen-Induced Growth of Breast Cancer by Targeting Mitrochondrial Oxidants

    DTIC Science & Technology

    2007-04-01

    that E2-induced cell growth was reduced by antioxidants N- acetyl -L- cysteine ( NAC ), catalase, and the glutathione peroxidase mimic ebselen. mtTFA...13. SUPPLEMENTARY NOTES 14. ABSTRACT We have completed proposed research in the First Year Task (i) both antioxidants, N- acetylcysteine ...induced conversion of normal cells to transformed cells is inhibited by treatment with N- acetylcysteine and ebselen, overexpression of MnSOD or catalase

  7. Strain-induced selective growth in 1.5% temper-rolled Fe;1%Si.

    PubMed

    Bennett, Tricia A; Kalu, Peter N; Rollett, Anthony D

    2011-06-01

    Strain-induced selective growth was investigated in a 1.5% temper-rolled Fe∼1%Si alloy using the electron backscatter diffraction (EBSD) technique. The EBSD technique was used to quantify the presence of orientation spreads within grains and to show that this particular case of selective growth can be directly related to differences in stored energy as reflected in the geometrically necessary dislocation content. The differences in stored energy were sufficient to give rise to selective growth as evidenced by bi-modal grain sizes.

  8. Impact of Surface Chemistry on Grain Boundary Induced Intrinsic Stress Evolution during Polycrystalline Thin Film Growth

    NASA Astrophysics Data System (ADS)

    Qi, Y.; Sheldon, B. W.; Guo, H.; Xiao, X.; Kothari, A. K.

    2009-02-01

    First principles calculations were integrated with cohesive zone and growth chemistry models to demonstrate that adsorbed species can significantly alter stresses associated with grain boundary formation during polycrystalline film growth. Using diamond growth as an example, the results show that lower substrate temperatures increase the hydrogen content at the surface, which reduces tensile stress, widens the grain boundary separations, and permits additional atom insertions that can induce compressive stress. More generally, this work demonstrates that surface heteroatoms can lead to behavior which is not readily described by existing models of intrinsic stress evolution.

  9. Growth behavior of laser-induced damage on fused silica optics under UV, ns laser irradiation.

    PubMed

    Negres, Raluca A; Norton, Mary A; Cross, David A; Carr, Christopher W

    2010-09-13

    The growth behavior of laser-induced damage sites is affected by a large number of laser parameters as well as site morphology. Here we investigate the effects of pulse duration on the growth rate of damage sites located on the exit surface of fused silica optics. Results demonstrate a significant dependence of the growth parameters on laser pulse duration at 351 nm from 1 ns to 15 ns, including the observation of a dominant exponential versus linear, multiple-shot growth behavior for long and short pulses, respectively. These salient behaviors are tied to the damage morphology and suggest a shift in the fundamental growth mechanisms for pulses in the 1-5 ns range.

  10. TGF beta-induced growth inhibition in primary fibroblasts requires the retinoblastoma protein.

    PubMed

    Herrera, R E; Mäkelä, T P; Weinberg, R A

    1996-09-01

    Transforming growth factor beta (TGF beta) inhibits cell proliferation by inducing a G1 cell-cycle arrest. Cyclin/CDK complexes have been implicated in this arrest, because TGF beta treatment leads to inhibition of cyclin/CDK activity. We have investigated the role of the retinoblastoma protein (pRb) in TGF beta-induced growth arrest by using RB+/+ and RB-/- primary mouse embryo fibroblasts. In both of these cell types, TGF beta inhibits CDK4-associated kinase activity. However, whereas CDK2-associated kinase activity was completely inhibited by TGF beta in the wild-type cells, it was reduced only slightly in the RB mutant cells. In addition, at high-cell density the growth-inhibitory effects of TGF beta are no longer observed in the RB-/- cells; on the contrary, TGF beta treatment promotes the growth of these mutant fibroblasts. Thus, under certain cellular growth conditions, elimination of pRb transforms the growth-inhibitory effects of TGF beta into growth-stimulatory effects. These observations could help to explain why TGF beta is often found to enhance tumorigenicity in vivo and why inactivation of the RB gene leads to tumorigenesis.

  11. Devazepide, a nonpeptide antagonist of CCK receptors, induces apoptosis and inhibits Ewing tumor growth.

    PubMed

    Carrillo, Jaime; Agra, Noelia; Fernández, Noemí; Pestaña, Angel; Alonso, Javier

    2009-08-01

    The Ewing family of tumors is a group of highly malignant tumors that mainly arise in bone and most often affect children and young adults in the first two decades of life. Despite the use of multimodal therapy, the long-term disease-free survival rate of patients with Ewing tumors is still disappointingly low, making the discovery of innovative therapeutic strategies all the more necessary. We have recently shown that cholecystokinin (CCK), a neuroendocrine peptide, involved in many biological functions, including cell growth and proliferation, is a relevant target of the EWS/FLI1 oncoprotein characteristic of Ewing tumors. CCK silencing inhibits cell proliferation and tumor growth in vivo, suggesting that CCK acts as an autocrine growth factor for Ewing cells. Here, we analyzed the impact of two CCK receptor antagonists, devazepide (a CCK1-R antagonist) and L365 260 (a CCK2-R antagonist), on the growth of Ewing tumor cells. Devazepide (10 micromol/l) inhibited cell growth of four different Ewing tumor cells in vitro (range 85-88%), whereas the effect of the CCK2-R antagonist on cell growth was negligible. In a mouse tumor xenograft model, devazepide reduced tumor growth by 40%. Flow cytometry experiments showed that devazepide, but not L365 260, induced apoptosis of Ewing tumor cells. In summary, devazepide induces cell death of Ewing tumor cells, suggesting that it could represent a new therapeutic approach in the management of Ewing's tumor patients.

  12. Diacylglycerol production induced by growth hormone in Ob1771 preadipocytes arises from phosphatidylcholine breakdown

    SciTech Connect

    Catalioto, R.M.; Ailhaud, G.; Negrel, R. )

    1990-12-31

    Growth Hormone has recently been shown to stimulate the formation of diacylglycerol in Ob1771 mouse preadipocyte cells without increasing inositol lipid turnover. Addition of growth hormone to Ob1771 cells prelabelled with ({sup 3}H)glycerol or ({sup 3}H)choline led to a rapid, transient and stoechiometric formation of labelled diacylglycerol and phosphocholine, respectively. In contrast, no change was observed in the level of choline and phosphatidic acid whereas the release of water-soluble metabolites in ({sup 3}H)ethanolamine prelabelled cells exposed to growth hormone was hardly detectable. Stimulation by growth hormone of cells prelabelled with (2-palmitoyl 9, 10 ({sup 3}H))phosphatidylcholine also induced the production of labelled diacyglycerol. Pertussis toxin abolished both diacylglycerol and phosphocholine formation induced by growth hormone. It is concluded that growth hormone mediates diacylglycerol production in Ob1771 cells by means of phosphatidylcholine breakdown involving a phospholipase C which is likely coupled to the growth hormone receptor via a pertussis toxin-sensitive G-protein.

  13. Shear induced collateral artery growth modulated by endoglin but not by ALK1

    PubMed Central

    Seghers, Leonard; de Vries, Margreet R; Pardali, Evangelia; Hoefer, Imo E; Hierck, Beerend P; ten Dijke, Peter ten; Goumans, Marie Jose; Quax, Paul HA

    2012-01-01

    Transforming growth factor-beta (TGF-β) stimulates both ischaemia induced angiogenesis and shear stress induced arteriogenesis by signalling through different receptors. How these receptors are involved in both these processes of blood flow recovery is not entirely clear. In this study the role of TGF-β receptors 1 and endoglin is assessed in neovascularization in mice. Unilateral femoral artery ligation was performed in mice heterozygous for either endoglin or ALK1 and in littermate controls. Compared with littermate controls, blood flow recovery, monitored by laser Doppler perfusion imaging, was significantly hampered by maximal 40% in endoglin heterozygous mice and by maximal 49% in ALK1 heterozygous mice. Collateral artery size was significantly reduced in endoglin heterozygous mice compared with controls but not in ALK1 heterozygous mice. Capillary density in ischaemic calf muscles was unaffected, but capillaries from endoglin and ALK1 heterozygous mice were significantly larger when compared with controls. To provide mechanistic evidence for the differential role of endoglin and ALK1 in shear induced or ischaemia induced neovascularization, murine endothelial cells were exposed to shear stress in vitro. This induced increased levels of endoglin mRNA but not ALK1. In this study it is demonstrated that both endoglin and ALK1 facilitate blood flow recovery. Importantly, endoglin contributes to both shear induced collateral artery growth and to ischaemia induced angiogenesis, whereas ALK1 is only involved in ischaemia induced angiogenesis. PMID:22436015

  14. Mechanisms behind bacteria induced plant growth promotion and Zn accumulation in Brassica juncea.

    PubMed

    Adediran, Gbotemi A; Ngwenya, Bryne T; Mosselmans, J Frederick W; Heal, Kate V; Harvie, Barbra A

    2015-01-01

    The growth and metal-extraction efficiency of plants exposed to toxic metals has been reported to be enhanced by inoculating plants with certain bacteria but the mechanisms behind this process remain unclear. We report results from glasshouse experiments on Brassica juncea plants exposed to 400mgZnkg(-1) that investigated the abilities of Pseudomonas brassicacearum and Rhizobium leguminosarum to promote growth, coupled with synchrotron based μXANES analysis to probe Zn speciation in the plant roots. P. brassicacearum exhibited the poorest plant growth promoting ability, while R. leguminosarum alone and in combination with P. brassicacearum enhanced plant growth and Zn phytoextraction. Reduced growth in un-inoculated plants was attributed to accumulation of Zn oxalate and Zn sulfate in roots. In plants inoculated with P. brassicacearum the high concentration of Zn polygalacturonic acid in the root may be responsible for the stunted growth and reduced Zn phytoextraction. The improved growth and increased metal accumulation observed in plants inoculated with R. leguminosarum and in combination with P. brassicacearum was attributed to the storage of Zn in the form of Zn phytate and Zn cysteine in the root. When combined with the observation that both bacteria do not statistically improve B. juncea growth in the absence of Zn, this work suggests that bacteria-induced metal chelation is the key mechanism of plant growth promoting bacteria in toxicity attenuation and microbial-assisted phytoremediation. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Competition induces allelopathy but suppresses growth and anti-herbivore defence in a chemically rich seaweed.

    PubMed

    Rasher, Douglas B; Hay, Mark E

    2014-02-22

    Many seaweeds and terrestrial plants induce chemical defences in response to herbivory, but whether they induce chemical defences against competitors (allelopathy) remains poorly understood. We evaluated whether two tropical seaweeds induce allelopathy in response to competition with a reef-building coral. We also assessed the effects of competition on seaweed growth and seaweed chemical defence against herbivores. Following 8 days of competition with the coral Porites cylindrica, the chemically rich seaweed Galaxaura filamentosa induced increased allelochemicals and became nearly twice as damaging to the coral. However, it also experienced significantly reduced growth and increased palatability to herbivores (because of reduced chemical defences). Under the same conditions, the seaweed Sargassum polycystum did not induce allelopathy and did not experience a change in growth or palatability. This is the first demonstration of induced allelopathy in a seaweed, or of competitors reducing seaweed chemical defences against herbivores. Our results suggest that the chemical ecology of coral-seaweed-herbivore interactions can be complex and nuanced, highlighting the need to incorporate greater ecological complexity into the study of chemical defence.

  16. Hepatocyte growth factor protects human endothelial cells against advanced glycation end products-induced apoposis

    SciTech Connect

    Zhou Yijun . E-mail: zhou-yijun@hotmail.com; Wang Jiahe; Zhang Jin

    2006-06-02

    Advanced glycation end products (AGEs) form by a non-enzymatic reaction between reducing sugars and biological proteins, which play an important role in the pathogenesis of atherosclerosis. In this study, we assessed AGEs effects on human umbilical vein endothelial cells (HUVECs) growth, proliferation and apoptosis. Additionally, we investigated whether hepatocyte growth factor (HGF), an anti-apoptotic factor for endothelial cells, prevents AGEs-induced apoptosis of HUVECs. HUVECs were treated with AGEs in the presence or absence of HGF. Treatment of HUVECs with AGEs changed cell morphology, decreased cell viability, and induced DNA fragmentation, leading to apoptosis. Apoptosis was induced by AGEs in a dose- and time-dependent fashion. AGEs markedly elevated Bax and decreased NF-{kappa}B, but not Bcl-2 expression. Additionally, AGEs significantly inhibited cell growth through a pro-apoptotic action involving caspase-3 and -9 activations in HUVECs. Most importantly, pretreatment with HGF protected against AGEs-induced cytotoxicity in the endothelial cells. HGF significantly promoted the expression of Bcl-2 and NF-{kappa}B, while decreasing the activities of caspase-3 and -9 without affecting Bax level. Our data suggest that AGEs induce apoptosis in endothelial cells. HGF effectively attenuate AGEs-induced endothelial cell apoptosis. These findings provide new perspectives in the role of HGF in cardiovascular disease.

  17. Competition induces allelopathy but suppresses growth and anti-herbivore defence in a chemically rich seaweed

    PubMed Central

    Rasher, Douglas B.; Hay, Mark E.

    2014-01-01

    Many seaweeds and terrestrial plants induce chemical defences in response to herbivory, but whether they induce chemical defences against competitors (allelopathy) remains poorly understood. We evaluated whether two tropical seaweeds induce allelopathy in response to competition with a reef-building coral. We also assessed the effects of competition on seaweed growth and seaweed chemical defence against herbivores. Following 8 days of competition with the coral Porites cylindrica, the chemically rich seaweed Galaxaura filamentosa induced increased allelochemicals and became nearly twice as damaging to the coral. However, it also experienced significantly reduced growth and increased palatability to herbivores (because of reduced chemical defences). Under the same conditions, the seaweed Sargassum polycystum did not induce allelopathy and did not experience a change in growth or palatability. This is the first demonstration of induced allelopathy in a seaweed, or of competitors reducing seaweed chemical defences against herbivores. Our results suggest that the chemical ecology of coral–seaweed–herbivore interactions can be complex and nuanced, highlighting the need to incorporate greater ecological complexity into the study of chemical defence. PMID:24403332

  18. AKIP1, a cardiac hypertrophy induced protein that stimulates cardiomyocyte growth via the Akt pathway.

    PubMed

    Yu, Hongjuan; Tigchelaar, Wardit; Lu, Bo; van Gilst, Wiek H; de Boer, Rudolf A; Westenbrink, B Daan; Silljé, Herman H W

    2013-10-28

    Cardiac adaptation to unremitting physiological stress typically involves hypertrophic growth of cardiomyocytes, a compensatory response that often fails and causes heart disease. Gene array analysis identified AKIP1 (A Kinase Interacting Protein 1) as a hypertrophic gene and we therefore hypothesized a potential role in the hypertrophic response. We show for the first time that both AKIP1 mRNA and protein levels increased in hypertrophic cardiomyocytes under conditions of sustained cardiac stress, including pressure overload and after myocardial infarction and in vitro in phenylephrine (PE) stimulated neonatal rat ventricular cardiomyocytes (NRVCs). AKIP1 overexpression in NRVCs markedly stimulated hypertrophic growth responses, including significantly increased cell size, augmented cytoskeletal organization and protein synthesis. Although, AKIP1 was not essential for PE induced hypertrophy in NRVCs, it did potentiate neurohormonal induced protein synthesis. AKIP1 did, however, not induce expression of pathological marker genes like ANP and β-MHC. ERK and Akt kinase signaling pathways have been linked to hypertrophy and AKIP1 specifically induced phosphorylation of Akt. This phosphorylation of Akt was essential for activation of ribosomal rpS6 and translation elongation factor eEF2 and this readily explains the increased protein synthesis. Akt inhibition fully blocked AKIP1 induced hypertrophy, showing that this pathway is critically involved. In conclusion, our results show that AKIP1 is induced in hypertrophic hearts and can stimulate adaptive cardiomyocyte growth, which involves Akt signaling.

  19. AKIP1, a Cardiac Hypertrophy Induced Protein that Stimulates Cardiomyocyte Growth via the Akt Pathway

    PubMed Central

    Yu, Hongjuan; Tigchelaar, Wardit; Lu, Bo; van Gilst, Wiek H.; de Boer, Rudolf A.; Westenbrink, B. Daan; Silljé, Herman H. W.

    2013-01-01

    Cardiac adaptation to unremitting physiological stress typically involves hypertrophic growth of cardiomyocytes, a compensatory response that often fails and causes heart disease. Gene array analysis identified AKIP1 (A Kinase Interacting Protein 1) as a hypertrophic gene and we therefore hypothesized a potential role in the hypertrophic response. We show for the first time that both AKIP1 mRNA and protein levels increased in hypertrophic cardiomyocytes under conditions of sustained cardiac stress, including pressure overload and after myocardial infarction and in vitro in phenylephrine (PE) stimulated neonatal rat ventricular cardiomyocytes (NRVCs). AKIP1 overexpression in NRVCs markedly stimulated hypertrophic growth responses, including significantly increased cell size, augmented cytoskeletal organization and protein synthesis. Although, AKIP1 was not essential for PE induced hypertrophy in NRVCs, it did potentiate neurohormonal induced protein synthesis. AKIP1 did, however, not induce expression of pathological marker genes like ANP and β-MHC. ERK and Akt kinase signaling pathways have been linked to hypertrophy and AKIP1 specifically induced phosphorylation of Akt. This phosphorylation of Akt was essential for activation of ribosomal rpS6 and translation elongation factor eEF2 and this readily explains the increased protein synthesis. Akt inhibition fully blocked AKIP1 induced hypertrophy, showing that this pathway is critically involved. In conclusion, our results show that AKIP1 is induced in hypertrophic hearts and can stimulate adaptive cardiomyocyte growth, which involves Akt signaling. PMID:24169435

  20. Seismic characteristics of tensile fracture growth induced by hydraulic fracturing

    NASA Astrophysics Data System (ADS)

    Eaton, D. W. S.; Van der Baan, M.; Boroumand, N.

    2014-12-01

    Hydraulic fracturing is a process of injecting high-pressure slurry into a rockmass to enhance its permeability. Variants of this process are used for unconventional oil and gas development, engineered geothermal systems and block-cave mining; similar processes occur within volcanic systems. Opening of hydraulic fractures is well documented by mineback trials and tiltmeter monitoring and is a physical requirement to accommodate the volume of injected fluid. Numerous microseismic monitoring investigations acquired in the audio-frequency band are interpreted to show a prevalence of shear-dominated failure mechanisms surrounding the tensile fracture. Moreover, the radiated seismic energy in the audio-frequency band appears to be a miniscule fraction (<< 1%) of the net injected energy, i.e., the integral of the product of fluid pressure and injection rate. We use a simple penny-shaped crack model as a predictive framework to describe seismic characteristics of tensile opening during hydraulic fracturing. This model provides a useful scaling relation that links seismic moment to effective fluid pressure within the crack. Based on downhole recordings corrected for attenuation, a significant fraction of observed microseismic events are characterized by S/P amplitude ratio < 5. Despite the relatively small aperture of the monitoring arrays, which precludes both full moment-tensor analysis and definitive identification of nodal planes or axes, this ratio provides a strong indication that observed microseismic source mechanisms have a component of tensile failure. In addition, we find some instances of periodic spectral notches that can be explained by an opening/closing failure mechanism, in which fracture propagation outpaces fluid velocity within the crack. Finally, aseismic growth of tensile fractures may be indicative of a scenario in which injected energy is consumed to create new fracture surfaces. Taken together, our observations and modeling provide evidence that

  1. Growth-induced non-stoichiometry in complex oxide systems

    NASA Astrophysics Data System (ADS)

    Breckenfeld, Eric

    Complex perovskite oxides have been studied extensively over the past few decades due to their wide range of functional properties and relative ease of epitaxial synthesis. These two factors have allowed such oxide systems to see a multitude of applications including sensors, memory, thermal management, and energy harvesting. The ability to access so many different functionalities is owed largely to the chemical diversity available to the perovskite unit cell, opening the door for metal-insulator-transitions, ferroelectricity, and superconductivity, to name a few. However, the same chemical diversity that enables so many potential applications also opens the door for a myriad of chemistry-related defects. Separating out the relative contributions of such extrinsic (or defect-driven) effects from the intrinsic material properties is crucial to enabling the use of these materials in high-performance, next-generation devices. In this work, we examine several model systems in order to explore the relationship between the pulsed laser deposition growth process, the film chemistry, and the subsequent effects on the defect landscape and film properties. We show that small changes to the laser fluence can have a marked impact on the chemical composition of the film, leading to cation stoichiometry deviations as large as 10% in SrTiO3, LaAlO3, and NdNiO3 systems. We demonstrate that such chemical deviations can lead to significant changes in the bulk thermal and dielectric properties of SrTiO3 and LaAlO3 films. We have also investigated the interface between SrTiO3 and LaAlO3, which has been studied extensively over the past 8 years due to the supposed presence of a 2-dimensional electron gas (2DEG). Our results indicate that the presence of cation defects in the LaAlO3 has a profound impact on the electronic properties of the 2DEG interface. Finally, we have similarly shown that cation non-stoichiometry can cause the metal-insulator-transition material NdNiO3 to behave

  2. Role of calcium in growth inhibition induced by a novel cell surface sialoglycopeptide

    NASA Technical Reports Server (NTRS)

    Betz, N. A.; Westhoff, B. A.; Johnson, T. C.; Spooner, B. S. (Principal Investigator)

    1995-01-01

    Our laboratory has purified an 18 kDa cell surface sialoglycopeptide growth inhibitor (CeReS-18) from intact bovine cerebral cortex cells. Evidence presented here demonstrates that sensitivity to CeReS-18-induced growth inhibition in BALB-c 3T3 cells is influenced by calcium, such that a decrease in the calcium concentration in the growth medium results in an increase in sensitivity to CeReS-18. Calcium did not alter CeReS-18 binding to its cell surface receptor and CeReS-18 does not bind calcium directly. Addition of calcium, but not magnesium, to CeReS-18-inhibited 3T3 cells results in reentry into the cell cycle. A greater than 3-hour exposure to increased calcium is required for escape from CeReS-18-induced growth inhibition. The calcium ionophore ionomycin could partially mimic the effect of increasing extracellular calcium, but thapsigargin was ineffective in inducing escape from growth inhibition. Increasing extracellular calcium 10-fold resulted in an approximately 7-fold increase in total cell-associated 45Ca+2, while free intracellular calcium only increased approximately 30%. However, addition of CeReS-18 did not affect total cell-associated calcium or the increase in total cell-associated calcium observed with an increase in extracellular calcium. Serum addition induced mobilization of intracellular calcium and influx across the plasma membrane in 3T3 cells, and pretreatment of 3T3 cells with CeReS-18 appeared to inhibit these calcium mobilization events. These results suggest that a calcium-sensitive step exists in the recovery from CeReS-18-induced growth inhibition. CeReS-18 may inhibit cell proliferation through a novel mechanism involving altering the intracellular calcium mobilization/regulation necessary for cell cycle progression.

  3. Ca2+ Efflux Is Involved in Cinnamaldehyde-Induced Growth Inhibition of Phytophthora capsici

    PubMed Central

    Chen, Jian; Xue, Yanfeng; Shi, Zhiqi

    2013-01-01

    As a destructive fungus-like plant pathogen, the oomycete Phytophthoracapsici is unable to synthesize its own ergosterol as the potential target of fungicide cinnamaldehyde (CA). In this study, CA exerted efficient inhibitory effects on both mycelial growth (EC50=0.75 mM) and zoospore germination (MIC=0.4 mM) of P. capsici. CA-induced immediate Ca2+ efflux from zoospores could be confirmed by the rapid decrease in intracellular Ca2+ content determined by using Fluo-3 AM and the increase in extracellular Ca2+ concentration determined by using ICP-AES (inductively coupled plasma atomic emission spectrometry). Blocking Ca2+ influx with ruthenium red and verapamil led to a higher level of CA-induced Ca2+ efflux, suggesting the simultaneous occurrence of Ca2+ influx along with the Ca2+ efflux under CA exposure. Further results showed that EGTA-induced decrease in intracellular Ca2+ gave rise to the impaired vitality of P. capsici while the addition of exogenous Ca2+ could suppress the growth inhibitory effect of CA. These results suggested that Ca2+ efflux played an important role in CA-induced growth inhibition of P. capsici. The application of 3-phenyl-1-propanal, a CA analog without α,β- unsaturated bond, resulted in a marked Ca2+ influx in zoospores but did not show any growth inhibitory effects. In addition, exogenous cysteine, an antagonist against the Michael addition (the nucleophilic addition of a carbanion or another nucleophile) between CA and its targets, could attenuate CA-induced growth inhibition of P. capsici by suppressing Ca2+ efflux. Our results suggest that CA inhibits the growth of P. capsici by stimulating a transient Ca2+ efflux via Michael addition, which provides important new insights into the antimicrobial action of CA. PMID:24098458

  4. A Histologically Distinctive Interstitial Pneumonia Induced by Overexpression of the Interleukin 6, Transforming Growth Factor β1, or Platelet-Derived Growth Factor B Gene

    NASA Astrophysics Data System (ADS)

    Yoshida, Mitsuhiro; Sakuma, Junko; Hayashi, Seiji; Abe, Kin'ya; Saito, Izumu; Harada, Shizuko; Sakatani, Mitsunoir; Yamamoto, Satoru; Matsumoto, Norinao; Kaneda, Yasufumi; Kishmoto, Tadamitsu

    1995-10-01

    Interstitial pneumonia is characterized by alveolitis with resulting fibrosis of the interstitium. To determine the relevance of humoral factors in the pathogenesis of interstitial pneumonia, we introduced expression vectors into Wistar rats via the trachea to locally overexpress humoral factors in the lungs. Human interleukin (IL) 6 and IL-6 receptor genes induced lymphocytic alveolitis without marked fibroblast proliferation. In contrast, overexpression of human transforming growth factor β1 or human platelet-derived growth factor B gene induced only mild or apparent cellular infiltration in the alveoli, respectively. However, both factors induced significant proliferation of fibroblasts and deposition of collagen fibrils. These histopathologic changes induced by the transforming growth factor β1 and platelet-derived growth factor B gene are partly akin to those changes seen in lung tissues from patients with pulmonary fibrosis and markedly contrast with the changes induced by overexpression of the IL-6 and IL-6 receptor genes that mimics lymphocytic interstitial pneumonia.

  5. Reactive oxygen species are involved in BMP-induced dendritic growth in cultured rat sympathetic neurons.

    PubMed

    Chandrasekaran, Vidya; Lea, Charlotte; Sosa, Jose Carlo; Higgins, Dennis; Lein, Pamela J

    2015-07-01

    Previous studies have shown that bone morphogenetic proteins (BMPs) promote dendritic growth in sympathetic neurons; however, the downstream signaling molecules that mediate the dendrite promoting activity of BMPs are not well characterized. Here we test the hypothesis that reactive oxygen species (ROS)-mediated signaling links BMP receptor activation to dendritic growth. In cultured rat sympathetic neurons, exposure to any of the three mechanistically distinct antioxidants, diphenylene iodinium (DPI), nordihydroguaiaretic acid (NGA) or desferroxamine (DFO), blocked de novo BMP-induced dendritic growth. Addition of DPI to cultures previously induced with BMP to extend dendrites caused dendritic retraction while DFO and NGA prevented further growth of dendrites. The inhibition of the dendrite promoting activity of BMPs by antioxidants was concentration-dependent and occurred without altering axonal growth or neuronal cell survival. Antioxidant treatment did not block BMP activation of SMAD 1,5 as determined by nuclear localization of these SMADs. While BMP treatment did not cause a detectable increase in intracellular ROS in cultured sympathetic neurons as assessed using fluorescent indicator dyes, BMP treatment increased the oxygen consumption rate in cultured sympathetic neurons as determined using the Seahorse XF24 Analyzer, suggesting increased mitochondrial activity. In addition, BMPs upregulated expression of NADPH oxidase 2 (NOX2) and either pharmacological inhibition or siRNA knockdown of NOX2 significantly decreased BMP-7 induced dendritic growth. Collectively, these data support the hypothesis that ROS are involved in the downstream signaling events that mediate BMP7-induced dendritic growth in sympathetic neurons, and suggest that ROS-mediated signaling positively modulates dendritic complexity in peripheral neurons.

  6. Early Growth Response-1 Induces and Enhances Vascular Endothelial Growth Factor-A Expression in Lung Cancer Cells

    PubMed Central

    Shimoyamada, Hiroaki; Yazawa, Takuya; Sato, Hanako; Okudela, Koji; Ishii, Jun; Sakaeda, Masashi; Kashiwagi, Korehito; Suzuki, Takehisa; Mitsui, Hideaki; Woo, Tetsukan; Tajiri, Michihiko; Ohmori, Takahiro; Ogura, Takashi; Masuda, Munetaka; Oshiro, Hisashi; Kitamura, Hitoshi

    2010-01-01

    Vascular endothelial growth factor-A (VEGF-A) is crucial for angiogenesis, vascular permeability, and metastasis during tumor development. We demonstrate here that early growth response-1 (EGR-1), which is induced by the extracellular signal–regulated kinase (ERK) pathway activation, activates VEGF-A in lung cancer cells. Increased EGR-1 expression was found in adenocarcinoma cells carrying mutant K-RAS or EGFR genes. Hypoxic culture, siRNA experiment, luciferase assays, chromatin immunoprecipitation, electrophoretic mobility shift assays, and quantitative RT-PCR using EGR-1–inducible lung cancer cells demonstrated that EGR-1 binds to the proximal region of the VEGF-A promoter, activates VEGF-A expression, and enhances hypoxia inducible factor 1α (HIF-1α)-mediated VEGF-A expression. The EGR-1 modulator, NAB-2, was rapidly induced by increased levels of EGR-1. Pathology samples of human lung adenocarcinomas revealed correlations between EGR-1/HIF-1α and VEGF-A expressions and relative elevation of EGR-1 and VEGF-A expression in mutant K-RAS- or EGFR-carrying adenocarcinomas. Both EGR-1 and VEGF-A expression increased as tumors dedifferentiated, whereas HIF-1α expression did not. Although weak correlation was found between EGR-1 and NAB-2 expressions on the whole, NAB-2 expression decreased as tumors dedifferentiated, and inhibition of DNA methyltransferase/histone deacetylase increased NAB-2 expression in lung cancer cells despite no epigenetic alteration in the NAB-2 promoter. These findings suggest that EGR-1 plays important roles on VEGF-A expression in lung cancer cells, and epigenetic silencing of transactivator(s) associated with NAB-2 expression might also contribute to upregulate VEGF-A expression. PMID:20489156

  7. Epidermal growth factor inhibits transforming growth factor-β-induced fibrogenic differentiation marker expression through ERK activation.

    PubMed

    Liu, Xiaoying; Hubchak, Susan C; Browne, James A; Schnaper, H William

    2014-10-01

    Transforming growth factor-β (TGF-β) signaling plays an important and complex role in renal fibrogenesis. The seemingly simple TGF-β/Smad cascade is intensively regulated at several levels, including crosstalk with other signaling pathways. Epidermal growth factor (EGF) is a potent mitogen for epithelial cells and is elevated in diseased kidneys. In this study, we examined its effect on TGF-β-induced fibrotic changes in human proximal tubular epithelial cells. Simultaneous treatment with EGF specifically inhibited basal and TGF-β-induced type-I collagen and α-smooth muscle actin (αSMA) expression at both mRNA and protein levels. These effects were prevented by inhibition of either the EGF receptor kinase or its downstream MEK kinase but not by blockade of either the JNK or PI3K pathway. Overexpression of a constitutively active MEK1 construct mimicked the inhibitory effect of EGF. Further, EGF suppressed Smad transcriptional activities, as shown by reduced activation of ARE-luc and SBE-luc. Both reductions were prevented by MEK inhibition. However, EGF did not block Smad2 or Smad3 phosphorylation by TGF-β, or Smad2/3 nuclear import. Finally EGF induced the phosphorylation and expression of TGIF, a known TGF-β/Smad repressor. Both the phosphorylation and the induction were blocked by a MEK inhibitor. Overexpression of TGIF abolished TGF-β-induced αSMA promoter activity. Together these results suggest that EGF inhibits two TGF-β-stimulated markers of EMT through EGF receptor tyrosine kinase and downstream ERK activation, but not through PI3K or JNK. The inhibition results from effector mechanisms downstream of Smads, and most likely involves the transcriptional repressor, TGIF. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Effect of growth hormone-releasing factor on growth hormone release in children with radiation-induced growth hormone deficiency

    SciTech Connect

    Lustig, R.H.; Schriock, E.A.; Kaplan, S.L.; Grumbach, M.M.

    1985-08-01

    Five male children who received cranial irradiation for extrahypothalamic intracranial neoplasms or leukemia and subsequently developed severe growth hormone (GH) deficiency were challenged with synthetic growth hormone-releasing factor (GRF-44), in an attempt to distinguish hypothalamic from pituitary dysfunction as a cause of their GH deficiency, and to assess the readily releasable GH reserve in the pituitary. In response to a pulse of GRF-44 (5 micrograms/kg intravenously), mean peak GH levels rose to values higher than those evoked by the pharmacologic agents L-dopa or arginine (6.4 +/- 1.3 ng/mL v 1.5 +/- 0.4 ng/mL, P less than .05). The peak GH value occurred at a mean of 26.0 minutes after administration of GRF-44. These responses were similar to those obtained in children with severe GH deficiency due to other etiologies (peak GH 6.3 +/- 1.7 ng/mL, mean 28.0 minutes). In addition, there was a trend toward an inverse relationship between peak GH response to GRF-44 and the postirradiation interval. Prolactin and somatomedin-C levels did not change significantly after the administration of a single dose of GRF-44. The results of this study support the hypothesis that cranial irradiation in children can lead to hypothalamic GRF deficiency secondary to radiation injury of hypothalamic GRF-secreting neurons. This study also lends support to the potential therapeutic usefulness of GRF-44 or an analog for GH deficiency secondary to cranial irradiation.

  9. Alcohol-induced brain growth restrictions (microencephaly) were not affected by concurrent exposure to cocaine during the brain growth spurt.

    PubMed

    Chen, W J; Andersen, K H; West, J R

    1994-09-01

    The prevalence of concomitant use of alcohol and cocaine among drug abusers has raised concern about the possible increased risk of fetal damage. The aim of this study was to assess the interactive effects of alcohol and cocaine on lethality, somatic growth, and brain growth using an animal model system. Sprague-Dawley rat pups were used as subjects. They were randomly assigned to 1 of the 9 artificially reared groups which varied with respect to the combination treatments of cocaine (0, 40, or 60 mg/kg) and alcohol (0, 3.3, or 4.5 g/kg). All artificially reared pups were given daily cocaine and alcohol treatments during a major part of the brain growth spurt period (postnatal days 4-9). An additional group of suckled control animals raised by their natural dams was included to control for artificial rearing. The results are summarized as follows: 1) Drug-induced lethality was higher in cocaine-treated groups when compared with non-cocaine-treated groups, and the concurrent administration of high doses of alcohol and cocaine significantly increased the mortality rate. 2) Somatic growth, in terms of body weight, was not affected by alcohol, cocaine, or the combination of both drugs using the artificial rearing technique. 3) Alcohol exposure during this brain growth spurt period significantly reduced whole brain weight, as well as forebrain, cerebellum, and brain stem weights. 4) In contrast to alcohol, cocaine failed to exert a detrimental effect on brain weight measures during this early postnatal period.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Dabigatran Potentiates Gemcitabine-Induced Growth Inhibition of Pancreatic Cancer in Mice

    PubMed Central

    Shi, Kun; Damhofer, Helene; Daalhuisen, Joost; ten Brink, Marieke; Richel, Dick J; Spek, C Arnold

    2017-01-01

    Pancreatic cancer is one of the most lethal solid malignancies, with few treatment options. We have recently shown that expression of protease activated receptor (PAR)-1 in the tumor microenvironment drives the progression and induces the chemoresistance of pancreatic cancer. As thrombin is the prototypical PAR-1 agonist, here we address the effects of the direct thrombin inhibitor dabigatran on pancreatic cancer growth and drug resistance in an orthotropic pancreatic cancer model. We show that dabigatran treatment did not affect primary tumor growth, whereas it significantly increased tumor dissemination throughout the peritoneal cavity. Increased dissemination was accompanied by intratumoral bleeding and increased numbers of aberrant and/or collapsed blood vessels in the primary tumors. In combination with gemcitabine, dabigatran treatment limited primary tumor growth, did not induce bleeding complications and prevented tumor cell dissemination. Dabigatran was, however, not as efficient as genetic ablation of PAR-1 in our previous study, suggesting that thrombin is not the main PAR-1 agonist in the setting of pancreatic cancer. Overall, we show that dabigatran potentiates gemcitabine-induced growth inhibition of pancreatic cancer but does not affect primary tumor growth when used as monotherapy. PMID:28182192

  11. Radiation-induced senescence-like terminal growth arrest in thyroid cells.

    PubMed

    Podtcheko, Alexei; Namba, Hiroyuki; Saenko, Vladimir; Ohtsuru, Akira; Starenki, Dmitriy; Meirmanov, Serik; Polona, Iryna; Rogounovitch, Tatiana; Yamashita, Shunichi

    2005-04-01

    Premature senescence may play an important role as an acute, drug-, or ionizing radiation (IR)-inducible growth arrest program along with interphase apoptosis and mitotic catastrophe. The aim of the study was to evaluate whether IR can induce senescence-like phenotype (SLP) associated with terminal growth arrest in the thyroid cells, and if so, to evaluate impact of terminal growth arrest associated with SLP in intrinsic radiosensitivity of various thyroid carcinomas. The induction of SLP in thyroid cells were identified by: (1) senescence associated beta-galactosidase (SA-beta-Gal) staining method, (2) dual-flow cytometric analysis of cell proliferation and side light scatter using vital staining with PKH-2 fluorescent dye, (3) double labeling for 5-bromodeoxyuridine and SA- beta-Gal, (4) Staining for SA-beta-Gal with consequent antithyroglobulin immunohistochemistry. IR induced SLP associated with terminal growth arrest in four thyroid cancer cells lines and in primary thyrocytes in time- and dose-dependent manner. Analysis of relationship between induction of SLP and radiosensitivity revealed a trend in which more radioresistant cell lines strongly tended to show lower specific SLP yields (r = -0.93, p = 0.068). We find out that SA-beta-Gal staining is detectable in irradiated ARO xenotransplants, but not in control tumors. We, therefore, conclude that induction of SLP with terminal growth arrest contribute to the elimination of clonogenic populations after IR.

  12. Thiol-reducing agents prevent sulforaphane-induced growth inhibition in ovarian cancer cells.

    PubMed

    Kim, Seung Cheol; Choi, Boyun; Kwon, Youngjoo

    2017-01-01

    The inhibitory potential of sulforaphane against cancer has been suggested for different types of cancer, including ovarian cancer. We examined whether this effect is mediated by mitogen-activated protein kinase (MAPK) and reactive oxygen species (ROS), important signaling molecules related to cell survival and proliferation, in ovarian cancer cells. Sulforaphane at a concentration of 10 μM effectively inhibited the growth of cancer cells. Use of specific inhibitors revealed that activation of MAPK pathways by sulforaphane is unlikely to mediate sulforaphane-induced growth inhibition. Sulforaphane did not generate significant levels of intracellular ROS. Pretreatment with thiol reducers, but not ROS scavengers, prevented sulforaphane-induced growth inhibition. Furthermore, diamide, a thiol-oxidizing agent, enhanced both growth inhibition and cell death induced by sulforaphane, suggesting that the effect of sulforaphane on cell growth may be related to oxidation of protein thiols or change in cellular redox status. Our data indicate that supplementation with thiol-reducing agents should be avoided when sulforaphane is used to treat cancer.

  13. Growth-induced anisotropy in bismuth - Rare-earth iron garnets

    NASA Technical Reports Server (NTRS)

    Fratello, V. J.; Slusky, S. E. G.; Brandle, C. D.; Norelli, M. P.

    1986-01-01

    The bismuth-doped rare-earth iron garnets, (R3-x-yBixPby)Fe5O12 (Bi:RIG, R = Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, and Y), were prepared under constant growth conditions to investigate the influence of ionic species on the bismuth-based growth-induced uniaxial anisotropy K(u) exp g. The effect of ionic species on growth-induced anisotropy in Bi:RIG was not consistent with the ionic size model of site ordering. In particular, Bi:SmIG, Bi:EuIG, and Bi:TbIG displayed high growth-induced anisotropies, up to 331,000 erg/cu cm at room temperature for x of about 0.5. The temperature dependence of these K(u) exp gs was somewhat higher than that of the well studied Bi:YIG. The site ordering of Bi can be modeled by assuming that small, low-oxygen-coordination BiOw exp +3-2 w melt complexes have a strong site selectivity for small, high-oxygen coordination sites at the growth interface.

  14. MECHANISMS OF ZN-INDUCED SIGNAL INITIATION THROUGH THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR)

    EPA Science Inventory

    MECHANISMS OF Zn-INDUCED SIGNAL INITIATION THROUGH THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR)
    James M. Samet*, Lee M. Graves? and Weidong Wu?. *Human Studies Division, NHEERL, ORD, Research Triangle Park, NC 27711, and ?Center for Environmental Medicine, University of North C...

  15. MECHANISMS OF ZN-INDUCED SIGNAL INITIATION THROUGH THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR)

    EPA Science Inventory

    MECHANISMS OF Zn-INDUCED SIGNAL INITIATION THROUGH THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR)
    James M. Samet*, Lee M. Graves? and Weidong Wu?. *Human Studies Division, NHEERL, ORD, Research Triangle Park, NC 27711, and ?Center for Environmental Medicine, University of North C...

  16. Investigation of Buckling Phenomenon Induced by Growth of Vertebral Bodies Using a Mechanical Spine Model

    NASA Astrophysics Data System (ADS)

    Sasaoka, Ryu; Azegami, Hideyuki; Murachi, Shunji; Kitoh, Junzoh; Ishida, Yoshito; Kawakami, Noriaki; Makino, Mitsunori; Matsuyama, Yukihiro

    A hypothesis that idiopathic scoliosis is a buckling phenomenon of the fourth or sixth mode, which is the second or third lateral bending mode, induced by the growth of vertebral bodies was presented in a previous paper by the authors using numerical simulations with a finite-element model of the spine. This paper presents experimental proof of the buckling phenomenon using mechanical spine models constructed with the geometrical data of the finite-element model used in a previous work. Using three spine mechanical models with different materials at intervertebral joints, the change in the natural vibration eigenvalue of the second lateral bending mode with the growth of vertebral bodies was measured by experimental modal analysis. From the result, it was observed that natural vibration eigenvalue decreased with the growth of vertebral bodies. Since the increase in primary factor inducing the buckling phenomenon decreases natural vibration eigenvalue, the obtained result confirms the buckling hypothesis.

  17. Growth hormone and nutrition as protective agents against methotrexate induced enteritis.

    PubMed

    Ortega, M; de Segura, I A; Vázquez, I; López, J M; De Miguel, E

    2001-03-01

    To determine whether exogenously administered growth hormone can reduce or prevent chemotherapy-induced intestinal mucosa injury. The expected results will allow to consider its potential clinical use. Experimental and randomized study. Experimental Surgery Service, La Paz University Hospital. Adult Wistar rats weighing 250-300 g. A chemotherapy protocol with methotrexate (MTX) (120 mg/kg) was employed. Animals fed either with a normoproteic or a hyperproteic liquid diet were treated with either saline or growth hormone (1 mg/kg/day) since three days before until four days after chemotherapy. Animals were sacrificed seven days after MTX administration for tissue sampling. Co-administration of growth hormone and a hyperproteic diet increased intestinal crypt proliferation and reduced MTX-induced apoptosis. Jejunal mucosal structure (morphometry), proliferation (Ki-67) and apoptosis (TUNNEL) were assessed.

  18. Impaired cutaneous wound healing in transforming growth factor-β inducible early gene1 knockout mice.

    PubMed

    Hori, Keijiro; Ding, Jie; Marcoux, Yvonne; Iwashina, Takashi; Sakurai, Hiroyuki; Tredget, Edward E

    2012-01-01

    Transforming growth factor-β inducible early gene (TIEG) is induced by transforming growth factor-β (TGF-β) and acts as the primary response gene in the TGF-β/Smad pathway. TGF-β is a multifunctional growth factor that affects dermal wound healing; however, the mechanism of how TGF-β affects wound healing is still not well understood because of the complexity of its function and signaling pathways. We hypothesize that TIEG may play a role in dermal wound healing, with involvement in wound closure, contraction, and reepithelialization. In this study, we have shown that TIEG1 knockout (TIEG1-/-) mice have a delay in wound closure related to an impairment in wound contraction, granulation tissue formation, collagen synthesis, and reepithelialization. We also found that Smad7 was increased in the wounds and appeared to play a role in this wound healing model in TIEG1-/- mice. © 2012 by the Wound Healing Society.

  19. A novel, nongenomic mechanism underlies retinoic acid-induced growth cone turning.

    PubMed

    Farrar, Nathan R; Dmetrichuk, Jennifer M; Carlone, Robert L; Spencer, Gaynor E

    2009-11-11

    The vitamin A metabolite, retinoic acid (RA), is well known for its roles in neural development and regeneration. We have previously shown that RA can induce positive growth cone turning in regenerating neurons in vitro. In this study, we address the subcellular mechanisms underlying this chemo-attractive response, using identified central neurons from the adult mollusc, Lymnaea stagnalis. We show that the RA-induced positive growth cone turning was maintained in the presence of the transcriptional inhibitor, actinomycin D. We also physically transected the neurites from the cell body and showed that isolated growth cones retain the capacity to turn toward a gradient of RA. Moreover, this attractive turning is dependent on de novo local protein synthesis and Ca(2+) influx. Most of RA's actions during neurite outgrowth and regeneration require gene transcription, although these data show for the first time in any species, that the chemotropic action of RA in guiding neurite outgrowth, involves a novel, nongenomic mechanism.

  20. Growth Mechanisms of Aluminum Dots Deposited by Laser-induced Decomposition of Trimethylamine Alane

    NASA Astrophysics Data System (ADS)

    Tonneau, Didier; Thuron, Frédéric; Correia, Antonio; Bouree, Jean; Pauleau, Yves

    1998-09-01

    Aluminum dots have been deposited by thermal decomposition of trimethylamine alane (TMAA) on silicon substrates irradiated with a tightly focused argon ion laser beam (λ=514 nm). Carbon free Al deposits containing less than 5 at.% of impurities (mainly oxygen) detected by Auger Electron Spectroscopy were grown. The growth kinetics of Al dots was investigated as a function of TMAA pressure and laser-induced temperature. The deposition of dots occurred at a laser-induced temperature as low as 210°C. The TMAA decomposition was thermally activated (activation energy of 18 kcal/mole) and the deposition rate at 300°C was equal to 2 µm/s. The effects of H2 or He (used as buffer gases) in the gas phase on the growth kinetics of dots was also studied. The growth mechanisms of dots are discussed and proposed on the basis of the results of this kinetic study.

  1. Repeated Microneedle Stimulation Induces Enhanced Hair Growth in a Murine Model

    PubMed Central

    Kim, Yoon Seob; Jeong, Kwan Ho; Kim, Jung Eun; Woo, Young Jun; Kim, Beom Joon

    2016-01-01

    Background Microneedle is a method that creates transdermal microchannels across the stratum corneum barrier layer of skin. No previous study showed a therapeutic effect of microneedle itself on hair growth by wounding. Objective The aim of this study is to investigate the effect of repeated microwound formed by microneedle on hair growth and hair growth-related genes in a murine model. Methods A disk microneedle roller was applied to each group of mice five times a week for three weeks. First, to identify the optimal length and cycle, microneedles of lengths of 0.15 mm, 0.25 mm, 0.5 mm, and 1 mm and cycles of 3, 6, 10, and 13 cycles were applied. Second, the effect of hair growth and hair-growth-related genes such as Wnt3a, β-catenin, vascular endothelial growth factor (VEGF), and Wnt10b was observed using optimized microneedle. Outcomes were observed using visual inspection, real-time polymerase chain reaction, and immunohistochemistry. Results We found that the optimal length and cycle of microneedle treatment on hair growth was 0.25 mm/10 cycles and 0.5 mm/10 cycles. Repeated microneedle stimulation promoted hair growth, and it also induced the enhanced expression of Wnt3a, β-catenin, VEGF, and Wnt10b. Conclusion Our study provides evidence that microneedle stimulation can induce hair growth via activation of the Wnt/β-catenin pathway and VEGF. Combined with the drug delivery effect, we believe that microneedle stimulation could lead to new approaches for alopecia. PMID:27746638

  2. Mammary tumorigenesis induced by fibroblast growth factor receptor 1 requires activation of the epidermal growth factor receptor.

    PubMed

    Bade, Lindsey K; Goldberg, Jodi E; Dehut, Hazel A; Hall, Majken K; Schwertfeger, Kathryn L

    2011-09-15

    Fibroblast growth factor receptor 1 (FGFR1) is an oncoprotein with known involvement in mammary tumorigenesis. To understand how FGFR1 signaling promotes mammary tumorigenesis, an inducible FGFR1 (iFGFR1) system was created previously. Previous studies have demonstrated that upon iFGFR1 activation in vivo, the epidermal growth factor (EGF) ligands amphiregulin (AREG) and epiregulin (EREG) are upregulated. Both AREG and EREG interact with the EGF receptor (EGFR). Here, we investigated whether the FGFR1-induced increase in AREG and EREG expression might coordinately increase EGFR signaling to promote mammary tumorigenesis. Treatment of mouse mammary epithelial cells with either AREG or EREG conferred a greater migratory potential, increased cellular proliferation and increased extracellular regulated kinase 1/2 (ERK1/2) activation. These effects could be blocked with the EGFR-specific inhibitor erlotinib, suggesting that they are EGFR-dependent. In transgenic mice with iFGFR1 under the control of the mouse mammary tumor virus (MMTV) promoter, iFGFR1 activation also led to increased mammary epithelial cell proliferation that was inhibited with erlotinib. Taken together, these data suggest that AREG and EREG mediate tumorigenic phenotypes by activating EGFR signaling, and that the oncogenic potential of FGFR1 requires EGFR activation to promote mammary tumorigenesis.

  3. Growth induced buckling instability of anisotropic tube and its application in wound edge instability

    NASA Astrophysics Data System (ADS)

    Yang, Le; Witten, Tarynn M.; Pidaparti, Ramana M.

    2017-01-01

    Fiber reinforced anisotropic material abounds in biological world. It has been demonstrated in previous theoretical and experimental works that growth of biological soft tubular tissue plays a significant role in morphogenesis and pathology. Here we investigate growth-induced buckling of anisotropic cylindrical tissue, focusing on the effects of type of growth(constraint/unconstraint, isotropic/anisotropic), fiber property(orientation, density and strength), geometry and any interaction between these factors. We studied one-layer and two-layer models and obtained a rich spectrum of results. For one-layer model, we demonstrate that circumferential fiber orientation has a consistent stabilizing effect under various scenarios of growth. Higher fiber density has a destabilizing effect by disabling high-mode buckling. For two-layer model, we found that critical buckling strain at inner boundary is an invariant under same isotropic growth rate ratio between inner/ outer layer(g1 /g0). Then we applied our model to wound healing and illustrate the effects of skin residual stress, fiber property, proliferation region width and wound size on the wound edge stability. We conclude that fiber-reinforcement is an important factor to consider when investigating growth induced instability of anisotropic soft tissue.

  4. Proliferative response and oncogene expression induced by epidermal growth factor in EL2 rat fibroblasts.

    PubMed

    Liboi, E; Pelosi, E; Testa, U; Peschle, C; Rossi, G B

    1986-06-01

    Extensive evidence supports a two-step model for the control of fibroblast growth, which includes first the action of a competence factor (e.g., platelet-derived growth factor) followed by the stimulus of a progression factor (e.g., epidermal growth factor [EGF]). We investigated whether this model may be applied to the euploid EL2 fibroblast line recently isolated from rat embryos (E. Liboi, M. Caruso, and C. Basilico, Mol. Cell. Biol. 4:2925-2928, 1984). Our results clearly show that EGF alone leads EL2 cells to proliferate in serum-free conditions at a rate corresponding to 50 to 60% of that observed in the presence of 10% calf serum. It is of interest that, when resting EL2 cells were exposed to EGF, transcription of both c-myc and c-fos was markedly induced. Altogether, these observations suggest that, in contrast with the model of fibroblast growth mentioned above, EL2 cells require the presence of a single growth factor (EGF) for induction of DNA synthesis, and the expression of myc and fos proto-oncogenes may represent an obligatory step in the pathway of commitment of EL2 cells to proliferation. In addition, we showed that EGF may induce EL2 cells to acquire some properties of transformed cells, such as growth in agar and loss of contact inhibition. This suggests that the particular response to EGF of the EL2 line may be strictly connected with the expression of a transformed phenotype.

  5. Chemical Etch Effects on Laser-Induced Surface Damage Growth in Fused Silica

    SciTech Connect

    Hrubesh, L W; Norton, M A; Molander, W A; Wegner, P J; Staggs, M; Demos, S G; Britten, J A; Summers, L J; Lindsey, E F; Kozlowski, M R

    2000-12-22

    We investigated chemical etching as a possible means to mitigate the growth of UV laser-induced surface damage on fused silica. The intent of this work is to examine the growth behavior of existing damage sites that have been processed to remove the UV absorbing, thermo-chemically modified material within the affected area. The study involved chemical etching of laser-induced surface damage sites on fused silica substrates, characterizing the etched sites using scanning electron microscopy (SEM) and laser fluorescence, and testing the growth behavior of the etched sites upon illumination with multiple pulses of 351nm laser light. The results show that damage sites that have been etched to depths greater than about 9 {micro}m have about a 40% chance for zero growth with 1000 shots at fluences of 6.8-9.4 J/cm{sup 2}. For the etched sites that grow, the growth rates are consistent with those for non-etched sites. There is a weak dependence of the total fluorescence emission with the etch depth of a site, but the total fluorescence intensity from an etched site is not well correlated with the propensity of the site to grow. Deep wet etching shows some promise for mitigating damage growth in fused silica, but fluorescence does not seem to be a good indicator of successful mitigation.

  6. Early growth response 3 (Egr-3) is induced by transforming growth factor-β and regulates fibrogenic responses.

    PubMed

    Fang, Feng; Shangguan, Anna J; Kelly, Kathleen; Wei, Jun; Gruner, Katherine; Ye, Boping; Wang, Wenxia; Bhattacharyya, Swati; Hinchcliff, Monique E; Tourtellotte, Warren G; Varga, John

    2013-10-01

    Members of the early growth response (Egr) gene family of transcription factors have nonredundant biological functions. Although Egr-3 is implicated primarily in neuromuscular development and immunity, its regulation and role in tissue repair and fibrosis has not been studied. We now show that in normal skin fibroblasts, Egr-3 was potently induced by transforming growth factor-β via canonical Smad3. Moreover, transient Egr-3 overexpression was sufficient to stimulate fibrotic gene expression, whereas deletion of Egr-3 resulted in substantially attenuated transforming growth factor-β responses. Genome-wide expression profiling in fibroblasts showed that genes associated with tissue remodeling and wound healing were prominently up-regulated by Egr-3. Notably, <5% of fibroblast genes regulated by Egr-1 or Egr-2 were found to be coregulated by Egr-3, revealing substantial functional divergence among these Egr family members. In a mouse model of scleroderma, development of dermal fibrosis was accompanied by accumulation of Egr-3-positive myofibroblasts in the lesional tissue. Moreover, skin biopsy samples from patients with scleroderma showed elevated Egr-3 levels in the dermis, and Egr-3 mRNA levels correlated with the extent of skin involvement. These results provide the first evidence that Egr-3, a functionally distinct member of the Egr family with potent effects on inflammation and immunity, is up-regulated in scleroderma and is necessary and sufficient for profibrotic responses, suggesting important and distinct roles in the pathogenesis of fibrosis.

  7. Prolyl oligopeptidase inhibition-induced growth arrest of human gastric cancer cells

    SciTech Connect

    Suzuki, Kanayo; Sakaguchi, Minoru; Tanaka, Satoshi; Yoshimoto, Tadashi; Takaoka, Masanori

    2014-01-03

    Highlights: •We examined the effects of prolyl oligopeptidase (POP) inhibition on p53 null gastric cancer cell growth. •POP inhibition-induced cell growth suppression was associated with an increase in a quiescent G{sub 0} state. •POP might regulate the exit from and/or reentry into the cell cycle. -- Abstract: Prolyl oligopeptidase (POP) is a serine endopeptidase that hydrolyzes post-proline peptide bonds in peptides that are <30 amino acids in length. We recently reported that POP inhibition suppressed the growth of human neuroblastoma cells. The growth suppression was associated with pronounced G{sub 0}/G{sub 1} cell cycle arrest and increased levels of the CDK inhibitor p27{sup kip1} and the tumor suppressor p53. In this study, we investigated the mechanism of POP inhibition-induced cell growth arrest using a human gastric cancer cell line, KATO III cells, which had a p53 gene deletion. POP specific inhibitors, 3-((4-[2-(E)-styrylphenoxy]butanoyl)-L-4-hydroxyprolyl)-thiazolidine (SUAM-14746) and benzyloxycarbonyl-thioprolyl-thioprolinal, or RNAi-mediated POP knockdown inhibited the growth of KATO III cells irrespective of their p53 status. SUAM-14746-induced growth inhibition was associated with G{sub 0}/G{sub 1} cell cycle phase arrest and increased levels of p27{sup kip1} in the nuclei and the pRb2/p130 protein expression. Moreover, SUAM-14746-mediated cell cycle arrest of KATO III cells was associated with an increase in the quiescent G{sub 0} state, defined by low level staining for the proliferation marker, Ki-67. These results indicate that POP may be a positive regulator of cell cycle progression by regulating the exit from and/or reentry into the cell cycle by KATO III cells.

  8. The effect of electronic energy loss on irradiation-induced grain growth in nanocrystalline oxides.

    PubMed

    Zhang, Yanwen; Aidhy, Dilpuneet S; Varga, Tamas; Moll, Sandra; Edmondson, Philip D; Namavar, Fereydoon; Jin, Ke; Ostrouchov, Christopher N; Weber, William J

    2014-05-07

    Grain growth of nanocrystalline materials is generally thermally activated, but can also be driven by irradiation at much lower temperature. In nanocrystalline ceria and zirconia, energetic ions deposit their energy to both atomic nuclei and electrons. Our experimental results have shown that irradiation-induced grain growth is dependent on the total energy deposited, where electronic energy loss and elastic collisions between atomic nuclei both contribute to the production of disorder and grain growth. Our atomistic simulations reveal that a high density of disorder near grain boundaries leads to locally rapid grain movement. The additive effect from both electronic excitation and atomic collision cascades on grain growth demonstrated in this work opens up new possibilities for controlling grain sizes to improve functionality of nanocrystalline materials.

  9. PGE{sub 2}-induced colon cancer growth is mediated by mTORC1

    SciTech Connect

    Dufour, Marc Faes, Seraina Dormond-Meuwly, Anne Demartines, Nicolas Dormond, Olivier

    2014-09-05

    Highlights: • PGE{sub 2} activates mTORC1 in colon cancer cells. • Inhibition of mTORC1 blocks PGE{sub 2} induced colon cancer cell growth. • mTORC1 is a signaling intermediary in PGE{sub 2} induced colon cancer cell responses. - Abstract: The inflammatory prostaglandin E{sub 2} (PGE{sub 2}) cytokine plays a key role in the development of colon cancer. Several studies have shown that PGE{sub 2} directly induces the growth of colon cancer cells and furthermore promotes tumor angiogenesis by increasing the production of the vascular endothelial growth factor (VEGF). The signaling intermediaries implicated in these processes have however not been fully characterized. In this report, we show that the mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in PGE{sub 2}-induced colon cancer cell responses. Indeed, stimulation of LS174T cells with PGE{sub 2} increased mTORC1 activity as observed by the augmentation of S6 ribosomal protein phosphorylation, a downstream effector of mTORC1. The PGE{sub 2} EP{sub 4} receptor was responsible for transducing the signal to mTORC1. Moreover, PGE{sub 2} increased colon cancer cell proliferation as well as the growth of colon cancer cell colonies grown in matrigel and blocking mTORC1 by rapamycin or ATP-competitive inhibitors of mTOR abrogated these effects. Similarly, the inhibition of mTORC1 by downregulation of its component raptor using RNA interference blocked PGE{sub 2}-induced LS174T cell growth. Finally, stimulation of LS174T cells with PGE{sub 2} increased VEGF production which was also prevented by mTORC1 inhibition. Taken together, these results show that mTORC1 is an important signaling intermediary in PGE{sub 2} mediated colon cancer cell growth and VEGF production. They further support a role for mTORC1 in inflammation induced tumor growth.

  10. Hypothyroxinemia induced by maternal mild iodine deficiency impairs hippocampal myelinated growth in lactational rats.

    PubMed

    Wei, Wei; Wang, Yi; Dong, Jing; Wang, Yuan; Min, Hui; Song, Binbin; Shan, Zhongyan; Teng, Weiping; Xi, Qi; Chen, Jie

    2015-11-01

    Hypothyroxinemia induced by maternal mild iodine deficiency causes neurological deficits and impairments of brain function in offspring. Hypothyroxinemia is prevalent in developing and developed countries alike. However, the mechanism underlying these deficits remains less well known. Given that the myelin plays an important role in learning and memory function, we hypothesize that hippocampal myelinated growth may be impaired in rat offspring exposed to hypothyroxinemia induced by maternal mild iodine deficiency. To test this hypothesis, the female Wistar rats were used and four experimental groups were prepared: (1) control; (2) maternal mild iodine deficiency diet inducing hypothyroxinemia; (3) hypothyroidism induced by maternal severe iodine deficiency diet; (4) hypothyroidism induced by maternal methimazole water. The rats were fed the diet from 3 months before pregnancy to the end of lactation. Our results showed that the physiological changes occuring in the hippocampal myelin were altered in the mild iodine deficiency group as indicated by the results of immunofluorescence of myelin basic proteins on postnatal day 14 and postnatal day 21. Moreover, hypothyroxinemia reduced the expressions of oligodendrocyte lineage transcription factor 2 and myelin-related proteins in the treatments on postnatal day 14 and postnatal day 21. Our data suggested that hypothyroxinemia induced by maternal mild iodine deficiency may impair myelinated growth of the offspring.

  11. Evaluation of h secretion relative to zeatin-induced growth of detached cucumber cotyledons.

    PubMed

    Ross, C W; Rayle, D L

    1982-11-01

    Cytokinins promote expansion of cotyledons detached from seedlings of more than a dozen species. The zeatin-enhanced expansion of cucumber (Cucumis sativus L. cv Marketer) cotyledons was investigated. In addition, whether acid secretion is involved in wall loosening accompanying such accelerated growth was evaluated. For cotyledons abraded with carborundum or cut into either eight or 18 pieces, we detected no zeatin-enhanced acidification of the growth medium during growth periods of 3 days. Measurements of pH values on each surface of zeatin-treated, abraded cotyledons after 3 days of growth also showed no detectable acidification caused by the hormone. Furthermore, with several buffers at pH values ranging from 5 to 8, growth of nonabraded, abraded, or cut cotyledons with or without zeatin was independent of external pH. However, experiments restricted to about 12 hours indicated that certain acidic buffers enhanced growth of cotyledons cut into 18 pieces. Lastly, concentrations of fusicoccin that caused growth promotion equal to that of zeatin initiated substantial acidification of the medium. Collectively, these data suggest that zeatin-induced expansion of detached cucumber cotyledons is independent of H(+) secretion.

  12. Fibroblast growth factor-1-inducible gene FR-17 encodes a nonmuscle alpha-actinin isoform.

    PubMed

    Hsu, D K; Guo, Y; Alberts, G F; Peifley, K A; Winkles, J A

    1996-05-01

    Polypeptide growth factor binding to cell surface receptors activates a cytoplasmic signaling cascade that ultimately promotes the expression of specific nuclear genes. As an approach to investigate the molecular mechanism of fibroblast growth factor (FGF)-1 mitogenic signaling, we have begun to identify and characterize FGF-1-inducible genes in murine NIH 3T3 cells. Here we report that one of these genes, termed FGF-regulated (FR)-17, is predicted to encode a nonmuscle isoform of alpha-actinin, an actin cross-linking protein found along microfilaments and in focal adhesion plaques. FGF-1 induction of alpha-actinin mRNA expression is first detectable at 2 h after mitogen addition and is dependent on the novo RNA and protein synthesis. Maximal alpha-actinin mRNA expression, corresponding to an approximately nineteenfold level of induction, is present after 12 h of FGF-1 stimulation. Western blot analysis indicated that FGF-1-stimulated cells also produce an increased amount of alpha-actinin protein. The FGF-1-related mitogen FGF-2, calf serum, several of the polypeptide growth factors present in serum, and the tumor promoter phorbol myristate acetate can also induce alpha-actinin mRNA expression. Finally, nonmuscle alpha-actinin mRNA is expressed in vivo in a tissue-specific manner, with relatively high levels detected in adult mouse intestine and kidney. These results indicate that nonmuscle alpha-actinin is a serum-, polypeptide growth factor-, and tumor promoter-inducible gene in mouse fibroblasts.

  13. Surface proteome analysis identifies platelet derived growth factor receptor-alpha as a critical mediator of transforming growth factor-beta-induced collagen secretion.

    PubMed

    Heinzelmann, Katharina; Noskovičová, Nina; Merl-Pham, Juliane; Preissler, Gerhard; Winter, Hauke; Lindner, Michael; Hatz, Rudolf; Hauck, Stefanie M; Behr, Jürgen; Eickelberg, Oliver

    2016-05-01

    Fibroblasts are extracellular matrix-producing cells in the lung. Fibroblast activation by transforming growth factor-beta leads to myofibroblast-differentiation and increased extracellular matrix deposition, a hallmark of pulmonary fibrosis. While fibroblast function with respect to migration, invasion, and extracellular matrix deposition has been well-explored, little is known about the surface proteome of lung fibroblasts in general and its specific response to fibrogenic growth factors, in particular transforming growth factor-beta. We thus performed a cell-surface proteome analysis of primary human lung fibroblasts in presence/absence of transforming growth factor-beta, followed by characterization of our findings using FACS analysis, Western blot, and siRNA-mediated knockdown experiments. We identified 213 surface proteins significantly regulated by transforming growth factor-beta, platelet derived growth factor receptor-alpha being one of the top down-regulated proteins. Transforming growth factor beta-induced downregulation of platelet derived growth factor receptor-alpha induced upregulation of platelet derived growth factor receptor-beta expression and phosphorylation of Akt, a downstream target of platelet derived growth factor signaling. Importantly, collagen type V expression and secretion was strongly increased after forced knockdown of platelet derived growth factor receptor-alpha, an effect that was potentiated by transforming growth factor-beta. We therefore show previously underappreciated cross-talk of transforming growth factor-beta and platelet derived growth factor signaling in human lung fibroblasts, resulting in increased extracellular matrix deposition in a platelet derived growth factor receptor-alpha dependent manner. These findings are of particular importance for the treatment of lung fibrosis patients with high pulmonary transforming growth factor-beta activity.

  14. Pin1 promotes transforming growth factor-beta-induced migration and invasion.

    PubMed

    Matsuura, Isao; Chiang, Keng-Nan; Lai, Chen-Yu; He, Dongming; Wang, Guannan; Ramkumar, Romila; Uchida, Takafumi; Ryo, Akihide; Lu, Kunping; Liu, Fang

    2010-01-15

    Transforming growth factor-beta (TGF-beta) regulates a wide variety of biological activities. It induces potent growth-inhibitory responses in normal cells but promotes migration and invasion of cancer cells. Smads mediate the TGF-beta responses. TGF-beta binding to the cell surface receptors leads to the phosphorylation of Smad2/3 in their C terminus as well as in the proline-rich linker region. The serine/threonine phosphorylation sites in the linker region are followed by the proline residue. Pin1, a peptidyl-prolyl cis/trans isomerase, recognizes phosphorylated serine/threonine-proline motifs. Here we show that Smad2/3 interacts with Pin1 in a TGF-beta-dependent manner. We further show that the phosphorylated threonine 179-proline motif in the Smad3 linker region is the major binding site for Pin1. Although epidermal growth factor also induces phosphorylation of threonine 179 and other residues in the Smad3 linker region the same as TGF-beta, Pin1 is unable to bind to the epidermal growth factor-stimulated Smad3. Further analysis suggests that phosphorylation of Smad3 in the C terminus is necessary for the interaction with Pin1. Depletion of Pin1 by small hairpin RNA does not significantly affect TGF-beta-induced growth-inhibitory responses and a number of TGF-beta/Smad target genes analyzed. In contrast, knockdown of Pin1 in human PC3 prostate cancer cells strongly inhibited TGF-beta-mediated migration and invasion. Accordingly, TGF-beta induction of N-cadherin, which plays an important role in migration and invasion, is markedly reduced when Pin1 is depleted in PC3 cells. Because Pin1 is overexpressed in many cancers, our findings highlight the importance of Pin1 in TGF-beta-induced migration and invasion of cancer cells.

  15. Platelet-derived growth factor B induces senescence and transformation in normal human fibroblasts.

    PubMed

    Vindrieux, David; Gras, Baptiste; Garcia-Belinchon, Merce; Mourah, Samia; Lebbe, Céleste; Augert, Arnaud; Bernard, David

    2013-07-01

    Normal cells enter a senescent state upon aberrant oncogenic signals and this response inhibits tumor initiation and progression. It is now well admitted that intracellular and membrane localized oncogenes can illicit oncogene induced senescence. However, the effect of mitogenic growth factor on cellular senescence is so far largely unknown. Here we show that normal human dermal fibroblasts display a complex response to Platelet derived growth factor B (PDGFB) expression. Indeed, PDGFB expression induces, in the same cell population, both senescence and cellular transformation. Remarkably both populations are sustained with passages suggesting that transformed cells eventually enter a senescent state. This senescence state is p53 dependent as inhibiting the p53 pathway blocks the ability of PDGFB to induce senescence and results in strong cellular transformation increase upon PDGFB expression. The relevance of these observations is supported by the fact that human dermatofibrosarcoma protuberans, skin tumors arising from constitutive PDGFB production with little aggressiveness, also display some senescence hallmarks. Together these data support the view that PDGFB, a mitogenic growth factor, has a limited ability to induce senescence. We propose that this low level of senescence might decrease the transforming ability of this factor without totally abolishing it.

  16. Neighbor Detection Induces Organ-Specific Transcriptomes, Revealing Patterns Underlying Hypocotyl-Specific Growth.

    PubMed

    Kohnen, Markus V; Schmid-Siegert, Emanuel; Trevisan, Martine; Petrolati, Laure Allenbach; Sénéchal, Fabien; Müller-Moulé, Patricia; Maloof, Julin; Xenarios, Ioannis; Fankhauser, Christian

    2016-12-01

    In response to neighbor proximity, plants increase the growth of specific organs (e.g., hypocotyls) to enhance access to sunlight. Shade enhances the activity of Phytochrome Interacting Factors (PIFs) by releasing these bHLH transcription factors from phytochrome B-mediated inhibition. PIFs promote elongation by inducing auxin production in cotyledons. In order to elucidate spatiotemporal aspects of the neighbor proximity response, we separately analyzed gene expression patterns in the major light-sensing organ (cotyledons) and in rapidly elongating hypocotyls of Arabidopsis thaliana PIFs initiate transcriptional reprogramming in both organs within 15 min, comprising regulated expression of several early auxin response genes. This suggests that hypocotyl growth is elicited by both local and distal auxin signals. We show that cotyledon-derived auxin is both necessary and sufficient to initiate hypocotyl growth, but we also provide evidence for the functional importance of the local PIF-induced response. With time, the transcriptional response diverges increasingly between organs. We identify genes whose differential expression may underlie organ-specific elongation. Finally, we uncover a growth promotion gene expression signature shared between different developmentally regulated growth processes and responses to the environment in different organs. © 2016 American Society of Plant Biologists. All rights reserved.

  17. Molecular-orientation-induced rapid roughening and morphology transition in organic semiconductor thin-film growth.

    PubMed

    Yang, Junliang; Yim, Sanggyu; Jones, Tim S

    2015-03-24

    We study the roughening process and morphology transition of organic semiconductor thin film induced by molecular orientation in the model of molecular semiconductor copper hexadecafluorophthalocyanine (F16CuPc) using both experiment and simulation. The growth behaviour of F16CuPc thin film with the thickness, D, on SiO2 substrate takes on two processes divided by a critical thickness: (1) D ≤ 40 nm, F16CuPc thin films are composed of uniform caterpillar-like crystals. The kinetic roughening is confirmed during this growth, which is successfully analyzed by Kardar-Parisi-Zhang (KPZ) model with scaling exponents α = 0.71 ± 0.12, β = 0.36 ± 0.03, and 1/z = 0.39 ± 0.12; (2) D > 40 nm, nanobelt crystals are formed gradually on the caterpillar-like crystal surface and the film growth shows anomalous growth behaviour. These new growth behaviours with two processes result from the gradual change of molecular orientation and the formation of grain boundaries, which conversely induce new molecular orientation, rapid roughening process, and the formation of nanobelt crystals.

  18. Growth arrest and apoptosis of human hepatocellular carcinoma cells induced by hexamethylene bisacetamide

    PubMed Central

    Ouyang, Gao-Liang; Cai, Qiu-Feng; Liu, Min; Chen, Rui-Chuan; Huang, Zhi; Jiang, Rui-Sheng; Chen, Fu; Hong, Shui-Gen; Bao, Shi-Deng

    2004-01-01

    AIM: To investigate the cellular effects of hybrid polar compound hexamethylene bisacetamide (HMBA) on the growth and apoptosis of human hepatocellular carcinoma cells and to provide the molecular mechanism for potential application of HMBA in the treatment of liver cancer. METHODS: Effects of HMBA on the growth of human hepatocellular carcinoma SMMC-7721 cells were assayed by MTT chronometry. Apoptosis induced by HMBA was detected by phase-contrast microscopy, flow cytometry, propidium iodide staining and immunocytochemical analysis. RESULTS: The growth of SMMC-7721 cells was significantly inhibited by HMBA, and the growth inhibitory rate was 51.1%, 62.6%, 68.7% and 73.9% respectively after treatment with 5.0, 7.5, 10.0 and 12.5 mmol/L of HMBA. In the cells treated with 10 mmol/L of HMBA for 72 h, the population of cells at sub-G1 phase significantly increased, and the apoptotic bodies and condensed nuclei were detected. Moreover, treatment of SMMC-7721 cells with 10 mmol/L of HMBA down-regulated the expression of Bcl-2 anti-apoptotic protein, while slightly up-regulated the level of pro-apoptotic protein Bax. CONCLUSION: Treatment with 10.0 mmol/L of HMBA can significantly inhibit the growth and induce apoptosis of human hepatocellular carcinoma SMMC-7721 cells by decreasing the ratio of Bcl-2 to Bax. PMID:15052673

  19. Molecular-Orientation-Induced Rapid Roughening and Morphology Transition in Organic Semiconductor Thin-Film Growth

    PubMed Central

    Yang, Junliang; Yim, Sanggyu; Jones, Tim S.

    2015-01-01

    We study the roughening process and morphology transition of organic semiconductor thin film induced by molecular orientation in the model of molecular semiconductor copper hexadecafluorophthalocyanine (F16CuPc) using both experiment and simulation. The growth behaviour of F16CuPc thin film with the thickness, D, on SiO2 substrate takes on two processes divided by a critical thickness: (1) D ≤ 40 nm, F16CuPc thin films are composed of uniform caterpillar-like crystals. The kinetic roughening is confirmed during this growth, which is successfully analyzed by Kardar-Parisi-Zhang (KPZ) model with scaling exponents α = 0.71 ± 0.12, β = 0.36 ± 0.03, and 1/z = 0.39 ± 0.12; (2) D > 40 nm, nanobelt crystals are formed gradually on the caterpillar-like crystal surface and the film growth shows anomalous growth behaviour. These new growth behaviours with two processes result from the gradual change of molecular orientation and the formation of grain boundaries, which conversely induce new molecular orientation, rapid roughening process, and the formation of nanobelt crystals. PMID:25801646

  20. Neighbor Detection Induces Organ-Specific Transcriptomes, Revealing Patterns Underlying Hypocotyl-Specific Growth[OPEN

    PubMed Central

    Trevisan, Martine; Petrolati, Laure Allenbach

    2016-01-01

    In response to neighbor proximity, plants increase the growth of specific organs (e.g., hypocotyls) to enhance access to sunlight. Shade enhances the activity of Phytochrome Interacting Factors (PIFs) by releasing these bHLH transcription factors from phytochrome B-mediated inhibition. PIFs promote elongation by inducing auxin production in cotyledons. In order to elucidate spatiotemporal aspects of the neighbor proximity response, we separately analyzed gene expression patterns in the major light-sensing organ (cotyledons) and in rapidly elongating hypocotyls of Arabidopsis thaliana. PIFs initiate transcriptional reprogramming in both organs within 15 min, comprising regulated expression of several early auxin response genes. This suggests that hypocotyl growth is elicited by both local and distal auxin signals. We show that cotyledon-derived auxin is both necessary and sufficient to initiate hypocotyl growth, but we also provide evidence for the functional importance of the local PIF-induced response. With time, the transcriptional response diverges increasingly between organs. We identify genes whose differential expression may underlie organ-specific elongation. Finally, we uncover a growth promotion gene expression signature shared between different developmentally regulated growth processes and responses to the environment in different organs. PMID:27923878

  1. The OXI1 Kinase Pathway Mediates Piriformospora indica-Induced Growth Promotion in Arabidopsis

    PubMed Central

    Camehl, Iris; Drzewiecki, Corinna; Vadassery, Jyothilakshmi; Shahollari, Bationa; Sherameti, Irena; Forzani, Celine; Munnik, Teun; Hirt, Heribert; Oelmüller, Ralf

    2011-01-01

    Piriformospora indica is an endophytic fungus that colonizes roots of many plant species and promotes growth and resistance to certain plant pathogens. Despite its potential use in agriculture, little is known on the molecular basis of this beneficial plant-fungal interaction. In a genetic screen for plants, which do not show a P. indica- induced growth response, we isolated an Arabidopsis mutant in the OXI1 (Oxidative Signal Inducible1) gene. OXI1 has been characterized as a protein kinase which plays a role in pathogen response and is regulated by H2O2 and PDK1 (3-PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE1). A genetic analysis showed that double mutants of the two closely related PDK1.1 and PDK1.2 genes are defective in the growth response to P. indica. While OXI1 and PDK1 gene expression is upregulated in P. indica-colonized roots, defense genes are downregulated, indicating that the fungus suppresses plant defense reactions. PDK1 is activated by phosphatidic acid (PA) and P. indica triggers PA synthesis in Arabidopsis plants. Under beneficial co-cultivation conditions, H2O2 formation is even reduced by the fungus. Importantly, phospholipase D (PLD)α1 or PLDδ mutants, which are impaired in PA synthesis do not show growth promotion in response to fungal infection. These data establish that the P. indica-stimulated growth response is mediated by a pathway consisting of the PLD-PDK1-OXI1 cascade. PMID:21625539

  2. The epidermis coordinates auxin-induced stem growth in response to shade.

    PubMed

    Procko, Carl; Burko, Yogev; Jaillais, Yvon; Ljung, Karin; Long, Jeff A; Chory, Joanne

    2016-07-01

    Growth of a complex multicellular organism requires coordinated changes in diverse cell types. These cellular changes generate organs of the correct size, shape, and functionality. In plants, the growth hormone auxin induces stem elongation in response to shade; however, which cell types of the stem perceive the auxin signal and contribute to organ growth is poorly understood. Here, we blocked the transcriptional response to auxin within specific tissues to show that auxin signaling is required in many cell types for correct hypocotyl growth in shade, with a key role for the epidermis. Combining genetic manipulations in Arabidopsis thaliana with transcriptional profiling of the hypocotyl epidermis from Brassica rapa, we show that auxin acts in the epidermis in part by inducing activity of the locally acting, growth-promoting brassinosteroid pathway. Our findings clarify cell-specific auxin function in the hypocotyl and highlight the complexity of cell type interactions within a growing organ. © 2016 Procko et al.; Published by Cold Spring Harbor Laboratory Press.

  3. Plant pathogen-induced water-soaking promotes Salmonella enterica growth on tomato leaves.

    PubMed

    Potnis, Neha; Colee, James; Jones, Jeffrey B; Barak, Jeri D

    2015-12-01

    Plant pathogen infection is a critical factor for the persistence of Salmonella enterica on plants. We investigated the mechanisms responsible for the persistence of S. enterica on diseased tomato plants by using four diverse bacterial spot Xanthomonas species that differ in disease severities. Xanthomonas euvesicatoria and X. gardneri infection fostered S. enterica growth, while X. perforans infection did not induce growth but supported the persistence of S. enterica. X. vesicatoria-infected leaves harbored S. enterica populations similar to those on healthy leaves. Growth of S. enterica was associated with extensive water-soaking and necrosis in X. euvesicatoria- and X. gardneri-infected plants. The contribution of water-soaking to the growth of S. enterica was corroborated by an increased growth of populations on water-saturated leaves in the absence of a plant pathogen. S. enterica aggregates were observed with bacterial spot lesions caused by either X. euvesicatoria or X. vesicatoria; however, more S. enterica aggregates formed on X. euvesicatoria-infected leaves as a result of larger lesion sizes per leaf area and extensive water-soaking. Sparsely distributed lesions caused by X. vesicatoria infection do not support the overall growth of S. enterica or aggregates in areas without lesions or water-soaking; S. enterica was observed as single cells and not aggregates. Thus, pathogen-induced water-soaking and necrosis allow S. enterica to replicate and proliferate on tomato leaves. The finding that the pathogen-induced virulence phenotype affects the fate of S. enterica populations in diseased plants suggests that targeting of plant pathogen disease is important in controlling S. enterica populations on plants. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  4. Orexin Plays a Role in Growth Impediment Induced by Obstructive Sleep Breathing in Rats

    PubMed Central

    Tarasiuk, Ariel; Levi, Avishag; Assadi, Mohammad H.; Troib, Ariel; Segev, Yael

    2016-01-01

    Study Objectives: The mechanisms linking sleep disordered breathing with impairment of sleep and bone metabolism/architecture are poorly understood. Here, we explored the role of the neuropeptide orexin, a respiratory homeostasis modulator, in growth retardation induced in an upper airway obstructed (AO) rat model. Methods: The tracheae of 22-day-old rats were narrowed; AO and sham-control animals were monitored for 5 to 7 w. Growth parameters, food intake, sleep/wake activity, and serum hormones were measured. After euthanasia, growth plate (GP) histology, morphometry, orexin receptors (OXR), and related mediators were analyzed. The effect of dual orexin receptor antagonist (almorexant 300 mg/kg) on sleep and GP histology were also investigated. Results: The AO group slept 32% less; the time spent in slow wave and paradoxical sleep during light period and slow wave activity was reduced. The AO group gained 46% less body weight compared to the control group, despite elevated food intake; plasma ghrelin increased by 275% and leptin level decreased by 44%. The impediment of bone elongation and bone mass was followed by a 200% increase in OX1R and 38% reduction of local GP ghrelin proteins and growth hormone secretagogue receptor 1a. Sry-related transcription factor nine (Sox9), a molecule mediating cartilage ossification, was downregulated and the level of transcription factor peroxisome proliferator-activated receptor gamma was upregulated, explaining the bone architecture abnormalities. Administration of almorexant restored sleep and improved GP width in AO animals. Conclusions: In AO animals, enhanced expression of orexin and OX1R plays a role in respiratory induced sleep and growth abnormalities. Citation: Tarasiuk A, Levi A, Assadi MH, Troib A, Segev Y. Orexin plays a role in growth impediment induced by obstructive sleep breathing in rats. SLEEP 2016;39(4):887–897. PMID:26943473

  5. Plant Pathogen-Induced Water-Soaking Promotes Salmonella enterica Growth on Tomato Leaves

    PubMed Central

    Potnis, Neha; Colee, James; Jones, Jeffrey B.

    2015-01-01

    Plant pathogen infection is a critical factor for the persistence of Salmonella enterica on plants. We investigated the mechanisms responsible for the persistence of S. enterica on diseased tomato plants by using four diverse bacterial spot Xanthomonas species that differ in disease severities. Xanthomonas euvesicatoria and X. gardneri infection fostered S. enterica growth, while X. perforans infection did not induce growth but supported the persistence of S. enterica. X. vesicatoria-infected leaves harbored S. enterica populations similar to those on healthy leaves. Growth of S. enterica was associated with extensive water-soaking and necrosis in X. euvesicatoria- and X. gardneri-infected plants. The contribution of water-soaking to the growth of S. enterica was corroborated by an increased growth of populations on water-saturated leaves in the absence of a plant pathogen. S. enterica aggregates were observed with bacterial spot lesions caused by either X. euvesicatoria or X. vesicatoria; however, more S. enterica aggregates formed on X. euvesicatoria-infected leaves as a result of larger lesion sizes per leaf area and extensive water-soaking. Sparsely distributed lesions caused by X. vesicatoria infection do not support the overall growth of S. enterica or aggregates in areas without lesions or water-soaking; S. enterica was observed as single cells and not aggregates. Thus, pathogen-induced water-soaking and necrosis allow S. enterica to replicate and proliferate on tomato leaves. The finding that the pathogen-induced virulence phenotype affects the fate of S. enterica populations in diseased plants suggests that targeting of plant pathogen disease is important in controlling S. enterica populations on plants. PMID:26386057

  6. Growth

    Treesearch

    John R. Jones; George A. Schier

    1985-01-01

    This chapter considers aspen growth as a process, and discusses some characteristics of the growth and development of trees and stands. For the most part, factors affecting growth are discussed elsewhere, particularly in the GENETICS AND VARIATION chapter and in chapters in PART 11. ECOLOGY. Aspen growth as it relates to wood production is examined in the WOOD RESOURCE...

  7. Syzygium cumini inhibits growth and induces apoptosis in cervical cancer cell lines: a primary study

    PubMed Central

    Barh, D; Viswanathan, G

    2008-01-01

    Cervical cancer is common among women in the Indian subcontinent and the incidences and death rates are gradually increasing over the years. Several dietary phytochemicals have been reported to have growth inhibitory and apoptotic effect on HeLa and other cervical cell lines. In this study, using Hoechst 33342 staining, MTT, Annexin V-FLUOS/PI and TUNEL assays we demonstrated that Syzygium cumini extract inhibits the growth and induces apoptosis in HeLa and SiHa cervical cancer cell lines in a dose- and time-dependent manner. The phytochemical, its mode of action and safety issues are yet to be determined. PMID:22275971

  8. Syzygium cumini inhibits growth and induces apoptosis in cervical cancer cell lines: a primary study.

    PubMed

    Barh, D; Viswanathan, G

    2008-01-01

    Cervical cancer is common among women in the Indian subcontinent and the incidences and death rates are gradually increasing over the years. Several dietary phytochemicals have been reported to have growth inhibitory and apoptotic effect on HeLa and other cervical cell lines. In this study, using Hoechst 33342 staining, MTT, Annexin V-FLUOS/PI and TUNEL assays we demonstrated that Syzygium cumini extract inhibits the growth and induces apoptosis in HeLa and SiHa cervical cancer cell lines in a dose- and time-dependent manner. The phytochemical, its mode of action and safety issues are yet to be determined.

  9. Measurement of longitudinal emittance growth using a laser-induced neutralization method

    SciTech Connect

    Yuan, V.W.; Garcia, R.; Johnson, K.F.; Saadatmand, K.; Sander, O.R.; Sandoval, D.; Shinas, M.

    1991-01-01

    A laser-induced neutralization technique, LINDA, has been used to study the longitudinal emittance of the 5-MeV H{sup {minus}} beam exiting the drift-tube Linac (DTL) of the Los Alamos Accelerator Test Stand (ATS). By using multiple laser intersection points, longitudinal emittance growths over drift distances of 23.6 and 30.6 cm were measured. Subsequently, a beam transport line, which consisted of one arm of a beam funnel, was substituted for the drift space. Measurements show that the elements of the funnel constrain emittance growth while the H{sup {minus}} beam is contained within these transport elements.

  10. [Sphingosine kinase regulates hepatocyte growth factor-induced migration of endothelial cells].

    PubMed

    Yi, Jun; Lu, Zhuao-Zhuang; Duan, Hai-Feng; Gai, Lu-Yue; Wang, Li-Sheng

    2006-05-01

    To elucidate the effect of sphingosine kinase (SPK) on the hepatocyte growth factor (HGF)-induced migration of endothelial cells. We constructed recombinant adenoviral vectors, which contain SPK gene and its mutant respectively. These adenoviral vectors were packaged and amplified in 293 cells. And intracellular SPK activity was assayed via measurement of [32]P radioisotope labeled S1P; the effect of SPK activation on HGF-induced migration of endothelial cell was observed by Transwell technique. Adenoviral mediated expression of SPK gene increased in ECV 304 cells intracellular SPK activity, which in turn enhanced the HGF-induced migration. Whereas these activities were blocked by the dominant negative SPK gene. These findings show that SPK activation plays important roles in the regulation of HGF-induced migration of endothelial cells.

  11. Plasma Kallikrein Mediates Vascular Endothelial Growth Factor–Induced Retinal Dysfunction and Thickening

    PubMed Central

    Clermont, Allen; Murugesan, Nivetha; Zhou, Qunfang; Kita, Takeshi; Robson, Peter A.; Rushbrooke, Louise J.; Evans, D. Michael; Aiello, Lloyd Paul; Feener, Edward P.

    2016-01-01

    Purpose Plasma kallikrein is a serine protease and circulating component of inflammation, which exerts clinically significant effects on vasogenic edema. This study examines the role of plasma kallikrein in VEGF-induced retinal edema. Methods Intravitreal injections of VEGF and saline vehicle were performed in plasma prekallikrein–deficient (KLKB1−/−) and wild-type (WT) mice, and in both rats and mice receiving a selective plasma kallikrein inhibitor, VA999272. Retinal vascular permeability (RVP) and retinal thickness were measured by Evans blue permeation and optical coherence tomography, respectively. The retinal kallikrein kinin system was examined by Western blotting and immunohistochemistry. Retinal neovascularization was investigated in KLKB1−/− and WT mice subjected to oxygen-induced retinopathy. Results Vascular endothelial growth factor–induced RVP and retinal thickening were reduced in KLKB1−/− mice by 68% and 47%, respectively, compared to VEGF responses in WT mice. Plasma kallikrein also contributes to TNFα-induced retinal thickening, which was reduced by 52% in KLKB1−/− mice. Systemic administration of VA999272 reduced VEGF-induced retinal thickening by 57% (P < 0.001) in mice and 53% (P < 0.001) in rats, compared to vehicle-treated controls. Intravitreal injection of VEGF in WT mice increased plasma prekallikrein in the retina, which was diffusely distributed throughout the inner and outer retinal layers. Avascular and neovascular areas induced by oxygen-induced retinopathy were similar in WT and KLKB1−/− mice. Conclusions Vascular endothelial growth factor increases extravasation of plasma kallikrein into the retina, and plasma kallikrein is required for the full effects of VEGF on RVP and retinal thickening in rodents. Systemic plasma kallikrein inhibition may provide a therapeutic opportunity to treat VEGF-induced retina edema. PMID:27138737

  12. The natural product peiminine represses colorectal carcinoma tumor growth by inducing autophagic cell death

    SciTech Connect

    Lyu, Qing; Tou, Fangfang; Su, Hong; Wu, Xiaoyong; Chen, Xinyi; Zheng, Zhi

    2015-06-19

    Autophagy is evolutionarily conservative in eukaryotic cells that engulf cellular long-lived proteins and organelles, and it degrades the contents through fusion with lysosomes, via which the cell acquires recycled building blocks for the synthesis of new molecules. In this study, we revealed that peiminine induces cell death and enhances autophagic flux in colorectal carcinoma HCT-116 cells. We determined that peiminine enhances the autophagic flux by repressing the phosphorylation of mTOR through inhibiting upstream signals. Knocking down ATG5 greatly reduced the peiminine-induced cell death in wild-type HCT-116 cells, while treating Bax/Bak-deficient cells with peiminine resulted in significant cell death. In summary, our discoveries demonstrated that peiminine represses colorectal carcinoma cell proliferation and cell growth by inducing autophagic cell death. - Highlights: • Peiminine induces autophagy and upregulates autophagic flux. • Peiminine represses colorectal carcinoma tumor growth. • Peiminine induces autophagic cell death. • Peiminine represses mTOR phosphorylation by influencing PI3K/Akt and AMPK pathway.

  13. Heterogeneous nucleation and growth dynamics in the light-induced phase transition in vanadium dioxide

    DOE PAGES

    Brady, Nathaniel F.; Appavoo, Kannatassen; Seo, Minah; ...

    2016-03-02

    Here we report on ultrafast optical investigations of the light-induced insulator-to-metal phase transition in vanadium dioxide with controlled disorder generated by substrate mismatch. These results reveal common dynamics of this optically-induced phase transition that are independent of this disorder. Lastly, above the fluence threshold for completing the transition to the rutile crystalline phase, we find a common time scale, independent of sample morphology, of 40.5 ± 2 ps that is consistent with nucleation and growth dynamics of the R phase from the parent M1 ground state.

  14. Connexin 26 induces growth suppression, apoptosis and increased efficacy of doxorubicin in prostate cancer cells.

    PubMed

    Tanaka, Motoyoshi; Grossman, H Barton

    2004-02-01

    Connexin 26 (Cx26) encodes a gap junction protein and is a putative tumor suppressor gene. We evaluated the effect of forced expression of Cx26 on three human prostate cancer cell lines, PC-3, LNCap, and DU-145. The three cell lines were infected with a Cx26 adenovirus vector (Ad-Cx26) or a control vector or were mock infected. We tested cell growth, cell cycle, apoptosis, and the efficacy of combined treatment with doxorubicin. Ad-Cx26 infection suppressed the growth of all the cell lines compared with controls and induced cell cycle arrest at the G2/M phase and apoptosis. Ad-Cx26 decreased the expression of Bcl-2. LNCaP cell growth was dramatically suppressed by Ad-Cx26 alone. PC-3 and DU-145 had greater growth suppression with combined gene therapy and chemotherapy than with either Ad-Cx26 or doxorubicin alone. Forced expression of Cx26 suppresses the growth of prostate cancer cells and decreases the expression of Bcl-2. Combining Cx26 gene therapy with doxorubicin results in greater growth suppression.

  15. Signal transduction induced in endothelial cells by growth factor receptors involved in angiogenesis

    PubMed Central

    Hofer, Erhard; Schweighofer, Bernhard

    2010-01-01

    Summary New vessel formation during development and in the adult is triggered by concerted signals of largely endothelial-specific receptors for ligands of the VEGF, angiopoietin and ephrin families. The signals and genes induced by these receptors operate in the context of additional signals transduced by non-endothelial specific growth factor receptors, inflammatory cytokine receptors as well as adhesion molecules. We summarize here available data on characteristic signaling of the VEGF receptor-2 and the current state of knowledge regarding the additional different receptor tyrosine kinases of the VEGF, Tie and Ephrin receptor families. Furthermore, the potential cross-talk with signals induced by other growth factors and inflammatory cytokines as well as the modulation by VE-cadherin is discussed. PMID:17334501

  16. Laser shock processing induced residual compression: Impact on predicted crack growth threshold performance

    NASA Astrophysics Data System (ADS)

    Shepard, M. J.

    2005-08-01

    Design credit is not currently taken for laser shock processing (LSP) induced compressive residual stresses in damage tolerant design. The inclusion of these and other compressive stresses in design practice has the potential to dramatically increase predicted fatigue crack growth threshold performance and damage tolerant design life. In the current effort, Ti-6Al-4V coupons will be subjected to shot peening, glass bead peening, and high intensity laser shock processing. The in-depth residual stresses due to processing will be analyzed and then input into a linear elastic fracture mechanics analysis code to predict fatigue crack growth threshold performance. This analysis establishes both the utility and feasibility of incorporating LSP-induced compressive residual stresses into damage tolerant design practice.

  17. The effects of combinatorial treatments with stress inducing molecules on growth of E. coli colonies.

    PubMed

    Middler, Steven L; Gomez, Salvador; Parker, Christapher D; Palenchar, Peter M

    2011-12-01

    Stress inducing molecules affect both the mean behavior of bacterial growth and also variations in the growth. While the mechanisms that cause changes in the mean behavior are well understood, little is known about changes in the variation of the population. A true understanding of how organisms respond to stress must include an understanding of the mechanisms and purposes of changes in variation and the distribution not directly related to changes in the mean of the population. We have explored the results of combinatorial treatments using EDTA, copper sulfate, hydrogen peroxide, and hydrochloric acid as stress inducing molecules on bacterial colony formation and area on LB-agar plates. Three different combinations of X-gal and IPTG were used to create different background conditions. Some treatments alter the variation and/or the distribution of the area without having a significant effect on the mean, others affect the mean without altering the distribution, and yet others affect distribution and the mean.

  18. The resveratrol analogue trimethoxystilbene inhibits cancer cell growth by inducing multipolar cell mitosis.

    PubMed

    Traversi, Gianandrea; Fiore, Mario; Percario, Zulema; Degrassi, Francesca; Cozzi, Renata

    2017-03-01

    Natural compounds are extensively studied for their potential use in traditional and non-traditional medicine. Several natural and synthetic Resveratrol analogues have shown interesting biological activities in the field of cancer chemoprevention. In the present study, we have focused on the ability of Resveratrol and two methoxylated derivatives (Trimethoxystilbene and Pterostilbene) to inhibit human cancer cell growth particularly analyzing their ability to interfere with tubulin dynamics at mitosis. We show that Trimethoxystilbene, differently from Resveratrol and Pterostilbene, alters microtubule polymerization dynamics in HeLa cells specifically inducing multipolar spindles and mitotic arrest coupled to a reduction of cell growth and an increase in apoptotic death by mitotic catastrophe. This work demonstrates that the structural modification of Rsv causes substantial changes in the mechanism of action of the derivatives. The presence of three extra methyl groups renders Trimethoxy very efficient in impairing cell proliferation by inducing mitotic catastrophe in cancer cells. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  19. A synthetic manassantin a derivative inhibits hypoxia-inducible factor 1 and tumor growth.

    PubMed

    Lang, Liwei; Liu, Xiaoyu; Li, Yan; Zhou, Qing; Xie, Ping; Yan, Chunhong; Chen, Xiaoguang

    2014-01-01

    The dineolignan manassantin A from Saururaceae was recently identified as a hypoxia-inducible factor 1 (HIF-1) inhibitor, but its in-vivo anti-tumor effect has not been explored. We synthesized a series of manassantin A derivatives, and found that replacing the central tetrahydrofuran moiety with a cyclopentane ring yielded a compound (LXY6006) with increased HIF-1-inhibitory activity yet decreased stereochemically complexity amenable to a simplified synthesis scheme. LXY6006 inhibited HIF-1α nuclear accumulation induced by hypoxia, and inhibited cancer cell growth as a consequence of G2/M arrest. Oral administration of LXY6006 significantly inhibited growth of breast, lung, and pancreatic tumors implanted in nude mice. These results indicate that LXY6006 represents a novel class of agents targeting a broad range of human cancers.

  20. A Synthetic Manassantin A Derivative Inhibits Hypoxia-Inducible Factor 1 and Tumor Growth

    PubMed Central

    Li, Yan; Zhou, Qing; Xie, Ping; Yan, Chunhong; Chen, Xiaoguang

    2014-01-01

    The dineolignan manassantin A from Saururaceae was recently identified as a hypoxia-inducible factor 1 (HIF-1) inhibitor, but its in-vivo anti-tumor effect has not been explored. We synthesized a series of manassantin A derivatives, and found that replacing the central tetrahydrofuran moiety with a cyclopentane ring yielded a compound (LXY6006) with increased HIF-1-inhibitory activity yet decreased stereochemically complexity amenable to a simplified synthesis scheme. LXY6006 inhibited HIF-1α nuclear accumulation induced by hypoxia, and inhibited cancer cell growth as a consequence of G2/M arrest. Oral administration of LXY6006 significantly inhibited growth of breast, lung, and pancreatic tumors implanted in nude mice. These results indicate that LXY6006 represents a novel class of agents targeting a broad range of human cancers. PMID:24925080

  1. Changes in the tibial growth plates of chickens with thiram-induced dyschondroplasia.

    PubMed

    Rath, N C; Richards, M P; Huff, W E; Huff, G R; Balog, J M

    2005-07-01

    Tibial dyschondroplasia (TD) is a metabolic cartilage disease of young poultry in which endochondral bone formation is disrupted leading to the retention of a non-calcified, avascular plug of cartilage in the tibial growth plate. Chicks aged 7 days were fed either a control diet or one containing thiram 100 ppm for 48 h to induce TD. Cell multiplication in the growth plate was determined thereafter with bromodeoxyuridine (BrdU) labelling, and metabolic changes by measuring alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP), and glutathione (GSH) activities. The effect on chondrocyte maturation was examined by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of gene expression. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) and DNA fragmentation were used to determine the effects of thiram on cell survival. The results showed that thiram-induced TD was not due to the multiplication of cells in the post-proliferative zones. Thiram did not affect ALP activity, which would have indicated a loss of calcification potential, but it reduced both TRAP and the glutathione concentrations, suggesting that the growth plate metabolism and remodelling functions were adversely affected. Thiram appeared to have no effect on the expression of type X collagen, transglutaminase, RUNX2, or matrix metalloproteinase-2 (MMP) genes suggesting that it did not alter the maturation potential of chondrocytes. On the contrary, the expressions of MMP-13 and vascular endothelial growth factor (VEGF) genes were "up-regulated," suggesting that thiram has pro-angiogenic activity. However, TUNEL assay showed that thiram induced endothelial cell apoptosis in the capillary vessels of the growth plates, as early as 10 days of age, when TD was not visually evident. The vascular death increased on subsequent days accompanied by massive death of chondrocytes in the transition zone of the growth plate. The induction of apoptosis in the

  2. Iron oxide nanoparticles induce Pseudomonas aeruginosa growth, induce biofilm formation, and inhibit antimicrobial peptide function.

    PubMed

    Borcherding, Jennifer; Baltrusaitis, Jonas; Chen, Haihan; Stebounova, Larissa; Wu, Chia-Ming; Rubasinghege, Gayan; Mudunkotuwa, Imali A; Caraballo, Juan Carlos; Zabner, Joseph; Grassian, Vicki H; Comellas, Alejandro P

    2014-04-01

    Given the increased use of iron-containing nanoparticles in a number of applications, it is important to understand any effects that iron-containing nanoparticles can have on the environment and human health. Since iron concentrations are extremely low in body fluids, there is potential that iron-containing nanoparticles may influence the ability of bacteria to scavenge iron for growth, affect virulence and inhibit antimicrobial peptide (AMP) function. In this study, Pseudomonas aeruginosa (PA01) and AMPs were exposed to iron oxide nanoparticles, hematite (α-Fe2O3), of different sizes ranging from 2 to 540 nm (2 ± 1, 43 ± 6, 85 ± 25 and 540 ± 90 nm) in diameter. Here we show that the greatest effect on bacterial growth, biofilm formation, and AMP function impairment is found when exposed to the smallest particles. These results are attributed in large part to enhanced dissolution observed for the smallest particles and an increase in the amount of bioavailable iron. Furthermore, AMP function can be additionally impaired by adsorption onto nanoparticle surfaces. In particular, lysozyme readily adsorbs onto the nanoparticle surface which can lead to loss of peptide activity. Thus, this current study shows that co-exposure of nanoparticles and known pathogens can impact host innate immunity. Therefore, it is important that future studies be designed to further understand these types of impacts.

  3. Iron oxide nanoparticles induce Pseudomonas aeruginosa growth, induce biofilm formation, and inhibit antimicrobial peptide function†

    PubMed Central

    Borcherding, Jennifer; Baltrusaitis, Jonas; Chen, Haihan; Stebounova, Larissa; Wu, Chia-Ming; Rubasinghege, Gayan; Mudunkotuwa, Imali A.; Caraballo, Juan Carlos; Zabner, Joseph

    2014-01-01

    Given the increased use of iron-containing nanoparticles in a number of applications, it is important to understand any effects that iron-containing nanoparticles can have on the environment and human health. Since iron concentrations are extremely low in body fluids, there is potential that iron-containing nanoparticles may influence the ability of bacteria to scavenge iron for growth, affect virulence and inhibit antimicrobial peptide (AMP) function. In this study, Pseudomonas aeruginosa (PA01) and AMPs were exposed to iron oxide nanoparticles, hematite (α-Fe2O3), of different sizes ranging from 2 to 540 nm (2 ± 1, 43 ± 6, 85 ± 25 and 540 ± 90 nm) in diameter. Here we show that the greatest effect on bacterial growth, biofilm formation, and AMP function impairment is found when exposed to the smallest particles. These results are attributed in large part to enhanced dissolution observed for the smallest particles and an increase in the amount of bioavailable iron. Furthermore, AMP function can be additionally impaired by adsorption onto nanoparticle surfaces. In particular, lysozyme readily adsorbs onto the nanoparticle surface which can lead to loss of peptide activity. Thus, this current study shows that co-exposure of nanoparticles and known pathogens can impact host innate immunity. Therefore, it is important that future studies be designed to further understand these types of impacts. PMID:25221673

  4. Effect of modeled microgravity on radiation-induced adaptive response of root growth in Arabidopsis thaliana.

    PubMed

    Deng, Chenguang; Wang, Ting; Wu, Jingjing; Xu, Wei; Li, Huasheng; Liu, Min; Wu, Lijun; Lu, Jinying; Bian, Po

    2017-02-01

    Space particles have an inevitable impact on organisms during space missions; radio-adaptive response (RAR) is a critical radiation effect due to both low-dose background and sudden high-dose radiation exposure during solar storms. Although it is relevant to consider RAR within the context of microgravity, another major space environmental factor, there is no existing evidence as to its effects on RAR. In the present study, we established an experimental method for detecting the effects of gamma-irradiation on the primary root growth of Arabidopsis thaliana, in which RAR of root growth was significantly induced by several dose combinations. Microgravity was simulated using a two-dimensional rotation clinostat. It was shown that RAR of root growth was significantly inhibited under the modeled microgravity condition, and was absent in pgm-1 plants that had impaired gravity sensing in root tips. These results suggest that RAR could be modulated in microgravity. Time course analysis showed that microgravity affected either the development of radio-resistance induced by priming irradiation, or the responses of plants to challenging irradiation. After treatment with the modeled microgravity, attenuation in priming irradiation-induced expressions of DNA repair genes (AtKu70 and AtRAD54), and reduced DNA repair efficiency in response to challenging irradiation were observed. In plant roots, the polar transportation of the phytohormone auxin is regulated by gravity, and treatment with an exogenous auxin (indole-3-acetic acid) prevented the induction of RAR of root growth, suggesting that auxin might play a regulatory role in the interaction between microgravity and RAR of root growth. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Tumors induce coordinate growth of artery, vein, and lymphatic vessel triads

    PubMed Central

    2014-01-01

    Background Tumors drive blood vessel growth to obtain oxygen and nutrients to support tumor expansion, and they also can induce lymphatic vessel growth to facilitate fluid drainage and metastasis. These processes have generally been studied separately, so that it is not known how peritumoral blood and lymphatic vessels grow relative to each other. Methods The murine B16-F10 melanoma and chemically-induced squamous cell carcinoma models were employed to analyze large red-colored vessels growing between flank tumors and draining lymph nodes. Immunostaining and microscopy in combination with dye injection studies were used to characterize these vessels. Results Each peritumoral red-colored vessel was found to consist of a triad of collecting lymphatic vessel, vein, and artery, that were all enlarged. Peritumoral veins and arteries were both functional, as detected by intravenous dye injection. The enlarged lymphatic vessels were functional in most mice by subcutaneous dye injection assay, however tumor growth sometimes blocked lymph drainage to regional lymph nodes. Large red-colored vessels also grew between benign papillomas or invasive squamous cell carcinomas and regional lymph nodes in chemical carcinogen-treated mice. Immunostaining of the red-colored vessels again identified the clustered growth of enlarged collecting lymphatics, veins, and arteries in the vicinity of these spontaneously arising tumors. Conclusions Implanted and spontaneously arising tumors induce coordinate growth of blood and lymphatic vessel triads. Many of these vessel triads are enlarged over several cm distance between the tumor and regional lymph nodes. Lymphatic drainage was sometimes blocked in mice before lymph node metastasis was detected, suggesting that an unknown mechanism alters lymph drainage patterns before tumors reach draining lymph nodes. PMID:24886322

  6. TAZ promotes cell growth and inhibits Celastrol-induced cell apoptosis

    PubMed Central

    Wang, Shuren; Ma, Kai; Chen, Lechuang; Zhu, Hongxia; Liang, Shufang; Liu, Mei; Xu, Ningzhi

    2016-01-01

    Hippo pathway is a highly conservative signalling pathway related to the development of organisms, which has been demonstrated to be strongly linked to the tumorigenesis and tumour progression. As the major downstream effector of Hippo pathway, yes-associated protein (YAP), is a transcriptional activator of target genes that are involved in cell proliferation and survival. As an oncogene, YAP can promote cell growth and inhibit cell apoptosis. Another major downstream effector of Hippo pathway, transcriptional co-activators with PDZ-binding motif (TAZ), is nearly 60% homologous with YAP. In the present study, we assume that TAZ probably has the similar function to YAP. To test this issue, we established an inducible and a stable expression system of TAZ in T-Rex-293 and HEK293 cells respectively. The results of cell growth curves, colony formation assay and tumour xenograft growth showed that overexpression of TAZ could promote cell growth in vitro and in vivo. Meanwhile, we found that up-regulated expression of TAZ could partially restore Celastrol-induced cell apoptosis. Induced overexpression of TAZ could up-regulate its target genes including ankyrin repeat domain-containing protein (ANKRD), cysteine-rich 61 (CYR61) and connective tissue growth factor (CTGF), increase the expression of B-cell lymphoma-2 (Bcl-2), decrease the expression of Bcl-2 associated X protein (Bax) and activate the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, which may be the mechanism underlying anti-apoptosis of TAZ. All these findings indicated that TAZ acts as an oncogene that could be a key regulator of cell proliferation and apoptosis. PMID:27515420

  7. TAZ promotes cell growth and inhibits Celastrol-induced cell apoptosis.

    PubMed

    Wang, Shuren; Ma, Kai; Chen, Lechuang; Zhu, Hongxia; Liang, Shufang; Liu, Mei; Xu, Ningzhi

    2016-10-01

    Hippo pathway is a highly conservative signalling pathway related to the development of organisms, which has been demonstrated to be strongly linked to the tumorigenesis and tumour progression. As the major downstream effector of Hippo pathway, yes-associated protein (YAP), is a transcriptional activator of target genes that are involved in cell proliferation and survival. As an oncogene, YAP can promote cell growth and inhibit cell apoptosis. Another major downstream effector of Hippo pathway, transcriptional co-activators with PDZ-binding motif (TAZ), is nearly 60% homologous with YAP. In the present study, we assume that TAZ probably has the similar function to YAP. To test this issue, we established an inducible and a stable expression system of TAZ in T-Rex-293 and HEK293 cells respectively. The results of cell growth curves, colony formation assay and tumour xenograft growth showed that overexpression of TAZ could promote cell growth in vitro and in vivo Meanwhile, we found that up-regulated expression of TAZ could partially restore Celastrol-induced cell apoptosis. Induced overexpression of TAZ could up-regulate its target genes including ankyrin repeat domain-containing protein (ANKRD), cysteine-rich 61 (CYR61) and connective tissue growth factor (CTGF), increase the expression of B-cell lymphoma-2 (Bcl-2), decrease the expression of Bcl-2 associated X protein (Bax) and activate the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, which may be the mechanism underlying anti-apoptosis of TAZ. All these findings indicated that TAZ acts as an oncogene that could be a key regulator of cell proliferation and apoptosis.

  8. Obesity and Postmenopausal Breast Cancer Risk: Determining the Role of Growth Factor-Induced Aromatase Expression

    DTIC Science & Technology

    2013-01-01

    Moreau T, Senouci K, Salmon RJ, Fourquet A, Asselain B. Is obesity an independent prognosis factor in woman breast cancer ? Breast Cancer Res Treat...1 AD__________________________ Award number: W81XWH-11-1-0132 Title: Obesity and Postmenopausal Breast Cancer Risk: Determining the Role... Obesity and Postmenopausal Breast Cancer Risk: Determining the Role of Growth Factor-Induced Aromatase Expression 5a. CONTRACT NUMBER 5b. GRANT

  9. Growth of gold nanoclusters and nanocrystals induced by lysozyme protein in thin film conformation

    NASA Astrophysics Data System (ADS)

    Bhowal, Ashim Chandra; Kundu, Sarathi

    2016-08-01

    Structures and growth behavior of gold nanoclusters and nanocrystals have been explored on thin films of globular protein lysozyme by using UV-vis and photoluminescence spectroscopy, X-ray diffraction (XRD) and atomic force microscopy (AFM). A simple and one-step environment friendly method has been used to grow nanocrystals on protein surface from HAuCl4 solution. It has been found that if different interaction times are provided between lysozyme films and HAuCl4 solution, then initially formed tiny gold nanoclusters on protein surface transform into nanocrystals with the passage of time. XRD analysis shows the formation of faced-centered cubic lattice along (1 1 1) crystalline direction and AFM images confirm the presence of circular, rod-like, triangular and hexagonal crystal structures. Langmuir-like growth behavior has been identified for both the gold nanoclusters and nanocrystals formation induced by the lysozyme films, however, nanocrystal growth is relatively slower than nanocluster.

  10. Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth

    PubMed Central

    Shukla, Surendra K.; Dasgupta, Aneesha; Mehla, Kamiya; Gunda, Venugopal; Vernucci, Enza; Souchek, Joshua; Goode, Gennifer; King, Ryan; Mishra, Anusha; Rai, Ibha; Nagarajan, Sangeetha; Chaika, Nina V.; Yu, Fang; Singh, Pankaj K.

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic cancer cells. Silibinin treatment diminishes c-MYC expression, a key regulator of cancer metabolism. Furthermore, we observed reduced STAT3 signaling in silibinin-treated cancer cells. Overexpression of constitutively active STAT3 was sufficient to substantially revert the silibinin-induced downregulation of c-MYC and the metabolic phenotype. Our in vivo investigations demonstrate that silibinin reduces tumor growth and proliferation in an orthotopic mouse model of pancreatic cancer and prevents the loss of body weight and muscle. It also improves physical activity including grip strength and latency to fall in tumor-bearing mice. In conclusion, silibinin-induced metabolic reprogramming diminishes cell growth and cachectic properties of pancreatic cancer cells and animal models. PMID:26510913

  11. Trichoderma asperellum Induces Maize Seedling Growth by Activating the Plasma Membrane H(+)-ATPase.

    PubMed

    López-Coria, M; J L Hernández-Mendoza; Sánchez-Nieto, S

    2016-10-01

    Although Trichoderma spp. have beneficial effects on numerous plants, there is not enough knowledge about the mechanism by which they improves plant growth. In this study, we evaluated the participation of plasma membrane (PM) H(+)-ATPase, a key enzyme involved in promoting cell growth, in the elongation induced by T. asperellum and compared it with the effect of 10 μM indol acetic acid (IAA) because IAA promotes elongation and PM H(+)-ATPase activation. Two seed treatments were tested: biopriming and noncontact. In neither were the tissues colonized by T. asperellum; however, the seedlings were longer than the control seedlings, which also accumulated IAA and increased root acidification. An auxin transport inhibitor (2,3,5 triiodobenzoic acid) reduced the plant elongation induced by Trichoderma spp. T. asperellum seed treatment increased the PM H(+)-ATPase activity in plant roots and shoots. Additionally, the T. asperellum extracellular extract (TE) activated the PM H(+)-ATPase activity of microsomal fractions of control plants, although it contained 0.3 μM IAA. Furthermore, the mechanism of activation of PM H(+)-ATPase was different for IAA and TE; in the latter, the activation depends on the phosphorylation state of the enzyme, suggesting that, in addition to IAA, T. asperellum excretes other molecules that stimulate PM H(+)-ATPase to induce plant growth.

  12. Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth.

    PubMed

    Shukla, Surendra K; Dasgupta, Aneesha; Mehla, Kamiya; Gunda, Venugopal; Vernucci, Enza; Souchek, Joshua; Goode, Gennifer; King, Ryan; Mishra, Anusha; Rai, Ibha; Nagarajan, Sangeetha; Chaika, Nina V; Yu, Fang; Singh, Pankaj K

    2015-12-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic cancer cells. Silibinin treatment diminishes c-MYC expression, a key regulator of cancer metabolism. Furthermore, we observed reduced STAT3 signaling in silibinin-treated cancer cells. Overexpression of constitutively active STAT3 was sufficient to substantially revert the silibinin-induced downregulation of c-MYC and the metabolic phenotype. Our in vivo investigations demonstrate that silibinin reduces tumor growth and proliferation in an orthotopic mouse model of pancreatic cancer and prevents the loss of body weight and muscle. It also improves physical activity including grip strength and latency to fall in tumor-bearing mice. In conclusion, silibinin-induced metabolic reprogramming diminishes cell growth and cachectic properties of pancreatic cancer cells and animal models.

  13. Shikonin inhibits TNF-α-induced growth and invasion of rat aortic vascular smooth muscle cells.

    PubMed

    Zhang, Xuemin; Hu, Wenyu; Wu, Fang; Yuan, Xue; Hu, Jian

    2015-08-01

    Shikonin is a naphthoquinone compound extracted from the Chinese herb purple gromwell. Shikonin has broad antibacterial, anti-inflammatory, and antitumor activities. The tumor necrosis factor-α (TNF-α)-induced proliferation and invasion of vascular smooth muscle cells (VSMCs) is an important factor that contributes to atherosclerosis. The effects of shikonin on the proliferation and apoptosis of VSMCs have been reported; however, the function of shikonin on TNF-α-mediated growth and invasion of VSMCs during atherosclerosis remains unclear. In this study, we used Western blot, flow cytometry, real-time quantitative PCR, and enzyme-linked immunosorbent assay to investigate the effect of shikonin on the TNF-α-induced growth and invasion of VSMCs and to determine the underlying mechanism. Our results showed that shikonin inhibits the TNF-α-mediated growth and invasion. Further study revealed that shikonin regulates the activation of nuclear factor kappa B and phosphatidyl inositol 3-kinase signaling pathways; modulates the expression of cyclin D1, cyclin E, B-cell lymphoma 2, and Bax; activates caspase-3 and caspase-9; induces cell cycle arrest; and promotes the apoptosis of VSMCs. Together, our results indicate that shikonin may become a promising agent for the treatment of atherosclerosis and they also establish foundation for the development of anti-atherosclerosis drugs.

  14. Hsp90 inhibitor celastrol reinstates growth plate angiogenesis in thiram-induced tibial dyschondroplasia.

    PubMed

    Nabi, Fazul; Shahzad, Muhammad; Liu, Jingying; Li, Kun; Han, Zhaoqing; Zhang, Ding; Iqbal, Muhammad Kashif; Li, Jiakui

    2016-01-01

    Tibial dyschondroplasia (TD) is an important long bone defect of broiler chickens that disturbs the proximal growth plate and is characterized by non-vascularized cartilage, a distended growth plate and lameness. Celastrol, a medicinal root extract from the plant Tripterygium wilfordii, is reported widely as a well-known heat-shock protein 90 (Hsp90) inhibitor. Recently, Hsp90 inhibition in chondrocyte differentiation and growth-plate vascularization were effective in restoring the morphology of the growth plate. The present study was aimed at investigating Hsp90 inhibition in TD using celastrol. The broiler chicks were divided into three groups; Control; TD induced (40 mg/kg thiram) and celastrol treatment. Hsp90, vascular endothelial growth factor and Flk-1 expressions were evaluated by quantitative real-time polymerase chain reaction and the protein levels of Hsp90 were measured by Western blot analysis. Antioxidant enzymes were determined to assess the liver damage caused by thiram and the protective effects of the medicine were evaluated by levels of serum biomarkers. The expression levels of Hsp90 and vascular endothelial growth factor mRNA transcripts were increased while Flk-1 receptor was decreased in TD-affected chicks. Celastrol therapy inhibited Hsp90 mRNA and protein levels and up-regulated the expressions of receptor Flk-1 in TD-affected tibial growth plates significantly (P < 0.05) in addition to rectifying the damaging effects of thiram on the liver by decreasing the levels of aspartate aminotransferase, alanine aminotransferase and malondialdehyde and correcting the oxidative imbalance. In conclusion, administering celastrol to dyschondroplastic chicks prevented un-vascularized growth plate, lameness and reinstated angiogenesis. Celastrol may be efficacious for the treatment of TD through the inhibition of Hsp90 expression and limiting the liver damage caused by thiram in broiler chickens.

  15. Muscle-specific growth hormone receptor (GHR) overexpression induces hyperplasia but not hypertrophy in transgenic zebrafish.

    PubMed

    Figueiredo, Marcio Azevedo; Mareco, Edson A; Silva, Maeli Dal Pai; Marins, Luis Fernando

    2012-06-01

    Even though growth hormone (GH) transgenesis has demonstrated potential for improved growth of commercially important species, the hormone excess may result in undesired collateral effects. In this context, the aim of this work was to develop a new model of transgenic zebrafish (Danio rerio) characterized by a muscle-specific overexpression of the GH receptor (GHR) gene, evaluating the effect of transgenesis on growth, muscle structure and expression of growth-related genes. In on line of transgenic zebrafish overexpressing GHR in skeletal muscle, no significant difference in total weight in comparison to non-transgenics was observed. This can be explained by a significant reduction in expression of somatotrophic axis-related genes, in special insulin-like growth factor I (IGF-I). In the same sense, a significant increase in expression of the suppressors of cytokine signaling 1 and 3 (SOCS) was encountered in transgenics. Surprisingly, expression of genes coding for the main myogenic regulatory factors (MRFs) was higher in transgenic than non-transgenic zebrafish. Genes coding for muscle proteins did not follow the MRFs profile, showing a significant decrease in their expression. These results were corroborated by the histological analysis, where a hyperplasic muscle growth was observed in transgenics. In conclusion, our results demonstrated that GHR overexpression does not induce hypertrophic muscle growth in transgenic zebrafish probably because of SOCS impairment of the GHR/IGF-I pathway, culminating in IGF-I and muscle proteins decrease. Therefore, it seems that hypertrophy and hyperplasia follow two different routes for entire muscle growth, both of them triggered by GHR activation, but regulated by different mechanisms.

  16. Exogenous nitrate induces root branching and inhibits primary root growth in Capsicum chinense Jacq.

    PubMed

    Celis-Arámburo, Teresita de Jesús; Carrillo-Pech, Mildred; Castro-Concha, Lizbeth A; Miranda-Ham, María de Lourdes; Martínez-Estévez, Manuel; Echevarría-Machado, Ileana

    2011-12-01

    The effects of nitrate (NO₃⁻) on the root system are complex and depend on several factors, such as the concentration available to the plant, endogenous nitrogen status and the sensitivity of the species. Though these effects have been widely documented on Arabidopsis and cereals, no reports are available in the Capsicum genus. In this paper, we have determined the effect of an exogenous in vitro application of this nutrient on root growth in habanero pepper (Capsicum chinense Jacq.). Exposure to NO₃⁻ inhibited primary root growth in both, dose- and time-dependent manners. The highest inhibition was attained with 0.1 mM NO₃⁻ between the fourth and fifth days of treatment. Inhibition of primary root growth was observed by exposing the root to both homogeneous and heterogeneous conditions of the nutrient; in contrast, ammonium was not able to induce similar changes. NO₃⁻-induced inhibition of primary root growth was reversed by treating the roots with IAA or NPA, a polar auxin transport inhibitor. Heterogeneous NO₃⁻ application stimulated the formation and elongation of lateral roots in the segment where the nutrient was present, and this response was influenced by exogenous phytohormones. These results demonstrate that habanero pepper responds to NO₃⁻ in a similar fashion to other species with certain particular differences. Therefore, studies in this model could help to elucidate the mechanisms by which roots respond to NO₃⁻ in fluctuating soil environments.

  17. Maternal Nutrient Restriction in Guinea Pigs as an Animal Model for Inducing Fetal Growth Restriction.

    PubMed

    Elias, Alexander A; Ghaly, Andrew; Matushewski, Brad; Regnault, Timothy R H; Richardson, Bryan S

    2016-02-01

    We determined the impact of moderate maternal nutrient restriction (MNR) in guinea pigs on pregnancy outcomes, maternal/fetal growth parameters, and blood analytes to further characterize the utility of this model for inducing fetal growth restriction (FGR). Thirty guinea pig sows were fed ad libitum (Control) or 70% of the control diet prepregnant switching to 90% at midpregnancy (MNR). Animals were necropsied near term with weights obtained on all sows, fetuses, and placenta. Fetal blood sampling and organ dissection were undertaken in appropriate for gestational age (AGA) fetuses from Control litters and FGR fetuses from MNR litters using > or < 80 g which approximated the 10th percentile for the population weight distribution of the Control fetuses. MNR fetal demise rates (1/43) were extremely low in contrast to that seen with uterine artery ligation/ablation models, albeit with increased preterm delivery in MNR sows (3 of 15). We confirm that MNR fetuses are smaller and have increased placental/fetal weight ratios as often seen in human FGR infants. We provide justification for using a fetal weight threshold for categorizing AGA Control and FGR-MNR cohorts reducing population variance, and show that FGR-MNR fetuses have asymmetrical organ growth, and are polycythemic and hypoglycemic which are also well associated with moderate FGR in humans. These findings further support the utility of moderate MNR in guinea pigs for inducing FGR with many similarities to that in humans with moderate growth restriction whether resulting from maternal undernourishment or placental insufficiency.

  18. Identification and characterization of a retinoid-induced class II tumor suppressor/growth regulatory gene.

    PubMed

    DiSepio, D; Ghosn, C; Eckert, R L; Deucher, A; Robinson, N; Duvic, M; Chandraratna, R A; Nagpal, S

    1998-12-08

    Retinoids, synthetic and natural analogs of retinoic acid, exhibit potent growth inhibitory and cell differentiation activities that account for their beneficial effects in treating hyperproliferative diseases such as psoriasis, actinic keratosis, and certain neoplasias. Tazarotene is a synthetic retinoid that is used in the clinic for the treatment of psoriasis. To better understand the mechanism of retinoid action in the treatment of hyperproliferative diseases, we used a long-range differential display-PCR to isolate retinoid-responsive genes from primary human keratinocytes. We have identified a cDNA, tazarotene-induced gene 3 (TIG3; Retinoic Acid Receptor Responder 3) showing significant homology to the class II tumor suppressor gene, H-rev 107. Tazarotene treatment increases TIG3 expression in primary human keratinocytes and in vivo in psoriatic lesions. Increased TIG3 expression is correlated with decreased proliferation. TIG3 is expressed in a number of tissues, and expression is reduced in cancer cell lines and some primary tumors. In breast cancer cell lines, retinoid-dependent TIG3 induction is observed in lines that are growth suppressed by retinoids but not in nonresponsive lines. Transient over-expression of TIG3 in T47D or Chinese hamster ovary cells inhibits colony expansion. Finally, studies in 293 cells expressing TIG3 linked to an inducible promoter demonstrated decreased proliferation with increased TIG3 levels. These studies suggest that TIG3 may be a growth regulator that mediates some of the growth suppressive effects of retinoids.

  19. Vasopressin and insulin-like growth factors synergistically induce myogenesis in serum-free medium.

    PubMed

    Minotti, S; Scicchitano, B M; Nervi, C; Scarpa, S; Lucarelli, M; Molinaro, M; Adamo, S

    1998-02-01

    Terminal differentiation of myogenic cells has long been known to be positively regulated by insulin-like growth factors (IGFs). Arg8-vasopressin (AVP) has been recently reported to potently induce myogenic differentiation. In the present study, the effects and the mechanisms of action of AVP and IGFs on myogenic cells have been investigated under conditions allowing growth and differentiation of myogenic cells in a simple serum-free medium. Under these conditions, L6 and L5 myogenic cells slowly proliferate and do not undergo differentiation (less than 1% fusion up to 7 days). AVP rapidly (2-3 days) and dose-dependently induces the formation of multinucleated myotubes. Creatine kinase activity and myosin accumulation are strongly up-regulated by AVP. Insulin or IGF-I or IGF-II, at concentrations that cause extensive differentiation in serum-containing medium, induces a modest degree of differentiation in serum-free medium. The simultaneous presence of AVP and of one of the IGFs in the synthetic medium induces maximal differentiation of L6, L5, and satellite cells. The expression of both myogenin and Myf-5 is dramatically stimulated by AVP. Our results indicate that AVP induces a significant level of myogenic differentiation in the absence of other factors. Furthermore, they suggest that to express their full myogenic potential, IGFs require the presence of other factors normally present in serum and fully mimicked by AVP. These studies support the conclusion that terminal myogenic differentiation may depend on the presence of differentiation factors rather than the absence of growth factors.

  20. Flavonoids inhibit cell growth and induce apoptosis in B16 melanoma 4A5 cells.

    PubMed

    Iwashita, K; Kobori, M; Yamaki, K; Tsushida, T

    2000-09-01

    We investigated the growth inhibitory activity of several flavonoids, including apigenin, luteolin, kaempherol, quercetin, butein, isoliquiritigenin, naringenin, genistein, and daizein against B16 mouse melanoma 4A5 cells. Isoliquiritigenin and butein, belonging to the chalcone group, markedly suppressed the growth of B16 melanoma cells and induced cell death. The other flavonoids tested showed little growth inhibitory activity and scarcely caused cell death. In cells treated with isoliquiritigenin or butein, condensation of nuclei and fragmentation of nuclear DNA, which are typical phenomena of apoptosis, were observed by Hoechst 33258 staining and by agarose gel electrophoresis of DNA. Flowcytometric analysis showed that isoliquiritigenin and butein increased the proportion of hypodiploid cells in the population of B16 melanoma cells. These results demonstrate that isoliquiritigenin and butein inhibit cell proliferation and induce apoptosis in B16 melanoma cells. Extracellular glucose decreased the proportion of hypodiploid cells that appeared as a result of isoliquiritigenin treatment. p53 was not detected in cells treated with either of these chalcones, however, protein of the Bcl-2 family were detected. The level of expression of Bax in cells treated with either of these chalcones was markedly elevated and the level of Bcl-XL decreased slightly. Isoliquiritigenin did not affect Bcl-2 expression, but butein down-regulated Bcl-2 expression. From these results, it seems that the pathway by which the chalcones induce apoptosis may be independent of p53 and dependent on proteins of the Bcl-2 family. It was supposed that isoliquiritigenin induces apoptosis in B16 cells by a mechanism involving inhibition of glucose transmembrane transport and promotion of Bax expression. On the other hand, it was suggested that butein induces apoptosis via down-regulation of Bcl-2 expression and promotion of Bax expression. This mechanism differs from the isoliquiritigenin induction

  1. Rearing temperature induces changes in muscle growth and gene expression in juvenile pacu (Piaractus mesopotamicus).

    PubMed

    Gutierrez de Paula, Tassiana; de Almeida, Fernanda Losi Alves; Carani, Fernanda Regina; Vechetti-Júnior, Ivan José; Padovani, Carlos Roberto; Salomão, Rondinelle Arthur Simões; Mareco, Edson Assunção; Dos Santos, Vander Bruno; Dal-Pai-Silva, Maeli

    2014-03-01

    growth-related genes and induced a delay in muscle growth in juvenile pacu (P. mesopotamicus). Our study provides a clear example of thermally induced phenotypic plasticity in pacu fish and shows that changing the rearing temperature during the juvenile stage can have a considerable effect on gene expression and muscle growth in this species. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces growth inhibition and enhances taxol-induced cell death in breast cancer.

    PubMed

    Shi, Yi-kang; Li, Zhong-hua; Han, Xi-qian; Yi, Ji-hu; Wang, Zhen-hua; Hou, Jing-li; Feng, Cong-ran; Fang, Qing-hong; Wang, Hui-hui; Zhang, Peng-fei; Wang, Feng-shan; Shen, Jie; Wang, Peng

    2010-11-01

    The histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) enhances taxol-induced antitumor effects against some human cancer cells. The aim of this study is to investigate whether SAHA can enhance taxol-induced cell death against human breast cancer cells and to illustrate the mechanism in detail. A panel of eight human breast cancer cell lines and an immortalized human breast epithelial cell line were used to determine the inhibitory effects of SAHA, taxol, or their combination by MTT assay. The effects of SAHA with or without taxol on cell cycle distributions, apoptosis, and protein expressions were also examined. The inhibitory effects on tumor growth were characterized in vivo in BALB/c nude mice bearing a breast cancer xenograft model. Taxol-resistant and multi-resistant breast cancer cells were as sensitive to SAHA as taxol-sensitive breast cancer cells. A dose-dependent synergistic growth inhibition was found in all the tested breast cancer cell lines treated with the SAHA/taxol combinations. The synergetic effect was also observed in the in vivo xenograft tumor model. The cell cycle analysis and apoptosis assay showed that the synergistic effects resulted from enhanced G2/M arrest and apoptosis. SAHA increased the anti-tumor effects of taxol in breast cancer in vitro and in vivo. The combination of SAHA and taxol may have therapeutic potential in the treatment of breast cancer.

  3. Involvement of reactive oxygen species in lanthanum-induced inhibition of primary root growth.

    PubMed

    Liu, Yang-Yang; Wang, Ru-Ling; Zhang, Ping; Sun, Liang-Liang; Xu, Jin

    2016-11-01

    Although lanthanum (La) has been used as an agricultural plant growth stimulant for approximately 50 years, high concentrations are toxic to plants. Despite significant advances in recent years, the mechanisms underlying the effects of La on root system development remain unclear. Here, we report that a high concentration of La inhibits primary root (PR) elongation and induces lateral root (LR) development. La results in cell death in PR tips, thereby leading to the loss of meristematic cell division potential, stem cell niche activity, and auxin distribution in PR tips. Further analysis indicated that La induces reactive oxygen species (ROS) over-accumulation in PR tips. Reduction in ROS accumulation partially alleviated the inhibitory effects of La on PR elongation by improving cell survival in PR tips and thereby improving meristematic cell division potential and auxin distribution in PR tips. We also found ROS to be involved in La-induced endocytosis. Genetic analyses supported the described phenotype. Overall, our results indicate that La affects root growth, at least partially, by modulating ROS levels in roots to induce cell death in PR tips and subsequent auxin redistribution in roots, leading to remodeling of the root system architecture.

  4. A three-dimensional phase diagram of growth-induced surface instabilities

    PubMed Central

    Wang, Qiming; Zhao, Xuanhe

    2015-01-01

    A variety of fascinating morphological patterns arise on surfaces of growing, developing or aging tissues, organs and microorganism colonies. These patterns can be classified into creases, wrinkles, folds, period-doubles, ridges and delaminated-buckles according to their distinctive topographical characteristics. One universal mechanism for the pattern formation has been long believed to be the mismatch strains between biological layers with different expanding or shrinking rates, which induce mechanical instabilities. However, a general model that accounts for the formation and evolution of these various surface-instability patterns still does not exist. Here, we take biological structures at their current states as thermodynamic systems, treat each instability pattern as a thermodynamic phase, and construct a unified phase diagram that can quantitatively predict various types of growth-induced surface instabilities. We further validate the phase diagram with our experiments on surface instabilities induced by mismatch strains as well as the reported data on growth-induced instabilities in various biological systems. The predicted wavelengths and amplitudes of various instability patterns match well with our experimental data. It is expected that the unified phase diagram will not only advance the understanding of biological morphogenesis, but also significantly facilitate the design of new materials and structures by rationally harnessing surface instabilities. PMID:25748825

  5. Role of oxidative stress and heme oxygenase activity in morphine-induced glomerular epithelial cell growth.

    PubMed

    Patel, Jaimita; Manjappa, Nagarathna; Bhat, Rajani; Mehrotra, Pavni; Bhaskaran, Madhu; Singhal, Pravin C

    2003-11-01

    Opiate addiction has been reported to contribute to the progression of renal injury. In addition, opiate addiction is a major risk factor for the development of human immunodeficiency virus-associated nephropathy. In the present study, we evaluated the effects of morphine, an active metabolite of heroin, on glomerular epithelial cell (GEC) growth and the involved molecular mechanism. At lower concentrations, morphine promoted GEC proliferation; however, at higher concentrations, morphine triggered apoptosis. Antioxidants inhibited morphine-induced proliferation as well as apoptosis. Similarly, free radical scavengers prevented morphine-induced GEC proliferation and apoptosis. Because proliferative and proapoptotic effects of morphine were inhibited by free radical scavengers as well as antioxidants, it appears that these effects of morphine are mediated through oxidative stress. Hemin, an inducer of heme oxygenase (HO) activity, inhibited GEC proliferation and promoted GEC apoptosis under basal and morphine-stimulated conditions. On the other hand, zinc protoporphyrin, an inhibitor of HO activity, promoted GEC proliferation and inhibited GEC apoptosis under basal as well as morphine-stimulated conditions. These findings suggest that HO activity is directly related to GEC apoptosis and inversely related to GEC proliferation. Morphine, de novo, had bimodal effects on HO activity: lower concentrations increased and higher concentrations decreased HO activity. It appears that HO activity may be modifying morphine-induced GEC growth.

  6. Inhibition of dipeptidyl peptidase 4 regulates microvascular endothelial growth induced by inflammatory cytokines

    SciTech Connect

    Takasawa, Wataru; Ohnuma, Kei; Hatano, Ryo; Endo, Yuko; Dang, Nam H.

    2010-10-08

    Research highlights: {yields} TNF-{alpha} or IL-1{beta} induces EC proliferation with reduction of CD26 expression. {yields} CD26 siRNA or DPP-4 inhibition enhances TNF-{alpha} or IL-1{beta}-induced EC proliferation. {yields} Loss of CD26/DPP-4 enhances aortic sprouting induced by TNF-{alpha} or IL-1{beta}. {yields} Capillary formation induced by TNF-{alpha} or IL-1{beta} is enahced in the CD26{sup -/-} mice. -- Abstract: CD26/DPP-4 is abundantly expressed on capillary of inflamed lesion as well as effector T cells. Recently, CD26/dipeptidyl peptidase 4 (DPP-4) inhibition has been used as a novel oral therapeutic approach for patients with type 2 diabetes. While accumulating data indicate that vascular inflammation is a key feature of both micro- and macro-vascular complications in diabetes, the direct role of CD26/DPP-4 in endothelial biology is to be elucidated. We herein showed that proinflammatory cytokines such as tumor necrosis factor or interleukin-1 reduce expression of CD26 on microvascular endothelial cells, and that genetical or pharmacological inhibition of CD26/DPP-4 enhances endothelial growth both in vitro and in vivo. With DPP-4 inhibitors being used widely in the treatment of type 2 diabetes, our data strongly suggest that DPP-4 inhibition plays a pivotal role in endothelial growth and may have a potential role in the recovery of local circulation following diabetic vascular complications.

  7. Involvement of reactive oxygen species in lanthanum-induced inhibition of primary root growth

    PubMed Central

    Liu, Yang-Yang; Wang, Ru-Ling; Zhang, Ping; Sun, Liang-liang; Xu, Jin

    2016-01-01

    Although lanthanum (La) has been used as an agricultural plant growth stimulant for approximately 50 years, high concentrations are toxic to plants. Despite significant advances in recent years, the mechanisms underlying the effects of La on root system development remain unclear. Here, we report that a high concentration of La inhibits primary root (PR) elongation and induces lateral root (LR) development. La results in cell death in PR tips, thereby leading to the loss of meristematic cell division potential, stem cell niche activity, and auxin distribution in PR tips. Further analysis indicated that La induces reactive oxygen species (ROS) over-accumulation in PR tips. Reduction in ROS accumulation partially alleviated the inhibitory effects of La on PR elongation by improving cell survival in PR tips and thereby improving meristematic cell division potential and auxin distribution in PR tips. We also found ROS to be involved in La-induced endocytosis. Genetic analyses supported the described phenotype. Overall, our results indicate that La affects root growth, at least partially, by modulating ROS levels in roots to induce cell death in PR tips and subsequent auxin redistribution in roots, leading to remodeling of the root system architecture. PMID:27811082

  8. A three-dimensional phase diagram of growth-induced surface instabilities

    NASA Astrophysics Data System (ADS)

    Wang, Qiming; Zhao, Xuanhe

    2015-03-01

    A variety of fascinating morphological patterns arise on surfaces of growing, developing or aging tissues, organs and microorganism colonies. These patterns can be classified into creases, wrinkles, folds, period-doubles, ridges and delaminated-buckles according to their distinctive topographical characteristics. One universal mechanism for the pattern formation has been long believed to be the mismatch strains between biological layers with different expanding or shrinking rates, which induce mechanical instabilities. However, a general model that accounts for the formation and evolution of these various surface-instability patterns still does not exist. Here, we take biological structures at their current states as thermodynamic systems, treat each instability pattern as a thermodynamic phase, and construct a unified phase diagram that can quantitatively predict various types of growth-induced surface instabilities. We further validate the phase diagram with our experiments on surface instabilities induced by mismatch strains as well as the reported data on growth-induced instabilities in various biological systems. The predicted wavelengths and amplitudes of various instability patterns match well with our experimental data. It is expected that the unified phase diagram will not only advance the understanding of biological morphogenesis, but also significantly facilitate the design of new materials and structures by rationally harnessing surface instabilities.

  9. A three-dimensional phase diagram of growth-induced surface instabilities.

    PubMed

    Wang, Qiming; Zhao, Xuanhe

    2015-03-09

    A variety of fascinating morphological patterns arise on surfaces of growing, developing or aging tissues, organs and microorganism colonies. These patterns can be classified into creases, wrinkles, folds, period-doubles, ridges and delaminated-buckles according to their distinctive topographical characteristics. One universal mechanism for the pattern formation has been long believed to be the mismatch strains between biological layers with different expanding or shrinking rates, which induce mechanical instabilities. However, a general model that accounts for the formation and evolution of these various surface-instability patterns still does not exist. Here, we take biological structures at their current states as thermodynamic systems, treat each instability pattern as a thermodynamic phase, and construct a unified phase diagram that can quantitatively predict various types of growth-induced surface instabilities. We further validate the phase diagram with our experiments on surface instabilities induced by mismatch strains as well as the reported data on growth-induced instabilities in various biological systems. The predicted wavelengths and amplitudes of various instability patterns match well with our experimental data. It is expected that the unified phase diagram will not only advance the understanding of biological morphogenesis, but also significantly facilitate the design of new materials and structures by rationally harnessing surface instabilities.

  10. STAT3 upregulation in pituitary somatotroph adenomas induces growth hormone hypersecretion.

    PubMed

    Zhou, Cuiqi; Jiao, Yonghui; Wang, Renzhi; Ren, Song-Guang; Wawrowsky, Kolja; Melmed, Shlomo

    2015-04-01

    Pituitary somatotroph adenomas result in dysregulated growth hormone (GH) hypersecretion and acromegaly; however, regulatory mechanisms that promote GH hypersecretion remain elusive. Here, we provide evidence that STAT3 directly induces somatotroph tumor cell GH. Evaluation of pituitary tumors revealed that STAT3 expression was enhanced in human GH-secreting adenomas compared with that in nonsecreting pituitary tumors. Moreover, STAT3 and GH expression were concordant in a somatotroph adenoma tissue array. Promoter and expression analysis in a GH-secreting rat cell line (GH3) revealed that STAT3 specifically binds the Gh promoter and induces transcription. Stable expression of STAT3 in GH3 cells induced expression of endogenous GH, and expression of a constitutively active STAT3 further enhanced GH production. Conversely, expression of dominant-negative STAT3 abrogated GH expression. In primary human somatotroph adenoma-derived cell cultures, STAT3 suppression with the specific inhibitor S3I-201 attenuated GH transcription and reduced GH secretion in the majority of derivative cultures. In addition, S3I-201 attenuated somatotroph tumor growth and GH secretion in a rat xenograft model. GH induced STAT3 phosphorylation and nuclear translocation, indicating a positive feedback loop between STAT3 and GH in somatotroph tumor cells. Together, these results indicate that adenoma GH hypersecretion is the result of STAT3-dependent GH induction, which in turn promotes STAT3 expression, and suggest STAT3 as a potential therapeutic target for pituitary somatotroph adenomas.

  11. Role for the Epidermal Growth Factor Receptor in Chemotherapy-Induced Alopecia

    PubMed Central

    Bichsel, Kyle J.; Gogia, Navdeep; Malouff, Timothy; Pena, Zachary; Forney, Eric; Hammiller, Brianna; Watson, Patrice; Hansen, Laura A.

    2013-01-01

    Treatment of cancer patients with chemotherapeutics like cyclophosphamide often causes alopecia as a result of premature and aberrant catagen. Because the epidermal growth factor receptor (EGFR) signals anagen hair follicles to enter catagen, we hypothesized that EGFR signaling may be involved in cyclophosphamide-induced alopecia. To test this hypothesis, skin-targeted Egfr mutant mice were generated by crossing floxed Egfr and Keratin 14 promoter-driven Cre recombinase mice. Cyclophosphamide treatment of control mice resulted in alopecia while Egfr mutant skin was resistant to cyclophosphamide-induced alopecia. Egfr mutant skin entered catagen normally, as indicated by dermal papilla condensation and decreased follicular proliferation, but did not progress to telogen as did Egfr wild type follicles. Egfr mutant follicles responded with less proliferation, apoptosis, and fewer p53-positive cells after cyclophosphamide. Treatment of control mice with the EGFR inhibitors erlotinib or gefitinib similarly suppressed alopecia and catagen progression by cyclophosphamide. Secondary analysis of clinical trials utilizing EGFR-targeted therapies and alopecia-inducing chemotherapy also revealed evidence for involvement of EGFR in chemotherapy-induced alopecia. Taken together, our results demonstrated the involvement of EGFR signaling in chemotherapy-induced alopecia, which will help in the design of novel therapeutic regimens to minimize chemotherapy-induced alopecia. PMID:23894460

  12. Nerve growth factor induced hyperalgesia in the rat hind paw is dependent on circulating neutrophils.

    PubMed

    Bennett, G; al-Rashed, S; Hoult, J R; Brain, S D

    1998-09-01

    The mechanisms by which nerve growth factor (NGF) induces thermal hyperalgesia and neutrophil accumulation have been investigated in the rat. Thermal nociceptive thresholds in rat hind paw were measured as the time taken for paw withdrawal from a heat source and neutrophil accumulation was measured in hind paw and dorsal skin samples using a myeloperoxidase assay. NGF (23-80 pmol intraplantar (i.pl.) injection) induced a significant (P < 0.05, n = 6-16) thermal hyperalgesia at 5 h after injection and significant neutrophil accumulation (P < 0.05, n = 6) was observed with NGF (40 pmol). In dorsal skin, where multiple samples can be assessed, intradermal (i.d.) NGF was 10-30 times less potent than interleukin-1beta in inducing neutrophil accumulation. The 5-lipoxygenase inhibitor ZM230487 (10 nmol co-injected with NGF) significantly attenuated neutrophil accumulation and hyperalgesia induced by NGF; unlike the histamine and 5-hydroxytryptamine antagonists (mepyramine and methysergide) which were without effect at the times measured. Furthermore, depletion of circulating neutrophils (using a rabbit anti-rat neutrophil antibody) abolished NGF induced hyperalgesia. These results indicate that neutrophils, which accumulate in response to a 5-lipoxygenase product, play a crucial role in NGF-induced hyperalgesia.

  13. Large plasma-membrane depolarization precedes rapid blue-light-induced growth inhibition in cucumber

    NASA Technical Reports Server (NTRS)

    Spalding, E. P.; Cosgrove, D. J.

    1989-01-01

    Blue-light (BL)-induced suppression of elongation of etiolated Cucumis sativus L. hypocotyls began after a 30-s lag time, which was halved by increasing the fluence rate from 10 to 100 micromoles m-2 s-1. Prior to the growth suppression, the plasma-membrane of the irradiated cells depolarized by as much as 100 mV, then returned within 2-3 min to near its initial value. The potential difference measured with surface electrodes changed with an identical time course but opposite polarity. The lag time for the change in surface potential showed an inverse dependence on fluence rate, similar to the lag for the growth inhibition. Green light and red light caused neither the electrical response nor the rapid inhibition of growth. The depolarization by BL did not propagate to nonirradiated regions and exhibited a refractory period of about 10 min following a BL pulse. Fluence-response relationships for the electrical and growth responses provide correlational evidence that the plasma-membrane depolarization reflects an event in the transduction chain of this light-growth response.

  14. Aggregate formation in a freshwater bacterial strain induced by growth state and conspecific chemical cues.

    PubMed

    Blom, Judith F; Horňák, Karel; Simek, Karel; Pernthaler, Jakob

    2010-09-01

    We investigated the induction of aggregate formation in the freshwater bacterium Sphingobium sp. strain Z007 by growth state and protistan grazing. Dialysis bag batch culture experiments were conducted in which these bacteria were grown spatially separated from bacteria or from co-cultures of bacteria and predators. In pure cultures of Sphingobium sp. strain Z007, the concentrations of single cells and aggregates inside and outside the dialysis membranes developed in a similar manner over 3 days of incubation, and the proportions of aggregates were highest during the exponential growth phase. Cell production of Sphingobium sp. strain Z007 was enhanced in the presence of another isolate, Limnohabitans planktonicus, from an abundant freshwater lineage (R-BT065) outside the bags, and even more so if that strain was additionally grazed upon by the bacterivorous flagellate Poterioochromonas sp. However, the ratios of single cells to aggregates of Sphingobium sp. strain Z007 were not affected in either case. By contrast, the feeding of flagellates on Sphingobium sp. strain Z007 outside the dialysis bags led to significantly higher proportions of aggregates inside the bags. This was not paralleled by an increase in growth rates, and all cultures were in a comparable growth state at the end of the experiment. We conclude that two mechanisms, growth state and the possible release of infochemicals by the predator, may induce aggregate formation of Sphingobium sp. strain Z007. Moreover, these infochemicals only appeared to be generated by predation on cells from the same species.

  15. Large plasma-membrane depolarization precedes rapid blue-light-induced growth inhibition in cucumber

    NASA Technical Reports Server (NTRS)

    Spalding, E. P.; Cosgrove, D. J.

    1989-01-01

    Blue-light (BL)-induced suppression of elongation of etiolated Cucumis sativus L. hypocotyls began after a 30-s lag time, which was halved by increasing the fluence rate from 10 to 100 micromoles m-2 s-1. Prior to the growth suppression, the plasma-membrane of the irradiated cells depolarized by as much as 100 mV, then returned within 2-3 min to near its initial value. The potential difference measured with surface electrodes changed with an identical time course but opposite polarity. The lag time for the change in surface potential showed an inverse dependence on fluence rate, similar to the lag for the growth inhibition. Green light and red light caused neither the electrical response nor the rapid inhibition of growth. The depolarization by BL did not propagate to nonirradiated regions and exhibited a refractory period of about 10 min following a BL pulse. Fluence-response relationships for the electrical and growth responses provide correlational evidence that the plasma-membrane depolarization reflects an event in the transduction chain of this light-growth response.

  16. Opposing functions of TFII-I spliced isoforms in growth factor-induced gene expression.

    PubMed

    Hakre, Shweta; Tussie-Luna, María Isabel; Ashworth, Todd; Novina, Carl D; Settleman, Jeffrey; Sharp, Phillip A; Roy, Ananda L

    2006-10-20

    Multifunctional transcription factor TFII-I has two spliced isoforms (Delta and beta) in murine fibroblasts. Here we show that these isoforms have distinct subcellular localization and mutually exclusive transcription functions in the context of growth factor signaling. In the absence of signaling, TFII-Ibeta is nuclear and recruited to the c-fos promoter in vivo. But upon growth factor stimulation, the promoter recruitment is abolished and it is exported out of the nucleus. Moreover, isoform-specific silencing of TFII-Ibeta results in transcriptional activation of the c-fos gene. In contrast, TFII-IDelta is largely cytoplasmic in the resting state but translocates to the nucleus upon growth factor signaling, undergoes signal-induced recruitment to the same site on the c-fos promoter, and activates the gene. Importantly, activated TFII-IDelta interacts with Erk1/2 (MAPK) kinase in the cell cytoplasm and imports the Erk1/2 to the nucleus, thereby transducing growth factor signaling. Our results identify a unique growth factor signaling pathway controlled by opposing activities of two TFII-I spliced isoforms.

  17. Developmental indices of nutritionally induced placental growth restriction in the adolescent sheep.

    PubMed

    Lea, Richard G; Hannah, Lisa T; Redmer, Dale A; Aitken, Raymond P; Milne, John S; Fowler, Paul A; Murray, Joanne F; Wallace, Jacqueline M

    2005-04-01

    Most intrauterine growth restriction cases are associated with reduced placental growth. Overfeeding adolescent ewes undergoing singleton pregnancies restricts placental growth and reduces lamb birth weight. We used this sheep model of adolescent pregnancy to investigate whether placental growth restriction is associated with altered placental cell proliferation and/or apoptosis at d 81 of pregnancy, equivalent to the apex in placental growth. Adolescent ewes with singleton pregnancies were offered a high or moderate level of a complete diet designed to induce restricted or normal placental size at term, respectively. Bromodeoxyuridine (Brd-U) was administered to H and M ewes 1 h before slaughter. Placental tissues were examined for a) Brd-U (immunohistochemistry) and b) apoptosis regulatory genes by in situ hybridization, Northern analyses (bax, mcl-1), immunohistochemistry, and Western analyses (bax). Quantification was carried out by image analysis. Total placentome weights were equivalent between groups. Brd-U predominantly localized to the trophectoderm and was significantly lower in the H group. Bax and mcl-1 mRNA were localized to the maternal-fetal interface. Bax protein was significantly increased in the H group and predominant in the uninuclear fetal trophectoderm. These observations indicate that reduced placental size at term may be due to reduced placental cell proliferation and possibly increased apoptosis occurring much earlier in gestation.

  18. Eyelash growth induced by topical prostaglandin analogues, bimatoprost, tafluprost, travoprost, and latanoprost in rabbits.

    PubMed

    Giannico, Amália Turner; Lima, Leandro; Russ, Heloisa Helena Abil; Montiani-Ferreira, Fabiano

    2013-11-01

    Prostaglandin analogues (PGA) are ocular hypotensive agents used for the treatment of glaucoma. Hypertrichosis of the eyelashes has been reported in humans as a side effect. Eyelash growth was investigated with clinical trials in people using bimatoprost. Scattered reports of eyelash growth during the treatment of glaucoma with other PGA are also found in the literature. We investigated the effect of 4 different topical PGA on eyelash length. Forty New Zealand white rabbits were divided into 4 groups and received daily topical application of bimatoprost, tafluprost, travoprost, and latanoprost in the left eye for 4 weeks. The right eye received no treatment. Eyelash length was measured in both eyes before and after treatment using a stainless steel digital caliper. Bimatoprost and tafluprost groups had significant increases in eyelash length. We did not observe significant eyelash growth in rabbits receiving travoprost and latanoprost after 1 month of treatment. Today, only bimatoprost is approved for growing eyelashes, and our research shows that tafluprost could be further explored by the cosmetic and pharmaceutical industry. Additional research using travoprost and latanoprost as agents for eyelash growth should be performed in the future using prolonged treatment periods to determine whether or not these PGA induce eyelash growth, and investigate other possible side effects.

  19. Adaptor protein p62 promotes skin tumor growth and metastasis and is induced by UVA radiation.

    PubMed

    Sample, Ashley; Zhao, Baozhong; Qiang, Lei; He, Yu-Ying

    2017-09-08

    Skin cancer is the most common cancer, and exposure to ultraviolet (UV) radiation, namely UVA and UVB, is the major risk factor for skin cancer development. UVA is significantly less effective in causing direct DNA damage than UVB, but UVA has been shown to increase skin cancer risk. The mechanism by which UVA contributes to skin cancer remains unclear. Here, using RNA-Seq, we show that UVA induces autophagy and lysosomal gene expression, including the autophagy receptor and substrate p62. We found that UVA activates transcription factor EB (TFEB), a known regulator of autophagy and lysosomal gene expression, which, in turn, induces p62 transcription. Next, we identified a novel relationship between p62 and cyclooxygenase-2 (COX-2), a prostaglandin synthase critical for skin cancer development. COX-2 expression was up-regulated by UVA-induced p62, suggesting that p62 plays a role in UVA-induced skin cancer. Moreover, we found that p62 stabilizes COX-2 protein through the p62 ubiquitin-associated domain and that p62 regulates prostaglandin E2 production in vitro In a syngeneic squamous cell carcinoma mouse model, p62 knockdown inhibited tumor growth and metastasis. Furthermore, p62-deficient tumors exhibited reduced immune cell infiltration and increased cell differentiation. Because prostaglandin E2 is known to promote pro-tumorigenic immune cell infiltration, increase proliferation, and inhibit keratinocyte differentiation in vivo, this work suggests that UVA-induced p62 acts through COX-2 to promote skin tumor growth and progression. These findings expand our understanding of UVA-induced skin tumorigenesis and tumor progression and suggest that targeting p62 can help prevent or treat UVA-associated skin cancer. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. Genetic networks inducing invasive growth in Saccharomyces cerevisiae identified through systematic genome-wide overexpression.

    PubMed

    Shively, Christian A; Eckwahl, Matthew J; Dobry, Craig J; Mellacheruvu, Dattatreya; Nesvizhskii, Alexey; Kumar, Anuj

    2013-04-01

    The budding yeast Saccharomyces cerevisiae can respond to nutritional and environmental stress by implementing a morphogenetic program wherein cells elongate and interconnect, forming pseudohyphal filaments. This growth transition has been studied extensively as a model signaling system with similarity to processes of hyphal development that are linked with virulence in related fungal pathogens. Classic studies have identified core pseudohyphal growth signaling modules in yeast; however, the scope of regulatory networks that control yeast filamentation is broad and incompletely defined. Here, we address the genetic basis of yeast pseudohyphal growth by implementing a systematic analysis of 4909 genes for overexpression phenotypes in a filamentous strain of S. cerevisiae. Our results identify 551 genes conferring exaggerated invasive growth upon overexpression under normal vegetative growth conditions. This cohort includes 79 genes lacking previous phenotypic characterization. Pathway enrichment analysis of the gene set identifies networks mediating mitogen-activated protein kinase (MAPK) signaling and cell cycle progression. In particular, overexpression screening suggests that nuclear export of the osmoresponsive MAPK Hog1p may enhance pseudohyphal growth. The function of nuclear Hog1p is unclear from previous studies, but our analysis using a nuclear-depleted form of Hog1p is consistent with a role for nuclear Hog1p in repressing pseudohyphal growth. Through epistasis and deletion studies, we also identified genetic relationships with the G2 cyclin Clb2p and phenotypes in filamentation induced by S-phase arrest. In sum, this work presents a unique and informative resource toward understanding the breadth of genes and pathways that collectively constitute the molecular basis of filamentation.

  1. A glucocorticoid-inducible gene expression system can cause growth defects in tobacco.

    PubMed

    Amirsadeghi, Sasan; McDonald, Allison E; Vanlerberghe, Greg C

    2007-07-01

    We find that an expression system widely used to chemically induce transgenes of interest in tobacco (Nicotiana tabacum Petit Havana SR1) can cause severe growth defects in this species. This gene expression system has been shown to cause non-specific effects (including growth retardation) in other plant species, but has until now been largely accepted to be a relatively problem-free system for use in tobacco. The expression system is based on the ability of the glucocorticoid dexamethasone (DEX) to activate a non-plant chimeric transcription factor (GVG), which then activates expression of a transgene of interest. The aberrant growth phenotype only manifests itself after DEX application and only occurs in plants in which the constitutive levels of GVG expression are higher than average. We found that approximately 30% of all transgenic plants produced showed some level of growth retardation under our standard growth conditions. However, by modulating irradiance levels following DEX application, we also showed that the manifestation and severity of the aberrant phenotype is highly dependent upon growth conditions, highlighting that such conditions are a critical parameter to consider during all stages of using this gene expression system. We also identified an increase in ACC oxidase gene expression as an early, sensitive and robust molecular marker for the aberrant phenotype. This molecular marker should be valuable to investigators wishing to readily identify transgenic plants in which GVG expression levels are beyond a threshold that begins to produce non-specific effects of the gene expression system under a defined set of growth conditions.

  2. Bone quality is affected by food restriction and by nutrition-induced catch-up growth.

    PubMed

    Pando, Rakefet; Masarwi, Majdi; Shtaif, Biana; Idelevich, Anna; Monsonego-Ornan, Efrat; Shahar, Ron; Phillip, Moshe; Gat-Yablonski, Galia

    2014-12-01

    Growth stunting constitutes the most common effect of malnutrition. When the primary cause of malnutrition is resolved, catch-up (CU) growth usually occurs. In this study, we have explored the effect of food restriction (RES) and refeeding on bone structure and mechanical properties. Sprague-Dawley male rats aged 24 days were subjected to 10 days of 40% RES, followed by refeeding for 1 (CU) or 26 days long-term CU (LTCU). The rats fed ad libitum served as controls. The growth plates were measured, osteoclasts were identified using tartrate-resistant acid phosphatase staining, and micro-computed tomography (CT) scanning and mechanical testing were used to study structure and mechanical properties. Micro-CT analysis showed that RES led to a significant reduction in trabecular BV/TV and trabecular number (Tb.N), concomitant with an increase in trabecular separation (Tb.Sp). Trabecular BV/TV and Tb.N were significantly greater in the CU group than in the RES in both short- and long-term experiments. Mechanical testing showed that RES led to weaker and less compliant bones; interestingly, bones of the CU group were also more fragile after 1 day of CU. Longer term of refeeding enabled correction of the bone parameters; however, LTCU did not achieve full recovery. These results suggest that RES in young rats attenuated growth and reduced trabecular bone parameters. While nutrition-induced CU growth led to an immediate increase in epiphyseal growth plate height and active bone modeling, it was also associated with a transient reduction in bone quality. This should be taken into consideration when treating children undergoing CU growth. © 2014 Society for Endocrinology.

  3. Topical Application of Oleuropein Induces Anagen Hair Growth in Telogen Mouse Skin

    PubMed Central

    Tong, Tao; Kim, Nahyun; Park, Taesun

    2015-01-01

    We observed that oleuropein, the main constituent of the leaves and unprocessed olive drupes of Olea europaea, protected mice from high-fat diet-induced adiposity by up-regulation of genes involved in Wnt10b-mediated signaling in adipose tissue. The activation of Wnt/β-catenin pathway is also well established to positively regulate the anagen phase of hair growth cycle in mice skin. Methodology and Principal Findings Oleuropein promoted cultured human follicle dermal papilla cell proliferation and induced LEF1 and Cyc-D1 mRNA expression and β-catenin protein expression in dermal papilla cells. Nuclear accumulation of β-catenin in dermal papilla cells was observed after oleuropein treatment. Topical application of oleuropein (0.4 mg/mouse/day) to C57BL/6N mice accelerated the hair-growth induction and increased the size of hair follicles in telogenic mouse skin. The oleuropein-treated mouse skin showed substantial upregulation of Wnt10b, FZDR1, LRP5, LEF1, Cyc-D1, IGF-1, KGF, HGF, and VEGF mRNA expression and β-catenin protein expression. Conclusions and Significance These results demonstrate that topical oleuroepin administration induced anagenic hair growth in telogenic C57BL/6N mouse skin. The hair-growth promoting effect of oleuropein in mice appeared to be associated with the stimulation of the Wnt10b/β-catenin signaling pathway and the upregulation of IGF-1, KGF, HGF, and VEGF gene expression in mouse skin tissue. PMID:26060936

  4. Chronic kidney disease induced by adenine: a suitable model of growth retardation in uremia.

    PubMed

    Claramunt, Débora; Gil-Peña, Helena; Fuente, Rocío; García-López, Enrique; Loredo, Vanessa; Hernández-Frías, Olaya; Ordoñez, Flor A; Rodríguez-Suárez, Julián; Santos, Fernando

    2015-07-01

    Growth retardation is a major manifestation of chronic kidney disease (CKD) in pediatric patients. The involvement of the various pathogenic factors is difficult to evaluate in clinical studies. Here, we present an experimental model of adenine-induced CKD for the study of growth failure. Three groups (n = 10) of weaning female rats were studied: normal diet (control), 0.5% adenine diet (AD), and normal diet pair fed with AD (PF). After 21 days, serum urea nitrogen, creatinine, parathyroid hormone (PTH), weight and length gains, femur osseous front advance as an index of longitudinal growth rate, growth plate histomorphometry, chondrocyte proliferative activity, bone structure, aorta calcifications, and kidney histology were analyzed. Results are means ± SE. AD rats developed renal failure (serum urea nitrogen: 70 ± 6 mg/dl and creatinine: 0.6 ± 0.1 mg/dl) and secondary hyperparathyroidism (PTH: 480 ± 31 pg/ml). Growth retardation of AD rats was demonstrated by lower weight (AD rats: 63.3 ± 4.8 g, control rats: 112.6 ± 4.7 g, and PF rats: 60.0 ± 3.8 g) and length (AD rats: 7.2 ± 0.2 cm, control rats: 11.1 ± 0.3 cm, and PF rats: 8.1 ± 0.3 cm) gains as well as lower osseous front advances (AD rats: 141 ± 13 μm/day, control rats: 293 ± 16 μm/day, and PF rats: 251 ± 10 μm/day). The processes of chondrocyte maturation and proliferation were impaired in AD rats, as shown by lower growth plate terminal chondrocyte height (21.7 ± 2.3 vs. 26.2 ± 1.9 and 23.9 ± 1.3 μm in control and PF rats) and proliferative activity index (AD rats: 30 ± 2%, control rats: 38 ± 2%, and PF rats: 42 ± 3%). The bone primary spongiosa structure of AD rats was markedly disorganized. In conclusion, adenine-induced CKD in young rats is associated with growth retardation and disturbed endochondral ossification. This animal protocol may be a useful new experimental model to study growth in CKD. Copyright © 2015 the American Physiological Society.

  5. Laminin-511, inducer of hair growth, is down-regulated and its suppressor in hair growth, laminin-332 up-regulated in chemotherapy-induced alopecia

    PubMed Central

    Imanishi, Hisayoshi; Tsuruta, Daisuke; Tateishi, Chiharu; Sugawara, Koji; Paus, Ralf; Tsuji, Tsutomu; Ishii, Masamitsu; Ikeda, Kazuo; Kunimoto, Hiroyuki; Nakajima, Koichi; Jones, Jonathan C.R.; Kobayashi, Hiromi

    2010-01-01

    Background Chemotherapy-induced alopecia (CIA) has a devastating cosmetic effect, especially in the young. Recent data indicate that two major basement membrane components (laminin-332 and -511) of the skin have opposing effects on hair growth. Objective In this study, we examined the role and localization of laminin-332 and -511 in CIA. Methods We examined the expression of laminin-332 and -511 during the dystrophic catagen form of CIA induced in C57BL/6 mice by cyclophosphamide (CYP) treatment. Results Our data indicate that both laminin-332 and its receptor α6β4 integrin are up-regulated (both quantitatively and spatially) after mid to late dystrophic catagen around the outer root sheath (ORS) in the lower third of hair follicles in CIA. This up-regulation also occurs at the transcriptional level. In contrast, laminin-511 is down-regulated after mid dystrophic catagen at the protein level, with transcriptional inactivation of laminin-511 occurring transiently at the early dystrophic catagen stage in both epidermal and ORS keratinocytes. Laminin-511 expression correlates with expression of α3 integrin in CIA and we also demonstrate that laminin-511 can up-regulate the activity of the α3 integrin promoter in cultured keratinocytes. Injection of a laminin-511 rich protein extract, but not recombinant laminin-332, in the back skin of mice delays hair loss in CYP-induced CIA. Conclusions We propose that abrupt hair loss in CIA is, at least in part, caused by down-regulation of laminin-511 and up-regulation of laminin-332 at the transcriptional and translational levels. PMID:20211547

  6. Laminin-511, inducer of hair growth, is down-regulated and its suppressor in hair growth, laminin-332 up-regulated in chemotherapy-induced alopecia.

    PubMed

    Imanishi, Hisayoshi; Tsuruta, Daisuke; Tateishi, Chiharu; Sugawara, Koji; Paus, Ralf; Tsuji, Tsutomu; Ishii, Masamitsu; Ikeda, Kazuo; Kunimoto, Hiroyuki; Nakajima, Koichi; Jones, Jonathan C R; Kobayashi, Hiromi

    2010-04-01

    Chemotherapy-induced alopecia (CIA) has a devastating cosmetic effect, especially in the young. Recent data indicate that two major basement membrane components (laminin-332 and -511) of the skin have opposing effects on hair growth. In this study, we examined the role and localization of laminin-332 and -511 in CIA. We examined the expression of laminin-332 and -511 during the dystrophic catagen form of CIA induced in C57BL/6 mice by cyclophosphamide (CYP) treatment. Our data indicate that both laminin-332 and its receptor alpha 6 beta 4 integrin are up-regulated (both quantitatively and spatially) after mid to late dystrophic catagen around the outer root sheath (ORS) in the lower third of hair follicles in CIA. This up-regulation also occurs at the transcriptional level. In contrast, laminin-511 is down-regulated after mid dystrophic catagen at the protein level, with transcriptional inactivation of laminin-511 occurring transiently at the early dystrophic catagen stage in both epidermal and ORS keratinocytes. Laminin-511 expression correlates with expression of alpha 3 integrin in CIA and we also demonstrate that laminin-511 can up-regulate the activity of the alpha 3 integrin promoter in cultured keratinocytes. Injection of a laminin-511 rich protein extract, but not recombinant laminin-332, in the back skin of mice delays hair loss in CYP-induced CIA. We propose that abrupt hair loss in CIA is, at least in part, caused by down-regulation of laminin-511 and up-regulation of laminin-332 at the transcriptional and translational levels. (c) 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  7. Midazolam Induces Cellular Apoptosis in Human Cancer Cells and Inhibits Tumor Growth in Xenograft Mice

    PubMed Central

    Mishra, Siddhartha Kumar; Kang, Ju-Hee; Lee, Chang Woo; Oh, Seung Hyun; Ryu, Jun Sun; Bae, Yun Soo; Kim, Hwan Mook

    2013-01-01

    Midazolam is a widely used anesthetic of the benzodiazepine class that has shown cytotoxicity and apoptosis-inducing activity in neuronal cells and lymphocytes. This study aims to evaluate the effect of midazolam on growth of K562 human leukemia cells and HT29 colon cancer cells. The in vivo effect of midazolam was investigated in BALB/c-nu mice bearing K562 and HT29 cells human tumor xenografts. The results show that midazolam decreased the viability of K562 and HT29 cells by inducing apoptosis and S phase cell-cycle arrest in a concentration-dependent manner. Midazolam activated caspase-9, capspase-3 and PARP indicating induction of the mitochondrial intrinsic pathway of apoptosis. Midazolam lowered mitochondrial membrane potential and increased apoptotic DNA fragmentation. Midazolam showed reactive oxygen species (ROS) scavenging activity through inhibition of NADPH oxidase 2 (Nox2) enzyme activity in K562 cells. Midazolam caused inhibition of pERK1/2 signaling which led to inhibition of the anti-apoptotic proteins Bcl-XL and XIAP and phosphorylation activation of the pro-apoptotic protein Bid. Midazolam inhibited growth of HT29 tumors in xenograft mice. Collectively our results demonstrate that midazolam caused growth inhibition of cancer cells via activation of the mitochondrial intrinsic pathway of apoptosis and inhibited HT29 tumor growth in xenograft mice. The mechanism underlying these effects of midazolam might be suppression of ROS production leading to modulation of apoptosis and growth regulatory proteins. These findings present possible clinical implications of midazolam as an anesthetic to relieve pain during in vivo anticancer drug delivery and to enhance anticancer efficacy through its ROS-scavenging and pro-apoptotic properties. PMID:24008365

  8. Orexin Plays a Role in Growth Impediment Induced by Obstructive Sleep Breathing in Rats.

    PubMed

    Tarasiuk, Ariel; Levi, Avishag; Assadi, Mohammad H; Troib, Ariel; Segev, Yael

    2016-04-01

    The mechanisms linking sleep disordered breathing with impairment of sleep and bone metabolism/architecture are poorly understood. Here, we explored the role of the neuropeptide orexin, a respiratory homeostasis modulator, in growth retardation induced in an upper airway obstructed (AO) rat model. The tracheae of 22-day-old rats were narrowed; AO and sham-control animals were monitored for 5 to 7 w. Growth parameters, food intake, sleep/wake activity, and serum hormones were measured. After euthanasia, growth plate (GP) histology, morphometry, orexin receptors (OXR), and related mediators were analyzed. The effect of dual orexin receptor antagonist (almorexant 300 mg/kg) on sleep and GP histology were also investigated. The AO group slept 32% less; the time spent in slow wave and paradoxical sleep during light period and slow wave activity was reduced. The AO group gained 46% less body weight compared to the control group, despite elevated food intake; plasma ghrelin increased by 275% and leptin level decreased by 44%. The impediment of bone elongation and bone mass was followed by a 200% increase in OX1R and 38% reduction of local GP ghrelin proteins and growth hormone secretagogue receptor 1a. Sry-related transcription factor nine (Sox9), a molecule mediating cartilage ossification, was downregulated and the level of transcription factor peroxisome proliferator-activated receptor gamma was upregulated, explaining the bone architecture abnormalities. Administration of almorexant restored sleep and improved GP width in AO animals. In AO animals, enhanced expression of orexin and OX1R plays a role in respiratory induced sleep and growth abnormalities. © 2016 Associated Professional Sleep Societies, LLC.

  9. Elastase induced lung epithelial cell apoptosis and emphysema through placenta growth factor

    PubMed Central

    Hou, H-H; Cheng, S-L; Liu, H-T; Yang, F-Z; Wang, H-C; Yu, C-J

    2013-01-01

    Chronic pulmonary obstructive disease (COPD) is the fourth leading cause of death worldwide, however, the pathogenic factors and mechanisms are not fully understood. Pulmonary emphysema is one of the major components of COPD and is thought to result from oxidative stress, chronic inflammation, protease–antiprotease imbalance and lung epithelial (LE) cell apoptosis. In our previous studies, COPD patients were noted to have higher levels of placenta growth factor (PlGF) in serum and bronchoalveolar lavage fluid than controls. In addition, transgenic mice overexpressing PlGF developed pulmonary emphysema and exposure to PlGF in LE cells induced apoptosis. Furthermore, intratracheal instillation of porcine pancreatic elastase (PPE) on to PlGF wild type mice induced emphysema, but not in PlGF knockout mice. Therefore, we hypothesized that PPE generates pulmonary emphysema through the upregulation of PlGF expression in LE cells. The elevation of PlGF then leads to LE cell apoptosis. In the present study, we investigated whether PPE induces PlGF expression, whether PlGF induces apoptosis and whether the downstream mechanisms of PlGF are related to LE cell apoptosis. We found that PPE increased PlGF secretion and expression both in vivo and in vitro. Moreover, PlGF-induced LE cell apoptosis and PPE-induced emphysema in the mice were mediated by c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) pathways. Given these findings, we suggest that the increase in PlGF and PlGF-induced JNK and p38 MAPK pathways contribute to PPE-induced LE cell apoptosis and emphysema. Regulatory control of PlGF and agents against its downstream signals may be potential therapeutic targets for COPD. PMID:24008737

  10. Accommodating the cost of growth and swimming in fish—the applicability of exercise-induced growth to juvenile hapuku (Polyprion oxygeneios)

    PubMed Central

    Khan, Javed R.; Trembath, Caroline; Pether, Steve; Bruce, Michael; Walker, Seumas P.; Herbert, Neill A.

    2014-01-01

    Induced-swimming can improve the growth and feed conversion efficiency of finfish aquaculture species, such as salmonids and Seriola sp., but some species, such as Atlantic cod, show no or a negative productivity response to exercise. As a possible explanation for these species-specific differences, a recent hypothesis proposed that the applicability of exercise training, as well as the exercise regime for optimal growth gain (ERopt growth), was dependent upon the size of available aerobic metabolic scope (AMS). This study aimed to test this hypothesis by measuring the growth and swimming metabolism of hapuku, Polyprion oxygeneios, to different exercise regimes and then reconciling the metabolic costs of swimming and specific dynamic action (SDA) against AMS. Two 8-week growth trials were conducted with ERs of 0.0, 0.25, 0.5, 0.75, 1, and 1.5 body lengths per second (BL s−1). Fish in the first trial showed a modest 4.8% increase in SGR over static controls in the region 0.5–0.75 BL s−1 whereas the fish in trial 2 showed no significant effect of ER on growth performance. Reconciling the SDA of hapuku with the metabolic costs of swimming showed that hapuku AMS is sufficient to support growth and swimming at all ERs. The current study therefore suggests that exercise-induced growth is independent of AMS and is driven by other factors. PMID:25520662

  11. CXCR2 signaling regulates KRAS(G12D)-induced autocrine growth of pancreatic cancer

    PubMed Central

    Purohit, Abhilasha; Varney, Michelle; Rachagani, Satyanarayana; Ouellette, Michel M.; Batra, Surinder K.; Singh, Rakesh K.

    2016-01-01

    Pharmacological inhibition of RAS, the master regulator of pancreatic ductal adenocarcinoma (PDAC), continues to be a challenge. Mutations in various isoforms of RAS gene, including KRAS are known to upregulate CXC chemokines; however, their precise role in KRAS-driven pancreatic cancer remains unclear. In this report, we reveal a previously unidentified tumor cell-autonomous role of KRAS(G12D)-induced CXCR2 signaling in mediating growth of neoplastic PDAC cells. Progressively increasing expression of mCXCR2 and its ligands was detected in the malignant ductal cells of Pdx1-cre;LSL-Kras(G12D) mice. Knocking-down CXCR2 in KRAS(G12D)-bearing human pancreatic duct-derived cells demonstrated a significant decrease in the in vitro and in vivo tumor cell proliferation. Furthermore, CXCR2 antagonists showed selective growth inhibition of KRAS(G12D)-bearing cells in vitro. Intriguingly, both genetic and pharmacological inhibition of CXCR2 signaling in KRAS(G12D)-bearing pancreatic ductal cells reduced the levels of KRAS protein, strongly implying the presence of a KRAS-CXCR2 feed-forward loop. Together, these data demonstrate the role of CXCR2 signaling in KRAS(G12D)-induced growth transformation and progression in PDAC. PMID:26771140

  12. Puerariae radix isoflavones and their metabolites inhibit growth and induce apoptosis in breast cancer cells

    SciTech Connect

    Lin, Y.-J.; Hou, Y.C.; Lin, C.-H.; Hsu, Y.-A.; Sheu, Jim J.C.; Lai, C.-H.; Chen, B.-H.; Lee Chao, Pei-Dawn; Wan Lei Tsai, F.-J.

    2009-01-23

    Puerariae radix (PR) is a popular natural herb and a traditional food in Asia, which has antithrombotic and anti-allergic properties and stimulates estrogenic activity. In the present study, we investigated the effects of the PR isoflavones puerarin, daidzein, and genistein on the growth of breast cancer cells. Our data revealed that after treatment with PR isoflavones, a dose-dependent inhibition of cell growth occurred in HS578T, MDA-MB-231, and MCF-7 cell lines. Results from cell cycle distribution and apoptosis assays revealed that PR isoflavones induced cell apoptosis through a caspase-3-dependent pathway and mediated cell cycle arrest in the G2/M phase. Furthermore, we observed that the serum metabolites of PR (daidzein sulfates/glucuronides) inhibited proliferation of the breast cancer cells at a 50% cell growth inhibition (GI{sub 50}) concentration of 2.35 {mu}M. These results indicate that the daidzein constituent of PR can be metabolized to daidzein sulfates or daidzein glucuronides that exhibit anticancer activities. The protein expression levels of the active forms of caspase-9 and Bax in breast cancer cells were significantly increased by treatment with PR metabolites. These metabolites also increased the protein expression levels of p53 and p21. We therefore suggest that PR may act as a chemopreventive and/or chemotherapeutic agent against breast cancer by reducing cell viability and inducing apoptosis.

  13. Bacterial sensing underlies artificial sweetener-induced growth of gut Lactobacillus.

    PubMed

    Daly, Kristian; Darby, Alistair C; Hall, Neil; Wilkinson, Mark C; Pongchaikul, Pisut; Bravo, David; Shirazi-Beechey, Soraya P

    2016-07-01

    Disruption in stable establishment of commensal gut microbiota by early weaning is an important factor in susceptibility of young animals to enteric disorders. The artificial sweetener SUCRAM [consisting of neohesperidin dihydrochalcone (NHDC) and saccharin] included in piglets' feed reduces incidence of enteric disease. Pyrosequencing of pig caecal 16S rRNA gene amplicons identified 25 major families encompassing seven bacterial classes with Bacteroidia, Clostridia and Bacilli dominating the microbiota. There were significant shifts in microbial composition in pigs maintained on a diet containing SUCRAM, establishing SUCRAM as a major influence driving bacterial community dynamics. The most notable change was a significant increase of Lactobacillaceae population abundance, almost entirely due to a single phylotype, designated Lactobacillus 4228. The sweetener-induced increase in Lactobacillaceae was observed in two different breeds of pigs signifying a general effect. We isolated Lactobacillus 4228, sequenced its genome and found it to be related to Lactobacillus amylovorus. In vitro analyses of Lactobacillus 4228 growth characteristics showed that presence of NHDC significantly reduces the lag phase of growth and enhances expression of specific sugar transporters, independently of NHDC metabolism. This study suggests that sensing of NHDC by a bacterial plasma membrane receptor underlies sweetener-induced growth of a health promoting gut bacterium. © 2015 Society for Applied Microbiology and John Wiley & Sons Ltd.

  14. Role of circulating Fibroblast Growth Factor-2 in lipopolysaccharide-induced acute kidney injury in mice

    PubMed Central

    Mattison, Parnell C.; Soler-García, Ángel A.; Das, Jharna R.; Jerebtsova, Marina; Perazzo, Sofia; Tang, Pingtao; Ray, Patricio E.

    2011-01-01

    Background Fibroblast Growth Factor (FGF-2) is an angiogenic growth factor involved in renal growth and regeneration. Previous studies in rodents showed that single intrarenal injections of FGF-2 improved the outcome of acute kidney injury (AKI). Septic children usually show elevated plasma levels of FGF-2, and are at risk of developing AKI. However, the role of circulating FGF-2 in the pathogenesis of AKI is not well understood. Methods Here, we developed a mouse model to determine how FGF-2 released into the circulation modulates the outcome of AKI induced by lipopolysaccharide (LPS). Young FVB/N mice were infected with adenoviruses carrying a secreted form of human FGF-2 or control LacZ vectors. Subsequently, when the circulating levels of FGF-2 were similar to those seen in septic children, mice were injected with a non-lethal dose of LPS or control buffer. Results All mice injected with LPS developed hypotension and AKI, and recovered after five days. FGF-2 did not improve the outcome of AKI, and induced more significant renal proliferative and apoptotic changes during the recovery phase. Conclusions These findings suggest that circulating FGF-2 may not necessarily prevent the development or improve the outcome of AKI. Moreover, the renal accumulation of FGF-2 might cause further renal damage. PMID:21959768

  15. Electromigration induced Kirkendall void growth in Sn-3.5Ag/Cu solder joints

    SciTech Connect

    Jung, Yong; Yu, Jin

    2014-02-28

    Effects of electric current flow on the Kirkendall void formation at solder joints were investigated using Sn-3.5Ag/Cu joints specially designed to have localized nucleation of Kirkendall voids at the Cu{sub 3}Sn/Cu interface. Under the current density of 1 × 10{sup 4} A/cm{sup 2}, kinetics of Kirkendall void growth and intermetallic compound thickening were affected by the electromigration (EM), and both showed the polarity effect. Cu{sub 6}Sn{sub 5} showed a strong susceptibility to the polarity effect, while Cu{sub 3}Sn did not. The electromigration force induced additional tensile (or compressive) stress at the cathode (or anode), which accelerated (or decelerated) the void growth. From the measurements of the fraction of void at the Cu{sub 3}Sn/Cu interface on SEM micrographs and analysis of the kinetics of void growth, the magnitude of the local stress induced by EM was estimated to be 9 MPa at the anode and −7 MPa at the cathode.

  16. Influence of selenium on the growth of N-nitrosomethylurea-induced mammary tumor cells in culture

    SciTech Connect

    Lewko, W.M.; McConnell, K.P.

    1985-10-01

    Selenium is an essential dietary trace element which has anticancer properties. Among its effects in rats, selenium has been shown to inhibit the development of carcinogen-induced mammary tumors by interfering with the post-initiation, promotion phase of carcinogenesis. We studied the effects of selenium on the growth of rat mammary tumor cells in primary culture. The objective was to determine whether selenium had any direct influence on cell growth which might explain its influence on tumor development. Rat mammary tumors were induced by N-nitrosomethylurea. The addition of low concentrations of sodium selenite, less than 1.0 ..mu..g/ml, stimulated tumor cell proliferation. Protein synthesis and the production of type IV collagen increased within the first hour of exposure, prior to any measurable increase in DNA synthesis. Concentrations of selenite greater than 1.0 ..mu..g/ml inhibited cell proliferation, the synthesis of protein, and the replication of DNA in a dose-related manner. These studies demonstrated that selenium has the potential to influence the post-initiation phase of rat mammary tumorigenesis by directly altering the growth of tumor cells, possibly through the regulation of protein synthesis.

  17. Thyroid hormone and estrogen regulate exercise-induced growth hormone release.

    PubMed

    Ignacio, Daniele Leão; da S Silvestre, Diego H; Cavalcanti-de-Albuquerque, João Paulo Albuquerque; Louzada, Ruy Andrade; Carvalho, Denise P; Werneck-de-Castro, João Pedro

    2015-01-01

    Growth hormone (GH) regulates whole body metabolism, and physical exercise is the most potent stimulus to induce its secretion in humans. The mechanisms underlying GH secretion after exercise remain to be defined. The aim of this study was to elucidate the role of estrogen and pituitary type 1 deiodinase (D1) activation on exercise-induced GH secretion. Ten days after bilateral ovariectomy, animals were submitted to 20 min of treadmill exercise at 75% of maximum aerobic capacity and tissues were harvested immediately or 30 min after exercise. Non-exercised animals were used as controls. A significant increase in D1 activity occurred immediately after exercise (~60%) in sham-operated animals and GH was higher (~6-fold) 30 min after exercise. Estrogen deficient rats exhibited basal levels of GH and D1 activity comparable to those found in control rats. However, after exercise both D1 activity and serum GH levels were blunted compared to sedentary rats. To understand the potential cause-effect of D1 activation in exercise-induced GH release, we pharmacologically blocked D1 activity by propylthiouracil (PTU) injection into intact rats and submitted them to the acute exercise session. D1 inhibition blocked exercise-induced GH secretion, although basal levels were unaltered. In conclusion, estrogen deficiency impairs the induction of thyroid hormone activating enzyme D1 in the pituitary, and GH release by acute exercise. Also, acute D1 activation is essential for exercise-induced GH response.

  18. Thyroid Hormone and Estrogen Regulate Exercise-Induced Growth Hormone Release

    PubMed Central

    Ignacio, Daniele Leão; da S. Silvestre, Diego H.; Cavalcanti-de-Albuquerque, João Paulo Albuquerque; Louzada, Ruy Andrade

    2015-01-01

    Growth hormone (GH) regulates whole body metabolism, and physical exercise is the most potent stimulus to induce its secretion in humans. The mechanisms underlying GH secretion after exercise remain to be defined. The aim of this study was to elucidate the role of estrogen and pituitary type 1 deiodinase (D1) activation on exercise-induced GH secretion. Ten days after bilateral ovariectomy, animals were submitted to 20 min of treadmill exercise at 75% of maximum aerobic capacity and tissues were harvested immediately or 30 min after exercise. Non-exercised animals were used as controls. A significant increase in D1 activity occurred immediately after exercise (~60%) in sham-operated animals and GH was higher (~6-fold) 30 min after exercise. Estrogen deficient rats exhibited basal levels of GH and D1 activity comparable to those found in control rats. However, after exercise both D1 activity and serum GH levels were blunted compared to sedentary rats. To understand the potential cause-effect of D1 activation in exercise-induced GH release, we pharmacologically blocked D1 activity by propylthiouracil (PTU) injection into intact rats and submitted them to the acute exercise session. D1 inhibition blocked exercise-induced GH secretion, although basal levels were unaltered. In conclusion, estrogen deficiency impairs the induction of thyroid hormone activating enzyme D1 in the pituitary, and GH release by acute exercise. Also, acute D1 activation is essential for exercise-induced GH response. PMID:25874614

  19. Flavonoids from the leaves of Carya cathayensis Sarg. inhibit vascular endothelial growth factor-induced angiogenesis.

    PubMed

    Tian, Sha-Sha; Jiang, Fu-Sheng; Zhang, Kun; Zhu, Xue-Xin; Jin, Bo; Lu, Jin-Jian; Ding, Zhi-Shan

    2014-01-01

    The total flavonoids (TFs) were isolated from the leaves of Carya cathayensis Sarg. (LCC), a well-known Chinese medicinal herb commercially cultivated in Tianmu Mountain district, a cross area of Zhejiang and Anhui provinces in China. Five flavonoids, i.e. cardamonin, pinostrobin chalcone (PC), wogonin, chrysin, and pinocembrin were the main components of the TFs. The TFs and these pure compounds suppressed vascular endothelial growth factor (VEGF)-induced angiogenesis as detected in the mouse aortic ring assay, and cardamonin showed the best effect among them. To further elucidate the mechanisms for suppressing angiogenesis of these flavonoids, assays of VEGF-induced proliferation and migration in human umbilical vein endothelial cells (HUVECs) were performed. The TFs, cardamonin, pinocembrin, and chrysin obviously suppressed both VEGF-induced HUVEC proliferation and migration. However, PC and wogonin not only slightly inhibited VEGF-induced proliferation but also remarkably suppressed those of migration in HUVECs. Our further study showed that cardamonin decreased the phosphorylation of ERK and AKT induced by VEGF with a dose-dependent manner in HUVECs. Our findings indicate that the TFs and these pure flavonoids may become potential preventive and/or therapeutic agents against angiogenesis-related diseases.

  20. Curcumin Inhibits Transforming Growth Factor β Induced Differentiation of Mouse Lung Fibroblasts to Myofibroblasts

    PubMed Central

    Liu, Daishun; Gong, Ling; Zhu, Honglan; Pu, Shenglan; Wu, Yang; Zhang, Wei; Huang, Guichuan

    2016-01-01

    Transforming growth factor β (TGF-β) induced differentiation of lung fibroblasts to myofibroblasts is a key event in the pathogenesis of pulmonary fibrosis. This study aimed to evaluate the effect of curcumin on TGF-β induced differentiation of lung fibroblasts to myofibroblasts and explore the underlying mechanism. Mouse lung fibroblasts were cultured and treated with TGF-β2 and curcumin or rosiglitazone. Cell vitality was examined by MTT assay. The secretion of collagen-1 was assessed by ELISA. α smooth muscle actin (α-SMA) was visualized by immunofluorescence technique. The expression of peroxisome proliferator activated receptor γ (PPAR-γ) and platelet derived growth factor R β (PDGFR-β) was detected by PCR and Western blot analysis. We found that curcumin and rosiglitazone inhibited the proliferation and TGF-β induced differentiation of mouse lung fibroblasts. In addition, curcumin and rosiglitazone inhibited collagen-1 secretion and α-SMA expression in mouse lung fibroblasts. Furthermore, curcumin and rosiglitazone upregulated PPAR-γ and downregulated PDGFR-β expression in mouse lung fibroblasts. In conclusion, our study reveals novel mechanism by which curcumin inhibits TGF-β2 driven differentiation of lung fibroblasts to myofibroblasts. Curcumin could potentially be used for effective treatment of pulmonary fibrosis. PMID:27877129

  1. Bone-induced c-kit expression in prostate cancer: a driver of intraosseous tumor growth.

    PubMed

    Mainetti, Leandro E; Zhe, Xiaoning; Diedrich, Jonathan; Saliganan, Allen D; Cho, Won Jin; Cher, Michael L; Heath, Elisabeth; Fridman, Rafael; Kim, Hyeong-Reh Choi; Bonfil, R Daniel

    2015-01-01

    Loss of BRCA2 function stimulates prostate cancer (PCa) cell invasion and is associated with more aggressive and metastatic tumors in PCa patients. Concurrently, the receptor tyrosine kinase c-kit is highly expressed in skeletal metastases of PCa patients and induced in PCa cells placed into the bone microenvironment in experimental models. However, the precise requirement of c-kit for intraosseous growth of PCa and its relation to BRCA2 expression remain unexplored. Here, we show that c-kit expression promotes migration and invasion of PCa cells. Alongside, we found that c-kit expression in PCa cells parallels BRCA2 downregulation. Gene rescue experiments with human BRCA2 transgene in c-kit-transfected PCa cells resulted in reduction of c-kit protein expression and migration and invasion, suggesting a functional significance of BRCA2 downregulation by c-kit. The inverse association between c-kit and BRCA2 gene expressions in PCa cells was confirmed using laser capture microdissection in experimental intraosseous tumors and bone metastases of PCa patients. Inhibition of bone-induced c-kit expression in PCa cells transduced with lentiviral short hairpin RNA reduced intraosseous tumor incidence and growth. Overall, our results provide evidence of a novel pathway that links bone-induced c-kit expression in PCa cells to BRCA2 downregulation and supports bone metastasis.

  2. Epidermal growth factor receptor expression in radiation-induced dog lung tumors by immunocytochemical localization

    SciTech Connect

    Leung, F.L.; Park, J.F.; Dagle, G.E.

    1993-06-01

    In studies to determine the role of growth factors in radiation-induced lung cancer, epidermal growth factor (EGFR) expression was examined by immunocytochemistry in 51 lung tumors from beagle dogs exposed to inhaled plutonium; 21 of 51 (41%) tumors were positive for EGFR. The traction of tumors positive for EGFR and the histological type of EGFR-positive tumors in the plutonium-exposed dogs were not different from spontaneous dog lung tumors, In which 36% were positive for EGFR. EGFR involvement in Pu-induced lung tumors appeared to be similar to that in spontaneous lung tumors. However, EGFR-positive staining was observed in only 1 of 16 tumors at the three lowest Pu exposure levels, compared to 20 of 35 tumors staining positive at the two highest Pu exposure levels. The results in dogs were in good agreement with the expression of EGFR reported in human non-small cell carcinoma of the lung, suggesting that Pu-induced lung tumors in the dog may be a suitable animal model to investigate the role of EGFR expression in lung carcinogenesis. In humans, EGFR expression in lung tumors has been primarily related to histological tumor types. In individual dogs with multiple primary lung tumors, the tumors were either all EGFR positive or EGFR negative, suggesting that EGFR expression may be related to the response of the individual dog as well as to the histological type of tumor.

  3. Retinoic acid induces neurite outgrowth and growth cone turning in invertebrate neurons.

    PubMed

    Dmetrichuk, Jennifer M; Carlone, Robert L; Spencer, Gaynor E

    2006-06-01

    Identification of molecules involved in neurite outgrowth during development and/or regeneration is a major goal in the field of neuroscience. Retinoic acid (RA) is a biologically important metabolite of vitamin A that acts as a trophic factor and has been implicated in neurite outgrowth and regeneration in many vertebrate species. Although abundant in the CNS of many vertebrates, the precise role of RA in neural regeneration has yet to be determined. Moreover, very little information is available regarding the role of RA in invertebrate nervous systems. Here, we demonstrate for the first time that RA induces neurite outgrowth from invertebrate neurons. Using individually identified neurons isolated from the CNS of Lymnaea stagnalis, we demonstrated that a significantly greater proportion of cells produced neurite outgrowth in RA. RA also extended the duration of time that cells remained electrically excitable in vitro, and we showed that exogenously applied RA acted as a chemoattractive factor and induced growth cone turning toward the source of RA. This is the first demonstration that RA can induce turning of an individual growth cone. These data strongly suggest that the actions of RA on neurite outgrowth and cell survival are highly conserved across species.

  4. Ethanol-induced loss of brain cyclic AMP binding proteins: correlation with growth suppression

    SciTech Connect

    Pennington, S.; Kalmus, G.

    1987-05-01

    Brain hypoplasia secondary to maternal ethanol consumption is a common fetal defect observed in all models of fetal alcohol syndrome. The molecular mechanism by which ethanol inhibits growth is unknown but has been hypothesized to involve ethanol-induced changes in the activity of cyclic-AMP stimulated protein kinase. Acute and chronic alcohol exposure elevate cyclic AMP level in many tissues, including brain. This increase in cyclic AMP should increase the phosphorylating activity of kinase by increasing the amount of dissociated (active) kinase catalytic subunit. In 7-day embryonic chick brains, ethanol-induced growth suppression was correlated with increased brain cyclic AMP content but neither basal nor cyclic AMP stimulated kinase catalytic activity was increased. However, the levels of cyclic AMP binding protein (kinase regulatory subunit) were significantly lowered by ethanol exposure. Measured as either /sup 3/H cyclic AMP binding or as 8-azido cyclic AM/sup 32/P labeling, ethanol-exposed brains had significantly less cyclic AMP binding activity (51 +/- 14 versus 29 +/- 10 units/..mu..g protein for 8-azido cyclic AMP binding). These findings suggest that ethanol's effect on kinase activity may involve more than ethanol-induced activation of adenylate cyclase.

  5. Shape changes induced by biologically active peptides and nerve growth factor in blood platelets of rabbits.

    PubMed

    Gudat, F; Laubscher, A; Otten, U; Pletscher, A

    1981-11-01

    1 Nerve growth factor (NGF), substance P (SP) and thymopoietin all caused shape change reactions of rapid onset in rabbit platelets. NGF had the highest maximal effect, and SP the lowest EC50 (concentration causing half maximal shape change). The action of SP was reversible within 5 min, whereas that of NGF lasted for at least 1 h. A series of other peptides were inactive. 2 After preincubation of platelets with SP, a second application of SP no longer caused a shape change reaction, whereas the effect of NGF was not influenced. 3 An oxidized NGF-derivative without biological activity did not cause a shape change reaction, neither did epidermal growth factor. 4 Prostaglandin E1 (PGE1) and pretreatment of the platelets with 3% butanol, which counteract the shape changes caused by 5-hydroxytryptamine (5-HT) and adenosine 3',5'-diphosphate, also antagonized those induced by NGF and SP. Neither heparin nor methysergide, an antagonist of 5-HT-receptors, influenced the shape change induced by NGF or SP. The action of NGF was also antagonized by a specific antibody to NGF. 5 Thymopoietin, like the basic polypeptide polyornithine (mol. wt. 40,000) was not antagonized by PGE1 and butanol. Heparin, which counteracted the effect of polyornithine, did not influence that of thymopoietin. 6 In conclusion, different modes of action are involved in the shape change of blood platelets induced by polypeptides and proteins. SP and NGF may act by stimulating specific membrane receptors.

  6. Bone-induced c-kit expression in prostate cancer: a driver of intraosseous tumor growth

    PubMed Central

    Mainetti, Leandro E.; Zhe, Xiaoning; Diedrich, Jonathan; Saliganan, Allen D.; Cho, Won Jin; Cher, Michael L.; Heath, Elisabeth; Fridman, Rafael; Kim, Hyeong-Reh Choi; Bonfil, R. Daniel

    2014-01-01

    Loss of BRCA2 function stimulates prostate cancer (PCa) cell invasion and is associated with more aggressive and metastatic tumors in PCa patients. Concurrently, the receptor tyrosine kinase c-kit is highly expressed in skeletal metastases of PCa patients and induced in PCa cells placed into the bone microenvironment in experimental models. However, the precise requirement of c-kit for intraosseous growth of PCa and its relation to BRCA2 expression remain unexplored. Here, we show that c-kit expression promotes migration and invasion of PCa cells. Alongside, we found that c-kit expression in PCa cells parallels BRCA2 downregulation. Gene rescue experiments with human BRCA2 transgene in c-kit-transfected PCa cells resulted in reduction of c-kit protein expression and migration and invasion, suggesting a functional significance of BRCA2 downregulation by c-kit. The inverse association between c-kit and BRCA2 gene expressions in PCa cells was confirmed using laser capture microdissection in experimental intraosseous tumors and bone metastases of PCa patients. Inhibition of bone-induced c-kit expression in PCa cells transduced with lentiviral short hairpin RNA reduced intraosseous tumor incidence and growth. Overall, our results provide evidence of a novel pathway that links bone-induced c-kit expression in PCa cells to BRCA2 downregulation and supports bone metastasis. PMID:24798488

  7. Thapsigargin induces rapid, transient growth inhibition and c-fos expression followed by sustained growth stimulation in mouse keratinocyte cultures.

    PubMed

    Harmon, C S; Ducote, J; Xiong, Y

    1996-08-01

    Although the sesquiterpene lactone thapsigargin has been shown to possess hyperplastic and tumor-promoting activities when applied topically to mouse skin in vivo, the cellular mechanism(s) which underlie these effects are unclear. We show here that thapsigargin treatment of Primary mouse epidermal keratinocytes increased intracellular free Ca2+ concentration (Cai) in a concentration-dependent manner. Thapsigargin induced a rapid, transient elevation in keratinocyte Cai, in part due to the release of Ca2+ from intracellular stores. This response was followed by a sustained elevation in Ca2+, resulting entirely from calcium influx. Thapsigargin elicited a biphasic effect on keratinocyte DNA synthesis: a rapid inhibitory effect (50-60% inhibition at 4-8 h), followed by a very marked and sustained elevation. Prolonged treatment of keratinocytes with thapsigargin at relatively high concentrations resulted in cytotoxicity (inhibition of neutral red uptake). The rapid antiproliferative effect of thapsigargin was not associated with cytotoxicity, as determined by either neutral red uptake or by trypan blue exclusion, and was not blocked by pretreatment with Ro 31-7349, a selective inhibitor of protein kinase C. The rapid antiproliferative effect of thapsigargin was associated with rapid, transient activation of keratinocyte c-fos expression and rapid inhibition of total protein synthesis. Taken together, these findings raise the possibility that the hyperplastic and tumor-promoting activities of thapsigargin on epidermis in vivo result from direct keratinocyte growth stimulation as a consequence of a prolonged elevation in levels of Cai.

  8. Sphingosine-1-phosphate mediates epidermal growth factor-induced muscle satellite cell activation

    SciTech Connect

    Nagata, Yosuke Ohashi, Kazuya; Wada, Eiji; Yuasa, Yuki; Shiozuka, Masataka; Nonomura, Yoshiaki; Matsuda, Ryoichi

    2014-08-01

    Skeletal muscle can regenerate repeatedly due to the presence of resident stem cells, called satellite cells. Because satellite cells are usually quiescent, they must be activated before participating in muscle regeneration in response to stimuli such as injury, overloading, and stretch. Although satellite cell activation is a crucial step in muscle regeneration, little is known of the molecular mechanisms controlling this process. Recent work showed that the bioactive lipid sphingosine-1-phosphate (S1P) plays crucial roles in the activation, proliferation, and differentiation of muscle satellite cells. We investigated the role of growth factors in S1P-mediated satellite cell activation. We found that epidermal growth factor (EGF) in combination with insulin induced proliferation of quiescent undifferentiated mouse myoblast C2C12 cells, which are also known as reserve cells, in serum-free conditions. Sphingosine kinase activity increased when reserve cells were stimulated with EGF. Treatment of reserve cells with the D-erythro-N,N-dimethylsphingosine, Sphingosine Kinase Inhibitor, or siRNA duplexes specific for sphingosine kinase 1, suppressed EGF-induced C2C12 activation. We also present the evidence showing the S1P receptor S1P2 is involved in EGF-induced reserve cell activation. Moreover, we demonstrated a combination of insulin and EGF promoted activation of satellite cells on single myofibers in a manner dependent on SPHK and S1P2. Taken together, our observations show that EGF-induced satellite cell activation is mediated by S1P and its receptor. - Highlights: • EGF in combination with insulin induces proliferation of quiescent C2C12 cells. • Sphingosine kinase activity increases when reserve cells are stimulated with EGF. • EGF-induced activation of reserve cells is dependent on sphingosine kinase and ERK. • The S1P receptor S1P2 is involved in EGF-induced reserve cell activation. • EGF-induced reserve cell activation is mediated by S1P and its

  9. Different intracellular signalling properties induced by human and porcine growth hormone.

    PubMed

    Hong, Pan; Lan, Hainan; Li, Yumeng; Fu, Zhiling; Zheng, Xin

    2016-04-01

    Growth hormone (GH) is reportedly species-specific. Primate growth hormone can trigger non-primate growth hormone receptor (GHR), but primates GHR cannot be activated by non-primate GH. However, it is also unclear that why primate GH and non-primate GH have different biological activities. Thus, we analysed primate growth hormone (human growth hormone (hGH)) or non-primate GH (porcine growth hormone (pGH))-induced intracellular signalling in 3T3-F442A cells and rat hepatocytes in a dose- and time-dependent manner to explore the different biological activities between them. The results revealed that both hGH and pGH can activate Janus kinase 2 (JAK2), Signal transducers and activators of transcription 1, 3 and 5 (STATs 1, 3 and 5) and extracellular signal-regulated kinase 1/2 (ERK1/2). There were no significant differences in JAK2 or ERK1/2 tyrosine phosphorylation after hGH and pGH treatment, but there were different between hGH and pGH in STAT/1/3/5 tyrosine phosphorylation, and JAK2, STAT/1/3/5 tyrosine phosphorylation was time-dependent and dose-dependent, whereas ERK1/2 was not. Both hGH and pGH demonstrated similar kinetics for STATs 1, 3 and 5 phosphorylation, but the pGH-mediated tyrosine phosphorylation was weaker than that mediated by hGH. Our observations indicated that the levels of main signalling proteins phosphorylation triggered by hGH or pGH were not exactly the same, which may explain the different biological activities showed by primate GH and non-primate GH. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Lipocortin 1 mediates dexamethasone-induced growth arrest of the A549 lung adenocarcinoma cell line.

    PubMed Central

    Croxtall, J D; Flower, R J

    1992-01-01

    The synthetic glucocorticoid dexamethasone (1 microM to 1 pM) strongly (maximum greater than 80%) inhibits proliferation of the A549 human lung adenocarcinoma line (EC50 greater than 1 nM) and leads to the appearance, or a further increase (approximately 3-fold) in the expression on the cell surface, of the calcium and phospholipid binding protein lipocortin (annexin) 1. Both these effects, which are shared by hydrocortisone (1 microM) but not by progesterone or aldosterone (1 microM), are inhibited by the antiglucocorticoids RU38486 and RU43044 (1 microM). The nonsteroidal antiinflammatory drugs indomethacin (1 microM) and naproxen (10 microM) and human recombinant lipocortin 1 (0.05-5.0 micrograms/ml) also produce growth arrest in this cell line. During proliferation A549 cells spontaneously release prostaglandin E2 [10-20 ng (28-57 pmol) per ml per 5-day period] into the growth medium. In concentrations that cause growth-arrest, dexamethasone, indomethacin, and lipocortin 1 abolish the generation of this eicosanoid by A549 cells. Prostaglandin E2 itself (0.01-1 pM) stimulates cell growth and partially reverses (approximately 50%) the inhibition of growth caused by dexamethasone and indomethacin. Addition of the neutralizing anti-lipocortin 1 monoclonal antibody 1A (5 micrograms/ml), but not the nonneutralizing anti-lipocortin monoclonal antibody 1B, substantially reversed (greater than 80%) the inhibitory activity of dexamethasone on both growth and prostaglandin E2 synthesis. The generation of prostaglandin E2 by A549 cells seems to be an important regulator of cell proliferation in vitro and the dexamethasone-induced suppression of proliferation in this model is attributable to eicosanoid inhibition caused by lipocortin 1. Images PMID:1533045

  11. Overexpression of A-myb induces basic fibroblast growth factor-dependent proliferation of chicken neuroretina cells.

    PubMed Central

    Turque, N; Plaza, S; Klempnauer, K H; Saule, S

    1997-01-01

    A-Myb behaves similarly to c-Myb in chicken neuroretina cells in its ability to induce fibroblast-like differentiation, to promote growth in the presence of basic fibroblast growth factor (bFGF), and to induce Pax-6 and mim-1 expression. The one difference between c-Myb and A-Myb in these cells is that the former but not the latter protein causes colony formation in soft agar in the presence of bFGF. PMID:9371644

  12. Sphingosine kinase activation regulates hepatocyte growth factor induced migration of endothelial cells.

    PubMed

    Duan, Hai-Feng; Wu, Chu-Tse; Lu, Ying; Wang, Hua; Liu, Hong-Jun; Zhang, Qun-Wei; Jia, Xiang-Xu; Lu, Zhu-Zhuang; Wang, Li-Sheng

    2004-08-15

    Hepatocyte growth factor (HGF)-induced migration of endothelial cells is critical for angiogenesis. Sphingosine kinase (SPK) is a key enzyme catalyzing the formation of sphingosine-1-phosphate (S1P), a lipid messenger that is implicated in the regulation of a wide variety of important cellular events through both intracellular and extracellular mechanisms. The aim of this study was to investigate whether activation of SPK is involved in the migration of endothelial cells induced by HGF. The biological functions of HGF are mediated through the activation of its high-affinity tyrosine kinase receptor, c-met protooncogene. In the present study, Treatment of ECV304 endothelial cells with HGF resulted in tyrosine phosphorylation of c-Met and activation of SPK in a concentration-dependent manner. Either Ly294002 or PD98059, specific inhibitor of the PI3K and ERK/MAPK pathways, respectively, blocked the HGF-induced activation of SPK. HGF stimulation significantly increased intracellular S1P level, but no detectable secretion of S1P into the cell culture medium was observed. Treatment of ECV304 cells with pertussis toxin (PTX) has no effect on the HGF-induced migration, indicating extracellular S1P is dispensable for this process. Overexpression of wild-type SPK gene in ECV 304 cells increased the intracellular S1P and enhanced the HGF-induced migration, whereas inhibition of cellular SPK activity by N,N-dimethylsphingosine (DMS), a potent inhibitor of SPK, or by expression of a dominant-negative SPK (DN-SK) blocked the HGF-induced migration of ECV 304 cells. It is suggested that PI3K and ERK/MAPK mediated the activation of SPK and would be involved in the HGF-induced migration of endothelial cells. These results elucidate a novel mechanism by which intracellularly generated S1P mediates signaling from HGF/c-Met to the endothelial cell migration.

  13. Sulindac metabolites induce proteosomal and lysosomal degradation of the epidermal growth factor receptor.

    PubMed

    Pangburn, Heather A; Ahnen, Dennis J; Rice, Pamela L

    2010-04-01

    The epidermal growth factor receptor (EGFR) is a member of the ErbB family of receptor tyrosine kinases. In response to ligand, EGFR is internalized and degraded by the ubiquitin-proteasome/lysosome pathway. We previously reported that metabolites of the nonsteroidal anti-inflammatory drug sulindac downregulate the expression of EGFR and inhibit basal and EGF-induced EGFR signaling through extracellular signal-regulated kinase 1/2. We now have evaluated the mechanisms of sulindac metabolite-induced downregulation of EGFR. EGF-induced downregulation of EGFR occurs within 10 minutes and lasts for 24 hours. By contrast, downregulation of EGFR by sulindac sulfide and sulindac sulfone was first evident at 4 and 24 hours, respectively, with maximal downregulation at 72 hours. Pretreatment with either the lysosomal inhibitor chloroquine or the proteosomal inhibitor MG132 blocked sulindac metabolite-induced downregulation of EGFR. Sulindac metabolites also increased the ubiquitination of EGFR. Whereas sulindac metabolites inhibited phosphorylation of EGFR pY1068, they increased phosphorylation of EGFR pY1045, the docking site where c-Cbl binds, thereby enabling receptor ubiquitination and degradation. Immunofluorescence analysis of EGF and EGFR distribution confirmed the biochemical observations that sulindac metabolites alter EGFR localization and EGFR internalization in a manner similar to that seen with EGF treatment. Expression of ErbB family members HER2 and HER3 was also downregulated by sulindac metabolites. We conclude that downregulation of EGFR expression by sulindac metabolites is mediated via lysosomal and proteosomal degradation that may be due to drug-induced phosphorylation at pY1045 with resultant ubiquitination of EGFR. Thus, sulindac metabolite-induced downregulation of EGFR seems to be mediated through mechanism(s) similar, at least in part, to those involved in EGF-induced downregulation of EGFR. (c) 2010 AACR.

  14. An epidermal growth factor receptor/Jak2 tyrosine kinase domain chimera induces tyrosine phosphorylation of Stat5 and transduces a growth signal in hematopoietic cells.

    PubMed

    Nakamura, N; Chin, H; Miyasaka, N; Miura, O

    1996-08-09

    The Jak family of tyrosine kinases and the Stat family of transcription factors have been implicated in transducing signals from the hematopoietic growth factor receptors. To explore the role played by a member of the Jak family, Jak2, in hematopoietic cell growth signaling, we constructed a chimeric cDNA coding for the Jak2 tyrosine kinase domain linked to the extracellular and transmembrane regions of the epidermal growth factor (EGF) receptor (EGFR) and expressed the chimera in an interleukin (IL)-3-dependent cell line, 32D. When deprived of IL-3, EGF prevented apoptosis of the transfected cells, induced dose-dependent proliferation, and supported long-term growth. EGF stimulation of the transfectants induced dose-dependent tyrosine phosphorylation of the EGFR/Jak2 chimera and Stat5, which correlated with the EGF dose dependence of cell proliferation. On the other hand, EGF did not induce tyrosine phosphorylation of other factors implicated in cytokine receptor signaling, including the IL-3 receptor beta subunit, Jak kinases, Stat proteins other than Stat5, Shc, Syp, and mitogen-activated protein kinases. These results suggest that the activation of Jak2 may be sufficient for transducing a growth signal in hematopoietic cells by activating the Stat5 pathway or previously unidentified signaling pathways. In addition, because EGF induces homodimerization of the EGFR to activate its tyrosine kinase activity, the present study, which shows EGF-dependent activation of the EGFR/Jak2 chimera, implies that Jak2 may also become activated by homodimerization.

  15. Topical cyclosporin induces hair growth in human split skin grafted onto nude mice.

    PubMed

    Gilhar, A; Etzioni, A; Moscona, R

    1991-01-01

    Previously we observed that systemic CyA induces hair growth in an experimental model of human scalp skin graft transplanted onto nude mice. In the present study we investigated the role of topical CyA in the murine transplantation model, using human split-thickness skin grafts (HSTSG). Ten mice grafted with 1-mm-thick skin and another 10 mice grafted with 0.4-mm-thick skin were treated topically with CyA in olive oil. Ten other mice, treated with olive oil only, served as a control group. At the end of the study we observed hair growth only on the grafted skin of the CyA-treated group. Four out of 10 grafts showed hair growth in each of the groups. Quantitative analysis of transverse sections of cylindrical punch biopsy specimens of HSTSG before transplantation revealed anagen follicles, including small ones and telogen/catagen follicles, whereas specimens after skin transplantation showed terminal follicles mostly in the anagen phase. The present study provides further support to previous observations regarding the beneficial effect of CyA on hair growth.

  16. Growth decline linked to warming-induced water limitation in hemi-boreal forests.

    PubMed

    Wu, Xiuchen; Liu, Hongyan; Guo, Dali; Anenkhonov, Oleg A; Badmaeva, Natalya K; Sandanov, Denis V

    2012-01-01

    Hemi-boreal forests, which make up the transition from temperate deciduous forests to boreal forests in southern Siberia, have experienced significant warming without any accompanying increase in precipitation during the last 80 years. This climatic change could have a profound impact on tree growth and on the stability of forest ecosystems in this region, but at present evidence for these impacts is lacking. In this study, we report a recent dramatic decline in the growth of hemi-boreal forests, based on ring width measurements from three dominant tree-species (Pinus sylvestris, Larix sibirica and Larix gmelinii), sampled from eight sites in the region. We found that regional tree growth has become increasingly limited by low soil water content in the pre- and early-growing season (from October of the previous year to July of the current year) over the past 80 years. A warming-induced reduction in soil water content has also increased the climate sensitivity of these three tree species. Beginning in the mid-1980s, a clear decline in growth is evident for both the pine forests and the larch forests, although there are increasing trends in the proxy of soil water use efficiencies. Our findings are consistent with those from other parts of the world and provide valuable insights into the regional carbon cycle and vegetation dynamics, and should be useful for devising adaptive forest management strategies.

  17. Salt-induced modulation in growth, photosynthesis and antioxidant system in two varieties of Brassica juncea

    PubMed Central

    Wani, Arif Shafi; Ahmad, Aqil; Hayat, Shamsul; Fariduddin, Qazi

    2013-01-01

    The present study was carried out to examine salt-induced modulation in growth, photosynthetic characteristics and antioxidant system in two cultivars of Brassica juncea Czern and Coss varieties (Varuna and RH-30). The surface sterilized seeds of these varieties were sown in the soil amended with different levels (2.8, 4.2 or 5.6 dsm−1) of sodium chloride under a simple randomized block design. The salt treatment significantly decreased growth, net photosynthetic rate and its related attributes, chlorophyll fluorescence, SPAD value of chlorophyll, leaf carbonic anhydrase activity and leaf water potential, whereas electrolyte leakage, proline content, and activity of catalase, peroxidase and superoxide dismutase enzymes increased in both the varieties at 30 d stage of growth. The variety Varuna was found more resistant than RH-30 to the salt stress and possessed higher values for growth, photosynthetic attributes and antioxidant enzymes. Out of the graded concentrations (2.8, 4.2 or 5.6 dsm−1) of sodium chloride, 2.8 sm−1 was least toxic and 5.6 dsm−1 was most harmful. The variation in the responses of these two varieties to salt stress is attributed to their differential photosynthetic traits, SPAD chlorophyll value and antioxidant capacity, which can be used as potential markers for screening mustard plants for salt tolerance. PMID:23961235

  18. PIF4 Promotes Expression of LNG1 and LNG2 to Induce Thermomorphogenic Growth in Arabidopsis.

    PubMed

    Hwang, Geonhee; Zhu, Jia-Ying; Lee, Young K; Kim, Sara; Nguyen, Thom T; Kim, Jungmook; Oh, Eunkyoo

    2017-01-01

    Arabidopsis plants adapt to high ambient temperature by a suite of morphological changes including elongation of hypocotyls and petioles and leaf hyponastic growth. These morphological changes are collectively called thermomorphogenesis and are believed to increase leaf cooling capacity by enhancing transpiration efficiency, thereby increasing tolerance to heat stress. The bHLH transcription factor PHYTOCHROME INTERACTING FACTOR4 (PIF4) has been identified as a major regulator of thermomorphogenic growth. Here, we show that PIF4 promotes the expression of two homologous genes LONGIFOLIA1 (LNG1) and LONGIFOLIA2 (LNG2) that have been reported to regulate leaf morphology. ChIP-Seq analyses and ChIP assays showed that PIF4 directly binds to the promoters of both LNG1 and LNG2. The expression of LNG1 and LNG2 is induced by high temperature in wild type plants. However, the high temperature activation of LNG1 and LNG2 is compromised in the pif4 mutant, indicating that PIF4 directly regulates LNG1 and LNG2 expression in response to high ambient temperatures. We further show that the activities of LNGs support thermomorphogenic growth. The expression of auxin biosynthetic and responsive genes is decreased in the lng quadruple mutant, implying that LNGs promote thermomorphogenic growth by activating the auxin pathway. Together, our results demonstrate that LNG1 and LNG2 are directly regulated by PIF4 and are new components for the regulation of thermomorphogenesis.

  19. Telomerase expression abrogates rapamycin-induced irreversible growth arrest of uterine fibroid smooth muscle cells.

    PubMed

    Suo, Guangli; Sadarangani, Anil; Tang, Wingchung; Cowan, Bryan D; Wang, Jean Y J

    2014-09-01

    Uterine fibroids are the most common solid tumors found in women of reproductive age. It has been reported that deregulation of the mammalian target of rapamycin (mTOR) pathway plays an important role in the etiology of leiomyoma. Here, we investigated the effect of rapamycin, an inhibitor of mTORC1, on the growth of primary fibroid smooth muscle cells (fSMCs) and human telomerase reverse transcriptase (hTERT)-transduced and immortalized fSMCs. With the primary fSMCs, a 24-hour treatment with rapamycin was sufficient to trigger a growth arrest that was not reversible upon drug removal. By contrast, the growth inhibitory effect of rapamycin on the hTERT-transduced fSMCs was readily reversible, as these cells resumed proliferation upon the withdrawal of the drug. These results suggest that rapamycin-induced irreversible growth arrest of fSMCs is dependent on the senescence barrier that is abrogated by the ectopic expression of telomerase.

  20. α-tomatine inhibits growth and induces apoptosis in HL-60 human myeloid leukemia cells

    PubMed Central

    HUANG, HUARONG; CHEN, SHAOHUA; VAN DOREN, JEREMIAH; LI, DONGLI; FARICHON, CHELSEA; HE, YAN; ZHANG, QIUYAN; ZHANG, KUN; CONNEY, ALLAN H; GOODIN, SUSAN; DU, ZHIYUN; ZHENG, XI

    2015-01-01

    α-tomatine is a glycoalkaloid that occurs naturally in tomatoes (Lycopersicon esculentum). In the present study, the effects of α-tomatine on human myeloid leukemia HL-60 cells were investigated. Treatment of HL-60 cells with α-tomatine resulted in growth inhibition and apoptosis in a concentration-dependent manner. Tomatidine, the aglycone of tomatine had little effect on the growth and apoptosis of HL-60 cells. Growth inhibition and apoptosis induced by α-tomatine in HL-60 cells was partially abrogated by addition of cholesterol indicating that interactions between α-tomatine and cell membrane-associated cholesterol may be important in mediating the effect of α-tomatine. Activation of nuclear factor-κB by the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate failed to prevent apoptosis in HL-60 cells treated with α-tomatine. In animal experiments, it was found that treatment of mice with α-tomatine inhibited the growth of HL-60 xenografts in vivo. Results from the present study indicated that α-tomatine may have useful anti-leukemia activities. PMID:25625536

  1. The Arabidopsis transcription factor ABIG1 relays ABA signaled growth inhibition and drought induced senescence

    PubMed Central

    Liu, Tie; Longhurst, Adam D; Talavera-Rauh, Franklin; Hokin, Samuel A; Barton, M Kathryn

    2016-01-01

    Drought inhibits plant growth and can also induce premature senescence. Here we identify a transcription factor, ABA INSENSITIVE GROWTH 1 (ABIG1) required for abscisic acid (ABA) mediated growth inhibition, but not for stomatal closure. ABIG1 mRNA levels are increased both in response to drought and in response to ABA treatment. When treated with ABA, abig1 mutants remain greener and produce more leaves than comparable wild-type plants. When challenged with drought, abig1 mutants have fewer yellow, senesced leaves than wild-type. Induction of ABIG1 transcription mimics ABA treatment and regulates a set of genes implicated in stress responses. We propose a model in which drought acts through ABA to increase ABIG1 transcription which in turn restricts new shoot growth and promotes leaf senescence. The results have implications for plant breeding: the existence of a mutant that is both ABA resistant and drought resistant points to new strategies for isolating drought resistant genetic varieties. DOI: http://dx.doi.org/10.7554/eLife.13768.001 PMID:27697148

  2. A Model for Surface Induced Growth of Inert Gas Bubbles in Irradiated Copper-Boron Alloys

    SciTech Connect

    Tiwari, G.P.; Ramadasan, E.

    2006-07-01

    A matrix containing inert gas bubbles dilates in direct proportion to the growth experienced by the gas bubbles. This phenomenon is termed as swelling. A model for the swelling induced by the growth of the helium gas bubbles in irradiated copper-boron alloys is presented. The bubbles grow by acquiring vacancies from the external surface, which acts as a source of vacancies. The vacancies reach the surface of the bubbles mainly via lattice diffusion and to a limited extent via diffusion through short-circuiting paths such as grain boundaries and dislocation pipes. The model predicts that overall swelling of the matrix varies as 1.5 power of time. Another consequence of the present model is that the growth rate of a gas bubble varies inversely as the cube of its distance from the external surface. The model has been applied to the data on irradiated copper-boron alloys and found to be in accord with the experimental results. The model is general and can be applied to the growth of all kinds of stationary inert gas bubbles trapped within a crystalline matrix. (authors)

  3. The Incompatibility of Living Systems: Characterizing Growth-Induced Incompatibilities in Expanded Skin.

    PubMed

    Tepole, Adrian Buganza; Gart, Michael; Purnell, Chad A; Gosain, Arun K; Kuhl, Ellen

    2016-05-01

    Skin expansion is a common surgical technique to correct large cutaneous defects. Selecting a successful expansion protocol is solely based on the experience and personal preference of the operating surgeon. Skin expansion could be improved by predictive computational simulations. Towards this goal, we model skin expansion using the continuum framework of finite growth. This approach crucially relies on the concept of incompatible configurations. However, aside from the classical opening angle experiment, our current understanding of growth-induced incompatibilities remains rather vague. Here we visualize and characterize incompatibilities in living systems using skin expansion in a porcine model: We implanted and inflated two expanders, crescent, and spherical, and filled them to 225 cc throughout a period of 21 days. To quantify the residual strains developed during this period, we excised the expanded skin patches and subdivided them into smaller pieces. Skin growth averaged 1.17 times the original area for the spherical and 1.10 for the crescent expander, and displayed significant regional variations. When subdivided into smaller pieces, the grown skin patches retracted heterogeneously and confirmed the existence of incompatibilities. Understanding skin growth through mechanical stretch will allow surgeons to improve-and ultimately personalize-preoperative treatment planning in plastic and reconstructive surgery.

  4. α-Tomatine inhibits growth and induces apoptosis in HL-60 human myeloid leukemia cells.

    PubMed

    Huang, Huarong; Chen, Shaohua; Van Doren, Jeremiah; Li, Dongli; Farichon, Chelsea; He, Yan; Zhang, Qiuyan; Zhang, Kun; Conney, Allan H; Goodin, Susan; Du, Zhiyun; Zheng, Xi

    2015-06-01

    α‑Tomatine is a glycoalkaloid that occurs naturally in tomatoes (Lycopersicon esculentum). In the present study, the effects of α‑tomatine on human myeloid leukemia HL‑60 cells were investigated. Treatment of HL‑60 cells with α‑tomatine resulted in growth inhibition and apoptosis in a concentration‑dependent manner. Tomatidine, the aglycone of tomatine had little effect on the growth and apoptosis of HL‑60 cells. Growth inhibition and apoptosis induced by α‑tomatine in HL‑60 cells was partially abrogated by addition of cholesterol indicating that interactions between α‑tomatine and cell membrane‑associated cholesterol may be important in mediating the effect of α‑tomatine. Activation of nuclear factor‑κB by the phorbol ester, 12‑O‑tetradecanoylphorbol‑13‑acetate failed to prevent apoptosis in HL‑60 cells treated with α‑tomatine. In animal experiments, it was found that treatment of mice with α‑tomatine inhibited the growth of HL‑60 xenografts in vivo. Results from the present study indicated that α‑tomatine may have useful anti‑leukemia activities.

  5. Amelioration of iron toxicity: A mechanism for aluminum-induced growth stimulation in tea plants.

    PubMed

    Hajiboland, Roghieh; Barceló, Juan; Poschenrieder, Charlotte; Tolrà, Roser

    2013-11-01

    Tea plants (Camellia sinensis) are well adapted to acid soils with high Al availability. These plants not only accumulate high leaf Al concentrations, but also respond to Al with growth stimulation. Decreased oxidative stress has been associated with this effect. Why tea plants not exposed to Al suffer from oxidative stress has not been clarified. In this study, hydroponically grown tea plants treated with 0 to 300 μM Al were analyzed for growth, Al and Fe accumulation, and Al distribution by means of morin and hematoxylin staining. Roots of control plants stained black with hematoxylin. This indicates the formation of a Fe-hematoxylin complex. Young leaves of controls accumulated more than 1000 mg Fe kg(-1) dry weight. This concentration is above the Fe-toxicity threshold in most species. Supply of Al stimulated growth and reduced Fe uptake and transport. These results indicate that Al-induced growth stimulation might be due to alleviation of a latent Fe toxicity occurring in tea plants without Al supply.

  6. Biomechanical force induces the growth factor production in human periodontal ligament-derived cells.

    PubMed

    Ichioka, Hiroaki; Yamamoto, Toshiro; Yamamoto, Kenta; Honjo, Ken-Ichi; Adachi, Tetsuya; Oseko, Fumishige; Mazda, Osam; Kanamura, Narisato; Kita, Masakazu

    2016-01-01

    Although many reports have been published on the functional roles of periodontal ligament (PDL) cells, the mechanisms involved in the maintenance and homeostasis of PDL have not been determined. We investigated the effects of biomechanical force on growth factor production, phosphorylation of MAPKs, and intracellular transduction pathways for growth factor production in human periodontal ligament (hPDL) cells using MAPK inhibitors. hPDL cells were exposed to mechanical force (6 MPa) using a hydrostatic pressure apparatus. The levels of growth factor mRNA and protein were examined by real-time RT-PCR and ELISA. The phosphorylation of MAPKs was measured using BD™ CBA Flex Set. In addition, MAPKs inhibitors were used to identify specific signal transduction pathways. Application of biomechanical force (equivalent to occlusal force) increased the synthesis of VEGF-A, FGF-2, and NGF. The application of biomechanical force increased the expression levels of phosphorylated ERK and p38, but not of JNK. Furthermore, the levels of VEGF-A and NGF expression were suppressed by ERK or p38 inhibitor. The growth factors induced by biomechanical force may play a role in the mechanisms of homeostasis of PDL.

  7. Excimer laser induced photolytic deposition of aluminum nitride: Film growth and properties

    SciTech Connect

    Radhakrishnan, G.; Adams, P.M.; Marquez, N.

    1996-12-31

    Excimer laser photolysis has been used for the growth of smooth and well-adhering thin films of aluminum nitride (AlN) on Si, fused quartz, and KBr substrates at temperatures as low as 350 K. The photolysis was carried out at 193 nm, with the laser beam propagating parallel to the substrate. Trimethylamine alane and ammonia were used as gas-phase precursors. The growth rate of these films was investigated as a function of laser fluence. These measurements, as well as other investigations of film growth with and without the photolysis laser, reveal that no AlN film is produced in the absence of laser-induced photolysis of the precursors. The morphology and physical properties of these laser-grown films have been studied by scanning electron microscopy, X-ray diffraction, and transmission electron microscopy. Optical absorption spectra of films grown on fused quartz were measured as a function of substrate temperature. A substrate temperature of 350 K was found to be optimum for obtaining good film quality while precluding any effects due to the thermal decomposition of the precursors. The films have excellent dielectric properties as shown by I-V and C-V measurements. The details of AlN film growth using low-temperature gas-phase photolysis at 193 nm and the characterization of these laser grown films will be discussed.

  8. Growth Decline Linked to Warming-Induced Water Limitation in Hemi-Boreal Forests

    PubMed Central

    Wu, Xiuchen; Liu, Hongyan; Guo, Dali; Anenkhonov, Oleg A.; Badmaeva, Natalya K.; Sandanov, Denis V.

    2012-01-01

    Hemi-boreal forests, which make up the transition from temperate deciduous forests to boreal forests in southern Siberia, have experienced significant warming without any accompanying increase in precipitation during the last 80 years. This climatic change could have a profound impact on tree growth and on the stability of forest ecosystems in this region, but at present evidence for these impacts is lacking. In this study, we report a recent dramatic decline in the growth of hemi-boreal forests, based on ring width measurements from three dominant tree-species (Pinus sylvestris, Larix sibirica and Larix gmelinii), sampled from eight sites in the region. We found that regional tree growth has become increasingly limited by low soil water content in the pre- and early-growing season (from October of the previous year to July of the current year) over the past 80 years. A warming-induced reduction in soil water content has also increased the climate sensitivity of these three tree species. Beginning in the mid-1980s, a clear decline in growth is evident for both the pine forests and the larch forests, although there are increasing trends in the proxy of soil water use efficiencies. Our findings are consistent with those from other parts of the world and provide valuable insights into the regional carbon cycle and vegetation dynamics, and should be useful for devising adaptive forest management strategies. PMID:22916142

  9. Morphology and growth speed of hcp domains during shock-induced phase transition in iron.

    PubMed

    Pang, Wei-Wei; Zhang, Ping; Zhang, Guang-Cai; Xu, Ai-Guo; Zhao, Xian-Geng

    2014-01-10

    Emergence and time evolution of micro-structured new-phase domains play a crucial role in determining the macroscopic physical and mechanical behaviors of iron under shock compression. Here, we investigate, through molecular dynamics simulations and theoretical modelings, shock-induced phase transition process of iron from body-centered-cubic (bcc) to hexagonal-close-packed (hcp) structure. We present a central-moment method and a rolling-ball algorithm to calculate and analyze the morphology and growth speed of the hcp phase domains, and then propose a phase transition model to clarify our derived growth law of the phase domains. We also demonstrate that the new-phase evolution process undergoes three distinguished stages with different time scales of the hcp phase fraction in the system.

  10. A review on radiation-induced nucleation and growth of colloidal metallic nanoparticles

    PubMed Central

    2013-01-01

    This review presents an introduction to the synthesis of metallic nanoparticles by radiation-induced method, especially gamma irradiation. This method offers some benefits over the conventional methods because it provides fully reduced and highly pure nanoparticles free from by-products or chemical reducing agents, and is capable of controlling the particle size and structure. The nucleation and growth mechanism of metallic nanoparticles are also discussed. The competition between nucleation and growth process in the formation of nanoparticles can determine the size of nanoparticles which is influenced by certain parameters such as the choice of solvents and stabilizer, the precursor to stabilizer ratio, pH during synthesis, and absorbed dose. PMID:24225302

  11. Soluble CD14 enriched in colostrum and milk induces B cell growth and differentiation.

    PubMed

    Filipp, D; Alizadeh-Khiavi, K; Richardson, C; Palma, A; Paredes, N; Takeuchi, O; Akira, S; Julius, M

    2001-01-16

    Induction of resting B cell growth and differentiation requires a complex series of temporally coordinated signals that are initiated on contact with activated helper T cells. These signals complement one another, each rendering the B cell susceptible to factors supporting progressive activation. Here, we demonstrate that soluble CD14 (sCD14) bypasses the physiological sequelae of events that limit B cell activation. B cell growth and differentiation in vitro is induced by both native and recombinant forms of sCD14 at nanomolar concentrations. sCD14-mediated cellular activation does not require membrane CD14 expression, depends on a region of CD14 that is not involved in lipopolysaccharide binding, and requires functional Toll-like receptor 4. Consistent with biological activity of sCD14 in vitro, its administration to neonatal mice enhances Ig secretion. The results presented establish sCD14 as a naturally occurring soluble B cell mitogen of mammalian origin.

  12. Acetylation of RNA polymerase II regulates growth-factor-induced gene transcription in mammalian cells.

    PubMed

    Schröder, Sebastian; Herker, Eva; Itzen, Friederike; He, Daniel; Thomas, Sean; Gilchrist, Daniel A; Kaehlcke, Katrin; Cho, Sungyoo; Pollard, Katherine S; Capra, John A; Schnölzer, Martina; Cole, Philip A; Geyer, Matthias; Bruneau, Benoit G; Adelman, Karen; Ott, Melanie

    2013-11-07

    Lysine acetylation regulates transcription by targeting histones and nonhistone proteins. Here we report that the central regulator of transcription, RNA polymerase II, is subject to acetylation in mammalian cells. Acetylation occurs at eight lysines within the C-terminal domain (CTD) of the largest polymerase subunit and is mediated by p300/KAT3B. CTD acetylation is specifically enriched downstream of the transcription start sites of polymerase-occupied genes genome-wide, indicating a role in early stages of transcription initiation or elongation. Mutation of lysines or p300 inhibitor treatment causes the loss of epidermal growth-factor-induced expression of c-Fos and Egr2, immediate-early genes with promoter-proximally paused polymerases, but does not affect expression or polymerase occupancy at housekeeping genes. Our studies identify acetylation as a new modification of the mammalian RNA polymerase II required for the induction of growth factor response genes.

  13. Concentration gradient induced morphology evolution of silica nanostructure growth on photoresist-derived carbon micropatterns

    NASA Astrophysics Data System (ADS)

    Liu, Dan; Shi, Tielin; Xi, Shuang; Lai, Wuxing; Liu, Shiyuan; Li, Xiaoping; Tang, Zirong

    2012-09-01

    The evolution of silica nanostructure morphology induced by local Si vapor source concentration gradient has been investigated by a smart design of experiments. Silica nanostructure or their assemblies with different morphologies are obtained on photoresist-derived three-dimensional carbon microelectrode array. At a temperature of 1,000°C, rope-, feather-, and octopus-like nanowire assemblies can be obtained along with the Si vapor source concentration gradient flow. While at 950°C, stringlike assemblies, bamboo-like nanostructures with large joints, and hollow structures with smaller sizes can be obtained along with the Si vapor source concentration gradient flow. Both vapor-liquid-solid and vapor-quasiliquid-solid growth mechanisms have been applied to explain the diverse morphologies involving branching, connecting, and batch growth behaviors. The present approach offers a potential method for precise design and controlled synthesis of nanostructures with different features.

  14. Unraveling irradiation induced grain growth with in situ transmission electron microscopy and coordinated modeling

    SciTech Connect

    Bufford, D. C.; Abdeljawad, F. F.; Foiles, S. M.; Hattar, K.

    2015-11-09

    Nanostructuring has been proposed as a method to enhance radiation tolerance, but many metallic systems are rejected due to significant concerns regarding long term grain boundary and interface stability. This work utilized recent advancements in transmission electron microscopy (TEM) to quantitatively characterize the grain size, texture, and individual grain boundary character in a nanocrystalline gold model system before and after in situ TEM ion irradiation with 10 MeV Si. The initial experimental measurements were fed into a mesoscale phase field model, which incorporates the role of irradiation-induced thermal events on boundary properties, to directly compare the observed and simulated grain growth with varied parameters. The observed microstructure evolution deviated subtly from previously reported normal grain growth in which some boundaries remained essentially static. In broader terms, the combined experimental and modeling techniques presented herein provide future avenues to enhance quantification and prediction of the thermal, mechanical, or radiation stability of grain boundaries in nanostructured crystalline systems.

  15. Concentration gradient induced morphology evolution of silica nanostructure growth on photoresist-derived carbon micropatterns

    PubMed Central

    2012-01-01

    The evolution of silica nanostructure morphology induced by local Si vapor source concentration gradient has been investigated by a smart design of experiments. Silica nanostructure or their assemblies with different morphologies are obtained on photoresist-derived three-dimensional carbon microelectrode array. At a temperature of 1,000°C, rope-, feather-, and octopus-like nanowire assemblies can be obtained along with the Si vapor source concentration gradient flow. While at 950°C, stringlike assemblies, bamboo-like nanostructures with large joints, and hollow structures with smaller sizes can be obtained along with the Si vapor source concentration gradient flow. Both vapor–liquid-solid and vapor-quasiliquid-solid growth mechanisms have been applied to explain the diverse morphologies involving branching, connecting, and batch growth behaviors. The present approach offers a potential method for precise design and controlled synthesis of nanostructures with different features. PMID:22938090

  16. Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model

    PubMed Central

    Kumasawa, Keiichi; Ikawa, Masahito; Kidoya, Hiroyasu; Hasuwa, Hidetoshi; Saito-Fujita, Tomoko; Morioka, Yuka; Takakura, Nobuyuki; Kimura, Tadashi; Okabe, Masaru

    2011-01-01

    Preeclampsia is a relatively common pregnancy-related disorder. Both maternal and fetal lives will be endangered if it proceeds unabated. Recently, the placenta-derived anti-angiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFLT1) and soluble endoglin (sENG), have attracted attention in the progression of preeclampsia. Here, we established a unique experimental model to test the role of sFLT1 in preeclampsia using a lentiviral vector-mediated placenta-specific expression system. The model mice showed hypertension and proteinuria during pregnancy, and the symptoms regressed after parturition. Intrauterine growth restriction was also observed. We further showed that pravastatin induced the VEGF-like angiogenic factor placental growth factor (PGF) and ameliorated the symptoms. We conclude that our experimental preeclamptic murine model phenocopies the human case, and the model identifies low-dose statins and PGF as candidates for preeclampsia treatment. PMID:21187414

  17. Effect of caffeic acid esters on carcinogen-induced mutagenicity and human colon adenocarcinoma cell growth.

    PubMed

    Rao, C V; Desai, D; Kaul, B; Amin, S; Reddy, B S

    1992-11-16

    Propolis, a honey bee hive product, is thought to exhibit a broad spectrum of activities including antibiotic, antiviral, anti-inflammatory and tumor growth inhibition; some of the observed biological activities may be due to caffeic acid (cinnamic acid) esters that are present in propolis. In the present study we synthesized three caffeic acid esters, namely methyl caffeate (MC), phenylethyl caffeate (PEC) and phenylethyl dimethylcaffeate (PEDMC) and tested them against the 3,2'-dimethyl-4-aminobiphenyl, (DMAB, a colon and mammary carcinogen)-induced mutagenicity in Salmonella typhimurium strains TA 98 and TA 100. Also, the effect of these agents on the growth of human colon adenocarcinoma, HT-29 cells and activities of ornithine decarboxylase (ODC) and protein tyrosine kinase (PTK) was studied. Mutagenicity was induced in Salmonella typhimurium strains TA 98 and TA 100 plus S9 activation using 5 and 10 micrograms DMAB and antimutagenic activities of 0-150 microM MC, 0-60 microM PEC and 0-80 microM PEDMC were determined. The results indicate that MC, PEC and PEDMC were not mutagenic in the Salmonella tester system. DMAB-induced mutagenicity was significantly inhibited with 150 microM MC, 40-60 microM PEC and 40-80 microM PEDMC in both tester systems. Treatment of HT-29 colon adenocarcinoma cells with > 150 microM MC, 30 microM PEC and 20 microM PEDMC significantly inhibited the cell growth and syntheses of RNA, DNA and protein. ODC and PTK activities were also inhibited in HT-29 cells treated with different concentrations of MC, PEC and PEDMC. These results demonstrate that caffeic acid esters which are present in Propolis possess chemopreventive properties when tested in short-term assay systems.

  18. hvTRA, a novel TRAIL receptor agonist, induces apoptosis and sustained growth retardation in melanoma

    PubMed Central

    Fleten, Karianne G; Flørenes, Vivi Ann; Prasmickaite, Lina; Hill, Oliver; Sykora, Jaromir; Mælandsmo, Gunhild M; Engesæter, Birgit

    2016-01-01

    In recent years, new treatment options for malignant melanoma patients have enhanced the overall survival for selected patients. Despite new hope, most melanoma patients still relapse with drug-resistant tumors or experience intrinsic resistance to the therapy. Therefore, novel treatment modalities beneficial for subgroups of patients are needed. TRAIL receptor agonists have been suggested as promising candidates for use in cancer treatment as they preferentially induce apoptosis in cancer cells. Unfortunately, the first generation of TRAIL receptor agonists showed poor clinical efficacy. hvTRA is a second-generation TRAIL receptor agonist with improved composition giving increased potency, and in the present study, we showed hvTRA-induced activation of apoptosis leading to an efficient and sustained reduction in melanoma cell growth in cell lines and xenograft models. Furthermore, the potential of hvTRA in a clinical setting was demonstrated by showing efficacy on tumor cells harvested from melanoma patients with lymph node metastasis in an ex vivo drug sensitivity assay. Inhibition of mutated BRAF has been shown to regulate proteins in the intrinsic apoptotic pathway, making the cells more susceptible for apoptosis induction. In an attempt to increase the efficacy of hvTRA, combination treatment with the mutated BRAF inhibitor vemurafenib was investigated. A synergistic effect by the combination was observed for several cell lines in vitro, and an initial cytotoxic effect was observed in vivo. Unfortunately, the initial increased reduction in tumor growth compared with hvTRA mono treatment was not sustained, and this was related to downregulation of the DR5 level by vemurafenib. Altogether, the presented data imply that hvTRA efficiently induce apoptosis and growth delay in melanoma models and patient material, and the potential of this TRAIL receptor agonist should be further evaluated for treatment of subgroups of melanoma patients. PMID:28028438

  19. hvTRA, a novel TRAIL receptor agonist, induces apoptosis and sustained growth retardation in melanoma.

    PubMed

    Fleten, Karianne G; Flørenes, Vivi Ann; Prasmickaite, Lina; Hill, Oliver; Sykora, Jaromir; Mælandsmo, Gunhild M; Engesæter, Birgit

    2016-01-01

    In recent years, new treatment options for malignant melanoma patients have enhanced the overall survival for selected patients. Despite new hope, most melanoma patients still relapse with drug-resistant tumors or experience intrinsic resistance to the therapy. Therefore, novel treatment modalities beneficial for subgroups of patients are needed. TRAIL receptor agonists have been suggested as promising candidates for use in cancer treatment as they preferentially induce apoptosis in cancer cells. Unfortunately, the first generation of TRAIL receptor agonists showed poor clinical efficacy. hvTRA is a second-generation TRAIL receptor agonist with improved composition giving increased potency, and in the present study, we showed hvTRA-induced activation of apoptosis leading to an efficient and sustained reduction in melanoma cell growth in cell lines and xenograft models. Furthermore, the potential of hvTRA in a clinical setting was demonstrated by showing efficacy on tumor cells harvested from melanoma patients with lymph node metastasis in an ex vivo drug sensitivity assay. Inhibition of mutated BRAF has been shown to regulate proteins in the intrinsic apoptotic pathway, making the cells more susceptible for apoptosis induction. In an attempt to increase the efficacy of hvTRA, combination treatment with the mutated BRAF inhibitor vemurafenib was investigated. A synergistic effect by the combination was observed for several cell lines in vitro, and an initial cytotoxic effect was observed in vivo. Unfortunately, the initial increased reduction in tumor growth compared with hvTRA mono treatment was not sustained, and this was related to downregulation of the DR5 level by vemurafenib. Altogether, the presented data imply that hvTRA efficiently induce apoptosis and growth delay in melanoma models and patient material, and the potential of this TRAIL receptor agonist should be further evaluated for treatment of subgroups of melanoma patients.

  20. [Progress of study on inhibitory effects of traditional Chinese herbs on growth factor induced proliferation of vascular smooth muscle cells].

    PubMed

    Yang, Guang; Zhang, Min-zhou; Jiang, Wei

    2005-10-01

    This paper sums up some studies in the last decade regarding the inhibitory effects of traditional Chinese herbs on growth factor induced proliferation of vascular smooth muscle cell (VSMC) via directly measuring the mRNA expression of its growth factors and the related receptors by electron microscope, immunohistochemistry, blot and hybridization in situ.

  1. Mobile phone radiation inhibits Vigna radiata (mung bean) root growth by inducing oxidative stress.

    PubMed

    Sharma, Ved Parkash; Singh, Harminder Pal; Kohli, Ravinder Kumar; Batish, Daizy Rani

    2009-10-15

    During the last couple of decades, there has been a tremendous increase in the use of cell phones. It has significantly added to the rapidly increasing EMF smog, an unprecedented type of pollution consisting of radiation in the environment, thereby prompting the scientists to study the effects on humans. However, not many studies have been conducted to explore the effects of cell phone EMFr on growth and biochemical changes in plants. We investigated whether EMFr from cell phones inhibit growth of Vigna radiata (mung bean) through induction of conventional stress responses. Effects of cell phone EMFr (power density: 8.55 microW cm(-2); 900 MHz band width; for 1/2, 1, 2, and 4 h) were determined by measuring the generation of reactive oxygen species (ROS) in terms of malondialdehyde and hydrogen peroxide (H(2)O(2)) content, root oxidizability and changes in levels of antioxidant enzymes. Our results showed that cell phone EMFr significantly inhibited the germination (at > or =2 h), and radicle and plumule growths (> or =1 h) in mung bean in a time-dependent manner. Further, cell phone EMFr enhanced MDA content (indicating lipid peroxidation), and increased H(2)O(2) accumulation and root oxidizability in mung bean roots, thereby inducing oxidative stress and cellular damage. In response to EMFr, there was a significant upregulation in the activities of scavenging enzymes, such as superoxide dismutases, ascorbate peroxidases, guaiacol peroxidases, catalases and glutathione reductases, in mung bean roots. The study concluded that cell phone EMFr inhibit root growth of mung bean by inducing ROS-generated oxidative stress despite increased activities of antioxidant enzymes.

  2. IGF-I overexpression does not promote compensatory islet cell growth in diet-induced obesity.

    PubMed

    Robertson, Katie; Dong, Jing; De Jesus, Kristine; Liu, Jun-Li

    2010-02-01

    Although IGF-I was known to stimulate the growth of pancreatic islet cells from early in vitro experiments and in vivo reports on rodents, recent gene targeting experiments have indicated that IGF-I and its receptor do not play a major role in normal islet cell growth. In our previous reports, liver- or pancreatic-specific IGF-I deficiency caused no decrease in β-cell mass; a general and β-cell-enriched IGF-I overexpression caused no change in normal islet cell growth. On the other hand, increased metabolic demands (such as in obesity and insulin resistance) result in β-cell compensation in cell number and insulin secretion. In order to test whether IGF-I could promote islet cell growth and facilitate islet compensation due to obesity-induced insulin resistance, we have challenged MT-IGF mice to a high-fat diet. After 28 weeks, both MT-IGF mice and wild-type littermates gained comparable 40-57% of body weight, with similar increases in fat masses; all mice maintained a normal sensitivity to insulin and did not become severely hyperglycemic. Nevertheless, compared to wild-type littermates, the equally obese MT-IGF mice maintained improved glucose tolerance and a diminished insulin level; similar to when fed a normal chow diet. More importantly, under IGF-I overexpression, there was no further increase in β-cell mass caused by obesity. Thus, IGF-I overexpression had no significant effect on weight gain and islet cell compensation in response to high-fat diet-induced obesity.

  3. Layer-by-layer growth of Ag on Ag(111) induced by enhanced nucleation: A model study for surfactant-mediated growth

    NASA Astrophysics Data System (ADS)

    Rosenfeld, Georg; Servaty, Roland; Teichert, Christian; Poelsema, Bene; Comsa, George

    1993-08-01

    It has been reported that the growth mode of Ag on Ag(111), which is usually multilayer (3D), changes to layer-by-layer (2D) growth if Sb is used as a surfactant. In a model study on the clean system Ag/Ag(111) (without any surfactant) we find that two-dimensional layers do grow, if the substrate is prepared with an anomalously high density of Ag nuclei. As an enhanced density of nuclei is also observed in the presence of Sb, this effect may explain the mechanism for surfactant-induced layer-by-layer growth.

  4. Lattice parameter evolution in Pt nanoparticles during photo-thermally induced sintering and grain growth

    DOE PAGES

    Kelly, B.G.; Loether, A.; DiChiara, A. D.; ...

    2017-04-20

    An in-situ optical pump/x-ray probe technique has been used to study the size dependent lattice parameter of Pt nanoparticles subjected to picosecond duration optical laser pulses. The as-prepared Pt nanoparticles exhibited a contracted lattice parameter consistent with the response of an isolated elastic sphere to a compressive surface stress. During photo-thermally induced sintering and grain growth, however, the Pt lattice parameter did not evolve with the inverse particle size dependence predicted by simple surface stress models. Lastly, the observed behavior could be attributed to the combined effects of a compressive surface/interface stress and a tensile stress arising from intergranular material.

  5. Irradiation-induced grain growth in nanocrystalline reduced activation ferrite/martensite steel

    SciTech Connect

    Liu, W. B.; Chen, L. Q.; Zhang, C. Yang, Z. G.; Ji, Y. Z.; Zang, H.; Shen, T. L.

    2014-09-22

    In this work, we investigate the microstructure evolution of surface-nanocrystallized reduced activation ferrite/martensite steels upon high-dose helium ion irradiation (24.3 dpa). We report a significant irradiation-induced grain growth in the irradiated buried layer at a depth of 300–500 nm, rather than at the peak damage region (at a depth of ∼840 nm). This phenomenon can be explained by the thermal spike model: minimization of the grain boundary (GB) curvature resulting from atomic diffusion in the cascade center near GBs.

  6. Effect of diamagnetic substitution on growth-induced anisotropy in (YBi)3Fe5O12

    NASA Technical Reports Server (NTRS)

    Fratello, V. J.; Slusky, S. E. G.; Brandle, C. D.; Norelli, M. P.

    1986-01-01

    Films of (Y/3-x-y/Bi/x/Pb/y/)(Fe/5-z/Ga/z/)O12(Z = 0-1.1) and (Y/3-x-y/Bi/x/PB/y/)(Fe/5-w/In/w/)O12(w = 0-O.6) garnets were prepared by liquid-phase epitaxy. The effects of tetrahedral Ga and octahedral In substitution on the Bi-based growth-induced uniaxial anisotropy in (Ybi)3Fe5O12 films were measured. Both Ga and In resulted in a linear decrease in the anisotropy with increasing substitution. The effect of octahedral In was twice that of tetrahedral Ga.

  7. Lattice parameter evolution in Pt nanoparticles during photo-thermally induced sintering and grain growth

    NASA Astrophysics Data System (ADS)

    Kelly, B. G.; Loether, A. B.; DiChiara, A. D.; Henning, R. W.; DeCamp, M. F.; Unruh, K. M.

    2017-09-01

    An in-situ optical pump/x-ray probe technique has been used to study the size dependent lattice parameter of Pt nanoparticles subjected to picosecond duration optical laser pulses. The as-prepared Pt nanoparticles exhibited a contracted lattice parameter consistent with the response of an isolated elastic sphere to a compressive surface stress. During photo-thermally induced sintering and grain growth, however, the Pt lattice parameter did not evolve with the inverse particle size dependence predicted by simple surface stress models. The observed behavior could be attributed to the combined effects of a compressive surface/interface stress and a tensile stress arising from intergranular material.

  8. Automated Heuristic Defect Classification (AHDC) for haze-induced defect growth management and mask requalification

    NASA Astrophysics Data System (ADS)

    Munir, Saghir; Qidwai, Gul

    2012-03-01

    This article presents results from a heuristic automated defect classification algorithm for reticle inspection that mimics the classification rules. AHDC does not require CAD data, thus it can be rapidly deployed in a high volume production environment without the need for extensive design data management. To ensure classification consistency a software framework tracks every defect in repeated inspections. Through its various image based derived metrics it is shown that such a system manages and tracks repeated defects in applications such as haze induced defect growth.

  9. Whisker growth on Sn thin film accelerated under gamma-ray induced electric field

    NASA Astrophysics Data System (ADS)

    Killefer, Morgan; Borra, Vamsi; Al-Bayati, Ahmed; Georgiev, Daniel G.; Karpov, Victor G.; Ishmael Parsai, E.; Shvydka, Diana

    2017-10-01

    We report on the growth of tin metal whiskers significantly accelerated under non-destructive gamma-ray irradiation. Sn thin film, evaporated on glass substrate, was subjected to a total of 60 h of irradiation. The irradiated samples demonstrated enhanced whisker development, in both densities and lengths, resulting in an acceleration factor of  ∼50. We attribute the observed enhancement to gamma-ray induced electrostatic fields, affecting whisker kinetics. These fields are due to the substrate charging under gamma-rays. We propose that gamma-ray irradiation can be a much needed tool for accelerated testing of whisker propensity.

  10. Space-charged-induced emittance growth in the transport of high-brightness electron beams

    SciTech Connect

    Jones, M.E.; Carlsten, B.E.

    1987-03-01

    The emittance induced by space charge in a drifting beam of finite length has been investigated, and a scaling law has been obtained from simple considerations of the different rates of expansion of different portions of the beam. The scaling law predicts the initial rate of emittance growth, before the beam shape has distorted significantly, and thus represents an upper bound on the rate of emittance increase. This scaling law has been substantiated by particle-in-cell simulation and the dependence on geometric factors evaluated for specific choices of the beam profile. For long, axially nonuniform beams, the geometric factors have been evaluated explicitly for Gaussian profiles, and other shapes.

  11. Effects of two different growth media on the postantifungal effect induced by polyenes on Candida species.

    PubMed

    Shu, M; Ellepola, A N; Samaranayake, L P

    2001-07-01

    There are no data on the effects of different growth media on polyene-induced postantifungal effect (PAFE) in Candida species. Hence, the nystatin- and amphotericin B-induced PAFEs in six Candida species (26 isolates) grown in Sabouraud's dextrose broth (SAB) and RPMI broth were evaluated, following limited exposure to the MICs of the two polyenes, using an automated turbidometric method. For nystatin, PAFE varied between 1.88 and 4.87 h in SAB and 0.66 and 6.89 h in RPMI, and for amphotericin B, the equivalent values were 3.13 to 10.98 h in SAB and 0.97 to 7.01 h in RPMI. These highly significant (P < 0.001) variations in the PAFE with both drugs, noted with most Candida strains grown in different media, call for standardization of intralaboratory methodology in measuring this parameter in order to obtain universally comparable data.

  12. Phase field modelling of strain induced crystal growth in an elastic matrix.

    PubMed

    Laghmach, Rabia; Candau, Nicolas; Chazeau, Laurent; Munch, Etienne; Biben, Thierry

    2015-06-28

    When a crystal phase grows in an amorphous matrix, such as a crystallisable elastomer, containing cross-links and/or entanglements, these "topological constraints" need to be pushed away from the crystal phase to allow further crystallization. The accumulation of these topological constraints in the vicinity of the crystal interface may store elastic energy and affect the phase transition. To evaluate the consequences of such mechanism, we introduce a phase field model based on the Flory theory of entropic elasticity. We show that the growth process is indeed sensibly affected, in particular, an exponential increase of the surface energy with the displacement of the interface is induced. This explains the formation of stable nano-crystallites as it is observed in the Strain Induced Crystallization (SIC) of natural rubber. Although simple, the model developed here is able to account for many interesting features of SIC, for instance, the crystallite shapes and their sizes which depend on the applied deformation.

  13. A Homeobox Gene Related to Drosophila Distal-Less Promotes Ovarian Tumorigenicity by Inducing Expression of Vascular Endothelial Growth Factor and Fibroblast Growth Factor-2

    PubMed Central

    Hara, Fumikata; Samuel, Shaija; Liu, Jinsong; Rosen, Daniel; Langley, Robert R.; Naora, Honami

    2007-01-01

    Homeobox genes control developmental patterning and are increasingly being found to be deregulated in tumors. The DLX4 homeobox gene maps to the 17q21.3-q22 region that is amplified in some epithelial ovarian cancers. Because amplification of this region correlates with poor prognosis, we investigated whether DLX4 overexpression contributes to aggressive behavior of this disease. DLX4 was not detected in normal ovary and cystadenomas, whereas its expression in ovarian carcinomas was strongly associated with high tumor grade and advanced disease stage. Overexpression of DLX4 in ovarian cancer cells promoted growth in low serum and colony formation. Imaging of mice bearing intraperitoneal tumors revealed that DLX4 overexpression substantially increased tumor burden. Tumors that overexpressed DLX4 were more vascularized than vector-control tumors. Conditioned medium of DLX4-overexpressing tumor cells was more effective than medium conditioned by vector-control cells in stimulating endothelial cell growth. These observations were associated with the ability of DLX4 to induce expression of vascular endothelial growth factor as well as intracellular and secreted isoforms of fibroblast growth factor-2. Moreover, increased levels of these fibroblast growth factor-2 isoforms induced vascular endothelial growth factor expression in tumor cells. This study reveals a novel role for a homeobox gene in ovarian tumorigenicity by its induction of a proangiogenic, growth-stimulatory molecular program. PMID:17456765

  14. Therapeutic concentrations of digitoxin inhibit endothelial focal adhesion kinase and angiogenesis induced by different growth factors.

    PubMed

    Trenti, Annalisa; Zulato, Elisabetta; Pasqualini, Lorenza; Indraccolo, Stefano; Bolego, Chiara; Trevisi, Lucia

    2017-09-01

    Cardiac glycosides are Na(+) /K(+) -ATPases inhibitors used to treat congestive heart failure and cardiac arrhythmias. Epidemiological studies indicate that patients on digitalis therapy are more protected from cancer. Evidence of a selective cytotoxicity against cancer cells has suggested their potential use as anticancer drugs. The effect on angiogenesis of clinically used cardiac glycosides has not been extensively explored. We studied the effect of digoxin, digitoxin and ouabain on early events of the angiogenic process in HUVECs. We determined HUVEC viability, proliferation, migration and differentiation into capillary tube-like structures. We also tested drug activity using an in vivo angiogenesis model. Activation of protein tyrosine kinase 2 (FAK) and signalling proteins associated with the Na(+) /K(+) -ATPase signalosome was determined by Western blotting. Digitoxin and ouabain (1-100 nM) inhibited HUVEC migration, concentration-dependently, without affecting cell viability, while digoxin induced apoptosis at the same concentrations. Digitoxin antagonized growth factor-induced migration and tubularization at concentrations (1-25 nM) within its plasma therapeutic range. The anti-angiogenic effect of digitoxin was confirmed also by in vivo studies. Digitoxin induced Src, Akt and ERK1/2 phosphorylation but did not affect FAK autophosphorylation at Tyr(397) . However, it significantly inhibited growth factor-induced FAK phosphorylation at Tyr(576/577) . Therapeutic concentrations of digitoxin inhibited angiogenesis and FAK activation by several pro-angiogenic stimuli. These novel findings suggest a potential repositioning of digitoxin as a broad-spectrum anti-angiogenic drug for diseases where pathological angiogenesis is involved. © 2017 The British Pharmacological Society.

  15. Senescence-inducible LEC2 enhances triacylglycerol accumulation in leaves without negatively affecting plant growth

    PubMed Central

    Kim, Hyun Uk; Lee, Kyeong-Ryeol; Jung, Su-Jin; Shin, Hyun A; Go, Young Sam; Suh, Mi-Chung; Kim, Jong Bum

    2017-01-01

    Summary The synthesis of fatty acids and glycerolipids in wild-type Arabidopsis leaves do not typically lead to strong triacylglycerol (TAG) accumulation. LEAFY COTYLEDON2 (LEC2) is a master regulator of seed maturation and oil accumulation in seeds. Constitutive ectopic LEC2 expression causes somatic embryogenesis and defects in seedling growth. Here, we report that senescence-inducible LEC2 expression caused a 3-fold increase in TAG levels in transgenic leaves compared with that in the leaves of wild-type plants. Plant growth was not severely affected by the accumulation the TAG in response to LEC2 expression. The levels of plastid-synthesized lipids, mono- and di-galactosyldiacylglycerol and phosphatidylglycerol, were reduced more in senescence-induced LEC2 than endoplasmic reticulum-synthesized lipids, including phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol. Senescence-induced LEC2 upregulated the expression of many genes involved in fatty acid and TAG biosynthesis at precise times in senescent leaves, including WRINKLED1 (WRI1), which encodes a fatty acid transcription factor. The expression of glycerol-3-phosphate dehydrogenase 1 and phospholipid:diacylglycerol 2 were increased in the transgenic leaves. Five seed-type oleosin-encoding genes, expressed during oil-body formation, and the seed-specific FAE1 gene, which encodes the enzyme responsible for the synthesis of C20:1 and C22:1 fatty acids, were also expressed at higher levels in senescing transgenic leaves than in wild-type leaves. Senescence-inducible LEC2 triggers the key metabolic steps that increase TAG accumulation in vegetative tissues. PMID:25790072

  16. Sphingosine-1-phosphate mediates epidermal growth factor-induced muscle satellite cell activation.

    PubMed

    Nagata, Yosuke; Ohashi, Kazuya; Wada, Eiji; Yuasa, Yuki; Shiozuka, Masataka; Nonomura, Yoshiaki; Matsuda, Ryoichi

    2014-08-01

    Skeletal muscle can regenerate repeatedly due to the presence of resident stem cells, called satellite cells. Because satellite cells are usually quiescent, they must be activated before participating in muscle regeneration in response to stimuli such as injury, overloading, and stretch. Although satellite cell activation is a crucial step in muscle regeneration, little is known of the molecular mechanisms controlling this process. Recent work showed that the bioactive lipid sphingosine-1-phosphate (S1P) plays crucial roles in the activation, proliferation, and differentiation of muscle satellite cells. We investigated the role of growth factors in S1P-mediated satellite cell activation. We found that epidermal growth factor (EGF) in combination with insulin induced proliferation of quiescent undifferentiated mouse myoblast C2C12 cells, which are also known as reserve cells, in serum-free conditions. Sphingosine kinase activity increased when reserve cells were stimulated with EGF. Treatment of reserve cells with the D-erythro-N,N-dimethylsphingosine, Sphingosine Kinase Inhibitor, or siRNA duplexes specific for sphingosine kinase 1, suppressed EGF-induced C2C12 activation. We also present the evidence showing the S1P receptor S1P2 is involved in EGF-induced reserve cell activation. Moreover, we demonstrated a combination of insulin and EGF promoted activation of satellite cells on single myofibers in a manner dependent on SPHK and S1P2. Taken together, our observations show that EGF-induced satellite cell activation is mediated by S1P and its receptor.

  17. Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis

    PubMed Central

    Chen, Zhenghu; Wang, Long; Yao, Dayong; Yang, Tianshu; Cao, Wen-Ming; Dou, Jun; Pang, Jonathan C.; Guan, Shan; Zhang, Huiyuan; Yu, Yang; Zhao, Yanling; Wang, Yongfeng; Xu, Xin; Shi, Yan; Patel, Roma; Zhang, Hong; Vasudevan, Sanjeev A.; Liu, Shangfeng; Yang, Jianhua; Nuchtern, Jed G.

    2016-01-01

    Neuroblastoma (NB) is the most common extracranial tumor in children. Unlike in most adult tumors, tumor suppressor protein 53 (p53) mutations occur with a relatively low frequency in NB and the downstream function of p53 is intact in NB cell lines. Wip1 is a negative regulator of p53 and hindrance of Wip1 activity by novel inhibitor GSK2830371 is a potential strategy to activate p53’s tumor suppressing function in NB. Yet, the in vivo efficacy and the possible mechanisms of GSK2830371 in NB have not yet been elucidated. Here we report that novel Wip1 inhibitor GSK2830371 induced Chk2/p53-mediated apoptosis in NB cells in a p53-dependent manner. In addition, GSK2830371 suppressed the colony-formation potential of p53 wild-type NB cell lines. Furthermore, GSK2830371 enhanced doxorubicin- (Dox) and etoposide- (VP-16) induced cytotoxicity in a subset of NB cell lines, including the chemoresistant LA-N-6 cell line. More importantly, GSK2830371 significantly inhibited tumor growth in an orthotopic xenograft NB mouse model by inducing Chk2/p53-mediated apoptosis in vivo. Taken together, this study suggests that GSK2830371 induces Chk2/p53-mediated apoptosis both in vitro and in vivo in a p53 dependent manner. PMID:27991505

  18. Interaction between human monocytes and vascular smooth muscle cells induces vascular endothelial growth factor expression.

    PubMed

    Hojo, Y; Ikeda, U; Maeda, Y; Takahashi, M; Takizawa, T; Okada, M; Funayama, H; Shimada, K

    2000-05-01

    The objective of this study was to investigate whether synthesis of vascular endothelial growth factor (VEGF), a major mitogen for vascular endothelial cells, was induced by a cell-to-cell interaction between monocytes and vascular smooth muscle cells (VSMCs). Human VSMCs and THP-1 cells (human monocytoid cell) were cocultured. VEGF levels in the coculture medium were determined by enzyme-linked immunosorbent assay. Northern blot analysis of VEGF mRNA was performed using a specific cDNA probe. Immunohistochemistry was performed to determine which types of cell produce VEGF. Adding THP-1 cells to VSMCs for 24 h increased VEGF levels of the culture media, 8- and 10-fold relative to those of THP-1 cells and VSMCs alone, respectively. Northern blot analysis showed that VEGF mRNA expression was induced in the cocultured cells and peaked after 12 h. Immunohistochemistry disclosed that both types of cell in the coculture produced VEGF. Separate coculture experiments revealed that both direct contact and a soluble factor(s) contributed to VEGF production. Neutralizing anti-interleukin (IL)-6 antibody inhibited VEGF production by the coculture of THP-1 cells and VSMCs. A cell-to-cell interaction between monocytes and VSMCs induced VEGF synthesis in both types of cell. An IL-6 mediated mechanism is at least partially involved in VEGF production by the cocultures. Local VEGF production induced by a monocyte-VSMC interaction may play an important role in atherosclerosis and vascular remodeling.

  19. Transforming growth factor β1 inhibition protects from noise-induced hearing loss

    PubMed Central

    Murillo-Cuesta, Silvia; Rodríguez-de la Rosa, Lourdes; Contreras, Julio; Celaya, Adelaida M.; Camarero, Guadalupe; Rivera, Teresa; Varela-Nieto, Isabel

    2015-01-01

    Excessive exposure to noise damages the principal cochlear structures leading to hearing impairment. Inflammatory and immune responses are central mechanisms in cochlear defensive response to noise but, if unregulated, they contribute to inner ear damage and hearing loss. Transforming growth factor β (TGF-β) is a key regulator of both responses and high levels of this factor have been associated with cochlear injury in hearing loss animal models. To evaluate the potential of targeting TGF-β as a therapeutic strategy for preventing or ameliorating noise-induced hearing loss (NIHL), we studied the auditory function, cochlear morphology, gene expression and oxidative stress markers in mice exposed to noise and treated with TGF-β1 peptidic inhibitors P17 and P144, just before or immediately after noise insult. Our results indicate that systemic administration of both peptides significantly improved both the evolution of hearing thresholds and the degenerative changes induced by noise-exposure in lateral wall structures. Moreover, treatments ameliorated the inflammatory state and redox balance. These therapeutic effects were dose-dependent and more effective if the TGF-β1 inhibitors were administered prior to inducing the injury. In conclusion, inhibition of TGF-β1 actions with antagonistic peptides represents a new, promising therapeutic strategy for the prevention and repair of noise-induced cochlear damage. PMID:25852546

  20. Epidermal growth factor-induced hydrogen peroxide production is mediated by dual oxidase 1.

    PubMed

    Sirokmány, Gábor; Pató, Anna; Zana, Melinda; Donkó, Ágnes; Bíró, Adrienn; Nagy, Péter; Geiszt, Miklós

    2016-08-01

    Stimulation of mammalian cells by epidermal growth factor (EGF) elicits complex signaling events, including an increase in hydrogen peroxide (H2O2) production. Understanding the significance of this response is limited by the fact that the source of EGF-induced H2O2 production is unknown. Here we show that EGF-induced H2O2 production in epidermal cell lines is dependent on the agonist-induced calcium signal. We analyzed the expression of NADPH oxidase isoforms and found both A431 and HaCaT cells to express the calcium-sensitive NADPH oxidase, Dual oxidase 1 (Duox1) and its protein partner Duox activator 1 (DuoxA1). Inhibition of Duox1 expression by small interfering RNAs eliminated EGF-induced H2O2 production in both cell lines. We also demonstrate that H2O2 production by Duox1 leads to the oxidation of thioredoxin-1 and the cytosolic peroxiredoxins. Our observations provide evidence for a new signaling paradigm in which changes of intracellular calcium concentration are transformed into redox signals through the calcium-dependent activation of Duox1. Copyright © 2016. Published by Elsevier Inc.

  1. NSAIDs induce apoptosis in nonproliferating ovarian cancer cells and inhibit tumor growth in vivo.

    PubMed

    Duncan, Kristal; Uwimpuhwe, Henriette; Czibere, Akos; Sarkar, Devanand; Libermann, Towia A; Fisher, Paul B; Zerbini, Luiz F

    2012-07-01

    Ovarian cancer (OC) is one of the most lethal gynaecological cancers, which usually has a poor prognosis due to late diagnosis. A large percentage of the OC cell population is in a nonproliferating and quiescent stage, which poses a barrier to success when using most chemotherapeutic agents. Recent studies have shown that several nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in the treatment of OC. Furthermore, we have previously described the molecular mechanisms of NSAIDs' induction of cancer apoptosis. In this report, we evaluated various structurally distinct NSAIDs for their efficacies in inducing apoptosis in nonproliferating OC cells. Although several NSAIDs-induced apoptosis, Flufenamic Acid, Flurbiprofen, Finasteride, Celocoxib, and Ibuprofen were the most potent NSAIDs inducing apoptosis. A combination of these agents resulted in an enhanced effect. Furthermore, we demonstrate that the combination of Flurbiprofen, which targets nonproliferative cells, and Sulindac Sulfide, that affects proliferative cells, strongly reduced tumor growth when compared with a single agent treatment. Our data strongly support the hypothesis that drug treatment regimens that target nonproliferating and proliferating cells may have significant efficacy against OC. These results also provide a rationale for employing compounds or even chemically modified NSAIDs, which selectively and efficiently induce apoptosis in cells during different stages of the cell cycle, to design more potent anticancer drugs.

  2. Ventilation-induced lung injury is not exacerbated by growth restriction in preterm lambs.

    PubMed

    Allison, Beth J; Hooper, Stuart B; Coia, Elise; Zahra, Valerie A; Jenkin, Graham; Malhotra, Atul; Sehgal, Arvind; Kluckow, Martin; Gill, Andrew W; Sozo, Foula; Miller, Suzanne L; Polglase, Graeme R

    2016-02-01

    Intrauterine growth restriction (IUGR) and preterm birth are frequent comorbidities and, combined, increase the risk of adverse respiratory outcomes compared with that in appropriately grown (AG) infants. Potential underlying reasons for this increased respiratory morbidity in IUGR infants compared with AG infants include altered fetal lung development, fetal lung inflammation, increased respiratory requirements, and/or increased ventilation-induced lung injury. IUGR was surgically induced in preterm fetal sheep (0.7 gestation) by ligation of a single umbilical artery. Four weeks later, preterm lambs were euthanized at delivery or delivered and ventilated for 2 h before euthanasia. Ventilator requirements, lung inflammation, early markers of lung injury, and morphological changes in lung parenchymal and vascular structure and surfactant composition were analyzed. IUGR preterm lambs weighed 30% less than AG preterm lambs, with increased brain-to-body weight ratio, indicating brain sparing. IUGR did not induce lung inflammation or injury or alter lung parenchymal and vascular structure compared with AG fetuses. IUGR and AG lambs had similar oxygenation and respiratory requirements after birth and had significant, but similar, increases in proinflammatory cytokine expression, lung injury markers, gene expression, and surfactant phosphatidylcholine species compared with unventilated controls. IUGR does not induce pulmonary structural changes in our model. Furthermore, IUGR and AG preterm lambs have similar ventilator requirements in the immediate postnatal period. This study suggests that increased morbidity and mortality in IUGR infants is not due to altered lung tissue or vascular structure, or to an altered response to early ventilation.

  3. Mycobacterium avium MAV2054 protein induces macrophage apoptosis by targeting mitochondria and reduces intracellular bacterial growth

    PubMed Central

    Lee, Kang-In; Whang, Jake; Choi, Han-Gyu; Son, Yeo-Jin; Jeon, Haet Sal; Back, Yong Woo; Park, Hye-Soo; Paik, Seungwha; Park, Jeong-Kyu; Choi, Chul Hee; Kim, Hwa-Jung

    2016-01-01

    Mycobacterium avium complex induces macrophage apoptosis. However, the M. avium components that inhibit or trigger apoptosis and their regulating mechanisms remain unclear. We recently identified the immunodominant MAV2054 protein by fractionating M. avium culture filtrate protein by multistep chromatography; this protein showed strong immuno-reactivity in M. avium complex pulmonary disease and in patients with tuberculosis. Here, we investigated the biological effects of MAV2054 on murine macrophages. Recombinant MAV2054 induced caspase-dependent macrophage apoptosis. Enhanced reactive oxygen species production and JNK activation were essential for MAV2054-mediated apoptosis and MAV2054-induced interleukin-6, tumour necrosis factor, and monocyte chemoattractant protein-1 production. MAV2054 was targeted to the mitochondrial compartment of macrophages treated with MAV2054 and infected with M. avium. Dissipation of the mitochondrial transmembrane potential (ΔΨm) and depletion of cytochrome c also occurred in MAV2054-treated macrophages. Apoptotic response, reactive oxygen species production, and ΔΨm collapse were significantly increased in bone marrow-derived macrophages infected with Mycobacterium smegmatis expressing MAV2054, compared to that in M. smegmatis control. Furthermore, MAV2054 expression suppressed intracellular growth of M. smegmatis and increased the survival rate of M. smegmatis-infected mice. Thus, MAV2054 induces apoptosis via a mitochondrial pathway in macrophages, which may be an innate cellular response to limit intracellular M. avium multiplication. PMID:27901051

  4. Keratinocyte growth factor protects against elastase-induced pulmonary emphysema in mice.

    PubMed

    Plantier, Laurent; Marchand-Adam, Sylvain; Antico Arciuch, Valeria G; Antico, Valeria G; Boyer, Laurent; De Coster, Cécile; Marchal, Joëlle; Bachoual, Rafik; Mailleux, Arnaud; Boczkowski, Jorge; Crestani, Bruno

    2007-11-01

    Pulmonary emphysema is characterized by persistent inflammation and progressive alveolar destruction. The keratinocyte growth factor (KGF) favorably influences alveolar maintenance and repair and possesses anti-inflammatory properties. We aimed to determine whether exogenous KGF prevented or corrected elastase-induced pulmonary emphysema in vivo. Treatment with 5 mg x kg(-1) x day(-1) KGF before elastase instillation prevented pulmonary emphysema. This effect was associated with 1) a sharp reduction in bronchoalveolar lavage fluid total protein and inflammatory cell recruitment, 2) a reduction in the pulmonary expression of the chemokines CCL2 (or monocyte chemoattractant protein-1) and CXCL2 (or macrophage inflammatory protein-2alpha) and of the adhesion molecules ICAM-1 and VCAM-1, 3) a reduction in matrix metalloproteinase (MMP)-2 and MMP-9 activity at day 3, and 4) a major reduction in DNA damage detected by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) in alveolar cells at day 7. Treatment with KGF after elastase instillation had no effect on elastase-induced emphysema despite the conserved expression of the KGF receptor in the lungs of elastase-instilled animals as determined by immunohistochemistry. In vitro, KGF abolished the elastase-induced increase in CCL2, CXCL2, and ICAM-1 mRNA in the MLE-12 murine alveolar epithelial cell line. We conclude that KGF pretreatment protected against elastase-induced pulmonary inflammation, activation of MMPs, alveolar cell DNA damage, and subsequent emphysema in mice.

  5. Cardamonin Regulates miR-21 Expression and Suppresses Angiogenesis Induced by Vascular Endothelial Growth Factor

    PubMed Central

    Jiang, Fu-Sheng; Tian, Sha-Sha; Lu, Jin-Jian; Ding, Xing-Hong; Qian, Chao-Dong; Ding, Bin; Ding, Zhi-Shan; Jin, Bo

    2015-01-01

    Cardamonin has promising potential in cancer prevention and therapy by interacting with proteins and modifying the expressions and activities, including factors of cell survival, proliferation, and angiogenesis. In our precious study, we have demonstrated that cardamonin suppressed vascular endothelial growth factor- (VEGF-) induced angiogenesis as evaluated in the mouse aortic ring assay. It is also known that microRNAs (miRNAs) play important roles in angiogenesis. Herein, we hypothesized whether antiangiogenesis effect of cardamonin in human umbilical vein endothelial cells (HUVECs) triggered by VEGF was associated with miRNAs. We found that cardamonin reduced the miR-21 expression induced by VEGF in HUVECs. Treatment with miR-21 mimics abolished the effects of cardamonin on VEGF-induced cell proliferation, migration, and angiogenesis in HUVECs. However, treatment with miR-21 inhibitors presented the opposite effects, indicating the vital role of miR-21 in this process. Our study provides a new insight of the preliminary mechanism of anti-VEGF-induced angiogenesis by cardamonin in HUVECs. PMID:26266258

  6. The onset and evolution of fatigue-induced abnormal grain growth in nanocrystalline Ni–Fe

    SciTech Connect

    Furnish, T. A.; Mehta, A.; Van Campen, D.; Bufford, D. C.; Hattar, K.; Boyce, B. L.

    2016-10-11

    Conventional structural metals suffer from fatigue-crack initiation through dislocation activity which forms persistent slip bands leading to notch-like extrusions and intrusions. Ultrafine-grained and nanocrystalline metals can potentially exhibit superior fatigue-crack initiation resistance by suppressing these cumulative dislocation activities. Prior studies on these metals have confirmed improved high-cycle fatigue performance. In the case of nano-grained metals, analyses of subsurface crack initiation sites have indicated that the crack nucleation is associated with abnormally large grains. But, these post-mortem analyses have led to only speculation about when abnormal grain growth occurs (e.g., during fatigue, after crack initiation, or during crack growth). In this study, a recently developed synchrotron X-ray diffraction technique was used to detect the onset and progression of abnormal grain growth during stress-controlled fatigue loading. Our study provides the first direct evidence that the grain coarsening is cyclically induced and occurs well before final fatigue failure—our results indicate that the first half of the fatigue life was spent prior to the detectable onset of abnormal grain growth, while the second half was spent coarsening the nanocrystalline structure and cyclically deforming the abnormally large grains until crack initiation. Post-mortem fractography, coupled with cycle-dependent diffraction data, provides the first details regarding the kinetics of this abnormal grain growth process during high-cycle fatigue testing. Finally, precession electron diffraction images collected in a transmission electron microscope after the in situ fatigue experiment also confirm the X-ray evidence that the abnormally large grains contain substantial misorientation gradients and sub-grain boundaries.

  7. Developmental hypothyroxinaemia induced by maternal mild iodine deficiency delays hippocampal axonal growth in the rat offspring.

    PubMed

    Wei, W; Wang, Y; Wang, Y; Dong, J; Min, H; Song, B; Teng, W; Xi, Q; Chen, J

    2013-09-01

    Iodine is essential for the biosynthesis of thyroid hormones, including triiodothyronine and thyroxine. Thyroid hormones are important for central nervous system development. Mild maternal iodine deficiency (ID)-induced hypothyroxinaemia causes neurological deficits and mental retardation of the foetus. However, the detailed mechanism underlying these deficits is still largely unknown. Given that the growth-associated protein of 43 kDa (GAP-43), semaphorin 3A (Sema3A) and the glycogen synthase kinase 3β (GSK3β)/collapsin response mediator protein 2 (CRMP2) pathway are essential for axonal development, we hypothesise that hippocampal axonal growth-related proteins may be impaired, which may contribute to hippocampal axonal growth delay in rat offspring exposed to maternal hypothyroxinaemia. To test this hypothesis, maternal hypothyroxinaemia models were established in Wistar rats using a mild ID diet. Besides a negative control group, two maternal hypothyroidism models were created with either a severe ID diet or methimazole in the water. Our results showed that maternal hypothyroxinaemia exposure delayed offspring axonal growth on gestational day 19, postnatal day (PN) 7, PN14 and PN21. Consistent with this, the mean intensity of hippocampal CRMP2 and Tau1 immunofluorescence axonal protein was reduced in the mild ID group. Moreover, maternal hypothyroxinaemia disrupted expressions of GAP-43 and Sema3A. Furthermore, the phosphorylation of GSK3β and CRMP2 was also affected in the treated offspring, implying a potential mechanism by which hypothyroxinaemia-exposure affects neurodevelopment. Taken together, our data support the hypothesis that maternal hypothyroxinaemia may impair axonal growth of the offspring. © 2013 British Society for Neuroendocrinology.

  8. FSGS as an Adaptive Response to Growth-Induced Podocyte Stress.

    PubMed

    Nishizono, Ryuzoh; Kikuchi, Masao; Wang, Su Q; Chowdhury, Mahboob; Nair, Viji; Hartman, John; Fukuda, Akihiro; Wickman, Larysa; Hodgin, Jeffrey B; Bitzer, Markus; Naik, Abhijit; Wiggins, Jocelyn; Kretzler, Matthias; Wiggins, Roger C

    2017-10-01

    Glomerular sclerotic lesions develop when the glomerular filtration surface area exceeds the availability of podocyte foot process coverage, but the mechanisms involved are incompletely characterized. We evaluated potential mechanisms using a transgenic (podocin promoter-AA-4E-BP1) rat in which podocyte capacity for hypertrophy in response to growth factor/nutrient signaling is impaired. FSGS lesions resembling human FSGS developed spontaneously by 7 months of age, and could be induced earlier by accelerating kidney hypertrophy by nephrectomy. Early segmental glomerular lesions occurred in the absence of a detectable reduction in average podocyte number per glomerulus and resulted from the loss of podocytes in individual glomerular capillary loops. Parietal epithelial cell division, accumulation on Bowman's capsule, and tuft invasion occurred at these sites. Three different interventions that prevented kidney growth and glomerular enlargement (calorie intake reduction, inhibition of mammalian target of rapamycin complex, and inhibition of angiotensin-converting enzyme) protected against FSGS lesion development, even when initiated late in the process. Ki67 nuclear staining and unbiased transcriptomic analysis identified increased glomerular (but not podocyte) cell cycling as necessary for FSGS lesion development. The rat FSGS-associated transcriptomic signature correlated with human glomerular transcriptomes associated with disease progression, compatible with similar processes occurring in man. We conclude that FSGS lesion development resulted from glomerular growth that exceeded the capacity of podocytes to adapt and adequately cover some parts of the filtration surface. Modest modulation of the growth side of this equation significantly ameliorated FSGS progression, suggesting that glomerular growth is an underappreciated therapeutic target for preservation of renal function. Copyright © 2017 by the American Society of Nephrology.

  9. α-Pinene Inhibits Growth and Induces Oxidative Stress in Roots

    PubMed Central

    SINGH, HARMINDER P.; BATISH, DAIZY R.; KAUR, SHALINDER; ARORA, KOMAL; KOHLI, RAVINDER K.

    2006-01-01

    • Background and Aims Determining the mode of action of allelochemicals is one of the challenging aspects in allelopathic studies. Recently, allelochemicals have been proposed to cause oxidative stress in target tissue and induce an antioxidant mechanism. α-Pinene, one of the common monoterpenoids emitted from several aromatic plants including forest trees, is known for its growth-inhibitory activity. However, its mechanism of action remains unexplored. The aim of the present study was to determine the inhibitory effect of α-pinene on root growth and generation of reactive oxygen species, as indicators of oxidative stress and changes in activities of antioxidant enzymes. • Methods Effects of α-pinene on early root growth were studied in five test species, Cassia occidentalis, Amaranthus viridis, Triticum aestivum, Pisum sativum and Cicer arietinum. Electrolyte leakage, lipid peroxidation, hydrogen peroxide generation, proline accumulation, and activities of the enzymes superoxide dismutase (SOD), ascorbate peroxidase (APX), guaiacol peroxidase (GPX), catalase (CAT) and glutathione reductase (GR) were studied in roots of C. occidentalis. • Key Results α-Pinene inhibited the radicle growth of all the test species. Exposure of C. occidentalis roots to α-pinene enhanced solute leakage, and increased levels of malondialdehyde, proline and hydrogen peroxide, indicating lipid peroxidation and induction of oxidative stress. Activities of the antioxidant enzymes SOD, CAT, GPX, APX and GR were significantly elevated, thereby indicating the enhanced generation of reactive oxygen species (ROS) upon α-pinene exposure. Increased levels of scavenging enzymes indicates their induction as a secondary defence mechanism in response to α-pinene. • Conclusions It is concluded that α-pinene inhibits early root growth and causes oxidative damage in root tissue through enhanced generation of ROS, as indicated by increased lipid peroxidation, disruption of membrane

  10. Low-temperature laser-induced selective area growth of compound semiconductor

    SciTech Connect

    Uppili, S.

    1990-01-01

    Laser induced epitaxial growth of gallium phosphide was investigated as a low temperature, spatially selective process using both pyrolytic and photolytic reaction. A focussed beam from an argon ion laser operating at 514.5 nm was used to direct-write epitaxial microstructures of homoepitaxial GaP using a pyrolytic process. The precursors were trimethyl gallium (TMG) and tertiary butylphosphine (TBP). Dependence of the epitaxial growth on several deposition parameters was examined. An ArF excimer laser was also used to achieve homoepitaxy and heteroepitaxy of gallium phosphide on gallium arsenide at 500 C using TMG and TBP as the precusor gases. Dependence of homoepitaxial growth of GaP on several parameters is examined. The crystalline properties of the film were determined using transmission electron microscopy (TEM). Electrical properties of p-n diodes fabricated via Zn doping were also examined. Defect structures in excimer laser-assisted epitaxial GaP on (100) GaP and (100) GaAs were examined using TEM. Periodic structures were obtained using nominally unpolarized excimer laser radiation, during heteroepitaxial growth of GaP on GaAs. Both crystalline properties and chemical composition of these structures were examined. Microanalysis showed modulation in composition in the ripple structure resulting from the thermal variation caused by the optical interference during growth. Electrical conductivity measurements of GaP during pulsed lasers irradiation indicated that in the absence of gases, there was appreciable heating of the semiconductor. However, a very small quantity of hydrogen or helium cooled the substrate appreciably. This suggested that the average temperature rise of the substrate was not an important factor in the temperature calculations used in the present investigation.

  11. The onset and evolution of fatigue-induced abnormal grain growth in nanocrystalline Ni–Fe

    DOE PAGES

    Furnish, T. A.; Mehta, A.; Van Campen, D.; ...

    2016-10-11

    Conventional structural metals suffer from fatigue-crack initiation through dislocation activity which forms persistent slip bands leading to notch-like extrusions and intrusions. Ultrafine-grained and nanocrystalline metals can potentially exhibit superior fatigue-crack initiation resistance by suppressing these cumulative dislocation activities. Prior studies on these metals have confirmed improved high-cycle fatigue performance. In the case of nano-grained metals, analyses of subsurface crack initiation sites have indicated that the crack nucleation is associated with abnormally large grains. But, these post-mortem analyses have led to only speculation about when abnormal grain growth occurs (e.g., during fatigue, after crack initiation, or during crack growth). In thismore » study, a recently developed synchrotron X-ray diffraction technique was used to detect the onset and progression of abnormal grain growth during stress-controlled fatigue loading. Our study provides the first direct evidence that the grain coarsening is cyclically induced and occurs well before final fatigue failure—our results indicate that the first half of the fatigue life was spent prior to the detectable onset of abnormal grain growth, while the second half was spent coarsening the nanocrystalline structure and cyclically deforming the abnormally large grains until crack initiation. Post-mortem fractography, coupled with cycle-dependent diffraction data, provides the first details regarding the kinetics of this abnormal grain growth process during high-cycle fatigue testing. Finally, precession electron diffraction images collected in a transmission electron microscope after the in situ fatigue experiment also confirm the X-ray evidence that the abnormally large grains contain substantial misorientation gradients and sub-grain boundaries.« less

  12. Effects of hypothalamic dopamine on growth hormone-releasing hormone-induced growth hormone secretion and thyrotropin-releasing hormone-induced prolactin secretion in goats.

    PubMed

    Jin, Jin; Hashizume, Tsutomu

    2015-06-01

    The aim of the present study was to clarify the effects of hypothalamic dopamine (DA) on the secretion of growth hormone (GH) in goats. The GH-releasing response to an intravenous (i.v.) injection of GH-releasing hormone (GHRH, 0.25 μg/kg body weight (BW)) was examined after treatments to augment central DA using carbidopa (carbi, 1 mg/kg BW) and L-dopa (1 mg/kg BW) in male and female goats under a 16-h photoperiod (16 h light, 8 h dark) condition. GHRH significantly and rapidly stimulated the release of GH after its i.v. administration to goats (P < 0.05). The carbi and L-dopa treatments completely suppressed GH-releasing responses to GHRH in both male and female goats (P < 0.05). The prolactin (PRL)-releasing response to an i.v. injection of thyrotropin-releasing hormone (TRH, 1 μg/kg BW) was additionally examined in male goats in this study to confirm modifications to central DA concentrations. The treatments with carbi and L-dopa significantly reduced TRH-induced PRL release in goats (P < 0.05). These results demonstrated that hypothalamic DA was involved in the regulatory mechanisms of GH, as well as PRL secretion in goats.

  13. Integrated modeling and parallel computation of laser-induced axisymmetric rod growth

    NASA Astrophysics Data System (ADS)

    Lan, Hong

    2005-07-01

    To fully investigate a pyrolytic Laser-induced chemical vapor deposition (LCVD) system for growing an axisymmetric rod, a novel integrated three-dimensional mathematical model was developed not only to describe the heat transport in the deposit and substrate, but also to simulate the gas-phase in the heated reaction zone and its effect on growth rate. The integrated model consists of three components: the substrate, rod, and gas-phase domains. Each component is a separate model and the three components are dynamically integrated into one model for simulating the iterative and complex process of rod deposition. The gas-phase reaction is modeled by the gas-phase component, an adaptive domain attached on the top part of the rod. Its size and mesh decomposition is dynamically determined by the rod temperature distribution and the chosen threshold. The temperature and molar ratio are predicted and used to adjust the growth rate, by taking into account the diffusion limited growth regime, and to improve the simulation of entire deposition process. The substrate component describes the heat flow into the substrate, and the substrate surface temperature can be used to predict the initial rod growth which may affect the successive growth of the rod. The rod growth process is simulated using a layer-by-layer axisymmetric model. For each layer, the rod grows along the outward normal direction at each point on the rod surface. This simplified model makes the process more predictable and easier to control by specifying the height of the rod and the number of total iterations. Finite difference schemes, iterative numerical methods, and parallel algorithms were developed for solving the model. The numerical computation is stable, convergent, and efficient. The model and numerical methods are implemented sequentially and in parallel using a standard C++ code and Message Passing Interface (MPI). The program can be easily installed and executed on different platforms, such as Unix

  14. Growth and decay of quantum turbulence induced by second sound shock pulses in helium II

    NASA Astrophysics Data System (ADS)

    Hilton, David K.

    2003-10-01

    New to physics, the experiments of this dissertation successfully acquired clear and extensive direct measurements in He II at 1.7 K of quantum turbulence induced by second sound shock pulses in a wide channel. Such pulses are moving volume sources of power flux density. The Vinen and Hall equation cannot be directly applied to describe the induced quantum turbulence dynamics. Alternatively, a leaky capacitor fit (LCF) to the excess attenuation coefficient measurements, based on an electric energy analogy, was developed to extract a growth and decay characterization of the corresponding induced turbulence. The fit parameters are tabulated to give a complete description of the measurements, indexed by the initial pulse duration and power flux density, with distance from the pulse heater as a table parameter. The quantum turbulence is induced in the presence of a background quantum turbulence resulting from the heaters of the second sound resonators monitoring in near real-time for the induced turbulence. This background is at steady-state, but not under experimental control. However, as a reasonable assumption, the apparent propagation of the induced quantum turbulence trailing the second sound shock pulse is mediated by the background. The nucleation of the induced turbulence by the pulse is not considered, since the background is prenucleation. The background, established in about 350 ms and estimated to be 22 Gm/m 3, is about one or two orders of magnitude larger than the induced turbulence measured. Accounting for pulse energy by plotting energy transport fraction versus initial pulse energy, a breakpoint initial pulse energy concept is suggested. This is in contrast with a breakpoint initial pulse power discussed by previous researchers. This breakpoint energy is about 75 J/m2 in the absence of the background estimated above. Being in quiescent He II then, this is a characteristic of all second sound shock pulses. The energy dropped beyond the breakpoint

  15. A Comparison of Oligogalacturonide- and Auxin-Induced Extracellular Alkalinization and Growth Responses in Roots of Intact Cucumber Seedlings1

    PubMed Central

    Spiro, Mark D.; Bowers, Jonathan F.; Cosgrove, Daniel J.

    2002-01-01

    Oligogalacturonic acid (OGA) affects plant growth and development in an antagonistic manner to that of the auxin indole-3-acetic acid (IAA), the mechanism by which remains to be determined. This study describes the relationship between IAA and OGA activity in intact cucumber (Cucumis sativus) seedlings. Both OGA and IAA induced rapid and transient extracellular alkalinization; however, the characteristics of the OGA and IAA responses differed in their kinetics, magnitude, calcium dependence, and region of the root in which they induced their maximal response. IAA (1 μm) induced a saturating alkalinization response of approximately 0.2 pH unit and a rapid reduction (approximately 80%) in root growth that only partially recovered over 20 h. OGAs, specifically those with a degree of polymerization of 10 to 13, induced a maximal alkalinization response of 0.48 pH unit, but OGA treatment did not alter root growth. Saturating concentrations of OGA did not block IAA-induced alkalinization or the initial IAA-induced inhibition of root growth but allowed IAA-treated roots to recover their initial growth rate within 270 min. IAA-induced alkalinization occurs primarily in the growing apical region of the root, whereas OGA induced its maximal response in the basal region of the root. This study demonstrates that OGA and IAA act by distinct mechanisms and that OGA does not simply act by inhibition of IAA action. These results also suggest that IAA-induced extracellular alkalinization is not sufficient to account for the mechanism by which IAA inhibits root growth. PMID:12376654

  16. Potential mechanisms for hypoalgesia induced by anti-nerve growth factor immunoglobulin are identified using autoimmune nerve growth factor deprivation

    PubMed Central

    Hoffman, E. Matthew; Zhang, Zijia; Anderson, Michael B.; Schechter, Ruben; Miller, Kenneth E.

    2011-01-01

    Nerve growth factor (NGF) antagonism has long been proposed as a chronic pain treatment. In 2010, the FDA suspended clinical trials using tanezumab, a humanized monoclonal anti-NGF antibody, to treat osteoarthritis due to worsening joint damage in 16 patients. Increased physical activity in the absence of acute pain which normally prevents self harm was purported as a potential cause. Such an adverse effect is consistent with an extension of tanezumab's primary mechanism of action by decreasing pain sensitivity below baseline levels. In animal inflammatory pain models, NGF antagonism decreases intraepidermal nerve fiber (IENF) density and attenuates increases in expression of nociception related proteins, such as calcitonin gene-related peptide (CGRP) and substance P (SP). Little is known of the effects of NGF antagonism in noninflamed animals and the hypoalgesia that ensues. In the current study, we immunized rats with NGF or cytochrome C (cytC) and examined 1) nocifensive behaviors with thermal latencies, mechanical thresholds, the hot plate test, and the tail flick test, 2) IENF density, and 3) expression of CGRP, SP, voltage-gated sodium channel 1.8 (Nav1.8), and glutaminase in subpopulations of dorsal root ganglion (DRG) neurons separated by size and isolectin B4 (IB4) labeling. Rats with high anti-NGF titers had delayed responses on the hot plate test but no other behavioral abnormalities. Delayed hot plate responses correlated with lower IENF density. CGRP and SP expression was decreased principally in medium (400-800 μm2) and small neurons (<400 μm2), respectively, regardless of IB4 labeling. Expression of Nav1.8 was only decreased in small and medium IB4 negative neurons. NGF immunization appears to result in a more profound antagonism of NGF than tanezumab therapy, but we hypothesize that decreases in IENF density and nociception related protein expression are potential mechanisms for tanezumab induced hypoalgesia. PMID:21802499

  17. Tetrahydrobiopterin Protects against Radiation-induced Growth Inhibition in H9c2 Cardiomyocytes

    PubMed Central

    Zhang, Zheng-Yi; Li, Yi; Li, Rui; Zhang, An-An; Shang, Bo; Yu, Jing; Xie, Xiao-Dong

    2016-01-01

    Background: Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthases (NOSs) for the synthesis of nitric oxide (NO). BH4 therapy can reverse the disease-related redox disequilibrium observed with BH4 deficiency. However, whether BH4 exerts a protective effect against radiation-induced damage to cardiomyocytes remains unknown. Methods: Clonogenic assays were performed to determine the effects of X-ray on H9c2 cells with or without BH4 treatment. The contents of lactate dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde (MDA) in H9c2 cells were measured to investigate oxidative stress levels. The cell cycle undergoing radiation with or without BH4 treatment was detected using flow cytometry. The expression levels of proteins in the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT)/P53 signaling pathway, inducible NOS (iNOS), and endothelial NOS (eNOS) were examined using Western blotting. Results: X-ray radiation significantly inhibited the growth of H9c2 cells in a dose-dependent manner, whereas BH4 treatment significantly reduced the X-ray radiation-induced growth inhibition (control group vs. X-ray groups, respectively, P < 0.01). X-ray radiation induced LDH release, apoptosis, and G0/G1 peak accumulation, significantly increasing the level of MDA and the production of NO, and decreased the level of SOD (control group vs. X-ray groups, respectively, P < 0.05 or P < 0.01). By contrast, BH4 treatment can significantly reverse these processes (BH4 treatment groups vs. X-ray groups, P < 0.05 or P < 0.01). BH4 reversed the X-ray radiation-induced expression alterations of apoptosis-related molecules, including B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein, and caspase-3, and molecules of the PI3K/Akt/P53 signaling pathway. BH4 enhanced the production of NO in 2 Gy and 4 Gy radiated groups by upregulating eNOS protein expression and downregulating iNOS protein expression. Conclusions: BH4 treatment can protect

  18. Secreted proteins induced by epidermal growth factor and transforming growth factor beta in EL2 rat fibroblasts. Role in the mitogenic response.

    PubMed

    Di Francesco, P; Favalli, C; Liboi, E

    1988-05-01

    Most growth active hormones and peptides are mitogenic only in the presence of other growth factors [e.g., Platelet Derived Growth Factor (PDGF) and Epidermal Growth Factor (EGF) in "competence-progression" fibroblast model]. We have previously described that EGF alone is able to induce the signals which appear necessary for the mitogenic stimulation of EL2 rat embryo fibroblast line. Recently, we have demonstrated that Transforming Growth Factor beta (TGF beta) slightly stimulates the mitogenic response in EL2 cells. Here, we show that in EGF-treated EL2 cells the induction of at least four inducible-secreted proteins (ISPs, range from 29,000 to 68,000 Mr) is accompanied by a marked increase in DNA synthesis. In contrast, TGF beta or different concentrations of EGF induce a slow increase of the ISPs proportional to slow induction in DNA synthesis. Our results suggest that the mitogenic response in EL2 cell line may be connected with the qualitative and quantitative induction of these secreted proteins.

  19. A film-rupture model of hydrogen-induced, slow crack growth in alpha-beta titanium

    NASA Technical Reports Server (NTRS)

    Nelson, H. G.

    1975-01-01

    The appearance of the terrace like fracture morphology of gaseous hydrogen induced crack growth in acicular alpha-beta titanium alloys is discussed as a function of specimen configuration, magnitude of applied stress intensity, test temperature, and hydrogen pressure. Although the overall appearance of the terrace structure remained essentially unchanged, a distinguishable variation is found in the size of the individual terrace steps, and step size is found to be inversely dependent upon the rate of hydrogen induced slow crack growth. Additionally, this inverse relationship is independent of all the variables investigated. These observations are quantitatively discussed in terms of the formation and growth of a thin hydride film along the alpha-beta boundaries and a qualitative model for hydrogen induced slow crack growth is presented, based on the film-rupture model of stress corrosion cracking.

  20. Kaempferol suppresses bladder cancer tumor growth by inhibiting cell proliferation and inducing apoptosis.

    PubMed

    Dang, Qiang; Song, Wenbin; Xu, Defeng; Ma, Yanmin; Li, Feng; Zeng, Jin; Zhu, Guodong; Wang, Xinyang; Chang, Luke S; He, Dalin; Li, Lei

    2015-09-01

    The effects of the flavonoid compound, kaempferol, which is an inhibitor of cancer cell proliferation and an inducer of cell apoptosis have been shown in various cancers, including lung, pancreatic, and ovarian, but its effect has never been studied in bladder cancer. Here, we investigated the effects of kaempferol on bladder cancer using multiple in vitro cell lines and in vivo mice studies. The MTT assay results on various bladder cancer cell lines showed that kaempferol enhanced bladder cancer cell cytotoxicity. In contrast, when analyzed by the flow cytometric analysis, DNA ladder experiment, and TUNEL assay, kaempferol significantly was shown to induce apoptosis and cell cycle arrest. These in vitro results were confirmed in in vivo mice studies using subcutaneous xenografted mouse models. Consistent with the in vitro results, we found that treating mice with kaempferol significant suppression in tumor growth compared to the control group mice. Tumor tissue staining results showed decreased expressions of the growth related markers, yet increased expressions in apoptosis markers in the kaempferol treated group mice tissues compared to the control group mice. In addition, our in vitro and in vivo data showed kaempferol can also inhibit bladder cancer invasion and metastasis. Further mechanism dissection studies showed that significant down-regulation of the c-Met/p38 signaling pathway is responsible for the kaempferol mediated cell proliferation inhibition. All these findings suggest kaempferol might be an effective and novel chemotherapeutic drug to apply for the future therapeutic agent to combat bladder cancer.

  1. Growth-induced optical anisotropy of epitaxial garnet films grown on (110)-oriented substrates

    NASA Astrophysics Data System (ADS)

    Kitamura, K.; Iyi, N.; Kimura, S.; Chevrier, F.; Devignes, J. M.; Le Gall, H.

    1986-08-01

    Garnet films of nominal composition (Y,Nd)3Ga5O12, were grown on (110) 1°-off Gd3Ga5O12 substrates for investigation of their growth-induced optical anisotropy. Optical birefringence and directions of the electric vectors of polarized rays passing through the films were measured under a polarizing microscope using a Brace-Köhler compensator. The growth-induced anisotropy of these films optically exhibited orthorhombic characteristics with the X, Y, and Z optic elasticity axes coinciding with the [001], [110], and [1¯10] directions, respectively. The crystallographic data obtained by means of single-crystal diffractometry suggested that the cubic crystal system of the garnet film was distorted, though very slightly, to an orthorhombic one with a,b, and c axes that coincided, respectively, with the [1¯10],[001], and [110] of the original cubic cell. In addition, by annealing at 1150 °C, this distortion disappeared and the crystal system reverted to cubic.

  2. Rapamycin Prevents Transforming Growth Factor-α–Induced Pulmonary Fibrosis

    PubMed Central

    Korfhagen, Thomas R.; Le Cras, Timothy D.; Davidson, Cynthia R.; Schmidt, Stephanie M.; Ikegami, Machiko; Whitsett, Jeffrey A.; Hardie, William D.

    2009-01-01

    Transforming growth factor (TGF)-α is a ligand for the epidermal growth factor receptor (EGFR). EGFR activation is associated with fibroproliferative processes in human lung disease and animal models of pulmonary fibrosis. Overexpression of TGF-α in transgenic mice causes progressive and severe pulmonary fibrosis; however, the intracellular signaling pathways downstream of EGFR mediating this response are unknown. Using a doxycycline-regulatable transgenic mouse model of lung-specific TGF-α expression, we observed increased PCNA protein and phosphorylation of Akt and p70S6K in whole lung homogenates in association with induction of TGF-α. Induction in the lung of TGF-α caused progressive pulmonary fibrosis over a 7-week period. Daily administration of rapamycin prevented accumulation of total lung collagen, weight loss, and changes in pulmonary mechanics. Treatment of mice with rapamycin 4 weeks after the induction of TGF-α prevented additional weight loss, increases in total collagen, and changes in pulmonary mechanics. Rapamycin prevented further increases in established pulmonary fibrosis induced by EGFR activation. This study demonstrates that mammalian target of rapamycin (mTOR) is a major effector of EGFR-induced pulmonary fibrosis, providing support for further studies to determine the role of mTOR in the pathogenesis and treatment of pulmonary fibrosis. PMID:19244201

  3. Hypoxia Induced Energy Stress Regulates mRNA Translation and Cell Growth

    PubMed Central

    Liu, Liping; Cash, Timothy P.; Jones, Russell G.; Keith, Brian; Thompson, Craig B.; Simon, M. Celeste

    2011-01-01

    Oxygen deprivation, or hypoxia, has profound effects on cell metabolism and growth. Cells can adapt to low O2 in part through activation of hypoxia-inducible factor (HIF). We report here that hypoxia inhibits mRNA translation by suppressing multiple key regulators including eIF2α, eEF2, and the mTOR effectors 4EBP1, p70S6K, and rpS6, independent of HIF. Hypoxia results in energy starvation and activation of the AMPK/TSC2/Rheb/mTOR pathway. Hypoxic AMPK activation also leads to eEF2 inhibition. Moreover, hypoxic effects on cellular bioenergetics and mTOR inhibition increase over time. Mutation of the TSC2 tumor suppressor gene confers a growth advantage to cells by repressing hypoxic mTOR inhibition and hypoxia-induced G1 arrest. Together, eIF2α, eEF2 and mTOR inhibition represent important HIF-independent mechanisms of energy conservation which promote survival under low O2 conditions. PMID:16483933

  4. Effect of ultraviolet light on topical minoxidil-induced hair growth in advanced male pattern baldness.

    PubMed

    Pestana, A; Olsen, E A; Delong, E R; Murray, J C

    1987-05-01

    Nine healthy men with type IVa or Va male pattern baldness completed a 4-month single-blinded controlled pilot study designed to assess the effect of ultraviolet light (UVL) on topical minoxidil-induced hair growth. Subjects applied 2% topical minoxidil solution twice daily to their balding scalps and to one target area on the upper arm. These men, all of whom had either skin type II or III, were randomized to also receive either incremental doses of UVB or PUVA (topical psoralen) twice weekly to one side of their scalp and to a 2.5 cm target area on the nonminoxidil-treated upper ipsilateral arm. Vellus, nonvellus, and total hair counts were done in two 1-inch in diameter circular target areas in symmetric regions of the scalp and on each upper arm at regular intervals. All nine subjects had an increase in target nonvellus hair and a net loss of vellus hair in scalp target area treated with topical minoxidil. Concomitant UVL did not have a significant synergistic nor adverse effect on topical minoxidil-induced hair growth.

  5. Isoliquiritigenin induces apoptosis and autophagy and inhibits endometrial cancer growth in mice

    PubMed Central

    Shieh, Tzong-Ming; Huang, Tsui-Chin; Lin, Li-Chun; Wang, Kai-Lee; Hsia, Shih-Min

    2016-01-01

    Endometrial cancer is the most common cancer in women, typically with onset after menopause. Isoliquiritigenin (ISL), a licorice flavonoid, was previously shown to have anti-oxidant, anti-inflammatory, and tumor suppression effects. In this study, we investigated the anti-tumor effect of ISL on human endometrial cancer both in vitro and in vivo. We used telomerase-immortalized human endometrial stromal cells (T-HESCs) and human endometrial cancer cell lines (Ishikawa, HEC-1A, and RL95-2 cells) as targets. The effects of ISL on cell proliferation, cell cycle regulation, and apoptosis or autophagy-related protein expression were examined. In addition, we conducted in vivo experiments to confirm the inhibitory effects of ISL on cancer cells. ISL significantly inhibited the viability of cancer cells in a dose- and time-dependent manner but with little toxicity on normal cells. In addition, flow cytometry analysis indicated that ISL induced sub-G1 or G2/M phase arrest. ISL treatment activated the extracellular signal regulated kinase signaling pathway to enhance the protein expression of caspase-7/LC3BII associated with apoptosis/autophagy. Furthermore, ISL suppressed xenograft tumor growth in vivo. Taken together, these findings suggest that ISL may induce apoptosis, autophagy, and cell growth inhibition, indicating its potential as a therapeutic agent for human endometrial cancer. PMID:27708238

  6. Growth hormone secretagogue receptor deficiency in mice protects against obesity‐induced hypertension

    PubMed Central

    Harris, Louise E.; Morgan, David G.; Balthasar, Nina

    2014-01-01

    Abstract Growth hormone secretagogue receptor (GHS‐R) signaling has been associated with growth hormone release, increases in food intake and pleiotropic cardiovascular effects. Recent data demonstrated that acute GHS‐R antagonism leads to increases in mean arterial pressure mediated by the sympathetic nervous system in rats; a highly undesirable effect if GHS‐R antagonism was to be used as a therapeutic approach to reducing food intake in an already obese, hypertensive patient population. However, our data in conscious, freely moving GHS‐R deficient mice demonstrate that chronic absence of GHS‐R signaling is protective against obesity‐induced hypertension. GHS‐R deficiency leads to reduced systolic blood pressure variability (SBPV); in response to acute high‐fat diet (HFD)‐feeding, increases in the sympathetic control of SBPV are suppressed in GHS‐R KO mice. Our data further suggest that GHS‐R signaling dampens the immediate HFD‐mediated increase in spontaneous baroreflex sensitivity. In diet‐induced obesity, absence of GHS‐R signaling leads to reductions in obesity‐mediated hypertension and tachycardia. Collectively, our findings thus suggest that chronic blockade of GHS‐R signaling may not result in adverse cardiovascular effects in obesity. PMID:24760503

  7. Copper-induced vascular endothelial growth factor expression and wound healing.

    PubMed

    Sen, Chandan K; Khanna, Savita; Venojarvi, Mika; Trikha, Prashant; Ellison, E Christopher; Hunt, Thomas K; Roy, Sashwati

    2002-05-01

    Angiogenesis plays a central role in wound healing. Among many known growth factors, vascular endothelial growth factor (VEGF) is believed to be the most prevalent, efficacious, and long-term signal that is known to stimulate angiogenesis in wounds. Whereas a direct role of copper to facilitate angiogenesis has been evident two decades ago, the specific targets of copper action remained unclear. This report presents first evidence showing that inducible VEGF expression is sensitive to copper and that the angiogenic potential of copper may be harnessed to accelerate dermal wound contraction and closure. At physiologically relevant concentrations, copper sulfate induced VEGF expression in primary as well as transformed human keratinocytes. Copper shared some of the pathways utilized by hypoxia to regulate VEGF expression. Topical copper sulfate accelerated closure of excisional murine dermal wound allowed to heal by secondary intention. Copper-sensitive pathways regulate key mediators of wound healing such as angiogenesis and extracellular matrix remodeling. Copper-based therapeutics represents a feasible approach to promote dermal wound healing.

  8. [Study on exogenous hormones inducing parthenocarpy fruit growth and development and quality of Siraitia grosvenorii].

    PubMed

    Huang, Jie; Tu, Dong-ping; Ma, Xiao-jun; Mo, Chang-ming; Pan, Li-mei; Bai, Long-hua; Feng, Shi-xin

    2015-09-01

    To explore the growth and development and analyze the quality of the parthenocarpy fruit induced by exogenous hormones of Siraitia grosvenorii. the horizontal and vertical diameter, volume of the fruit were respectively measured by morphological and the content of endogenous hormones were determined by ELISA. The size and seed and content of mogrosides of mature fruit were determined. The results showed that the fruit of parthenocarpy was seedless and its growth and development is similar to the diploid fruit by hand pollination and triploid fruit by hand pollination or hormones. But the absolute value of horizontal and vertical diameter, volume of parthenocarpy fruit was less than those of fruit by hand pollination, while triploid was opposite. The content of IAA, ABA and ratio of ABA/GA was obviously wavy. At 0-30 d the content of IAA and ABA of parthenocarpy fruit first reduced then increased, content of IAA and GA parthenocarpy fruit was higher than that of fruit by hand pollination. Mogrosides of parthenocarpy fruit was close to pollination fruit. Hormones can induce S. grosvenorii parthenocarpy to get seedless fruit and the fruit shape and size and quality is close to normal diploid fruit by hand pollination and better than triploid fruit by hormone or hand pollination.

  9. Cannabidiol rather than Cannabis sativa extracts inhibit cell growth and induce apoptosis in cervical cancer cells.

    PubMed

    Lukhele, Sindiswa T; Motadi, Lesetja R

    2016-09-01

    Cervical cancer remains a global health related issue among females of Sub-Saharan Africa, with over half a million new cases reported each year. Different therapeutic regimens have been suggested in various regions of Africa, however, over a quarter of a million women die of cervical cancer, annually. This makes it the most lethal cancer amongst black women and calls for urgent therapeutic strategies. In this study we compare the anti-proliferative effects of crude extract of Cannabis sativa and its main compound cannabidiol on different cervical cancer cell lines. To achieve our aim, phytochemical screening, MTT assay, cell growth analysis, flow cytometry, morphology analysis, Western blot, caspase 3/7 assay, and ATP measurement assay were conducted. Results obtained indicate that both cannabidiol and Cannabis sativa extracts were able to halt cell proliferation in all cell lines at varying concentrations. They further revealed that apoptosis was induced by cannabidiol as shown by increased subG0/G1 and apoptosis through annexin V. Apoptosis was confirmed by overexpression of p53, caspase 3 and bax. Apoptosis induction was further confirmed by morphological changes, an increase in Caspase 3/7 and a decrease in the ATP levels. In conclusion, these data suggest that cannabidiol rather than Cannabis sativa crude extracts prevent cell growth and induce cell death in cervical cancer cell lines.

  10. Interrelationship between growth factor-induced pH changes and intracellular Ca/sup 2 +/

    SciTech Connect

    Ives, H.E.; Daniel, T.O.

    1987-04-01

    Many mitogens cause rapid changes in intracellular pH and Ca/sup 2 +/. The authors studied the patterns of pH and Ca/sup 2 +/ changes after exposure of murine fibroblasts to platelet-derived growth factor (PDGF), bombesin, phorbol 12-myristate 13-acetate (PMA), and the vasoactive peptide bradykinin. Intracellular pH and Ca/sup 2 +/ were measured by using the fluorescent dyes 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein and fura-2. Three distinct patterns of intracellular pH change were observed. (i) PDGF and bombesin caused a rapid cytoplasmic acidification of 0.03 pH unit followed by a slower alkalinization of approx. = 0.11 pH unit above the resting pH of 6.88. (ii) PMA caused alkalinization without causing the early acidification. (iii) Bradykinin caused rapid acidification without the slower net alkalinization. All acidification responses were amiloride resistant. Patterns of intracellular Ca/sup 2 +/ response were also determined for each agent. In Ca/sup 2 +/-buffered cells, PDGF, bombesin, bradykinin, and ionomycin failed to induce cellular acidification, but alkalinization responses to PDGF, bombesin, and PMA persisted. They propose that the transient acidification seen with PDGF, bombesin, and other agents is the result of increased intracellular Ca/sup 2 +/. However, growth factor-induced alkalinization via the Na/sup +//H/sup +/ exchanger is independent of changes in Ca/sup 2 +/.

  11. Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors.

    PubMed

    Stylianopoulos, Triantafyllos; Martin, John D; Chauhan, Vikash P; Jain, Saloni R; Diop-Frimpong, Benjamin; Bardeesy, Nabeel; Smith, Barbara L; Ferrone, Cristina R; Hornicek, Francis J; Boucher, Yves; Munn, Lance L; Jain, Rakesh K

    2012-09-18

    The presence of growth-induced solid stresses in tumors has been suspected for some time, but these stresses were largely estimated using mathematical models. Solid stresses can deform the surrounding tissues and compress intratumoral lymphatic and blood vessels. Compression of lymphatic vessels elevates interstitial fluid pressure, whereas compression of blood vessels reduces blood flow. Reduced blood flow, in turn, leads to hypoxia, which promotes tumor progression, immunosuppression, inflammation, invasion, and metastasis and lowers the efficacy of chemo-, radio-, and immunotherapies. Thus, strategies designed to alleviate solid stress have the potential to improve cancer treatment. However, a lack of methods for measuring solid stress has hindered the development of solid stress-alleviating drugs. Here, we present a simple technique to estimate the growth-induced solid stress accumulated within animal and human tumors, and we show that this stress can be reduced by depleting cancer cells, fibroblasts, collagen, and/or hyaluronan, resulting in improved tumor perfusion. Furthermore, we show that therapeutic depletion of carcinoma-associated fibroblasts with an inhibitor of the sonic hedgehog pathway reduces solid stress, decompresses blood and lymphatic vessels, and increases perfusion. In addition to providing insights into the mechanopathology of tumors, our approach can serve as a rapid screen for stress-reducing and perfusion-enhancing drugs.

  12. Surgical treatment of denture-induced fibrous hyperplasia with plasma rich in growth factors.

    PubMed

    Mozzati, Marco; Mortellaro, Carmen; Gallesio, Giorgia; Ruggiero, Tiziana; Pol, Renato

    2015-05-01

    Denture-induced fibrous hyperplasia is a fibrous connective tissue lesion that commonly occurs in oral mucosa in patients showing important alveolar ridge atrophy. In this study, we propose Plasma Rich in Growth Factors (PRGF) to overcome constrains of traditional surgical treatment. Herein, we demonstrated that PRGF represents an autologous source of growth factors able to reduce the healing time of the alveolar mucosa and the discomfort of those patients. These properties are the result of PRGF's precise biological features that result in the following: reduction of duration and intensity of postsurgical pain, acceleration of re-epithelialization of the wound, and reduction of bleeding events and of edema. In conclusion, we showed that using PRGF on patients affected by denture-induced fibrous hyperplasia allows a short healing time, thereby reducing complications and overall improving their quality of life. The aims of this study were to evaluate the influence of PRGF-ENDORET on secondary re-epithelialization in vestibuloplasty after excision of denture irritation fibrous hyperplasia, with an explorative randomized case control trial with 10 patients, 5 patients treated with PRGF and 5 patients with traditional hemostasis, and to analyze differences with simple surgery, considering postoperative rapidity of re-epithelialization, comfort, and discomfort of patients, pain, swelling, and infections.

  13. Noscapine inhibits human hepatocellular carcinoma growth through inducing apoptosis in vitro and in vivo.

    PubMed

    Xu, G; Niu, Z; Dong, J; Zhao, Y; Zhang, Y; Li, X

    2016-01-01

    Noscapine, a phthalideisoquinoline alkaloid derived from opium, has been demonstrated as a promising anti-tumor compound against various cancers. However, the anti-cancer activity of noscapine in hepatocellular carcinoma has not been defined. In this study, we investigate the inhibitive effects of noscapine on human hepatocellular carcinoma (HCC) using both in vitro and in vivo models. In vitro proliferation assay showed that noscapine suppressed HepG2 and Huh7 cells in dose- and time-dependent manners. With a mouse xenograft model, noscapine showed notable inhibition on HCC tumor growth in vivo without suppression of body weight. Moreover, apoptotic induction and regulation of related signalings by noscapine were examined by nuclear DNA staining, TUNEL, and western blotting assays. Results showed that noscapine induced apoptosis in HCC cells both in vitro and in vivo. Further studies indicated that noscapine induced antive-capsase-3, cleavage PARP, and decreased the ratio of Bcl-2/Bax. Hence, these data indicates that noscapine selectively suppresses HCC cell growth through apoptosis induction, providing evidence for application of noscapine as a novel agent against human hepatocellular carcinoma.

  14. Effects of 5-Fluorouracil and 5-Fluorodeoxyuridine on Growth and Tumor-Inducing Ability of Agrobacterium tumefaciens

    PubMed Central

    Beardsley, Robert E.; Lipetz, Jacques

    1966-01-01

    Beardsley, Robert E. (Manhattan College, Bronx, N.Y.), and Jacques Lipetz Effects of 5-fluorouracil and 5-fluorodeoxyuridine on growth and tumor-inducing ability of Agrobacterium tumefaciens. J. Bacteriol. 92:346–348. 1966.—Agrobacterium tumefaciens B6, grown in the presence of 5-fluorouracil or 5-fluodeoxyuridine, exhibited a prolonged lag phase. The tumor-inducing ability of bacteria grown in the presence of these compounds was decreased even after exposures as short as 40 min. A positive correlation was found between the growth-inhibitory effects of these compounds and their effects on the tumor-inducing ability of the bacteria. PMID:16562118

  15. Auxin-Induced Ethylene Triggers Abscisic Acid Biosynthesis and Growth Inhibition1

    PubMed Central

    Hansen, Hauke; Grossmann, Klaus

    2000-01-01

    The growth-inhibiting effects of indole-3-acetic acid (IAA) at high concentration and the synthetic auxins 7-chloro-3-methyl-8-quinolinecarboxylic acid (quinmerac), 2-methoxy-3,6-dichlorobenzoic acid (dicamba), 4-amino-3,6,6-trichloropicolinic acid (picloram), and naphthalene acetic acid, were investigated in cleavers (Galium aparine). When plants were root treated with 0.5 mm IAA, shoot epinasty and inhibition of root and shoot growth developed during 24 h. Concomitantly, 1-aminocyclopropane-1-carboxylic acid (ACC) synthase activity, and ACC and ethylene production were transiently stimulated in the shoot tissue within 2 h, followed by increases in immunoreactive (+)-abscisic acid (ABA) and its precursor xanthoxal (xanthoxin) after 5 h. After 24 h of treatment, levels of xanthoxal and ABA were elevated up to 2- and 24-fold, relative to control, respectively. In plants treated with IAA, 7-chloro-3-methyl-8-quinolinecarboxylic acid, naphthalene acetic acid, 2-methoxy-3,6-dichlorobenzoic acid, and 4-amino-3,6,6-trichloropicolinic acid, levels of ethylene, ACC, and ABA increased in close correlation with inhibition of shoot growth. Aminoethoxyvinyl-glycine and cobalt ions, which inhibit ethylene synthesis, decreased ABA accumulation and growth inhibition, whereas the ethylene-releasing ethephon promoted ABA levels and growth inhibition. In accordance, tomato mutants defective in ethylene perception (never ripe) did not produce the xanthoxal and ABA increases and growth inhibition induced by auxins in wild-type plants. This suggests that auxin-stimulated ethylene triggers ABA accumulation and the consequent growth inhibition. Reduced catabolism most probably did not contribute to ABA increase, as indicated by immunoanalyses of ABA degradation and conjugation products in shoot tissue and by pulse experiments with [3H]-ABA in cell suspensions of G. aparine. In contrast, studies using inhibitors of ABA biosynthesis (fluridone, naproxen, and tungstate), ABA

  16. Injectable gelatin derivative hydrogels with sustained vascular endothelial growth factor release for induced angiogenesis

    PubMed Central

    Li, Zhe; Qu, Tiejun; Ding, Chen; Ma, Chi; Sun, Hongchen; Li, Shirong; Liu, Xiaohua

    2014-01-01

    Injectable biomaterials are attractive for soft tissue regeneration because they are handled in a minimally invasive manner and can easily adapt to complex defects. However, inadequate vascularization of the injectable constructs has long been a barrier, leading to necrosis or volume reduction after implantation. In this work, we developed a three-step process to synthesize injectable gelatin-derived hydrogels that are capable of controlling growth factor delivery to induce angiogenesis. In our approach, tyramine was first introduced into gelatin chains to provide enzymatical crosslinking points for gel formation after injection. Next, heparin, a polysaccharide with binding domains to many growth factors, was covalently linked to the tyramine-modified gelatin. Finally, vascular endothelial growth factor (VEGF) was incorporated into the gelatin derivative by binding with the heparin in the gelatin derivative, and an injectable gel with controlled VEGF release was formed by an enzymatic catalytic reaction with hydrogen peroxide (H2O2) and horseradish peroxidase (HRP). The gelation time, mechanical properties and degradation of the gel was readily tailored by the gelatin concentration and the ratio of H2O2/HRP. Binding VEGF to heparin stabilizes this growth factor, protects it from denaturation and proteolytic degradation, and subsequently prolongs the sustained release. An in vitro release study and bioactivity assay indicated that the VEGF was released in a sustained manner with high bioactivity for over 3 weeks. Furthermore, a chicken chorioallantoic membrane (CAM) assay and animal experiments were performed to evaluate in vivo bioactivity of the VEGF released from the hydrogels. After 5 days of incubation on CAM, the number of blood vessels surrounding the heparin-modified hydrogels was 2.4-fold increase than that of the control group. Deeper and denser cell infiltration and angiogenesis in the heparin-modified gelatin/VEGF gels were observed than in the controls

  17. Injectable gelatin derivative hydrogels with sustained vascular endothelial growth factor release for induced angiogenesis.

    PubMed

    Li, Zhe; Qu, Tiejun; Ding, Chen; Ma, Chi; Sun, Hongchen; Li, Shirong; Liu, Xiaohua

    2015-02-01

    Injectable biomaterials are attractive for soft tissue regeneration because they are handled in a minimally invasive manner and can easily adapt to complex defects. However, inadequate vascularization of the injectable constructs has long been a barrier, leading to necrosis or volume reduction after implantation. In this work, we developed a three-step process to synthesize injectable gelatin-derived hydrogels that are capable of controlling growth factor delivery to induce angiogenesis. In our approach, tyramine was first introduced into gelatin chains to provide enzymatic crosslinking points for gel formation after injection. Next, heparin, a polysaccharide with binding domains to many growth factors, was covalently linked to the tyramine-modified gelatin. Finally, vascular endothelial growth factor (VEGF) was incorporated into the gelatin derivative by binding with the heparin in the gelatin derivative, and an injectable gel with controlled VEGF release was formed by an enzymatic catalytic reaction with hydrogen peroxide (H2O2) and horseradish peroxidase (HRP). The gelation time, mechanical properties and degradation of the gel was readily tailored by the gelatin concentration and the ratio of H2O2/HRP. Binding VEGF to heparin stabilizes this growth factor, protects it from denaturation and proteolytic degradation and subsequently prolongs the sustained release. An in vitro release study and bioactivity assay indicated that the VEGF was released in a sustained manner with high bioactivity for over 3 weeks. Furthermore, a chicken chorioallantoic membrane (CAM) assay and animal experiments were performed to evaluate in vivo bioactivity of the VEGF released from the hydrogels. After 5 days of incubation on CAM, the number of blood vessels surrounding the heparin-modified hydrogels was increased by 2.4-fold compared with that of the control group. Deeper and denser cell infiltration and angiogenesis in the heparin-modified gelatin/VEGF gels were observed compared to

  18. Effects of lipopolysaccharide-induced inflammation on expression of growth-associated genes by corticospinal neurons.

    PubMed

    Hossain-Ibrahim, M K; Rezajooi, K; MacNally, J K; Mason, M R J; Lieberman, A R; Anderson, P N

    2006-01-24

    Inflammation around cell bodies of primary sensory neurons and retinal ganglion cells enhances expression of neuronal growth-associated genes and stimulates axonal regeneration. We have asked if inflammation would have similar effects on corticospinal neurons, which normally show little response to spinal cord injury. Lipopolysaccharide (LPS) was applied onto the pial surface of the motor cortex of adult rats with or without concomitant injury of the corticospinal tract at C4. Inflammation around corticospinal tract cell bodies in the motor cortex was assessed by immunohistochemistry for OX42 (a microglia and macrophage marker). Expression of growth-associated genes c-jun, ATF3, SCG10 and GAP-43 was investigated by immunohistochemistry or in situ hybridisation. Application of LPS induced a gradient of inflammation through the full depth of the motor cortex and promoted c-Jun and SCG10 expression for up to 2 weeks, and GAP-43 upregulation for 3 days by many corticospinal neurons, but had very limited effects on neuronal ATF3 expression. However, many glial cells in the subcortical white matter upregulated ATF3. LPS did not promote sprouting of anterogradely labelled corticospinal axons, which did not grow into or beyond a cervical lesion site. Inflammation produced by topical application of LPS promoted increased expression of some growth-associated genes in the cell bodies of corticospinal neurons, but was insufficient to promote regeneration of the corticospinal tract.

  19. Quantitative observations of hydrogen-induced, slow crack growth in a low alloy steel

    NASA Technical Reports Server (NTRS)

    Nelson, H. G.; Williams, D. P.

    1973-01-01

    Hydrogen-induced slow crack growth, da/dt, was studied in AISI-SAE 4130 low alloy steel in gaseous hydrogen and distilled water environments as a function of applied stress intensity, K, at various temperatures, hydrogen pressures, and alloy strength levels. At low values of K, da/dt was found to exhibit a strong exponential K dependence (Stage 1 growth) in both hydrogen and water. At intermediate values of K, da/dt exhibited a small but finite K dependence (Stage 2), with the Stage 2 slope being greater in hydrogen than in water. In hydrogen, at a constant K, (da/dt) sub 2 varied inversely with alloy strength level and varied essentially in the same complex manner with temperature and hydrogen pressure as noted previously. The results of this study provide support for most of the qualitative predictions of the lattice decohesion theory as recently modified by Oriani. The lack of quantitative agreement between data and theory and the inability of theory to explain the observed pressure dependence of slow crack growth are mentioned and possible rationalizations to account for these differences are presented.

  20. Wnt5a induces Ryk-dependent and -independent effects on callosal axon and dendrite growth.

    PubMed

    Clark, Charlotte E J; Richards, Linda J; Stacker, Steven A; Cooper, Helen M

    2014-02-01

    The non-canonical Wnt receptor, Ryk, promotes chemorepulsive axon guidance in the developing mouse brain and spinal cord in response to Wnt5a. Ryk has also been identified as a major suppressor of axonal regrowth after spinal cord injury. Thus, a comprehensive understanding of how growing axons and dendrites respond to Wnt5a-mediated Ryk activation is required if we are to overcome this detrimental activity. Here we undertook a detailed analysis of the effect of Wnt5a/Ryk interactions on axonal and dendritic growth in dissociated embryonic mouse cortical neuron cultures, focusing on callosal neurons known to be responsive to Ryk-induced chemorepulsion. We show that Ryk inhibits axonal growth in response to Wnt5a. We also show that Wnt5a inhibits dendrite growth independently of Ryk. However, this inhibition is relieved when Ryk is present. Therefore, Wnt5a-mediated Ryk activation triggers divergent responses in callosal axons and dendrites in the in vitro context.

  1. Reversible growth factor dependency and autonomy during murine myelomonocytic leukemia induced by oncogenes

    PubMed Central

    Metcalf, Donald; Glaser, Stefan P.; Xu, Zhen; Di Rago, Ladina; Mifsud, Sandra

    2013-01-01

    When murine fetal liver cells were transduced with either of the human acute myeloid leukemia fusion oncogenes MLL-ENL or MLL-AF9 and then transplanted to irradiated recipient mice, myelomonocyte leukemias rapidly developed from the transplanted cells. Analysis of initial events following transduction showed that both oncogenes immediately induced a wide range of enhanced proliferative states, the most extreme of which could generate continuous lines of cells. Maturation defects accompanied the enhanced proliferative states. At all times, the transformed cells exhibited complete dependency on hematopoietic growth factors, particularly GM-CSF and IL-3. Myelomonocytic leukemic cells from primary or transplanted mice formed colonies in semisolid agar. The large majority were dependent on hematopoietic growth factors, but a low frequency of autonomous colonies was also detected. Unexpectedly, reculture of autonomous leukemic colonies generated large numbers of growth factor-dependent clonogenic progeny. Similarly, transplanted clonal autonomous leukemic cells produced leukemias containing a majority of factor-dependent cells. Conversely, recultures of factor-dependent colonies in vitro always produced small numbers of autonomous colonies among the dependent progeny. The reversible relationship between factor dependency and autonomy is surprising because autonomy would have been presumed to represent the final, irreversible, leukemic state. PMID:24082086

  2. Troglitazone enhances tamoxifen-induced growth inhibitory activity of MCF-7 cells

    SciTech Connect

    Yu, Hong-Nu; Noh, Eun-Mi; Lee, Young-Rae; Roh, Si-Gyun; Song, Eun-Kyung; Han, Myung-Kwan; Lee, Yong-Chul; Shim, In Kyong; Lee, Seung Jin; Jung, Sung Hoo; Kim, Jong-Suk Youn, Hyun Jo

    2008-12-05

    Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) ligands have been identified as a potential source of therapy for human cancers. However, PPAR{gamma} ligands have a limitation for breast cancer therapy, since estrogen receptor {alpha} (ER{sub {alpha}}) negatively interferes with PPAR{gamma} signaling in breast cancer cells. Here we show that ER{sub {alpha}} inhihits PPAR{gamma} transactivity and ER{sub {alpha}}-mediated inhibition of PPAR{gamma} transactivity is blocked by tamoxifen, an estrogen receptor blocker. The activation of ER{sub {alpha}} with 17-{beta}-estradiol blocked PPRE transactivity induced by troglitazone, a PPAR{gamma} ligand, indicating the resistance of ER{sub {alpha}}-positive breast cancer cells to troglitazone. Indeed, troglitazone inhibited the growth of ER{sub {alpha}}-negative MDA-MB-231 cells more than that of ER{sub {alpha}}-positive MCF-7 cells. Combination of troglitazone with tamoxifen led to a marked increase in growth inhibition of ER{sub {alpha}}-positive MCF-7 cells compared to either agent alone. Our data indicates that troglitazone enhances the growth inhibitory activity of tamoxifen in ER{sub {alpha}}-positive MCF-7 cells.

  3. Diffusion-induced growth of nanowires: Generalized boundary conditions and self-consistent kinetic equation

    NASA Astrophysics Data System (ADS)

    Dubrovskii, V. G.; Hervieu, Yu. Yu.

    2014-09-01

    In this work, we present a theoretical analysis of the diffusion-induced growth of "vapor-liquid-solid" nanowires, based on the stationary equations with generalized boundary conditions. We discuss why and how the earlier results are modified when the adatom chemical potential is discontinuous at the nanowire base. Several simplified models for the adatom diffusion flux are discussed, yielding the 1 /Rp radius dependence of the length, with p ranging from 0.5 to 2. The self-consistent approach is used to couple the diffusion transport with the kinetics of 2D nucleation under the droplet. This leads to a new growth equation that contains only two dimensional parameters and the power exponents p and q, where q=1 or 2 depends on the nucleus position. We show that this equation describes the size-dependent depression of the growth rate of narrow nanowires much better than the Gibbs-Thomson correction in several important cases. Overall, our equation fits very well the experimental data on the length-radius correlations of III-V and group IV nanowires obtained by different epitaxy techniques.

  4. SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC.

    PubMed

    Lee, Namgyu; Ryu, Hye Guk; Kwon, Jung-Hee; Kim, Dae-Kyum; Kim, Sae Rom; Wang, Hee Jung; Kim, Kyong-Tai; Choi, Kwan Yong

    2016-01-01

    The role of Sirtuin 6 (SIRT6) as a tumor suppressor or oncogene in liver cancer remains controversial. Thus, we identified the specific role of SIRT6 in the progression of hepatocellular carcinoma (HCC). SIRT6 expression was significantly higher in HCC cell lines and HCC tissues from 138 patients than in an immortalized hepatocyte cell line, THLE-2 and non-tumor tissues, respectively. SIRT6 knockdown by shRNA suppressed the growth of HCC cells and inhibited HCC tumor growth in vivo. In addition, SIRT6 silencing significantly prevented the growth of HCC cell lines by inducing cellular senescence in the p16/Rb- and p53/p21-pathway independent manners. Microarray analysis revealed that the expression of genes involved in nucleosome assembly was apparently altered in SIRT6-depleted Hep3B cells. SIRT6 knockdown promoted G2/M phase arrest and downregulation of genes encoding histone variants associated with nucleosome assembly, which could be attributed to DNA damage. Taken together, our findings suggest that SIRT6 acts as a tumor promoter by preventing DNA damage and cellular senescence, indicating that SIRT6 represents a potential therapeutic target for the treatment of HCC.

  5. Fibroblast growth factor signalling induces loss of progesterone receptor in breast cancer cells

    PubMed Central

    Piasecka, Dominika; Kitowska, Kamila; Czaplinska, Dominika; Mieczkowski, Kamil; Mieszkowska, Magdalena; Turczyk, Lukasz; Skladanowski, Andrzej C.; Zaczek, Anna J.; Biernat, Wojciech; Kordek, Radzislaw; Romanska, Hanna M.; Sadej, Rafal

    2016-01-01

    We have recently demonstrated that, fibroblast growth factor 2 (FGFR2), signalling via ribosomal S6 kinase 2 (RSK2), promotes progression of breast cancer (BCa). Loss of progesterone receptor (PR), whose activity in BCa cells can be stimulated by growth factor receptors (GFRs), is associated with poor patient outcome. Here we showed that FGF7/FGFR2 triggered phosphorylation of PR at Ser294, PR ubiquitination and subsequent receptor`s degradation via the 26S proteasome pathway in BCa cells. We further demonstrated that RSK2 mediated FGF7/FGFR2-induced PR downregulation. In addition, a strong synergistic effect of FGF7 and progesterone (Pg), reflected in the enhanced anchorage-independent growth and cell migration, was observed. Analysis of clinical material demonstrated that expression of PR inversely correlated with activated RSK (RSK-P) (p = 0.016). Patients with RSK-P(+)/PR(–) tumours had 3.629-fold higher risk of recurrence (p = 0.002), when compared with the rest of the cohort. Moreover, RSK-P(+)/PR(–) phenotype was shown as an independent prognostic factor (p = 0.006). These results indicate that the FGF7/FGFR2-RSK2 axis promotes PR turnover and activity, which may sensitize BCa cells to stromal stimuli and contribute to the progression toward steroid hormone negative BCa. PMID:27852068

  6. SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

    PubMed Central

    Lee, Namgyu; Ryu, Hye Guk; Kwon, Jung-Hee; Kim, Dae-Kyum; Kim, Sae Rom; Wang, Hee Jung; Kim, Kyong-Tai; Choi, Kwan Yong

    2016-01-01

    The role of Sirtuin 6 (SIRT6) as a tumor suppressor or oncogene in liver cancer remains controversial. Thus, we identified the specific role of SIRT6 in the progression of hepatocellular carcinoma (HCC). SIRT6 expression was significantly higher in HCC cell lines and HCC tissues from 138 patients than in an immortalized hepatocyte cell line, THLE-2 and non-tumor tissues, respectively. SIRT6 knockdown by shRNA suppressed the growth of HCC cells and inhibited HCC tumor growth in vivo. In addition, SIRT6 silencing significantly prevented the growth of HCC cell lines by inducing cellular senescence in the p16/Rb- and p53/p21-pathway independent manners. Microarray analysis revealed that the expression of genes involved in nucleosome assembly was apparently altered in SIRT6-depleted Hep3B cells. SIRT6 knockdown promoted G2/M phase arrest and downregulation of genes encoding histone variants associated with nucleosome assembly, which could be attributed to DNA damage. Taken together, our findings suggest that SIRT6 acts as a tumor promoter by preventing DNA damage and cellular senescence, indicating that SIRT6 represents a potential therapeutic target for the treatment of HCC. PMID:27824900

  7. Temperature-induced gene expression associated with different thermal reaction norms for growth rate.

    PubMed

    Ellers, Jacintha; Mariën, Janine; Driessen, Gerard; van Straalen, Nico M

    2008-03-15

    Although nearly all organisms are subject to fluctuating temperature regimes in their natural habitat, little is known about the genetics underlying the response to thermal conditions, and even less about the genetic differences that cause individual variation in thermal response. Here, we aim to elucidate possible pathways involved in temperature-induced phenotypic plasticity of growth rate. Our model organism is the collembolan Orchesella cincta that occurs in a wide variety of habitats and is known to be adapted to local thermal conditions. Because sequence information is lacking in O. cincta, we constructed cDNA libraries enriched for temperature-responsive genes using suppression subtractive hybridization. We compared gene expression of O. cincta with steep thermal reaction norms (high plasticity) to those with flat thermal reaction norms (low plasticity) for juvenile growth after exposure to a temperature switch composed of a cooling or a warming treatment. Using suppression subtractive hybridization, we found differential expression of ten nuclear genes, including several genes involved in energy metabolism, such as pantothenate kinase and carbonic anhydrase. In addition, seven mitochondrial genes were found in the cloned subtracted library, but further analysis showed this was caused by allelic variation in mitochondrial genes in our founder population, and that a specific haplotype was associated with high thermal responsiveness. Future work will focus on candidate genes from pathways such as the oxidative phosphorylation and biosynthesis of coenzyme A which are possibly involved in thermal responsiveness of juvenile growth rate.

  8. Small Regulatory RNA-Induced Growth Rate Heterogeneity of Bacillus subtilis

    PubMed Central

    Mars, Ruben A. T.; Nicolas, Pierre; Ciccolini, Mariano; Reilman, Ewoud; Reder, Alexander; Schaffer, Marc; Mäder, Ulrike; Völker, Uwe; van Dijl, Jan Maarten; Denham, Emma L.

    2015-01-01

    Isogenic bacterial populations can consist of cells displaying heterogeneous physiological traits. Small regulatory RNAs (sRNAs) could affect this heterogeneity since they act by fine-tuning mRNA or protein levels to coordinate the appropriate cellular behavior. Here we show that the sRNA RnaC/S1022 from the Gram-positive bacterium Bacillus subtilis can suppress exponential growth by modulation of the transcriptional regulator AbrB. Specifically, the post-transcriptional abrB-RnaC/S1022 interaction allows B. subtilis to increase the cell-to-cell variation in AbrB protein levels, despite strong negative autoregulation of the abrB promoter. This behavior is consistent with existing mathematical models of sRNA action, thus suggesting that induction of protein expression noise could be a new general aspect of sRNA regulation. Importantly, we show that the sRNA-induced diversity in AbrB levels generates heterogeneity in growth rates during the exponential growth phase. Based on these findings, we hypothesize that the resulting subpopulations of fast- and slow-growing B. subtilis cells reflect a bet-hedging strategy for enhanced survival of unfavorable conditions. PMID:25790031

  9. Small regulatory RNA-induced growth rate heterogeneity of Bacillus subtilis.

    PubMed

    Mars, Ruben A T; Nicolas, Pierre; Ciccolini, Mariano; Reilman, Ewoud; Reder, Alexander; Schaffer, Marc; Mäder, Ulrike; Völker, Uwe; van Dijl, Jan Maarten; Denham, Emma L

    2015-03-01

    Isogenic bacterial populations can consist of cells displaying heterogeneous physiological traits. Small regulatory RNAs (sRNAs) could affect this heterogeneity since they act by fine-tuning mRNA or protein levels to coordinate the appropriate cellular behavior. Here we show that the sRNA RnaC/S1022 from the Gram-positive bacterium Bacillus subtilis can suppress exponential growth by modulation of the transcriptional regulator AbrB. Specifically, the post-transcriptional abrB-RnaC/S1022 interaction allows B. subtilis to increase the cell-to-cell variation in AbrB protein levels, despite strong negative autoregulation of the abrB promoter. This behavior is consistent with existing mathematical models of sRNA action, thus suggesting that induction of protein expression noise could be a new general aspect of sRNA regulation. Importantly, we show that the sRNA-induced diversity in AbrB levels generates heterogeneity in growth rates during the exponential growth phase. Based on these findings, we hypothesize that the resulting subpopulations of fast- and slow-growing B. subtilis cells reflect a bet-hedging strategy for enhanced survival of unfavorable conditions.

  10. Nerve growth factor partially recovers inflamed skin from stress-induced worsening in allergic inflammation.

    PubMed

    Peters, Eva M J; Liezmann, Christiane; Spatz, Katharina; Daniltchenko, Maria; Joachim, Ricarda; Gimenez-Rivera, Andrey; Hendrix, Sven; Botchkarev, Vladimir A; Brandner, Johanna M; Klapp, Burghard F

    2011-03-01

    Neuroimmune dysregulation characterizes atopic disease, but its nature and clinical impact remain ill-defined. Induced by stress, the neurotrophin nerve growth factor (NGF) may worsen cutaneous inflammation. We therefore studied the role of NGF in the cutaneous stress response in a mouse model for atopic dermatitis-like allergic dermatitis (AlD). Combining several methods, we found that stress increased cutaneous but not serum or hypothalamic NGF in telogen mice. Microarray analysis showed increased mRNAs of inflammatory and growth factors associated with NGF in the skin. In stress-worsened AlD, NGF-neutralizing antibodies markedly reduced epidermal thickening together with NGF, neurotrophin receptor (tyrosine kinase A and p75 neurotrophin receptor), and transforming growth factor-β expression by keratinocytes but did not alter transepidermal water loss. Moreover, NGF expression by mast cells was reduced; this corresponded to reduced cutaneous tumor necrosis factor-α (TNF-α) mRNA levels but not to changes in mast cell degranulation or in the T helper type 1 (Th1)/Th2 cytokine balance. Also, eosinophils expressed TNF receptor type 2, and we observed reduced eosinophil infiltration after treatment with NGF-neutralizing antibodies. We thus conclude that NGF acts as a local stress mediator in perceived stress and allergy and that increased NGF message contributes to worsening of cutaneous inflammation mainly by enhancing epidermal hyperplasia, pro-allergic cytokine induction, and allergy-characteristic cellular infiltration.

  11. H₂O Dissociation-Induced Aluminum Oxide Growth on Oxidized Al(111) Surfaces.

    PubMed

    Liu, Qianqian; Tong, Xiao; Zhou, Guangwen

    2015-12-08

    The interaction of water vapor with amorphous aluminum oxide films on Al(111) is studied using X-ray photoelectron spectroscopy to elucidate the passivation mechanism of the oxidized Al(111) surfaces. Exposure of the aluminum oxide film to water vapor results in self-limiting Al2O3/Al(OH)3 bilayer film growth via counter-diffusion of both ions, Al outward and OH inward, where a thinner starting aluminum oxide film is more reactive toward H2O dissociation-induced oxide growth because of the thickness-dependent ionic transport in the aluminum oxide film. The aluminum oxide film exhibits reactivity toward H2O dissociation in both low-vapor pressure [p(H2O) = 1 × 10(-6) Torr] and intermediate-vapor pressure [p(H2O) = 5 Torr] regimes. Compared to the oxide film growth by exposure to a p(H2O) of 1 × 10(-6) Torr, the exposure to a p(H2O) of 5 Torr results in the formation of a more open structure of the inner Al(OH)3 layer and a more compact outer Al2O3 layer, demonstrating the vapor-pressure-dependent atomic structure in the passivating layer.

  12. Assessment of growth and metabolism characteristics in offspring of dehydroepiandrosterone-induced polycystic ovary syndrome adults

    PubMed Central

    Huang, Ying; Gao, Jiang-Man; Zhang, Chun-Mei; Zhao, Hong-Cui; Qiao, Jie

    2016-01-01

    Polycystic ovary syndrome (PCOS) is a common reproductive disorder that has many characteristic features including hyperandrogenemia, insulin resistance and obesity, which may have significant implications for pregnancy outcomes and long-term health of women. Daughters born to PCOS mothers constitute a high-risk group for metabolic and reproductive derangements, but no report has described potential growth and metabolic risk factors for such female offspring. Hence, we used a mouse model of dehydroepiandrosterone (DHEA)-induced PCOS to study the mechanisms underlying the pathology of PCOS by investigating the growth, developmental characteristics, metabolic indexes and expression profiles of key genes of offspring born to the models. We found that the average litter size was significantly smaller in the DHEA group, and female offspring had sustained higher body weight, increased body fat and triglyceride content in serum and liver; they also exhibited decreased energy expenditure, oxygen consumption and impaired glucose tolerance. Genes related to glucolipid metabolism such as Pparγ, Acot1/2, Fgf21, Pdk4 and Inhbb were upregulated in the liver of the offspring in DHEA group compared with those in controls, whereas Cyp17a1 expression was significantly decreased. However, the expression of these genes was not detected in male offspring. Our results show that female offspring in DHEA group exhibit perturbed growth and glucolipid metabolism that were not observed in male offspring. PMID:27798284

  13. TAZ induces growth factor-independent proliferation through activation of EGFR ligand amphiregulin

    PubMed Central

    Yang, Nuo; Morrison, Carl D.; Liu, Peijun; Miecznikowski, Jeff; Bshara, Wiam; Han, Suxia; Zhu, Qing; Omilian, Angela R.; Li, Xu; Zhang, Jianmin

    2012-01-01

    The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. We previously showed that the pivotal effector of this pathway, YAP, is amplified in tumors and promotes epithelial-to-mesenchymal transition (EMT) and malignant transformation. Here, we report that overexpression of TAZ, a paralog of YAP, in human mammary epithelial cells promotes EMT and, in particular, some invasive structures in 3D cultures. TAZ also leads to cell migration and anchorage-independent growth in soft agar. Furthermore, we identified amphiregulin (AREG), an epidermal growth factor receptor (EGFR) ligand, as a target of TAZ. We show that AREG functions in a non-cell-autonomous manner to mediate EGF-independent growth and malignant behavior of mammary epithelial cells. In addition, ablation of TEAD binding completely abolishes the TAZ-induced phenotype. Last, analysis of breast cancer patient samples reveals a positive correlation between TAZ and AREG in vivo. In summary, TAZ-dependent secretion of AREG indicates that activation of the EGFR signaling is an important non-cell-autonomous effector of the Hippo pathway, and TAZ as well as its targets may play significant roles in breast tumorigenesis and metastasis. PMID:22825057

  14. Chemokines induce axon outgrowth downstream of Hepatocyte Growth Factor and TCF/β-catenin signaling

    PubMed Central

    Bhardwaj, Deepshikha; Náger, Mireia; Camats, Judith; David, Monica; Benguria, Alberto; Dopazo, Ana; Cantí, Carles; Herreros, Judit

    2013-01-01

    Axon morphogenesis is a complex process regulated by a variety of secreted molecules, including morphogens and growth factors, resulting in the establishment of the neuronal circuitry. Our previous work demonstrated that growth factors [Neurotrophins (NT) and Hepatocyte Growth Factor (HGF)] signal through β-catenin during axon morphogenesis. HGF signaling promotes axon outgrowth and branching by inducing β-catenin phosphorylation at Y142 and transcriptional regulation of T-Cell Factor (TCF) target genes. Here, we asked which genes are regulated by HGF signaling during axon morphogenesis. An array screening indicated that HGF signaling elevates the expression of chemokines of the CC and CXC families. In line with this, CCL7, CCL20, and CXCL2 significantly increase axon outgrowth in hippocampal neurons. Experiments using blocking antibodies and chemokine receptor antagonists demonstrate that chemokines act downstream of HGF signaling during axon morphogenesis. In addition, qPCR data demonstrates that CXCL2 and CCL5 expression is stimulated by HGF through Met/b-catenin/TCF pathway. These results identify CC family members and CXCL2 chemokines as novel regulators of axon morphogenesis downstream of HGF signaling. PMID:23641195

  15. Keratinocyte growth factor induces proliferation of hepatocytes and epithelial cells throughout the rat gastrointestinal tract.

    PubMed

    Housley, R M; Morris, C F; Boyle, W; Ring, B; Biltz, R; Tarpley, J E; Aukerman, S L; Devine, P L; Whitehead, R H; Pierce, G F

    1994-11-01

    Keratinocyte growth factor (KGF), a member of the fibroblast growth factor (FGF) family, was identified as a specific keratinocyte mitogen after isolation from a lung fibroblast line. Recently, recombinant (r)KGF was found to influence proliferation and differentiation patterns of multiple epithelial cell lineages within skin, lung, and the reproductive tract. In the present study, we designed experiments to identify additional target tissues, and focused on the rat gastrointestinal (GI) system, since a putative receptor, K-sam, was originally identified in a gastric carcinoma. Expression of KGF receptor and KGF mRNA was detected within the entire GI tract, suggesting the gut both synthesized and responded to KGF. Therefore, rKGF was administered to adult rats and was found to induce markedly increased proliferation of epithelial cells from the foregut to the colon, and of hepatocytes, one day after systemic treatment. Daily treatment resulted in the marked selective induction of mucin-producing cell lineages throughout the GI tract in a dose-dependent fashion. Other cell lineages were either unaffected (e.g., Paneth cells), or relatively decreased (e.g., parietal cells, enterocytes) in rKGF-treated rats. The direct effect of rKGF was confirmed by demonstrating markedly increased carcinoembryonic antigen production in a human colon carcinoma cell line, LIM1899. Serum levels of albumin were specifically and significantly elevated after daily treatment. These results demonstrate rKGF can induce epithelial cell activation throughout the GI tract and liver. Further, endogenous KGF may be a normal paracrine mediator of growth within the gut.

  16. Induced metabolic disturbance and growth depression in rabbits infected with Eimeria coecicola.

    PubMed

    Metwaly, Mahmoud S; Dkhil, Mohamed A; Gewik, Mohamed M; Al-Ghamdy, Ali O; Al-Quraishy, Saleh

    2013-09-01

    Eimeria coecicola causes intestinal coccidiosis in rabbits and, thereby, enormous economic losses in rabbit farms. This study aimed to investigate the effect of intestinal coccidial infection, E. coecicola on metabolic status and growth of rabbits. Animals were allocated into two groups with eight rabbits each; one group was orally inoculated with saline and served as control while the other group was orally inoculated with 5 × 10(4) sporulated oocysts. On day 7 postinfection, fecal expulsion of E. coecicola oocysts is maximal (1.2 × 10(6) oocyst/g feces) and rabbits have lost approximately 23% of their weight. Infection induced a severe depletion in plasma growth hormone level. In addition, the energy metabolic status was significantly (P ≤ 0.05) altered by the infection as, both blood glucose and total lipid levels were significantly elevated with mutual depletion in carbohydrate stores in liver sections. Also, the thyroid-stimulating hormone and cortisol concentrations were raised as a consequence of the infection. Moreover, protein status was affected by the infection as both liver and plasma total proteins were significantly decreased with concurrent disturbance in the blood protein electrophoretic pattern and duplication of blood urea nitrogen concentration. Finally, the infection induced plasma electrolyte imbalance as indicated by a significant decrease in sodium, potassium, calcium, phosphorus, ferrous, and selenium ions. Our data suggested that the intestinal coccidial infection of rabbits with E. coecicola has serious effects on rabbit growth and metabolism and could disrupt endocrine and electrolyte homeostasis.

  17. Growth Inhibition and Apoptosis Induced by Osthole, A Natural Coumarin, in Hepatocellular Carcinoma

    PubMed Central

    Zhang, Lurong; Jiang, Guorong; Yao, Fei; He, Yan; Liang, Guoqiang; Zhang, Yinsheng; Hu, Bo; Wu, Yan; Li, Yunsen; Liu, Haiyan

    2012-01-01

    Background Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed tumors worldwide and is known to be resistant to conventional chemotherapy. New therapeutic strategies are urgently needed for treating HCC. Osthole, a natural coumarin derivative, has been shown to have anti-tumor activity. However, the effects of osthole on HCC have not yet been reported. Methods and Findings HCC cell lines were treated with osthole at various concentrations for 24, 48 and 72 hours. The proliferations of the HCC cells were measured by MTT assays. Cell cycle distribution and apoptosis were determined by flow cytometry. HCC tumor models were established in mice by subcutaneously injection of SMMC-7721 or Hepa1-6 cells and the effect of osthole on tumor growths in vivo and the drug toxicity were studied. NF-κB activity after osthole treatment was determined by electrophoretic mobility shift assays and the expression of caspase-3 was measured by western blotting. The expression levels of other apoptosis-related genes were also determined by real-time PCR (PCR array) assays. Osthole displayed a dose- and time-dependent inhibition of the HCC cell proliferations in vitro. It also induced apoptosis and caused cell accumulation in G2 phase. Osthole could significantly suppress HCC tumor growth in vivo with no toxicity at the dose we used. NF-κB activity was significantly suppressed by osthole at the dose- and time-dependent manner. The cleaved caspase-3 was also increased by osthole treatment. The expression levels of some apoptosis-related genes that belong to TNF ligand family, TNF receptor family, Bcl-2 family, caspase family, TRAF family, death domain family, CIDE domain and death effector domain family and CARD family were all increased with osthole treatment. Conclusion Osthole could significantly inhibit HCC growth in vitro and in vivo through cell cycle arrest and inducing apoptosis by suppressing NF-κB activity and promoting the expressions of apoptosis

  18. Apigenin induces apoptosis and blocks growth of medroxyprogesterone acetate-dependent BT-474 xenograft tumors.

    PubMed

    Mafuvadze, Benford; Liang, Yayun; Besch-Williford, Cynthia; Zhang, Xu; Hyder, Salman M

    2012-08-01

    Recent clinical and epidemiological evidence shows that hormone replacement therapy (HRT) containing both estrogen and progestin increases the risk of primary and metastatic breast cancer in post-menopausal women while HRT containing only estrogen does not. We and others previously showed that progestins promote the growth of human breast cancer cells in vitro and in vivo. In this study, we sought to determine whether apigenin, a low molecular weight anti-carcinogenic flavonoid, inhibits the growth of aggressive Her2/neu-positive BT-474 xenograft tumors in nude mice exposed to medroxyprogesterone acetate (MPA), the most commonly used progestin in the USA. Our data clearly show that apigenin (50 mg/kg) inhibits progression and development of these xenograft tumors by inducing apoptosis, inhibiting cell proliferation, and reducing expression of Her2/neu. Moreover, apigenin reduced levels of vascular endothelial growth factor (VEGF) without altering blood vessel density, indicating that continued expression of VEGF may be required to promote tumor cell survival and maintain blood flow. While previous studies showed that MPA induces receptor activator of nuclear factor kappa-B ligand (RANKL) expression in rodent mammary gland, MPA reduced levels of RANKL in human tumor xenografts. RANKL levels remained suppressed in the presence of apigenin. Exposure of BT-474 cells to MPA in vitro also resulted in lower levels of RANKL; an effect that was independent of progesterone receptors since it occurred both in the presence and absence of the antiprogestin RU-486. In contrast to our in vivo observations, apigenin protected against MPA-dependent RANKL loss in vitro, suggesting that MPA and apigenin modulate RANKL levels differently in breast cancer cells in vivo and in vitro. These preclinical findings suggest that apigenin has potential as an agent for the treatment of progestin-dependent breast disease.

  19. Keratin 17 Is Induced in Oral Cancer and Facilitates Tumor Growth

    PubMed Central

    Khanom, Rumana; Nguyen, Chi Thi Kim; Kayamori, Kou; Zhao, Xin; Morita, Keiichi; Miki, Yoshio; Katsube, Ken-ichi; Yamaguchi, Akira; Sakamoto, Kei

    2016-01-01

    Keratin subtypes are selectively expressed depending on the cell type. They not only provide structural support, but regulate the metabolic processes and signaling pathways that control the growth of the epithelium. KRT17 (keratin 17) is induced in the regenerative epithelium and acts on diverse signaling pathways. Here, we demonstrate that KRT17 is invariably and permanently induced in oral squamous cell carcinoma (OSCC), as revealed by immunohistochemistry and cDNA microarray analysis. Two representative OSCC cell lines; KRT17-weakly expressing Ca9-22 and KRT17-highly expressing HSC3 were used to establish KRT17-overexpressing Ca9-22 and KRT17-knockdown HSC3 cells. Analysis of these cells revealed that KRT17 promoted cell proliferation and migration by stimulating the Akt/mTOR pathway. KRT17 also upregulated the expression of SLC2A1 (solute carrier family 2 member 1/Glut1) and glucose uptake. To further investigate the effect of KRT17 on tumorigenesis, KRT17-knockout HSC3 cells were established and were transplanted to the cephalic skin of nude mice. The tumors that developed from KRT17-knockout HSC3 cells had a lower Ki-67 labeling index and were significantly smaller compared to the controls. These results indicate that KRT17 stimulates the Akt/mTOR pathway and glucose uptake, thereby facilitating tumor growth. We could not confirm the relationship between KRT17 and SFN (stratifin) in the cells examined in this study. However, our study reinforces the concept that the cellular properties of cancer are regulated by a series of molecules similar to those found in wound healing. In OSCC, KRT17 acts as a pathogenic keratin that facilitates tumor growth through the stimulation of multiple signaling pathways, highlighting the importance of KRT17 as a multifunctional promoter of tumorigenesis. PMID:27512993

  20. Coccidia-induced mucogenesis promotes the onset of necrotic enteritis by supporting Clostridium perfringens growth.

    PubMed

    Collier, C T; Hofacre, C L; Payne, A M; Anderson, D B; Kaiser, P; Mackie, R I; Gaskins, H R

    2008-03-15

    This study tested the hypothesis that a host mucogenic response to an intestinal coccidial infection promotes the onset of necrotic enteritis (NE). A chick NE model was used in which birds were inoculated with Eimeria acervulina and E. maxima and subsequently with Clostridium perfringens (EAM/CP). A second group of EAM/CP-infected birds was treated with the ionophore narasin (NAR/EAM/CP). These groups were compared to birds that were either non-infected (NIF), or infected only with E. acervulina and E. maxima (EAM), or C. perfringens (CP). The impact of intestinal coccidial infection and anti-coccidial treatment on host immune responses and microbial community structure were evaluated with histochemical-, cultivation- and molecular-based techniques. Barrier function was compromised in EAM/CP-infected birds as indicated by elevated CFUs for anaerobic bacteria and C. perfringens in the spleen when compared to NIF controls at day 20, with a subsequent increase in intestinal NE lesions and mortality at day 22. These results correlate positively with a host inflammatory response as evidenced by increased ileal interleukin (IL)-4, IL-10 and IFN-gamma RNA expression. Concurrent increases in chicken intestinal mucin RNA expression, and goblet cell number and theca size indicate that EAM/CP induced an intestinal mucogenic response. Correspondingly, the growth of mucolytic bacteria and C. perfringens as well as alpha toxin production was greatest in EAM/CP-infected birds. The ionophore narasin, which directly eliminates coccidia, reduced goblet cell theca size, IL-10 and IFN-gamma expression, the growth of mucolytic bacteria including C. perfringens, coccidial and NE lesions and mortality in birds that were co-infected with coccidia and C. perfringens. Collectively the data support the hypothesis that coccidial infection induces a host mucogenic response providing a growth advantage to C. perfringens, the causative agent of NE.

  1. mTOR pathway inhibition attenuates skeletal muscle growth induced by stretching.

    PubMed

    Aoki, Marcelo Saldanha; Miyabara, Elen Haruka; Soares, Antonio Garcia; Saito, Elisa Tiemi; Moriscot, Anselmo Sigari

    2006-04-01

    The present study has aimed to verify the influence of calcineurin and mTOR pathways in skeletal muscle longitudinal growth induced by stretching. Male Wistar rats were treated with cyclosporin-A or rapamycin for 10 days. To promote muscle stretching, casts were positioned so as completely to dorsiflex the plantar-flexor muscles at the ankle in one hind limb during the last 4 days of treatment with either cyclosporin-A or rapamycin. Thereafter, we determined soleus length, weight, protein content, and phenotype. In addition, NFATc1, Raptor, S6K1, 4E-BP1, iNOS, and nNOS gene expression in the soleus were determined by real-time polymerase chain reaction. Soleus length, weight, and protein content were significantly reduced by rapamycin treatment in animals submitted to stretching (P<0.05). In contrast, cyclosporin-A treatment did not alter these parameters. In all cyclosporin-A treated groups, there was a significant reduction in NFATc1 expression (P<0.001). Similarly, a significant reduction was noted in Raptor (P<0.001) and S6K1 (P<0.01) expression in all rapamycin-treated groups. No alteration was observed in 4E-BP1 gene expression among rapamycin-treated groups. Stretching increased gene expression of both NOS isoforms in skeletal muscle. Rapamycin treatment did not interfere with NOS gene expression (P<0.05). Cyclosporin-A treatment did not impair muscle growth induced by stretching but instead caused a marked slow-to-fast fiber shift in the soleus; this was attenuated by stretching. The data presented herein indicate that mTOR pathway is involved in skeletal muscle longitudinal growth.

  2. Responses of growth performance and tryptophan metabolism to oxidative stress induced by diquat in weaned pigs.

    PubMed

    Lv, M; Yu, B; Mao, X B; Zheng, P; He, J; Chen, D W

    2012-06-01

    During many pathological conditions, the tryptophan concentration in blood may be reduced. However, the effects of oxidative stress on tryptophan metabolism remain unknown. In this study, we investigated the effects of oxidative stress on growth performance and tryptophan metabolism in weaned pigs. A total of 24 weaned pigs were assigned to one of three treatments that included pigs fed ad libitum (control), pigs challenged with diquat at a dose of 10 mg/kg BW and fed ad libitum (oxidative stress) or pigs pair-fed to receive the same amount of feed as the diquat-challenged pigs. The trial lasted for 7 days. The growth performance and activities of antioxidant enzymes were declined in diquat-challenged pigs. The diquat challenge decreased the tryptophan concentration in serum and the 5-hydroxytryptamine concentration in the hypothalamus, and increased large neutral amino acids, kynurenine (Kyn) and malondialdehyde in serum. The 544-bp porcine partial mRNA sequence of the tryptophan 2,3-dioxygenase (TDO) gene was obtained according to the conserved region in the human gene sequence. In addition, the oxidative stress induced by the diquat challenge stimulated TDO-relative mRNA abundance in the liver and γ-glutamyl transpeptidase activity in intestinal mucosa, but did not affect the mRNA levels of Na+-neutral amino acid transporter B0. These results suggested that oxidative stress induced by diquat depressed growth performance and increased metabolism of tryptophan via Kyn pathway that upregulated TDO mRNA expression in weaned pigs.

  3. Iron nanoparticle growth induced by Kr-F excimer laser photolysis of Fe(CO)5

    NASA Astrophysics Data System (ADS)

    Eremin, A. V.; Gurentsov, E. V.; Priemchenko, K. Yu

    2013-06-01

    In this article the process of nanoparticle formation under the condensation of highly supersaturated atomic vapor produced by the photodissociation of metal-bearing compounds was investigated. The iron nanoparticles were synthesized by Kr-F laser pulse photolysis of Fe(CO)5. The measurements of an optical density of condensed phase were performed using a laser light extinction at a wavelength 633 nm. The particle size during their formation process was measured by a two-color time-resolved laser-induced incandescence. The final iron particle sizes and their structure were analyzed by a transmission electron microscopy. It has been shown that the process of iron particle formation in the investigated conditions could be divided onto three stages: the fast nucleation of iron atoms during 1-2 μs, the surface growth of particles up to the sizes of 1-6 nm with increasing volume fraction of condensed phase during 100-250 μs, and the relatively slow particle coagulation up to the final sizes of 5-9 nm. The effective rate constants of iron clusters and particle growth were extracted using laser light extinction measurements. The essential role of the reactions of iron clusters and particles with the parental Fe(CO)5 molecules was established. The kinetic mechanism of iron nanoparticle growth induced by photo-dissociation of Fe(CO)5 at room temperature based on obtained experimental results and known literature data has been suggested. The results obtained could be used for the developments of methods of synthesis of catalysts, magnetic nanopowders, and others nanomaterials at room temperature. Besides that, the presented experimental data could be useful for the validation of kinetic models of gas-phase condensation of supersaturated vapor of solids.

  4. Eccentric contraction-induced myofiber growth in tumor-bearing mice.

    PubMed

    Hardee, Justin P; Mangum, Joshua E; Gao, Song; Sato, Shuichi; Hetzler, Kimbell L; Puppa, Melissa J; Fix, Dennis K; Carson, James A

    2016-01-01

    Cancer cachexia is characterized by the progressive loss of skeletal muscle mass. While mouse skeletal muscle's response to an acute bout of stimulated low-frequency concentric muscle contractions is disrupted by cachexia, gaps remain in our understanding of cachexia's effects on eccentric contraction-induced muscle growth. The purpose of this study was to determine whether repeated bouts of stimulated high-frequency eccentric muscle contractions [high-frequency electrical muscle stimulation (HFES)] could stimulate myofiber growth during cancer cachexia progression, and whether this training disrupted muscle signaling associated with wasting. Male Apc(Min/+) mice initiating cachexia (N = 9) performed seven bouts of HFES-induced eccentric contractions of the left tibialis anterior muscle over 2 wk. The right tibialis anterior served as the control, and mice were killed 48 h after the last stimulation. Age-matched C57BL/6 mice (N = 9) served as wild-type controls. Apc(Min/+) mice lost body weight, muscle mass, and type IIA, IIX, and IIB myofiber cross-sectional area. HFES increased myofiber cross-sectional area of all fiber types, regardless of cachexia. Cachexia increased muscle noncontractile tissue, which was attenuated by HFES. Cachexia decreased the percentage of high succinate dehydrogenase activity myofibers, which was increased by HFES, regardless of cachexia. While cachexia activated AMP kinase, STAT3, and ERK1/2 signaling, HFES decreased AMP kinase phosphorylation, independent of the suppression of STAT3. These results demonstrate that cachectic skeletal muscle can initiate a growth response to repeated eccentric muscle contractions, despite the presence of a systemic cachectic environment.

  5. RhoA Modulates Smad Signaling during Transforming Growth Factor-β-induced Smooth Muscle Differentiation*

    PubMed Central

    Chen, Shiyou; Crawford, Michelle; Day, Regina M.; Briones, Victorino R.; Leader, Jennifer E.; Jose, Pedro A.; Lechleider, Robert J.

    2007-01-01

    We recently reported that transforming growth factor (TGF)-β induced the neural crest stem cell line Monc-1 to differentiate into a spindle-like contractile smooth muscle cell (SMC) phenotype and that Smad signaling played an important role in this phenomenon. In addition to Smad signaling, other pathways such as mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase, and RhoA have also been shown to mediate TGF-β actions. The objectives of this study were to examine whether these signaling pathways contribute to TGF-β-induced SMC development and to test whether Smad signaling cross-talks with other pathway(s) during SMC differentiation induced by TGF-β. We demonstrate here that RhoA signaling is critical to TGF-β-induced SMC differentiation. RhoA kinase (ROCK) inhibitor Y27632 significantly blocks the expression of multiple SMC markers such as smooth muscle α-actin, SM22α, and calponin in TGF-β-treated Monc-1 cells. In addition, Y27632 reversed the cell morphology and abolished the contractility of TGF-β-treated cells. RhoA signaling was activated as early as 5 min following TGF-β addition. Dominant negative RhoA blocked nuclear translocation of Smad2 and Smad3 because of the inhibition of phosphorylation of both Smads and inhibited Smad-dependent SBE promoter activity, whereas constitutively active RhoA significantly enhanced SBE promoter activity. Consistent with these results, C3 exotoxin, an inhibitor of RhoA activation, significantly attenuated SBE promoter activity and inhibited Smad nuclear translocation. Taken together, these data point to a new role for RhoA as a modulator of Smad activation while regulating TGF-β-induced SMC differentiation. PMID:16317010

  6. Apelin-induced cardioprotection against ischaemia/reperfusion injury: roles of epidermal growth factor and Src.

    PubMed

    Folino, A; Accomasso, L; Giachino, C; Montarolo, P G; Losano, G; Pagliaro, P; Rastaldo, R

    2017-07-27

    Apelin, the ligand of the G-protein-coupled receptor (GPCR) APJ, exerts a post-conditioning-like protection against ischaemia/reperfusion injury through activation of PI3K-Akt-NO signalling. The pathway connecting APJ to PI3K is still unknown. As other GPCR ligands act through transactivation of epidermal growth factor receptor (EGFR) via a matrix metalloproteinase (MMP) or Src kinase, we investigated whether EGFR transactivation is involved in the following three features of apelin-induced cardioprotection: limitation of infarct size, suppression of contracture and improvement of post-ischaemic contractile recovery. Isolated rat hearts underwent 30 min of global ischaemia and 2 h of reperfusion. Apelin (0.5 μm) was infused during the first 20 min of reperfusion. EGFR, MMP or Src was inhibited to study the pathway connecting APJ to PI3K. Key components of RISK pathway, namely PI3K, guanylyl cyclase or mitochondrial K(+) -ATP channels, were also inhibited. Apelin-induced EGFR and phosphatase and tensing homolog (PTEN) phosphorylation were assessed. Left ventricular pressure and infarct size were measured. Apelin-induced reductions in infarct size and myocardial contracture were prevented by the inhibition of EGFR, Src, MMP or RISK pathway. The involvement of EGFR was confirmed by its phosphorylation. However, neither direct EGFR nor MMP inhibition affected apelin-induced improvement of early post-ischaemic contractile recovery, which was suppressed by Src and RISK inhibitors only. Apelin also increased PTEN phosphorylation, which was removed by Src inhibition. While EGFR and MMP limit infarct size and contracture, Src or RISK pathway inhibition suppresses the three features of cardioprotection. Src does not only transactivate EGFR, but also inhibits PTEN by phosphorylation thus playing a crucial role in apelin-induced cardioprotection. © 2017 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

  7. Hydrogen Sulfide Inhibits Transforming Growth Factor-β1-Induced EMT via Wnt/Catenin Pathway.

    PubMed

    Guo, Lin; Peng, Wen; Tao, Jie; Lan, Zhen; Hei, Hongya; Tian, Lulu; Pan, Wanma; Wang, Li; Zhang, Xuemei

    2016-01-01

    Hydrogen sulfide (H2S) has anti-fibrotic potential in lung, kidney and other organs. The exogenous H2S is released from sodium hydrosulfide (NaHS) and can influence the renal fibrosis by blocking the differentiation of quiescent renal fibroblasts to myofibroblasts. But whether H2S affects renal epithelial-to-mesenchymal transition (EMT) and the underlying mechanisms remain unknown. Our study is aimed at investigating the in vitro effects of H2S on transforming growth factor-β1 (TGF-β1)-induced EMT in renal tubular epithelial cells (HK-2 cells) and the associated mechanisms. The induced EMT is assessed by Western blotting analysis on the expressions of α-SMA, E-cadherin and fibronectin. HK-2 cells were treated with NaHS before incubating with TGF-β1 to investigate its effect on EMT and the related molecular mechanism. Results demonstrated that NaHS decreased the expression of α-SMA and fibronectin, and increased the expression of E-cadherin. NaHS reduced the expression of TGF-β receptor type I (TβR I) and TGF-β receptor type II (TβR II). In addition, NaHS attenuated TGF-β1-induced increase of β-catenin expression and ERK phosphorylation. Moreover, it inhibited the TGF-β1-induced nuclear translocation of ββ-catenin. These effects of NaHS on fibronectin, E-cadherin and TβR I were abolished by the ERK inhibitor U0126 or β-catenin inhibitor XAV939, or β-catenin siRNA interference. We get the conclusion that NaHS attenuated TGF-β1-induced EMT in HK-2 cells through both ERK-dependent and β-catenin-dependent pathways.

  8. Flavonoids inhibit hypoxia-induced vascular endothelial growth factor expression by a HIF-1 independent mechanism.

    PubMed

    Ansó, Elena; Zuazo, Alicia; Irigoyen, Marta; Urdaci, María C; Rouzaut, Ana; Martínez-Irujo, Juan J

    2010-06-01

    Flavonoids are a group of polyphenolic dietary compounds that have been proposed to possess chemopreventive properties against lung cancer. In this work we analyzed the effect of a group of 20 structurally related flavonoids, including flavones, flavonols and isoflavones, on the production of vascular endothelial growth factor (VEGF) induced by hypoxia in NCI-H157 cells. VEGF is the main regulator of physiological and pathological angiogenesis and is highly stimulated by hypoxia-inducible factor 1 (HIF-1). We found that apigenin, luteolin, fisetin and quercetin inhibited hypoxia-induced VEGF expression in the low micromolar range. Structure-activity relationships demonstrated that flavone derivatives were the most active compounds and that hydroxylation of the A ring at the positions 5 and 7 and of the B ring at the 4' position were important for this activity. Interestingly, only a group of VEGF inhibitors, including apigenin, flavone and 4',7-dihydroxiflavone, reduced the expression of HIF-1alpha under these conditions, whereas others, such as fisetin, luteolin, galangin or quercetin, induced HIF-1alpha expression while reducing those of VEGF. When cells were exposed to hypoxia in the presence of these flavonoids, HIF-1alpha translocated to the nucleus and interacted with p300/CBP, but this complex was transcriptionally inactive. Taken together these findings indicate that flavonoids impair VEGF transcription by an alternative mechanism that did not depend on nuclear HIF levels. We also found that flavonoids suppressed hypoxia-induced STAT3 tyrosine phosphorylation and that this activity correlated with their potency as VEGF inhibitors, suggesting that inhibition of STAT3 function may play a role in this process.

  9. Malondialdehyde-modified low density lipoprotein (MDA-LDL)-induced cell growth was suppressed by polycyclic aromatic hydrocarbons (PAHs).

    PubMed

    Suzuki, Hiroyuki; Sasaki, Takamitsu; Kumagai, Takeshi; Sakaguchi, Shuhei; Nagata, Kiyoshi

    2010-04-01

    Malondialdehyde-modified low-density lipoprotein (MDA-LDL) and oxidized LDL (Ox-LDL), which accelerate the pathogenesis of arteriosclerosis, are thought to be involved in parthenogenesis caused by smooth muscle cell proliferation. In this study, we investigated the suppression mechanism of polycyclic aromatic hydrocarbons (PAHs) on the growth of an MDA-LDL-induced human acute monocyte leukemia suspension cell line (THP-1 cells). We found that PAHs suppressed MDA-LDL-induced THP-1 cell growth. Cotreatment with benzo[a]pyrene (BaP) or 3-methylchoranthrene (3-MC) decreased MDA-LDL-induced THP-1 cell growth, whereas treatment with benzo[e]pyrene (BeP) or pyrene, which is not a ligand for the arylhydrocarbon receptor (AhR), did not decrease THP-1 cell growth. Our findings clearly demonstrated that THP-1 cell growth, which was suppressed by PAHs, was restored by the addition of alpha-naphtoflavone, which is a partial antagonist to AhR. Moreover, it was shown that cotreatment with MDA-LDL and BaP markedly induced the expression of human cytochrome P4501A1 (hCYP1A1) messenger ribonucleic acid (mRNA) and significantly induced the expressions of p53 and p21 mRNAs. In support of these findings, AhR small interfering RNA suppressed the induced level of p21 mRNA and by BaP and the overexpression of hCYP1A1 significantly induced levels of p21 mRNA. On the other hand, the uptake rate of [(14)C]BaP into cells was increased more significantly by cotreatment with MDA-LDL than by treatment with [(14)C]BaP alone. These results strongly suggest that the suppression of MDA-LDL-induced THP-1 cell growth is caused by the increased uptake of PAHs, which strongly activate the AhR signal pathway accompanying DNA damage.

  10. Effects of induced precocious puberty on cranial growth in female Wistar rats.

    PubMed

    Izquierdo, Antonio de Moraes; Mishima, Fernanda Danielle; Carrard, Vinícius Coelho; Farina, Marcos; Nojima, Matilde da Cunha Gonçalves

    2012-04-01

    This investigation examined the effects of pharmacologically induced precocious puberty on cranial growth in Wistar rats. Forty-eight female newborn Wistar rats were divided into two groups: a control group (C) and an experimental group (E), with four subgroups of six animals each. The time interval from birth until sacrifice differed between the subgroups, and was set at 30, 60, 90, and 120 days. An intramuscular single dose (300 μg) of steroid hormone danazol was administered on day 5 after birth, as a means of inducing precocious puberty. Alizarin (2 mg/100 g) was administered to three animals in each subgroup three days prior to sacrifice. Body mass and dates corresponding to the beginning of the oestrous cycle were recorded. Craniometric measurements were undertaken. Histological analysis using light and fluorescence microscopy was then carried out to qualitatively and quantitatively evaluate the spheno-occipital synchondrosis and to visualize bone deposition patterns. The results were analysed with a Student's t-test and analysis of variance. Precocious puberty was effectively induced and differences between groups denoted an earlier maturation in the experimental rats. In qualitative analysis, a significant increase of total synchondrosis width was noted only in group E60, in comparison with C60, and an increase in the E90 subgroup cortical bone width compared with the C90 subgroup. Histomorphometrically, a statistical difference between total width values of subgroups E60 (434.3 μm) and C60 (323.5 μm) was detected. However, body mass and macroscopic measurements did not show statistically significant differences. An appropriate model for studying bone growth associated with precocious puberty in Wistar female rats was not achieved using steroid hormone danazol, when evaluated at 30 day intervals.

  11. Potassium Inhibits Dietary Salt-Induced Transforming Growth Factor-β Production

    PubMed Central

    Ying, Wei-Zhong; Aaron, Kristal; Wang, Pei-Xuan; Sanders, Paul W.

    2009-01-01

    Human and animal studies demonstrate an untoward effect of excess dietary NaCl (salt) intake on cardiovascular function and life span. The endothelium in particular augments the production of transforming growth factor (TGF)-β, a fibrogenic growth factor, in response to excess dietary salt intake. This study explored the initiating mechanism that regulates salt-induced endothelial cell production of TGF-β. Male Sprague-Dawley rats were given diets containing different amounts of NaCl and potassium for 4 days. A bioassay for TGF-β demonstrated increased (35.2%) amounts of active TGF-β in the medium of aortic ring segments from rats on the high-salt diet compared with rats maintained on a 0.3% NaCl diet. Inhibition of the large-conductance, calcium-activated potassium channel inhibited dietary salt-induced vascular production of TGF-β but did not affect production of TGF-β by ring segments from rats on the low-salt diet. Immunohistochemical and Western analyses demonstrated the α subunit of the calcium-activated potassium channel in endothelial cells. Increasing medium [K+] inhibited production of dietary salt-induced vascular production levels of total and active TGF-β but did not alter TGF-β production by aortic rings from rats on the 0.3% NaCl diet. Increasing dietary potassium content decreased urinary active TGF-β in animals receiving the high-salt diet but did not change urinary active TGF-β in animals receiving the low-salt diet. The findings demonstrated an interesting interaction between the dietary intake of potassium and excess NaCl and further showed the fundamental role of the endothelial calcium-activated potassium channel in the vascular response to excess salt intake. PMID:19738156

  12. Exploring bacteria-induced growth and morphogenesis in the green macroalga order Ulvales (Chlorophyta)

    PubMed Central

    Wichard, Thomas

    2015-01-01

    Green macroalgae, such as Ulvales, lose their typical morphology completely when grown under axenic conditions or in the absence of the appropriate microbiome. As a result, slow growing aberrant phenotypes or even callus-like morphotypes are observed in Ulvales. The cross-kingdom interactions between marine algae and microorganisms are hence not only restricted by the exchange of macronutrients, including vitamins and nutrients, but also by infochemicals such as bacterial morphogenetic compounds. The latter are a fundamental trait mediating the mutualism within the chemosphere where the organisms interact with each other via compounds in their surroundings. Approximately 60 years ago, pilot studies demonstrated that certain bacteria promote growth, whereas other bacteria induce morphogenesis; this is particularly true for the order of Ulvales. However, only slow progress was made towards the underlying mechanism due to the complexity of, for example, algal cultivation techniques, and the lack of standardized experiments in the laboratory. A breakthrough in this research was the discovery of the morphogenetic compound thallusin, which was isolated from an epiphytic bacterium and induces normal germination restoring the foliaceous morphotypes of Monostroma. Owing to the low concentration, the purification and structure elucidation of highly biologically active morphogenetic compounds are still challenging. Recently, it was found that only the combination of two specific bacteria from the Rhodobacteraceae and Flavobacteriaceae can completely recover the growth and morphogenesis of axenic Ulva mutabilis cultures forming a symbiotic tripartite community by chemical communication. This review combines literature detailing evidences of bacteria-induced morphogenesis in Ulvales. A set of standardized experimental approaches is further proposed for the preparation of axenic algal tissues, bacteria isolation, co-cultivation experiments, and the analysis of the chemosphere

  13. Potassium inhibits dietary salt-induced transforming growth factor-beta production.

    PubMed

    Ying, Wei-Zhong; Aaron, Kristal; Wang, Pei-Xuan; Sanders, Paul W

    2009-11-01

    Human and animal studies demonstrate an untoward effect of excess dietary NaCl (salt) intake on cardiovascular function and life span. The endothelium in particular augments the production of transforming growth factor (TGF)-beta, a fibrogenic growth factor, in response to excess dietary salt intake. This study explored the initiating mechanism that regulates salt-induced endothelial cell production of TGF-beta. Male Sprague-Dawley rats were given diets containing different amounts of NaCl and potassium for 4 days. A bioassay for TGF-beta demonstrated increased (35.2%) amounts of active TGF-beta in the medium of aortic ring segments from rats on the high-salt diet compared with rats maintained on a 0.3% NaCl diet. Inhibition of the large-conductance, calcium-activated potassium channel inhibited dietary salt-induced vascular production of TGF-beta but did not affect production of TGF-beta by ring segments from rats on the low-salt diet. Immunohistochemical and Western analyses demonstrated the alpha subunit of the calcium-activated potassium channel in endothelial cells. Increasing medium [K+] inhibited production of dietary salt-induced vascular production levels of total and active TGF-beta but did not alter TGF-beta production by aortic rings from rats on the 0.3% NaCl diet. Increasing dietary potassium content decreased urinary active TGF-beta in animals receiving the high-salt diet but did not change urinary active TGF-beta in animals receiving the low-salt diet. The findings demonstrated an interesting interaction between the dietary intake of potassium and excess NaCl and further showed the fundamental role of the endothelial calcium-activated pota