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Sample records for induces local suppression

  1. Cellular target of UVB-induced DNA damage resulting in local suppression of contact hypersensitivity

    NARCIS (Netherlands)

    Vink, A.A.; Shreedhar, V.; Roza, L.; Krutmann, J.; Kripke, M.L.

    1998-01-01

    Experimental data are reviewed that lend support to the hypothesis that formation of DNA damage is the initiation event of local suppression of contact hypersensitivity (CHS) after exposure to ultraviolet (UV) radiaton and that the antigen-presenting cell (APC) is an important traget for this DNA da

  2. Local suppression of T cell responses by arginase-induced L-arginine depletion in nonhealing leishmaniasis.

    Directory of Open Access Journals (Sweden)

    Manuel Modolell

    Full Text Available The balance between T helper (Th 1 and Th2 cell responses is a major determinant of the outcome of experimental leishmaniasis, but polarized Th1 or Th2 responses are not sufficient to account for healing or nonhealing. Here we show that high arginase activity, a hallmark of nonhealing disease, is primarily expressed locally at the site of pathology. The high arginase activity causes local depletion of L-arginine, which impairs the capacity of T cells in the lesion to proliferate and to produce interferon-gamma, while T cells in the local draining lymph nodes respond normally. Healing, induced by chemotherapy, resulted in control of arginase activity and reversal of local immunosuppression. Moreover, competitive inhibition of arginase as well as supplementation with L-arginine restored T cell effector functions and reduced pathology and parasite growth at the site of lesions. These results demonstrate that in nonhealing leishmaniasis, arginase-induced L-arginine depletion results in impaired T cell responses. Our results identify a novel mechanism in leishmaniasis that contributes to the failure to heal persistent lesions and suggest new approaches to therapy.

  3. Depletion of CD4+CD25+ regulatory T cells can promote local immunity to suppress tumor growth in benzo[a]pyrene-induced forestomach carcinoma

    Institute of Scientific and Technical Information of China (English)

    Yi-Ling Chen; Jung-Hua Fang; Ming-Derg Lai; Yan-Shen Shan

    2008-01-01

    AIM: To elucidate the distribution of CD4+CD25+ regulatory T cells (Tregs) in different lymphoid tissues and its local enhancement on tumor growth before and after depletion of CD4+CD25+ Tregs.METHODS: Female ICR mice were gavaged with benzo[a]pyrene (BaP) to induce forestomach carcinoma. CD4+CD25+ Tregs were intraperitoneally depleted with monoclonal antibody PC61. These mice were divided into BaP-only, BaP+IgG, BaP+PC61, and control groups. The forestomach of mice was dissected for histological analysis, and tunnel test was performed for apoptosis of tumor cells. CD4+CD25+ Tregs were sorted from different lymphoid tissues and expression of Foxp3, IL-10, and chemokine receptors was analyzed by flow cytometry, semi-quantitative and real-time polymerase chain reaction.RESULTS: The mice gavaged with only BaP showed increased forestomach papilloma and carcinoma at wk 16 and 32. The proportion of CD4+CD25+ Tregs was significantly higher in peri-stomach regional lymph nodes than in other lymphoid tissues. These CD4+CD25+ Tregs in regional lymph nodes expressed higher levels of Foxp3 and IL-10, enriched in the CD62L-subset, and CCR1 and CCR5 chemokine receptors. In mice gavaged with BaP+PC61, the number of tumor nodules and tumor volume decreased significantly with massive infiltrating cells and apoptosis of tumor cells. In the draining regional lymph nodes, the number of CD4+CD25+ Tregs also decreased significantly.CONCLUSION: Inducible and activated CD4+CD25+ Tregs in the draining regional lymph nodes suppress host local immunity during tumor growth. Depletion of CD4+CD25+ Tregs can promote host local immunity to suppress tumor growth.

  4. Genomic structure, chromosomal localization and expression profile of a novel melanoma differentiation associated (mda-7) gene with cancer specific growth suppressing and apoptosis inducing properties.

    Energy Technology Data Exchange (ETDEWEB)

    Huang, E. Y.; Madireddi, M. T.; Gopalkrishnan, R. V.; Leszczyniecka, M.; Su, Z. Z.; Lebedeva, I. V.; Kang, D. C.; Jian, H.; Lin, J. J.; Alexandre, D.; Chen, Y.; Vozhilla, N.; Mei, M. X.; Christiansen, K. A.; Sivo, F.; Goldstein, N. I.; Chada, S.; Huberman, E.; Pestka, S.; Fisher, P. B.; Biochip Technology Center; Columbia Univ.; Introgen Therapeutics Inc.; UMDNJ-Robert Wood Johnson Medical School

    2001-10-25

    Abnormalities in cellular differentiation are frequent occurrences in human cancers. Treatment of human melanoma cells with recombinant fibroblast interferon (IFN-beta) and the protein kinase C activator mezerein (MEZ) results in an irreversible loss in growth potential, suppression of tumorigenic properties and induction of terminal cell differentiation. Subtraction hybridization identified melanoma differentiation associated gene-7 (mda-7), as a gene induced during these physiological changes in human melanoma cells. Ectopic expression of mda-7 by means of a replication defective adenovirus results in growth suppression and induction of apoptosis in a broad spectrum of additional cancers, including melanoma, glioblastoma multiforme, osteosarcoma and carcinomas of the breast, cervix, colon, lung, nasopharynx and prostate. In contrast, no apparent harmful effects occur when mda-7 is expressed in normal epithelial or fibroblast cells. Human clones of mda-7 were isolated and its organization resolved in terms of intron/exon structure and chromosomal localization. Hu-mda-7 encompasses seven exons and six introns and encodes a protein with a predicted size of 23.8 kDa, consisting of 206 amino acids. Hu-mda-7 mRNA is stably expressed in the thymus, spleen and peripheral blood leukocytes. De novo mda-7 mRNA expression is also detected in human melanocytes and expression is inducible in cells of melanocyte/melanoma lineage and in certain normal and cancer cell types following treatment with a combination of IFN-beta plus MEZ. Mda-7 expression is also induced during megakaryocyte differentiation induced in human hematopoietic cells by treatment with TPA (12-O-tetradecanoyl phorbol-13-acetate). In contrast, de novo expression of mda-7 is not detected nor is it inducible by IFN-beta+MEZ in a spectrum of additional normal and cancer cells. No correlation was observed between induction of mda-7 mRNA expression and growth suppression following treatment with IFN-beta+MEZ and

  5. Strong suppression of weak localization in graphene

    NARCIS (Netherlands)

    Morozov, S.V.; Novoselov, K.S.; Katsnelson, M.I.; Schedin, F.; Ponomarenko, L.A.; Jiang, D.; Geim, A.K.

    2006-01-01

    Low-field magnetoresistance is ubiquitous in low-dimensional metallic systems with high resistivity and well understood as arising due to quantum interference on self-intersecting diffusive trajectories. We have found that in graphene this weak-localization magnetoresistance is strongly suppressed a

  6. Characterization of Immune Suppression Induced by Polyribonucleotides.

    Science.gov (United States)

    1985-12-01

    RD-0162 482 CHARACTERIZATION OF IMMUNE SUPPRESSION INDUCED Y v i POLYRIDONUCLEOTIDES(U) MINNESOTA UNIV DULUTH DEPT OF MEDICAL MICROBIOLOGY AND...Polyribonucleotides by Marilyn J. Odean and Arthur G. Johnson Dept. of Medical Microbiology /Immunology University of Minnesota-Duluth 55812 DTICS ELECTE DEC 18

  7. In Vivo Quantitation of Local Anesthetic Suppression of Leukocyte Adherence

    Science.gov (United States)

    Giddon, D. B.; Lindhe, J.

    1972-01-01

    Using intravital microscopy, topically applied amide-type local anesthetics suppressed the adherence of leukocytes to the venular endothelium within surgical defects in the hamster cheek pouch. The response was reversible with physiologic saline and was localized to venules within the defect. Quantitation in terms of the percent of initially adhering leukocytes remaining in place on the venule wall at each minute following application of lidocaine and physiologic saline, respectively, revealed the suppression to be reliably related to the concentration, viz: 20.0 >10.0 >5.0 >0.0 mg ml of commercially available Xylocaine® (lidocaine) HCl. ImagesFig 1Fig 1 PMID:5049429

  8. Suppressing Anomalous Localized Waffle Behavior in Least Squares Wavefront Reconstructors

    Energy Technology Data Exchange (ETDEWEB)

    Gavel, D

    2002-10-08

    A major difficulty with wavefront slope sensors is their insensitivity to certain phase aberration patterns, the classic example being the waffle pattern in the Fried sampling geometry. As the number of degrees of freedom in AO systems grows larger, the possibility of troublesome waffle-like behavior over localized portions of the aperture is becoming evident. Reconstructor matrices have associated with them, either explicitly or implicitly, an orthogonal mode space over which they operate, called the singular mode space. If not properly preconditioned, the reconstructor's mode set can consist almost entirely of modes that each have some localized waffle-like behavior. In this paper we analyze the behavior of least-squares reconstructors with regard to their mode spaces. We introduce a new technique that is successful in producing a mode space that segregates the waffle-like behavior into a few ''high order'' modes, which can then be projected out of the reconstructor matrix. This technique can be adapted so as to remove any specific modes that are undesirable in the final reconstructor (such as piston, tip, and tilt for example) as well as suppress (the more nebulously defined) localized waffle behavior.

  9. Suppression of spiral waves using intermittent local electric shock

    Institute of Scientific and Technical Information of China (English)

    Ma Jun; Ying He-Ping; Li Yan-Long

    2007-01-01

    In this paper, an intermittent local electric shock scheme is proposed to suppress stable spiral waves in the Barkley model by a weak electric shock (about 0.4 to 0.7) imposed on a random selected n × n grids (n = 1-5, compared with the original 256×256 lattice) and monitored synchronically the evolutions of the activator on the grids as the sampled signal of the activator steps out a given threshold (i.e., the electric shock works on the n × n grids if the activator u (≤) 0.4 or u (≥) 0.8). The numerical simulations show that a breakup of spiral is observed in the media state evolution to finally obtain homogeneous states if the electric shock with appropriate intensity is imposed.

  10. Cold suppresses agonist-induced activation of TRPV1.

    Science.gov (United States)

    Chung, M-K; Wang, S

    2011-09-01

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

  11. Suppression of martensitic transformation in Fe50Mn23Ga27 by local symmetry breaking

    Science.gov (United States)

    Ma, Tianyu; Liu, Xiaolian; Yan, Mi; Wu, Chen; Ren, Shuai; Li, Huiying; Fang, Minxia; Qiu, Zhiyong; Ren, Xiaobing

    2015-05-01

    Defects-induced local symmetry breaking has led to unusual properties in nonferromagnetic ferroelastic materials upon suppressing their martensitic transformation. Thus, it is of interest to discover additional properties by local symmetry breaking in one important class of the ferroelastic materials, i.e., the ferromagnetic shape memory alloys. In this letter, it is found that local symmetry breaking including both tetragonal nano-inclusions and anti-phase boundaries (APBs), suppresses martensitic transformation of a body-centered-cubic Fe50Mn23Ga27 alloy, however, does not affect the magnetic ordering. Large electrical resistivity is retained to the low temperature ferromagnetic state, behaving like a half-metal ferromagnet. Lower ordering degree at APBs and local stress fields generated by the lattice expansion of tetragonal nanoparticles hinder the formation of long-range-ordered martensites. The half-metal-like conducting behavior upon suppressing martensitic transformation extends the regime of ferromagnetic shape memory materials and may lead to potential applications in spintronic devices.

  12. Reversing Breast Cancer-Induced Immune Suppression

    Science.gov (United States)

    2014-09-01

    GCL (Glutamate-Cysteine Ligase), and cystine transport genes xCT and 4F2 [19, 23] Cystine transport and Nrf2 may contribute to MDSC survival. We... cystine (via the xC - cystine /glutamate antiporter) and its reduction to cysteine are rate-limiting for the synthesis of the antioxidant glutathione (GSH...Nr2 regulates tumor-bearer survival and MDSC suppressive activity. Aim 3: Determine if blocking cystine transport into MDSC while providing T cells

  13. Suppression of oocyte release in rats by local administration of the noradrenergic neurotoxin DSP4.

    Science.gov (United States)

    Goldman, J M; Stoker, T E; Cooper, R L; McElroy, W K; Parrish, M B

    1996-03-01

    The presence of noradrenergic neuronal innervation in the ovaries and cyclic alterations in ovarian noradrenaline suggest a role for such innervation in oocyte release. The current experiments evaluated the relationship between ovulation and alterations in ovarian concentrations of noradrenaline induced by unilateral, intrabursal administration of the specific noradrenergic neurotoxin DSP4. Intrabursal injections of DSP4 (0-10 mumoles per ovary) given at 19:00 h at pro-oestrus induced a prompt, dose-related reduction in ovarian noradrenaline on the injected and non-injected sides. Although this result suggests that injected material was reaching the contralateral ovary, ovulation was suppressed only on the injected side. This suppression was persistent, and lasted through at least the next two cycles following either unilateral or bilateral treatment. The reductions in noradrenaline could be mostly, if not entirely, attenuated by prior administration of desipramine which blocks re-uptake of noradrenaline, while the ipsilateral ovulatory effects remained unchanged. Although it has been reported that DSP4 binds the opiate receptor, intrabursal co-administration of the antagonist naloxone was ineffective in altering ovulatory suppression. These results suggest that while decreases in ovarian noradrenaline in response to local exposure to a noradrenergic neurotoxin may accompany a reduction in oocyte release or a block in ovulation, the anti-ovulatory effect of DSP4 is independent of the changes in noradrenaline concentrations and may be due to some other ovarian response.

  14. Magnesium induces neuronal apoptosis by suppressing excitability

    OpenAIRE

    Dribben, W H; Eisenman, L N; Mennerick, S

    2010-01-01

    In clinical obstetrics, magnesium sulfate (MgSO4) use is widespread, but effects on brain development are unknown. Many agents that depress neuronal excitability increase developmental neuroapoptosis. In this study, we used dissociated cultures of rodent hippocampus to examine the effects of Mg++ on excitability and survival. Mg++-induced caspase-3-associated cell loss at clinically relevant concentrations. Whole-cell patch-clamp techniques measured Mg++ effects on action potential threshold,...

  15. Suppression of Rayleigh-scattering-induced noise in OEOs.

    Science.gov (United States)

    Okusaga, Olukayode; Cahill, James P; Docherty, Andrew; Menyuk, Curtis R; Zhou, Weimin; Carter, Gary M

    2013-09-23

    Optoelectronic oscillators (OEOs) are hybrid RF-photonic devices that promise to be environmentally robust high-frequency RF sources with very low phase noise. Previously, we showed that Rayleigh-scattering-induced noise in optical fibers coupled with amplitude-to-phase noise conversion in photodetectors and amplifiers leads to fiber-length-dependent noise in OEOs. In this work, we report on two methods for the suppression of this fiber-length-dependent noise: altering the amplitude-dependent phase delay of the OEO loops and suppressing the Rayleigh-scattering-induced noise in optical fibers. We report a 20 dB reduction in the flicker phase noise of a 6 km OEO via these suppression techniques.

  16. Measles virus-induced suppression of immune responses

    Science.gov (United States)

    Griffin, Diane E.

    2010-01-01

    Summary Measles is an important cause of child mortality that has a seemingly paradoxical interaction with the immune system. In most individuals, the immune response is successful in eventually clearing measles virus (MV) infection and in establishing life-long immunity. However, infection is also associated with persistence of viral RNA and several weeks of immune suppression, including loss of delayed type hypersensitivity responses and increased susceptibility to secondary infections. The initial T-cell response includes CD8+ and T-helper 1 CD4+ T cells important for control of infectious virus. As viral RNA persists, there is a shift to a T-helper 2 CD4+ T-cell response that likely promotes B-cell maturation and durable antibody responses but may suppress macrophage activation and T-helper 1 responses to new infections. Suppression of mitogen-induced lymphocyte proliferation can be induced by lymphocyte infection with MV or by lymphocyte exposure to a complex of the hemagglutinin and fusion surface glycoproteins without infection. Dendritic cells are susceptible to infection and can transmit infection to lymphocytes. MV-infected dendritic cells are unable to stimulate a mixed lymphocyte reaction and can induce lymphocyte unresponsiveness through expression of MV glycoproteins. Thus, multiple factors may contribute both to measles-induced immune suppression and to the establishment of durable protective immunity. PMID:20636817

  17. Rosmarinus officinalis extract suppresses Propionibacterium acnes-induced inflammatory responses.

    Science.gov (United States)

    Tsai, Tsung-Hsien; Chuang, Lu-Te; Lien, Tsung-Jung; Liing, Yau-Rong; Chen, Wei-Yu; Tsai, Po-Jung

    2013-04-01

    Propionibacterium acnes is a key pathogen involved in the progression of acne inflammation. The development of a new agent possessing antimicrobial and anti-inflammatory activity against P. acnes is therefore of interest. In this study, we investigated the inhibitory effect of rosemary (Rosmarinus officinalis) extract on P. acnes-induced inflammation in vitro and in vivo. The results showed that ethanolic rosemary extract (ERE) significantly suppressed the secretion and mRNA expression of proinflammatory cytokines, including interleukin (IL)-8, IL-1β, and tumor necrosis factor-α in P. acnes-stimulated monocytic THP-1 cells. In an in vivo mouse model, concomitant intradermal injection of ERE attenuated the P. acnes-induced ear swelling and granulomatous inflammation. Since ERE suppressed the P. acnes-induced nuclear factor kappa-B (NF-κB) activation and mRNA expression of Toll-like receptor (TLR) 2, the suppressive effect of ERE might be due, at least partially, to diminished NF-κB activation and TLR2-mediated signaling pathways. Furthermore, three major constituents of ERE, carnosol, carnosic acid, and rosmarinic acid, exerted different immumodulatory activities in vitro. In brief, rosmarinic acid significantly suppressed IL-8 production, while the other two compounds inhibited IL-1β production. Further study is needed to explore the role of bioactive compounds of rosemary in mitigation of P. acnes-induced inflammation.

  18. Global Enhancement but Local Suppression in Feature-based Attention.

    Science.gov (United States)

    Forschack, Norman; Andersen, Søren K; Müller, Matthias M

    2017-04-01

    A key property of feature-based attention is global facilitation of the attended feature throughout the visual field. Previously, we presented superimposed red and blue randomly moving dot kinematograms (RDKs) flickering at a different frequency each to elicit frequency-specific steady-state visual evoked potentials (SSVEPs) that allowed us to analyze neural dynamics in early visual cortex when participants shifted attention to one of the two colors. Results showed amplification of the attended and suppression of the unattended color as measured by SSVEP amplitudes. Here, we tested whether the suppression of the unattended color also operates globally. To this end, we presented superimposed flickering red and blue RDKs in the center of a screen and a red and blue RDK in the left and right periphery, respectively, also flickering at different frequencies. Participants shifted attention to one color of the superimposed RDKs in the center to discriminate coherent motion events in the attended from the unattended color RDK, whereas the peripheral RDKs were task irrelevant. SSVEP amplitudes elicited by the centrally presented RDKs confirmed the previous findings of amplification and suppression. For peripherally located RDKs, we found the expected SSVEP amplitude increase, relative to precue baseline when color matched the one of the centrally attended RDK. We found no reduction in SSVEP amplitude relative to precue baseline, when the peripheral color matched the unattended one of the central RDK, indicating that, while facilitation in feature-based attention operates globally, suppression seems to be linked to the location of focused attention.

  19. Suppression of narrow-band transparency in a metasurface induced by a strongly enhanced electric field

    CERN Document Server

    Tamayama, Yasuhiro; Yasui, Kanji

    2015-01-01

    We realize a suppression of an electromagnetically induced transparency (EIT) like transmission in a metasurface induced by a local electric field that is strongly enhanced based on two approaches: squeezing of electromagnetic energy in resonant metasurfaces and enhancement of electromagnetic energy density associated with a low group velocity. The EIT-like metasurface consists of a pair of radiatively coupled cut-wire resonators, and it can effect both field enhancement approaches simultaneously. The strongly enhanced local electric field generates an air discharge plasma at either of the gaps of the cut-wire resonators, which causes the EIT-like metasurface to change into two kinds of Lorentz type metasurfaces.

  20. Caffeine-Induced Suppression of GABAergic Inhibition and Calcium-Independent Metaplasticity

    Directory of Open Access Journals (Sweden)

    Masako Isokawa

    2016-01-01

    Full Text Available GABAergic inhibition plays a critical role in the regulation of neuron excitability; thus, it is subject to modulations by many factors. Recent evidence suggests the elevation of intracellular calcium ([Ca2+]i and calcium-dependent signaling molecules underlie the modulations. Caffeine induces a release of calcium from intracellular stores. We tested whether caffeine modulated GABAergic transmission by increasing [Ca2+]i. A brief local puff-application of caffeine to hippocampal CA1 pyramidal cells transiently suppressed GABAergic inhibitory postsynaptic currents (IPSCs by 73.2 ± 6.98%. Time course of suppression and the subsequent recovery of IPSCs resembled DSI (depolarization-induced suppression of inhibition, mediated by endogenous cannabinoids that require a [Ca2+]i rise. However, unlike DSI, caffeine-induced suppression of IPSCs (CSI persisted in the absence of a [Ca2+]i rise. Intracellular applications of BAPTA and ryanodine (which blocks caffeine-induced calcium release from intracellular stores failed to prevent the generation of CSI. Surprisingly, ruthenium red, an inhibitor of multiple calcium permeable/release channels including those of stores, induced metaplasticity by amplifying the magnitude of CSI independently of calcium. This metaplasticity was accompanied with the generation of a large inward current. Although ionic basis of this inward current is undetermined, the present result demonstrates that caffeine has a robust Ca2+-independent inhibitory action on GABAergic inhibition and causes metaplasticity by opening plasma membrane channels.

  1. Cold Suppresses Agonist-induced Activation of TRPV1

    OpenAIRE

    2011-01-01

    Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppress...

  2. Lumped Mass Modeling for Local-Mode-Suppressed Element Connectivity

    DEFF Research Database (Denmark)

    Joung, Young Soo; Yoon, Gil Ho; Kim, Yoon Young

    2005-01-01

    for the standard element density method. Local modes are artificial, numerical modes resulting from the intrinsic modeling technique of the topology optimization method. Even with existing local mode controlling techniques, the convergence of the topology optimization of vibrating structures, especially...... experiencing large structural changes, appears to be still poor. In ECP, the nodes of the domain-discretizing elements are connected by zero-length one-dimensional elastic links having varying stiffness. For computational efficiency, every elastic link is now assumed to have two lumped masses at its ends......For successful topology design optimization of crashworthy “continuum” structures, unstable element-free and local vibration mode-free transient analyses should be ensured. Among these two issues, element instability was shown to be overcome if a recently-developed formulation, the element...

  3. Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling

    Energy Technology Data Exchange (ETDEWEB)

    Lovelace, Erica S.; Wagoner, Jessica; MacDonald, James; Bammler, Theo; Bruckner, Jacob; Brownell, Jessica; Beyer, Richard; Zink, Erika M.; Kim, Young-Mo; Kyle, Jennifer E.; Webb-Robertson, Bobbie-Jo M.; Waters, Katrina M.; Metz, Thomas O.; Farin, Federico; Oberlies, Nicholas H.; Polyak, Steve

    2015-08-28

    Silymarin (SM), a natural product, is touted as a liver protectant and preventer of both chronic inflammation and diseases. To define how SM elicits these effects at a systems level, we performed transcriptional profiling, metabolomics, and signaling studies in human liver and T cell lines. Multiple pathways associated with cellular stress and metabolism were modulated by SM treatment within 0.5 to four hours: activation of Activating Transcription Factor 4 (ATF-4) and adenosine monophosphate protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) signaling, the latter being associated with induction of DNA-damage-inducible transcript 4 (DDIT4). Metabolomics analyses revealed suppression of glycolytic, TCA cycle, and amino acid metabolism by SM treatment. Antiinflammatory effects arose with prolonged (i.e. 24 hours) SM exposure, with suppression of multiple proinflammatory mRNAs and nuclear factor kappa B (NF-κB) and forkhead box O (FOXO) signaling. Studies with murine knock out cells revealed that SM inhibition of both mTOR and NF-κB was partially AMPK dependent, while SM inhibition of the mTOR pathway in part required DDIT4. Thus, SM activates stress and repair responses that culminate in an anti-inflammatory phenotype. Other natural products induced similar stress responses, which correlated with their ability to suppress inflammation. Therefore, natural products like SM may be useful as tools to define how metabolic, stress, and repair pathways regulate cellular inflammation.

  4. Interleukin-35 induces regulatory B cells that suppress autoimmune disease.

    Science.gov (United States)

    Wang, Ren-Xi; Yu, Cheng-Rong; Dambuza, Ivy M; Mahdi, Rashid M; Dolinska, Monika B; Sergeev, Yuri V; Wingfield, Paul T; Kim, Sung-Hye; Egwuagu, Charles E

    2014-06-01

    Interleukin-10 (IL-10)-producing regulatory B (Breg) cells suppress autoimmune disease, and increased numbers of Breg cells prevent host defense to infection and promote tumor growth and metastasis by converting resting CD4(+) T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of Breg cells remain unclear. Here we show that IL-35 induces Breg cells and promotes their conversion to a Breg subset that produces IL-35 as well as IL-10. Treatment of mice with IL-35 conferred protection from experimental autoimmune uveitis (EAU), and mice lacking IL-35 (p35 knockout (KO) mice) or defective in IL-35 signaling (IL-12Rβ2 KO mice) produced less Breg cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of Breg cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 (TH17) and TH1 cells while promoting Treg cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12Rβ2 and IL-27Rα subunits. As IL-35 also induced the conversion of human B cells into Breg cells, these findings suggest that IL-35 may be used to induce autologous Breg and IL-35(+) Breg cells and treat autoimmune and inflammatory disease.

  5. Population viscosity suppresses disease emergence by preserving local herd immunity.

    Science.gov (United States)

    Reluga, Timothy C; Shim, Eunha

    2014-12-01

    Animal reservoirs for infectious diseases pose ongoing risks to human populations. In this theory of zoonoses, the introduction event that starts an epidemic is assumed to be independent of all preceding events. However, introductions are often concentrated in communities that bridge the ecological interfaces between reservoirs and the general population. In this paper, we explore how the risks of disease emergence are altered by the aggregation of introduction events within bridge communities. In viscous bridge communities, repeated introductions can elevate the local prevalence of immunity. This local herd immunity can form a barrier reducing the opportunities for disease emergence. In some situations, reducing exposure rates counterintuitively increases the emergence hazards because of off-setting reductions in local immunity. Increases in population mixing can also increase emergence hazards, even when average contact rates are conserved. Our theory of bridge communities may help guide prevention and explain historical emergence events, where disruption of stable economic, political or demographic processes reduced population viscosity at ecological interfaces.

  6. Measuring natural pest suppression at different spatial scales affects the importance of local variables.

    Science.gov (United States)

    Bennett, A B; Gratton, C

    2012-10-01

    The role biodiversity plays in the provision of ecosystem services is widely recognized, yet few ecological studies have identified characteristics of natural systems that support and maintain ecosystem services. The purpose of this study was to identify landscape variables correlated with natural pest suppression carried out by arthropod natural enemies, predators and parasitoids. We conducted two field experiments, one observational and one experimental, where landscape variables at broad and local scales were measured and related to natural pest suppression. The first experiment measured natural pest suppression at 16 sites across an urban to rural landscape gradient in south central Wisconsin. We found natural enemy diversity positively affected natural pest suppression, whereas flower diversity negatively affected pest suppression. No relationship was found between natural pest suppression and broad scale variables, which measured the percentage of different land cover classes in the surrounding landscape. In the second experiment, we established small (2- by 3-m) replicated plots that experimentally varied flower diversity (0, 1, or 7 species) within a plot. We found no significant relationship between natural pest suppression and the different levels of flower diversity. The fact that we only found differences in natural pest suppression in our first experiment, which measured natural pest suppression at sites separated by larger distances than our second experiment, suggests the more appropriate scale for measuring ecosystem services performed by mobile organisms like insects, is across broad spatial scales where variation in natural enemies communities and the factors that affect them become more apparent.

  7. Hyperinsulinism induced by targeted suppression of beta cell KATP channels.

    Science.gov (United States)

    Koster, J C; Remedi, M S; Flagg, T P; Johnson, J D; Markova, K P; Marshall, B A; Nichols, C G

    2002-12-24

    ATP-sensitive K+ (K(ATP)) channels couple cell metabolism to electrical activity. To probe the role of K(ATP) in glucose-induced insulin secretion, we have generated transgenic mice expressing a dominant-negative, GFP-tagged K(ATP) channel subunit in which residues 132-134 (Gly-Tyr-Gly) in the selectivity filter were replaced by Ala-Ala-Ala, under control of the insulin promoter. Transgene expression was confirmed by both beta cell-specific green fluorescence and complete suppression of channel activity in those cells ( approximately 70%) that did fluoresce. Transgenic mice developed normally with no increased mortality and displayed normal body weight, blood glucose levels, and islet architecture. However, hyperinsulinism was evident in adult mice as (i) a disproportionately high level of circulating serum insulin for a given glucose concentration ( approximately 2-fold increase in blood insulin), (ii) enhanced glucose-induced insulin release from isolated islets, and (iii) mild yet significant enhancement in glucose tolerance. Enhanced glucose-induced insulin secretion results from both increased glucose sensitivity and increased release at saturating glucose concentration. The results suggest that incomplete suppression of K(ATP) channel activity can give rise to a maintained hyperinsulinism.

  8. Emodin suppresses cadmium-induced osteoporosis by inhibiting osteoclast formation.

    Science.gov (United States)

    Chen, Xiao; Ren, Shuai; Zhu, Guoying; Wang, Zhongqiu; Wen, Xiaolin

    2017-09-01

    Environmental level of cadmium (Cd) exposure can induce bone loss. Emodin, a naturally compound found in Asian herbal medicines, could influence osteoblast/osteoclast differentiation. However, the effects of emodin on Cd-induced bone damage are not clarified. The aim of this study was to investigate the role of emodin on Cd-induced osteoporosis. Sprague-Dawley male rats were divided into three groups which were given 0mg/L, 50mg Cd/L and 50mg Cd/L plus emodin (50mg/kg body weight). Bone histological investigation, microCT analysis, metabolic biomarker determination and immunohistochemical staining were performed at the 12th week. The bone mass and bone microstructure index of rats treated with Cd were obviously lower than in control. Cd markedly enhanced the osteoclast formation compared with control. Emodin significantly abolished the Cd-induced bone microstructure damage (p<0.05), osteoclast formation and increase of tartrate-resistant acid phosphatase 5b level (p<0.05). Our data further showed that emodin attenuated the Cd-induced inhibition of osteoprotegerin expression and stimulation of receptor activator for nuclear factor-κ B ligand expression. Our data show that emodin suppresses the Cd-induced osteoporosis by inhibiting osteoclast formation. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Suppression of T cell-induced osteoclast formation

    Energy Technology Data Exchange (ETDEWEB)

    Karieb, Sahar; Fox, Simon W., E-mail: Simon.fox@plymouth.ac.uk

    2013-07-12

    Highlights: •Genistein and coumestrol prevent activated T cell induced osteoclast formation. •Anti-TNF neutralising antibodies prevent the pro-osteoclastic effect of activated T cells. •Phytoestrogens inhibit T cell derived TNF alpha and inflammatory cytokine production. •Phytoestrogens have a broader range of anti-osteoclastic actions than other anti-resorptives. -- Abstract: Inhibition of T cell derived cytokine production could help suppress osteoclast differentiation in inflammatory skeletal disorders. Bisphosphonates are typically prescribed to prevent inflammatory bone loss but are not tolerated by all patients and are associated with an increased risk of osteonecrosis of the jaw. In light of this other anti-resorptives such as phytoestrogens are being considered. However the effect of phytoestrogens on T cell-induced osteoclast formation is unclear. The effect of genistein and coumestrol on activated T cell-induced osteoclastogenesis and cytokine production was therefore examined. Concentrations of genistein and coumestrol (10{sup −7} M) previously shown to directly inhibit osteoclast formation also suppressed the formation of TRAP positive osteoclast induced by con A activated T cells, which was dependent on inhibition of T cell derived TNF-α. While both reduced osteoclast formation their mechanism of action differed. The anti-osteoclastic effect of coumestrol was associated with a dual effect on con A induced T cell proliferation and activation; 10{sup −7} M coumestrol significantly reducing T cell number (0.36) and TNF-α (0.47), IL-1β (0.23) and IL-6 (0.35) expression, whereas genistein (10{sup −7} M) had no effect on T cell number but a more pronounced effect on T cell differentiation reducing expression of TNF-α (0.49), IL-1β (0.52), IL-6 (0.71) and RANKL (0.71). Phytoestrogens therefore prevent the pro-osteoclastic action of T cells suggesting they may have a role in the control of inflammatory bone loss.

  10. Suppression of edge localized mode crashes by multi-spectral non-axisymmetric fields in KSTAR

    Science.gov (United States)

    Kim, Jayhyun; Park, Gunyoung; Bae, Cheonho; Yoon, Siwoo; Han, Hyunsun; Yoo, Min-Gu; Park, Young-Seok; Ko, Won-Ha; Juhn, June-Woo; Na, Yong Su; The KSTAR Team

    2017-02-01

    Among various edge localized mode (ELM) crash control methods, only non-axisymmetric magnetic perturbations (NAMPs) yield complete suppression of ELM crashes beyond their mitigation, and thus attract more attention than others. No other devices except KSTAR, DIII-D, and recently EAST have successfully achieved complete suppression with NAMPs. The underlying physics mechanisms of these successful ELM crash suppressions in a non-axisymmetric field environment, however, still remain uncertain. In this work, we investigate the ELM crash suppression characteristics of the KSTAR ELMy H-mode discharges in a controlled multi-spectral field environment, created by both n=2 middle reference and n=1 top/bottom proxy in-vessel control coils. Interestingly, the attempts have produced a set of contradictory findings, one expected (ELM crash suppression enhancement with the addition of n  =  1 to the n  =  2 field at relatively low heating discharges) and another unexpected (ELM crash suppression degradation at relatively high heating discharges) from the earlier findings in DIII-D. This contradiction indicates the dependence of the ELM crash suppression characteristics on the heating level and the associated kink-like plasma responses. Preliminary linear resistive MHD plasma response simulation shows the unexpected suppression performance degradation to be likely caused by the dominance of kink-like plasma responses over the island gap-filling effects.

  11. Non-local and nonlinear background suppression method controlled by multi-scale clutter metric

    Science.gov (United States)

    Gong, Jinnan; Hou, Qingyu; Zhang, Wei; Zhi, Xiyang

    2015-07-01

    To improve the detection performance for non-morphological multi-scale target in IR image containing complex cloud clutter, on basis of cloud scenario self-similarity feature, a non-local and nonlinear background suppression algorithm controlled by multi-scale clutter metric is presented. According to the classical achievements on cloud structure, self-similarity and relativity of cloud clutter on image for target detection is deeply analyzed by classical indicators firstly. Then we establish multi-scale clutter metric method based on LoG operator to describe scenes feature for controlled suppression method. After that, non-local means based on optimal strength similarity metric as non-local processing, and multi-scale median filter and on minimum gradient direction as local processing are set up. Finally linear fusing principle adopting clutter metric for local and non-local processing is put forward. Experimental results by two kinds of infrared imageries show that compared with classical and similar methods, the proposed method solves the existing problems of targets energy attenuation and suppression degradation in strongly evolving regions in previous methods. By evaluating indicators, the proposed method has a superior background suppression performance by increasing the BSF and ISCR 2 times at least.

  12. Suppression of collagen induced arthritis by idiotype coupled lymphoid cells

    Energy Technology Data Exchange (ETDEWEB)

    Nagler-Anderson, C.; Gurish, M.F.; Robinson, M.E.; Thorbecke, G.J.

    1986-03-01

    Studies were initiated to evaluate the regulatory influence of idiotype (Id) networks in an experimental auto-immune disease. Collagen induced arthritis is an animal model of polyarthritis induced in susceptible mice by immunization with collagen II (CII). A humoral immune response to CII appears to be critical for the development of diseases. If subpopulations of the anti-CII abs, important for the induction of arthritis, could be identified and manipulated through the presence of a major Id, it should be possible to decrease arthritis incidence by suppressing the production of these Ids. Specifically purified anti-CII abs from arthritic DBA/1 mice were coupled to syngeneic spleen cells and administered IV prior to intradermal immunization with CII. By day 34 after 1/sup 0/ immunization, 100% of control mice and 50% of treated mice had developed arthritis. Suppression of the Id population administered to the treated group was confirmed by RIA. Sera from individual mice were tested as inhibitors of binding of /sup 125/I-labelled polyclonal DBA/1 anti-CII to a rabbit anti-Id directed against polyclonal anti-CII isolated from the sera of arthritic mice. Mean percentage of inhibition of binding of /sup 125/I-Id to rabbit anti-Id by sera from non-arthritic treated mice was found to be significantly lower than that observed in the arthritic control group (p = .045), but did not correlate with total anti-CII ab titers.

  13. Nardosinone Suppresses RANKL-Induced Osteoclastogenesis and Attenuates Lipopolysaccharide-Induced Alveolar Bone Resorption

    Science.gov (United States)

    Niu, Chenguang; Xiao, Fei; Yuan, Keyong; Hu, XuChen; Lin, Wenzhen; Ma, Rui; Zhang, Xiaoling; Huang, Zhengwei

    2017-01-01

    Periodontitis is a chronic inflammatory disease that damages the integrity of the tooth-supporting tissues, known as the periodontium, and comprising the gingiva, periodontal ligament and alveolar bone. In this study, the effects of nardosinone (Nd) on bone were tested in a model of lipopolysaccharide (LPS)-induced alveolar bone loss, and the associated mechanisms were elucidated. Nd effectively suppressed LPS-induced alveolar bone loss and reduced osteoclast (OC) numbers in vivo. Nd suppressed receptor activator of nuclear factor-κB ligand (RANKL)-mediated OC differentiation, bone resorption, and F-actin ring formation in a dose-dependent manner. Further investigation revealed that Nd suppressed osteoclastogenesis by suppressing the ERK and JNK signaling pathways, scavenging reactive oxygen species, and suppressing the activation of PLCγ2 that consequently affects the expression and/or activity of the OC-specific transcription factors, c-Fos and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). In addition, Nd significantly reduced the expression of OC-specific markers in mouse bone marrow-derived pre-OCs, including c-Fos, cathepsin K (Ctsk), VATPase d2, and Nfatc1. Collectively, these findings suggest that Nd has beneficial effects on bone, and the suppression of OC number implies that the effect is exerted directly on osteoclastogenesis. PMID:28955231

  14. Randomly distributed spin induced suppression of superconducting properties in Gd-123

    Science.gov (United States)

    Biswas, B.; Haldar, S.; Mukherjee, I.; Kumar Ghosh, Ajay

    2017-02-01

    Suppression of superconducting property in presence of inhomogeneous spin distribution in GdBa2Cu3-xCoxO6.9 has been studied. A superconducting sample without Co exhibits superconducting transition at 56.1 K. The current-voltage (I-V) characteristics exhibit nonlinear to linear transformation above a certain temperature. Two other samples (i) with Co and (ii) without Cu are found to be nonsuperconducting with very high resistive in nature at lower temperature. Localization length decreases with the increase in Co substitution. Suppression of the superconducting transition has been attributed to the change in the magnetic fluctuations induced by the randomness in spin substitution. An exponent has been extracted to understand the current-voltage behaviour. Kosterlitz-Thouless (KT) transition may be affected strongly by the shifting of magnetic fluctuations.

  15. Programmed Death Ligand 2 in Cancer-Induced Immune Suppression

    Directory of Open Access Journals (Sweden)

    Esdy N. Rozali

    2012-01-01

    Full Text Available Inhibitory molecules of the B7/CD28 family play a key role in the induction of immune tolerance in the tumor microenvironment. The programmed death-1 receptor (PD-1, with its ligands PD-L1 and PD-L2, constitutes an important member of these inhibitory pathways. The relevance of the PD-1/PD-L1 pathway in cancer has been extensively studied and therapeutic approaches targeting PD-1 and PD-L1 have been developed and are undergoing human clinical testing. However, PD-L2 has not received as much attention and its role in modulating tumor immunity is less clear. Here, we review the literature on the immunobiology of PD-L2, particularly on its possible roles in cancer-induced immune suppression and we discuss the results of recent studies targeting PD-L2 in cancer.

  16. Loss-induced suppression and revival of lasing

    CERN Document Server

    Peng, B; Rotter, S; Yilmaz, H; Liertzer, M; Monifi, F; Bender, C M; Nori, F; Yang, L

    2014-01-01

    Controlling and reversing the effects of loss are major challenges in optical systems. For lasers losses need to be overcome by a sufficient amount of gain to reach the lasing threshold. We show how to turn losses into gain by steering the parameters of a system to the vicinity of an exceptional point (EP), which occurs when the eigenvalues and the corresponding eigenstates of a system coalesce. In our system of coupled microresonators, EPs are manifested as the loss-induced suppression and revival of lasing. Below a critical value, adding loss annihilates an existing Raman laser. Beyond this critical threshold, lasing recovers despite the increasing loss, in stark contrast to what would be expected from conventional laser theory. Our results exemplify the counterintuitive features of EPs and present an innovative method for reversing the effect of loss.

  17. Inorganic polyphosphate suppresses lipopolysaccharide-induced inducible nitric oxide synthase (iNOS expression in macrophages.

    Directory of Open Access Journals (Sweden)

    Kana Harada

    Full Text Available In response to infection, macrophages produce a series of inflammatory mediators, including nitric oxide (NO, to eliminate pathogens. The production of these molecules is tightly regulated via various mechanisms, as excessive responses are often detrimental to host tissues. Here, we report that inorganic polyphosphate [poly(P], a linear polymer of orthophosphate ubiquitously found in mammalian cells, suppresses inducible nitric oxide synthase (iNOS expression induced by lipopolysaccharide (LPS, a cell wall component of Gram-negative bacteria, in mouse peritoneal macrophages. Poly(P with longer chains is more potent than those with shorter chains in suppressing LPS-induced iNOS expression. In addition, poly(P decreased LPS-induced NO release. Moreover, poly(P suppressed iNOS mRNA expression induced by LPS stimulation, thereby indicating that poly(P reduces LPS-induced iNOS expression by down-regulation at the mRNA level. In contrast, poly(P did not affect the LPS-induced release of TNF, another inflammatory mediator. Poly(P may serve as a regulatory factor of innate immunity by modulating iNOS expression in macrophages.

  18. Suppression of Spiral Waves and Spatiotemporal Chaos Under Local Self-adaptive Coupling Interactions

    Institute of Scientific and Technical Information of China (English)

    MA Jun; WU Ning-Jie; YING He-Ping; YUAN Li-Hua

    2006-01-01

    In this paper, a close-loop feedback control is imposed locally on the Fitzhugh-Nagumo (FHN) system to suppress the stable spirals and spatiotemporal chaos according to the principle of self-adaptive coupling interaction. The simulation results show that an expanding target wave is stimulated by the spiral waves under dynamic control period when a local area of 5 x 5 grids is controlled, or the spiral tip is driven to the board of the system. It is adso found that the spatiotemporal chaos can be suppressed to get a stable homogeneous state within 50 time units as two local grids are controlled mutually. The mechanism of the scheme is briefly discussed.

  19. Localization of Cortical Oscillations Induced by SCS Using Coherence

    Directory of Open Access Journals (Sweden)

    P. Sovka

    2007-12-01

    Full Text Available This paper suggests a method based on coherence analysis and scalp mapping of coherence suitable for more accurate localization of cortical oscillations induced by electric stimulation of the dorsal spinal cord (SCS, which were previously detected using spectral analysis. While power spectral density shows the increase of power during SCS only at small number of electrodes, coherence extends this area and sharpens its boundary simultaneously. Parameters of the method were experimentally optimized to maximize its reliability. SCS is applied to suppress chronic, intractable pain by patients, whom pharmacotherapy does not relieve. In our study, the pain developed in lower back and lower extremity as the result of unsuccessful vertebral discotomy, which is called failed-back surgery syndrome (FBSS. Our method replicated the results of previous analysis using PSD and extended them with more accurate localization of the area influenced by SCS.

  20. Light-induced electron localization in a quantum Hall system

    Science.gov (United States)

    Arikawa, T.; Hyodo, K.; Kadoya, Y.; Tanaka, K.

    2017-07-01

    An insulating bulk state is a prerequisite for the protection of topological edge states. In quantum Hall systems, the thermal excitation of delocalized electrons is the main route to breaking bulk insulation. In equilibrium, the only way to achieve a clear bulk gap is to use a high-quality crystal under high magnetic field at low temperature. However, bulk conduction could also be suppressed in a system driven out of equilibrium such that localized states in the Landau levels are selectively occupied. Here we report a transient suppression of bulk conduction induced by terahertz wave excitation between the Landau levels in a GaAs quantum Hall system. Strikingly, the Hall resistivity almost reaches the quantized value at a temperature where the exact quantization is normally disrupted by thermal fluctuations. The electron localization is realized by the long-range potential fluctuations, which are a unique and inherent feature of quantum Hall systems. Our results demonstrate a new means of effecting dynamical control of topology by manipulating bulk conduction using light.

  1. Volume localized spin echo correlation spectroscopy with suppression of 'diagonal' peaks.

    Science.gov (United States)

    Banerjee, Abhishek; Chandrakumar, N

    2014-02-01

    Two dimensional homonuclear (1)H correlation spectroscopy is of considerable interest for volume localized spectral studies, both in vivo and in vitro, of biological as well as material objects. The information principally sought from correlation spectra resides in the cross-peaks, which are often masked however by the presence of diagonal peaks in COSY, or 'pseudo-diagonal' peaks at F1=0 in SECSY. It has therefore been a concern to suppress these diagonal or 'pseudo-diagonal' peaks, in order to ensure that cross-peak information is fully discernible. We present here a report of our work on volume localized DIagonal Suppressed Spin Echo Correlation specTroscopy (LDISSECT) and demonstrate its performance in comparison to the standard volume localized SECSY experiment, employing brain metabolite phantoms in a gel. The sequence works in the inhomogeneous, multi-component environment by exploiting the short acquisition time to suppress undesired information by employing an additional rf pulse. A brief description of the pulse sequence, its theory, and simulations are also included, besides experimental benchmarking on two brain metabolite phantoms in gel phase.

  2. Tumor Growth Suppression Induced by Biomimetic Silk Fibroin Hydrogels

    Science.gov (United States)

    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.

  3. UVB-induced immune suppression and infection with Schistosoma mansoni

    Energy Technology Data Exchange (ETDEWEB)

    Noonan, F.P.; Lewis, F.A. [George Washington Univ., Washington, DC (United States). School of Medicine]|[Biomedical Research Inst., Rockville, MD (United States)

    1995-01-01

    Irradiation with ultraviolet B (UVB, 290-320 nm) causes a systematic immunosuppression of cell-mediated immunity. The question of whether UV immunosuppression modulates the course of infectious diseases is important because UVB levels in sunlight are sufficient to predict significant UV-induced immunosuppression at most latitudes. We have investigated the effect of immunosuppressive doses of UVB on the disease caused by the helminth parasite Schistosoma mansoni. C57BL/6 mice were irradiated once or three times weekly over 60-80 days with UV from a bank of FS40 sunlamps. Each UV treatment consisted of an immunosuppressive UV dose, as determined by suppression of contact hypersensitivity to trinitrochlorobenzene, corresponding to about 15-30 min of noonday tropical sunlight exposure under ideal clear sky conditions. Cumulative UV doses were between 80 and 170 kJ/m{sup 2}. Worm and egg burdens, liver granuloma diameters and liver fibrosis showed minimal changes (< 20%) compared with parameters in unirradiated animals. Ultraviolet irradiation (a total of 55 kJ/m{sup 2} administered in six treatments) did not impair the resistance to rechallenge conferred by vaccination with {sup 60}Co-irradiated cercariae. We have observed a dichotomy between UV immnosuppression and both disease and vaccination in this helminth infection, in contrast to the effects of UVB shown in other infectious diseases. (author).

  4. Suppressing molecular vibrations in organic semiconductors by inducing strain.

    Science.gov (United States)

    Kubo, Takayoshi; Häusermann, Roger; Tsurumi, Junto; Soeda, Junshi; Okada, Yugo; Yamashita, Yu; Akamatsu, Norihisa; Shishido, Atsushi; Mitsui, Chikahiko; Okamoto, Toshihiro; Yanagisawa, Susumu; Matsui, Hiroyuki; Takeya, Jun

    2016-01-01

    Organic molecular semiconductors are solution processable, enabling the growth of large-area single-crystal semiconductors. Improving the performance of organic semiconductor devices by increasing the charge mobility is an ongoing quest, which calls for novel molecular and material design, and improved processing conditions. Here we show a method to increase the charge mobility in organic single-crystal field-effect transistors, by taking advantage of the inherent softness of organic semiconductors. We compress the crystal lattice uniaxially by bending the flexible devices, leading to an improved charge transport. The mobility increases from 9.7 to 16.5 cm(2) V(-1) s(-1) by 70% under 3% strain. In-depth analysis indicates that compressing the crystal structure directly restricts the vibration of the molecules, thus suppresses dynamic disorder, a unique mechanism in organic semiconductors. Since strain can be easily induced during the fabrication process, we expect our method to be exploited to build high-performance organic devices.

  5. Local CO2-induced swelling of shales

    Science.gov (United States)

    Pluymakers, Anne; Dysthe, Dag Kristian

    2017-04-01

    In heterogeneous shale rocks, CO2 adsorbs more strongly to organic matter than to the other components. CO2-induced swelling of organic matter has been shown in coal, which is pure carbon. The heterogeneity of the shale matrix makes an interesting case study. Can local swelling through adsorption of CO2 to organic matter induce strain in the surrounding shale matrix? Can fractures close due to CO2-induced swelling of clays and organic matter? We have developed a new generation of microfluidic high pressure cells (up to 100 bar), which can be used to study flow and adsorption phenomena at the microscale in natural geo-materials. The devices contain one transparent side and a shale sample on the other side. The shale used is the Pomeranian shale, extracted from 4 km depth in Poland. This formation is a potential target of a combined CO2-storage and gas extraction project. To answer the first question, we place the pressure cell under a Veeco NT1100 Interferometer, operated in Vertical Scanning Interferometry mode and equipped with a Through Transmissive Media objective. This allows for observation of local swelling or organic matter with nanometer vertical resolution and micrometer lateral resolution. We expose the sample to CO2 atmospheres at different pressures. Comparison of the interferometry data and using SEM-EDS maps plus optical microscopy delivers local swelling maps where we can distinguish swelling of different mineralogies. Preliminary results indicate minor local swelling of organic matter, where the total amount is both time- and pressure-dependent.

  6. Suppression of Carrageenan- and Collagen II-Induced Inflammation in Mice by Geranium Oil

    Directory of Open Access Journals (Sweden)

    2006-01-01

    Full Text Available To obtain experimental evidence on the therapeutic efficacy of essential oils in aromatherapy for inflammatory diseases, we examined the effects of geranium oil on carrageenan-induced and collagen II-induced inflammation in mice, to assess acute and chronic anti-inflammatory activities of the oil. Single intraperitoneal injection of 5μL of geranium oil clearly suppressed the carrageenan-induced footpaw edema and increase in tissue myeloperoxidase activity, and repeated administration of the oil suppressed collagen-induced arthritis. These results revealed that geranium oil suppressed both acute and chronic inflammatory responses in mice

  7. Suppression of Carrageenan- and Collagen II-Induced Inflammation in Mice by Geranium Oil

    Directory of Open Access Journals (Sweden)

    Naho Maruyama

    2006-01-01

    Full Text Available To obtain experimental evidence on the therapeutic efficacy of essential oils in aromatherapy for inflammatory diseases, we examined the effects of geranium oil on carrageenan-induced and collagen II-induced inflammation in mice, to assess acute and chronic anti-inflammatory activities of the oil. Single intraperitoneal injection of 5 μL of geranium oil clearly suppressed the carrageenan-induced footpaw edema and increase in tissue myeloperoxidase activity, and repeated administration of the oil suppressed collagen-induced arthritis. These results revealed that geranium oil suppressed both acute and chronic inflammatory responses in mice.

  8. Dietary grape-seed proanthocyanidin inhibition of ultraviolet B-induced immune suppression is associated with induction of IL-12.

    Science.gov (United States)

    Sharma, Som D; Katiyar, Santosh K

    2006-01-01

    We have shown previously that dietary grape seed proanthocyanidins (GSPs) inhibit UVB-induced photocarcinogenesis in mice. As UVB-induced immune suppression has been implicated in the development of skin cancer risk, we investigated whether dietary GSPs can modulate the effects of UVB on the immune system. We found that the UVB-induced (180 mJ/cm2) ear swelling response (inflammatory reaction) was significantly lower in mice fed with a GSP-supplemented (0.5 and 1.0%, w/w) diet than mice fed with the standard AIN76A diet. Dietary GSPs markedly inhibited UVB-induced (180 mJ/cm2) suppression of contact hypersensitivity responses in a local model of immunosuppression but had only moderate inhibitory effect in a systemic model of immunosuppression. Dietary GSPs reduced the UVB-induced increase in immunosuppressive cytokine interleukin (IL)-10 in skin and draining lymph nodes compared with mice that did not receive GSPs. In contrast, GSPs enhanced the production of immunostimulatory cytokine IL-12 in the draining lymph nodes. Intraperitoneal injection of GSPs-fed mice with a neutralizing anti-IL-12 antibody abrogated the protective effects of the GSPs against UVB-induced suppression of the contact hypersensitivity response. These data indicate for the first time that GSPs modulate UVB-induced immunosuppression and suggest that this may be one of the possible mechanisms by which they prevent photocarcinogenesis in mice.

  9. Measurement-Induced Localization of an Ultracold Lattice Gas

    Science.gov (United States)

    Patil, Y. S.; Chakram, S.; Vengalattore, M.

    2015-10-01

    The process of measurement can modify the state of a quantum system and its subsequent evolution. Here, we demonstrate the control of quantum tunneling in an ultracold lattice gas by the measurement backaction imposed by the act of imaging the atoms, i.e., light scattering. By varying the rate of light scattering from the atomic ensemble, we show the crossover from the weak measurement regime, where position measurements have little influence on tunneling dynamics, to the strong measurement regime, where measurement-induced localization causes a large suppression of tunneling—a manifestation of the quantum Zeno effect. Our study realizes an experimental demonstration of the paradigmatic Heisenberg microscope and sheds light on the implications of measurement on the coherent evolution of a quantum system.

  10. Acquired Localized Hypertrichosis Induced by Rivastigmine

    Science.gov (United States)

    Imbernón-Moya, Adrian; Podlipnik, Sebastian; Burgos, Fernando; Vargas-Laguna, Elena; Aguilar-Martínez, Antonio; Fernández-Cogolludo, Eva; Gallego-Valdes, Miguel Angel

    2016-01-01

    Hypertrichosis is the excessive hair growth in any area of the skin surface. Acquired localized hypertrichosis may be secondary to multiple causes and there is a secondary form due to several drugs, which is usually reversible with discontinuation of the causative agent. Rivastigmine is a reversible and competitive inhibitor of acetylcholinesterase and butyrylcholinesterase used for symptomatic treatment of Alzheimer dementia and Parkinson's disease. It has an adequate safety profile and cutaneous side effects are unusual. Irritant contact dermatitis, allergic dermatitis, baboon syndrome, and cutaneous rash due to rivastigmine have been reported. We report on a Caucasian 80-year-old male with personal history of Alzheimer's disease. The patient started therapy with oral rivastigmine one month prior to clinical presentation of localized hypertrichosis on both forearms. Norgalanthamine has been shown to promote hair growth activity via the proliferation of dermal papilla. Acetylcholinesterase inhibitors can induce hair growth. PMID:27073702

  11. Acquired Localized Hypertrichosis Induced by Rivastigmine

    Directory of Open Access Journals (Sweden)

    Adrian Imbernón-Moya

    2016-01-01

    Full Text Available Hypertrichosis is the excessive hair growth in any area of the skin surface. Acquired localized hypertrichosis may be secondary to multiple causes and there is a secondary form due to several drugs, which is usually reversible with discontinuation of the causative agent. Rivastigmine is a reversible and competitive inhibitor of acetylcholinesterase and butyrylcholinesterase used for symptomatic treatment of Alzheimer dementia and Parkinson’s disease. It has an adequate safety profile and cutaneous side effects are unusual. Irritant contact dermatitis, allergic dermatitis, baboon syndrome, and cutaneous rash due to rivastigmine have been reported. We report on a Caucasian 80-year-old male with personal history of Alzheimer’s disease. The patient started therapy with oral rivastigmine one month prior to clinical presentation of localized hypertrichosis on both forearms. Norgalanthamine has been shown to promote hair growth activity via the proliferation of dermal papilla. Acetylcholinesterase inhibitors can induce hair growth.

  12. High volume microinfusion suppresses local astrocyte response within nucleus basalis of rat.

    Science.gov (United States)

    Bjelobaba, I; Saponjic, J

    2013-03-01

    Our study investigates the impact of different volume sham control and excitotoxin microinfusions in vivo on local reactive astroglial response within rat nucleus basalis (NB). We followed the effects of unilateral 200, 100, and 50 nL of sham-control (phosphate buffer PBS) versus ibotenic acid (IBO) microinfusions, mechanical NB lesion (10 µL Hamylton syringe needle positioned into NB for 5 min), or physiological control (intact brain), on the local reactive astroglial response within the NB site, by immunoreactivity against glial fibrillary acidic protein (GFAP). NB lesions were identified by NADPHdiaphorase histochemistry. Local astrocytes responses within NB were suppressed by both high volume microinfusions, PBS and IBO (200 and 100 nL) versus mechanical lesion. Our study has proved, for the first time, the volume of microinfusion as critical for any selective pharmacological stimulation or lesion in vivo, and suggest the microinfusion volume less than 50nL as protective for physiological astroglial reactivity.

  13. Prasugrel suppresses development of lithium-induced nephrogenic diabetes insipidus in mice.

    Science.gov (United States)

    Zhang, Yue; Peti-Peterdi, János; Brandes, Anna U; Riquier-Brison, Anne; Carlson, Noel G; Müller, Christa E; Ecelbarger, Carolyn M; Kishore, Bellamkonda K

    2017-02-23

    Previously, we localized ADP-activated P2Y12 receptor (R) in rodent kidney and showed that its blockade by clopidogrel bisulfate (CLPD) attenuates lithium (Li)-induced nephrogenic diabetes insipidus (NDI). Here, we evaluated the effect of prasugrel (PRSG) administration on Li-induced NDI in mice. Both CLPD and PRSG belong to the thienopyridine class of ADP receptor antagonists. Groups of age-matched adult male B6D2 mice (N = 5/group) were fed either regular rodent chow (CNT), or with added LiCl (40 mmol/kg chow) or PRSG in drinking water (10 mg/kg bw/day) or a combination of LiCl and PRSG for 14 days and then euthanized. Water intake and urine output were determined and blood and kidney tissues were collected and analyzed. PRSG administration completely suppressed Li-induced polydipsia and polyuria and significantly prevented Li-induced decreases in AQP2 protein abundance in renal cortex and medulla. However, PRSG either alone or in combination with Li did not have a significant effect on the protein abundances of NKCC2 or NCC in the cortex and/or medulla. Immunofluorescence microscopy revealed that PRSG administration prevented Li-induced alterations in cellular disposition of AQP2 protein in medullary collecting ducts. Serum Li, Na, and osmolality were not affected by the administration of PRSG. Similar to CLPD, PRSG administration had no effect on Li-induced increase in urinary Na excretion. However, unlike CLPD, PRSG did not augment Li-induced increase in urinary arginine vasopressin (AVP) excretion. Taken together, these data suggest that the pharmacological inhibition of P2Y12-R by the thienopyridine group of drugs may potentially offer therapeutic benefits in Li-induced NDI.

  14. Suppression of local invasion of ameloblastoma by inhibition of matrix metalloproteinase-2 in vitro

    Science.gov (United States)

    Wang, Anxun; Zhang, Bin; Huang, Hongzhang; Zhang, Leitao; Zeng, Donglin; Tao, Qian; Wang, Jianguang; Pan, Chaobin

    2008-01-01

    Background Ameloblastomas are odontogenic neoplasms characterized by local invasiveness. This study was conducted to address the role of matrix metalloproteinase-2 (MMP-2) in the invasiveness of ameloblastomas. Methods Plasmids containing either MMP-2 siRNA or tissue inhibitor of metalloproteinase-2 (TIMP-2) cDNA were created and subsequently transfected into primary ameloblastoma cells. Zymography, RT-PCR, and Western blots were used to assess MMP-2 activity and expression of MMP-2 and TIMP-2, as well as protein levels. Results Primary cultures of ameloblastoma cells expressed cytokeratin (CK) 14 and 16, and MMP-2, but only weakly expressed CK18 and vimentin. MMP-2 mRNA and protein levels were significantly inhibited by RNA interference (P ameloblastoma. Conclusion These results indicate that inhibition of MMP-2 activity suppresses the local invasiveness of ameloblastoma cells. This mechanism may serve as a novel therapeutic target in ameloblastomas pursuant to additional research. PMID:18588710

  15. Testicular steroidogenesis is locally regulated by androgen via suppression of Nur77.

    Science.gov (United States)

    Song, Chin-Hee; Gong, Eun-Yeung; Park, Ji soo; Lee, Keesook

    2012-06-01

    Steroidogenesis in the testis is regulated by a negative feedback mechanism through the hypothalamus-pituitary-testis axis. Recent studies suggest that besides this long-loop regulation, testicular steroidogenesis is also locally regulated by androgen. However, the molecular mechanism behind this additional regulatory pathway has been poorly addressed. In the present study, we demonstrate that liganded androgen receptor (AR) suppresses the transcriptional activity of Nur77 on steroidogenic enzyme gene promoters, affecting testicular steroidogenesis. AR physically interacts and colocalizes with Nur77 in the nucleus in the presence of androgen. AR inhibits Nur77 transactivation by competing mainly with coactivators such as SRC-1 for Nur77 binding. These results suggest that androgen, through binding to AR, directly acts as a signal inhibiting the expression of steroidogenic enzyme genes in Leydig cells, eventually resulting in decreased testicular steroidogenesis. These findings strongly support the hypothesis that androgen acts locally to regulate testicular steroidogenesis, and may provide its action mechanism.

  16. Requirements on localized current drive for the suppression of neoclassical tearing modes

    Science.gov (United States)

    Bertelli, N.; De Lazzari, D.; Westerhof, E.

    2011-10-01

    A heuristic criterion for the full suppression of an NTM was formulated as ηNTM ≡ jCD,max/jBS >= 1.2 (Zohm et al 2005 J. Phys. Conf. Ser. 25 234), where jCD,max is the maximum in the driven current density profile applied to stabilize the mode and jBS is the local bootstrap current density. In this work we subject this criterion to a systematic theoretical analysis on the basis of the generalized Rutherford equation. Taking into account only the effect of jCD inside the island, a new criterion for full suppression by a minimum applied total current is obtained in the form of a maximum allowed value for the width of the driven current, wdep, combined with a required minimum for the total driven current in the form of wdepηNTM, where both limits depend on the marginal and saturated island sizes. These requirements can be relaxed when additional effects are taken into account, such as a change in the stability parameter Δ' from the current driven outside the island, power modulation, the accompanying heating inside the island or when the current drive is applied preemptively. When applied to ITER scenario 2, the requirement for full suppression of either the 3/2 or 2/1 NTM becomes wdep ~ 5 cm in agreement with (Sauter et al 2010 Plasma Phys. Control. Fusion 52 025002). Optimization of the ITER ECRH Upper Port Launcher design towards minimum required power for full NTM suppression requires an increase in the toroidal injection angle of the lower steering mirror of several degrees compared with its present design value, while for the upper steering mirror the present design value is close to the optimum.

  17. Delayed ischemic electrocortical suppression during rapid repeated cerebral ischemia and kainate-induced seizures in rat

    DEFF Research Database (Denmark)

    Ilie, Andrei; Spulber, Stefan; Avramescu, Sinziana;

    2006-01-01

    Global cerebral ischemia induces, within seconds, suppression of spontaneous electrocortical activity, partly due to alterations in synaptic transmission. In vitro studies have found that repeated brief hypoxic episodes prolong the persistence of synaptic transmission due to weakened adenosine re...

  18. Application of chemokine receptor antagonist with stents reduces local inflammation and suppresses cancer growth.

    Science.gov (United States)

    Mao, Ai-Wu; Jiang, Ting-Hui; Sun, Xian-Jun; Peng, Jian

    2015-11-01

    Severe pain and obstructive jaundice resulting from invasive cholangiocarcinoma or pancreatic carcinoma can be alleviated by implantation of biliary and duodenal stents. However, stents may cause local inflammation to have an adverse effect on the patients' condition and survival. So far, no efficient approaches have been applied to prevent the occurrence of stents-related inflammation. Here, we reported significantly higher levels of serum stromal cell-derived factor 1 (SDF-1) in the patients that developed stents-associated inflammation. A higher number of inflammatory cells have been detected in the cancer close to stent in the patients with high serum SDF-1. Since chemokine plays a pivotal role in the development of inflammation, we implanted an Alzet osmotic pump with the stents to gradually release AMD3100, a specific inhibitor binding of SDF-1 and its receptor C-X-C chemokine receptor 4 (CXCR4), at the site of stents in mice that had developed pancreatic cancer. We found that AMD3100 significantly reduced local inflammation and significantly inhibited cancer cell growth, resulting in improved survival of the mice that bore cancer. Moreover, the suppression of cancer growth may be conducted through modulation of CyclinD1, p21, and p27 in the cancer cells. Together, these data suggest that inhibition of chemokine signaling at the site of stents may substantially improve survival through suppression of stent-related inflammation and tumor growth.

  19. Simvastatin suppresses breast cancer cell proliferation induced by senescent cells

    NARCIS (Netherlands)

    Liu, Su; Uppal, Harpreet; Demaria, Marco; Desprez, Pierre-Yves; Campisi, Judith; Kapahi, Pankaj

    2015-01-01

    Cellular senescence suppresses cancer by preventing the proliferation of damaged cells, but senescent cells can also promote cancer though the pro-inflammatory senescence-associated secretory phenotype (SASP). Simvastatin, an HMG-coA reductase inhibitor, is known to attenuate inflammation and preven

  20. Local brain heavy ion irradiation induced Immunosuppression

    Science.gov (United States)

    Lei, Runhong; Deng, Yulin; Huiyang Zhu, Bitlife.; Zhao, Tuo; Wang, Hailong; Yu, Yingqi; Ma, Hong; Wang, Xiao; Zhuang, Fengyuan; Qing, Hong

    Purpose: To investigate the long term effect of acute local brain heavy ion irradiation on the peripheral immune system in rat model. Methodology: Only the brain of adult male Wistar rats were radiated by heavy ions at the dose of 15 Gy. One, two and three months after irradiation, thymus and spleen were analyzed by four ways. Tunel assay was performed to evaluate the percentage of apoptotic cells in thymus and spleen, level of Inflammatory cytokines (IL-2, IL-6, SSAO, and TNF-α) was detected by ELISA assay, the differentiation of thymus T lymphocyte subsets were measured by flow cytometry and the relative expression levels of genes related to thymus immune cell development were measured by using quantitative real-time PCR. Results: Thymus and spleen showed significant atrophy from one month to three months after irradiation. A high level of apoptosis in thymus and spleen were obtained and the latter was more vulnerable, also, high level of inflammatory cytokines were found. Genes (c-kit, Rag1, Rag2 and Sca1) related to thymus lymphocytes’ development were down-regulated. Conclusion: Local area radiation in the rat brain would cause the immunosuppression, especially, the losing of cell-mediated immune functions. In this model, radiation caused inflammation and then induced apoptosis of cells in the immune organs, which contributed to immunosuppression.

  1. Melatonin Suppresses Hypoxia-Induced Migration of HUVECs via Inhibition of ERK/Rac1 Activation

    Directory of Open Access Journals (Sweden)

    Ling Yang

    2014-08-01

    Full Text Available Melatonin, a naturally-occurring hormone, possesses antioxidant properties and ameliorates vascular endothelial dysfunction. In this study, we evaluate the impact of melatonin on the migratory capability of human umbilical vein endothelial cells (HUVECs to hypoxia and further investigate whether ERK/Rac1 signaling is involved in this process. Here, we found that melatonin inhibited hypoxia-stimulated hypoxia-inducible factor-1α (HIF-1α expression and cell migration in a dose-dependent manner. Mechanistically, melatonin inhibited Rac1 activation and suppressed the co-localized Rac1 and F-actin on the membrane of HUVECs under hypoxic condition. In addition, the blockade of Rac1 activation with ectopic expression of an inactive mutant form of Rac1-T17N suppressed HIF-1α expression and cell migration in response to hypoxia, as well, but constitutive activation of Rac1 mutant Rac1-V12 restored HIF-1α expression, preventing the inhibition of melatonin on cell migration. Furthermore, the anti-Rac1 effect of melatonin in HUVECs appeared to be associated with its inhibition of ERK phosphorylation, but not that of the PI3k/Akt signaling pathway. Taken together, our work indicates that melatonin exerts an anti-migratory effect on hypoxic HUVECs by blocking ERK/Rac1 activation and subsequent HIF-1α upregulation.

  2. Modulation of Interleukin-15-induced Suppression of Human Neutrophil Apoptosis by TNFα

    Institute of Scientific and Technical Information of China (English)

    LIU Xiuping; XIONG Changyun; LI Chunhong; YANG Deguang

    2007-01-01

    Human interleukin-15 (IL-15) is a proinflammatory cytokine to suppress neutrophil apoptosis, which is a potential therapeutic agent. The modulatory effect of TNFα was investigated in IL-15-induced suppression of human neutrophil apoptosis. TNFα was shown to reverse the ability of IL-15 to delay neutrophil apoptosis within certain time course. Moreover, this reverse effect by TNFα might be associated with a reduction of the expression of the anti-apoptotic Bcl-Xl protein detected by Western blotting. It is concluded that TNFα can be used to modulate IL-15-induced suppression of neutrophil apoptosis within certain time course.

  3. BMP2-induced inflammation can be suppressed by the osteoinductive growth factor NELL-1.

    Science.gov (United States)

    Shen, Jia; James, Aaron W; Zara, Janette N; Asatrian, Greg; Khadarian, Kevork; Zhang, James B; Ho, Stephanie; Kim, Hyun Ju; Ting, Kang; Soo, Chia

    2013-11-01

    Bone-morphogenetic protein 2 (BMP2) is currently the only Food and Drug Administration-approved osteoinductive growth factor used in clinical settings for bone regeneration and repair. However, the use of BMP2 is encumbered by numerous clinical complications, including postoperative inflammation and life-threatening cervical swelling. Thus, methods to prevent BMP2-induced inflammation would have far-reaching clinical implications toward improving current BMP2-based methods for bone regeneration. For the first time, we investigate the potential role of the growth factor Nel-like molecule-1 (NELL-1) in inhibiting BMP2-induced inflammation. Adult rats underwent a femoral bone onlay procedure, treated with either BMP2 protein (4 mg/mL), NELL-1 protein (4 mg/mL), or both proteins combined. Animals were evaluated at 3, 7, and 14 days postoperatively by histology, histomorphometry, immunohistochemistry, and real-time PCR for markers of inflammation (TNFα, IL6). The relative levels of TNFα and IL6 in serum were also detected by ELISA. The mechanism for NELL-1's anti-inflammatory effect was further assessed through examining inflammatory markers and generation of reactive oxygen species (ROS) in the mouse embryonic fibroblast NIH3T3 cells. BMP2 significantly induced local inflammation, including an early and pronounced polymorphonuclear cell infiltration accompanied by increased expression of TNFα and IL6. Treatment with NELL-1 alone elicited no significant inflammatory response. However, NELL-1 significantly attenuated BMP2-induced inflammation by all markers and at all timepoints. These local findings were also confirmed using systemic serum inflammatory biomarkers (TNFα, IL6). In each case, NELL-1 fully reversed BMP2-induced systemic inflammation. Lastly, our findings were recapitulated in vitro, where NELL-1 suppressed BMP2 induced expression of inflammatory markers, as well as NF-κB transcriptional activity and generation of ROS. BMP2-induced inflammation is a

  4. Perillyl alcohol suppresses antigen-induced immune responses in the lung

    Energy Technology Data Exchange (ETDEWEB)

    Imamura, Mitsuru; Sasaki, Oh; Okunishi, Katsuhide; Nakagome, Kazuyuki; Harada, Hiroaki; Kawahata, Kimito; Tanaka, Ryoichi; Yamamoto, Kazuhiko [Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Dohi, Makoto, E-mail: mdohi-tky@umin.ac.jp [Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Institute of Respiratory Immunology, Shibuya Clinic for Respiratory Diseases and Allergology, Tokyo (Japan)

    2014-01-03

    Highlights: •Perillyl alcohol (POH) is an isoprenoid which inhibits the mevalonate pathway. •We examined whether POH suppresses immune responses with a mouse model of asthma. •POH treatment during sensitization suppressed Ag-induced priming of CD4{sup +} T cells. •POH suppressed airway eosinophila and cytokine production in thoracic lymph nodes. -- Abstract: Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes, its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4{sup +} T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects.

  5. Spatial variation in automated burst suppression detection in pharmacologically induced coma.

    Science.gov (United States)

    An, Jingzhi; Jonnalagadda, Durga; Moura, Valdery; Purdon, Patrick L; Brown, Emery N; Westover, M Brandon

    2015-01-01

    Burst suppression is actively studied as a control signal to guide anesthetic dosing in patients undergoing medically induced coma. The ability to automatically identify periods of EEG suppression and compactly summarize the depth of coma using the burst suppression probability (BSP) is crucial to effective and safe monitoring and control of medical coma. Current literature however does not explicitly account for the potential variation in burst suppression parameters across different scalp locations. In this study we analyzed standard 19-channel EEG recordings from 8 patients with refractory status epilepticus who underwent pharmacologically induced burst suppression as medical treatment for refractory seizures. We found that although burst suppression is generally considered a global phenomenon, BSP obtained using a previously validated algorithm varies systematically across different channels. A global representation of information from individual channels is proposed that takes into account the burst suppression characteristics recorded at multiple electrodes. BSP computed from this representative burst suppression pattern may be more resilient to noise and a better representation of the brain state of patients. Multichannel data integration may enhance the reliability of estimates of the depth of medical coma.

  6. Curcumin suppresses gelatinase B mediated norepinephrine induced stress in H9c2 cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Shrey Kohli

    Full Text Available BACKGROUND: Extracellular matrix (ECM remodeling facilitates biomechanical signals in response to abnormal physiological conditions. This process is witnessed as one of the major effects of the stress imposed by catecholamines, such as epinephrine and norepinephrine (NE, on cardiac muscle cells. Matrix metalloproteinases (MMPs are the key proteases involved in degradation of the ECM in heart. OBJECTIVES: The present study focuses on studying the effect of curcumin on Gelatinase B (MMP-9, an ECM remodeling regulatory enzyme, in NE-induced cardiac stress. Curcumin, a bioactive polyphenol found in the spice turmeric, has been studied for its multi-fold beneficial properties. This study focuses on investigating the role of curcumin as a cardio-protectant. METHODS: H9c2 cardiomyocytes were subjected to NE and curcumin treatments to study the response in stress conditions. Effect on total collagen content was studied using Picrosirus red staining. Gelatinase B activity was assessed through Gel-Diffusion Assay and Zymographic techniques. RT-PCR, Western Blotting and Immunocytochemistry were performed to study effect on expression of gelatinase B. Further, the effect of curcumin on the localization of NF-κB, known to regulate gelatinase B, was also examined. RESULTS: Curcumin suppressed the increase in the total collagen content under hypertrophic stress and was found to inhibit the in-gel and in-situ gelatinolytic activity of gelatinase B. Moreover, it was found to suppress the mRNA and protein expression of gelatinase B. CONCLUSIONS: The study provides an evidence for an overall inhibitory effect of curcumin on Gelatinase B in NE-induced hypertrophic stress in H9c2 cardiomyocytes which may contribute in the prevention of ECM remodeling.

  7. Curcumin Suppresses Gelatinase B Mediated Norepinephrine Induced Stress in H9c2 Cardiomyocytes

    Science.gov (United States)

    Kohli, Shrey; Chhabra, Aastha; Jaiswal, Astha; Rustagi, Yashika; Sharma, Manish; Rani, Vibha

    2013-01-01

    Background Extracellular matrix (ECM) remodeling facilitates biomechanical signals in response to abnormal physiological conditions. This process is witnessed as one of the major effects of the stress imposed by catecholamines, such as epinephrine and norepinephrine (NE), on cardiac muscle cells. Matrix metalloproteinases (MMPs) are the key proteases involved in degradation of the ECM in heart. Objectives The present study focuses on studying the effect of curcumin on Gelatinase B (MMP-9), an ECM remodeling regulatory enzyme, in NE-induced cardiac stress. Curcumin, a bioactive polyphenol found in the spice turmeric, has been studied for its multi-fold beneficial properties. This study focuses on investigating the role of curcumin as a cardio-protectant. Methods H9c2 cardiomyocytes were subjected to NE and curcumin treatments to study the response in stress conditions. Effect on total collagen content was studied using Picrosirus red staining. Gelatinase B activity was assessed through Gel-Diffusion Assay and Zymographic techniques. RT-PCR, Western Blotting and Immunocytochemistry were performed to study effect on expression of gelatinase B. Further, the effect of curcumin on the localization of NF-κB, known to regulate gelatinase B, was also examined. Results Curcumin suppressed the increase in the total collagen content under hypertrophic stress and was found to inhibit the in-gel and in-situ gelatinolytic activity of gelatinase B. Moreover, it was found to suppress the mRNA and protein expression of gelatinase B. Conclusions The study provides an evidence for an overall inhibitory effect of curcumin on Gelatinase B in NE-induced hypertrophic stress in H9c2 cardiomyocytes which may contribute in the prevention of ECM remodeling. PMID:24116115

  8. Chemerin aggravates DSS-induced colitis by suppressing M2 macrophage polarization.

    Science.gov (United States)

    Lin, Yuli; Yang, Xuguang; Yue, Wenjie; Xu, Xiaofei; Li, Bingji; Zou, Linlin; He, Rui

    2014-07-01

    Chemerin is present in various inflammatory sites and is closely involved in tissue inflammation. Recent studies have demonstrated that chemerin treatment can cause either anti-inflammatory or pro-inflammatory effects according to the disease model being investigated. Elevated circulating chemerin was recently found in patients with inflammatory bowel disease (IBD); however, the role of chemerin in intestinal inflammation remains unknown. In this study, we demonstrated that the administration of exogenous chemerin (aa17-156) aggravated the severity of dextran sulfate sodium (DSS)-induced colitis, which was characterized by higher clinical scores, extensive mucosal damage and significantly increased local and systemic production of pro-inflammatory cytokines, including IL-6, TNF-α and interferon (IFN-γ). Interestingly, chemerin did not appear to influence the magnitudes of inflammatory infiltrates in the colons, but did result in significantly decreased colonic expression of M2 macrophage-associated genes, including Arginase 1 (Arg-1), Ym1, FIZZ1 and IL-10, following DSS exposure, suggesting an impaired M2 macrophage skewing in vivo. Furthermore, an in vitro experiment showed that the addition of chemerin directly suppressed M2 macrophage-associated gene expression and STAT6 phosphorylation in IL-4-stimulated macrophages. Significantly elevated chemerin levels were found in colons from DSS-exposed mice and from ulcerative colitis (UC) patients and appeared to positively correlate with disease severity. Moreover, the in vivo administration of neutralizing anti-chemerin antibody significantly improved intestinal inflammation following DSS exposure. Taken together, our findings reveal a pro-inflammatory role for chemerin in DSS-induced colitis and the ability of chemerin to suppress the anti-inflammatory M2 macrophage response. Our study also suggests that upregulated chemerin in inflamed colons may contribute to the pathogenesis of IBD.

  9. Niclosamide suppresses RANKL-induced osteoclastogenesis and prevents LPS-induced bone loss

    Energy Technology Data Exchange (ETDEWEB)

    Cheon, Yoon-Hee [Center for Metabolic Function Regulation, Wonkwang University School of Medicine, Iksan, Jeonbuk 570-749 (Korea, Republic of); Kim, Ju-Young [Imaging Science-based Lung and Bone Diseases Research Center, Wonkwang University School of Medicine, Iksan, Jeonbuk 570-749 (Korea, Republic of); Baek, Jong Min; Ahn, Sung-Jun [Department of Anatomy, School of Medicine, Wonkwang University School of Medicine, Iksan, Jeonbuk 570-749 (Korea, Republic of); So, Hong-Seob, E-mail: jeanso@wku.ac.kr [Center for Metabolic Function Regulation, Wonkwang University School of Medicine, Iksan, Jeonbuk 570-749 (Korea, Republic of); Oh, Jaemin, E-mail: jmoh@wku.ac.kr [Imaging Science-based Lung and Bone Diseases Research Center, Wonkwang University School of Medicine, Iksan, Jeonbuk 570-749 (Korea, Republic of); Department of Anatomy, School of Medicine, Wonkwang University School of Medicine, Iksan, Jeonbuk 570-749 (Korea, Republic of); Institute for Skeletal Disease, Wonkwang University School of Medicine, Iksan, Jeonbuk 570-749 (Korea, Republic of)

    2016-02-05

    Niclosamide (5-chloro-salicyl-(2-chloro-4-nitro) anilide) is an oral anthelmintic drug used for treating intestinal infection of most tapeworms. Recently, niclosamide was shown to have considerable efficacy against some tumor cell lines, including colorectal, prostate, and breast cancers, and acute myelogenous leukemia. Specifically, the drug was identified as a potent inhibitor of signal transducer and activator of transcription 3 (STAT3), which is associated with osteoclast differentiation and function. In this study, we assessed the effect of niclosamide on osteoclastogenesis in vitro and in vivo. Our in vitro study showed that receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast differentiation was inhibited by niclosamide, due to inhibition of serine–threonine protein kinase (Akt) phosphorylation, inhibitor of nuclear factor-kappaB (IκB), and STAT3 serine{sup 727}. Niclosamide decreased the expression of the major transcription factors c-Fos and NFATc1, and thereafter abrogated the mRNA expression of osteoclast-specific genes, including TRAP, OSCAR, αv/β3 integrin (integrin αv, integrin β3), and cathepsin K (CtsK). In an in vivo model, niclosamide prevented lipopolysaccharide-induced bone loss by diminishing osteoclast activity. Taken together, our results show that niclosamide is effective in suppressing osteoclastogenesis and may be considered as a new and safe therapeutic candidate for the clinical treatment of osteoclast-related diseases such as osteoporosis. - Highlights: • We first investigated the anti-osteoclastogenic effects of niclosamide in vitro and in vivo. • Niclosamide impairs the activation of the Akt-IκB-STAT3 ser{sup 727} signaling axis. • Niclosamide acts a negative regulator of actin ring formation during osteoclast differentiation. • Niclosamide suppresses LPS-induced bone loss in vivo. • Niclosamide deserves new evaluation as a potential treatment target in various bone diseases.

  10. Dioscin suppresses TGF-β1-induced epithelial-mesenchymal transition and suppresses A549 lung cancer migration and invasion.

    Science.gov (United States)

    Lim, Won-Chul; Kim, Hyunhee; Kim, Young-Joo; Choi, Kyung-Chul; Lee, In Ho; Lee, Ki Heon; Kim, Mi Kyung; Ko, Hyeonseok

    2017-08-01

    Epithelial-to-mesenchymal transition (EMT), an important cellular process, occurs during cancer development and progression, has a crucial role in metastasis by enhancing the motility of tumor cells. Dioscin is a polyphenolic component isolated from Phyllanthus amarus, which exhibits a wide range of pharmacological and physiological activities, such as anti-tumor, anti-inflammatory, anti-obesity, anti-fungal, and anti-viral activities. However, the possible role of dioscin in the EMT is unclear. We investigated the suppressive effect of dioscin on the EMT. Transforming growth factor-beta 1 (TGF-β1) is known to induce EMT in a number of cancer cell types and promote lung adenocarcinoma migration and invasion. To verify the inhibitory role of dioscin in lung cancer migration and invasion, we investigated the use of dioscin as inhibitors of TGF-β1-induced EMT in A549 lung cancer cells in vitro. Here, we found that dioscin prominently increased expression of the epithelial marker E-cadherin and expression of the mesenchymal marker N-cadherin and Snail during the TGF-β1-induced EMT. In addition, dioscin inhibited the TGF-β1-induced increase in cell migration and invasion of A549 lung cancer cells. Also, dioscin remarkably inhibited TGF-β1-regulated activation of MMP-2/9, Smad2, and p38. Taken together, our findings provide new evidence that dioscin suppresses lung cancer migration, and invasion in vitro by inhibiting the TGF-β1-induced EMT. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Truncated SSX protein suppresses synovial sarcoma cell proliferation by inhibiting the localization of SS18-SSX fusion protein.

    Directory of Open Access Journals (Sweden)

    Yasushi Yoneda

    Full Text Available Synovial sarcoma is a relatively rare high-grade soft tissue sarcoma that often develops in the limbs of young people and induces the lung and the lymph node metastasis resulting in poor prognosis. In patients with synovial sarcoma, specific chromosomal translocation of t(X; 18 (p11.2;q11.2 is observed, and SS18-SSX fusion protein expressed by this translocation is reported to be associated with pathogenesis. However, role of the fusion protein in the pathogenesis of synovial sarcoma has not yet been completely clarified. In this study, we focused on the localization patterns of SS18-SSX fusion protein. We constructed expression plasmids coding for the full length SS18-SSX, the truncated SS18 moiety (tSS18 and the truncated SSX moiety (tSSX of SS18-SSX, tagged with fluorescent proteins. These plasmids were transfected in synovial sarcoma SYO-1 cells and we observed the expression of these proteins using a fluorescence microscope. The SS18-SSX fusion protein showed a characteristic speckle pattern in the nucleus. However, when SS18-SSX was co-expressed with tSSX, localization of SS18-SSX changed from speckle patterns to the diffused pattern similar to the localization pattern of tSSX and SSX. Furthermore, cell proliferation and colony formation of synovial sarcoma SYO-1 and YaFuSS cells were suppressed by exogenous tSSX expression. Our results suggest that the characteristic speckle localization pattern of SS18-SSX is strongly involved in the tumorigenesis through the SSX moiety of the SS18-SSX fusion protein. These findings could be applied to further understand the pathogenic mechanisms, and towards the development of molecular targeting approach for synovial sarcoma.

  12. Propolis suppresses tumor angiogenesis by inducing apoptosis in tube-forming endothelial cells.

    Science.gov (United States)

    Ohta, Toshiro; Kunimasa, Kazuhiro; Kobayashi, Tomomi; Sakamoto, Miwa; Kaji, Kazuhiko

    2008-09-01

    We have reported that propolis suppresses tumor-induced angiogenesis in vivo and in vitro, but antiangiogenic mechanism of propolis at cellular level remains unclear. In this study, we observed that propolis not only inhibited tube formation but also induced apoptosis of endothelial cells. These results suggest that propolis exerts its antiangiogenic effects at least in part through induction of apoptosis.

  13. Suppression of starvation-induced autophagy by recombinant toxic shock syndrome toxin-1 in epithelial cells.

    Directory of Open Access Journals (Sweden)

    Krisana Asano

    Full Text Available Toxic shock syndrome toxin-1 (TSST-1, a superantigen produced from Staphylococcus aureus, has been reported to bind directly to unknown receptor(s and penetrate into non-immune cells but its function is unclear. In this study, we demonstrated that recombinant TSST-1 suppresses autophagosomal accumulation in the autophagic-induced HeLa 229 cells. This suppression is shared by a superantigenic-deficient mutant of TSST-1 but not by staphylococcal enterotoxins, suggesting that autophagic suppression of TSST-1 is superantigenic-independent. Furthermore, we showed that TSST-1-producing S. aureus suppresses autophagy in the response of infected cells. Our data provides a novel function of TSST-1 in autophagic suppression which may contribute in staphylococcal persistence in host cells.

  14. Ursolic acid inhibits leucine-stimulated mTORC1 signaling by suppressing mTOR localization to lysosome.

    Directory of Open Access Journals (Sweden)

    Xiang Ou

    Full Text Available Ursolic acid (UA, a pentacyclic triterpenoid widely found in medicinal herbs and fruits, has been reported to possess a wide range of beneficial properties including anti-hyperglycemia, anti-obesity, and anti-cancer. However, the molecular mechanisms underlying the action of UA remain largely unknown. Here we show that UA inhibits leucine-induced activation of the mechanistic target of rapamycin complex 1 (mTORC1 signaling pathway in C2C12 myotubes. The UA-mediated inhibition of mTORC1 is independent of Akt, tuberous sclerosis complex 1/2 (TSC1/2, and Ras homolog enriched in brain (Rheb, suggesting that UA negatively regulates mTORC1 signaling by targeting at a site downstream of these mTOR regulators. UA treatment had no effect on the interaction between mTOR and its activator Raptor or inhibitor Deptor, but suppressed the binding of RagB to Raptor and inhibited leucine-induced mTOR lysosomal localization. Taken together, our study identifies UA as a direct negative regulator of the mTORC1 signaling pathway and suggests a novel mechanism by which UA exerts its beneficial function.

  15. Spironolactone induces apoptosis in human mononuclear cells. Association between apoptosis and cytokine suppression

    DEFF Research Database (Denmark)

    Mikkelsen, Martin; Sønder, S U; Nersting, J;

    2006-01-01

    Spironolactone (SPIR) has been described to suppress accumulation of pro-inflammatory cytokines. Here, the suppression of TNF-alpha in lipopolysaccharide (LPS)-stimulated mononuclear cell cultures was confirmed. However, SPIR was also found to induce apoptosis, prompting the investigations...... of a possible association between the two effects: The apoptosis-inducing and the cytokine-suppressive effects of SPIR correlated with regard to the effective concentration range. Also, pre-incubation experiments demonstrated a temporal separation of the two effects of TNF-alpha suppression...... preceding apoptosis. An association between the two effects was also seen when testing several SPIR analogues. Contrary to TNF-alpha, the levels of IL-1beta increased in SPIR-treated cultures. However, the amount of IL-1beta in the supernatants depended upon the order of SPIR and LPS addition, as IL-1beta...

  16. 15-deoxy-Δ12,14-PGJ2 induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats

    Science.gov (United States)

    Kawahito, Yutaka; Kondo, Motoharu; Tsubouchi, Yasunori; Hashiramoto, Akira; Bishop-Bailey, David; Inoue, Ken-ichiro; Kohno, Masataka; Yamada, Ryoji; Hla, Timothy; Sano, Hajime

    2000-01-01

    Peroxisome proliferator–activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and have a dominant regulatory role in adipocyte and monocyte differentiation. PPAR-γ agonists are also negative regulators of macrophage activation and have modulatory effects on tumorigenesis. In this study we demonstrate that synovial tissue localized expression of PPAR-γ in patients with rheumatoid arthritis (RA). We detected markedly enhanced expression of PPAR-γ in macrophages, as well as modestly enhanced expression in the synovial lining layer, fibroblasts, and endothelial cells. Activation of the PPAR-γ by 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and the synthetic PPAR-γ ligand (troglitazone) induced RA synoviocyte apoptosis in vitro. Moreover, intraperitoneal administration of these PPAR-γ ligands ameliorated adjuvant-induced arthritis with suppression of pannus formation and mononuclear cell infiltration in female Lewis rats. Anti-inflammatory effects of 15d-PGJ2 were more potent than troglitazone. These findings suggest that PPAR-γ may be an important immunoinflammatory mediator and its ligands, especially 15d-PGJ2, may be useful in the treatment of RA. PMID:10903334

  17. Dexamethasone Suppresses Oxysterol-Induced Differentiation of Monocytic Cells

    Directory of Open Access Journals (Sweden)

    Yonghae Son

    2016-01-01

    Full Text Available Oxysterol like 27-hydroxycholesterol (27OHChol has been reported to induce differentiation of monocytic cells into a mature dendritic cell phenotype. We examined whether dexamethasone (Dx affects 27OHChol-induced differentiation using THP-1 cells. Treatment of monocytic cells with Dx resulted in almost complete inhibition of transcription and surface expression of CD80, CD83, and CD88 induced by 27OHChol. Elevated surface levels of MHC class I and II molecules induced by 27OHChol were reduced to basal levels by treatment with Dx. A decreased endocytosis ability caused by 27OHChol was recovered by Dx. We also examined effects of Dx on expression of CD molecules involved in atherosclerosis. Increased levels of surface protein and transcription of CD105, CD137, and CD166 by treatment with 27OHChol were significantly inhibited by cotreatment with Dx. These results indicate that Dx inhibits 27OHChol-induced differentiation of monocytic cells into a mature dendritic cell phenotype and expression of CD molecules whose levels are associated with atherosclerosis. In addition, we examined phosphorylation of AKT induced by 27OHChol and effect of Dx, where cotreatment with Dx inhibited the phosphorylation of AKT. The current study reports that Dx regulates oxysterol-mediated dendritic cell differentiation of monocytic cells.

  18. Hanging-induced burst suppression pattern in EEG

    Directory of Open Access Journals (Sweden)

    Nilgun Cinar

    2012-01-01

    Full Text Available Lethal suspension (hanging is one of the most common methods of attempting suicide. Spinal fractures, cognitive and motor deficits as well as epileptic seizures can be detected after unsuccessful hanging attempts. Introduced here is the case of a 25-year-old man exemplifying the clinical observations stated hereafter, who was conveyed to our emergency room after having survived attempted suicide by hanging, with his post-anoxic burst-suppression electroencephalography (BS-EEG pattern and clinical diagnoses in the post-comatose stage. The patient′s state of consciousness was gradually improved over a period of time. His neuropsychiatric assessment proved that memory deficit, a slight lack of attention and minor executive dysfunction was observed a month after the patient was discharged. Although the BS-EEG pattern indicates severe brain dysfunction, it is a poor prognostic factor; rarely, patients survive with minor cognitive deficits and can perform their normal daily activities.

  19. Anthocyan does not suppress transformation of aryl hydrocarbon receptor induced by dioxin.

    Science.gov (United States)

    Mukai, Rie; Fukuda, Itsuko; Nishiumi, Shin; Hosokawa, Keizo; Kanazawa, Kazuki; Ashida, Hitoshi

    2004-01-01

    Dioxins cause a variety of toxic effects through transformation of a cytosolic aryl hydrocarbon receptor (AhR). We have previously demonstrated that certain natural flavones and flavonols at the dietary levels suppress AhR transformation. In this study, we investigated whether 5 anthocyanidins, 15 anthocyanins, and protocatechuic acid suppress AhR transformation in mouse hepatoma Hepa-1c1c7 cells. All the compounds tested here at 5 microM unexpectedly failed to suppress the transformation induced by 0.1 nM TCDD, indicating that anthocyan does not have a potential to prevent dioxin toxicity.

  20. A synthetic gene drive system for local, reversible modification and suppression of insect populations.

    Science.gov (United States)

    Akbari, Omar S; Matzen, Kelly D; Marshall, John M; Huang, Haixia; Ward, Catherine M; Hay, Bruce A

    2013-04-22

    Replacement of wild insect populations with genetically modified individuals unable to transmit disease provides a self-perpetuating method of disease prevention but requires a gene drive mechanism to spread these traits to high frequency. Drive mechanisms requiring that transgenes exceed a threshold frequency in order to spread are attractive because they bring about local but not global replacement, and transgenes can be eliminated through dilution of the population with wild-type individuals. These features are likely to be important in many social and regulatory contexts. Here we describe the first creation of a synthetic threshold-dependent gene drive system, designated maternal-effect lethal underdominance (UD(MEL)), in which two maternally expressed toxins, located on separate chromosomes, are each linked with a zygotic antidote able to rescue maternal-effect lethality of the other toxin. We demonstrate threshold-dependent replacement in single- and two-locus configurations in Drosophila. Models suggest that transgene spread can often be limited to local environments. They also show that in a population in which single-locus UD(MEL) has been carried out, repeated release of wild-type males can result in population suppression, a novel method of genetic population manipulation.

  1. Geraniin suppresses RANKL-induced osteoclastogenesis in vitro and ameliorates wear particle-induced osteolysis in mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Xiao, Fei; Zhai, Zanjing; Jiang, Chuan; Liu, Xuqiang; Li, Haowei; Qu, Xinhua [Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People' s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Ouyang, Zhengxiao [Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People' s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Department of Orthopaedics, Hunan Provincial Tumor Hospital and Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013 (China); Fan, Qiming; Tang, Tingting [Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People' s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Qin, An, E-mail: dr.qinan@gmail.com [Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People' s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Gu, Dongyun, E-mail: dongyungu@gmail.com [Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People' s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Engineering Research Center of Digital Medicine and Clinical Translation, Ministry of Education of PR China (China); School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030 (China)

    2015-01-01

    Wear particle-induced osteolysis and subsequent aseptic loosening remains the most common complication that limits the longevity of prostheses. Wear particle-induced osteoclastogenesis is known to be responsible for extensive bone erosion that leads to prosthesis failure. Thus, inhibition of osteoclastic bone resorption may serve as a therapeutic strategy for the treatment of wear particle induced osteolysis. In this study, we demonstrated for the first time that geraniin, an active natural compound derived from Geranium thunbergii, ameliorated particle-induced osteolysis in a Ti particle-induced mouse calvaria model in vivo. We also investigated the mechanism by which geraniin exerts inhibitory effects on osteoclasts. Geraniin inhibited RANKL-induced osteoclastogenesis in a dose-dependent manner, evidenced by reduced osteoclast formation and suppressed osteoclast specific gene expression. Specially, geraniin inhibited actin ring formation and bone resorption in vitro. Further molecular investigation demonstrated geraniin impaired osteoclast differentiation via the inhibition of the RANKL-induced NF-κB and ERK signaling pathways, as well as suppressed the expression of key osteoclast transcriptional factors NFATc1 and c-Fos. Collectively, our data suggested that geraniin exerts inhibitory effects on osteoclast differentiation in vitro and suppresses Ti particle-induced osteolysis in vivo. Geraniin is therefore a potential natural compound for the treatment of wear particle induced osteolysis in prostheses failure. - Highlights: • Geraniin suppresses osteoclasts formation and function in vitro. • Geraniin impairs RANKL-induced nuclear factor-κB and ERK signaling pathway. • Geraniin suppresses osteolysis in vivo. • Geraniin may be used for treating osteoclast related diseases.

  2. Speech-induced suppression of evoked auditory fields in children who stutter.

    Science.gov (United States)

    Beal, Deryk S; Quraan, Maher A; Cheyne, Douglas O; Taylor, Margot J; Gracco, Vincent L; De Nil, Luc F

    2011-02-14

    Auditory responses to speech sounds that are self-initiated are suppressed compared to responses to the same speech sounds during passive listening. This phenomenon is referred to as speech-induced suppression, a potentially important feedback-mediated speech-motor control process. In an earlier study, we found that both adults who do and do not stutter demonstrated a reduced amplitude of the auditory M50 and M100 responses to speech during active production relative to passive listening. It is unknown if auditory responses to self-initiated speech-motor acts are suppressed in children or if the phenomenon differs between children who do and do not stutter. As stuttering is a developmental speech disorder, examining speech-induced suppression in children may identify possible neural differences underlying stuttering close to its time of onset. We used magnetoencephalography to determine the presence of speech-induced suppression in children and to characterize the properties of speech-induced suppression in children who stutter. We examined the auditory M50 as this was the earliest robust response reproducible across our child participants and the most likely to reflect a motor-to-auditory relation. Both children who do and do not stutter demonstrated speech-induced suppression of the auditory M50. However, children who stutter had a delayed auditory M50 peak latency to vowel sounds compared to children who do not stutter indicating a possible deficiency in their ability to efficiently integrate auditory speech information for the purpose of establishing neural representations of speech sounds. Copyright © 2010 Elsevier Inc. All rights reserved.

  3. Type I neuregulin1α is a novel local mediator to suppress hepatic gluconeogenesis in mice

    Science.gov (United States)

    Arai, Takatomo; Ono, Yumika; Arimura, Yujiro; Sayama, Keimon; Suzuki, Tomohiro; Shinjo, Satoko; Kanai, Mai; Abe, Shin-ichi; Semba, Kentaro; Goda, Nobuhito

    2017-01-01

    Neuregulin1 is an epidermal growth factor (EGF)-like domain-containing protein that has multiple isoforms and functions as a local mediator in the control of various cellular functions. Here we show that type I isoform of neuregulin1 with an α-type EGF-like domain (Nrg1α) is the major isoform in mouse liver and regulates hepatic glucose production. Forced expression of Nrg1α in mouse liver enhanced systemic glucose disposal and decreased hepatic glucose production with reduced fasting blood glucose levels. Nuclear forkhead box protein O1 (FoxO1) and its downstream targets, PEPCK and G6Pase, were suppressed in liver and isolated hepatocytes by Nrg1α overexpression. In contrast, silencing of Nrg1α enhanced glucose production with increased PEPCK and G6Pase expressions in cAMP/dexamethasone-stimulated hepatocytes. Mechanistically, the recombinant α-type EGF-like domain of NRG1α (rNRG1α) stimulated the ERBB3 signalling pathway in hepatocytes, resulting in decreased nuclear FoxO1 accumulation via activation of both the AKT and ERK pathways. In addition, acute treatment with rNRG1α also suppressed elevation of blood glucose levels after both glucose and pyruvate challenge. Although a liver-specific deletion of Nrg1 gene in mice showed little effect on systemic glucose metabolism, these results suggest that NRG1α have a novel regulatory function in hepatic gluconeogenesis by regulating the ERBB3-AKT/ERK-FoxO1 cascade. PMID:28218289

  4. Substance P ameliorates collagen II-induced arthritis in mice via suppression of the inflammatory response

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Hyun Sook [College of Medicine, East-West Medical Research Institute, Kyung Hee University, 1, Hoegi-dong, Dongdaemun-gu, Seoul 130-702 (Korea, Republic of); Son, Youngsook, E-mail: ysson@khu.ac.kr [Graduate School of Biotechnology and Department of Genetic Engineering, College of Life Science, Kyung Hee University Global Campus, Seochun-dong, Kiheung-ku, Yong In 441-706 (Korea, Republic of)

    2014-10-10

    Highlights: • SP can increase IL-10 levels and reduce TNF-α and IL-17 levels in RA. • SP causes the increase in T{sub reg}, M2 macrophage, and MSCs in RA. • SP-induced immune suppression leads to the blockade of RA progression. • SP can be used as the therapeutics for autoimmune-related inflammatory diseases. - Abstract: Current rheumatoid arthritis (RA) therapies such as biologics inhibiting pathogenic cytokines substantially delay RA progression. However, patient responses to these agents are not always complete and long lasting. This study explored whether substance P (SP), an 11 amino acids long endogenous neuropeptide with the novel ability to mobilize mesenchymal stem cells (MSC) and modulate injury-mediated inflammation, can inhibit RA progression. SP efficacy was evaluated by paw swelling, clinical arthritis scoring, radiological analysis, histological analysis of cartilage destruction, and blood levels of tumor necrosis factor-alpha (TNF-α) interleukin (IL)-10, and IL-17 in vivo. SP treatment significantly reduced local inflammatory signs, mean arthritis scores, degradation of joint cartilage, and invasion of inflammatory cells into the synovial tissues. Moreover, the SP treatment markedly reduced the size of spleens enlarged by excessive inflammation in CIA, increased IL-10 levels, and decreased TNF-α and IL-17 levels. Mobilization of stem cells and induction of T{sub reg} and M2 type macrophages in the circulation were also increased by the SP treatment. These effect of SP might be associated with the suppression of inflammatory responses in RA and, furthermore, blockade of RA progression. Our results propose SP as a potential therapeutic for autoimmune-related inflammatory diseases.

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

    Science.gov (United States)

    Zhu, Yao; Zhang, Ya-Jie; Liu, Wei-Wei; Shi, Ai-Wu; Gu, Ning

    2016-08-09

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

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

    Directory of Open Access Journals (Sweden)

    Yao Zhu

    2016-08-01

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

  7. Filaria-induced IL-10 suppresses murine cerebral malaria.

    Science.gov (United States)

    Specht, Sabine; Ruiz, Daniel Fernández; Dubben, Bettina; Deininger, Susanne; Hoerauf, Achim

    2010-08-01

    Filarial nematodes achieve long survival in their hosts due to their capacity to modulate immune responses. Therefore, immunomodulation by filarial nematodes may alter responses to concomitant infections such as malaria. Cerebral malaria (CM), a severe complication of Plasmodium falciparum infections, is triggered as a consequence of the immune response developed against malaria parasites. The question arises whether prior infection with helminth parasites is beneficial against CM. In the present work a murine model for subsequent has been used to assess this hypothesis. C57BL/6 mice were infected with the rodent filarial parasite Litomosoides sigmodontis and the murine model parasite for CM, Plasmodium berghei ANKA. Previously filaria-infected C57BL/6 mice showed significantly reduced CM rates. CD8(+) T cell recruitment to the brain, a hallmark for CM development, was reduced in protected mice. Furthermore, in contrast to P. berghei single-infected animals, filaria-infected mice had significantly higher levels of circulating IL-10. The requirement for IL-10 in CM protection was demonstrated by the lack of protection in IL-10 KO mice. This suggests that the anti-inflammatory IL-10 elicited by filarial nematodes is able to suppress the overwhelming inflammatory reaction otherwise triggered against malaria parasites in C57BL/6 mice, preventing full progress to CM.

  8. Prostaglandin E2 Promotes UV Radiation-Induced Immune Suppression through DNA Hypermethylation

    Directory of Open Access Journals (Sweden)

    Ram Prasad

    2013-07-01

    Full Text Available Exposure of mice to UV radiation results in suppression of the contact hypersensitivity (CHS response. Here, we report that the UV-induced suppression of CHS is associated with increases in the levels of cyclooxygenase-2 (COX-2, prostaglandin E2 (PGE2, and PGE2 receptors in the exposed skin. UV radiation.induced suppression of CHS was inhibited by topical treatment of the skin with celecoxib or indomethacin (inhibitors of COX-2 or AH6809 (an EP2 antagonist. Moreover, mice deficient in COX-2 were found to be resistant to UV-induced suppression of CHS. The exposure of wild-typemice to UVB radiation resulted in DNA hypermethylation, increased DNA methyltransferase (Dnmt activity, and elevated levels of Dnmt1, Dnmt3a, and Dnmt3b proteins in the skin, and these responses were downregulated on topical treatment of the site of exposure after irradiation with indomethacin or EP2 antagonist. Topical treatment of UVB-exposed COX-2.deficient mice with PGE2 enhanced the UVB-induced suppression of CHS as well as global DNA methylation and elevated the levels of Dnmt activity and Dnmt proteins in the skin. Intraperitoneal injection of 5-aza-2′-deoxycytidine (5-Aza-dc, a DNA demethylating agent, restored the CHS response to 2,4-dinitrofluorobenzene in UVB-exposed skin and this was associated with the reduction in global DNA methylation and Dnmt activity and reduced levels of Dnmt proteins. Furthermore, treatment with 5-Aza-dc reversed the effect of PGE2 on UV-induced suppression of CHS in COX-2.deficient mice. These findings reveal a previously unrecognized role for PGE2 in the promotion of UVB-induced immunosuppression and indicate that it is mediated through PGE2 regulation of DNA methylation.

  9. Double-strand break repair-adox: Restoration of suppressed double-strand break repair during mitosis induces genomic instability.

    Science.gov (United States)

    Terasawa, Masahiro; Shinohara, Akira; Shinohara, Miki

    2014-12-01

    Double-strand breaks (DSBs) are one of the severest types of DNA damage. Unrepaired DSBs easily induce cell death and chromosome aberrations. To maintain genomic stability, cells have checkpoint and DSB repair systems to respond to DNA damage throughout most of the cell cycle. The failure of this process often results in apoptosis or genomic instability, such as aneuploidy, deletion, or translocation. Therefore, DSB repair is essential for maintenance of genomic stability. During mitosis, however, cells seem to suppress the DNA damage response and proceed to the next G1 phase, even if there are unrepaired DSBs. The biological significance of this suppression is not known. In this review, we summarize recent studies of mitotic DSB repair and discuss the mechanisms of suppression of DSB repair during mitosis. DSB repair, which maintains genomic integrity in other phases of the cell cycle, is rather toxic to cells during mitosis, often resulting in chromosome missegregation and aberration. Cells have multiple safeguards to prevent genomic instability during mitosis: inhibition of 53BP1 or BRCA1 localization to DSB sites, which is important to promote non-homologous end joining or homologous recombination, respectively, and also modulation of the non-homologous end joining core complex to inhibit DSB repair. We discuss how DSBs during mitosis are toxic and the multiple safeguard systems that suppress genomic instability.

  10. p53-dependent apoptosis suppresses radiation-induced teratogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Norimura, Toshiyuki [Univ. of Occupational and Environmental Health, Kitakyushu, Fukuoka (Japan). School of Medicine

    1999-06-01

    About half of human conceptions are estimated not to be implanted in the uterus, resulting in unrecognizable spontaneous abortions. Experimental studies with mice have established that irradiation during the preimplantation period of the embryo induces a high incidence of prenatal deaths but virtually no malformations. This suggests that some mechanism is screening out the damaged fetuses. In order to elucidate the mechanisms of tissue repair of radiation-induced teratogenic injury, we compared the incidences of radiation-induced malformations and abortions in p53 null (p53{sup -/-}) and wild-type (p53{sup +/+}) mice. After X-irradiation with 2 Gy on day 9.5 of gestation, p53{sup -/-} mice showed a 70% incidence of anomalies and a 7% incidence of deaths, whereas p53{sup +/+} mice had a 20% incidence of anomalies and a 60% incidence of deaths. Similar results were obtained after irradiation on day 3.5 of gestation. This reciprocal relationship of radiosensitivity to anomalies and to embryonic or fetal lethality supports the notion that the p53 gene protects embryos and fetuses against the teratogenic effects of radiation by eliminating cells that have been badly damaged. In fact, after X-irradiation, the frequency of dying cells by apoptosis was greatly increased in tissues of the p53{sup +/+} fetuses but not at all in those of the p53{sup -/-} fetuses. Mammals are protected from radiation-induced injury by two mechanisms, p53-dependent apoptotic tissue repair in addition to well known DNA repair. Therefore, there are threshold doses below which there is no induction of teratogenic and carcinogenic effects after exposure to low-level radiation. (author)

  11. Exercise Training suppresses vascular fibrosis in aging obesity induced rats

    Science.gov (United States)

    Kim, Shin Young; Lee, Jin

    2014-01-01

    [Purpose] The aim of this study was to investigate the effects of exercise training (ET) on vascular fibrosis in aging model rats with diet-induced obesity. [Methods] Twenty-four male Sprague-Dawley rats were divided into 3 groups: Aging control (A-C), A-C with high fat diet (AHF), AHF with ET (AHF + ET). Aging was induced by D-galactose (D-gal) and obesity was induced by HFD (60% fat) for 9 weeks. The experimental rats performed swimming (60 min/day, 5 days/week) for 8 weeks. All rat aorta samples were harvested for RT-PCR and morphologic analyses. [Results] The exercise training significantly decreased levels of AT-1, TGF-ß and Coll-1 gene expression compared to AHF group. The AHF + ET group showed a reduced collagen accumulation in the aorta media compared to AHF group. [Conclusion] These results suggest that ET could protect the aging obesity aorta against down-regulation of fibrotic factors (AT-1, TGF-ß and Coll-1 gene) and fibrosis by inhibition of collagen accumulation in the aorta media. PMID:25566453

  12. Combinatorial MicroRNAs Suppress Hypoxia-Induced Cardiomyocytes Apoptosis

    Directory of Open Access Journals (Sweden)

    Yingqi Xu

    2015-09-01

    Full Text Available Background/Aims: Our previous in silico analysis revealed potential synergy in the activities of micro(miRNAs in myocardial infarction. The present study investigated whether miR-1 and -21 act synergistically to protect against cardiomyocytes apoptosis. Methods: Cell survival was analyzed with cell viability assay; apoptosis was detected by flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labeling, and the caspase-3 activity assay; and protein expression level was determined by western blotting. Results: MiR-1:miR-21 and several other miRNA pairs were evaluated for their potentially synergistic effects against myocardial hypoxia in neonatal rat ventricular cardiomyocytes. Lower combination indices suggested that miRNA pairs acted synergistically to inhibit apoptosis; miR-1 and -21 jointly blocked hypoxia-induced cardiomyocytes apoptosis. Moreover, combined application of miR-1 and -21 activated Akt and blocked hypoxia-induced upregulation of p53 in these cells. Conclusion: MiR-1 and -21 exert synergistic effects against hypoxia-induced cardiomyocytes apoptosis. These results provide a basis for the development of combined miRNA-based therapeutics to treat cardiovascular diseases.

  13. Suppression and Revival of Weak Localization of Ultra-Cold Atoms by Manipulation of Time-Reversal Symmetry

    Science.gov (United States)

    Aspect, Alain

    In the early 1980's, observation of a magneto-resistance anomaly in metallic thin films was attributed to the phenomenon of weak localization of electrons and to time-reversal symmetry breaking due to a magnetic field acting upon charged particles. We have observed weak localization of ultra-cold atoms in a 2D configuration, placed in a disordered potential created by a laser speckle. In order to manipulate time-reversal symmetry with our neutral atoms, we take advantage of the slow evolution of our system, and we observe the suppression and revival of weak localization when time reversal symmetry is cancelled and reestablished. References: K. Muller, J. Richard, V. V. Volchkov, V. Denechaud, P. Bouyer, A. Aspect, and V. Josse, ''Suppression and Revival of Weak Localization through Control of Time-Reversal Symmetry,'' Physical Review Letters 114 (20) (2015) and references in. Work supported by the ERC Avanced Grant Quantatop.

  14. Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice.

    Science.gov (United States)

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

    2016-06-01

    The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcomes compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of preinvasive foci. We investigated the effects of radiation therapy in p48(Cre);LSL-Kras(G12D) (KC) and p48(Cre);LSLKras(G12D);LSL-Trp53(R172H) (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony-stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2 to 12 Gy and analyzed by flow cytometry. Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from radiation treated invasive and preinvasive pancreatic tumors had an immune-suppressive, M2-like phenotype compared with control mice. Pancreata from mice exposed to radiation had fewer CD8(+) T cells than controls, and greater numbers of CD4(+) T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. A neutralizing antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Radiation treatment causes macrophages

  15. Radiation Therapy Induces Macrophages to Suppress Immune Responses Against Pancreatic Tumors in Mice

    Science.gov (United States)

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Ly, Nancy Ngoc Giao; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R.; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

    2016-01-01

    Background & Aims The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcome, compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of pre-invasive foci. Methods We investigated the effects of radiation in p48Cre;LSL-KrasG12D (KC) and p48Cre;LSLKrasG12D;LSL-Trp53R172H (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2–12 Gy and analyzed by flow cytometry. Results Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from invasive and pre-invasive pancreatic tumors had an immune-suppressive, M2-like phenotype, compared with control mice. Pancreata from mice exposed to radiation had fewer CD8+ T cells than controls and greater numbers of CD4+ T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. An antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Conclusions Radiation exposure causes macrophages in PDAs

  16. UV-induced immune suppression and photocarcinogenesis: chemoprevention by dietary botanical agents.

    Science.gov (United States)

    Katiyar, Santosh K

    2007-09-18

    Studies of immune-suppressed transplant recipients and patients with biopsy-proven skin cancer have confirmed that ultraviolet (UV) radiation-induced immune suppression is a risk factor for the development of skin cancer in humans. UV radiation suppresses the immune system in several ways. The UVB spectrum inhibits antigen presentation, induces the release of immunosuppressive cytokines, and elicits DNA damage that is a molecular trigger of UV-mediated immunosuppression. It is therefore important to elucidate the mechanisms underlying UV-induced immunosuppression as a basis for developing strategies to protect individuals from this effect and subsequent development of skin cancer. Dietary botanicals are of particular interest as they have been shown to inhibit UV-induced immune suppression and photocarcinogenesis. In this review, we summarize the most recent investigations and mechanistic studies regarding the photoprotective efficacy of selected dietary agents, including, green tea polyphenols, grape seed proanthocyanidins and silymarin. We present evidence that these chemopreventive agents prevent UVB-induced immunosuppression and photocarcinogenesis through: (i) the induction of immunoregulatory cytokine interleukin (IL)-12; (ii) IL-12-dependent DNA repair; and (iii) stimulation of cytotoxic T cells in the tumor microenvironment. The new information regarding the mechanisms of action of these agents supports their potential use as adjuncts in the prevention of photocarcinogenesis.

  17. Fetuin-A induces cytokine expression and suppresses adiponectin production.

    Directory of Open Access Journals (Sweden)

    Anita M Hennige

    Full Text Available BACKGROUND: The secreted liver protein fetuin-A (AHSG is up-regulated in hepatic steatosis and the metabolic syndrome. These states are strongly associated with low-grade inflammation and hypoadiponectinemia. We, therefore, hypothesized that fetuin-A may play a role in the regulation of cytokine expression, the modulation of adipose tissue expression and plasma concentration of the insulin-sensitizing and atheroprotective adipokine adiponectin. METHODOLOGY AND PRINCIPAL FINDINGS: Human monocytic THP1 cells and human in vitro differenttiated adipocytes as well as C57BL/6 mice were treated with fetuin-A. mRNA expression of the genes encoding inflammatory cytokines and the adipokine adiponectin (ADIPOQ was assessed by real-time RT-PCR. In 122 subjects, plasma levels of fetuin-A, adiponectin and, in a subgroup, the multimeric forms of adiponectin were determined. Fetuin-A treatment induced TNF and IL1B mRNA expression in THP1 cells (p<0.05. Treatment of mice with fetuin-A, analogously, resulted in a marked increase in adipose tissue Tnf mRNA as well as Il6 expression (27- and 174-fold, respectively. These effects were accompanied by a decrease in adipose tissue Adipoq mRNA expression and lower circulating adiponectin levels (p<0.05, both. Furthermore, fetuin-A repressed ADIPOQ mRNA expression of human in vitro differentiated adipocytes (p<0.02 and induced inflammatory cytokine expression. In humans in plasma, fetuin-A correlated positively with high-sensitivity C-reactive protein, a marker of subclinical inflammation (r = 0.26, p = 0.01, and negatively with total- (r = -0.28, p = 0.02 and, particularly, high molecular weight adiponectin (r = -0.36, p = 0.01. CONCLUSIONS AND SIGNIFICANCE: We provide novel evidence that the secreted liver protein fetuin-A induces low-grade inflammation and represses adiponectin production in animals and in humans. These data suggest an important role of fatty liver in the pathophysiology of insulin resistance and

  18. Spironolactone induces apoptosis in human mononuclear cells. Association between apoptosis and cytokine suppression

    DEFF Research Database (Denmark)

    Mikkelsen, Martin; Sønder, S U; Nersting, J;

    2006-01-01

    Spironolactone (SPIR) has been described to suppress accumulation of pro-inflammatory cytokines. Here, the suppression of TNF-alpha in lipopolysaccharide (LPS)-stimulated mononuclear cell cultures was confirmed. However, SPIR was also found to induce apoptosis, prompting the investigations...... of a possible association between the two effects: The apoptosis-inducing and the cytokine-suppressive effects of SPIR correlated with regard to the effective concentration range. Also, pre-incubation experiments demonstrated a temporal separation of the two effects of ... preceding apoptosis. An association between the two effects was also seen when testing several SPIR analogues. Contrary to TNF-alpha, the levels of IL-1beta increased in SPIR-treated cultures. However, the amount of IL-1beta in the supernatants depended upon the order of SPIR and LPS addition, as IL-1beta...

  19. Biomimetic proopiomelanocortin suppresses capsaicin-induced sensory irritation in humans

    Directory of Open Access Journals (Sweden)

    Sayed Ali Fatemi

    2016-01-01

    Full Text Available Sensitive skin is a frequently mentioned cosmetic complaint. Addition of a biomimetic of neuromediator has recently appeared as a promising new way to cure skin care product problems. This study was aimed to assess the inhibitory effect of a biomimetic lipopeptide derived from proopiomelanocortin (bPOMC on capsaicin-induced sensory irritation in human volunteers and also to compare its protective effect with that of the well-known anti irritant strontium chloride. The effect of each test compound was studied on 28 selected healthy volunteers with sensitive skin in accordance with a double-blind vehicle-controlled protocol. From day 1 to day 13 each group was applied the test compound (bPOMC or strontium chloride to one wing of the nose and the corresponding placebo (vehicle to the other side twice daily. On days 0 and 14, acute skin irritation was induced by capsaicin solution and quantified using clinical stinging test assessments. Following the application of capsaicin solution, sensory irritation was evaluated using a 4-point numeric scale. The sensations perceived before and after treatment (on days 0 and 14 was calculated for the two zones (test materials and vehicle. Ultimately the percentage of variation between each sample and the placebo and also the inhibitory effect of bPOMC compared to that of strontium chloride were reported. Clinical results showed that after two weeks treatment, the levels of skin comfort reported in the group treated with bPOMC were significantly higher than those obtained in the placebo group and the inhibitory effect of bPOMC was about 47% higher than that of strontium chloride. The results of the present study support the hypothesis that biomimetic peptides may be effective on sensitive skin.

  20. Sirt2 suppresses inflammatory responses in collagen-induced arthritis

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Jiangtao [Department of Orthopaedics, Qilu Hospital, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012 (China); Department of Orthopaedics, Yantaishan Hospital, 91 Jiefang Road, Yantai, Shandong 264001 (China); Sun, Bing; Jiang, Chuanqiang; Hong, Huanyu [Department of Orthopaedics, Yantaishan Hospital, 91 Jiefang Road, Yantai, Shandong 264001 (China); Zheng, Yanping, E-mail: yanpingzheng@yahoo.com [Department of Orthopaedics, Qilu Hospital, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012 (China)

    2013-11-29

    Highlights: •Sirt2 expression decreases in collagen-induced arthritis (CIA). •Sirt2 knockout aggravates severity of arthritis in mice with CIA. •Sirt2 knockout increases levels of pro-inflammatory factors in the serum. •Sirt2 deacetylates p65 and inhibits pro-inflammatory factors expression. •Sirt2 rescue abates severity of arthritis in mice with CIA. -- Abstract: Arthritis is a common autoimmune disease that is associated with progressive disability, systemic complications and early death. However, the underling mechanisms of arthritis are still unclear. Sirtuins are a NAD{sup +}-dependent class III deacetylase family, and regulate cellular stress, inflammation, genomic stability, carcinogenesis, and energy metabolism. Among the sirtuin family members, Sirt1 and Sirt6 are critically involved in the development of arthritis. It remains unknown whether other sirtuin family members participate in arthritis. Here in this study, we demonstrate that Sirt2 inhibits collagen-induced arthritis (CIA) using in vivo and in vitro evidence. The protein and mRNA levels of Sirt2 significantly decreased in joint tissues of mice with CIA. When immunized with collagen, Sirt2-KO mice showed aggravated severity of arthritis based on clinical scores, hind paw thickness, and radiological and molecular findings. Mechanically, Sirt2 deacetylated p65 subunit of nuclear factor-kappa B (NF-κB) at lysine 310, resulting in reduced expression of NF-κB-dependent genes, including interleukin 1β (IL-1β), IL-6, monocyte chemoattractant protein 1(MCP-1), RANTES, matrix metalloproteinase 9 (MMP-9) and MMP-13. Importantly, our rescue experiment showed that Sirt2 re-expression abated the severity of arthritis in Sirt2-KO mice. Those findings strongly indicate Sirt2 as a considerably inhibitor of the development of arthritis.

  1. Surface-plasmon-polariton-induced suppressed transmission through ultrathin metal disk arrays

    DEFF Research Database (Denmark)

    Xiao, Sanshui; Mortensen, Asger

    2011-01-01

    We report surface-plasmon-polariton-induced suppressed transmission through two-dimensional arrays of isolated metal disks with a thickness comparable to optical skin depth of the metal. A transmittance dip of −17:5 dB is achieved at the resonant wavelength of 1524 nm, compared to −12 dB for closed...

  2. Limited Role of Murine ATM in Oncogene-Induced Senescence and p53-Dependent Tumor Suppression

    Science.gov (United States)

    Martinez-Pastor, Barbara; Ortega-Molina, Ana; Soria, Rebeca; Collado, Manuel; Fernandez-Capetillo, Oscar; Serrano, Manuel

    2009-01-01

    Recent studies in human fibroblasts have provided a new general paradigm of tumor suppression according to which oncogenic signaling produces DNA damage and this, in turn, results in ATM/p53-dependent cellular senescence. Here, we have tested this model in a variety of murine experimental systems. Overexpression of oncogenic Ras in murine fibroblasts efficiently induced senescence but this occurred in the absence of detectable DNA damage signaling, thus suggesting a fundamental difference between human and murine cells. Moreover, lung adenomas initiated by endogenous levels of oncogenic K-Ras presented abundant senescent cells, but undetectable DNA damage signaling. Accordingly, K-Ras-driven adenomas were also senescent in Atm-null mice, and the tumorigenic progression of these lesions was only modestly accelerated by Atm-deficiency. Finally, we have examined chemically-induced fibrosarcomas, which possess a persistently activated DNA damage response and are highly sensitive to the activity of p53. We found that the absence of Atm favored genomic instability in the resulting tumors, but did not affect the persistent DNA damage response and did not impair p53-dependent tumor suppression. All together, we conclude that oncogene-induced senescence in mice may occur in the absence of a detectable DNA damage response. Regarding murine Atm, our data suggest that it plays a minor role in oncogene-induced senescence or in p53-dependent tumor suppression, being its tumor suppressive activity probably limited to the maintenance of genomic stability. PMID:19421407

  3. Limited role of murine ATM in oncogene-induced senescence and p53-dependent tumor suppression.

    Directory of Open Access Journals (Sweden)

    Alejo Efeyan

    Full Text Available Recent studies in human fibroblasts have provided a new general paradigm of tumor suppression according to which oncogenic signaling produces DNA damage and this, in turn, results in ATM/p53-dependent cellular senescence. Here, we have tested this model in a variety of murine experimental systems. Overexpression of oncogenic Ras in murine fibroblasts efficiently induced senescence but this occurred in the absence of detectable DNA damage signaling, thus suggesting a fundamental difference between human and murine cells. Moreover, lung adenomas initiated by endogenous levels of oncogenic K-Ras presented abundant senescent cells, but undetectable DNA damage signaling. Accordingly, K-Ras-driven adenomas were also senescent in Atm-null mice, and the tumorigenic progression of these lesions was only modestly accelerated by Atm-deficiency. Finally, we have examined chemically-induced fibrosarcomas, which possess a persistently activated DNA damage response and are highly sensitive to the activity of p53. We found that the absence of Atm favored genomic instability in the resulting tumors, but did not affect the persistent DNA damage response and did not impair p53-dependent tumor suppression. All together, we conclude that oncogene-induced senescence in mice may occur in the absence of a detectable DNA damage response. Regarding murine Atm, our data suggest that it plays a minor role in oncogene-induced senescence or in p53-dependent tumor suppression, being its tumor suppressive activity probably limited to the maintenance of genomic stability.

  4. Blackcurrant Suppresses Metabolic Syndrome Induced by High-Fructose Diet in Rats

    Directory of Open Access Journals (Sweden)

    Ji Hun Park

    2015-01-01

    Full Text Available Increased fructose ingestion has been linked to obesity, hyperglycemia, dyslipidemia, and hypertension associated with metabolic syndrome. Blackcurrant (Ribes nigrum; BC is a horticultural crop in Europe. To induce metabolic syndrome, Sprague-Dawley rats were fed 60% high-fructose diet. Treatment with BC (100 or 300 mg/kg/day for 8 weeks significantly suppressed increased liver weight, epididymal fat weight, C-reactive protein (CRP, total bilirubin, leptin, and insulin in rats with induced metabolic syndrome. BC markedly prevented increased adipocyte size and hepatic triglyceride accumulation in rats with induced metabolic syndrome. BC suppressed oral glucose tolerance and protein expression of insulin receptor substrate-1 (IRS-1 and phosphorylated AMP-activated protein kinase (p-AMPK in muscle. BC significantly suppressed plasma total cholesterol, triglyceride, and LDL content. BC suppressed endothelial dysfunction by inducing downregulation of endothelin-1 and adhesion molecules in the aorta. Vascular relaxation of thoracic aortic rings by sodium nitroprusside and acetylcholine was improved by BC. The present study provides evidence of the potential protective effect of BC against metabolic syndrome by demonstrating improvements in dyslipidemia, hypertension, insulin resistance, and obesity in vivo.

  5. DIBROMOACETIC ACID ATTENUATES A DIMETHYLDITHIOCARBAMATE-INDUCED SUPPRESSION OF THE RAT LH SURGE

    Science.gov (United States)

    DIBROMOACETIC ACID ATTENUATES A DITHIOCARBAMATE-INDUCED SUPPRESSION OF THE LH SURGE IN THE RAT. Jerome M. Goldman, Ashley S. Murr, Angela R. Buckelew, W. Keith McElroy and Janet M. Ferrell. Repro. Toxicol. Div., NHEERL, ORD, US EPA, RTP, NCAt elevated concentrations, the ...

  6. Trehalose enhances osmotic tolerance and suppresses lysophosphatidylcholine-induced acrosome reaction in ram spermatozoon.

    Science.gov (United States)

    Ahmad, E; Naseer, Z; Aksoy, M; Küçük, N; Uçan, U; Serin, I; Ceylan, A

    2015-09-01

    This study was aimed to investigate the influence of trehalose on osmotic tolerance and the ability of ram spermatozoon to undergo acrosome reaction induced by lysophosphatidylcholine (LPC). In experiment 1, the diluted ejaculates were exposed to anisosmotic fructose solutions (70, 500, 750 and 1000 mOsm l(-1) ) with or without 50 mm trehalose. The presence of trehalose in hyperosmotic conditions enhanced (P ram spermatozoon and suppresses their ability to undergo LPC and cryo-induced acrosome reaction.

  7. Lake destratification induced by local air injection

    NARCIS (Netherlands)

    Kranenburg, C.

    1979-01-01

    Mathematical and physical modelling makes possible quantitative predictions regarding the destratification process brought about by the local injection of air at the bottom of a thermally stratified lake or reservoir. The mathematical model developed distinguishes between a near field and a far fiel

  8. Median raphe stimulation-induced motor inhibition concurrent with suppression of type 1 and type 2 hippocampal theta.

    Science.gov (United States)

    Bland, Brian H; Bland, Cheryl E; MacIver, M Bruce

    2016-03-01

    This study investigated behavioral, anatomical and electrophysiological effects produced by electrical stimulation of posterior hypothalamic (PH) or median raphe (MR) nuclei, independently and during combined stimulation of both PH and MR. These three stimulation conditions were applied during spontaneous behavior in an open field and during PH stimulation-induced wheel running, while simultaneously recording hippocampal (HPC) field activity. An additional objective was to determine the effects of MR stimulation on Type 1 movement related theta and Type 2 sensory processing related theta. To achieve the latter, when behavioral studies were completed we studied the same rats under urethane anesthesia and then during urethane anesthesia with the addition of atropine sulfate (ATSO4). Here we demonstrated that electrical stimulation of a localized region of the MR nucleus resulted in a profound inhibition of both spontaneously occurring theta related motor behaviors and the theta related motor behaviors induced by electrical stimulation of the PH nucleus. Furthermore, this motor inhibition occurred concurrently with strong suppression of hippocampal theta field oscillations in the freely moving rat, a condition where the theta recorded is Type 2 sensory processing theta occurring coincidently with Type 1 movement related theta (Bland, 1986). Our results indicate that motor inhibition resulted from stimulation of neurons located in the mid central region of the MR, while stimulation in adjacent regions produced variable responses, including movements and theta activity. The present study provided evidence that the pharmacological basis of the suppression of Type 2 sensory processing HPC theta was cholinergic. However, MR inhibition of PH-induced wheel running was not affected by cholinergic blockade, which blocks Type 2 theta, indicating that MR stimulation-induced motor inhibition also requires the suppression of Type 1 theta.

  9. Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production.

    Science.gov (United States)

    Kearney, C J; Cullen, S P; Tynan, G A; Henry, C M; Clancy, D; Lavelle, E C; Martin, S J

    2015-08-01

    TNF promotes a regulated form of necrosis, called necroptosis, upon inhibition of caspase activity in cells expressing RIPK3. Because necrosis is generally more pro-inflammatory than apoptosis, it is widely presumed that TNF-induced necroptosis may be detrimental in vivo due to excessive inflammation. However, because TNF is intrinsically highly pro-inflammatory, due to its ability to trigger the production of multiple cytokines and chemokines, rapid cell death via necroptosis may blunt rather than enhance TNF-induced inflammation. Here we show that TNF-induced necroptosis potently suppressed the production of multiple TNF-induced pro-inflammatory factors due to RIPK3-dependent cell death. Similarly, necroptosis also suppressed LPS-induced pro-inflammatory cytokine production. Consistent with these observations, supernatants from TNF-stimulated cells were more pro-inflammatory than those from TNF-induced necroptotic cells in vivo. Thus necroptosis attenuates TNF- and LPS-driven inflammation, which may benefit intracellular pathogens that evoke this mode of cell death by suppressing host immune responses.

  10. Suppression of the HPA axis during extrahepatic biliary obstruction induces cholangiocyte proliferation in the rat.

    Science.gov (United States)

    Quinn, Matthew; Ueno, Yoshiyuki; Pae, Hae Yong; Huang, Li; Frampton, Gabriel; Galindo, Cheryl; Francis, Heather; Horvat, Darijana; McMillin, Matthew; Demorrow, Sharon

    2012-01-01

    Cholestatic patients often present with clinical features suggestive of adrenal insufficiency. In the bile duct-ligated (BDL) model of cholestasis, the hypothalamic-pituitary-adrenal (HPA) axis is suppressed. The consequences of this suppression on cholangiocyte proliferation are unknown. We evaluated 1) HPA axis activity in various rat models of cholestasis and 2) effects of HPA axis modulation on cholangiocyte proliferation. Expression of regulatory molecules of the HPA axis was determined after BDL, partial BDL, and α-naphthylisothiocyanate (ANIT) intoxication. The HPA axis was suppressed by inhibition of hypothalamic corticotropin-releasing hormone (CRH) expression by central administration of CRH-specific Vivo-morpholinos or by adrenalectomy. After BDL, the HPA axis was reactivated by 1) central administration of CRH, 2) systemic ACTH treatment, or 3) treatment with cortisol or corticosterone for 7 days postsurgery. There was decreased expression of 1) hypothalamic CRH, 2) pituitary ACTH, and 3) key glucocorticoid synthesis enzymes in the adrenal glands. Serum corticosterone and cortisol remained low after BDL (but not partial BDL) compared with sham surgery and after 2 wk of ANIT feeding. Experimental suppression of the HPA axis increased cholangiocyte proliferation, shown by increased cytokeratin-19- and proliferating cell nuclear antigen-positive cholangiocytes. Conversely, restoration of HPA axis activity inhibited BDL-induced cholangiocyte proliferation. Suppression of the HPA axis is an early event following BDL and induces cholangiocyte proliferation. Knowledge of the role of the HPA axis during cholestasis may lead to development of innovative treatment paradigms for chronic liver disease.

  11. The regulation of induced depression during a frustrating situation: benefits of expressive suppression in Chinese individuals.

    Directory of Open Access Journals (Sweden)

    Jiajin Yuan

    Full Text Available BACKGROUND: Studies from European-American cultures consistently reported that expressive suppression was associated with worse emotional consequence (e.g. depression in comparison with acceptance. However, this conclusion may not apply to Chinese, as suppressing emotional displays to maintain relational harmony is culturally valued in East Asian countries. Thus, the present study examined the effects of suppression and acceptance on the depressive mood induced by a frustrating task in a Chinese sample. METHOD: Sixty-four subjects were randomly assigned to one of three instructions: suppression, acceptance or no-regulation during a frustrating arithmetic task. The experience of depressive emotion and skin conductance response (SCR were recorded during pre-frustration baseline, frustration induction and post-frustration recovery phases, respectively. RESULTS: Compared with the control and acceptance instructions, suppression instruction was associated with decreased depressive experiences and smaller SCR activity during frustration. There were no significant differences between acceptance and control groups in both subjective depression and SCR activity during frustration. Moreover, the suppression group showed a better emotional recovery after the frustrating task, in comparison with the acceptance and control groups. Correlation analyses verified that SCR reactivity was a reliable index of experienced depression during the frustration. CONCLUSIONS: Expressive suppression is effective in reducing depressive experiences and depression-related physiological activity (SCR when Chinese people are involved. By contrast, the acceptance of depressive emotion in Chinese people does not produce a similar regulation effect. These findings suggest that cultural context should be considered in understanding the emotional consequences of suppression and acceptance strategies.

  12. Anthocyans fail to suppress transformation of aryl hydrocarbon receptor induced by dioxin.

    Science.gov (United States)

    Mukai, Rie; Fukuda, Itsuko; Hosokawa, Keizo; Nishiumi, Shin; Kaneko, Atsushi; Ashida, Hitoshi

    2005-05-01

    Dioxins induce adverse effects through transformation of the cytosolic aryl hydrocarbon receptor (AhR). Our previous study found that flavones and flavonols at dietary levels suppress AhR transformation. In the present study, we investigated whether 20 anthocyans dissolved in trifluoroacetic acid (TFA)-MeOH suppressed AhR transformation in a cell-free system and in Hepa-1c1c7 cells. Although four compounds at 50 muM suppressed 0.1 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced AhR transformation and their effects were dose-dependent in the cell-free system, they were ineffective at 0.5 muM, which is close to physiological concentration. Moreover, no anthocyan at 50 muM tested here suppressed 0.1 nM TCDD-induced AhR transformation in Hepa-1c1c7 cells. We also confirmed that protocatechuic acid and related compounds, which are possible metabolites of anthocyans, did not affect the transformation in the cell-free system. It is concluded that anthocyans are not suitable candidates for protection from dioxin toxicity.

  13. Light-induced melatonin suppression at night after exposure to different wavelength composition of morning light.

    Science.gov (United States)

    Kozaki, Tomoaki; Kubokawa, Ayaka; Taketomi, Ryunosuke; Hatae, Keisuke

    2016-03-11

    Bright nocturnal light has been shown to suppress melatonin secretion. However, bright light exposure during the day might reduce light-induced melatonin suppression at night. The human circadian system is sensitive to short wavelength light. This study evaluated the preventive effect of different wavelengths of daytime light on light-induced melatonin suppression at night. Twelve male subjects were exposed to various light conditions (dim, white, and bluish white light) between the hours of 09:00 and 10:30 (daytime light conditions). They were then exposed to light (300lx) again between 01:00 and 02:30 (night-time light exposure). Subjects provided saliva samples before (00:55) and after night-time light exposure (02:30). A two-tailed paired t-test yielded significant decrements in melatonin concentrations after night-time light exposure under daytime dim and white light conditions. No significant differences were found in melatonin concentrations between pre- and post-night-time light exposure with bluish-white light. Present findings suggest that daytime blue light exposure has an acute preventive impact on light-induced melatonin suppression in individuals with a general life rhythm (sleep/wake schedule). These findings may be useful for implementing artificial light environments for humans in, for example, hospitals and underground shopping malls to reduce health risks.

  14. Nonlinear Transition from Mitigation to Suppression of the Edge Localized Mode with Resonant Magnetic Perturbations in the EAST Tokamak.

    Science.gov (United States)

    Sun, Y; Liang, Y; Liu, Y Q; Gu, S; Yang, X; Guo, W; Shi, T; Jia, M; Wang, L; Lyu, B; Zhou, C; Liu, A; Zang, Q; Liu, H; Chu, N; Wang, H H; Zhang, T; Qian, J; Xu, L; He, K; Chen, D; Shen, B; Gong, X; Ji, X; Wang, S; Qi, M; Song, Y; Yuan, Q; Sheng, Z; Gao, G; Fu, P; Wan, B

    2016-09-01

    Evidence of a nonlinear transition from mitigation to suppression of the edge localized mode (ELM) by using resonant magnetic perturbations (RMPs) in the EAST tokamak is presented. This is the first demonstration of ELM suppression with RMPs in slowly rotating plasmas with dominant radio-frequency wave heating. Changes of edge magnetic topology after the transition are indicated by a gradual phase shift in the plasma response field from a linear magneto hydro dynamics modeling result to a vacuum one and a sudden increase of three-dimensional particle flux to the divertor. The transition threshold depends on the spectrum of RMPs and plasma rotation as well as perturbation amplitude. This means that edge topological changes resulting from nonlinear plasma response plays a key role in the suppression of ELM with RMPs.

  15. Intensity constrained flat kernel filter for local dark feature suppression: application to removal of hair artifacts in dermatoscopic images

    Science.gov (United States)

    Gutenev, Alex A.

    2012-03-01

    The Intensity Constrained Flat Kernel Filtering (ICFK) scheme is a dual domain (spatial and intensity) nonlinear framework which has been shown to generate useful filters for image processing. This paper proposes a new filter developed within the ICFK framework. Although local in nature the filter is designed to suppress large scale spatial features within the image. As in every other filter derived within the scheme the suppressed features are defined by two parameters: size of the kernel and intensity range. The filter, a single-step procedure, is applied to removal of hair artifacts in skin lesion epiluminescence microscopy images, the task essential in assisting in automated segmentation of imaged area into lesion and surrounding skin. Results of the experiments on 400 dermatoscopic images of lesions with hair indicate suitability of the method as an aid in lesion segmentation by suppressing hair or vascular features near the lesion borders.

  16. Schisantherin A suppresses osteoclast formation and wear particle-induced osteolysis via modulating RANKL signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    He, Yi; Zhang, Qing; Shen, Yi; Chen, Xia; Zhou, Feng; Peng, Dan, E-mail: xyeypd@163.com

    2014-07-04

    Highlights: • Schisantherin A suppresses osteoclasts formation and function in vitro. • Schisantherin A impairs RANKL signaling pathway. • Schisantherin A suppresses osteolysis in vivo. • Schisantherin A may be used for treating osteoclast related diseases. - Abstract: Receptor activator of NF-κB ligand (RANKL) plays critical role in osteoclastogenesis. Targeting RANKL signaling pathways has been a promising strategy for treating osteoclast related bone diseases such as osteoporosis and aseptic prosthetic loosening. Schisantherin A (SA), a dibenzocyclooctadiene lignan isolated from the fruit of Schisandra sphenanthera, has been used as an antitussive, tonic, and sedative agent, but its effect on osteoclasts has been hitherto unknown. In the present study, SA was found to inhibit RANKL-induced osteoclast formation and bone resorption. The osteoclastic specific marker genes induced by RANKL including c-Src, SA inhibited OSCAR, cathepsin K and TRAP in a dose dependent manner. Further signal transduction studies revealed that SA down-regulate RANKL-induced nuclear factor-kappaB (NF-κB) signaling activation by suppressing the phosphorylation and degradation of IκBα, and subsequently preventing the NF-κB transcriptional activity. Moreover, SA also decreased the RANKL-induced MAPKs signaling pathway, including JNK and ERK1/2 posphorylation while had no obvious effects on p38 activation. Finally, SA suppressed the NF-κB and MAPKs subsequent gene expression of NFATc1 and c-Fos. In vivo studies, SA inhibited osteoclast function and exhibited bone protection effect in wear-particle-induced bone erosion model. Taken together, SA could attenuate osteoclast formation and wear particle-induced osteolysis by mediating RANKL signaling pathways. These data indicated that SA is a promising therapeutic natural compound for the treatment of osteoclast-related prosthesis loosening.

  17. Caspase-6 Induces 7A6 Antigen Localization to Mitochondria During FAS-induced Apoptosis of Jurkat Cells.

    Science.gov (United States)

    Suita, Hiroaki; Shinomiya, Takahisa; Nagahara, Yukitoshi

    2017-04-01

    Mitochondria are central to apoptosis. However, apoptosis progression involving mitochondria is not fully understood. A factor involved in mitochondria-mediated apoptosis is 7A6 antigen. 7A6 localizes to mitochondria from the cytosol during apoptosis, which seems to involve 'effector' caspases. In this study, we investigated the precise role of effector caspases in 7A6 localization to mitochondria during apoptosis. Human T-cell lymphoma Jurkat cells were treated with an antibody against FAS. 7A6 localization was analyzed by confocal laser scanning microscopy and flow cytometry. Caspases activation was determined by western blot analysis. 7A6 localization to mitochondria during anti-FAS-induced apoptosis was significantly reduced by the caspase-6 inhibitor, N-acetyl-Val-Glu-Ile-Asp-aldehyde, but not by the caspase-3 inhibitor, N-acetyl-Asp-Asn-Leu-Asp-aldehyde, nor caspase-7/3 inhibitor, N-acetyl-Asp-Gln-Thr-Asp-aldehyde. Moreover, caspase-6 down-regulation suppressed 7A6 localization to mitochondria. Caspase-6 regulates 7A6 localization to mitochondria during anti-FAS-induced apoptosis of Jurkat cells. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  18. QUANTIFYING LOCAL RADIATION-INDUCED LUNG DAMAGE FROM COMPUTED TOMOGRAPHY

    NARCIS (Netherlands)

    Ghobadi, Ghazaleh; Hogeweg, Laurens E.; Faber, Hette; Tukker, Wim G. J.; Schippers, Jacobus M.; Brandenburg, Sytze; Langendijk, Johannes A.; Coppes, Robert P.; van Luijk, Peter

    2010-01-01

    Purpose: Optimal implementation of new radiotherapy techniques requires accurate predictive models for normal tissue complications. Since clinically used dose distributions are nonuniform, local tissue damage needs to be measured and related to local tissue dose. In lung, radiation-induced damage re

  19. Flow shear induced fluctuation suppression in finite aspect ratio shaped tokamak plasma

    Energy Technology Data Exchange (ETDEWEB)

    Hahm, T.S. [Princeton Univ., NJ (United States). Plasma Physics Lab.; Burrell, K.H. [General Atomics, San Diego, CA (United States)

    1995-01-01

    The suppression of turbulence by the E {times} B flow shear and parallel flow shear is studied in an arbitrary shape finite aspect ratio tokamak plasma using the two point nonlinear analysis previously utilized in a high aspect rat& tokamak plasma. The result shows that only the E {times} B flow shear is responsible for the suppression of flute-like fluctuations. This suppression occurs regardless of the plasma rotation direction and is therefore, relevant for the VH mode plasma core as well as for the H mode plasma edge. Experimentally observed in-out asymmetry of fluctuation reduction behavior can be addressed in the context of flux expansion and magnetic field pitch variation on a given flux surface. The adverse effect of neutral particles on confinement improvement is also discussed in the context of the charge exchange induced parallel momentum damping.

  20. Perceptual suppression revealed by adaptive multi-scale entropy analysis of local field potential in monkey visual cortex.

    Science.gov (United States)

    Hu, Meng; Liang, Hualou

    2013-04-01

    Generalized flash suppression (GFS), in which a salient visual stimulus can be rendered invisible despite continuous retinal input, provides a rare opportunity to directly study the neural mechanism of visual perception. Previous work based on linear methods, such as spectral analysis, on local field potential (LFP) during GFS has shown that the LFP power at distinctive frequency bands are differentially modulated by perceptual suppression. Yet, the linear method alone may be insufficient for the full assessment of neural dynamic due to the fundamentally nonlinear nature of neural signals. In this study, we set forth to analyze the LFP data collected from multiple visual areas in V1, V2 and V4 of macaque monkeys while performing the GFS task using a nonlinear method - adaptive multi-scale entropy (AME) - to reveal the neural dynamic of perceptual suppression. In addition, we propose a new cross-entropy measure at multiple scales, namely adaptive multi-scale cross-entropy (AMCE), to assess the nonlinear functional connectivity between two cortical areas. We show that: (1) multi-scale entropy exhibits percept-related changes in all three areas, with higher entropy observed during perceptual suppression; (2) the magnitude of the perception-related entropy changes increases systematically over successive hierarchical stages (i.e. from lower areas V1 to V2, up to higher area V4); and (3) cross-entropy between any two cortical areas reveals higher degree of asynchrony or dissimilarity during perceptual suppression, indicating a decreased functional connectivity between cortical areas. These results, taken together, suggest that perceptual suppression is related to a reduced functional connectivity and increased uncertainty of neural responses, and the modulation of perceptual suppression is more effective at higher visual cortical areas. AME is demonstrated to be a useful technique in revealing the underlying dynamic of nonlinear/nonstationary neural signal.

  1. Local Modulation of Double Electromagnetically Induced Transparency Spectrum

    Institute of Scientific and Technical Information of China (English)

    HOU Bang-Pin; WANG Shun-Jin; YU Wan-Lun; SUN Wei-Li

    2007-01-01

    The double electromagnetically induced transparency induced by two coupling fields can be realized in a fourlevel tripod-type atom. Such double transparency spectra can be locally modulated by using the weak coherent fields to perturb the coupling transitions. These investigations within this scheme can be independent of Doppler broadening by properly orienting these fields.

  2. Crocin suppresses tumor necrosis factor-alpha-induced cell death of neuronally differentiated PC-12 cells.

    Science.gov (United States)

    Soeda, S; Ochiai, T; Paopong, L; Tanaka, H; Shoyama, Y; Shimeno, H

    2001-11-01

    Crocus sativus L. is used in Chinese traditional medicine to treat some disorders of the central nervous system. Crocin is an ethanol-extractable component of Crocus sativus L.; it is reported to prevent ethanol-induced impairment of learning and memory in mice. In this study, we demonstrate that crocin suppresses the effect of tumor necrosis factor (TNF)-alpha on neuronally differentiated PC-12 cells. PC-12 cells dead from exposure to TNF-alpha show apoptotic morphological changes and DNA fragmentation. These hallmark features of cell death did not appear in cells treated in the co-presence of 10 microM crocin. Moreover, crocin suppressed the TNF-alpha-induced expression of Bcl-Xs and LICE mRNAs and simultaneously restored the cytokine-induced reduction of Bcl-X(L) mRNA expression. The modulating effects of crocin on the expression of Bcl-2 family proteins led to a marked reduction of a TNF-alpha-induced release of cytochrome c from the mitochondria. Crocin also blocked the cytochrome c-induced activation of caspase-3. To learn how crocin exhibits these anti-apoptotic actions in PC-12 cells, we tested the effect of crocin on PC-12 cell death induced by daunorubicin. We found that crocin inhibited the effect of daunorubicin as well. Our findings suggest that crocin inhibits neuronal cell death induced by both internal and external apoptotic stimuli.

  3. Teuvincenone F Suppresses LPS-Induced Inflammation and NLRP3 Inflammasome Activation by Attenuating NEMO Ubiquitination.

    Science.gov (United States)

    Zhao, Xibao; Pu, Debing; Zhao, Zizhao; Zhu, Huihui; Li, Hongrui; Shen, Yaping; Zhang, Xingjie; Zhang, Ruihan; Shen, Jianzhong; Xiao, Weilie; Chen, Weilin

    2017-01-01

    Inflammation causes many diseases that are serious threats to human health. However, the molecular mechanisms underlying regulation of inflammation and inflammasome activation are not fully understood which has delayed the discovery of new anti-inflammatory drugs of urgent clinic need. Here, we found that the natural compound Teuvincenone F, which was isolated and purified from the stems and leaves of Premna szemaoensis, could significantly inhibit lipopolysaccharide (LPS)-induced pro-inflammatory cytokines production and NLRP3 inflammasome activation. Our results showed that Teuvincenone F attenuated K63-linked ubiquitination of NF-κB-essential modulator (NEMO, also known as IKKγ) to suppress LPS-induced phosphorylation of NF-κB, and inhibited mRNA expression of IL-1β, IL-6, TNF-α, and NLRP3. In addition, we found that decreased NLRP3 expression by Teuvincenone F suppressed NLRP3 inflammasome activation and IL-1β/IL-18 maturation. In vivo, we revealed that Teuvincenone F treatment relieved LPS-induced inflammation. In conclusion, Teuvincenone F is a highly effective natural compound to suppress LPS-induced inflammation by attenuating K63-linked ubiquitination of NEMO, highlighting that Teuvincenone F may be a potential new anti-inflammatory drug for the treatment of inflammatory and NLRP3 inflammasome-driven diseases.

  4. Cardiac Sirt1 mediates the cardioprotective effect of caloric restriction by suppressing local complement system activation after ischemia-reperfusion.

    Science.gov (United States)

    Yamamoto, Tsunehisa; Tamaki, Kayoko; Shirakawa, Kohsuke; Ito, Kentaro; Yan, Xiaoxiang; Katsumata, Yoshinori; Anzai, Atsushi; Matsuhashi, Tomohiro; Endo, Jin; Inaba, Takaaki; Tsubota, Kazuo; Sano, Motoaki; Fukuda, Keiichi; Shinmura, Ken

    2016-04-15

    Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion (I/R) injury. We previously found the essential roles of endothelial nitric oxide synthase in the development of CR-induced cardioprotection and Sirt1 activation during CR (Shinmura K, Tamaki K, Ito K, Yan X, Yamamoto T, Katsumata Y, Matsuhashi T, Sano M, Fukuda K, Suematsu M, Ishii I. Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury.Am J Physiol Heart Circ Physiol 308: H894-H903, 2015). However, the exact mechanism by which Sirt1 in cardiomyocytes mediates the cardioprotective effect of CR remains undetermined. We subjected cardiomyocyte-specific Sirt1 knockout (CM-Sirt1(-/-)) mice and the corresponding control mice to either 3-mo ad libitum feeding or CR (-40%). Isolated perfused hearts were subjected to 25-min global ischemia, followed by 60-min reperfusion. The recovery of left ventricle function after I/R was improved, and total lactate dehydrogenase release into the perfusate during reperfusion was attenuated in the control mice treated with CR, but a similar cardioprotective effect of CR was not observed in the CM-Sirt1(-/-)mice. The expression levels of cardiac complement component 3 (C3) at baseline and the accumulation of C3 and its fragments in the ischemia-reperfused myocardium were attenuated by CR in the control mice, but not in the CM-Sirt1(-/-)mice. Resveratrol treatment also attenuated the expression levels of C3 protein in cultured neonatal rat ventricular cardiomyocytes. Moreover, the degree of myocardial I/R injury in conventional C3 knockout (C3(-/-)) mice treated with CR was similar to that in the ad libitum-fed C3(-/-)mice, although the expression levels of Sirt1 were enhanced by CR. These results demonstrate that cardiac Sirt1 plays an essential role in CR-induced cardioprotection against I/R injury by suppressing cardiac C3 expression. This is the first report suggesting

  5. Noise-Induced Subdiffusion in Strongly Localized Quantum Systems

    Science.gov (United States)

    Gopalakrishnan, Sarang; Islam, K. Ranjibul; Knap, Michael

    2017-07-01

    We consider the dynamics of strongly localized systems subject to dephasing noise with arbitrary correlation time. Although noise inevitably induces delocalization, transport in the noise-induced delocalized phase is subdiffusive in a parametrically large intermediate-time window. We argue for this intermediate-time subdiffusive regime both analytically and using numerical simulations on single-particle localized systems. Furthermore, we show that normal diffusion is restored in the long-time limit, through processes analogous to variable-range hopping. With numerical simulations based on Lanczos exact diagonalization, we demonstrate that our qualitative conclusions are also valid for interacting systems in the many-body localized phase.

  6. Mosquito and Drosophila entomobirnaviruses suppress dsRNA- and siRNA-induced RNAi.

    Science.gov (United States)

    van Cleef, Koen W R; van Mierlo, Joël T; Miesen, Pascal; Overheul, Gijs J; Fros, Jelke J; Schuster, Susan; Marklewitz, Marco; Pijlman, Gorben P; Junglen, Sandra; van Rij, Ronald P

    2014-07-01

    RNA interference (RNAi) is a crucial antiviral defense mechanism in insects, including the major mosquito species that transmit important human viruses. To counteract the potent antiviral RNAi pathway, insect viruses encode RNAi suppressors. However, whether mosquito-specific viruses suppress RNAi remains unclear. We therefore set out to study RNAi suppression by Culex Y virus (CYV), a mosquito-specific virus of the Birnaviridae family that was recently isolated from Culex pipiens mosquitoes. We found that the Culex RNAi machinery processes CYV double-stranded RNA (dsRNA) into viral small interfering RNAs (vsiRNAs). Furthermore, we show that RNAi is suppressed in CYV-infected cells and that the viral VP3 protein is responsible for RNAi antagonism. We demonstrate that VP3 can functionally replace B2, the well-characterized RNAi suppressor of Flock House virus. VP3 was found to bind long dsRNA as well as siRNAs and interfered with Dicer-2-mediated cleavage of long dsRNA into siRNAs. Slicing of target RNAs by pre-assembled RNA-induced silencing complexes was not affected by VP3. Finally, we show that the RNAi-suppressive activity of VP3 is conserved in Drosophila X virus, a birnavirus that persistently infects Drosophila cell cultures. Together, our data indicate that mosquito-specific viruses may encode RNAi antagonists to suppress antiviral RNAi.

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

    Science.gov (United States)

    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.

  8. Signaling mechanisms underlying group I mGluR-induced persistent AHP suppression in CA3 hippocampal neurons.

    Science.gov (United States)

    Young, Steven R; Bianchi, Riccardo; Wong, Robert K S

    2008-03-01

    Activation of group I metabotropic glutamate receptors (mGluRs) leads to a concerted modulation of spike afterpotentials in guinea pig hippocampal neurons including a suppression of both medium and slow afterhyperpolarizations (AHPs). Suppression of AHPs may be long-lasting, in that it persists after washout of the agonist. Here, we show that persistent AHP suppression differs from short-term, transient suppression in that distinct and additional signaling processes are required to render the suppression persistent. Persistent AHP suppression followed DHPG application for 30 min, but not DHPG application for 5 min. Persistent AHP suppression was temperature dependent, occurring at 30-31 degrees C, but not at 25-26 degrees C. Preincubation of slices in inhibitors of protein synthesis (cycloheximide or anisomycin) prevented the persistent suppression of AHPs by DHPG. Similarly, preincubation of slices in an inhibitor of p38 MAP kinase (SB 203580) prevented persistent AHP suppression. In contrast, a blocker of p42/44 MAP kinase activation (PD 98059) had no effect on persistent AHP suppression. Additionally, we show that the mGluR5 antagonist MPEP, but not the mGluR1 antagonist LY 367385, prevented DHPG-induced persistent AHP suppression. Thus persistent AHP suppression by DHPG in hippocampal neurons requires activation of mGluR5. In addition, activation of p38 MAP kinase signaling and protein synthesis are required to impart persistence to the DHPG-activated AHP suppression.

  9. Follistatin-like protein 1 suppressed pro-inflammatory cytokines expression during neuroinflammation induced by lipopolysaccharide.

    Science.gov (United States)

    Cheng, Kai-Yuan; Liu, Yi; Han, Ying-Guang; Li, Jing-Kun; Jia, Jia-Lin; Chen, Bin; Yao, Zhi-Xiao; Nie, Lin; Cheng, Lei

    2017-04-01

    Follistain-like protein 1 (FSTL1), has been recently demonstrated to be involved in the embryo development of nervous system and glioblastoma. However, the role of FSTL1 in neuroinflammation remains unexplored. In this study, the expression of FSTL1 in astrocytes was verified and its role was studied in neuroinflammation induced by in vivo intracerebroventricular (ICV) injection of lipopolysaccharide (LPS) or LPS treatment to astrocytes in vitro. FSTL1 was significantly induced after ICV LPS injection or LPS treatment. FSTL1 suppressed upregulation of pro-inflammatory cytokines in astrocytes after LPS treatment. Moreover, FSTL1 downregulated expression of pro-inflammatory cytokines through suppressing MAPK/p-ERK1/2 pathway in astrocytes. Our results suggest that FSTL1 may play an anti-inflammatory role in neuroinflammation mediated by astrocytes.

  10. Rebamipide suppresses mite-induced asthmatic responses in NC/Nga mice.

    Science.gov (United States)

    Murakami, Ikuo; Zhang, Ran; Kubo, Masayuki; Nagaoka, Kenjiro; Eguchi, Eri; Ogino, Keiki

    2015-10-15

    Allergic asthma caused by continuous allergen exposure evokes allergen-specific Th2 responses and is characterized by chronic airway inflammation and hyperresponsiveness. A previous report showed that rebamipide improved asthmatic symptoms in an ovalbumin/trypsin mice model. However, it is still unclear how rebamipide exerts its effects in asthma. In this study, rebamipide improved the asthmatic responses induced by mite exposure in NC/Nga mice, revealing the mechanism of this therapeutic effect. Rebamipide suppressed the infiltration of eosinophils into the airways and lung as well as attenuating the production of reactive oxygen species in tissues. In addition to these anti-inflammatory effects, rebamipide inhibited the production of IL-33, a member of the IL-1 family that drives the subsequent production of Th2-associated cytokines. These observations identify the point where rebamipide exerts its suppressive action on asthma and suggest that rebamipide has therapeutic potential in preventing mite-induced asthma. Copyright © 2015 the American Physiological Society.

  11. Hyperglycemia Induces Cellular Hypoxia through Production of Mitochondrial ROS Followed by Suppression of Aquaporin-1.

    Directory of Open Access Journals (Sweden)

    Kiminori Sada

    Full Text Available We previously proposed that hyperglycemia-induced mitochondrial reactive oxygen species (mtROS generation is a key event in the development of diabetic complications. Interestingly, some common aspects exist between hyperglycemia and hypoxia-induced phenomena. Thus, hyperglycemia may induce cellular hypoxia, and this phenomenon may also be involved in the pathogenesis of diabetic complications. In endothelial cells (ECs, cellular hypoxia increased after incubation with high glucose (HG. A similar phenomenon was observed in glomeruli of diabetic mice. HG-induced cellular hypoxia was suppressed by mitochondria blockades or manganese superoxide dismutase (MnSOD overexpression, which is a specific SOD for mtROS. Overexpression of MnSOD also increased the expression of aquaporin-1 (AQP1, a water and oxygen channel. AQP1 overexpression in ECs suppressed hyperglycemia-induced cellular hypoxia, endothelin-1 and fibronectin overproduction, and apoptosis. Therefore, hyperglycemia-induced cellular hypoxia and mtROS generation may promote hyperglycemic damage in a coordinated manner.

  12. Salidroside protects against kainic acid-induced status epilepticus via suppressing oxidative stress.

    Science.gov (United States)

    Si, Pei-Pei; Zhen, Jun-Li; Cai, Yun-Lei; Wang, Wen-Jing; Wang, Wei-Ping

    2016-04-01

    There are numerous mechanisms by which the brain generates seizures. It is well known that oxidative stress plays a pivotal role in status epilepticus (SE). Salidroside (SDS) extracted from Rhodiola rosea L. shows multiple bioactive properties, such as neuroprotection and antioxidant activity in vitro and in vivo. This study explored the role of SDS in kainic acid (KA)-induced SE and investigated the underlying mechanism. Latency to SE increased in the SDS-pretreated mice compared to the KA group, while the percentage of incidence of SE was significantly reduced. These results suggested that pretreatment with SDS not only delayed SE, but it also decreased the incidence of SE induced by KA. KA increased MDA level and reduced the production of SOD and GSH at multiple timepoints after KA administration. SDS inhibited the change of MDA, SOD and GSH induced by KA prior to SE onset, indicating that SDS protects against KA-induced SE via suppressing oxidative stress. Based on these results, we investigated the possible molecular mechanism of SDS. Pretreatment with SDS reversed the KA-induced decrease in AMP-activated protein kinase (AMPK); increased the sirtuin 1 (SIRT1) deacetylase activity in KA-treated mice, which had no demonstrable effect on SIRT1 mRNA and protein; and suppressed the KA-induced increase in Ace-FoxO1. These results showed that AMPK/SIRT1/FoxO1 signaling is possibly the molecular mechanism of neuroprotection by SDS.

  13. Luteolin suppresses TCDD-induced wasting syndrome in a cultured adipocyte model.

    Science.gov (United States)

    Ashida, Hitoshi; Harada, Kiyonari; Mishima, Sakiho; Mitani, Takakazu; Yamashita, Yoko; Matsumura, Fumio

    2015-05-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes various toxic effects, including wasting syndrome, through activation of an aryl hydrocarbon receptor (AhR). Our previous report demonstrated that certain flavonoids inhibit the activation of AhR and suppress its DNA binding activity. In this study, we searched for an active compound among 13 flavonoids that suppressed TCDD-induced loss of lipid accumulation using 3T3-L1 adipocytes as a cell culture model for wasting syndrome. Two flavonoids, luteolin and epigallocatechin gallate, suppressed TCDD-induced loss of lipid accumulation in this model. We further investigated luteolin to clarify the underlying molecular mechanism and confirmed that luteolin inhibited nuclear translocation of AhR caused by TCDD. Luteolin also inhibited the TCDD-driven decrease in protein expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα). Although TCDD alone did not change protein expression of C/EBPβ and C/EBPδ, luteolin and TCDD up-regulated C/EBPδ expression in a dose-dependent manner. On the other hand, TCDD significantly decreased DNA binding of C/EBPβ and C/EBPδ, and luteolin completely canceled TCDD-decreased DNA binding of them. We conclude that luteolin suppresses the TCDD-induced loss of lipid accumulation in 3T3-L1 adipocytes by preventing a decrease in protein expression of PPARγ and C/EBPα, the master regulators of adipocyte differentiation and in DNA binding of C/EBPβ and C/EBPδ. Moreover, luteolin was rapidly incorporated and accumulated in 3T3-L1 adipocytes. Thus, luteolin is an attractive compound for the prevention of TCDD-induced wasting syndrome.

  14. Conditions for coherent-synchrotron-radiation-induced microbunching suppression in multibend beam transport or recirculation arcs

    Science.gov (United States)

    Tsai, C.-Y.; Di Mitri, S.; Douglas, D.; Li, R.; Tennant, C.

    2017-02-01

    The coherent synchrotron radiation (CSR) of a high-brightness electron beam traversing a series of dipoles, such as transport or recirculation arcs, may result in beam phase space degradation. On one hand, CSR can perturb electron transverse motion in dispersive regions along the beam line and possibly cause emittance growth. On the other hand, the CSR effect on the longitudinal beam dynamics could result in microbunching instability. For transport arcs, several schemes have been proposed to suppress the CSR-induced emittance growth. Correspondingly, a few scenarios have been introduced to suppress CSR-induced microbunching instability, which however mostly aim for linac-based machines. In this paper we provide sufficient conditions for suppression of CSR-induced microbunching instability along transport or recirculation arcs. Examples are presented with the relevant microbunching analyses carried out by our developed semianalytical Vlasov solver [C.-Y. Tsai, D. Douglas, R. Li, and C. Tennant, Linear microbunching analysis for recirculation machines, Phys. Rev. ST Accel. Beams 19, 114401 (2016), 10.1103/PhysRevAccelBeams.19.114401]. The example lattices include low-energy (˜100 MeV ) and high-energy (˜1 GeV ) recirculation arcs, and medium-energy compressor arcs. Our studies show that lattices satisfying the proposed conditions indeed have microbunching gain suppressed. Beam current dependences of maximal CSR microbunching gains are also demonstrated, which should help outline a beam line design for different scales of nominal currents. We expect this analysis can shed light on the lattice design approach that aims to control the CSR-induced microbunching.

  15. Conditions for coherent-synchrotron-radiation-induced microbunching suppression in multibend beam transport or recirculation arcs

    Directory of Open Access Journals (Sweden)

    C.-Y. Tsai

    2017-02-01

    Full Text Available The coherent synchrotron radiation (CSR of a high-brightness electron beam traversing a series of dipoles, such as transport or recirculation arcs, may result in beam phase space degradation. On one hand, CSR can perturb electron transverse motion in dispersive regions along the beam line and possibly cause emittance growth. On the other hand, the CSR effect on the longitudinal beam dynamics could result in microbunching instability. For transport arcs, several schemes have been proposed to suppress the CSR-induced emittance growth. Correspondingly, a few scenarios have been introduced to suppress CSR-induced microbunching instability, which however mostly aim for linac-based machines. In this paper we provide sufficient conditions for suppression of CSR-induced microbunching instability along transport or recirculation arcs. Examples are presented with the relevant microbunching analyses carried out by our developed semianalytical Vlasov solver [C.-Y. Tsai, D. Douglas, R. Li, and C. Tennant, Linear microbunching analysis for recirculation machines, Phys. Rev. ST Accel. Beams 19, 114401 (2016PRABFM1098-440210.1103/PhysRevAccelBeams.19.114401]. The example lattices include low-energy (∼100  MeV and high-energy (∼1  GeV recirculation arcs, and medium-energy compressor arcs. Our studies show that lattices satisfying the proposed conditions indeed have microbunching gain suppressed. Beam current dependences of maximal CSR microbunching gains are also demonstrated, which should help outline a beam line design for different scales of nominal currents. We expect this analysis can shed light on the lattice design approach that aims to control the CSR-induced microbunching.

  16. Probiotic Cheese Attenuates Exercise-induced Immune Suppression In Wistar Rats

    OpenAIRE

    Lollo P.C.B.; Cruz A.G.; Morato P.N.; Moura C.S.; Carvalho-Silva L.B.; Oliveira C.A.F.; Faria J.A.F.; Amaya-Farfan J.

    2012-01-01

    Intense physical activity results in a substantial volume of stress and hence a significant probability of immunosuppression in athletes, with milk proteins being, perhaps, the most recommended protein supplements. Consumption of a probiotic cheese can attenuate immune suppression induced by exhausting exercise in rats. A popular Brazilian fresh cheese (Minas Frescal cheese) containing Lactobacillus acidophilus LA14 and Bifidobacterium longum BL05 was fed for 2 wk to adult Wistar rats, which ...

  17. Suppression of dislocations at high strain rate deformation in a twinning-induced plasticity steel

    Energy Technology Data Exchange (ETDEWEB)

    Liang, Z.Y. [Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen (China); Department of Mechanical Engineering, The University of Hong Kong, Hong Kong (China); Huang, W., E-mail: whuang@szu.edu.cn [Department of Civil Engineering, Shenzhen University, Shenzhen (China); Huang, M.X., E-mail: mxhuang@hku.hk [Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen (China); Department of Mechanical Engineering, The University of Hong Kong, Hong Kong (China)

    2015-03-25

    The increase of strain rate generally enhances dislocation evolution in face-centred cubic (FCC) metals. However, by synchrotron X-ray diffraction experiments, the present work demonstrates for the first time that a higher strain rate leads to a lower dislocation density in a twinning-induced plasticity steel with an FCC structure. This unexpected suppression of dislocation evolution has been attributed to the temperature increase due to dissipative heating at high strain rate deformation.

  18. Selective Suppression of Local Circuits during Movement Preparation in the Mouse Motor Cortex

    Directory of Open Access Journals (Sweden)

    Masashi Hasegawa

    2017-03-01

    Full Text Available Prepared movements are more efficient than those that are not prepared for. Although changes in cortical activity have been observed prior to a forthcoming action, the circuits involved in motor preparation remain unclear. Here, we use in vivo two-photon calcium imaging to uncover changes in the motor cortex during variable waiting periods prior to a forepaw reaching task in mice. Consistent with previous reports, we observed a subset of neurons with increased activity during the waiting period; however, these neurons did not account for the degree of preparation as defined by reaction time (RT. Instead, the suppression of activity of distinct neurons in the same cortical area better accounts for RT. This suppression of neural activity resulted in a distinct and reproducible pattern when mice were well prepared. Thus, the selective suppression of network activity in the motor cortex may be a key feature of prepared movements.

  19. Coumestrol Counteracts Interleukin-1β-Induced Catabolic Effects by Suppressing Inflammation in Primary Rat Chondrocytes.

    Science.gov (United States)

    You, Jae-Seek; Cho, In-A; Kang, Kyeong-Rok; Oh, Ji-Su; Yu, Sang-Joun; Lee, Gyeong-Je; Seo, Yo-Seob; Kim, Su-Gwan; Kim, Chun Sung; Kim, Do Kyung; Im, Hee-Jeong; Kim, Jae-Sung

    2017-02-01

    In the present study, we investigated the anti-catabolic effects of coumestrol, a phytoestrogen derived from herbal plants, against interleukin-1β-induced cartilage degeneration in primary rat chondrocytes and articular cartilage. Coumestrol did not affect the viability of human normal oral keratinocytes and primary rat chondrocytes treated for 24 h and 21 days, respectively. Although coumestrol did not significantly increase the proteoglycan contents in long-term culture, it abolished the interleukin-1β-induced loss of proteoglycans in primary rat chondrocytes and knee articular cartilage. Furthermore, coumestrol suppressed the expression of matrix-degrading enzymes such as matrix metalloproteinase-13, -3, and -1 in primary rat chondrocytes stimulated with interleukin-1β. Moreover, the expression of catabolic factors such as nitric oxide synthase, cyclooxygenase-2, prostaglandin E2, and inflammatory cytokines in interleukin-1β-stimulated primary rat chondrocytes was suppressed by coumestrol. In summary, these results indicate that coumestrol counteracts the catabolic effects induced by interleukin-1β through the suppression of inflammation. Therefore, based on its biological activity and safety profile, coumestrol could be used as a potential anti-catabolic biomaterial for osteoarthritis.

  20. Asparagine deprivation mediated by Salmonella asparaginase causes suppression of activation-induced T cell metabolic reprogramming.

    Science.gov (United States)

    Torres, AnnMarie; Luke, Joanna D; Kullas, Amy L; Kapilashrami, Kanishk; Botbol, Yair; Koller, Antonius; Tonge, Peter J; Chen, Emily I; Macian, Fernando; van der Velden, Adrianus W M

    2016-02-01

    Salmonellae are pathogenic bacteria that induce immunosuppression by mechanisms that remain largely unknown. Previously, we showed that a putative type II l-asparaginase produced by Salmonella Typhimurium inhibits T cell responses and mediates virulence in a murine model of infection. Here, we report that this putative L-asparaginase exhibits L-asparagine hydrolase activity required for Salmonella Typhimurium to inhibit T cells. We show that L-asparagine is a nutrient important for T cell activation and that L-asparagine deprivation, such as that mediated by the Salmonella Typhimurium L-asparaginase, causes suppression of activation-induced mammalian target of rapamycin signaling, autophagy, Myc expression, and L-lactate secretion. We also show that L-asparagine deprivation mediated by the Salmonella Typhimurium L-asparaginase causes suppression of cellular processes and pathways involved in protein synthesis, metabolism, and immune response. Our results advance knowledge of a mechanism used by Salmonella Typhimurium to inhibit T cell responses and mediate virulence, and provide new insights into the prerequisites of T cell activation. We propose a model in which l-asparagine deprivation inhibits T cell exit from quiescence by causing suppression of activation-induced metabolic reprogramming.

  1. The skin microbiome: Is it affected by UV-induced immune suppression?

    Directory of Open Access Journals (Sweden)

    Vijaykumar Patra

    2016-08-01

    Full Text Available Human skin apart from functioning as a physical barricade to stop the entry of pathogens, also hosts innumerable commensal organisms. The skin cells and the immune system constantly interact with microbes, to maintain cutaneous homeostasis, despite the challenges offered by various environmental factors. A major environmental factor affecting the skin is ultraviolet radiation UV-R from sunlight. UV-R is well known to modulate the immune system, which can be both beneficial and deleterious. By targeting the cells and molecules within skin, UV-R can trigger the production and release of antimicrobial peptides (AMPs, affect the innate immune system and ultimately suppress the adaptive cellular immune response. This can contribute to skin carcinogenesis and the promotion of infectious agents such as herpes simplex virus and possibly others. On the other hand, a UV-established immunosuppressive environment may protect against the induction of immunologically mediated skin diseases including some of photodermatoses such as polymorphic light eruption. In this article, we share our perspective about the possibility that UV-induced immune suppression may alter the landscape of the skin's microbiome and its components. Alternatively, or in concert with this, direct UV-induced DNA and membrane damage to the microbiome may result in pathogen associated molecular patterns (PAMPs that interfere with UV-induced immune suppression.

  2. Epigallocatechin gallate (EGCG) suppresses lipopolysaccharide-induced inflammatory bone resorption, and protects against alveolar bone loss in mice.

    Science.gov (United States)

    Tominari, Tsukasa; Matsumoto, Chiho; Watanabe, Kenta; Hirata, Michiko; Grundler, Florian M W; Miyaura, Chisato; Inada, Masaki

    2015-01-01

    Epigallocatechin gallate (EGCG), a major polyphenol in green tea, possesses antioxidant properties and regulates various cell functions. Here, we examined the function of EGCG in inflammatory bone resorption. In calvarial organ cultures, lipopolysaccharide (LPS)-induced bone resorption was clearly suppressed by EGCG. In osteoblasts, EGCG suppressed the LPS-induced expression of COX-2 and mPGES-1 mRNAs, as well as prostaglandin E2 production, and also suppressed RANKL expression, which is essential for osteoclast differentiation. LPS-induced bone resorption of mandibular alveolar bones was attenuated by EGCG in vitro, and the loss of mouse alveolar bone mass was inhibited by the catechin in vivo.

  3. Role of Metabolism by Intestinal Bacteria in Arbutin-Induced Suppression of Lymphoproliferative Response in vitro

    Science.gov (United States)

    Kang, Mi Jeong; Ha, Hyun Woo; Kim, Ghee Hwan; Lee, Sang Kyu; Ahn, Young Tae; Kim, Dong Hyun; Jeong, Hye Gwang; Jeong, Tae Cheon

    2012-01-01

    Role of metabolism by intestinal bacteria in arbutin-induced immunotoxicity was investigated in splenocyte cultures. Following an incubation of arbutin with 5 different intestinal bacteria for 24 hr, its aglycone hydroquinone could be produced and detected in the bacterial culture media with different amounts. Toxic effects of activated arbutin by intestinal bacteria on lymphoproliferative response were tested in splenocyte cultures from normal mice. Lipopolysaccharide and concanavalin A were used as mitogens for B- and T-cells, respectively. When bacteria cultured medium with arbutin was treated into the splenocytes for 3 days, the medium cultured with bacteria producing large amounts of hydroquinone induced suppression of lymphoproliferative responses, indicating that metabolic activation by intestinal bacteria might be required in arbutin-induced toxicity. The results indicated that the present testing system might be applied for determining the possible role of metabolism by intestinal bacteria in certain chemical-induced immunotoxicity in animal cell cultures. PMID:24116295

  4. Epigallocatechin-3-gallate attenuates lipopolysaccharide-induced mastitis in rats via suppressing MAPK mediated inflammatory responses and oxidative stress.

    Science.gov (United States)

    Chen, Jinglou; Xu, Jun; Li, Jingjing; Du, Lifen; Chen, Tao; Liu, Ping; Peng, Sisi; Wang, Mingwei; Song, Hongping

    2015-05-01

    Green tea (Camellia sinensis) is an extremely popular beverage worldwide. Epigallocatechin-3-gallate (EGCG) is one of the major catechins isolated from green tea and contributes to its beneficial therapeutic functions including antioxidant, anti-inflammatory and anti-cancer effects. However, the effect of EGCG on mastitis is not yet known. This study was to investigate the protective potential of EGCG against mastitis in rats. The rat mastitis model was induced by injecting lipopolysaccharide (LPS) into the duct of mammary gland. The mammary gland was collected after the experimental period. The levels of mammary oxidative stress and inflammatory responses were assessed by measuring the local activities of antioxidant enzymes and the levels of inflammatory cytokines. The mammary expressions of mitogen-activated protein kinases (MAPKs), nuclear factor κB-p65 (NFκB-p65) and hypoxia-inducible factor-1α (HIF-1α) were evaluated by western blot analysis. It was found that EGCG obviously normalized LPS-induced low activities of antioxidant enzymes as well as decreased the high levels of inflammatory cytokines. Additionally, EGCG inhibited the mammary over-expression of MAPKs, NFκB-p65 and HIF-1α. These results indicated that EGCG was able to attenuate LPS-induced mastitis in rats by suppressing MAPK related oxidative stress and inflammatory responses. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. The avian head induces cues for sound localization in elevation.

    Directory of Open Access Journals (Sweden)

    Hans A Schnyder

    Full Text Available Accurate sound source localization in three-dimensional space is essential for an animal's orientation and survival. While the horizontal position can be determined by interaural time and intensity differences, localization in elevation was thought to require external structures that modify sound before it reaches the tympanum. Here we show that in birds even without external structures like pinnae or feather ruffs, the simple shape of their head induces sound modifications that depend on the elevation of the source. Based on a model of localization errors, we show that these cues are sufficient to locate sounds in the vertical plane. These results suggest that the head of all birds induces acoustic cues for sound localization in the vertical plane, even in the absence of external ears.

  6. The avian head induces cues for sound localization in elevation.

    Science.gov (United States)

    Schnyder, Hans A; Vanderelst, Dieter; Bartenstein, Sophia; Firzlaff, Uwe; Luksch, Harald

    2014-01-01

    Accurate sound source localization in three-dimensional space is essential for an animal's orientation and survival. While the horizontal position can be determined by interaural time and intensity differences, localization in elevation was thought to require external structures that modify sound before it reaches the tympanum. Here we show that in birds even without external structures like pinnae or feather ruffs, the simple shape of their head induces sound modifications that depend on the elevation of the source. Based on a model of localization errors, we show that these cues are sufficient to locate sounds in the vertical plane. These results suggest that the head of all birds induces acoustic cues for sound localization in the vertical plane, even in the absence of external ears.

  7. The Cell Death Triggered by the Nuclear Localized RxLR Effector PITG_22798 from Phytophthora infestans Is Suppressed by the Effector AVR3b.

    Science.gov (United States)

    Wang, Hongyang; Ren, Yajuan; Zhou, Jing; Du, Juan; Hou, Juan; Jiang, Rui; Wang, Haixia; Tian, Zhendong; Xie, Conghua

    2017-02-14

    Phytopathogenic oomycetes, such as Phytophthora infestans, potentially secrete many RxLR effector proteins into plant cells to modulate plant immune responses and promote colonization. However, the molecular mechanisms by which these RxLR effectors suppress plant immune responses are largely unknown. Here we describe an RxLR effector PITG_22798 (Gene accession: XM_002998349) that was upregulated during early infection of potato by P. infestans. By employment of agroinfiltration, we observed that PITG_22798 triggers cell death in Nicotiana benthamiana. Confocal microscopic examination showed that PITG_22798-GFP (Green Fluorescent Protein) located in the host nucleus when expressed transiently in N. benthamiana leaves. A nuclear localization signal (NLS) domain of PITG_22798 is important for nuclear localization and cell death-inducing activity. Sequence alignment and transient expression showed that PITG_22798 from diverse P. infestans isolates are conserved, and transient expression of PITG_22798 enhances P. infestans colonization of N. benthamiana leaves, which suggests that PITG_22798 contributes to P. infestans infection. PITG_22798-triggered cell death is dependent on SGT1-mediated signaling and is suppressed by the P. infestans avirulence effector 3b (AVR3b). The present research provides a clue for further investigation of how P. infestans effector PITG_22798 associates with and modulates host immunity.

  8. Changes induced by Trichoderma harzianum in suppressive compost controlling Fusarium wilt.

    Science.gov (United States)

    Blaya, Josefa; López-Mondéjar, Rubén; Lloret, Eva; Pascual, Jose Antonio; Ros, Margarita

    2013-09-01

    The addition of species of Trichoderma to compost is a widespread technique used to control different plant diseases. The biological control activity of these species is mainly attributable to a combination of several mechanisms of action, which may affect the microbiota involved in the suppressiveness of compost. This study was therefore performed to determine the effect of inoculation of Trichoderma harzianum (T. harzianum) on compost, focusing on bacterial community structure (16S rRNA) and chitinase gene diversity. In addition, the ability of vineyard pruning waste compost, amended (GCTh) or not (GC) with T. harzianum, to suppress Fusarium wilt was evaluated. The addition of T. harzianum resulted in a high relative abundance of certain chitinolytic bacteria as well as in remarkable protection against Fusarium oxysporum comparable to that induced by compost GC. Moreover, variations in the abiotic characteristics of the media, such as pH, C, N and iron levels, were observed. Despite the lower diversity of chitinolytic bacteria found in GCTh, the high relative abundance of Streptomyces spp. may be involved in the suppressiveness of this growing media. The higher degree of compost suppressiveness achieved after the addition of T. harzianum may be due not only to its biocontrol ability, but also to changes promoted in both abiotic and biotic characteristics of the growing media.

  9. Suppression of ion-implantation induced porosity in germanium by a silicon dioxide capping layer

    Science.gov (United States)

    Tran, Tuan T.; Alkhaldi, Huda S.; Gandhi, Hemi H.; Pastor, David; Huston, Larissa Q.; Wong-Leung, Jennifer; Aziz, Michael J.; Williams, J. S.

    2016-08-01

    Ion implantation with high ion fluences is indispensable for successful use of germanium (Ge) in the next generation of electronic and photonic devices. However, Ge readily becomes porous after a moderate fluence implant ( ˜1 ×1015 ion cm-2 ) at room temperature, and for heavy ion species such as tin (Sn), holding the target at liquid nitrogen (LN2) temperature suppresses porosity formation only up to a fluence of 2 ×1016 ion cm-2 . We show, using stylus profilometry and electron microscopy, that a nanometer scale capping layer of silicon dioxide significantly suppresses the development of the porous structure in Ge during a S n - implant at a fluence of 4.5 ×1016 ion cm-2 at LN2 temperature. The significant loss of the implanted species through sputtering is also suppressed. The effectiveness of the capping layer in preventing porosity, as well as suppressing sputter removal of Ge, permits the attainment of an implanted Sn concentration in Ge of ˜15 at.% , which is about 2.5 times the maximum value previously attained. The crystallinity of the Ge-Sn layer following pulsed-laser-melting induced solidification is also greatly improved compared with that of uncapped material, thus opening up potential applications of the Ge-Sn alloy as a direct bandgap material fabricated by an ion beam synthesis technique.

  10. Lift Enhancement and Oscillatory Suppression of Vortex-induced Vibration in Shear Flow by Loentz Force

    Institute of Scientific and Technical Information of China (English)

    张辉; 范宝春; 李鸿志

    2012-01-01

    The flow of the weak electrolyte solution can be controlled by Lorentz force achieved with the suitable magnetic and electric fields, and it has the advantages of vortex street suppression, drag reduction, lift enhancement and oscillatory suppression for the flow over a bluff body. The electro-magnetic control of vortex-induced vibration (VIV) of a circular cyl- inder in the shear flow was investigated numerically in the exponential-polar coordinates attached on the moving cylinder for Re = 150. With the effect of background vorticity, the vortex street of VIV cylinder was composed of two parallel rows with an opposite sign of the vortices which inclines toward the lower side and the strength of upper vortex is larger than that of lower vortex. The lift force vibrated periodically with the effect of vortex shedding and the mean value was negative due to the background vorticity. The Lorentz force for controlling the VIV cylinder was classified into the field Lorentz force and the wall Lorentz force. The field Lorentz force suppresses the lift oscillation, and in turn, suppresses the VIV, whereas the wall Loreutz force increases the lift.

  11. Transcutaneous carbon dioxide induces mitochondrial apoptosis and suppresses metastasis of oral squamous cell carcinoma in vivo.

    Directory of Open Access Journals (Sweden)

    Daisuke Takeda

    Full Text Available Squamous cell carcinoma (SCC is the main histological type of oral cancer. Its growth rate and incidence of metastasis to regional lymph nodes is influenced by various factors, including hypoxic conditions. We have previously reported that transcutaneous CO2 induces mitochondrial apoptosis and decreases lung metastasis by reoxygenating sarcoma cells. However, previous studies have not determined the sequential mechanism by which transcutaneous CO2 suppresses growth of epithelial tumors, including SCCs. Moreover, there is no report that transcutaneous CO2 suppresses lymphogenous metastasis using human cell lines xenografts. In this study, we examined the effects of transcutaneous CO2 on cancer apoptosis and lymphogenous metastasis using human SCC xenografts. Our results showed that transcutaneous CO2 affects expressions of PGC-1α and TFAM and protein levels of cleavage products of caspase-3, caspase-9 and PARP, which relatives mitochondrial apoptosis. They also showed that transcutaneous CO2 significantly inhibits SCC tumor growth and affects expressions of HIF-1α, VEGF, MMP-2 and MMP-9, which play essential roles in tumor angiogenesis, invasion and metastasis. In conclusion, transcutaneous CO2 suppressed tumor growth, increased mitochondrial apoptosis and decreased the number of lymph node metastasis in human SCC by decreasing intra-tumoral hypoxia and suppressing metastatic potential with no observable effect in vivo. Our findings indicate that transcutaneous CO2 could be a novel therapeutic tool for treating human SCC.

  12. Antagonistic effect of polyamines on ABA-induced suppression of mitosis in Allium cepa L.

    Science.gov (United States)

    Mahajan, Arpana; Sharma, Shashi

    2009-02-01

    Effect of abscisic acid (ABA) and polyamines (PAs) [putrescine (Put), spermidine (Spd) and spermine (Spm)] on mitosis in root tips of A. cepa was studied. Treatment with ABA (0.1 to 100 microM) for 24 hr suppressed the mitosis, measured as mitotic index (MI), in a concentration-dependent manner with approx. 50% suppression at 10 microM of ABA. Treatment with different PAs (1 to 100 microM) had differential mitosis suppression effect. Spm was most inhibitory followed by Spd and Put, respectively. The higher concentrations of PAs (1 mM Put; 0.1 and 1 mM Spd or Spm) caused cell distortion. Remarkably, a 24 hr pretreatment of root tips with PAs prior to ABA (100 microM) treatment resulted in a general concentration-dependent reversal of ABA-induced suppression of MI. Catalase (CAT) activity in the root tips, an indicator of redox metabolism, increased due to ABA treatment in a concentration-dependent manner, remained unaltered in response to Put and declined due to Spd and Spm (> or = 0.1 mM). However, all PAs, irrespective of their individual effects, generally antagonized the ABA-dependent increase in CAT activity. Data indicate the possibility of ABA-PA interaction in the regulation of mitosis.

  13. Serum thymic factor, FTS, attenuates cisplatin nephrotoxicity by suppressing cisplatin-induced ERK activation.

    Science.gov (United States)

    Kohda, Yuka; Kawai, Yoshiko; Iwamoto, Noriaki; Matsunaga, Yoshiko; Aiga, Hiromi; Awaya, Akira; Gemba, Munekazu

    2005-11-01

    Serum thymic factor (FTS), a thymic peptide hormone, has been reported to attenuate the bleomycin-induced pulmonary injury and also experimental pancreatitis and diabetes. In the present study, we investigated the effect of FTS on cis-diamminedichloroplatinum II (cisplatin)-induced nephrotoxicity. We have already demonstrated that cephaloridine, a nephrotoxic antibiotic, leads to extracellular signal-regulated protein kinase (ERK) activation in the rat kidney, which probably contributes to cephaloridine-induced renal dysfunction. The aim of this study was to examine the effect of cisplatin on ERK activation in the rat kidney and also the effect of FTS on cisplatin-induced nephrotoxicity in rats. In vitro treatment of LLC-PK1 cells with FTS significantly ameliorated cisplatin-induced cell injury. Treatment of rats with intravenous cisplatin for 3 days markedly induced renal dysfunction and increased platinum contents in the kidney cortex. An increase in pERK was detected in the nuclear fraction prepared from the rat kidney cortex from days 1 to 3 after injection of cisplatin. FTS suppressed cisplatin-induced renal dysfunction and ERK activation in the kidney. FTS did not influence any Pt contents in the kidney after cisplatin administration. FTS has been shown to enhance the in vivo expression of heat shock protein (HSP) 70 in the kidney cortex. The beneficial role of FTS against cisplatin nephrotoxicity may be mediated in part by HSP70, as suggested by its up-regulation in the kidney cortex treated with FTS alone. Our results suggest that FTS participates in protection from cisplatin-induced nephrotoxicity by suppressing ERK activation caused by cisplatin.

  14. Glutamine synthetase localization in cortisol-induced chick embryo retinas

    OpenAIRE

    1980-01-01

    We report here for the first time, in chick retina, Muller cell localization of glutamine synthetase (GS) activity by an immunohistochemical technique, in agreement with previous reports of glial localization of this enzyme in rat brain and retina. Age- dependent changes in the endogenous enzyme activity as well as cortisol- induced changes in GS activity, both in ovo and in vitro, measured biochemically, reflect the changes observed by staining.

  15. Suppression of wind-induced vibrations of a seesaw-type oscillator by means of a dynamic absorber

    NARCIS (Netherlands)

    Lumbantobing, H.

    2003-01-01

    In this paper the suppression of wind-induced vibrations of a seesaw-type oscillator by means of a dynamic absorber is considered. With suppression the shift of the critical flow velocity to higher values as well as the reduction of vibration amplitudes is meant. The equations of motion are derived

  16. Protection Against Lung Cancer Patient Plasma-Induced Lymphocyte Suppression by Ganoderma Lucidum Polysaccharides

    Directory of Open Access Journals (Sweden)

    Li-Xin Sun

    2014-01-01

    Full Text Available Background/Aims: This study was conducted to determine the potential of Ganoderma lucidum polysaccharides (Gl-PS in protection against lung cancer patient plasma-induced suppression of lymphocytes. Lung cancer is a major cause of disease and loss of life in the United States and worldwide. Cancer cells release immunosuppressive mediators, such as PGE2, TGF-β, IL-10, and VEGF, to inhibit the immune response to escape from immune surveillance. Gl-PS has been shown to counteract this immune inhibition in an animal cell culture model, and thus to facilitate tumor control. The present study explored whether or not such an effect could also be demonstrated in human lung cancer patients. Methods: Immunofluorescence, flow cytometry, MTT, immunocytochemistry, and western blot analysis were used to assess lymphocyte activation with PHA. Results: The plasma of lung cancer patients suppressed proliferation, CD69 expression, and perforin and granzyme B production in lymphocytes upon activation by PHA, effects that were partially of fully reversed by Gl-PS. Conclusion: Lung cancer patient plasma-induced suppression of lymphocyte activation by phytohemagglutinin may be antagonized fully or partially by Gl-PS, an observation suggesting the potential of Gl-PS in cancer therapy.

  17. Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Phuoc T Tran

    Full Text Available KRAS mutant lung cancers are generally refractory to chemotherapy as well targeted agents. To date, the identification of drugs to therapeutically inhibit K-RAS have been unsuccessful, suggesting that other approaches are required. We demonstrate in both a novel transgenic mutant Kras lung cancer mouse model and in human lung tumors that the inhibition of Twist1 restores a senescence program inducing the loss of a neoplastic phenotype. The Twist1 gene encodes for a transcription factor that is essential during embryogenesis. Twist1 has been suggested to play an important role during tumor progression. However, there is no in vivo evidence that Twist1 plays a role in autochthonous tumorigenesis. Through two novel transgenic mouse models, we show that Twist1 cooperates with Kras(G12D to markedly accelerate lung tumorigenesis by abrogating cellular senescence programs and promoting the progression from benign adenomas to adenocarcinomas. Moreover, the suppression of Twist1 to physiological levels is sufficient to cause Kras mutant lung tumors to undergo senescence and lose their neoplastic features. Finally, we analyzed more than 500 human tumors to demonstrate that TWIST1 is frequently overexpressed in primary human lung tumors. The suppression of TWIST1 in human lung cancer cells also induced cellular senescence. Hence, TWIST1 is a critical regulator of cellular senescence programs, and the suppression of TWIST1 in human tumors may be an effective example of pro-senescence therapy.

  18. Adiponectin Suppresses UVB-Induced Premature Senescence and hBD2 Overexpression in Human Keratinocytes.

    Science.gov (United States)

    Kim, MinJeong; Park, Kui Young; Lee, Mi-Kyung; Jin, Taewon; Seo, Seong Jun

    2016-01-01

    Recent studies have revealed that adiponectin can suppress cellular inflammatory signaling pathways. This study aimed to elucidate the effect of adiponectin on the unregulated production of hBD2 in UVB-induced premature senescent keratinocytes. We constructed an in vitro model of premature senescent keratinocytes through repeated exposure to low energy UVB. After repeated low energy UVB exposure, there was significant generation of reactive oxygen species (ROS) and induction of senescence-associated markers, including senescence associated beta-galactosidase activity and expression of p16INK4a and histone H2AX. In addition, the present clinical study showed higher expression of hBD2 in sun-exposed skin of elderly group, and the overexpression of hBD2 was observed by c-Fos activation in vitro. Adiponectin has the ability to scavenge ROS and consequently inhibit MAPKs and SA-markers in UVB-exposed keratinocytes. An inhibitor study demonstrated that adiponectin downregulated hBD2 mRNA expression through suppression of the AP-1 transcription factor components c-Fos via inactivation of p38 MAPK. Collectively, the dysregulated production of hBD2 by the induction of oxidative stress was attenuated by adiponectin through the suppression of p38 and JNK/SAPK MAPK signaling in UVB-mediated premature senescent inducible conditions. These results suggest the feasibility of adiponectin as an anti-photoaging and anti-inflammatory agent in the skin.

  19. Curcumol suppresses RANKL-induced osteoclast formation by attenuating the JNK signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Mingxiang, E-mail: yu.mingxiang@zs-hospital.sh.cn [Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai (China); Chen, Xianying [Department of Endocrinology and Metabolism, Hainan Provincial Nong Ken Hospital, Hainan (China); Lv, Chaoyang [Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai (China); Yi, Xilu [Department of Endocrinology and Metabolism, Shanghai Songjiang District Central Hospital, Shanghai (China); Zhang, Yao; Xue, Mengjuan; He, Shunmei [Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai (China); Zhu, Guoying [Institute of Radiation Medicine, Fudan University, Shanghai (China); Wang, Hongfu, E-mail: hfwang@shmu.edu.cn [Institute of Radiation Medicine, Fudan University, Shanghai (China)

    2014-05-02

    Highlights: • Curcumol suppresses osteoclasts differentiation in vitro. • Curcumol impairs JNK/AP-1 signaling pathway. • Curcumol may be used for treating osteoclast related diseases. - Abstract: Osteoclasts, derived from hemopoietic progenitors of the monocyte/macrophage lineage, have a unique role in bone resorption, and are considered a potential therapeutic target in the treatment of such pathologic bone diseases as osteoporosis, rheumatoid arthritis, and periodontitis. In the present study, we demonstrate that curcumol, one of the major components of the essential oil of Rhizoma Curcumae, exhibits an inhibitory effect on receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast differentiation with both bone marrow-derived macrophages and RAW264.7 cells in a dose-dependent manner. In addition, RANKL-induced mRNA expression of osteoclast-specific genes, such as tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K, is prominently reduced in the presence of curcumol. Furthermore, the molecular mechanism of action was investigated, and curcumol inhibited osteoclastogenesis by specifically impairing RANKL-induced c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) signaling, which was further identified in rescue studies by means of anisomycin, a JNK signaling-specific activator. Taken together, these findings suggest that curcumol suppresses RANKL-induced osteoclast differentiation through the JNK/AP-1 signaling pathway, and may be useful as a therapeutic treatment for bone resorption-associated diseases.

  20. Dietary selenium protect against redox-mediated immune suppression induced by methylmercury exposure.

    Science.gov (United States)

    Li, Xuan; Yin, Daqiang; Yin, Jiaoyang; Chen, Qiqing; Wang, Rui

    2014-10-01

    The antagonism between selenium (Se) and mercury (Hg) has been widely recognized, however, the protective role of Se against methylmercury (MeHg) induced immunotoxicity and the underlying mechanism is still unclear. In the current study, MeHg exposure (0.01 mM via drinking water) significantly inhibited the lymphoproliferation and NK cells functions of the female Balb/c mice, while dietary Se supplementation (as Se-rich yeast) partly or fully recovered the observed immunotoxicity, indicating the protective role of Se against MeHg-induced immune suppression in mice. Besides, MeHg exposure promoted the generation of the reactive oxygen species (ROS), reduced the levels of nonenzymic and enzymic antioxidants in target organs, while dietary Se administration significantly diminished the MeHg-induced oxidative stress and subsequent cellular dysfunctions (lipid peroxidation and protein oxidation). Two possible mechanisms of Se's protective effects were further revealed. Firstly, the reduction of mercury concentrations (less than 25%, modulated by Se supplementation) in the target organs might contribute, but not fully explain the alleviated immune suppression. Secondly and more importantly, Se could help to maintain/or elevate the activities of several key antioxidants, therefore protect the immune cells against MeHg-induced oxidative damage.

  1. Periploca forrestii Saponin Ameliorates Murine CFA-Induced Arthritis by Suppressing Cytokine Production.

    Science.gov (United States)

    Liu, Yingqin; Li, Minghui; He, Qiuhong; Yang, Xinping; Ruan, Fang; Sun, Guangchen

    2016-01-01

    Periploca forrestii Schltr. has been used as a Chinese folk medicine due to its versatile pharmacological effects such as promoting wounds and rheumatoid arthritis. However, the antiarthritic activity of Periploca forrestii saponin (PFS) and its active compound Periplocin has still not been demonstrated. Here, we evaluated the antiarthritic effects of PFS in adjuvant-induced arthritis (AIA) rats by intragastric administration at a dose of 50 mg/kg. The anti-inflammatory activities of Periplocin were also examined in LPS-induced AIA splenocytes and synoviocytes. PFS significantly ameliorated joint swelling; inhibited bone erosion in joints; lowered levels of IL-6 and TGF-β1 in AIA rat splenocyte; and reduced joint protein expression levels of phospho-STAT3 and IKKα. Using LPS-induced AIA splenocytes, we demonstrate that Periplocin suppressed the key proinflammatory cytokines levels of IL-6, IFN-γ, TGF-β1, and IL-13 and IL-22 and transcription factor levels of T-bet, GATA3, and C-Jun genes. Periplocin also suppressed LPS-induced cytokine secretion from synoviocytes. Our study highlights the antiarthritic activity of PFS and its derived Periplocin and the underlying mechanisms. These results provide a strong rationale for further testing and validation of the use of Periploca forrestii Schltr. as an alternative modality for the treatment of RA.

  2. Heparin suppresses cyclosporine-induced endothelin-1 synthesis in rat endothelial cells.

    Science.gov (United States)

    Yokokawa, K; Kohno, M; Minami, M; Yasunari, K; Mandal, A K; Yoshikawa, J

    1998-01-01

    Cyclosporine stimulates vasoconstrictor endothelin-1 (ET-1) synthesis. This study examined the effect of heparin on cyclosporine-induced ET-1 synthesis in Wistar rat aortic endothelial cells in culture. Cyclosporine (0.01-5 mumol/L) stimulated ET-1 mRNA expression in a dose-dependent manner. A nitric oxide synthesis inhibitor, NG-monomethyl-L-arginine (L-NMMA) (10(-5) mol/L), did not affect cyclosporine-induced ET-1 mRNA expression. Heparin (1-20 U/ml) suppressed cyclosporine-induced ET-1 mRNA expression in a dose-dependent manner. The inhibitory effect of heparin was blunted in the presence of either L-NMMA (10(-5) mol/L) or calmodulin inhibitors such as N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) (5 x 10(-5) mol/L) or calmidazolium (5 x 10(-5) mol/L) in the presence of the phosphodiesterase inhibitor 3-isobutyl 1-methylxanthine (0.1 mmol/L). These results suggest that heparin suppresses cyclosporine-induced ET-1 mRNA expression via both NO- and calmodulin-dependent pathways.

  3. Doxycycline Attenuates Leptospira-Induced IL-1β by Suppressing NLRP3 Inflammasome Priming

    Directory of Open Access Journals (Sweden)

    Wenlong Zhang

    2017-07-01

    Full Text Available Doxycycline (Dox, a semisynthetic antibiotic, has been reported to exert multiple immunomodulatory effects. Treatment with Dox has a satisfactory curative effect against leptospirosis. In addition to its antibacterial action, we supposed that Dox also modulated immune response in controlling leptospira infection. Using J774A.1 mouse macrophages, the effects of Dox on protein and mRNA levels of IL-1β and TNF-α were investigated after infection with live or sonicated Leptospira interrogans serovar Lai strain Lai (56601. Specifically, the level of IL-1β but not TNF-α was sharply decreased when treated with Dox in leptospira-infected macrophages. Western blot analysis showed that Dox suppressed the activation of leptospira-induced MAPK and NF-κB signaling pathways. Using NLRP3-deficient and NLRC4-deficient mice, the data showed that the expression of leptospira-induced IL-1β was mainly dependent on the presence of NLRP3 inflammasome in macrophages. Meanwhile, Dox suppressed leptospira-induced NLRP3 inflammasome priming with the upregulation of the Na/K-ATPase Pump β1 subunit. The inhibition effect of Dox on IL-1β was also conspicuous in cells with lipopolysaccharide and ATP stimulation. These results were confirmed in vivo, as peritoneal fluids of mice and organs of hamsters expressed less IL-1β after treatment of leptospiral infection with Dox. Our results indicated that Dox also modulated immune response to attenuate leptospira-induced IL-1β by suppressing p38, JNK, p65, and NLRP3 inflammasome priming.

  4. Exosomes from Human Dental Pulp Stem Cells Suppress Carrageenan-Induced Acute Inflammation in Mice.

    Science.gov (United States)

    Pivoraitė, Ugnė; Jarmalavičiūtė, Akvilė; Tunaitis, Virginijus; Ramanauskaitė, Giedrė; Vaitkuvienė, Aida; Kašėta, Vytautas; Biziulevičienė, Genė; Venalis, Algirdas; Pivoriūnas, Augustas

    2015-10-01

    The primary goal of this study was to examine the effects of human dental pulp stem cell-derived exosomes on the carrageenan-induced acute inflammation in mice. Exosomes were purified by differential ultracentrifugation from the supernatants of stem cells derived from the dental pulp of human exfoliated deciduous teeth (SHEDs) cultivated in serum-free medium. At 1 h post-carrageenan injection, exosomes derived from supernatants of 2 × 10(6) SHEDs were administered by intraplantar injection to BALB/c mice; 30 mg/kg of prednisolone and phosphate-buffered saline (PBS) were used as positive and negative controls, respectively. Edema was measured at 6, 24, and 48 h after carrageenan injection. For the in vivo imaging experiments, AngioSPARK750, Cat B 750 FAST, and MMPSense 750 FAST were administered into the mouse tail vein 2 h post-carrageenan injection. Fluorescence images were acquired at 6, 24, and 48 h after edema induction by IVIS Spectrum in vivo imaging system. Exosomes significantly reduced the carrageenan-induced edema at all the time points studied (by 39.5, 41.6, and 25.6% at 6, 24, and 48 h after injection, respectively), to similar levels seen with the positive control (prednisolone). In vivo imaging experiments revealed that, both exosomes and prednisolone suppress activities of cathepsin B and matrix metalloproteinases (MMPs) at the site of carrageenan-induced acute inflammation, showing more prominent effects of prednisolone at the early stages, while exosomes exerted their suppressive effects gradually and at later time points. Our study demonstrates for the first time that exosomes derived from human dental pulp stem cells suppress carrageenan-induced acute inflammation in mice.

  5. Sangivamycin induces apoptosis by suppressing Erk signaling in primary effusion lymphoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Wakao, Kazufumi [Department of Biotechnology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Kofu-shi 400-8511 (Japan); Watanabe, Tadashi [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan); Takadama, Tadatoshi; Ui, Sadaharu [Department of Biotechnology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Kofu-shi 400-8511 (Japan); Shigemi, Zenpei; Kagawa, Hiroki [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan); Higashi, Chizuka; Ohga, Rie; Taira, Takahiro [Department of Molecular Cell Biology, Faculty of Medicine, University of Yamanashi, Chuoh-shi 409-3898 (Japan); Fujimuro, Masahiro, E-mail: fuji2@mb.kyoto-phu.ac.jp [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan)

    2014-02-07

    Highlights: • Sangivamycin induces the apoptosis of B cell lymphoma PEL cells. • Sangivamycin suppresses Erk signaling by inhibiting Erk phosphorylation in PEL cells. • The activation of Erk signaling is essential for PEL cell survival. • Sangivamycin induces the apoptosis of PEL cells without production of progeny virus. • Sangivamycin may serve as a novel drug for the treatment of PEL. - Abstract: Sangivamycin, a structural analog of adenosine and antibiotic exhibiting antitumor and antivirus activities, inhibits protein kinase C and the synthesis of both DNA and RNA. Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients and HIV-infected homosexual males. PEL cells are derived from post-germinal center B cells, and are infected with KSHV. Herein, we asked if sangivamycin might be useful to treat PEL. We found that sangivamycin killed PEL cells, and we explored the underlying mechanism. Sangivamycin treatment drastically decreased the viability of PEL cell lines compared to KSHV-uninfected B lymphoma cell lines. Sangivamycin induced the apoptosis of PEL cells by activating caspase-7 and -9. Further, sangivamycin suppressed the phosphorylation of Erk1/2 and Akt, thus inhibiting activation of the proteins. Inhibitors of Akt and MEK suppressed the proliferation of PEL cells compared to KSHV-uninfected cells. It is known that activation of Erk and Akt signaling inhibits apoptosis and promotes proliferation in PEL cells. Our data therefore suggest that sangivamycin induces apoptosis by inhibiting Erk and Akt signaling in such cells. We next investigated whether sangivamycin, in combination with an HSP90 inhibitor geldanamycin (GA) or valproate (valproic acid), potentiated the cytotoxic effects of the latter drugs on PEL cells. Compared to treatment with GA or valproate alone, the addition of sangivamycin enhanced cytotoxic activity. Our data thus indicate that

  6. KAI1/CD82 suppresses hepatocyte growth factor-induced migration of hepatoma cells via upregulation of Sprouty2

    Institute of Scientific and Technical Information of China (English)

    MU ZhenBin; WANG Hua; ZHANG Jing; LI QingFang; WANG LiSheng; GUO XiaoZhong

    2008-01-01

    We conducted a study concerning the suppressive mechanism of KAI1/CD82 on hepatoma cell metas-tasis. Hepatocyte growth factor (HGF) induces the migration of hepatoma cells through activation of cellular sphingosine kinase 1 (SphK1). Adenovirus-mediated gene transfer of KAI1 (Ad-KAI1) down-regulates the SphK1 expression and suppresses the HGF-induced migration of SMMC-7721 human hepatocellcular carcinoma cells. Overexpression of KAI1/CD82 significantly elevates Sprouty2 at the protein level. Ablation of Sprouty2 with RNA interference can block the KAI1/CD82-induced suppres-sion of hepatoma cell migration and downregulation of SphK1 expression. It is demonstrated that KAI1/CD82 suppresses HGF-induced migration of hepatoma cells via upregulation of Sprouty2.

  7. Clean HMBC: Suppression of strong-coupling induced artifacts in HMBC spectra

    DEFF Research Database (Denmark)

    Würtz, Peter; Permi, Perttu; Nielsen, Niels Chr.;

    2008-01-01

    A new experiment, clean HMBC, is introduced for suppression of strong-coupling induced artifacts in HMBC spectra. The culprits of these artifacts are an inherent shortcoming of low-pass J filters in the presence of strong coupling and the 1H p pulse in the middle of the evolution period aimed...... at suppressing evolution under heteronuclear J couplings and 1H chemical shifts. A p pulse causes coherence transfer in strongly coupled spin systems and, as is well known in e.g., homonuclear J spectra, this leads to peaks that would not be there in the absence of strong coupling. Similar artifacts occur...... protons, such as carbohydrates, and the new technique is demonstrated on D-mannose. Finally, a fundamental difference between HMBC and H2BC explains why strong-coupling artifacts are much less of a problem in the latter type of spectra....

  8. MicroRNA-125b Induces Cancer Cell Apoptosis Through Suppression of Bcl-2 Expression

    Institute of Scientific and Technical Information of China (English)

    Aihua Zhao; Quan Zeng; Xiaoyan Xie; unnian Zhou; Wen Yue; Yali Li; Xuetao Pei

    2012-01-01

    MicroRNAs (miRNAs) are small,noncoding RNAs which can often act as an oncogene or a tumor suppressor.Several miRNAs are associated with the development of hepatocellular carcinoma (HCC).We demonstrated that miR-125b significantly suppresses HCC cell proliferation and promotes apoptosis by inhibiting the gene expression of the anti-apoptotic protein,Bcl-2.Bioinformatic analysis indicated that the 3'UTR of Bcl-2 has binding sites for miR-125b.Luciferase reporter assay confirmed the ability of miR-125b to dramatically suppress Bcl-2 transcription,suggesting that Bcl-2 is a target gene for miR-125b.We concluded that miR-125b acts as a tumor suppressor in hepatic tumor development by targeting Bcl-2 and inducing cancer cell apoptosis.

  9. Isolating Soil Drought-Induced Genes from Maize Seedling Leaves Through Suppression Subtractive Hybridization

    Institute of Scientific and Technical Information of China (English)

    LI Hui-yong; HUANG Su-hua; SHI Yun-su2; SONG Yan-chun; ZHAO Jiu-ran; WANG Feng-ge; WANG Tian-yu; LI Yu

    2007-01-01

    In this study, a forward cDNA library was constructed by suppression subtractive hybridization using seedling leaves of CN165, a drought-tolerant maize inbred line. In the suppression subtractive hybridization (SSH) library, 672 positive clones were picked up randomly. After polymerase chain reaction (PCR) of each clone, all the single clones were sequenced. Totally 598 available sequences were obtained. After cluster analysis of the EST sequences, 80 uniESTs were obtained, among which 57 uniESTs were contigs and 23 uniESTs were singlets. The results of BLASTN showed that all the uniESTs had homologous sequences in the nr database. The BLASTX results indicated that 68 uniESTs had significant protein homology, 8 uniESTs with homology of unknown proteins and putative proteins, and 4 uniESTs without protein homology. Those drought stress-induced genes were involved in many metabolism pathways to regulate plant growth and development under drought stress.

  10. Indirubin-3′-monoxime suppresses amyloid-beta-induced apoptosis by inhibiting tau hyperphosphorylation

    Institute of Scientific and Technical Information of China (English)

    Shu-gang Zhang; Xiao-shan Wang; Ying-dong Zhang; Qing Di; Jing-ping Shi; Min Qian; Li-gang Xu; Xing-jian Lin; Jie Lu

    2016-01-01

    Indirubin-3′-monoxime is an effective inhibitor of cyclin-dependent protein kinases, and may play an obligate role in neuronal apopto-sis in Alzheimer’s disease. Here, we found that indirubin-3′-monoxime improved the morphology and increased the survival rate of SH-SY5Y cells exposed to amyloid-beta 25–35 (Aβ25–35), and also suppressed apoptosis by reducing tau phosphorylation at Ser199 and Thr205. Furthermore, indirubin-3′-monoxime inhibited phosphorylation of glycogen synthase kinase-3β (GSK-3β). Our results suggest that in-dirubin-3′-monoxime reduced Aβ25–35-induced apoptosis by suppressing tau hyperphosphorylationvia a GSK-3β-mediated mechanism. Indirubin-3′-monoxime is a promising drug candidate for Alzheimer’s disease.

  11. Pressure Induced Suppression to the Valence Change Transition in EuPdAs

    Directory of Open Access Journals (Sweden)

    Baoxuan Li

    2015-01-01

    Full Text Available By applying a hydrostatic pressure, we have successfully suppressed the valence change transition in EuPdAs. The studied compound EuPdAs crystallizes in a P63/mmc space group. Through resistivity and magnetic susceptibility measurements, we find that EuPdAs shows a phase transition at 180 K and another transition below 10 K at ambient pressure, as was reported before. The overall transport and magnetic behavior is to some extent similar to that of the parent phase of iron based superconductors. With application of a hydrostatic pressure, the transition at 180 K is sensitively suppressed with a pressure as low as 0.48 GPa. However, superconductivity has not been induced with pressure up to 1.90 GPa.

  12. Effects of pirenzepine on omeprazole-induced hypergastrinemia and acid suppression in peptic ulcer patients.

    Science.gov (United States)

    Tari, A; Hamada, M; Kamiyasu, T; Fukino, Y; Sumii, M; Haruma, K; Sumii, K; Inoue, M; Kajiyama, G

    1996-04-01

    Omeprazole effectively suppresses acid secretion, resulting in the long-term elevation of intragastric pH and serum gastrin level. Pirenzepine has been reported to inhibit gastrin secretion. This study was carried out to examine the effects of additional pirenzepine treatment on the hypergastrinemia and gastric acid suppression induced by omeprazole. Concentrations of serum gastrin and plasma somatostatin were measured in 28 peptic ulcer patients before treatment, after omeprazole treatment (20 mg/day) for 2 weeks, and after omeprazole and pirenzepine (100 mg/day) treatment for 2 weeks. The acid inhibitory effect of pirenzepine treatment in addition to omeprazole was evaluated by 24-h intragastric pH measurement in six healthy volunteers. Serum gastrin level was increased significantly, to 2.4-fold the pretreatment level, by omeprazole treatment. Additional treatment with pirenzepine suppressed serum gastrin level to 0.6-fold the omeprazole-treatment level. The serum somatostatin level was not altered significantly either by omeprazole treatment or by omeprazole and pirenzepine treatment. In healthy volunteers whose pH 3 holding time on 24-h intragastric pH monitoring was 70% by omeprazole treatment, omeprazole and pirenzepine treatment markedly increased the pH 3 holding time, to 89%. These findings suggest that pirenzepine is useful in reducing the undesirable effects of omeprazole-induced hypergastrinemia, i.e., the excessive trophic effect of omeprazole on the acid-secreting part of the stomach and the overstimulation of acid secretion. The additional pirenzepine treatment is also effective in suppressing acid secretion.

  13. Citrus nobiletin suppresses inducible nitric oxide synthase gene expression in interleukin-1β-treated hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Yoshigai, Emi [Department of Biomedical Sciences, College of Life Sciences, Kusatsu, Shiga (Japan); Ritsumeikan Global Innovation Research Organization (R-GIRO), Kusatsu, Shiga (Japan); Machida, Toru [Department of Biomedical Sciences, College of Life Sciences, Kusatsu, Shiga (Japan); Okuyama, Tetsuya [Ritsumeikan Global Innovation Research Organization (R-GIRO), Kusatsu, Shiga (Japan); Mori, Masatoshi; Murase, Hiromitsu; Yamanishi, Ryota [Department of Biomedical Sciences, College of Life Sciences, Kusatsu, Shiga (Japan); Okumura, Tadayoshi [Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Shiga (Japan); Department of Surgery, Kansai Medical University, Hirakata, Osaka (Japan); Ikeya, Yukinobu [Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga (Japan); Nishino, Hoyoku [Ritsumeikan Global Innovation Research Organization (R-GIRO), Kusatsu, Shiga (Japan); Department of Biochemistry, Kyoto Prefectural University of Medicine, Kyoto (Japan); Nishizawa, Mikio, E-mail: nishizaw@sk.ritsumei.ac.jp [Department of Biomedical Sciences, College of Life Sciences, Kusatsu, Shiga (Japan)

    2013-09-13

    Highlights: •Nobiletin is a polymethoxylated flavone that is abundant in citrus peels. •Nobiletin is a major constituent of the Citrus unshiu peel extract. •Nobiletin suppresses induction of NO and reduces iNOS expression in hepatocytes. •Nobiletin reduces the iNOS promoter activity and the DNA-binding activity of NF-κB. -- Abstract: Background: Nobiletin is a polymethoxylated flavone that is abundant in the peels of citrus fruits, such as Citrus unshiu (Satsuma mandarin) and Citrus sinensis. The dried peels of C. unshiu (chinpi) have been included in several formulae of Japanese Kampo medicines. Nobiletin may suppress the induction of inducible nitric oxide synthase (iNOS), which synthesizes the inflammatory mediator nitric oxide (NO) in hepatocytes. Methods: A C. unshiu peel (CUP) extract was prepared. Primary cultured rat hepatocytes were treated with the CUP extract or nobiletin in the presence of interleukin 1β (IL-1β), which induces iNOS expression. NO production and iNOS gene expression were analyzed. Results: High-performance liquid chromatography analyses revealed that the nobiletin content in the CUP extract was 0.14%. Nobiletin dose-dependently reduced the NO levels and decreased iNOS expression at the protein, mRNA and antisense transcript levels. Flavone, which does not contain any methoxy groups, also suppressed iNOS induction. Nobiletin reduced the transcriptional activity of iNOS promoter-luciferase constructs and the DNA-binding activity of nuclear factor κB (NF-κB) in the nuclei. Conclusions: The suppression of iNOS induction by nobiletin suggests that nobiletin may be responsible for the anti-inflammatory effects of citrus peels and have a therapeutic potential for liver diseases.

  14. Absolute quantitative proton NMR spectroscopy based on the amplitude of the local water suppression pulse. Quantification of brain water and metabolites

    DEFF Research Database (Denmark)

    Danielsen, E R; Henriksen, O

    1994-01-01

    the locally optimized amplitude of a chemical shift selective water suppression pulse and the acquired signal. Validity and feasibility of quantification using the method of the water suppression pulse is demonstrated. Brain water and cerebral metabolites have been quantified in a study of 12 healthy...

  15. Two-dimensional atom localization induced by a squeezed vacuum

    Science.gov (United States)

    Wang, Fei; Xu, Jun

    2016-10-01

    A scheme of two-dimensional (2D) atom localization induced by a squeezed vacuum is proposed, in which the three-level V-type atoms interact with two classical standing-wave fields. It is found that when the environment is changed from an ordinary vacuum to a squeezed vacuum, the 2D atom localization is realized by detecting the position-dependent resonance fluorescence spectrum. For comparison, we demonstrate that the atom localization originating from the quantum interference effect is distinct from that induced by a squeezed vacuum. Furthermore, the combined effects of the squeezed vacuum and quantum interference are also discussed under appropriate conditions. The internal physical mechanism is analyzed in terms of dressed-state representation. Project supported by the National Natural Science Foundation of China (Grant Nos. 11574179 and 11204099) and the Natural Science Foundation of Hubei Province, China (Grant No. 2014CFC1148).

  16. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression.

    Science.gov (United States)

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Barilla, Rocky; Daley, Donnele; Greco, Stephanie H; Torres-Hernandez, Alejandro; Pergamo, Matthew; Ochi, Atsuo; Zambirinis, Constantinos P; Pansari, Mridul; Rendon, Mauricio; Tippens, Daniel; Hundeyin, Mautin; Mani, Vishnu R; Hajdu, Cristina; Engle, Dannielle; Miller, George

    2016-04-14

    Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis. Conversely, cancer cells often disrupt apoptosis to survive. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs. Here we report that the principal components of the necrosome, receptor-interacting protein (RIP)1 and RIP3, are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumour microenvironment associated with intact RIP1/RIP3 signalling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SAP130 (a subunit of the histone deacetylase complex) was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle--its cognate receptor--was upregulated in tumour-infiltrating myeloid cells. Ligation of Mincle by SAP130 promoted oncogenesis, whereas deletion of Mincle protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumour microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or Mincle is deleted. Accordingly, T cells

  17. HPV16-E7 expression in squamous epithelium creates a local immune suppressive environment via CCL2- and CCL5- mediated recruitment of mast cells.

    Science.gov (United States)

    Bergot, Anne-Sophie; Ford, Neill; Leggatt, Graham R; Wells, James W; Frazer, Ian H; Grimbaldeston, Michele A

    2014-10-01

    Human Papillomavirus (HPV) 16 E7 protein promotes the transformation of HPV infected epithelium to malignancy. Here, we use a murine model in which the E7 protein of HPV16 is expressed as a transgene in epithelium to show that mast cells are recruited to the basal layer of E7-expressing epithelium, and that this recruitment is dependent on the epithelial hyperproliferation induced by E7 by inactivating Rb dependent cell cycle regulation. E7 induced epithelial hyperplasia is associated with increased epidermal secretion of CCL2 and CCL5 chemokines, which attract mast cells to the skin. Mast cells in E7 transgenic skin, in contrast to those in non-transgenic skin, exhibit degranulation. Notably, we found that resident mast cells in E7 transgenic skin cause local immune suppression as evidenced by tolerance of E7 transgenic skin grafts when mast cells are present compared to the rejection of mast cell-deficient E7 grafts in otherwise competent hosts. Thus, our findings suggest that mast cells, recruited towards CCL2 and CCL5 expressed by epithelium induced to proliferate by E7, may contribute to an immunosuppressive environment that enables the persistence of HPV E7 protein induced pre-cancerous lesions.

  18. HPV16-E7 expression in squamous epithelium creates a local immune suppressive environment via CCL2- and CCL5- mediated recruitment of mast cells.

    Directory of Open Access Journals (Sweden)

    Anne-Sophie Bergot

    2014-10-01

    Full Text Available Human Papillomavirus (HPV 16 E7 protein promotes the transformation of HPV infected epithelium to malignancy. Here, we use a murine model in which the E7 protein of HPV16 is expressed as a transgene in epithelium to show that mast cells are recruited to the basal layer of E7-expressing epithelium, and that this recruitment is dependent on the epithelial hyperproliferation induced by E7 by inactivating Rb dependent cell cycle regulation. E7 induced epithelial hyperplasia is associated with increased epidermal secretion of CCL2 and CCL5 chemokines, which attract mast cells to the skin. Mast cells in E7 transgenic skin, in contrast to those in non-transgenic skin, exhibit degranulation. Notably, we found that resident mast cells in E7 transgenic skin cause local immune suppression as evidenced by tolerance of E7 transgenic skin grafts when mast cells are present compared to the rejection of mast cell-deficient E7 grafts in otherwise competent hosts. Thus, our findings suggest that mast cells, recruited towards CCL2 and CCL5 expressed by epithelium induced to proliferate by E7, may contribute to an immunosuppressive environment that enables the persistence of HPV E7 protein induced pre-cancerous lesions.

  19. 5α-Reductase Inhibition Suppresses Testosterone-Induced Initial Regrowth of Regressed Xenograft Prostate Tumors in Animal Models

    Science.gov (United States)

    Masoodi, Khalid Z.; Ramos Garcia, Raquel; Pascal, Laura E.; Wang, Yujuan; Ma, Hei M.; O'Malley, Katherine; Eisermann, Kurtis; Shevrin, Daniel H.; Nguyen, Holly M.; Vessella, Robert L.; Nelson, Joel B.; Parikh, Rahul A.

    2013-01-01

    Androgen deprivation therapy (ADT) is the standard treatment for patients with prostate-specific antigen progression after treatment for localized prostate cancer. An alternative to continuous ADT is intermittent ADT (IADT), which allows recovery of testosterone during off-cycles to stimulate regrowth and differentiation of the regressed prostate tumor. IADT offers patients a reduction in side effects associated with ADT, improved quality of life, and reduced cost with no difference in overall survival. Our previous studies showed that IADT coupled with 5α-reductase inhibitor (5ARI), which blocks testosterone conversion to DHT could prolong survival of animals bearing androgen-sensitive prostate tumors when off-cycle duration was fixed. To further investigate this clinically relevant observation, we measured the time course of testosterone-induced regrowth of regressed LuCaP35 and LNCaP xenograft tumors in the presence or absence of a 5ARI. 5α-Reductase inhibitors suppressed the initial regrowth of regressed prostate tumors. However, tumors resumed growth and were no longer responsive to 5α-reductase inhibition several days after testosterone replacement. This finding was substantiated by bromodeoxyuridine and Ki67 staining of LuCaP35 tumors, which showed inhibition of prostate tumor cell proliferation by 5ARI on day 2, but not day 14, after testosterone replacement. 5α-Reductase inhibitors also suppressed testosterone-stimulated proliferation of LNCaP cells precultured in androgen-free media, suggesting that blocking testosterone conversion to DHT can inhibit prostate tumor cell proliferation via an intracrine mechanism. These results suggest that short off-cycle coupled with 5α-reductase inhibition could maximize suppression of prostate tumor growth and, thus, improve potential survival benefit achieved in combination with IADT. PMID:23671262

  20. Synchronization and suppression of chaos in non-locally coupled map lattices

    Indian Academy of Sciences (India)

    R M Szmoski; S E De S Pinto; M T Van Kan; A M Batista; R L Viana; S R Lopes

    2009-12-01

    We considered coupled map lattices with long-range interactions to study the spatiotemporal behaviour of spatially extended dynamical systems. Coupled map lattices have been intensively investigated as models to understand many spatiotemporal phenomena observed in extended system, and consequently spatiotemporal chaos. We used the complex order parameter to quantify chaos synchronization for a one-dimensional chain of coupled logistic maps with a coupling strength which varies with the lattice in a power-law fashion. Depending on the range of the interactions, complete chaos synchronization and chaos suppression may be attained. Furthermore, we also calculated the Lyapunov dimension and the transversal distance to the synchronization manifold.

  1. miR-100 induces epithelial-mesenchymal transition but suppresses tumorigenesis, migration and invasion.

    Directory of Open Access Journals (Sweden)

    Dahu Chen

    2014-02-01

    Full Text Available Whether epithelial-mesenchymal transition (EMT is always linked to increased tumorigenicity is controversial. Through microRNA (miRNA expression profiling of mammary epithelial cells overexpressing Twist, Snail or ZEB1, we identified miR-100 as a novel EMT inducer. Surprisingly, miR-100 inhibits the tumorigenicity, motility and invasiveness of mammary tumor cells, and is commonly downregulated in human breast cancer due to hypermethylation of its host gene MIR100HG. The EMT-inducing and tumor-suppressing effects of miR-100 are mediated by distinct targets. While miR-100 downregulates E-cadherin by targeting SMARCA5, a regulator of CDH1 promoter methylation, this miRNA suppresses tumorigenesis, cell movement and invasion in vitro and in vivo through direct targeting of HOXA1, a gene that is both oncogenic and pro-invasive, leading to repression of multiple HOXA1 downstream targets involved in oncogenesis and invasiveness. These findings provide a proof-of-principle that EMT and tumorigenicity are not always associated and that certain EMT inducers can inhibit tumorigenesis, migration and invasion.

  2. Topical application of Scutellaria baicalensis suppresses 2,4-dinitrochlorobenzene-induced contact dermatitis.

    Science.gov (United States)

    Kim, Tae-Won; Choi, Jae-Mook; Kim, Myoung-Seok; Son, Hwa-Young; Lim, Jong-Hwan

    2016-01-01

    Allergic contact dermatitis (ACD) is a prototypic T-cell-mediated cutaneous inflammatory response. In the present study we describe the anti-allergic effect of topically applied Scutellaria bacalensis aqueous extract (WSBE) in suppressing 2,4-dinitrochlorobenzene (DNCB)-induced ACD in BALB/c mice. Topically applied WSBE attenuated the epidermal thickness and mast cell infiltration into the skin in DNCB-induced contact dermatitis. Furthermore, WSBE suppressed DNCB-induced production of serum IgE as well as IL-4, IFN-γ, and TNF-α in the skin. Topical application of WSBE also ameliorated the significant decrease in dermal glutathione and superoxide dismutase levels. Moreover, present results demonstrated that the baicalin, bioactive compound of WSBE, was able to penetrate into the skin following topical application, which was confirmed by the HPLC analysis using rat model. Taken together, topical application of WSBE exerts beneficial effects in contact dermatitis model, suggesting that WSBE might be a candidate for the treatment of contact dermatitis.

  3. Anthrax lethal toxin suppresses high glucose induced VEGF over secretion through a post-translational mechanism

    Institute of Scientific and Technical Information of China (English)

    Wei-Wei; Zhang; Xin; Wang; Ping; Xie; Song-Tao; Yuan; Qing-Huai; Liu

    2015-01-01

    AIM: To prove anthrax lethal toxin(Le Tx) blocks the mitogen activated protein kinases(MAPKs) activation by degrading the MAPK/ERK kinases(MEKs) to suppress vascular endothelial growth factor(VEGF) secretion.METHODS: Human adult retinal pigmented epithelium(ARPE) cells were cultured and treated with normal glucose, high glucose or high glucose with Le Tx for additional 24, 48 or 72 h for viable cell count. Total RNA from the ARPE was isolated for reverse transcription polymerase chain reaction(RT-PCR). The conditioned medium of ARPE cells treated in different group for 48 h was filtered and diluted to detect the concentration of VEGF by enzyme-linked immunosorbant assays.Evaluate the role of MEK/MAPK pathway in the secretion of VEGF by immunoblotting. RESULTS: In this study, we proved high glucose induced activation of the MAPK extracellular signal-regulated kinase(ERK1/2) and p38 in the ARPE cell line was blocked by anthrax Le Tx. Le Tx also inhibited high glucose induced ARPE cell over proliferation.CONCLUSION: Le Tx suppressed high glucose induced VEGF over secretion in the ARPE cells, mainly through a post-translational mechanism.

  4. Retinoic Acid Upregulates Preadipocyte Genes to Block Adipogenesis and Suppress Diet-Induced Obesity

    Science.gov (United States)

    Berry, Daniel C.; DeSantis, David; Soltanian, Hooman; Croniger, Colleen M.; Noy, Noa

    2012-01-01

    Retinoic acid (RA) protects mice from diet-induced obesity. The activity is mediated in part through activation of the nuclear receptors RA receptors (RARs) and peroxisome proliferator–activated receptor β/δ and their associated binding proteins cellular RA binding protein type II (CRABP-II) and fatty acid binding protein type 5 in adipocytes and skeletal muscle, leading to enhanced lipid oxidation and energy dissipation. It was also reported that RA inhibits differentiation of cultured preadipocytes. However, whether the hormone suppresses adipogenesis in vivo and how the activity is propagated remained unknown. In this study, we show that RA inhibits adipocyte differentiation by activating the CRABP-II/RARγ path in preadipose cells, thereby upregulating the expression of the adipogenesis inhibitors Pref-1, Sox9, and Kruppel-like factor 2 (KLF2). In turn, KLF2 induces the expression of CRABP-II and RARγ, further potentiating inhibition of adipocyte differentiation by RA. The data also indicate that RA suppresses adipogenesis in vivo and that the activity significantly contributes to the ability of the hormone to counteract diet-induced obesity. PMID:22396202

  5. Depolarization Induced Suppression of Excitation and the Emergence of Ultraslow Rhythms in Neural Networks

    Science.gov (United States)

    Hlinka, J.; Coombes, S.

    2010-02-01

    Ultraslow fluctuations (0.01-0.1 Hz) are a feature of intrinsic brain activity of as yet unclear origin. We propose a candidate mechanism based on retrograde endocannabinoid signaling in a synaptically coupled network of excitatory neurons. This is known to cause depolarization-induced suppression of excitation (DISE), which we model phenomenologically. We construct emergent network oscillations in a globally coupled network and show that for strong synaptic coupling DISE can lead to a synchronized population burst at the frequencies of resting brain rhythms.

  6. Supernova neutrino halo and the suppression of self-induced flavor conversion

    CERN Document Server

    Sarikas, Srdjan; Raffelt, Georg; Hüdepohl, Lorenz; Janka, Hans-Thomas

    2012-01-01

    Neutrinos streaming from a supernova (SN) core occasionally scatter in the envelope, producing a small "neutrino halo" with a much broader angle distribution than the primary flux originating directly from the core. Cherry et al. (2012) have recently pointed out that, during the accretion phase, the halo actually dominates neutrino-neutrino refraction at distances exceeding some 100 km. However, the multi-angle matter effect (which increases if the angle distribution is broader) still appears to suppress self-induced flavor conversion during the accretion phase.

  7. cAMP Modulates Macrophage Development by Suppressing M-CSF-Induced MAPKs Activation

    Institute of Scientific and Technical Information of China (English)

    Ning Zhu; Jian Cui; Chunxia Qiao; Yan Li; Yuanfang Ma; Jiyan Zhang; Beifen Shen

    2008-01-01

    M-CSF is a key cytokine in macrophage development by inducing MAPKs activation, and cAMP can inhibit MAPKs activation induced by inflammatory stimuli. To explore the effects of cAMP on M-CSF-induced MAPKs activation and on macrophage development, the model of bone marrow-derived murine macrophages (BMMs) was used. The effects of cAMP on M-CSF-induced MAPKs activation were analyzed by Western blotting assay, and the effects of cAMP on CD14 and F4/80 expression during macrophage development were examined by FACS analysis.Macrophage morphology showed the successful establishment of the model of macrophage development. Western blotting assay revealed that M-CSF activated ERK, JNK and p38 in both mature and immature macrophages, and cAMP inhibited M-CSF-induced ERK, JNK and p38 activation in a time-dependent manner. FACS analysis revealed that macrophage development was impaired with cAMP pretreatment. In conclusion, cAMP modulates macrophage development by suppressing M-CSF-induced MAPKs activation.

  8. Shikonin ameliorates isoproterenol (ISO)-induced myocardial damage through suppressing fibrosis, inflammation, apoptosis and ER stress.

    Science.gov (United States)

    Yang, Jun; Wang, Zhao; Chen, Dong-Lin

    2017-09-01

    Shikonin, isolated from the roots of herbal plant Lithospermum erythrorhizon, is a naphthoquinone. It has been reported to exert beneficial anti-inflammatory effects and anti-oxidant properties in various diseases. Isoproterenol (ISO) has been widely used to establish cardiac injury in vivo and in vitro. However, shikonin function in ISO-induced cardiac injury remains uncertain. In our study, we attempted to investigate the efficiency and possible molecular mechanism of shikonin in cardiac injury treatment induced by ISO. In vivo, C57BL6 mice were subcutaneously injected with 5mg/kg ISO to induce heart failure. And mice were given a gavage of shikonin (2 or 4mg/kg/d, for four weeks). Cardiac function, fibrosis indices, inflammation response, apoptosis and endoplasmic reticulum (ER) stress were calculated. Pathological alterations, fibrosis-, inflammation-, apoptosis- and ER stress-related molecules were examined. In ISO-induced cardiac injury, shikonin significantly ameliorated heart function, decreased myocardial fibrosis, suppressed inflammation, attenuated apoptosis and ER stress through impeding collagen accumulation, Toll like receptor 4/nuclear transcription factor κB (TLR4/NF-κB), Caspase-3 and glucose-regulated protein 78 (GRP78) signaling pathways activity, relieving heart failure in vivo. Also, in vitro, shikonin attenuated ISO-induced cardiac muscle cells by reducing fibrosis, inflammation, apoptosis and ER stress. Our findings indicated that shikonin treatment attenuated ISO-induced heart injury, providing an effective therapeutic strategy for heart failure treatment for future. Copyright © 2017. Published by Elsevier Masson SAS.

  9. Ethanol suppresses carbamylcholine-induced intracellular calcium oscillation in mouse pancreatic acinar cells.

    Science.gov (United States)

    Yoon, Mi Na; Kim, Min Jae; Koong, Hwa Soo; Kim, Dong Kwan; Kim, Se Hoon; Park, Hyung Seo

    2017-09-01

    Oscillation of intracellular calcium levels is closely linked to initiating secretion of digestive enzymes from pancreatic acinar cells. Excessive alcohol consumption is known to relate to a variety of disorders in the digestive system, including the exocrine pancreas. In this study, we have investigated the role and mechanism of ethanol on carbamylcholine (CCh)-induced intracellular calcium oscillation in murine pancreatic acinar cells. Ethanol at concentrations of 30 and 100 mM reversibly suppressed CCh-induced Ca(2+) oscillation in a dose-dependent manner. Pretreatment of ethanol has no effect on the store-operated calcium entry induced by 10 μM of CCh. Ethanol significantly reduced the initial calcium peak induced by low concentrations of CCh and therefore, the CCh-induced dose-response curve of the initial calcium peak was shifted to the right by ethanol pretreatment. Furthermore, ethanol significantly dose-dependently reduced inositol 1,4,5-trisphosphate-induced calcium release from the internal stores in permeabilized acinar cells. These results provide evidence that excessive alcohol intake could impair cytosolic calcium oscillation through inhibiting calcium release from intracellular stores in mouse pancreatic acinar cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Infection with the Lyme disease pathogen suppresses innate immunity in mice with diet-induced obesity.

    Science.gov (United States)

    Zlotnikov, Nataliya; Javid, Ashkan; Ahmed, Mijhgan; Eshghi, Azad; Tang, Tian Tian; Arya, Anoop; Bansal, Anil; Matar, Fatima; Parikh, Maitry; Ebady, Rhodaba; Koh, Adeline; Gupta, Nupur; Song, Peng; Zhang, Yang; Newbigging, Susan; Wormser, Gary P; Schwartz, Ira; Inman, Robert; Glogauer, Michael; Moriarty, Tara J

    2017-05-01

    Obesity is a major global public health concern. Immune responses implicated in obesity also control certain infections. We investigated the effects of high-fat diet-induced obesity (DIO) on infection with the Lyme disease bacterium Borrelia burgdorferi in mice. DIO was associated with systemic suppression of neutrophil- and macrophage-based innate immune responses. These included bacterial uptake and cytokine production, and systemic, progressive impairment of bacterial clearance, and increased carditis severity. B. burgdorferi-infected mice fed normal diet also gained weight at the same rate as uninfected mice fed high-fat diet, toll-like receptor 4 deficiency rescued bacterial clearance defects, which greater in female than male mice, and killing of an unrelated bacterium (Escherichia coli) by bone marrow-derived macrophages from obese, B. burgdorferi-infected mice was also affected. Importantly, innate immune suppression increased with infection duration and depended on cooperative and synergistic interactions between DIO and B. burgdorferi infection. Thus, obesity and B. burgdorferi infection cooperatively and progressively suppressed innate immunity in mice. © 2016 The Authors Cellular Microbiology Published by John Wiley & Sons Ltd.

  11. Suppression of E-cadherin mediates gallotannin induced apoptosis in Hep G2 hepatocelluar carcinoma cells.

    Science.gov (United States)

    Han, Hee Jeong; Kwon, Hee Young; Sohn, Eun Jung; Ko, Hyunsuk; Kim, Bogeun; Jung, Kwon; Lew, Jae Hwan; Kim, Sung-Hoon

    2014-01-01

    Though gallotannin was known to have anti-oxidant and antitumor activity, the underlying antitumor mechanism of gallotannin still remains unclear. Thus, in the present study, antitumor mechanism of gallotannin was elucidated in hepatocellular carcinoma cells. Gallotannin significantly exerted cytotoxicity against Hep G2 and Chang hepatocellular carcinoma cells with the accumulation of the sub-G1 population and increase of terminal deoxynucleotidyltransferasedUTP nick end labeling (TUNEL) positive cells as an apoptotic feature. Also, gallotannin attenuated the expression of pro-caspase9, pro-caspase3, Bcl2 and integrin β1 and cleaved poly(ADP)-ribose polymerase (PARP) in Hep G2 and Chang cancer cells. Furthermore, gallotannin suppressed cell repair motility by wound healing assay and also inhibited cell adhesion in Hep G2 cells. Of note, gallotannin attenuated the expression of epithelial cadherin (E-cadherin) to form cell-cell adhesion from the early stage, and also beta-catenin at late phase in Hep G2 cells. Consistently, Immunofluorescence assay showed that E-cadherin or β-catenin expression was suppressed in a time dependent manner by gallotannin. Furthermore, silencing of E-cadherin by siRNA transfection method enhanced PAPR cleavage, caspase 3 activation and sub G1 population and attenuated the cell adhesion induced by gallotannin in Hep G2 cells. Overall, our findings demonstrate that the disruption of cell adhesion junction by suppression of E-cadherin mediates gallotannin enhanced apoptosis in Hep G2 liver cancer cells.

  12. Melatonin Suppresses Autophagy Induced by Clinostat in Preosteoblast MC3T3-E1 Cells.

    Science.gov (United States)

    Yoo, Yeong-Min; Han, Tae-Young; Kim, Han Sung

    2016-04-08

    Microgravity exposure can cause cardiovascular and immune disorders, muscle atrophy, osteoporosis, and loss of blood and plasma volume. A clinostat device is an effective ground-based tool for simulating microgravity. This study investigated how melatonin suppresses autophagy caused by simulated microgravity in preosteoblast MC3T3-E1 cells. In preosteoblast MC3T3-E1 cells, clinostat rotation induced a significant time-dependent increase in the levels of the autophagosomal marker microtubule-associated protein light chain (LC3), suggesting that autophagy is induced by clinostat rotation in these cells. Melatonin treatment (100, 200 nM) significantly attenuated the clinostat-induced increases in LC3 II protein, and immunofluorescence staining revealed decreased levels of both LC3 and lysosomal-associated membrane protein 2 (Lamp2), indicating a decrease in autophagosomes. The levels of phosphorylation of mammalian target of rapamycin (p-mTOR) (Ser2448), phosphorylation of extracellular signal-regulated kinase (p-ERK), and phosphorylation of serine-threonine protein kinase (p-Akt) (Ser473) were significantly reduced by clinostat rotation. However, their expression levels were significantly recovered by melatonin treatment. Also, expression of the Bcl-2, truncated Bid, Cu/Zn- superoxide dismutase (SOD), and Mn-SOD proteins were significantly increased by melatonin treatment, whereas levels of Bax and catalase were decreased. The endoplasmic reticulum (ER) stress marker GRP78/BiP, IRE1α, and p-PERK proteins were significantly reduced by melatonin treatment. Treatment with the competitive melatonin receptor antagonist luzindole blocked melatonin-induced decreases in LC3 II levels. These results demonstrate that melatonin suppresses clinostat-induced autophagy through increasing the phosphorylation of the ERK/Akt/mTOR proteins. Consequently, melatonin appears to be a potential therapeutic agent for regulating microgravity-related bone loss or osteoporosis.

  13. Peripheral and central mediators of lipopolysaccharide induced suppression of defensive rage behavior in the cat.

    Science.gov (United States)

    Bhatt, S; Bhatt, R S; Zalcman, S S; Siegel, A

    2009-11-10

    LPS induced suppression of defensive rage. The results demonstrate that LPS suppresses defensive rage by acting through peripheral TNF-alpha in periphery and that central effects of LPS suppression of defensive rage are mediated through PGE(2) and 5-HT(1A) receptors in the medial hypothalamus.

  14. Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-alpha expression.

    Science.gov (United States)

    Lai, Jiann-Jyh; Lai, Kuo-Pao; Chuang, Kuang-Hsiang; Chang, Philip; Yu, I-Chen; Lin, Wen-Jye; Chang, Chawnshang

    2009-12-01

    Cutaneous wounds heal more slowly in elderly males than in elderly females, suggesting a role for sex hormones in the healing process. Indeed, androgen/androgen receptor (AR) signaling has been shown to inhibit cutaneous wound healing. AR is expressed in several cell types in healing skin, including keratinocytes, dermal fibroblasts, and infiltrating macrophages, but the exact role of androgen/AR signaling in these different cell types remains unclear. To address this question, we generated and studied cutaneous wound healing in cell-specific AR knockout (ARKO) mice. General and myeloid-specific ARKO mice exhibited accelerated wound healing compared with WT mice, whereas keratinocyte- and fibroblast-specific ARKO mice did not. Importantly, the rate of wound healing in the general ARKO mice was dependent on AR and not serum androgen levels. Interestingly, although dispensable for wound closure, keratinocyte AR promoted re-epithelialization, while fibroblast AR suppressed it. Further analysis indicated that AR suppressed wound healing by enhancing the inflammatory response through a localized increase in TNF-alpha expression. Furthermore, AR enhanced local TNF-alpha expression via multiple mechanisms, including increasing the inflammatory monocyte population, enhancing monocyte chemotaxis by upregulating CCR2 expression, and enhancing TNF-alpha expression in macrophages. Finally, targeting AR by topical application of a compound (ASC-J9) that degrades AR protein resulted in accelerated healing, suggesting a potential new therapeutic approach that may lead to better treatment of wound healing.

  15. Management of Nonsteroidal Anti-Inflammatory Drug-Induced Gastroduodenal Disease by Acid Suppression

    Directory of Open Access Journals (Sweden)

    R Lad

    1999-01-01

    Full Text Available One major cause of peptic ulceration is the use of nonsteroidal anti-inflammatory drugs (NSAIDs. The precise mechanisms through which NSAIDs cause peptic ulceration are unknown, but the discovery that they reduce the production of ‘cytoprotective’ prostaglandins led to the hypothesis that coadministration of exogenous prostaglandins heals and prevents NSAID-induced gastroduodenal ulcers and other mucosal lesions. Studies using high doses of misoprostol have shown that it does have a protective effect; however, gastrointestinal intolerance of this prostaglandin E2 analogue is common. Early indications that acid suppression was effective in the management of NSAID-related peptic ulcers came from studies showing that gastric ulcers could be healed by omeprazole in patients who continued to take NSAIDs. Other studies suggested that acid suppression reduces the incidence of mucosal lesions but that standard dose ranitidine protects only against duodenal lesions. Subsequent studies reported that higher dose H2 receptor antagonist therapy can protect against both gastric and duodenal ulcers during continued NSAID therapy. An ideal therapeutic strategy would heal NSAID-related ulcers and prevent the development of new NSAID-related lesions and complications in patients who are unable to discontinue NSAID therapy. A number of recent studies indicate that effective acid-suppressive treatment with the proton pump inhibitor omeprazole can achieve these aims. Overall, data from recent studies show that acid suppression with the proton pump inhibitor omeprazole at a dose of 20 mg daily is the most effective means of healing NSAID-associated gastroduodenal lesions and that it is the most effective prophylactic therapy. In the long run, the role of omeprazole will have to be evaluated with respect to its cost effectiveness compared with other strategies and with respect to the development of less damaging NSAIDs.

  16. 10 Hz Amplitude Modulated Sounds Induce Short-Term Tinnitus Suppression

    Directory of Open Access Journals (Sweden)

    Patrick Neff

    2017-05-01

    noise: t(27 = −4.22, p < 0.0001]. Finally, variants of the AM sound matched to the tinnitus frequency reduced in sound level resulted in less suppression while there was no significant difference observed for a longer stimulation duration. Moreover, feasibility of the overall procedure could be confirmed as scores of both tinnitus loudness and questionnaires were lower after the experiment [tinnitus loudness: t(27 = 2.77, p < 0.01; Tinnitus Questionnaire: t(27 = 2.06, p < 0.05; Tinnitus Handicap Inventory: t(27 = 1.92, p = 0.065].Conclusion: Taken together, these results imply that AM sounds, especially in or around the tinnitus frequency, may induce larger suppression than unmodulated sounds. Future studies should thus evaluate this approach in longitudinal studies and real life settings. Furthermore, the putative neural relation of these sound stimuli with a modulation rate in the EEG α band to the observed tinnitus suppression should be probed with respective neurophysiological methods.

  17. Emodin suppresses LPS-induced inflammation in RAW264.7 cells through a PPARγ-dependent pathway.

    Science.gov (United States)

    Zhu, Tao; Zhang, Wei; Feng, She-jun; Yu, Hua-peng

    2016-05-01

    Inflammation is a defense and protective response to multiple harmful stimuli. Over and uncontrolled inflammation can lead to local tissues or even systemic damages and injuries. Actually, uncontrolled and self-amplified inflammation is the fundament of the pathogenesis of a variety of inflammatory diseases, including sepsis shock, acute lung injury and acute respiratory distress syndrome (ALI/ARDS). Our recent study showed that emodin, the main active component of Radix rhizoma Rhei, could significantly ameliorate LPS-induced ALI/ARDS in mice. However, its underlying signal pathway was not still very clear. Then, the aim of current study was to explore whether emodin could attenuate LPS-induced inflammation in RAW264.7 cells, and its involved potential mechanism. The mRNA and protein expression of ICAM-1, MCP-1 and PPARγ were measured by qRCR and western blotting, the production of TNF-α was evaluated by ELISA. Then, the phosphorylation of NF-κB p65 was also detected by western blotting. And NF-κB p65 DNA binding activity was analyzed by ELISA as well. Meanwhile, siRNA-PPARγ transfection was performed to knockdown PPARγ expression in cells. Our data revealed that LPS-induced the up-regulation of ICAM-1, MCP-1 and TNF-α, LPS-induced the down-regulation of PPARγ, and LPS-enhanced NF-κB p65 activation and DNA binding activity were substantially suppressed by emdoin in RAW264.7 cells. Furthermore, our data also figured out that these effects of emdoin were largely abrogated by siRNA-PPARγ transfection. Taken together, our results indicated that LPS-induced inflammation were potently compromised by emodin very likely through the PPARγ-dependent inactivation of NF-κB in RAW264.7 cells.

  18. Infection of Mice with Mycobacterium bovis–Bacillus Calmette-Guérin (BCG) Suppresses Allergen-induced Airway Eosinophilia

    Science.gov (United States)

    Erb, Klaus Josef; Holloway, John W.; Sobeck, Alexandra; Moll, Heidrun; Le Gros, Graham

    1998-01-01

    It has been proposed that the increase in prevalence and severity of atopic disorders inversely correlates with exposure to infectious diseases such as tuberculosis. We have investigated this issue by combining an intranasal Mycobacterium bovis–Bacillus Calmette-Guérin (BCG) infection with a murine model of allergen, (ovalbumin [OVA]) induced airway eosinophilia. BCG infection either 4 or 12 wk before allergen airway challenge resulted in a 90–95 and 60–70% reduction in eosinophilia within the lungs, respectively, compared to uninfected controls. The inhibition of airway eosinophilia correlated with a reduced level of IL-5 production by T cells from the lymph node draining the site of OVA challenge. Interestingly, BCG infection of the lung had no effect on IgG1 and IgE OVA-specific serum immunoglobulin or blood eosinophil levels. Furthermore, BCG-induced inhibition of airway eosinophilia was strongly reduced in interferon (IFN)-γ receptor–deficient mice and could be partially reversed by intranasal IL-5 application. Intranasal BCG infections could also reduce the degree of lung eosinophilia and IL-5 produced by T cells after Nippostrongylus brasiliensis infection. Taken together, our data suggest that IFN-γ produced during the T helper cell (Th)1 immune response against BCG suppresses the development of local inflammatory Th2 responses in the lung. Most importantly, this inhibition did not extend to the systemic immunoglobulin response against OVA. Our data support the view that mycobacterial infections have the potential to suppress the development of atopic disorders in humans. PMID:9463406

  19. Chaos suppression and desynchronization phenomena in periodically coupled pendula subjected to localized heterogeneous forces

    Energy Technology Data Exchange (ETDEWEB)

    Chacon, R. [Departamento de Fisica Aplicada, Escuela de Ingenierias Industriales, Universidad de Extremadura, Apartado Postal 382, E-06071 Badajoz (Spain)], E-mail: rchacon@unex.es; Martinez, P.J. [Departamento de Fisica Aplicada, E.U.I.T.I., Universidad de Zaragoza, Spain and Instituto de Ciencia de Materiales de Aragon, CSIC-Universidad de Zaragoza, E-50009 Zaragoza (Spain); Martinez, J.A. [Departamento de Ingenieria Electrica, Electronica y Automatica, E.P.S., Universidad de Castilla-La Mancha, E-02071 Albacete (Spain); Lenci, S. [Dipartimento di Architettura, Costruzioni e Strutture, Universita Politecnica delle Marche, via Brecce Bianche, 60131 Ancona (Italy)

    2009-11-30

    The suppressory effects of localized heterogeneous periodic pulses on the chaotic behaviour of sinusoidally coupled nonlinear pendula are studied. We assume that when the pendula are driven synchronously, i.e., all driving pulses have the same waveform, the chains display chaotic dynamics. It is shown that decreasing the impulse transmitted by the pulses of a minimal number of pendula results in regularization with the whole array exhibiting frequency synchronization over a wide range of coupling periods. These findings demonstrate that decreasing the impulse transmitted by localized external forces can tame chaos and lead to frequency-locked states in networks of periodically coupled dissipative systems.

  20. The Necrosome Promotes Pancreas Oncogenesis via CXCL1 and Mincle Induced Immune Suppression

    Science.gov (United States)

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Barilla, Rocky; Daley, Donnele; Greco, Stephanie H.; Torres-Hernandez, Alejandro; Pergamo, Matthew; Ochi, Atsuo; Zambirinis, Constantinos P.; Pansari, Mridul; Rendon, Mauricio; Tippens, Daniel; Hundeyin, Mautin; Mani, Vishnu R.; Hajdu, Cristina; Engle, Dannielle; Miller, George

    2016-01-01

    Neoplastic pancreatic epithelial cells are widely believed to die via Caspase 8-dependant apoptotic cell death and chemotherapy is thought to further promote tumor apoptosis1. Conversely, disruption of apoptosis is a basic modality cancer cells exploit for survival2,3. However, the role of necroptosis, or programmed necrosis, in pancreatic ductal adenocarcinoma (PDA) is uncertain. There are a multitude of potential inducers of necroptosis in PDA including ligation of TNFR1, CD95, TRAIL receptors, Toll-like receptors, ROS, and Chemotherapeutics4,5. Here we report that the principal components of the necrosome, RIP1 and RIP3, are highly expressed in PDA and are further upregulated by chemotherapy. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo RIP3 deletion or RIP1 inhibition was protective against oncogenic progression and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumor microenvironment (TME) associated with intact RIP1/RIP3 signaling was in-part contingent on necroptosis-induced CXCL1 expression whereas CXCL1 blockade was protective against PDA. Moreover, we found that cytoplasmic SAP130 was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle – its cognate receptor – was upregulated in tumor-infiltrating myeloid cells. Mincle ligation by SAP130 promoted oncogenesis whereas Mincle deletion was protective and phenocopied the immunogenic reprogramming of the TME characteristic of RIP3 deletion. Cellular depletion experiments suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects in the context of RIP3 or Mincle deletion. As such, T cells which are dispensable to PDA progression in hosts with intact RIP3 or Mincle signaling become reprogrammed into indispensable mediators of anti-tumor immunity in absence of RIP3 or Mincle. Our work

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

    Science.gov (United States)

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

    2015-12-01

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

  2. A comparative study of EEG suppressions induced by global cerebral ischemia and anoxia.

    Science.gov (United States)

    Zagrean, L; Vatasescu, R; Oprica, M; Nutiu, O; Ferechide, D

    1995-01-01

    Cerebral ischemia and anoxia induce sequential changes that include ionic redistribution, alteration of enzimatic reactions governing metabolism and intracellular signaling. Despite high technology instrumentation including positron emission, tomography and magnetic resonance imaging used to unravel the intricacies of cerebral blood flow and metabolism, the electroencephalography (EEG) retains a useful place in the evaluation of processes induced by cerebral ischemia, especially in experimental conditions. We have investigated in this study EEG suppression and recovery following global cerebral ischemia, obtained by "four vessel occlusion model", reperfusion and anoxia. Both cerebral ischemia and anoxia have produced a sudden diminution of electrical brain activity and flat line was recorded after 8-10 sec. in the ischemic rats, but after 35-40 sec. in the anoxic rats. After same period of time (2 min) of ischemia and anoxia EEG recovery has been faster in the ischemic rat.

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

    Science.gov (United States)

    Baek, Seung-Soo; Kim, Sang-Hoon

    2016-01-01

    Alzheimer disease (AD) is a most common form of dementia and eventually causes impairments of learning ability and memory function. In the present study, we investigated the effects of treadmill exercise on the symptoms of AD focusing on the microglial activation-induced apoptosis. AD was made by bilateral intracerebroventricular injection of streptozotocin. The rats in the exercise groups were made to run on a treadmill once a day for 30 min during 4 weeks. The distance and latency in the Morris water maze task and the latency in the step-down avoidance task were increased in the AD rats, in contrast, treadmill exercise shortened these parameters. The numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive and caspase-3-positive cells in the hippocampal dentate gyrus were decreased in the AD rats, in contrast, treadmill exercise suppressed these numbers. Expressions of glial fibrillary acidic protein (GFAP) and cluster of differentiation molecule 11B (CD11b) in the hippocampal dentate gyrus were increased in the AD rats, in contrast, treadmill exercise suppressed GFAP and CD11b expressions. Bax expression was increased and Bcl-2 expression was decreased in the hippocampus of AD rats, in contrast, treadmill exercise decreased Bax expression and increased Bcl-2 expression. The present results demonstrated that treadmill exercise ameliorated AD-induced impairments of spatial learning ability and short-term memory through suppressing apoptosis. The antiapoptotic effect of treadmill exercise might be ascribed to the inhibitory effect of treadmill exercise on microglial activation. PMID:28119873

  4. Obesity-induced endoplasmic reticulum stress suppresses nuclear factor-Y expression.

    Science.gov (United States)

    Liu, Yulan; Zhang, Yuwei; Zhang, Yanjie; Zhang, Jinlong; Liu, Yin; Feng, Peiqun; Su, Zhiguang

    2017-02-01

    Nuclear transcription factor Y (NF-Y) is an evolutionarily conserved transcription factor composed of three subunits, NF-YA, NF-YB, and NF-YC. NF-Y plays crucial roles in pre-adipocyte maintenance and/or commitment to adipogenesis. NF-YA dysfunction in adipocyte resulted in an age-dependent progressive loss of adipose tissue associated with metabolic complications. Endoplasmic reticulum (ER) stress has emerged as an important mediator in the pathogenesis of obesity. However, it is not known if NF-YA is involved in the ER stress-mediated pathogenesis of obesity. We first examined the effects of ER stress on the NF-YA expression in cultured 3T3-L1 adipocytes; then in ob/ob genetic obesity mice, we tested the effect of chemical chaperones alleviating ER stress on the expression levels of NF-YA. Subsequently, we inhibited the new mRNA synthesis using actinomycin D in 3T3-L1 cells to explore the mechanism modulating NF-YA expression. Finally, we evaluated the involvement of PPARg in the regulation of NF-YA expression by ER stress. We demonstrated that both obesity- and chemical chaperone -induced ER stress suppressed NF-YA expression and alleviation of ER stress by chemical chaperone could recover NF-YA expression in ob/ob mice. Moreover, we showed that ER stress suppressed NF-YA mRNA transcription through the involvement of peroxisome proliferator-activated receptor gamma (PPARg). Activation of PPARg ameliorates the ER stress-induced NF-YA suppression. Our findings may point to a possible role of NF-YA in stress conditions that occur in chronic obesity, ER stress might be involved in the pathogenesis of obesity through NF-YA depletion.

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

    Science.gov (United States)

    Baek, Seung-Soo; Kim, Sang-Hoon

    2016-12-01

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

  6. Cepharanthine attenuates lipopolysaccharide-induced mice mastitis by suppressing the NF-κB signaling pathway.

    Science.gov (United States)

    Ershun, Zhou; Yunhe, Fu; Zhengkai, Wei; Yongguo, Cao; Naisheng, Zhang; Zhengtao, Yang

    2014-04-01

    Cepharanthine (CEP), a biscoclaurine alkaloid isolated from Stephania cepharantha Hayata, has been reported to have potent anti-inflammatory properties. However, the anti-inflammatory effects of CEP on a mouse model of lipopolysaccharide (LPS)-induced mastitis and its underlying molecular mechanisms remain to be elucidated. The purpose of the present study was to investigate the effects of CEP on LPS-induced mouse mastitis. The mouse model of mastitis was induced by inoculation of LPS through the canals of the mammary gland. CEP was administered intraperitoneally at 1 h before and 12 h after induction of LPS. The results show that CEP significantly attenuates the infiltration of neutrophils, suppresses myeloperoxidase activity, and reduces the levels of TNF-α, IL-1β, and IL-6 in LPS-induced mouse mastitis. Furthermore, CEP inhibited the phosphorylation of NF-κB p65 subunit and the degradation of its inhibitor IκBα. All the results suggest that CEP exerts potent anti-inflammatory effects on LPS-induced mouse mastitis. Accordingly, CEP might be a potential therapeutic agent for mastitis.

  7. Induced plant-defenses suppress herbivore reproduction but also constrain predation of their offspring.

    Science.gov (United States)

    Ataide, Livia M S; Pappas, Maria L; Schimmel, Bernardus C J; Lopez-Orenes, Antonio; Alba, Juan M; Duarte, Marcus V A; Pallini, Angelo; Schuurink, Robert C; Kant, Merijn R

    2016-11-01

    Inducible anti-herbivore defenses in plants are predominantly regulated by jasmonic acid (JA). On tomato plants, most genotypes of the herbivorous generalist spider mite Tetranychus urticae induce JA defenses and perform poorly on it, whereas the Solanaceae specialist Tetranychus evansi, who suppresses JA defenses, performs well on it. We asked to which extent these spider mites and the predatory mite Phytoseiulus longipes preying on these spider mites eggs are affected by induced JA-defenses. By artificially inducing the JA-response of the tomato JA-biosynthesis mutant def-1 using exogenous JA and isoleucine (Ile), we first established the relationship between endogenous JA-Ile-levels and the reproductive performance of spider mites. For both mite species we observed that they produced more eggs when levels of JA-Ile were low. Subsequently, we allowed predatory mites to prey on spider mite-eggs derived from wild-type tomato plants, def-1 and JA-Ile-treated def-1 and observed that they preferred, and consumed more, eggs produced on tomato plants with weak JA defenses. However, predatory mite oviposition was similar across treatments. Our results show that induced JA-responses negatively affect spider mite performance, but positively affect the survival of their offspring by constraining egg-predation. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  8. Quercetin Suppresses Twist to Induce Apoptosis in MCF-7 Breast Cancer Cells.

    Science.gov (United States)

    Ranganathan, Santhalakshmi; Halagowder, Devaraj; Sivasithambaram, Niranjali Devaraj

    2015-01-01

    Quercetin is a dietary flavonoid which exerts anti-oxidant, anti-inflammatory and anti-cancer properties. In this study, we investigated the anti-proliferative effect of quercetin in two breast cancer cell lines (MCF-7 and MDA-MB-231), which differed in hormone receptor. IC50 value (37μM) of quercetin showed significant cytotoxicity in MCF-7 cells, which was not observed in MDA-MB-231 cells even at 100μM of quercetin treatment. To study the response of cancer cells to quercetin, with respect to different hormone receptors, both the cell lines were treated with a fixed concentration (40μM) of quercetin. MCF-7 cells on quercetin treatment showed more apoptotic cells with G1 phase arrest. In addition, quercetin effectively suppressed the expression of CyclinD1, p21, Twist and phospho p38MAPK, which was not observed in MDA-MB-231 cells. To analyse the molecular mechanism of quercetin in exerting an apoptotic effect in MCF-7 cells, Twist was over-expressed and the molecular changes were observed after quercetin administration. Quercetin effectively regulated the expression of Twist, in turn p16 and p21 which induced apoptosis in MCF-7 cells. In conclusion, quercetin induces apoptosis in breast cancer cells through suppression of Twist via p38MAPK pathway.

  9. Peroxisome proliferator-activated receptor γ ligands suppress liver carcinogenesis induced by diethylnitrosamine in rats

    Institute of Scientific and Technical Information of China (English)

    Yan-Tong Guo; Xi-Sheng Leng; Tao Li; Jing-Ming Zhao; Xi-Hou Lin

    2004-01-01

    AIM: Peroxisome proliferator-activated receptor γ (PPARγ)is known to regulate growth arrest and terminal differentiation of adipocytes and is used clinically as a new class of antidiabetic drugs. Recently, several studies have reported that treatment of cancer cells with PPARγ ligands could induce cell differentiation and apoptosis, suggesting a potential application as chemopreventive agents against carcinogenesis. In the present study, 3 different kinds of PPARγ ligands were subjected to the experiments to confirm their suppressive effects on liver carcinogenesis.METHODS: Three PPARγ ligands, pioglitazone (Pio) (200 ppm),rosiglitazone (Rosi) (200 ppm), and troglitazone (Tro)(1 000 ppm) were investigated on the induction of the placental form of rat glutathione S-transferase (rGST P)positive foci, a precancerous lesion of the liver, and liver cancer formation using a diethylnitrosamine-induced liver cancer model in Wistar rats, and dose dependency of a PPARγ ligand was also examined.RESULTS: PPARγ ligands reduced the formation of rGST P-positive foci by diethylnitrosamine and induction of liver cancers was also markedly suppressed by a continuous feeding of Pio at 200 ppm.CONCLUSION: PPARγ ligands are potential chemopreventive agents for liver carcinogenesis.

  10. Hydrodynamic mechanism behind the suppression of vortex-induced vibration with permeable meshes

    Science.gov (United States)

    Assi, Gustavo R. S.; Cicolin, Murilo M.; Freire, Cesar M.

    2016-11-01

    Vortex-induced vibration (VIV) induces resonant vibrations on elastic bluff bodies when exposed to a flow. A VIV suppressor called "ventilated trousers" (VT) - consisting of a flexible net with tens of bobbins fitted every other node - has been developed as a commercial solution. Only a few experiments in the literature have evaluated the effectiveness of the VT, but very little is know about the underlying mechanism behind the suppression. Experiments have been carried out in a water channel with models of circular cylinders fitted with three different permeable meshes. VIV response and drag were obtained for models free to oscillate in the cross-flow direction with low mass and damping (Re = 5 , 000 to 25,000). All meshes achieved an average 50% reduction of the peak amplitude and reduced the mean drag when compared to that of a bare cylinder. PIV visualization of the wake revealed that the VT produced a much longer vortex-formation length, thus explaining its enhanced efficiency in suppressing VIV and reducing drag. The geometry and distribution of the bobbins proved to be important parameters. PIV also revealed the rich three-dimensional flow structures created by the bobbins that disrupt the formation of a coherent vortex wake. FAPESP 11/00205-6, 14/50279-4; CNPq 306917/2015-7.

  11. Quercetin Suppresses Twist to Induce Apoptosis in MCF-7 Breast Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Santhalakshmi Ranganathan

    Full Text Available Quercetin is a dietary flavonoid which exerts anti-oxidant, anti-inflammatory and anti-cancer properties. In this study, we investigated the anti-proliferative effect of quercetin in two breast cancer cell lines (MCF-7 and MDA-MB-231, which differed in hormone receptor. IC50 value (37μM of quercetin showed significant cytotoxicity in MCF-7 cells, which was not observed in MDA-MB-231 cells even at 100μM of quercetin treatment. To study the response of cancer cells to quercetin, with respect to different hormone receptors, both the cell lines were treated with a fixed concentration (40μM of quercetin. MCF-7 cells on quercetin treatment showed more apoptotic cells with G1 phase arrest. In addition, quercetin effectively suppressed the expression of CyclinD1, p21, Twist and phospho p38MAPK, which was not observed in MDA-MB-231 cells. To analyse the molecular mechanism of quercetin in exerting an apoptotic effect in MCF-7 cells, Twist was over-expressed and the molecular changes were observed after quercetin administration. Quercetin effectively regulated the expression of Twist, in turn p16 and p21 which induced apoptosis in MCF-7 cells. In conclusion, quercetin induces apoptosis in breast cancer cells through suppression of Twist via p38MAPK pathway.

  12. Danshen (Salvia miltiorrhiza injection suppresses kidney injury induced by iron overload in mice.

    Directory of Open Access Journals (Sweden)

    Shengjiang Guan

    Full Text Available OBJECTIVES: Excessive iron can accumulate in the kidney and induce tissue damage. Danshen (Salvia miltiorrhiza injection is a traditional Chinese medicinal preparation used for preventing and treating chronic renal failure. The aim of the present study was to evaluate the effects of treatment with Danshen injection on iron overload-induced kidney damage. METHODS: Mice were mock-treated with saline (control group or given a single dose of iron dextran without treatment (iron overload group, 50 mg/kg/day for 2 weeks or with daily treatments of low-dose Danshen (3 g/kg/day, high-dose Danshen (6 g/kg/day or deferoxamine (100 mg/kg/day. RESULTS: Treatment of iron-overloaded mice with Danshen injection led to significant improvements of body weight and decreased iron levels in the kidney. Danshen injection treatment also reduced concentrations of blood urea nitrogen, creatinine and malondialdehyde and enhanced glutathione peroxidase and superoxide dismutase activities. Histopathological examinations showed that Danshen injection ameliorated pathological changes and reduced iron deposition in kidneys of iron overloaded mice. Furthermore, the treatment was demonstrated to suppress apoptosis in nephrocytes. CONCLUSIONS: These results indicated that Danshen injection exerted significant renal protective effects in iron-overloaded mice, which were closely associated with the decrease of iron deposition and suppression of lipid peroxidation and apoptosis in the kidney.

  13. Suppression of Kasha's rule as a mechanism for fluorescent molecular rotors and aggregation-induced emission

    Science.gov (United States)

    Qian, Hai; Cousins, Morgan E.; Horak, Erik H.; Wakefield, Audrey; Liptak, Matthew D.; Aprahamian, Ivan

    2017-01-01

    Although there are some proposed explanations for aggregation-induced emission, a phenomenon with applications that range from biosensors to organic light-emitting diodes, current understanding of the quantum-mechanical origin of this photophysical behaviour is limited. To address this issue, we assessed the emission properties of a series of BF2-hydrazone-based dyes as a function of solvent viscosity. These molecules turned out to be highly efficient fluorescent molecular rotors. This property, in addition to them being aggregation-induced emission luminogens, enabled us to probe deeper into their emission mechanism. Time-dependent density functional theory calculations and experimental results showed that the emission is not from the S1 state, as predicted from Kasha's rule, but from a higher energy (>S1) state. Furthermore, we found that suppression of internal conversion to the dark S1 state by restricting the rotor rotation enhances fluorescence, which leads to the proposal that suppression of Kasha's rule is the photophysical mechanism responsible for emission in both viscous solution and the solid state.

  14. Histamine 2 blocker potentiates the effects of histamine 1 blocker in suppressing histamine-induced wheal

    Directory of Open Access Journals (Sweden)

    Dhanya N

    2008-01-01

    Full Text Available Background : Histamine is responsible for the wheal and flare reaction in various allergic conditions. Classical antihistamines are the drugs which block the H 1 receptors and are widely used in various allergic conditions, whereas H 2 blockers are mainly used for acid peptic disease. Although H 1 receptor-mediated actions of histamine are primarily responsible for vasodilatation, vasopermeability, and itching, it has been observed that combined blocking of both H 1 and H 2 receptors may provide better relief. Aim: To compare the efficacy of levocetirizine (H 1 blocker versus levocetirizine and ranitidine (H 2 blocker in suppressing histamine-induced wheal. Methods: Fifteen volunteers were given a single dose of levocetirizine 5 mg on day 1 and a single dose of levocetirizine 5 mg with ranitidine 150 mg twice a day on day 7. A pretest was performed by intradermal histamine prick test. After administration of the drugs, the prick test was repeated at 1 hour, 2, 3, 6, and 24 hours, and the size of the wheal measured and statistically analyzed. Results: At 1 hour, there was no statistically significant difference in the wheal size between levocetirizine alone and the combination of levocetirizine and ranitidine. Levocetirizine with ranitidine resulted in statistically significant reduction of wheal size at 2, 3, 6, and 24 hours when compared with levocetirizine alone. Conclusion: H2 blocker potentiates the effects of an H1 blocker in suppressing histamine-induced wheal.

  15. Copper chelation with tetrathiomolybdate suppresses adjuvant-induced arthritis and inflammation-associated cachexia in rats

    Science.gov (United States)

    Omoto, Atsushi; Kawahito, Yutaka; Prudovsky, Igor; Tubouchi, Yasunori; Kimura, Mizuho; Ishino, Hidetaka; Wada, Makoto; Yoshida, Makie; Kohno, Masataka; Yoshimura, Rikio; Yoshikawa, Toshikazu; Sano, Hajime

    2005-01-01

    Tetrathiomolybdate (TM), a drug developed for Wilson's disease, produces an anti-angiogenic and anti-inflammatory effect by reducing systemic copper levels. TM therapy has proved effective in inhibiting the growth of tumors in animal tumor models and in cancer patients. We have hypothesized that TM may be used for the therapy of rheumatoid arthritis and have examined the efficacy of TM on adjuvant-induced arthritis in the rat, which is a model of acute inflammatory arthritis and inflammatory cachexia. TM delayed the onset of and suppressed the severity of clinical arthritis on both paw volume and the arthritis score. Histological examination demonstrated that TM significantly reduces the synovial hyperplasia and inflammatory cell invasion in joint tissues. Interestingly, TM can inhibit the expression of vascular endothelial growth factor in serum synovial tissues, especially in endothelial cells and macrophages. Moreover, the extent of pannus formation, which leads to bone destruction, is correlated with the content of vascular endothelial growth factor in the serum. There was no mortality in TM-treated rat abnormalities. TM also suppressed inflammatory cachexia. We suggest that copper deficiency induced by TM is a potent approach both to inhibit the progression of rheumatoid arthritis with minimal adverse effects and to improve the well-being of rheumatoid arthritis patients. PMID:16277669

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

    Directory of Open Access Journals (Sweden)

    Amanda R Lorier

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

  17. Focused ultrasound-mediated suppression of chemically-induced acute epileptic EEG activity

    Directory of Open Access Journals (Sweden)

    Chung Yong-An

    2011-03-01

    Full Text Available Abstract Background Epilepsy is a common neurological disorder, which is attributed to uncontrollable abnormal hyper-excitability of neurons. We investigated the feasibility of using low-intensity, pulsed radiation of focused ultrasound (FUS to non-invasively suppress epileptic activity in an animal model (rat, which was induced by the intraperitonial injection of pentylenetetrazol (PTZ. Results After the onset of induced seizures, FUS was transcranially administered to the brain twice for three minutes each while undergoing electroencephalographic (EEG monitoring. An air-backed, spherical segment ultrasound transducer (diameter: 6 cm; radius-of-curvature: 7 cm operating at a fundamental frequency of 690 KHz was used to deliver a train of 0.5 msec-long pulses of sonication at a repetitive rate of 100 Hz to the thalamic areas of the brain. The acoustic intensity (130 mW/cm2 used in the experiment was sufficiently within the range of safety guidelines for the clinical ultrasound imaging. The occurrence of epileptic EEG bursts from epilepsy-induced rats significantly decreased after sonication when it was compared to the pre-sonication epileptic state. The PTZ-induced control group that did not receive any sonication showed a sustained number of epileptic EEG signal bursts. The animals that underwent sonication also showed less severe epileptic behavior, as assessed by the Racine score. Histological analysis confirmed that the sonication did not cause any damage to the brain tissue. Conclusions These results revealed that low-intensity, pulsed FUS sonication suppressed the number of epileptic signal bursts using acute epilepsy model in animal. Due to its non-invasiveness and spatial selectivity, FUS may offer new perspectives for a possible non-invasive treatment of epilepsy.

  18. Cohesin Is limiting for the suppression of DNA damage-induced recombination between homologous chromosomes.

    Directory of Open Access Journals (Sweden)

    Shay Covo

    2010-07-01

    Full Text Available Double-strand break (DSB repair through homologous recombination (HR is an evolutionarily conserved process that is generally error-free. The risk to genome stability posed by nonallelic recombination or loss-of-heterozygosity could be reduced by confining HR to sister chromatids, thereby preventing recombination between homologous chromosomes. Here we show that the sister chromatid cohesion complex (cohesin is a limiting factor in the control of DSB repair and genome stability and that it suppresses DNA damage-induced interactions between homologues. We developed a gene dosage system in tetraploid yeast to address limitations on various essential components in DSB repair and HR. Unlike RAD50 and RAD51, which play a direct role in HR, a 4-fold reduction in the number of essential MCD1 sister chromatid cohesion subunit genes affected survival of gamma-irradiated G(2/M cells. The decreased survival reflected a reduction in DSB repair. Importantly, HR between homologous chromosomes was strongly increased by ionizing radiation in G(2/M cells with a single copy of MCD1 or SMC3 even at radiation doses where survival was high and DSB repair was efficient. The increased recombination also extended to nonlethal doses of UV, which did not induce DSBs. The DNA damage-induced recombinants in G(2/M cells included crossovers. Thus, the cohesin complex has a dual role in protecting chromosome integrity: it promotes DSB repair and recombination between sister chromatids, and it suppresses damage-induced recombination between homologues. The effects of limited amounts of Mcd1and Smc3 indicate that small changes in cohesin levels may increase the risk of genome instability, which may lead to genetic diseases and cancer.

  19. Heparin inhibits burn-induced spleen cell apoptosis by suppressing interleukin-1 expression

    Institute of Scientific and Technical Information of China (English)

    Zhao Songfeng; Zhang Xiao; Zhang Xiaojian; Shi Xiuqin; Yu Zujiang; Kan Quancheng

    2014-01-01

    Background Epidermal burn injury may trigger significant apoptosis of the spleen cells,which might be caused by a burninduced systemic inflammatory reaction.Heparin has been shown to possess anti-inflammatory properties.Interleukin 1 (IL-1) is centrally important among pro-inflammatory cytokines.We hypothesized that heparin might inhibit burn-induced apoptosis in the spleen via suppression of the IL-1 pathway.Methods Burn injury was performed on IL-1 R+/+ (IL-1 receptor wild-type mouse) and IL-1 R-/-(IL-1 receptor knockout mouse) mice,and they were then treated with heparin,saline or IL-1 receptor antagonist IL-Ra.Apoptosis,IL-1α and IL-1β expression were assessed in the spleens and serum.Survival curve analysis was further applied to elucidate the mechanism of heparin's protective properties.Results Burn induced significant apoptosis (sham:3.6%±2.1% vs.burn:28.8%±5.9%; P <0.001)and remarkable expression o IL-1α and IL-1β in the mouse spleens and serum.Heparin reduced the burn-induced apoptosis in the spleens (heparin treated:8.6%±3.4%,P <0.005),which could be blocked by IL-1Ra.Heparin markedly decreased both IL-1α and IL-1β expression in the spleens and serum of burned mica.IL-1 R-/-mice demonstrated considerably less apoptosis in the spleens and had a higher survival rate after burns.Heparin did not significantly decrease apoptosis in the spleen and the mortality rate in IL-1 R-/-mice after burns.Conclusion Heparin inhibits burn-induced apoptosis of the spleen cells by suppressing IL-1 expression in mice.

  20. Turnabout Is Fair Play: Herbivory-Induced Plant Chitinases Excreted in Fall Armyworm Frass Suppress Herbivore Defenses in Maize.

    Science.gov (United States)

    Ray, Swayamjit; Alves, Patrick C M S; Ahmad, Imtiaz; Gaffoor, Iffa; Acevedo, Flor E; Peiffer, Michelle; Jin, Shan; Han, Yang; Shakeel, Samina; Felton, Gary W; Luthe, Dawn S

    2016-05-01

    The perception of herbivory by plants is known to be triggered by the deposition of insect-derived factors such as saliva and oral secretions, oviposition materials, and even feces. Such insect-derived materials harbor chemical cues that may elicit herbivore and/or pathogen-induced defenses in plants. Several insect-derived molecules that trigger herbivore-induced defenses in plants are known; however, insect-derived molecules suppressing them are largely unknown. In this study, we identified two plant chitinases from fall armyworm (Spodoptera frugiperda) larval frass that suppress herbivore defenses while simultaneously inducing pathogen defenses in maize (Zea mays). Fall armyworm larvae feed in enclosed whorls of maize plants, where frass accumulates over extended periods of time in close proximity to damaged leaf tissue. Our study shows that maize chitinases, Pr4 and Endochitinase A, are induced during herbivory and subsequently deposited on the host with the feces. These plant chitinases mediate the suppression of herbivore-induced defenses, thereby increasing the performance of the insect on the host. Pr4 and Endochitinase A also trigger the antagonistic pathogen defense pathway in maize and suppress fungal pathogen growth on maize leaves. Frass-induced suppression of herbivore defenses by deposition of the plant-derived chitinases Pr4 and Endochitinase A is a unique way an insect can co-opt the plant's defense proteins for its own benefit. It is also a phenomenon unlike the induction of herbivore defenses by insect oral secretions in most host-herbivore systems.

  1. Sulforaphane suppresses LPS-induced or TPA-induced downregulation of PDCD4 in RAW 264.7 cells.

    Science.gov (United States)

    Cho, Jong-Ho; Kim, Young-Woo; Keum, Young-Sam

    2014-11-01

    Sulforaphane is a natural chemopreventive isothiocyanate and abundantly found in various cruciferous vegetables. Although chemopreventive activity of sulforaphane is well documented, the detailed biochemical mechanism(s), underlying how it regulates the protein translation process to antagonize pro-inflammatory responses are largely unclear. In the present study, we show that lipopolysaccharide (LPS) or 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment reduces cellular levels of PDCD4, and this event is mediated by affecting both transcription and proteolysis in RAW 264.7 cells. We show that LPS-mediated or TPA-mediated PDCD4 downregulation is catalyzed by the activation of intracellular Akt1 or S6K1 kinases and that sulforaphane suppresses LPS-induced or TPA-induced Akt1 or S6K1 activation, thereby resulting in the attenuation of PDCD4 downregulation in RAW 264.7 cells. We propose that sulforaphane suppression of PDCD4 downregulation serves as a novel molecular mechanism to control proliferation in response to pro-inflammatory signals. Copyright © 2014 John Wiley & Sons, Ltd.

  2. Amygdalin suppresses lipopolysaccharide-induced expressions of cyclooxygenase-2 and inducible nitric oxide synthase in mouse BV2 microglial cells.

    Science.gov (United States)

    Yang, Hye-Young; Chang, Hyun-Kyung; Lee, Jin-Woo; Kim, Young-Sick; Kim, Hong; Lee, Myoung-Hwa; Shin, Mal-Soon; Ham, Dae-Hyun; Park, Hun-Kuk; Lee, Hyejung; Kim, Chang-Ju

    2007-01-01

    Amygdalin (D-mandelonitrile-beta-D-gentiobioside) is a cynogenic compound found in sweet and bitter almonds, Persicae semen and Armeniacae semen. Amygdalin has been used for the treatment of cancers and for the relief of the pain. We made an aqueous extraction of amygdalin from Armeniacae semen. In this study, the effect of amygdalin on the lipopolysaccharide (LPS)-induced inflammation was investigated. The effects of amygdalin extracted from Armeniacae semen on the LPS-stimulated mRNA expressions of cyclooxygenase (COX)-1, COX-2 and inducible nitric oxide synthase (iNOS) in the mouse BV2 microglial cells were investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, reverse transcription-polymerase chain reaction (RT-PCR). The effects of amygdalin on the prostaglandins E(2) synthesis and the nitric oxide production were also studied by performing prostaglandins E(2) immunoassay and by detecting nitric oxide. The present results showed that amygdalin suppressed the prostaglandin E(2) synthesis and the nitric oxide production by inhibiting the LPS-stimulated mRNA expressions of COX-2 and iNOS in the mouse BV2 cells. These results show that amygdalin exerts anti-inflammatory and analgesic effects and it dose so probably by suppressing the mRNA expressions of COX-2 and iNOS.

  3. Canceling disorder-induced localization in nanophotonic cavity arrays

    CERN Document Server

    Sokolov, Sergei; Yüce, Emre; Combrié, Sylvain; De Rossi, Alfredo; Mosk, Allard P

    2016-01-01

    Optical circuits containing high-Q photonic crystal nanocavities have been proposed for delay lines, optical memory storage, optomechanics and quantum communication. However, unavoidable fabrication disorder in nanophotonic structures causes scattering which leads to frequency detuning, signal attenuation, and eventually localizes optical modes which ruins the transmission properties of the whole system. Even state-of-the-art nanofabrication with random spatial variations of only $\\Delta x=1\\ \\rm{nm}$ can lead to resonance wavelength detunings of more than $\\Delta \\lambda =1\\ \\rm{nm}$. In this work, we present a new method to cancel disorder-induced localization of light in a system of coupled nanocavities. We use holographic laser-induced heating to tune individual cavities, introduce a thermal response matrix approach and as a result we observe fully hybridized resonances of three coupled nanocavities, indicating that the effect of the disorder has been canceled. Our method is scalable to large arrays and e...

  4. Electrical signaling in Aloe vera induced by localized thermal stress.

    Science.gov (United States)

    Volkov, Alexander G; Lang, Ryan D; Volkova-Gugeshashvili, Maia I

    2007-11-01

    Action potentials in higher plants are theorized as the information carriers in intercellular and intracellular communication in the presence of environmental stressors. Among the most common stressors is heat shock. Under stressful conditions, the response reactions of plant tissues and organs can be local or transmitted over long distances. In this article, the speeds of propagation of thermally induced action potentials in green plants are discussed, and their speeds were found to be comparable to those occurring in various mammalian species. These rapid action potentials in green plants were recorded in real time using modern data acquisition techniques. According to our measurements, a single application of localized heat stress induces fast action potentials in Aloe vera (67 m/s). Electrical signals propagated along all leaves of the A. vera plants were studied. Possible pathways for electrical signal propagation in vascular plants are also discussed.

  5. Delay-induced depinning of localized structures in a spatially inhomogeneous Swift-Hohenberg model

    Science.gov (United States)

    Tabbert, Felix; Schelte, Christian; Tlidi, Mustapha; Gurevich, Svetlana V.

    2017-03-01

    We report on the dynamics of localized structures in an inhomogeneous Swift-Hohenberg model describing pattern formation in the transverse plane of an optical cavity. This real order parameter equation is valid close to the second-order critical point associated with bistability. The optical cavity is illuminated by an inhomogeneous spatial Gaussian pumping beam and subjected to time-delayed feedback. The Gaussian injection beam breaks the translational symmetry of the system by exerting an attracting force on the localized structure. We show that the localized structure can be pinned to the center of the inhomogeneity, suppressing the delay-induced drift bifurcation that has been reported in the particular case where the injection is homogeneous, assuming a continuous wave operation. Under an inhomogeneous spatial pumping beam, we perform the stability analysis of localized solutions to identify different instability regimes induced by time-delayed feedback. In particular, we predict the formation of two-arm spirals, as well as oscillating and depinning dynamics caused by the interplay of an attracting inhomogeneity and destabilizing time-delayed feedback. The transition from oscillating to depinning solutions is investigated by means of numerical continuation techniques. Analytically, we use an order parameter approach to derive a normal form of the delay-induced Hopf bifurcation leading to an oscillating solution. Additionally we model the interplay of an attracting inhomogeneity and destabilizing time delay by describing the localized solution as an overdamped particle in a potential well generated by the inhomogeneity. In this case, the time-delayed feedback acts as a driving force. Comparing results from the later approach with the full Swift-Hohenberg model, we show that the approach not only provides an instructive description of the depinning dynamics, but also is numerically accurate throughout most of the parameter regime.

  6. TDP-43 suppresses CGG repeat-induced neurotoxicity through interactions with HnRNP A2/B1

    Science.gov (United States)

    He, Fang; Krans, Amy; Freibaum, Brian D.; Taylor, J. Paul; Todd, Peter K.

    2014-01-01

    Nucleotide repeat expansions can elicit neurodegeneration as RNA by sequestering specific RNA-binding proteins, preventing them from performing their normal functions. Conversely, mutations in RNA-binding proteins can trigger neurodegeneration at least partly by altering RNA metabolism. In Fragile X-associated tremor/ataxia syndrome (FXTAS), a CGG repeat expansion in the 5′UTR of the fragile X gene (FMR1) leads to progressive neurodegeneration in patients and CGG repeats in isolation elicit toxicity in Drosophila and other animal models. Here, we identify the amyotrophic lateral sclerosis (ALS)-associated RNA-binding protein TAR DNA-binding protein (TDP-43) as a suppressor of CGG repeat-induced toxicity in a Drosophila model of FXTAS. The rescue appears specific to TDP-43, as co-expression of another ALS-associated RNA-binding protein, FUS, exacerbates the toxic effects of CGG repeats. Suppression of CGG RNA toxicity was abrogated by disease-associated mutations in TDP-43. TDP-43 does not co-localize with CGG RNA foci and its ability to bind RNA is not required for rescue. TDP-43-dependent rescue does, however, require fly hnRNP A2/B1 homologues Hrb87F and Hrb98DE. Deletions in the C-terminal domain of TDP-43 that preclude interactions with hnRNP A2/B1 abolish TDP-43-dependent rescue of CGG repeat toxicity. In contrast, suppression of CGG repeat toxicity by hnRNP A2/B1 is not affected by RNAi-mediated knockdown of the fly TDP-43 orthologue, TBPH. Lastly, TDP-43 suppresses CGG repeat-triggered mis-splicing of an hnRNP A2/B1-targeted transcript. These data support a model in which TDP-43 suppresses CGG-mediated toxicity through interactions with hnRNP A2/B1 and suggest a convergence of pathogenic cascades between repeat expansion disorders and RNA-binding proteins implicated in neurodegenerative disease. PMID:24920338

  7. The Suppression of Star Formation in Low-Mass Galaxies Caused by the Reionization of their Local Patch

    Science.gov (United States)

    Dawoodbhoy, Taha; Shapiro, Paul R.; Choi, Jun-Hwan; Ocvirk, Pierre; Gillet, Nicolas; Aubert, Dominique; Iliev, Ilian T.; Teyssier, Romain; Yepes, Gustavo; Sullivan, David; Knebe, Alexander; Gottloeber, Stefan; D'Aloisio, Anson; Park, Hyunbae; Hoffman, Yehuda; Stranex, Timothy

    2017-01-01

    The first stars and galaxies released enough ionizing radiation into the intergalactic medium (IGM) to ionize almost all the hydrogen atoms there by redshift z ~ 6. This process was "patchy" --- ionized zones grew in size over time until they overlapped to finish reionization.The photoheating associated with reionization caused a negative feedback on the galactic sources of reionization that suppressed star formation in low-mass galactic halos, especially those below 109 M⊙. To establish the causal connection between reionization and this suppression, we analyze the results of CoDa ("Cosmic Dawn"), the first fully-coupled radiation-hydrodynamical simulation of reionization and galaxy formation in the Local Universe, in a volume large enough to model reionization globally but with enough resolving power to follow all the atomic-cooling galactic halos in that volume. A 90 Mpc box was simulated from a constrained realization of primordial fluctuations, chosen to reproduce present-day features of the Local Group, including the Milky Way and M31, and the local universe beyond, including the Virgo cluster, with 40963 N-body particles for the dark matter and 40963 cells for the atomic gas and ionizing radiation. We use these results to show that the star formation rate in haloes below 109 M⊙ in different patches of the universe declined when each patch was reionized. Star formation in much more massive haloes continued, however. As a result, the earliest patches to develop structure and reionize ultimately produced more stars than they needed to reionize themselves, exporting their starlight to help reionize the regions that developed structure late.

  8. Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis.

    Science.gov (United States)

    Kreisel, T; Frank, M G; Licht, T; Reshef, R; Ben-Menachem-Zidon, O; Baratta, M V; Maier, S F; Yirmiya, R

    2014-06-01

    The limited success in understanding the pathophysiology of major depression may result from excessive focus on the dysfunctioning of neurons, as compared with other types of brain cells. Therefore, we examined the role of dynamic alterations in microglia activation status in the development of chronic unpredictable stress (CUS)-induced depressive-like condition in rodents. We report that following an initial period (2-3 days) of stress-induced microglial proliferation and activation, some microglia underwent apoptosis, leading to reductions in their numbers within the hippocampus, but not in other brain regions, following 5 weeks of CUS exposure. At that time, microglia displayed reduced expression of activation markers as well as dystrophic morphology. Blockade of the initial stress-induced microglial activation by minocycline or by transgenic interleukin-1 receptor antagonist overexpression rescued the subsequent microglial apoptosis and decline, as well as the CUS-induced depressive-like behavior and suppressed neurogenesis. Similarly, the antidepressant drug imipramine blocked the initial stress-induced microglial activation as well as the CUS-induced microglial decline and depressive-like behavior. Treatment of CUS-exposed mice with either endotoxin, macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor, all of which stimulated hippocampal microglial proliferation, partially or completely reversed the depressive-like behavior and dramatically increased hippocampal neurogenesis, whereas treatment with imipramine or minocycline had minimal or no anti-depressive effects, respectively, in these mice. These findings provide direct causal evidence that disturbances in microglial functioning has an etiological role in chronic stress-induced depression, suggesting that microglia stimulators could serve as fast-acting anti-depressants in some forms of depressive and stress-related conditions.

  9. Local Turbulence Suppression and Flow Shear Dynamics During qmin-Triggered Internal Transport Barriers

    Science.gov (United States)

    Shafer, M. W.; McKee, G. R.; Schlossberg, D. J.; Austin, M. E.; Waltz, R. E.; Candy, J.

    2007-11-01

    Turbulence is observed to transiently decrease locally during the formation of internal transport barriers (ITBs) following the appearance of low-order rational qmin surfaces in negative central shear discharges on DIII-D. Simultaneously, increased poloidal flow shear is observed. To further study this phenomenon, localized 2D density fluctuation measurements of turbulence and turbulence flow were obtained over 0.3 < r/a < 0.7 via the high-sensitivity beam emission spectroscopy diagnostic. Both the reduction in fluctuations and the poloidal velocity shear are found to propagate radially outward at about 1 m/s. Initial observations suggest that these effects follow the q=2 surface. Related GYRO simulations suggest transient zonal flows form near the q=2 surface to trigger these ITBs. High-frequency poloidal velocity measurements will be used to examine this mechanism.

  10. Local administration of siRNA through Microneedle: Optimization, Bio-distribution, Tumor Suppression and Toxicity

    Science.gov (United States)

    Tang, Tao; Deng, Yan; Chen, Jiao; Zhao, Yi; Yue, Ruifeng; Choy, Kwong Wai; Wang, Chi Chiu; Du, Quan; Xu, Yan; Han, Linxiao; Chung, Tony Kwok Hung

    2016-07-01

    Although RNA interference may become a novel therapeutic approach for cancer treatment, target-site accumulation of siRNA to achieve therapeutic dosage will be a major problem. Microneedle represents a better way to deliver siRNAs and we have evaluated for the first time the capability of a silicon microneedle array for delivery of Gapdh siRNA to the skin in vivo and the results showed that the microneedle arrays could effectively deliver siRNA to relevant regions of the skin noninvasively. For the further study in this field, we evaluated the efficacy of the injectable microneedle device for local delivery of siRNA to the mouse xenograft. The results presented here indicate that local administration of siRNA through injectable microneedle could effectively deliver siRNA into the tumor region, and inhibit tumor progression without major adverse effects.

  11. Alpha interferon induces distinct translational control programs to suppress hepatitis C virus RNA replication.

    Science.gov (United States)

    Wang, Chunfu; Pflugheber, Jill; Sumpter, Rhea; Sodora, Donald L; Hui, Daniel; Sen, Ganes C; Gale, Michael

    2003-04-01

    Hepatitis C virus (HCV) infection is treated with interferon (IFN)-based therapy. The mechanisms by which IFN suppresses HCV replication are not known, and only limited efficacy is achieved with therapy because the virus directs mechanisms to resist the host IFN response. In the present study we characterized the effects of IFN action upon the replication of two distinct quasispecies of an HCV replicon whose encoded NS5A protein exhibited differential abilities to bind and inhibit protein kinase R (PKR). Metabolic labeling experiments revealed that IFN had little overall effect upon HCV protein stability or polyprotein processing but specifically blocked translation of the HCV RNA, such that the replication of both viral quasispecies was suppressed by IFN treatment of the Huh7 host cells. However, within cells expressing an NS5A variant that inhibited PKR, we observed a reduced level of eukaryotic initiation factor 2 alpha subunit (eIF2alpha) phosphorylation and a concomitant increase in HCV protein synthetic rates, enhancement of viral RNA replication, and a partial rescue of viral internal ribosome entry site (IRES) function from IFN suppression. Assessment of the ribosome distribution of the HCV replicon RNA demonstrated that the NS5A-mediated block in eIF2alpha phosphorylation resulted in enhanced recruitment of the HCV RNA into polyribosome complexes in vivo but only partially rescued the RNA from polyribosome dissociation induced by IFN treatment. Examination of cellular proteins associated with HCV-translation complexes in IFN-treated cells identified the P56 protein as an eIF3-associated factor that fractionated with the initiator ribosome-HCV RNA complex. Importantly, we found that P56 could independently suppress HCV IRES function both in vitro and in vivo, but a mutant P56 that was unable to bind eIF3 had no suppressive action. We conclude that IFN blocks HCV replication through translational control programs involving PKR and P56 to, respectively

  12. Aurora B suppresses microtubule dynamics and limits central spindle size by locally activating KIF4A

    Science.gov (United States)

    Nunes Bastos, Ricardo; Gandhi, Sapan R.; Baron, Ryan D.; Gruneberg, Ulrike; Nigg, Erich A.

    2013-01-01

    Anaphase central spindle formation is controlled by the microtubule-stabilizing factor PRC1 and the kinesin KIF4A. We show that an MKlp2-dependent pool of Aurora B at the central spindle, rather than global Aurora B activity, regulates KIF4A accumulation at the central spindle. KIF4A phosphorylation by Aurora B stimulates the maximal microtubule-dependent ATPase activity of KIF4A and promotes its interaction with PRC1. In the presence of phosphorylated KIF4A, microtubules grew more slowly and showed long pauses in growth, resulting in the generation of shorter PRC1-stabilized microtubule overlaps in vitro. Cells expressing only mutant forms of KIF4A lacking the Aurora B phosphorylation site overextended the anaphase central spindle, demonstrating that this regulation is crucial for microtubule length control in vivo. Aurora B therefore ensures that suppression of microtubule dynamic instability by KIF4A is restricted to a specific subset of microtubules and thereby contributes to central spindle size control in anaphase. PMID:23940115

  13. Permittivity disorder induced Anderson localization in magnetophotonic crystals

    Energy Technology Data Exchange (ETDEWEB)

    Abdi-Ghaleh, R., E-mail: r.abdi@bonabu.ac.ir [Department of Laser and Optical Engineering, University of Bonab, 5551761167 Bonab (Iran, Islamic Republic of); Namdar, A. [Faculty of Physics, University of Tabriz, 5166614766 Tabriz (Iran, Islamic Republic of)

    2016-11-15

    This theoretical study was carried out to investigate the permittivity disorder induced Anderson localization of light in one-dimensional magnetophotonic crystals. It was shown that the disorder create the resonant transmittance modes associated with enhanced Faraday rotations inside the photonic band gap. The average localization length of the right- and left-handed circular polarizations (RCP and LCP), the total transmittance together with the ensemble average of the RCP and LCP phases, and the Faraday rotation of the structure were also investigated. For this purpose, the off-diagonal elements of the permittivity tensor were varied for various wavelengths of incident light. The obtained results revealed the nonreciprocal property of circular eigen modes. This study can potentially open up a new aspect for utilizing the disorder magnetophotonic structures in nonreciprocal systems such as isolators and circulators. - Highlights: • We theoretically investigated the permittivity disorder induced Anderson localization of light in magnetophotonic crystals. • The disorder considered in the diagonal elements of the permittivity tensor of magneto-optical layers. • The disorder create the resonant transmittance modes associated with enhanced Faraday rotations in the photonic band gap. • The average localization length of the circular polarizations and the ensemble average of their phases were investigated. • The obtained results revealed the nonreciprocal property of circular eigen modes.

  14. Suppression of noise in SEM images using weighted local hysteresis smoothing filter.

    Science.gov (United States)

    Mazhari, Mohadeseh; Hasanzadeh, Reza P R

    2016-11-01

    It has been proven that Hysteresis Smoothing (HS) has several advantages for Scanning Electron Microscopy (SEM) image noise reduction. HS uses hysteresis thresholding to remove noise besides preserving important details of images. Determination of optimal threshold values (cursor width) plays an effective role in improving the performance of HS based filters. Recently, a novel local technique, named Local Adaptive Hysteresis Smoothing (LAHS), has been proposed to compute an optimal cursor width. In this paper, a new method is proposed to improve the performance of LAHS in noise reduction and detail preservation. In the proposed approach which is based on weighted averaging, local statistical characteristics of the image are used in order to modify the final values of estimated pixels by LAHS method. Proposed method is applied to SEM images corrupted by different levels of noise. Noise reduction and detail preservation performance of the proposed method is compared in both objective and subjective manners with other HS based filters. Experimental results demonstrate that the proposed method is successful in improving the performance of LAHS and also it achieves better performance in noise reduction besides detail preservation of SEM images in comparison with other HS based filters. SCANNING 38:634-643, 2016. © 2016 Wiley Periodicals, Inc.

  15. Prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERβ suppression in the amygdala.

    Science.gov (United States)

    Zou, Yuanlin; Lu, Qiaomei; Zheng, Dan; Chu, Zhigang; Liu, Zhaoyu; Chen, Haijia; Ruan, Qiongfang; Ge, Xiaohu; Zhang, Ziyun; Wang, Xiaoyan; Lou, Wenting; Huang, Yongjian; Wang, Yifei; Huang, Xiaodong; Liu, Zhengxiang; Xie, Weiguo; Zhou, Yikai; Yao, Paul

    2017-01-01

    Autism spectrum disorder (ASD) is characterized by impairments in social communication and restricted or repetitive behaviors or interests. ASD is now diagnosed in more than one out of 100 children and is biased towards males by a ratio of at least 4:1. Many possible explanations and potential causative factors have been reported, such as genetics, sex, and environmental factors, although the detailed mechanisms of ASD remain unclear. The dams were exposed through oral contraceptives to either vehicle control (VEH) alone, levonorgestrel (LNG) alone, ethinyl estradiol (EE) alone, or a combination of LNG/EE for 21 days during their pregnancy. The subsequent 10-week-old offspring were used for autism-like behavior testing, and the limbic tissues were isolated for analysis. In another experimental group, 8-week-old male offspring were treated by infusion of ERβ overexpression/knockdown lentivirus in the amygdala, and the offspring were analyzed after 2 weeks. We show that prenatal exposure of either LNG alone or a LNG/EE combination, but not EE alone, results in suppression of ERβ (estrogen receptor β) and its target genes in the amygdala with autism-like behavior in male offspring, while there is a much smaller effect on female offspring. However, we find that there is no effect on the hippocampus and hypothalamus. Further investigation shows that ERβ suppression is due to LNG-mediated altered methylation on the ERβ promoter and results in tissue damage with oxidative stress and the dysfunction of mitochondria and fatty acid metabolism, which subsequently triggers autism-like behavior. Overexpression of ERβ in the amygdala completely restores LNG-induced ERβ suppression and autism-like behaviors in offspring, while ERβ knockdown mimics this effect, indicating that ERβ expression in the amygdala plays an important role in autism-like behavior development. We conclude that prenatal levonorgestrel exposure induces autism-like behavior in offspring through ER

  16. Mangiferin induces apoptosis in multiple myeloma cell lines by suppressing the activation of nuclear factor kappa B-inducing kinase.

    Science.gov (United States)

    Takeda, Tomoya; Tsubaki, Masanobu; Kino, Toshiki; Yamagishi, Misa; Iida, Megumi; Itoh, Tatsuki; Imano, Motohiro; Tanabe, Genzoh; Muraoka, Osamu; Satou, Takao; Nishida, Shozo

    2016-05-05

    Mangiferin is a naturally occurring glucosyl xanthone, which induces apoptosis in various cancer cells. However, the molecular mechanism underlying mangiferin-induced apoptosis has not been clarified thus far. Therefore, we examined the molecular mechanism underlying mangiferin-induced apoptosis in multiple myeloma (MM) cell lines. We found that mangiferin decreased the viability of MM cell lines in a concentration-dependent manner. We also observed an increased number of apoptotic cells, caspase-3 activation, and a decrease in the mitochondrial membrane potential. In addition, mangiferin inhibited the nuclear translocation of nuclear factor kappa B (NF-κB) and expression of phosphorylated inhibitor kappa B (IκB) and increased the expression of IκB protein, whereas no changes were observed in the phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase 1/2 (JNK1/2), and mammalian target of rapamycin (mTOR). The molecular mechanism responsible for mangiferin-induced inhibition of nuclear translocation of NF-κB was a decrease in the expression of phosphorylated NF-κB-inducing kinase (NIK). Moreover, mangiferin decreased the expression of X-linked inhibitor of apoptosis protein (XIAP), survivin, and Bcl-xL proteins. Knockdown of NIK expression showed results similar to those observed with mangiferin treatment. Our results suggest that mangiferin induces apoptosis through the inhibition of nuclear translocation of NF-κB by suppressing NIK activation in MM cell lines. Our results provide a new insight into the molecular mechanism of mangiferin-induced apoptosis. Importantly, since the number of reported NIK inhibitors is limited, mangiferin, which targets NIK, may be a potential anticancer agent for the treatment of MM.

  17. Norathyriol Suppresses Skin Cancers Induced by Solar Ultraviolet Radiation by Targeting ERK Kinases

    Energy Technology Data Exchange (ETDEWEB)

    Li, Jixia; Malakhova, Margarita; Mottamal, Madhusoodanan; Reddy, Kanamata; Kurinov, Igor; Carper, Andria; Langfald, Alyssa; Oi, Naomi; Kim, Myoung Ok; Zhu, Feng; Sosa, Carlos P.; Zhou, Keyuan; Bode, Ann M.; Dong, Zigang (Cornell); (Guangdong); (UMM)

    2012-06-27

    Ultraviolet (UV) irradiation is the leading factor in the development of skin cancer, prompting great interest in chemopreventive agents for this disease. In this study, we report the discovery of norathyriol, a plant-derived chemopreventive compound identified through an in silico virtual screening of the Chinese Medicine Library. Norathyriol is a metabolite of mangiferin found in mango, Hypericum elegans, and Tripterospermum lanceolatum and is known to have anticancer activity. Mechanistic investigations determined that norathyriol acted as an inhibitor of extracellular signal-regulated kinase (ERK)1/2 activity to attenuate UVB-induced phosphorylation in mitogen-activated protein kinases signaling cascades. We confirmed the direct and specific binding of norathyriol with ERK2 through a cocrystal structural analysis. The xanthone moiety in norathyriol acted as an adenine mimetic to anchor the compound by hydrogen bonds to the hinge region of the protein ATP-binding site on ERK2. Norathyriol inhibited in vitro cell growth in mouse skin epidermal JB6 P+ cells at the level of G{sub 2}-M phase arrest. In mouse skin tumorigenesis assays, norathyriol significantly suppressed solar UV-induced skin carcinogenesis. Further analysis indicated that norathyriol mediates its chemopreventive activity by inhibiting the ERK-dependent activity of transcriptional factors AP-1 and NF-{kappa}B during UV-induced skin carcinogenesis. Taken together, our results identify norathyriol as a safe new chemopreventive agent that is highly effective against development of UV-induced skin cancer.

  18. Identification of differentially expressed radiation-induced genes in cervix carcinoma cells using suppression subtractive hybridization

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jun Sang; Lee, Young Sook; Lee, Jeung Hoon; Lee, Woong Hee; Seo, Eun Young; Cho, Moon June [Chungnam National University, Daejeon (Korea, Republic of)

    2005-03-15

    A number of genes and their products are induced early or late following exposure of cells to ionizing radiation. These radiation-induced genes have various effects of irradiated cells and tissues. Suppression subtractive hybridization (SSH) based on PCR was used to identify the differentially expressed genes by radiation in cervix carcinoma cells. Total RNA and poly (A){sup +} mRNA were isolated from irradiated and non-irradiated HeLa cells. Forward-and reverse-subtracted cDNA libraries were constructed using SSH. Eighty-eight clones of each were used to randomly select differentially expressed genes using reverse Northern blotting (dot blot analysis). Northern blotting was used to verify the screened genes. Of the 176 clones, 10 genes in the forward-subtracted library and 9 genes in the reverse-subtracted library were identified as differentially expressed radiation-induced genes by PCR-select differential screening. Three clones from the forward-subtracted library were confirmed by Northern blotting, and showed increased expression in a dose-dependent manner, including a telomerase catalytic subunit and sodium channel-like protein gene, and an ESTs (expressed sequence tags) gene. We identified differentially expressed radiation-induced genes with low-abundance genes with SSH, but further characterization of theses genes are necessary to clarify the biological functions of them.

  19. Exogenous surfactant suppresses inflammation in experimental endotoxin-induced lung injury.

    Science.gov (United States)

    Mittal, Neha; Sanyal, Sankar Nath

    2009-01-01

    Our objective was to evaluate the anti-inflammatory effects of exogenous surfactant and surfactant phospholipids on the lipopolysaccharide (LPS)-induced lung injury. Exogenous surfactant (porcine surfactant) and surfactant phospholipid (dipalmitoyl phospholipid DPPC, hexadecanol, tylaxopol) were instilled intratracheally with LPS in rats. Expression of surfactant apoproteins (SP-A) and the cyclooxygenase enzymes (COX-1 and -2) was studied by immunohistochemistry, and apoptosis was analyzed by in situ terminal dUTP nick end labeling TUNEL assay. The intracellular reactive oxygen species (ROS) was measured in the isolated macrophages by fluorescence measurement with dichlorofluorescein diacetate (DCFH-DA). LPS-induced oxidative burst and apoptosis at 72 hours were reduced by both porcine and synthetic surfactant. SP-A as well as COX-1 and -2 expressions were suppressed with synthetic surfactant treatment, whereas with porcine surfactant (P-SF) the SP-A expression was enhanced in response to LPS administration. These results indicate that exogenous surfactant inhibits LPS-induced inflammation. This anti-inflammatory activity may be an important outcome of surfactant therapy in endotoxin-induced respiratory distress.

  20. Spent coffee ground extract suppresses ultraviolet B-induced photoaging in hairless mice.

    Science.gov (United States)

    Choi, Hyeon-Son; Park, Eu Ddeum; Park, Yooheon; Suh, Hyung Joo

    2015-12-01

    The aim of this study is to evaluate the effect of spent coffee ground (SCG) ethanol extract on UVB-induced skin aging in hairless mice. An ethanol extract of SCG (ESCG) was prepared using the residue remaining after extraction of oil from roasted SCG. High performance liquid chromatography (HPLC) analysis showed that the content of caffeine (41.58 ± 0.54 μg/mg) was higher than that of chlorogenic acid isomers (~9.17 μg/mg) in ESCG. ESCG significantly decreased the UVB-induced intracellular reactive oxygen species in HaCaT cells. UVB-induced wrinkle formation in mice dorsal skin was effectively reduced by ESCG administration; high dose of ESCG (5 g/L) caused the reduction of wrinkle area by 30% compared with UVB-treated control (UVBC). This result correlated with the ESCG-mediated decrease in epidermis thickness (25%). In addition, ESCG administration significantly reduced transdermal water loss (20%) and erythema formation (35%) derived from UVB exposure. Collagen type I (COL-1) level in dorsal skin was effectively recovered by ESCG administration. These results were supported by down-regulation of collagen-degrading matrix metalloproteinase 2 (MMP2) and 9 (MMP9) expressions. Our results indicate that ESCG protects mouse skin from UVB-induced photoaging by suppressing the expression of matrix metalloproteinases. Our study suggests that ESCG may be anti-photoaging agent.

  1. Tart cherry anthocyanins suppress inflammation-induced pain behavior in rat.

    Science.gov (United States)

    Tall, Jill M; Seeram, Navindra P; Zhao, Chengshui; Nair, Muraleedharan G; Meyer, Richard A; Raja, Srinivasa N

    2004-08-12

    The use of complementary and alternative medicine (CAM) has increased in the United States and more patients are seeking CAM therapies for control of pain. The present investigation tested the efficacy of orally administered anthocyanins extracted from tart cherries on inflammation-induced pain behavior in rats. Paw withdrawal latency to radiant heat and paw withdrawal threshold to von Frey probes were measured. The first set of experiments examined the effects of tart cherry anthocyanins (400 mg/kg) on the nociceptive behaviors and edema associated with inflammation induced by intraplantar injection of 1% carrageenan. These studies also included tests of motor coordination. The second set of experiments determined if tart cherry anthocyanins (15, 85, and 400 mg/kg) dose-dependently affected the inflammation induced by intraplantar injection of 25% complete Freund's adjuvant. We found that tart cherry extracts reduce inflammation-induced thermal hyperalgesia, mechanical hyperalgesia and paw edema. The suppression of thermal hyperalgesia was dose-dependent and the efficacy of highest dose (400 mg/kg) was similar to indomethacin (5 mg/kg). The highest dose anthocyanin (400 mg/kg) had no effects on motor function. These data suggest that tart cherry anthocyanins may have a beneficial role in the treatment of inflammatory pain. The antihyperalgesic effects may be related to the anti-inflammatory and antioxidant properties of anthocyanins. A better understanding of the modulatory role of dietary constituents and phytonutrients on pain will offer further therapeutic options for treating patients with persistent and chronic pain conditions.

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

    Directory of Open Access Journals (Sweden)

    Radhakrishnan Sridhar

    2010-05-01

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

  3. Cytoplasmic localization of p21 protects trophoblast giant cells from DNA damage induced apoptosis.

    Science.gov (United States)

    de Renty, Christelle; DePamphilis, Melvin L; Ullah, Zakir

    2014-01-01

    Proliferating trophoblast stem cells (TSCs) can differentiate into nonproliferating but viable trophoblast giant cells (TGCs) that are resistant to DNA damage induced apoptosis. Differentiation is associated with selective up-regulation of the Cip/Kip cyclin-dependent kinase inhibitors p57 and p21; expression of p27 remains constant. Previous studies showed that p57 localizes to the nucleus in TGCs where it is essential for endoreplication. Here we show that p27 also remains localized to the nucleus during TSC differentiation where it complements the role of p57. Unexpectedly, p21 localized to the cytoplasm where it was maintained throughout both the G- and S-phases of endocycles, and where it prevented DNA damage induced apoptosis. This unusual status for a Cip/Kip protein was dependent on site-specific phosphorylation of p21 by the Akt1 kinase that is also up-regulated in TGCs. Although cytoplasmic p21 is widespread among cancer cells, among normal cells it has been observed only in monocytes. The fact that it also occurs in TGCs reveals that p57 and p21 serve nonredundant functions, and suggests that the role of p21 in suppressing apoptosis is restricted to terminally differentiated cells.

  4. Cytoplasmic localization of p21 protects trophoblast giant cells from DNA damage induced apoptosis.

    Directory of Open Access Journals (Sweden)

    Christelle de Renty

    Full Text Available Proliferating trophoblast stem cells (TSCs can differentiate into nonproliferating but viable trophoblast giant cells (TGCs that are resistant to DNA damage induced apoptosis. Differentiation is associated with selective up-regulation of the Cip/Kip cyclin-dependent kinase inhibitors p57 and p21; expression of p27 remains constant. Previous studies showed that p57 localizes to the nucleus in TGCs where it is essential for endoreplication. Here we show that p27 also remains localized to the nucleus during TSC differentiation where it complements the role of p57. Unexpectedly, p21 localized to the cytoplasm where it was maintained throughout both the G- and S-phases of endocycles, and where it prevented DNA damage induced apoptosis. This unusual status for a Cip/Kip protein was dependent on site-specific phosphorylation of p21 by the Akt1 kinase that is also up-regulated in TGCs. Although cytoplasmic p21 is widespread among cancer cells, among normal cells it has been observed only in monocytes. The fact that it also occurs in TGCs reveals that p57 and p21 serve nonredundant functions, and suggests that the role of p21 in suppressing apoptosis is restricted to terminally differentiated cells.

  5. Does the histaminergic system mediate bombesin/GRP-induced suppression of food intake?

    Science.gov (United States)

    Merali, Z; Banks, K

    1994-12-01

    Bombesin (BN) and its mammalian homologue, gastrin-releasing peptide (GRP), are potent satiety agents and have been implicated in the physiological regulation of food intake. The mechanism(s) of action of this effect remains unclear. There is a functional and anatomic overlap between histamine and BN in relationship to feeding, which led us to hypothesize that BN may mediate its satiety effects through activation of the histaminergic system. To assess this contention, we examined the effects of R-alpha-methylhistamine (alpha-MH) and Imetit, selective H3-receptor agonists that inhibit the release and synthesis of histamine, on BN- or cholecystokinin (CCK)-induced satiety. In this report we present the first evidence for the role of histamine H3 receptors in the mediation of BN-elicited satiety. During the first hour of the 4-h daily feeding session, BN reduced food intake by > 50% relative to the control condition; this suppression was blocked by prior treatment with the H3-receptor agonist, alpha-MH. This blockade of BN-induced satiety was dose related and selective to BN as alpha-MH failed to attenuate sulfated CCK-8-induced satiety. When alpha-MH was administered alone, it failed to significantly affect food intake. The specificity of this effect was further supported by the demonstration that another H3 agonist, Imetit, was also able to block the feeding-suppressant effects of BN. Furthermore, thioperamide, an H3-receptor antagonist, blocked these effects of Imetit.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Genistein suppresses leptin-induced proliferation and migration of vascular smooth muscle cells and neointima formation.

    Science.gov (United States)

    Tsai, Yung-Chieh; Leu, Sy-Ying; Peng, Yi-Jen; Lee, Yen-Mei; Hsu, Chih-Hsiung; Chou, Shen-Chieh; Yen, Mao-Hsiung; Cheng, Pao-Yun

    2017-03-01

    Obesity is a strong risk factor for the development of cardiovascular diseases and is associated with a marked increase in circulating leptin concentration. Leptin is a peptide hormone mainly produced by adipose tissue and is regulated by energy level, hormones and various inflammatory mediators. Genistein is an isoflavone that exhibits diverse health-promoting effects. Here, we investigated whether genistein suppressed the atherogenic effect induced by leptin. The A10 cells were treated with leptin and/or genistein, and then the cell proliferation and migration were analysed. The reactive oxygen species (ROS) and proteins levels were also measured, such as p44/42MAPK, cell cycle-related protein (cyclin D1 and p21) and matrix metalloproteinase-2 (MMP-2). Immunohistochemistry and morphometric analysis were used for the neointima formation in a rat carotid artery injury model. Genistein (5 μM) significantly inhibited both the proliferation and migration of leptin (10 ng/ml)-stimulated A10 cells. In accordance with these finding, genistein decreased the leptin-stimulated ROS production and phosphorylation of the p44/42MAPK signal transduction pathway. Meanwhile, genistein reversed the leptin-induced expression of cyclin D1, and cyclin-dependent kinase inhibitor, p21. Genistein attenuated leptin-induced A10 cell migration by inhibiting MMP-2 activity. Furthermore, the leptin (0.25 mg/kg)-augmented neointima formation in a rat carotid artery injury model was attenuated in the genistein (5 mg/kg body weight)-treated group when compared with the balloon injury plus leptin group. Genistein was capable of suppressing the atherogenic effects of leptin in vitro and in vivo, and may be a promising candidate drug in the clinical setting. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  7. Drosophila clueless is highly expressed in larval neuroblasts, affects mitochondrial localization and suppresses mitochondrial oxidative damage.

    Directory of Open Access Journals (Sweden)

    Aditya Sen

    Full Text Available Mitochondria are critical for neuronal function due to the high demand of ATP in these cell types. During Drosophila development, neuroblasts in the larval brain divide asymmetrically to populate the adult central nervous system. While many of the proteins responsible for maintaining neuroblast cell fate and asymmetric cell divisions are known, little is know about the role of metabolism and mitochondria in neuroblast division and maintenance. The gene clueless (clu has been previously shown to be important for mitochondrial function. clu mutant adults have severely shortened lifespans and are highly uncoordinated. Part of their lack of coordination is due to defects in muscle, however, in this study we have identified high levels of Clu expression in larval neuroblasts and other regions of the dividing larval brain. We show while mitochondria in clu mutant neuroblasts are mislocalized during the cell cycle, surprisingly, overall brain morphology appears to be normal. This is explained by our observation that clu mutant larvae have normal levels of ATP and do not suffer oxidative damage, in sharp contrast to clu mutant adults. Mutations in two other genes encoding mitochondrial proteins, technical knockout and stress sensitive B, do not cause neuroblast mitochondrial mislocalization, even though technical knockout mutant larvae suffer oxidative damage. These results suggest Clu functions upstream of electron transport and oxidative phosphorylation, has a role in suppressing oxidative damage in the cell, and that lack of Clu's specific function causes mitochondria to mislocalize. These results also support the previous observation that larval development relies on aerobic glycolysis, rather than oxidative phosphorylation. Thus Clu's role in mitochondrial function is not critical during larval development, but is important for pupae and adults.

  8. Quercetin induces autophagy via FOXO1-dependent pathways and autophagy suppression enhances quercetin-induced apoptosis in PASMCs in hypoxia.

    Science.gov (United States)

    He, Yuanzhou; Cao, Xiaopei; Guo, Pujian; Li, Xiaochen; Shang, Huihui; Liu, Jin; Xie, Min; Xu, Yongjian; Liu, Xiansheng

    2017-02-01

    Quercetin, an important dietary flavonoid has been demonstrated to potentially reverse or even prevent pulmonary arterial hypertension (PAH) progression. However, the effects of quercetin on apoptosis and autophagy in pulmonary arterial smooth muscle cells (PASMCs) have not yet been clearly elucidated. The current study found that quercetin significantly induce the apoptotic and autophagic capacities of PASMCs in vitro and in vivo in hypoxia. In addition, we found that quercetin increases FOXO1 (a major mediator in autophagy regulation) expression and transcriptional activity. Moreover, FOXO1 knockdown by siRNAs inhibited the phosphorylation of mTOR and 4E-BPI, which is downstream of P70-S6K, and markedly blocked quercetin-induced autophagy. We also observed that FOXO1-mediated autophagy was achieved via SESN3 not Rictor upregulation and after mTOR suppression. Furthermore, Treatment with autophagy-specific inhibitors could markedly enhance quercetin-induced apoptosis in PASMCs under hypoxia. Finally, quercetin in combination with autophagy inhibition treatment could enhance the therapeutic effects of quercetin in hypoxia-associated PAH in vivo. Taken together, quercetin could enhance hypoxia-induced autophagy through the FOXO1-SENS3-mTOR pathway in PASMCs. Combining quercetin and autophagy inhibitors may be a novel therapeutic strategy for treating hypoxia-associated PAH. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Vocal sequences suppress spiking in the bat auditory cortex while evoking concomitant steady-state local field potentials

    Science.gov (United States)

    Hechavarría, Julio C.; Beetz, M. Jerome; Macias, Silvio; Kössl, Manfred

    2016-12-01

    The mechanisms by which the mammalian brain copes with information from natural vocalization streams remain poorly understood. This article shows that in highly vocal animals, such as the bat species Carollia perspicillata, the spike activity of auditory cortex neurons does not track the temporal information flow enclosed in fast time-varying vocalization streams emitted by conspecifics. For example, leading syllables of so-called distress sequences (produced by bats subjected to duress) suppress cortical spiking to lagging syllables. Local fields potentials (LFPs) recorded simultaneously to cortical spiking evoked by distress sequences carry multiplexed information, with response suppression occurring in low frequency LFPs (i.e. 2–15 Hz) and steady-state LFPs occurring at frequencies that match the rate of energy fluctuations in the incoming sound streams (i.e. >50 Hz). Such steady-state LFPs could reflect underlying synaptic activity that does not necessarily lead to cortical spiking in response to natural fast time-varying vocal sequences.

  10. Mitochondrial APE1/Ref-1 suppressed protein kinase C-induced mitochondrial dysfunction in mouse endothelial cells.

    Science.gov (United States)

    Joo, Hee Kyoung; Lee, Yu Ran; Park, Myoung Soo; Choi, Sunga; Park, Kyoungsook; Lee, Sang Ki; Kim, Cuk-Seong; Park, Jin Bong; Jeon, Byeong Hwa

    2014-07-01

    Protein kinase C (PKC) induces mitochondrial dysfunction, which is an important pathological factor in cardiovascular diseases. The role of apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) on PKC-induced mitochondrial dysfunction has not been variously investigated. In this study, phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, induced mitochondrial hyperpolarization and reactive oxygen species generation and also increased mitochondrial translocation of APE1/Ref-1. APE1/Ref-1 overexpression suppressed PMA-induced mitochondrial dysfunction. In contrast, gene silencing of APE1/Ref-1 increased the sensitivity of mitochondrial dysfunction. Moreover, mitochondrial targeting sequence (MTS)-fused APE1/Ref-1 more effectively suppressed PMA-induced mitochondrial dysfunctions. These results suggest that mitochondrial APE1/Ref-1 is contributed to the protective role to protein kinase C-induced mitochondrial dysfunction in endothelial cells.

  11. The Ketogenic Diet Suppresses the Cathepsin E Expression Induced by Kainic Acid in the Rat Brain

    Science.gov (United States)

    Jeong, Hyun Jeong; Kim, Hojeong; Kim, Yoon-Kyoung; Park, Sang-Kyu; Kang, Dong-Won

    2010-01-01

    Purpose The ketogenic diet has long been used to treat epilepsy, but its mechanism is not yet clearly understood. To explore the potential mechanism, we analyzed the changes in gene expression induced by the ketogenic diet in the rat kainic acid (KA) epilepsy model. Materials and Methods KA-administered rats were fed the ketogenic diet or a normal diet for 4 weeks, and microarray analysis was performed with their brain tissues. The effects of the ketogenic diet on cathepsin E messenger ribonucleic acid (mRNA) expression were analyzed in KA-administered and normal saline-administered groups with semi-quantitative and real-time reverse transcription polymerase chain reaction (RT-PCR). Brain tissues were dissected into 8 regions to compare differential effects of the ketogenic diet on cathepsin E mRNA expression. Immunohistochemistry with an anti-cathepsin E antibody was performed on slides of hippocampus obtained from whole brain paraffin blocks. Results The microarray data and subsequent RT-PCR experiments showed that KA increased the mRNA expression of cathepsin E, known to be related to neuronal cell death, in most brain areas except the brain stem, and these increases of cathepsin E mRNA expression were suppressed by the ketogenic diet. The expression of cathepsin E mRNA in the control group, however, was not significantly affected by the ketogenic diet. The change in cathepsin E mRNA expression was greatest in the hippocampus. The protein level of cathepsin E in the hippocampus of KA-administered rat was elevated in immunohistochemistry and the ketogenic diet suppressed this increase. Conclusion Our results showed that KA administration increased cathepsin E expression in the rat brain and its increase was suppressed by the ketogenic diet. PMID:20635438

  12. Butyrate enhances antibacterial effects while suppressing other features of alternative activation in IL-4-induced macrophages.

    Science.gov (United States)

    Fernando, Maria R; Saxena, Alpana; Reyes, José-Luis; McKay, Derek M

    2016-05-15

    The short-chain fatty acid butyrate is produced by fermentation of dietary fiber by the intestinal microbiota; butyrate is the primary energy source of colonocytes and has immunomodulatory effects. Having shown that macrophages differentiated with IL-4 [M(IL-4)s] can suppress colitis, we hypothesized that butyrate would reinforce an M(IL-4) phenotype. Here, we show that in the presence of butyrate M(IL-4)s display reduced expression of their hallmark markers Arg1 and Ym1 and significantly suppressed LPS-induced nitric oxide, IL-12p40, and IL-10 production. Butyrate treatment likely altered the M(IL-4) phenotype via inhibition of histone deacetylation. Functionally, M(IL-4)s treated with butyrate showed increased phagocytosis and killing of bacteria, compared with M(IL-4) and this was not accompanied by enhanced proinflammatory cytokine production. Culture of regulatory T cells with M(IL-4)s and M(IL-4 + butyrate)s revealed that both macrophage subsets suppressed expression of the regulatory T-cell marker Foxp3. However, Tregs cocultured with M(IL-4 + butyrate) produced less IL-17A than Tregs cocultured with M(IL-4). These data illustrate the importance of butyrate, a microbial-derived metabolite, in the regulation of gut immunity: the demonstration that butyrate promotes phagocytosis in M(IL-4)s that can limit T-cell production of IL-17A reveals novel aspects of bacterial-host interaction in the regulation of intestinal homeostasis.

  13. Periodic Lateralized Epileptiform Discharges can Survive Anesthesia and Result in Asymmetric Drug-induced Burst Suppression

    Science.gov (United States)

    Mader, Edward C.; Cannizzaro, Louis A.; Williams, Frank J.; Lalan, Saurabh; Olejniczak, Piotr W.

    2017-01-01

    Drug-induced burst suppression (DIBS) is bihemispheric and bisymmetric in adults and older children. However, asymmetric DIBS may occur if a pathological process is affecting one hemisphere only or both hemispheres disproportionately. The usual suspect is a destructive lesion; an irritative or epileptogenic lesion is usually not invoked to explain DIBS asymmetry. We report the case of a 66-year-old woman with new-onset seizures who was found to have a hemorrhagic cavernoma and periodic lateralized epileptiform discharges (PLEDs) in the right temporal region. After levetiracetam and before anesthetic antiepileptic drugs (AEDs) were administered, the electroencephalogram (EEG) showed continuous PLEDs over the right hemisphere with maximum voltage in the posterior temporal region. Focal electrographic seizures also occurred occasionally in the same location. Propofol resulted in bihemispheric, but not in bisymmetric, DIBS. Remnants or fragments of PLEDs that survived anesthesia increased the amplitude and complexity of the bursts in the right hemisphere leading to asymmetric DIBS. Phenytoin, lacosamide, ketamine, midazolam, and topiramate were administered at various times in the course of EEG monitoring, resulting in suppression of seizures but not of PLEDs. Ketamine and midazolam reduced the rate, amplitude, and complexity of PLEDs but only after producing substantial attenuation of all burst components. When all anesthetics were discontinued, the EEG reverted to the original preanesthesia pattern with continuous non-fragmented PLEDs. The fact that PLEDs can survive anesthesia and affect DIBS symmetry is a testament to the robustness of the neurodynamic processes underlying PLEDs. PMID:28286626

  14. Fucoidan Suppresses Hypoxia-Induced Lymphangiogenesis and Lymphatic Metastasis in Mouse Hepatocarcinoma.

    Science.gov (United States)

    Teng, Hongming; Yang, Yazong; Wei, Hengyun; Liu, Zundong; Liu, Zhichao; Ma, Yanhong; Gao, Zixiang; Hou, Lin; Zou, Xiangyang

    2015-06-03

    Metastasis, the greatest clinical challenge associated with cancer, is closely connected to multiple biological processes, including invasion and adhesion. The hypoxic environment in tumors is an important factor that causes tumor metastasis by activating HIF-1α. Fucoidan, extracted from brown algae, is a sulfated polysaccharide and, as a novel marine biological material, has been used to treat various disorders in China, Korea, Japan and other countries. In the present study, we demonstrated that fucoidan derived from Undaria pinnatifida sporophylls significantly inhibits the hypoxia-induced expression, nuclear translocation and activity of HIF-1α, the synthesis and secretion of VEGF-C and HGF, cell invasion and lymphatic metastasis in a mouse hepatocarcinoma Hca-F cell line. Fucoidan also suppressed lymphangiogenesis in vitro and in vivo. In addition, accompanied by a reduction in the HIF-1α nuclear translocation and activity, fucoidan significantly reduced the levels of p-PI3K, p-Akt, p-mTOR, p-ERK, NF-κB, MMP-2 and MMP-9, but increased TIMP-1 levels. These results indicate strongly that the anti-metastasis and anti-lymphangiogenesis activities of fucoidan are mediated by suppressing HIF-1α/VEGF-C, which attenuates the PI3K/Akt/mTOR signaling pathways.

  15. Fucoidan Suppresses Hypoxia-Induced Lymphangiogenesis and Lymphatic Metastasis in Mouse Hepatocarcinoma

    Directory of Open Access Journals (Sweden)

    Hongming Teng

    2015-06-01

    Full Text Available Metastasis, the greatest clinical challenge associated with cancer, is closely connected to multiple biological processes, including invasion and adhesion. The hypoxic environment in tumors is an important factor that causes tumor metastasis by activating HIF-1α. Fucoidan, extracted from brown algae, is a sulfated polysaccharide and, as a novel marine biological material, has been used to treat various disorders in China, Korea, Japan and other countries. In the present study, we demonstrated that fucoidan derived from Undaria pinnatifida sporophylls significantly inhibits the hypoxia-induced expression, nuclear translocation and activity of HIF-1α, the synthesis and secretion of VEGF-C and HGF, cell invasion and lymphatic metastasis in a mouse hepatocarcinoma Hca-F cell line. Fucoidan also suppressed lymphangiogenesis in vitro and in vivo. In addition, accompanied by a reduction in the HIF-1α nuclear translocation and activity, fucoidan significantly reduced the levels of p-PI3K, p-Akt, p-mTOR, p-ERK, NF-κB, MMP-2 and MMP-9, but increased TIMP-1 levels. These results indicate strongly that the anti-metastasis and anti-lymphangiogenesis activities of fucoidan are mediated by suppressing HIF-1α/VEGF-C, which attenuates the PI3K/Akt/mTOR signaling pathways.

  16. The habitat disruption induces immune-suppression and oxidative stress in honey bees

    Science.gov (United States)

    Morimoto, Tomomi; Kojima, Yuriko; Toki, Taku; Komeda, Yayoi; Yoshiyama, Mikio; Kimura, Kiyoshi; Nirasawa, Keijiro; Kadowaki, Tatsuhiko

    2011-01-01

    The honey bee is a major insect used for pollination of many commercial crops worldwide. Although the use of honey bees for pollination can disrupt the habitat, the effects on their physiology have never been determined. Recently, honey bee colonies have often collapsed when introduced in greenhouses for pollination in Japan. Thus, suppressing colony collapses and maintaining the number of worker bees in the colonies is essential for successful long-term pollination in greenhouses and recycling of honey bee colonies. To understand the physiological states of honey bees used for long-term pollination in greenhouses, we characterized their gene expression profiles by microarray. We found that the greenhouse environment changes the gene expression profiles and induces immune-suppression and oxidative stress in honey bees. In fact, the increase of the number of Nosema microsporidia and protein carbonyl content was observed in honey bees during pollination in greenhouses. Thus, honey bee colonies are likely to collapse during pollination in greenhouses when heavily infested with pathogens. Degradation of honey bee habitat by changing the outside environment of the colony, during pollination services for example, imposes negative impacts on honey bees. Thus, worldwide use of honey bees for crop pollination in general could be one of reasons for the decline of managed honey bee colonies. PMID:22393496

  17. Mutator suppression and escape from replication error-induced extinction in yeast.

    Directory of Open Access Journals (Sweden)

    Alan J Herr

    2011-10-01

    Full Text Available Cells rely on a network of conserved pathways to govern DNA replication fidelity. Loss of polymerase proofreading or mismatch repair elevates spontaneous mutation and facilitates cellular adaptation. However, double mutants are inviable, suggesting that extreme mutation rates exceed an error threshold. Here we combine alleles that affect DNA polymerase δ (Pol δ proofreading and mismatch repair to define the maximal error rate in haploid yeast and to characterize genetic suppressors of mutator phenotypes. We show that populations tolerate mutation rates 1,000-fold above wild-type levels but collapse when the rate exceeds 10⁻³ inactivating mutations per gene per cell division. Variants that escape this error-induced extinction (eex rapidly emerge from mutator clones. One-third of the escape mutants result from second-site changes in Pol δ that suppress the proofreading-deficient phenotype, while two-thirds are extragenic. The structural locations of the Pol δ changes suggest multiple antimutator mechanisms. Our studies reveal the transient nature of eukaryotic mutators and show that mutator phenotypes are readily suppressed by genetic adaptation. This has implications for the role of mutator phenotypes in cancer.

  18. Inhibition of Cdc42 is essential for Mig-6 suppression of cell migration induced by EGF.

    Science.gov (United States)

    Jiang, Xinni; Niu, MengMeng; Chen, Deshi; Chen, Jing; Cao, Yang; Li, Xiaorong; Ying, Haoqiang; Bergholz, Johann; Zhang, Yujun; Xiao, Zhi-Xiong

    2016-08-02

    The adaptor protein Mig-6 is a negative regulator of EGF signaling. It is shown that Mig-6 inhibits cell migration via direct interaction with the ErbB receptors, thereby inhibiting cross-phosphorylation or targeting the receptors for degradation. Mig-6 has also been shown to bind to and inhibit the Rho GTPase Cdc42 to suppress cytoskeletal rearrangement. However, the molecular mechanism(s) by which Mig-6 inhibits cell migration via Cdc42 is still not entirely clear. Here, we show that Mig-6 binding to Cdc42 is necessary and sufficient to inhibit EGF-induced filopodia formation and migration. This binding, mediated by four specific residues (I11, R12, M26, R30) in the Mig-6 CRIB domain, is essential for Mig-6 function. In addition, ectopic expression of Cdc42 reverses Mig-6 inhibition of cell migration. Mig-6 CRIB domain, alone, is sufficient to inhibit cell migration. Conversely, Mig-6 binding to EGFR is dispensable for Mig-6-mediated inhibition of cell migration. Moreover, we found that decreased Mig-6 expression correlates with cancer progression in breast and prostate cancers. Together, our results demonstrate that Mig-6 inhibition of Cdc42 signaling is critical in Mig-6 function to suppress cell migration and that dysregulation of this pathway may play a critical role in cancer development.

  19. Hydroxysafflor yellow A suppresses oxidized low density lipoprotein induced proliferation of vascular smooth muscle cells

    Directory of Open Access Journals (Sweden)

    Lin Sheng

    2012-06-01

    Full Text Available To investigate the relationship between the suppression of Hydroxysafflor yellow A (HSYA on the oxidized low density lipoprotein (ox-LDL induced proliferation of vascular smooth muscle cells (VSMCs and the mRNA and protein expression of extracellular signal-regulated protein kinase 1/2 (ERK1/2 and mitogen activated protein kinase phospholipase-1 (MAKP-1, VSMCs were treated with HSYA at 10 ?mol/L and/or ox-LDL at 35 mg/L for 48 h. MTT assay was done to measure cell survival rate, flow cytometry to detect cell cycle, reverse transcription PCR and Western blot to detect the expression of ERK1/2 and MAKP-1. When compared to cells treated with ox-LDL alone, the survival rate of cells treated with two reagents was reduced and the proportion of cells in G0/G1 phase significantly increased, with increased MKP-1 expression. The study suggests HSYA can inhibit VSMC proliferation via increasing MKP-1 expression, reducing p-ERK1/2 activity and suppressing cell cycle.

  20. Apocynin Improves Insulin Resistance through Suppressing Inflammation in High-Fat Diet-Induced Obese Mice

    Directory of Open Access Journals (Sweden)

    Ran Meng

    2010-01-01

    Full Text Available We investigated the effects of apocynin on high-fat diet- (HFD- induced insulin resistance in C57BL/6 mice. After 12 weeks of HFD, the mice that exhibited insulin resistance then received 5 weeks of apocynin (2.4 g/L, in water. Following apocynin treatment, fasting glucose, insulin, and glucose tolerance test showed significant improvement in insulin sensitivity in HFD-fed mice. We demonstrated that serum levels of tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6, and leptin were remarkably reduced with apocynin treatment. We also found that mRNA expression of TNF-α, IL-6, and monocyte chemoattractant protein-1 (MCP-1 in the liver and mRNA expression of TNF-α, IL-6, MCP-1, and leptin in adipose tissue were suppressed by apocynin. Furthermore, the activity of transcription factor NF-κB in the liver was significantly suppressed with apocynin treatment. These results suggest that apocynin may reduce inflammatory factors in the blood, liver, and adipose tissue, resulting in amelioration of insulin resistance in HFD-fed mice.

  1. Curcumin increases exosomal TCF21 thus suppressing exosome-induced lung cancer

    Science.gov (United States)

    Zeng, Chao; Wu, Da; Mu, Zhimin; Chen, Baokun; Xie, Yuancai; Ye, Yiwang; Liu, Jixian

    2016-01-01

    Curcumin is a novel drug for lung cancer treatment. However, the mechanism underlying the anti-tumor effect of curcumin remains elusive. Previous evidences indicated that, the methylating transferase DNMT1 is downregulated by curcumin, and the transcription factor 21 (TCF21) is suppressed by DNMT1. We hereby attempt to elucidate the correlation between curcumin treatment and TCF21 expression. Exosomes derived from curcumin-pretreated H1299 cells were used to treat BEAS-2B cells, which induced proliferation, colony formation and migration of BEAS-2B cells. An increase in TCF21 expression in response to curcumin was also seen, as revealed by real-time PCR (RT-PCR) and western blot. Analysis using the GEO database (access #GSE21210) indicated that a positive correlation existed between TCF21 levels and lung cancer patient survival. TCF21 overexpression and knockdown was introduced to H1299 cells through lentiviral system, which led to suppression and promotion of tumor growth, respectively. We also demonstrated that DNMT1 expression was downregulated by curcumin. Therefore, curcumin exerts its anti-cancer function by downregulating DNMT1, thereby upregulating TCF21. PMID:27894084

  2. Periodic lateralized epileptiform discharges can survive anesthesia and result in asymmetric drug-induced burst suppression

    Directory of Open Access Journals (Sweden)

    Edward C. Mader Jr.

    2017-02-01

    Full Text Available Drug-induced burst suppression (DIBS is bihemispheric and bisymmetric in adults and older children. However, asymmetric DIBS may occur if a pathological process is affecting one hemisphere only or both hemispheres disproportionately. The usual suspect is a destructive lesion; an irritative or epileptogenic lesion is usually not invoked to explain DIBS asymmetry. We report the case of a 66-year-old woman with new-onset seizures who was found to have a hemorrhagic cavernoma and periodic lateralized epileptiform discharges (PLEDs in the right temporal region. After levetiracetam and before anesthetic antiepileptic drugs (AEDs were administered, the electroencephalogram (EEG showed continuous PLEDs over the right hemisphere with maximum voltage in the posterior temporal region. Focal electrographic seizures also occurred occasionally in the same location. Propofol resulted in bihemispheric, but not in bisymmetric, DIBS. Remnants or fragments of PLEDs that survived anesthesia increased the amplitude and complexity of the bursts in the right hemisphere leading to asymmetric DIBS. Phenytoin, lacosamide, ketamine, midazolam, and topiramate were administered at various times in the course of EEG monitoring, resulting in suppression of seizures but not of PLEDs. Ketamine and midazolam reduced the rate, amplitude, and complexity of PLEDs but only after producing substantial attenuation of all burst components. When all anesthetics were discontinued, the EEG reverted to the original preanesthesia pattern with continuous non-fragmented PLEDs. The fact that PLEDs can survive anesthesia and affect DIBS symmetry is a testament to the robustness of the neurodynamic processes underlying PLEDs.

  3. Application of the local similarity filter for the suppression of multiplicative noise in medical ultrasound images

    Science.gov (United States)

    Kusnik, Damian; Smolka, Bogdan; Cyganek, Boguslaw

    2016-04-01

    In this paper we address the problem of the reduction of multiplicative noise in digital images. This kind of image distortion, also known as speckle noise, severely decreases the quality of medical ultrasound images and therefore their effective enhancement and restoration is of vital importance for proper visual inspection and quantitative measurements. The structure of the proposed Pixel-Patch Similarity Filter (PPSF) is a weighted average of pixels in a processing block and the weights are determined calculating the sum of squared differences between the mean of a patch and the intensities of pixels of the local window at the block center. The structure of the proposed design is similar to the bilateral and non-local means filters, however we neglect the topographic distance between pixels, which decreases substantially its computational complexity. The new technique was evaluated on standard gray scale test images contaminated with multiplicative noise modelled using Gaussian and uniform distribution. Its efficiency was also assessed utilizing a set of simulated ultrasonographic images distorted by means of the Field II simulation software and real ultrasound images of a finger joint. The comparison with the state-of-the-art techniques revealed very high efficiency of the proposed filtering framework, especially for strongly degraded images. Visually, the homogeneous areas are smoother, while image edges and small details are better preserved. The experiments have shown that satisfactory results were obtained with patches consisting of only 9 samples belonging to a relatively small processing block of 7x7 pixels, which ensures low computational complexity of the proposed denoising scheme and allows its application in real-time image processing scenarios.

  4. Simulation study of induced EMFs and the suppression during SST-1 start-up

    Energy Technology Data Exchange (ETDEWEB)

    Jain, V., E-mail: vishal@ipr.res.in; Sharma, D.; Vardhrajulu, A.; Gupta, C.N.; Srinivasan, R.; Daniel, R.

    2015-11-15

    Highlights: • Induced EMFs study in PF coils during SST-1 start up using MATlab simulink. • Integration of wave shaping network to generate practical OT current profile. • This study would protect coil insulation with identifying RC circulating network. • Study of MOV technique for circulation of current through RC. - Abstract: Steady State Superconducting Tokamak (SST-1) comprises of various copper and superconducting coils for generating magnetic field for initiation, providing equilibrium and shaping of plasma in tokamak. In this paper, an attempt is made to study the induced EMF in superconducting poloidal field coils (PF coils) due to fast ramp down of current in ohmic transformer copper coils (OT coils) for SST-1 plasma initiation. The fast ramp down of current, from few kA to zero amperes in just 50–100 ms in OT coils, is required to achieve plasma breakdown and ramp up of plasma current in tokamak. However, it induces nearly 5 kV EMF in one of the SST-1 PF coils that can damage the coil insulation and also bias negatively the electronic switching of power supply. It is necessary to maintain induced EMF below 1 kV in all PF coils for safe operation of SST-1. The induced EMF up to 1 kV can be clamped without any need of protection and circulating current. If the induced EMF is in excess of 1 kV, then it has to allow the circulation of current through RC network for coil protection from overvoltage. These circulating currents in PF coils will affect the shaping of plasma. In this paper, the induced EMF in PF coils are simulated using MATlab simulink for a typical SST-1 current profile of OT coils. Further, this simulation study is used to design the protection system for PF coils. In this paper, the worst-case induced EMF scenario is considered by excluding the effect of passive elements like vacuum vessel and cryostat on mutual coupling parameters. However, the implementation of the EMF suppression scheme need more elaborated study with considering

  5. Extraordinary Light-Induced Local Angular Momentum near Metallic Nanoparticles.

    Science.gov (United States)

    Alabastri, Alessandro; Yang, Xiao; Manjavacas, Alejandro; Everitt, Henry O; Nordlander, Peter

    2016-04-26

    The intense local field induced near metallic nanostructures provides strong enhancements for surface-enhanced spectroscopies, a major focus of plasmonics research over the past decade. Here we consider that plasmonic nanoparticles can also induce remarkably large electromagnetic field gradients near their surfaces. Sizeable field gradients can excite dipole-forbidden transitions in nearby atoms or molecules and provide unique spectroscopic fingerprinting for chemical and bimolecular sensing. Specifically, we investigate how the local field gradients near metallic nanostructures depend on geometry, polarization, and wavelength. We introduce the concept of the local angular momentum (LAM) vector as a useful figure of merit for the design of nanostructures that provide large field gradients. This quantity, based on integrated fields rather than field gradients, is particularly well-suited for optimization using numerical grid-based full wave electromagnetic simulations. The LAM vector has a more compact structure than the gradient matrix and can be straightforwardly associated with the angular momentum of the electromagnetic field incident on the plasmonic structures.

  6. Suppression of the emittance growth induced by coherent synchrotron radiation in triple-bend achromat

    CERN Document Server

    Huang, Xiyang; Cui, Xiaohao; Xu, Gang

    2014-01-01

    Coherent synchrotron radiation (CSR) effect at a bending path plays an important role in transverse emittance dilution in high-brightness light sources and linear colliders, where the electron beams are of short bunch length and of high peak current. Suppression of the emittance growth induced by CSR is essential and critical to preserve the beam quality and to help improve the machine performance. To evaluate the CSR effect analytically, we have proposed a novel method, which enabled us to obtain generic conditions of cancelling the CSR linear effect in a two-dipole achromat. In this paper, it illustrates that with this method the CSR-cancellation condition can be obtained for a TBA with symmetric layout, which is independent of concrete element parameters, and to a large extent, the initial beam distribution. Implementation of found condition in concrete optics design of a TBA is discussed, and the proposed condition is verified through numerical simulations.

  7. Suppression of two-dimensional vortex-induced vibration with active velocity feedback controller

    Science.gov (United States)

    Ma, B.; Srinil, N.

    2016-09-01

    Vortex-induced vibrations (VIV) establish key design parameters for offshore and subsea structures subject to current flows. Understanding and predicting VIV phenomena have been improved in recent years. Further, there is a need to determine how to effectively and economically mitigate VIV effects. In this study, linear and nonlinear velocity feedback controllers are applied to actively suppress the combined cross-flow and in-line VIV of an elastically-mounted rigid circular cylinder. The strongly coupled fluid-structure interactions are numerically modelled and investigated using a calibrated reduced-order wake oscillator derived from the vortex strength concept. The importance of structural geometrical nonlinearities is studied which highlights the model ability in matching experimental results. The effectiveness of linear vs nonlinear controllers are analysed with regard to the control direction, gain and power. Parametric studies are carried out which allow us to choose the linear vs nonlinear control, depending on the target controlled amplitudes and associated power requirements.

  8. Obesity and type 2 diabetes impair insulin-induced suppression of glycogenolysis as well as gluconeogenesis.

    Science.gov (United States)

    Basu, Rita; Chandramouli, Visvanathan; Dicke, Betty; Landau, Bernard; Rizza, Robert

    2005-07-01

    To determine whether the hepatic insulin resistance of obesity and type 2 diabetes is due to impaired insulin-induced suppression of glycogenolysis as well as gluconeogenesis, 10 lean nondiabetic, 10 obese nondiabetic, and 11 obese type 2 diabetic subjects were studied after an overnight fast and during a hyperinsulinemic-euglycemic clamp. Gluconeogenesis and glycogenolysis were measured using the deuterated water method. Before the clamp, when glucose and insulin concentrations differed among the three groups, gluconeogenesis was higher in the diabetic than in the obese nondiabetic subjects (P glycogenolysis was higher in the diabetic than in the lean nondiabetic subjects (P glycogenolysis and gluconeogenesis were higher (P glycogenolysis and gluconeogenesis were higher (P glycogenolysis during the clamp (P glycogenolysis as well as gluconeogenesis cause hepatic insulin resistance in obese nondiabetic and type 2 diabetic humans.

  9. Olopatadine Suppresses the Migration of THP-1 Monocytes Induced by S100A12 Protein

    Directory of Open Access Journals (Sweden)

    2006-01-01

    Full Text Available Olopatadine hydrochloride (olopatadine is an antiallergic drug with histamine H 1 receptor antagonistic activity. Recently, olopatadine has been shown to bind to S100A12 which is a member of the S100 family of calcium-binding proteins, and exerts multiple proinflammatory activities including chemotaxis for monocytes and neutrophils. In this study, we examined the possibility that the interaction of olopatadine with S100A12 inhibits the proinflammatory effects of S100A12. Pretreatment of olopatadine with S100A12 reduced migration of THP-1, a monocyte cell line, induced by S100A12 alone, but did not affect recombinant human regulated upon activation, normal T cell expressed and secreted (RANTES-induced migration. Amlexanox, which also binds to S100A12, inhibited the THP-1 migration induced by S100A12. However, ketotifen, another histamine H 1 receptor antagonist, had little effect on the activity of S100A12. These results suggest that olopatadine has a new mechanism of action, that is, suppression of the function of S100A12, in addition to histamine H 1 receptor antagonistic activity.

  10. Acupuncture suppresses kainic acid-induced neuronal death and inflammatory events in mouse hippocampus.

    Science.gov (United States)

    Kim, Seung-Tae; Doo, Ah-Reum; Kim, Seung-Nam; Kim, Song-Yi; Kim, Yoon Young; Kim, Jang-Hyun; Lee, Hyejung; Yin, Chang Shik; Park, Hi-Joon

    2012-09-01

    The administration of kainic acid (KA) causes seizures and produces neurodegeneration in hippocampal CA3 pyramidal cells. The present study investigated a possible role of acupuncture in reducing hippocampal cell death and inflammatory events, using a mouse model of kainic acid-induced epilepsy. Male C57BL/6 mice received acupuncture treatments at acupoint HT8 or in the tail area bilaterally once a day for 2 days and again immediately after an intraperitoneal injection of KA (30 mg/kg). HT8 is located on the palmar surface of the forelimbs, between the fourth and fifth metacarpal bones. Twenty-four hours after the KA injection, neuronal cell survival, the activations of microglia and astrocytes, and mRNA expression of two proinflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were measured in the hippocampus. Acupuncture stimulation at HT8, but not in the tail area, significantly reduced the KA-induced seizure, neuron death, microglial and astrocyte activations, and IL-1β mRNA expression in the hippocampus. The acupuncture stimulation also decreased the mRNA expression of TNF-α, but it was not significant. These results indicate that acupuncture at HT8 can inhibit hippocampal cell death and suppress KA-induced inflammatory events, suggesting a possible role for acupuncture in the treatment of epilepsy.

  11. Tetrandrine suppresses lipopolysaccharide-induced microglial activation by inhibiting NF-κB pathway

    Institute of Scientific and Technical Information of China (English)

    Yang XUE; Ying WANG; De-chun FENG; Bao-guo XIAO; Ling-yun XU

    2008-01-01

    Aim: Microglial activation has been implicated in many neurological diseases. In this study, we examined the effects of tetrandrine (TET), a major pharmacologi-cally-active compound of Chinese herb Stephania tetrandra S Moore on micro-glial activation. Methods: The microglia pretreated with or without TET were activated by lipoopolysaccharide (LPS) in vitro. Nitric oxide (NO) release, superox-ide anion (O2-) generation, as well as TNF-α and intedeukin-6 (IL-6) production by microglia were measured afterwards. Electrophoretic mobility shift assay was performed to determine whether NF-κB activity in microglia was affected by TET treatment. Results: We found that TET inhibited the LPS-induced activation of microglia by decreasing the production of NO and O2-, consequently affecting the release of TNF-α and IL-6 in LPS-induced microglial activation. Such suppressive effect was accompanied by inhibiting transcription factor NF-κB activation. Conclusion: Our results suggest that TET might modulate LPS-induced microglial activation by inhibiting the NF-κB-mediated release of inflammatory factors.

  12. Baicalein suppresses the SOS response system of Staphylococcus aureus induced by ciprofloxacin.

    Science.gov (United States)

    Peng, Qing; Zhou, Shuqin; Yao, Fen; Hou, Bing; Huang, Yuanchun; Hua, Dexing; Zheng, Yanshan; Qian, Yuanshu

    2011-01-01

    Numerous antibiotics can induce an SOS repair system in bacteria that leads to antibiotic-resistant mutation of the bacterium. Therefore, searching for drugs that can prevent the SOS response and thus improve the long-term viability of some antibiotics is important. In this study, we aimed to detect the suppressive effects of baicalein on the SOS system and rifampin-resistant mutation in Staphylococcus aureus. We determined the reactive oxygen species (ROS) formation and intracellular ATP level in S. aureus with baicalein treatment to investigate the mechanisms involved in its effects on the SOS system. The results showed that baicalein was a potent inhibitor of the expression of the SOS genes RecA, LexA and SACOL1400. The rifampin-resistant mutation rate of S. aureus induced by ciprofloxacin was significantly reduced after treatment with baicalein. Treatment with baicalein led to a significant decrease in intracellular reactive oxygen species (ROS) formation and ATP level. Our findings indicate that baicalein may be an SOS-response inhibitor in S. aureus through inhibiting ROS formation and ATP production and may be used to prevent excessive mutation induced by antibiotics. Copyright © 2011 S. Karger AG, Basel.

  13. Suppression of STAT3 Signaling by Δ9-Tetrahydrocannabinol (THC Induces Trophoblast Dysfunction

    Directory of Open Access Journals (Sweden)

    Xinwen Chang

    2017-06-01

    Full Text Available Aims: Marijuana is a widely used illicit drug and its consumption during pregnancy has been associated with adverse reproductive outcomes. The purpose of this study was to determine the effects of chronic intake of Δ9-tetrahydrocannabinol (THC, the major component of marijuana, on trophoblast function, placental development, and birth outcomes. Methods: The pathological characteristics and distribution of cannabinoid receptors in placenta were observed by immunohistochemical (IHC staining. Cell migration in response to THC was measured by transwell assays. The levels of cannabinoid receptors and Signal Transducer and Activator of Transcription 3 (STAT3 were detected by western blot. Results: We found the placenta expressed two main cannabinoid receptors, suggesting that THC induced biological responses in placental cells. Supporting this hypothesis, we observed dramatic alterations of placental morphology in marijuana users. Using THC and inhibitors of cannabinoid receptors, we demonstrated that THC impaired trophoblast cell migration and invasion partly via cannabinoid receptors. Additionally, pregnant mice injected with THC showed adverse reproductive events including reduced number of fetuses, lower maternal and placental weights. Mechanistically, STAT3 signaling pathway was involved in the THC-induced suppression of trophoblast cell motility and pregnancy outcomes. Conclusion: Our study indicates that the STAT3 signaling pathway plays a critical role in THC-induced trophoblast dysfunction.

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

    Science.gov (United States)

    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.

  15. Suppressive effects of 17β-estradiol on hepatic fibrosis in CCl4-induced rat model

    Institute of Scientific and Technical Information of China (English)

    Qing-Hua Liu; Ding-Guo Li; Xin Huang; Chun-Hua Zong; Qin-Fang Xu; Han-Ming Lu

    2004-01-01

    AIM: To investigate the pathway via which 17β-estradiol (β-Est) exerts suppressive effects on rat hepatic fibrosis.METHODS: In vivo study was done in CCl4-induced female hepatofibrotic rats. Fibrosis-suppressive effect of β-Est rat models. Six weeks after the treatment, all the rats were sacrificed and specimens of serum or liver tissue were collected for the studies. Serum liver enzymes,fibrosis markers and estradiol levels were determined by standard enzymatic methods, ELISA and RIA, respectively.Degrees of fibrosis and areas of hepatic stellate cells (HSCs) positive for alpha-smooth muscle actin (α-SMA) in the liver were determined by van Gieson (VG) stain and immunohistochemistry.In vitro studies, HSCs were isolated by a combination of pronase-collagenase perfusion and density gradient centrifugation. First-passage HSCs were randomly divided into 10 groups, and different concentrations of β-Est, 2-hydroxyestradiol (2OHE) or 2-methoxyestradiol (2MeOE) were separately added to the cell groups. After incubation for 72 h, the degree of cell proliferation, collagen production, α-SMA or estrogen receptor (ER) expression was determined by MTT assay, ELISA and immunohistochemistry,respectively.RESULTS: β-Est treatment reduced aspartate aminotransferase (AST), alanine aminotransferase (ALT), hyaluronic acid (HA) and type Ⅳ collagen (C Ⅳ) in sera, suppressed hepatic collagen content, decreased the areas of HSCs positive for α-SMA significantly in both intact and ovariectomized female hepatofibrotic rats. There was a negative correlation between the percentage of fibrotic area of liver tissue and the serum estradiol level; the calculated correlation coefficient was -0.57 (P<0.01). β-Est and its metabolites concentration-dependently (10-9 mol/L-10-7 mol/L) inhibited HSC proliferation and collagen synthesis. At the concentration of 10-7 mol/L, they could inhibit α-SMA expression. The order of potency was 2MeOE>2OHE>β-Est.CONCLUSION: β-Est may suppress

  16. Involvement of the histaminergic system in leptin-induced suppression of food intake.

    Science.gov (United States)

    Morimoto, T; Yamamoto, Y; Mobarakeh, J I; Yanai, K; Watanabe, T; Watanabe, T; Yamatodani, A

    1999-11-01

    The ob gene product leptin is secreted from white adipose tissue, and may regulate food intake by acting on the hypothalamus in the central nervous system. But the mechanism of this effect is still unclear. The central histaminergic system has been suggested to participate in the control of various physiological functions, particularly in feeding behavior, as it mediates anorectic signals like leptin. Thus, we hypothesized that the central histaminergic system is a target for leptin in its control of feeding. To prove this, we first examined the effect of i.p. administration of alpha-fluoromethylhistidine (FMH), a specific and irreversible inhibitor of histidine decarboxylase, on leptin-induced suppression of food intake in normal C57BL strain mice. Leptin treatment (1.3 mg/kg, i.p.) significantly reduced food intake by 60% of that of control at 6 h and by 84% at 24 h compared with control. When mice were injected with FMH (100 mg/kg, i.p.) before being given leptin, leptin-induced suppression of food intake was abolished and there was no significant difference compared with that of control. Additionally, we further examined the effects of leptin on food intake in mutant mice lacking histamine H, receptors (H1R-KO mice). Leptin injection significantly reduced food intake by 56% of that of control at 6 h and by 79% at 24 h in wild-type mice (WT mice), but not in H1R-KO mice. This finding suggests that leptin affects the feeding behavior through activation of the central histaminergic system via histamine H1 receptors.

  17. Betahistine attenuates murine collagen-induced arthritis by suppressing both inflammatory and Th17 cell responses.

    Science.gov (United States)

    Tang, Kuo-Tung; Chao, Ya-Hsuan; Chen, Der-Yuan; Lim, Yun-Ping; Chen, Yi-Ming; Li, Yi-Rong; Yang, Deng-Ho; Lin, Chi-Chen

    2016-10-01

    The objective of this study was to evaluate the potential therapeutic effects of betahistine dihydrochloride (betahistine) in a collagen-induced arthritis (CIA) mouse model. CIA was induced in DBA/1 male mice by primary immunization with 100μl of emulsion containing 2mg/ml chicken type II collagen (CII) mixed with complete Freund's adjuvant (CFA) in an 1:1 ratio, and booster immunization with 100μl of emulsion containing 2mg/ml CII mixed with incomplete Freund's adjuvant (IFA) in an 1:1 ratio. Immunization was performed subcutaneously at the base of the tail. After being boosted on day 21, betahistine (1 and 5mg/kg) was orally administered daily for 2weeks. The severity of CIA was determined by arthritic scores and assessment of histopathological joint destruction. Expression of cytokines in the paw and anti-CII antibodies in the serum was evaluated by ELISA. The proliferative response against CII in the lymph node cells was measured by (3)H-thymidine incorporation assay. The frequencies of different CII specific CD4(+) T cell subsets in the lymph node were determined by flow-cytometric analysis. Betahistine treatment attenuated the severity of arthritis and reduced the levels of pro-inflammatory cytokines, including TNF-α, IL-6, IL-23 and IL-17A, in the paw tissues of CIA mice. Lymph node cells from betahistine-treated mice showed a decrease in proliferation, as well as a lower frequency of Th17 cells. In vitro, betahistine suppressed CD4(+) T cell differentiation into Th17 cells. These results indicate that betahistine is effective in suppressing both inflammatory and Th17 responses in mouse CIA and that it may have therapeutic value as an adjunct treatment for rheumatoid arthritis.

  18. Local heterogeneities in cardiac systems suppress turbulence by generating multi-armed rotors

    Science.gov (United States)

    Zhang, Zhihui; Steinbock, Oliver

    2016-05-01

    Ventricular fibrillation is an extremely dangerous cardiac arrhythmia that is linked to rotating waves of electric activity and chaotically moving vortex lines. These filaments can pin to insulating, cylindrical heterogeneities which swiftly become the new rotation backbone of the local wave field. For thin cylinders, the stabilized rotation is sufficiently fast to repel the free segments of the turbulent filament tangle and annihilate them at the system boundaries. The resulting global wave pattern is periodic and highly ordered. Our cardiac simulations show that also thicker cylinders can establish analogous forms of tachycardia. This process occurs through the spontaneous formation of pinned multi-armed vortices. The observed number of wave arms N depends on the cylinder radius and is associated to stability windows that for N = 2, 3 partially overlap. For N = 1, 2, we find a small gap in which the turbulence is removed but the pinned rotor shows complex temporal dynamics. The relevance of our findings to human cardiology are discussed in the context of vortex pinning to more complex-shaped anatomical features and remodeled myocardium.

  19. Physics of defect induced local moments in pnictide superconductors

    Energy Technology Data Exchange (ETDEWEB)

    Grinenko, Vadim; Drechsler, Stefan-Ludwig; Abdel-Hafiez, Mahmoud; Aswartham, Saicharan; Wolter-Giraud, Anja; Hess, Christian; Kumar, Manoj; Wurmehl, Sabine; Fuchs, Guenter; Nenkov, Konstantin; Hammerath, Franziska; Lang, Guillaume; Grafe, Hans-Joachim; Holzapfel, Bernhard; Brink, Jeroen van den; Buechner, Bernd; Schultz, Ludwig [IFW Dresden (Germany); Kikoin, Konstatin [School of Physics and Astronomy, Tel-Aviv University (Israel)

    2012-07-01

    Many unusual physical properties of Fe-pnictide superconductors are related to the presence of local magnetic moments induced by point-defects, e.g. As-vacancies. In the La-1111 system they improve the superconducting properties as compared with As-stoichiometric samples enhancing T{sub c} and the -dH{sub c2}/dT at T{sub c}. But they also enhance strongly the spin susceptibility, which governs the Pauli limiting behavior of the As-deficient La-1111. In heavily hole doped K-122 superconducting single crystals the local moments leads to a complex phase diagram with a Griffith and a spin glass phase. The local moments picture explains also the observed non-Fermi-liquid behavior and the large effective mass enhancement of the quasi-particles in K-122. In Co-doped Ba-122 superconducting single crystals the local moments form also a spin glass state and lead to a strong Pauli limiting behavior.

  20. Bilirubin prevents acute DSS-induced colitis by inhibiting leukocyte infiltration and suppressing upregulation of inducible nitric oxide synthase.

    Science.gov (United States)

    Zucker, Stephen D; Vogel, Megan E; Kindel, Tammy L; Smith, Darcey L H; Idelman, Gila; Avissar, Uri; Kakarlapudi, Ganesh; Masnovi, Michelle E

    2015-11-15

    Bilirubin is thought to exert anti-inflammatory effects by inhibiting vascular cell adhesion molecule-1 (VCAM-1)-dependent leukocyte migration and by suppressing the expression of inducible nitric oxide synthase (iNOS). As VCAM-1 and iNOS are important mediators of tissue injury in the dextran sodium sulfate (DSS) murine model of inflammatory colitis, we examined whether bilirubin prevents colonic injury in DSS-treated mice. Male C57BL/6 mice were administered 2.5% DSS in the drinking water for 7 days, while simultaneously receiving intraperitoneal injections of bilirubin (30 mg/kg) or potassium phosphate vehicle. Disease activity was monitored, peripheral blood counts and serum nitrate levels were determined, and intestinal specimens were analyzed for histological injury, leukocyte infiltration, and iNOS expression. The effect of bilirubin on IL-5 production by HSB-2 cells and on Jurkat cell transendothelial migration also was determined. DSS-treated mice that simultaneously received bilirubin lost less body weight, had lower serum nitrate levels, and exhibited reduced disease severity than vehicle-treated animals. Concordantly, histopathological analyses revealed that bilirubin-treated mice manifested significantly less colonic injury, including reduced infiltration of eosinophils, lymphocytes, and monocytes, and diminished iNOS expression. Bilirubin administration also was associated with decreased eosinophil and monocyte infiltration into the small intestine, with a corresponding increase in peripheral blood eosinophilia. Bilirubin prevented Jurkat migration but did not alter IL-5 production. In conclusion, bilirubin prevents DSS-induced colitis by inhibiting the migration of leukocytes across the vascular endothelium and by suppressing iNOS expression.

  1. Perilla frutescens extract ameliorates DSS-induced colitis by suppressing proinflammatory cytokines and inducing anti-inflammatory cytokines.

    Science.gov (United States)

    Urushima, Hayato; Nishimura, Junichi; Mizushima, Tsunekazu; Hayashi, Noriyuki; Maeda, Kazuhisa; Ito, Toshinori

    2015-01-01

    Anti-inflammatory effects have been reported in Perilla frutescens leaf extract (PE), which is a plant of the genus belonging to the Lamiaceae family. We examined the effect of PE on dextran sulfate sodium (DSS)-induced colitis. Preliminarily, PE was safely administered for 7 wk without any adverse effects. In the preventive protocol, mice were fed 1.5% DSS solution dissolved in distilled water (control group) or 0.54% PE solution (PE group) ad libitum for 7 days. In the therapeutic protocol, distilled water or 0.54% PE solution was given for 10 days just after administration of 1.5% DSS for 5 days. PE intake significantly improved body weight loss. The serum cytokine profile demonstrated that TNF-α, IL-17A, and IL-10 were significantly lower in the PE group than in the control group. In the therapeutic protocol, mice in the PE group showed significantly higher body weight and lower histological colitis scores compared with mice in the control group on day 15. The serum cytokine profile demonstrated that TGF-β was significantly higher in the PE group than in the control group. In distal colon mRNA expression, TNF-α, and IL-17A were significantly downregulated. In vitro analyses of biologically active ingredients, such as luteolin, apigenin, and rosmarinic acid, in PE were performed. Luteolin suppressed production of proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IL-17A. Apigenin also suppressed secretion of IL-17A and increased the anti-inflammatory cytokine IL-10. Rosmarinic acid increased the regulatory T cell population. We conclude that PE might be useful in treatment and prevention of DSS-induced colitis.

  2. Permittivity disorder induced Anderson localization in magnetophotonic crystals

    Science.gov (United States)

    Abdi-Ghaleh, R.; Namdar, A.

    2016-11-01

    This theoretical study was carried out to investigate the permittivity disorder induced Anderson localization of light in one-dimensional magnetophotonic crystals. It was shown that the disorder create the resonant transmittance modes associated with enhanced Faraday rotations inside the photonic band gap. The average localization length of the right- and left-handed circular polarizations (RCP and LCP), the total transmittance together with the ensemble average of the RCP and LCP phases, and the Faraday rotation of the structure were also investigated. For this purpose, the off-diagonal elements of the permittivity tensor were varied for various wavelengths of incident light. The obtained results revealed the nonreciprocal property of circular eigen modes. This study can potentially open up a new aspect for utilizing the disorder magnetophotonic structures in nonreciprocal systems such as isolators and circulators.

  3. CPU 86017, p-chlorobenzyltetrahydroberberine chloride, attenuates monocrotaline-induced pulmonary hypertension by suppressing endothelin pathway.

    Science.gov (United States)

    Zhang, Tian-tai; Cui, Bing; Dai, De-zai; Su, Wei

    2005-11-01

    To elucidate the involvement of the endothelin (ET) pathway in the pathogenesis of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and the therapeutic effect of CPU 86017 (p-chlorobenzyltetrahydroberberine chloride) in rats. Rats were injected with a single dose (60 mg/kg, sc) of MCT and given CPU 86017 (20, 40, and 80 mg/kg-1/d-1, po) or saline for 28 d. The hemodynamics, mRNA expression, and vascular activity were evaluated. Right ventricular systolic pressure and central venous pressures were elevated markedly in the PAH model and decreased by CPU 86017. In the PAH group, the endothelin-1 (ET-1) in serum and lungs was dramatically increased by 54% (79.9 pg/mL, PCPU 86017 decreased the content of ET-1 to the normal level in lung tissue, but was less effective in serum. The level of NO was significantly increased in CPU 86017 at 80 and 40 mg/kg-1/d-1 groups in tissue, whereas the difference in serum was not significant. A significant reduction in MDA production and an increase in the SOD activity in the serum and lungs was observed in all three CPU 86017 groups. CPU 86017 80 mg/kg-1/d-1 po increased the activity of cNOS by 33% (PCPU 86017 groups, and preproET-1 mRNA abundance was also reduced notably in CPU 86017 80 mg/kg-1/d-1 group vs the PAH group. The KCl-induced vasoconstrictions in the calcium-free medium decreased markedly in PAH group but recovered partially after CPU 86017 intervention. The constrictions in the presence of Ca(2+) was not improved by CPU 86017. The phenylephrine-induced vasoconstrictions in the calcium-free medium decreased markedly in PAH group but not recovered after CPU 86017 intervention. The constrictions in the presence of Ca(2+) completely returned to the normal after CPU 86017 intervention. CPU 86017 suppressed MCT-induced PAH mainly through an indirect suppression of the ET-1 system, which was involved in the pathogenesis of the disease.

  4. Pur-Alpha Induces JCV Gene Expression and Viral Replication by Suppressing SRSF1 in Glial Cells.

    Directory of Open Access Journals (Sweden)

    Ilker Kudret Sariyer

    Full Text Available PML is a rare and fatal demyelinating disease of the CNS caused by the human polyomavirus, JC virus (JCV, which occurs in AIDS patients and those on immunosuppressive monoclonal antibody therapies (mAbs. We sought to identify mechanisms that could stimulate reactivation of JCV in a cell culture model system and targeted pathways which could affect early gene transcription and JCV T-antigen production, which are key steps of the viral life cycle for blocking reactivation of JCV. Two important regulatory partners we have previously identified for T-antigen include Pur-alpha and SRSF1 (SF2/ASF. SRSF1, an alternative splicing factor, is a potential regulator of JCV whose overexpression in glial cells strongly suppresses viral gene expression and replication. Pur-alpha has been most extensively characterized as a sequence-specific DNA- and RNA-binding protein which directs both viral gene transcription and mRNA translation, and is a potent inducer of the JCV early promoter through binding to T-antigen.Pur-alpha and SRSF1 both act directly as transcriptional regulators of the JCV promoter and here we have observed that Pur-alpha is capable of ameliorating SRSF1-mediated suppression of JCV gene expression and viral replication. Interestingly, Pur-alpha exerted its effect by suppressing SRSF1 at both the protein and mRNA levels in glial cells suggesting this effect can occur independent of T-antigen. Pur-alpha and SRSF1 were both localized to oligodendrocyte inclusion bodies by immunohistochemistry in brain sections from patients with HIV-1 associated PML. Interestingly, inclusion bodies were typically positive for either Pur-alpha or SRSF1, though some cells appeared to be positive for both proteins.Taken together, these results indicate the presence of an antagonistic interaction between these two proteins in regulating of JCV gene expression and viral replication and suggests that they play an important role during viral reactivation leading to

  5. Suppression Effects of Betaine-Enriched Spinach on Hyperhomocysteinemia Induced by Guanidinoacetic Acid and Choline Deficiency in Rats

    Directory of Open Access Journals (Sweden)

    Yi-Qun Liu

    2014-01-01

    Full Text Available Betaine is an important natural component of rich food sources, especially spinach. Rats were fed diets with betaine or spinach powder at the same level of betaine for 10 days to investigate the dose-dependent effects of spinach powder supplementation on hyperhomocysteinemia induced by guanidinoacetic acid (GAA addition and choline deprivation. The GAA-induced hyperhomocysteinemia in rats fed 25% casein diet (25C was significantly suppressed by supplementation with betaine or spinach, and it was completely suppressed by taking 11.0% spinach supplementation. The choline deprivation-induced enhancement of plasma homocysteine concentration in rats fed 25% soybean protein diet (25S was markedly suppressed by 3.82% spinach. Supplementation with betaine or spinach partially prevented the effects of GAA on hepatic concentrations of methionine metabolites. The decrease in activity of betaine-homocysteine S-methyltransferase (BHMT and cystathionine β-synthase (CBS in GAA-induced hyperhomocysteinemia was recovered by supplementation with betaine or spinach. Supplementation with betaine or spinach did not affect BHMT activity, whereas it partially restored CBS activity in choline-deprived 25S. The results indicated that betaine or spinach could completely suppress the hyperhomocysteinemia induced by choline deficiency resulting from stimulating the homocysteine removal by both remethylation and cystathionine formation.

  6. Elimination of dysfunctional mitochondria through mitophagy suppresses benzo[a]pyrene-induced apoptosis.

    Science.gov (United States)

    Das, Durgesh Nandini; Naik, Prajna Paramita; Mukhopadhyay, Subhadip; Panda, Prashanta Kumar; Sinha, Niharika; Meher, Biswa Ranjan; Bhutia, Sujit K

    2017-11-01

    Mitophagy, a special type of autophagy, plays an important role in the mitochondria quality control and cellular homeostasis. In this study, we examined the molecular mechanism of mitophagy induction with benzo[a]pyrene (B[a]P), a ubiquitous polycyclic aromatic hydrocarbon, which acts as a prosurvival response against apoptotic cell death. Our study showed that B[a]P displayed higher cytotoxicity in autophagy-deficient HaCaT cells as compared to control. Further, we showed that B[a]P triggered the Beclin-1-dependent autophagy through the mammalian target of rapamycin (mTOR)/AMP-activated protein kinase (AMPK) pathway. Moreover, our study indicated that the B[a]P-induced autophagy was initiated through the activation of cytochrome P450 1B1 (CYP1B1) and the aryl hydrocarbon receptor (AhR) in HaCaT cells. Intriguingly, the B[a]P-induced Beclin-1-mediated mitophagy was suppressed in CYP1B1 and AhR knockdown HaCaT cells, indicating a crucial role of B[a]P activation in the mitophagy induction to regulate cell death. B[a]P was shown to increase the mitochondrial dysfunction and decrease the mitochondrial membrane potential, resulting in depletion of ATP level along with the inhibition of the oxygen consumption rate in HaCaT cells. Importantly, the supplementation of methyl pyruvate compensated for the B[a]P-induced drop in the ATP level and mitigated the reactive oxygen species burden and autophagy. Mechanistically, B[a]P inhibited the manganese superoxide dismutase (MnSOD) activity and we found that the activated mitochondrial CYP1B1 interacted with MnSOD, inflicting mitophagy to protect from B[a]P-induced apoptosis. In summary, our study reveals mitophagy induction as a cellular protection mechanism against B[a]P-triggered toxicity and carcinogenesis. Copyright © 2017. Published by Elsevier Inc.

  7. Kaempferol targets RSK2 and MSK1 to suppress UV radiation-induced skin cancer.

    Science.gov (United States)

    Yao, Ke; Chen, Hanyong; Liu, Kangdong; Langfald, Alyssa; Yang, Ge; Zhang, Yi; Yu, Dong Hoon; Kim, Myoung Ok; Lee, Mee-Hyun; Li, Haitao; Bae, Ki Beom; Kim, Hong-Gyum; Ma, Wei-Ya; Bode, Ann M; Dong, Ziming; Dong, Zigang

    2014-09-01

    Solar UV (SUV) irradiation is a major factor in skin carcinogenesis, the most common form of cancer in the United States. The MAPK cascades are activated by SUV irradiation. The 90 kDa ribosomal S6 kinase (RSK) and mitogen and stress-activated protein kinase (MSK) proteins constitute a family of protein kinases that mediate signal transduction downstream of the MAPK cascades. In this study, phosphorylation of RSK and MSK1 was upregulated in human squamous cell carcinoma (SCC) and SUV-treated mouse skin. Kaempferol, a natural flavonol, found in tea, broccoli, grapes, apples, and other plant sources, is known to have anticancer activity, but its mechanisms and direct target(s) in cancer chemoprevention are unclear. Kinase array results revealed that kaempferol inhibited RSK2 and MSK1. Pull-down assay results, ATP competition, and in vitro kinase assay data revealed that kaempferol interacts with RSK2 and MSK1 at the ATP-binding pocket and inhibits their respective kinase activities. Mechanistic investigations showed that kaempferol suppresses RSK2 and MSK1 kinase activities to attenuate SUV-induced phosphorylation of cAMP-responsive element binding protein (CREB) and histone H3 in mouse skin cells. Kaempferol was a potent inhibitor of SUV-induced mouse skin carcinogenesis. Further analysis showed that skin from the kaempferol-treated group exhibited a substantial reduction in SUV-induced phosphorylation of CREB, c-Fos, and histone H3. Overall, our results identify kaempferol as a safe and novel chemopreventive agent against SUV-induced skin carcinogenesis that acts by targeting RSK2 and MSK1.

  8. Cold-inducible RNA-binding protein inhibits neuron apoptosis through the suppression of mitochondrial apoptosis.

    Science.gov (United States)

    Zhang, Hai-Tao; Xue, Jing-Hui; Zhang, Zhi-Wen; Kong, Hai-Bo; Liu, Ai-Jun; Li, Shou-Chun; Xu, Dong-Gang

    2015-10-01

    Cold-inducible RNA-binding protein (CIRP) is induced by mild hypothermia in several mammals, but the precise mechanism by which CIRP mediates hypothermia-induced neuroprotection remains unknown. We aimed to investigate the molecular mechanisms by which CIRP protects the nervous system during mild hypothermia. Rat cortical neurons were isolated and cultured in vitro under mild hypothermia (32°C). Apoptosis was measured by annexin V and propidium iodide staining, visualized by flow cytometry. Neuron ultrastructure was visualized by transmission electron microscopy. CIRP overexpression and knockdown were achieved via infection with pL/IRES/GFP-CIRP and pL/shRNA/F-CIRP-A lentivirus. RT(2) Profiler PCR Array Pathway Analysis and western blotting were used to evaluate the effects of CIRP overexpresion/knockdown on the neurons׳ transcriptome. Neuron late apoptosis was significantly reduced at day 7 of culture by 12h hypothermia, but neuron ultrastructure remained relatively intact. RT(2) Profiler PCR Array Pathway Analysis of 84 apoptosis pathway-associated factors revealed that mild hypothermia and CIRP overexpression induce similar gene expression profiles, specifically alterations of genes implicated in the mitochondrial apoptosis pathway. Mild hypothermia-treated neurons up-regulated 12 and down-regulated 38 apoptosis pathway-associated genes. CIRP-overexpressing neurons up-regulated 15 and down-regulated 46 genes. CIRP-knocked-down hypothermia-treated cells up-regulated 9 and down-regulated 40 genes. Similar results were obtained at the protein level. In conclusion, CIRP may inhibit neuron apoptosis through the suppression of the mitochondria apoptosis pathway during mild hypothermia.

  9. Cannabidivarin (CBDV suppresses pentylenetetrazole (PTZ-induced increases in epilepsy-related gene expression

    Directory of Open Access Journals (Sweden)

    Naoki Amada

    2013-11-01

    Full Text Available To date, anticonvulsant effects of the plant cannabinoid, cannabidivarin (CBDV, have been reported in several animal models of seizure. However, these behaviourally observed anticonvulsant effects have not been confirmed at the molecular level. To examine changes to epilepsy-related gene expression following chemical convulsant treatment and their subsequent control by phytocannabinoid administration, we behaviourally evaluated effects of CBDV (400 mg/kg, p.o. on acute, pentylenetetrazole (PTZ: 95 mg/kg, i.p.-induced seizures, quantified expression levels of several epilepsy-related genes (Fos, Casp 3, Ccl3, Ccl4, Npy, Arc, Penk, Camk2a, Bdnf and Egr1 by qPCR using hippocampal, neocortical and prefrontal cortical tissue samples before examining correlations between expression changes and seizure severity. PTZ treatment alone produced generalised seizures (median: 5.00 and significantly increased expression of Fos, Egr1, Arc, Ccl4 and Bdnf. Consistent with previous findings, CBDV significantly decreased PTZ-induced seizure severity (median: 3.25 and increased latency to the first sign of seizure. Furthermore, there were correlations between reductions of seizure severity and mRNA expression of Fos, Egr1, Arc, Ccl4 and Bdnf in the majority of brain regions in the CBDV+PTZ treated group. When CBDV treated animals were grouped into CBDV responders (criterion: seizure severity ≤3.25 and non-responders (criterion: seizure severity >3.25, PTZ-induced increases of Fos, Egr1, Arc, Ccl4 and Bdnf expression were suppressed in CBDV responders. These results provide the first molecular confirmation of behaviourally observed effects of the non-psychoactive, anticonvulsant cannabinoid, CBDV, upon chemically-induced seizures and serve to underscore its suitability for clinical development.

  10. Light induced suppression of Kondo effect at amorphous LaAlO3/SrTiO3 interface

    Science.gov (United States)

    Liu, G. Z.; Qiu, J.; Jiang, Y. C.; Zhao, R.; Yao, J. L.; Zhao, M.; Feng, Y.; Gao, J.

    2016-07-01

    We report photoelectric properties of two-dimensional electron gas (2DEG) at an amorphous LaAlO3/SrTiO3 interface. Under visible light illumination (650 nm), an enhancement of electric conductivity is observed over the temperature range from 2 to 300 K. Particularly, a resistance upturn appearing below 25 K, which is further proved to from the Kondo effect, is suppressed by the 650 nm visible light. From the results of light-assisted Hall measurements, light irradiation increases the carrier mobility rather than carrier density in the Kondo regime. It is suggested that light induces the decoherence effect of localized spin states, hence the electron scattering is weakened and the carrier mobility is improved accordingly. Moreover, the enhancement of electrical conductivity by visible light verifies that in-gap states located in the SrTiO3 side of the interface play an important role in the electrical transport of the amorphous SrTiO3-based oxide 2DEG system. Our results provide deeper insight into the photoinduced effects in the 2DEG system, paving the way for the design of optoelectronic devices based on oxides.

  11. Absolute quantitative proton NMR spectroscopy based on the amplitude of the local water suppression pulse. Quantification of brain water and metabolites

    DEFF Research Database (Denmark)

    Danielsen, E R; Henriksen, O

    1994-01-01

    Quantification in localized proton NMR spectroscopy has been achieved by various methods in recent years. A new method for absolute quantification is described in this paper. The method simultaneously rules out problems with B1 field inhomogeneity and coil loading, utilizing a relation between...... the locally optimized amplitude of a chemical shift selective water suppression pulse and the acquired signal. Validity and feasibility of quantification using the method of the water suppression pulse is demonstrated. Brain water and cerebral metabolites have been quantified in a study of 12 healthy...

  12. p53 mediates the suppression of cancer cell invasion by inducing LIMA1/EPLIN.

    Science.gov (United States)

    Ohashi, Tomoko; Idogawa, Masashi; Sasaki, Yasushi; Tokino, Takashi

    2017-04-01

    The tumor suppressor gene p53 is frequently mutated in human cancer. p53 executes various functions, such as apoptosis induction and cell cycle arrest, by modulating transcriptional regulation. In this study, LIM domain and Actin-binding protein 1 (LIMA1) was identified as a target of the p53 family using a cDNA microarray. We also evaluated genome-wide occupancy of the p53 protein by performing chromatin immunoprecipitation-sequencing (ChIP-seq) and identified two p53 response elements in the LIMA1 gene. LIMA1 protein levels were increased by treatment with nutlin-3a, a small molecule that activates endogenous p53. In addition, LIMA1 expression was significantly downregulated in cancers compared with normal tissues. Knockdown of LIMA1 significantly enhanced cancer cell invasion and partially inhibited p53-induced suppression of cell invasion. Furthermore, low expression of LIMA1 in cancer patients correlated with decreased survival and poor prognosis. Thus, p53-induced LIMA1 inhibits cell invasion, and the downregulation of LIMA1 caused by p53 mutation results in decreased survival in cancer patients. Collectively, this study reveals the molecular mechanism of LIMA1 downregulation in various cancers and suggests that LIMA1 may be a novel prognostic predictor and a therapeutic target for cancer.

  13. Docosahexaenoic acid suppresses arachidonic acid-induced proliferation of LS-174T human colon carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    Piet Habbel; Karsten H Weylandt; Katja Lichopoj; Johannes Nowak; Martin Purschke; Jing-Dong Wang; Cheng-Wei He; Daniel C Baumgart; Jing X Kang

    2009-01-01

    AIM: To investigate the impact of arachidonic acid (AA) and docosahexaenoic acid (DHA) and their combination on colon cancer cell growth.METHODS: The LS-174T colon cancer cell line was used to study the role of the prostaglandin precursor AA and the omega-3 polyunsaturated fatty acid DHA on cell growth. Cell viability was assessed in XTT assays. For analysis of cell cycle and cell death, flow cytometry and DAPI staining were applied. Expression of cyclooxygenase-2 (COX-2), p21 and bcl-2 in cells incubated with AA or DHA was examined by real-time RT-PCR. Prostaglandin E2 (PGE2) generation in the presence of AA and DHA was measured using a PGE2ELISA.RESULTS: AA increased cell growth, whereas DHA reduced viability of LS 174T cells in a time- and dosedependent manner. Furthermore, DHA down- regulated mRNA of bcl-2 and up-regulated p21. Interestingly,DHA was able to suppress AA-induced cell proliferation and significantly lowered AA-derived PGE2 formation.DHA also down-regulated COX-2 expression. In addition to the effect on PGE2 formation, DHA directly reduced PGE2-induced cell proliferation in a dosedependent manner.CONCLUSION: These results suggest that DHA can inhibit the pro-proliferative effect of abundant AA or PGE2.

  14. Role of phyto-stabilised silver nanoparticles in suppressing adjuvant induced arthritis in rats.

    Science.gov (United States)

    Mani, Aparna; Vasanthi, C; Gopal, V; Chellathai, Darling

    2016-12-01

    The present study was aimed to evaluate the anti-arthritic effects of silver nanoparticles synthesised using Piper nigrum extract and to further establish its mechanism of action in a rat model of adjuvant induced arthritis (AA). Adjuvant arthritis was induced by injecting complete Freund's adjuvant (0.1mL) into the left hind paw of 36 albino Wistar rats (n=6). Silver nanoparticles stabilised with Piper nigrum extract (25 and 50mg/kg). Commercial silver nanoparticles (50mg/kg) and methotrexate (0.1mg/kg) were administered by intraperitoneal route from day 11 to day 22 on alternate days. It was found that treatment with silver nanoparticles stabilised with Piper nigrum (S-AgNPs) significantly reduced the paw edema and alleviated the histopathological changes of cell infiltration, synovial hyperplasia, bone and cartilage destruction. Furthermore, the phytostabilised silver nanoparticles (S-AgNPs) inhibited the protein expression of NF-kβ p65 and TNF-α as evidenced by immunohistochemistry analysis. Our current findings suggest that silver nanoparticles stabilised with Piper nigrum extract (S-AgNPs) have potent anti-arthritic activity which is mediated by inhibition of TNF-α and suppression of pro-inflammatory cytokines that are secreted in response to activated transcription factors of NF-kβ. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Capsaicin triggers immunogenic PEL cell death, stimulates DCs and reverts PEL-induced immune suppression.

    Science.gov (United States)

    Granato, Marisa; Gilardini Montani, Maria Saveria; Filardi, Mariarosari; Faggioni, Alberto; Cirone, Mara

    2015-10-06

    Capsaicin, the pungent alkaloid of red pepper has been extensively studied for its many properties, especially the anti-inflammatory and anti-oxidant ones. It binds to vanilloid receptor 1, although it has been reported to be able to mediate some effects independently of its receptor. Another important property of Capsaicin is the anticancer activity against highly malignant tumors, alone or in combination with other chemotherapeutic agents. In this study, we found that Capsaicin induced an apoptotic cell death in PEL cells correlated with the inhibition of STAT3. STAT3 pathway, constitutively activated in PEL cells, is essential for their survival. By STAT3 de-phosphorylation, Capsaicin reduced the Mcl-1 expression level and this could represent one of the underlying mechanisms leading to the Capsaicin-mediated cell death and autophagy induction. Next, by pharmacological or genetic inhibition, we found that autophagy played a pro-survival role, suggesting that its inhibition could be exploited to increase the Capsaicin cytotoxic effect against PEL cells. Finally, we show that Capsaicin induced DAMP exposure, as for an immunogenic cell death, directly promoted DC activation and, more importantly, that it counteracted the immune-suppression, in terms of DC differentiation, mediated by the PEL released factors.

  16. Kaempferol suppresses bladder cancer tumor growth by inhibiting cell proliferation and inducing apoptosis.

    Science.gov (United States)

    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.

  17. Suppression of the antiferroelectric phase during polarization cycling of an induced ferroelectric phase

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Xiaoming; Tan, Xiaoli, E-mail: xtan@iastate.edu [Department of Materials Science and Engineering, Iowa State University, Ames, Iowa 50011 (United States)

    2015-08-17

    The ceramic Pb{sub 0.99}Nb{sub 0.02}[(Zr{sub 0.57}Sn{sub 0.43}){sub 0.92}Ti{sub 0.08}]{sub 0.98}O{sub 3} can exist in either an antiferroelectric or a ferroelectric phase at room temperature, depending on the thermal and electrical history. The antiferroelectric phase can be partially recovered from the induced ferroelectric phase when the applied field reverses polarity. Therefore, polarization cycling of the ferroelectric phase in the ceramic under bipolar fields at room temperature is accompanied with repeated phase transitions. In this letter, the stability of the recovered antiferroelectric phase upon electrical cycling of the ceramic is investigated. Ex-situ X-ray diffraction reveals that bipolar cycling suppresses the antiferroelectric phase; this is indirectly supported by piezoelectric coefficient d{sub 33} measurements. It is speculated that the accumulated charged point defects during polarization cycling stabilize the polar ferroelectric phase. The findings presented are important to the fundamental studies of electric fatigue and field-induced phase transitions in ferroelectrics.

  18. Extract of Rhus verniciflua Bark Suppresses 2,4-Dinitrofluorobenzene-Induced Allergic Contact Dermatitis

    Directory of Open Access Journals (Sweden)

    Dong Ki Park

    2013-01-01

    Full Text Available Rhus verniciflua Stokes (RV has traditionally been used as a food supplement and a traditional herbal medicine for centuries in Korea. Recent studies suggest that RV has potent antioxidative, antitumor, and anti-inflammatory properties. In this study, the anti-inflammatory effects of RV from mice sensitized with 2,4-dinitrofluorobenzene (DNFB and activated macrophages were investigated. The results showed that RV reduced ear swelling and hyperplasia of ear tissue as well as an increase in vascular permeability, which are characteristics of allergic contact dermatitis (ACD with evident histomorphological changes in epidermis and dermis. Decreased numbers of infiltrated mast cells were seen in RV extract treated group, using toluidine blue staining. RV extract significantly regulates the expression of inducible nitric oxide synthase (iNOS at the translational level in activated macrophages. Furthermore, RV extract and its active compound, fisetin, attenuated the level of tumor necrosis factor-α (TNF-α and interleukin 6 (IL-6 mRNA in LPS-stimulated macrophages. Anti-ACD effect of RV extract may be due to the suppression of iNOS and proinflammatory cytokines which might be mediated via the NFκB signaling pathways. Collectively, RV extract has potential for alleviating ACD-like symptoms induced by DNFB in the mouse.

  19. MET Suppresses Epithelial VEGFR2 via Intracrine VEGF-induced Endoplasmic Reticulum-associated Degradation

    Directory of Open Access Journals (Sweden)

    Tom T. Chen

    2015-05-01

    Full Text Available Hepatocyte growth factor (HGF and vascular endothelial growth factor (VEGF drive cancer through their respective receptors, MET and VEGF receptor 2 (VEGFR2. VEGFR2 inhibits MET by promoting MET dephosphorylation. However, whether MET conversely regulates VEGFR2 remains unknown. Here we show that MET suppresses VEGFR2 protein by inducing its endoplasmic-reticulum-associated degradation (ERAD, via intracrine VEGF action. HGF–MET signaling in epithelial cancer cells promoted VEGF biosynthesis through PI3-kinase. In turn, VEGF and VEGFR2 associated within the ER, activating inositol-requiring enzyme 1α, and thereby facilitating ERAD-mediated depletion of VEGFR2. MET disruption upregulated VEGFR2, inducing compensatory tumor growth via VEGFR2 and MEK. However, concurrent disruption of MET and either VEGF or MEK circumvented this, enabling more profound tumor inhibition. Our findings uncover unique cross-regulation between MET and VEGFR2—two RTKs that play significant roles in tumor malignancy. Furthermore, these results suggest rational combinatorial strategies for targeting RTK signaling pathways more effectively, which has potentially important implications for cancer therapy.

  20. Suppression of endothelin-3-induced nitric oxide synthesis by triglyceride in human endothelial cells.

    Science.gov (United States)

    Minami, M; Yokokawa, K; Kohno, M; Yasunari, K; Yoshikawa, J

    1998-01-01

    Reduced endothelium-derived nitric oxide (NO) production characterizes several vascular diseases. This study examined the effect of triglyceride on NO production induced by endothelin-3 (ET-3) in cultured human umbilical vein endothelial cells. Triglyceride-rich human plasma obtained after a high-carbohydrate diet with white wine was used in an ex vivo study. The plasma triglyceride fraction was found to consist of large amounts of palmitic and oleic acids detected by gas-liquid chromatography. Therefore, the effect of synthetic tripalmitin and triolein emulsion on NO production was also examined. ET-3 stimulated NO and guanosine 3',5'-cyclic monophosphate production and increased cytosolic Ca2+ levels in the endothelial cells (ECs). After incubation of the ECs with the triglyceride-rich plasma for 2 h, these responses to ET-3 were ameliorated in a triglyceride concentration-dependent manner (50-200 mg/dl). A synthesized emulsion of tripalmitin (100 mg/dl) and triolein (100 mg/dl) also blunted the responses to ET-3. Neither endothelial constitutive NO synthase mRNA expression nor its protein level was affected by treatment with triglycerides. These results suggest that triglyceride suppresses ET-3-induced NO synthesis in human ECs by inhibiting cytosolic Ca2+ elevation.

  1. Local inflammation induces complement crosstalk which amplifies the antimicrobial response.

    Directory of Open Access Journals (Sweden)

    Jing Zhang

    2009-01-01

    Full Text Available By eliciting inflammatory responses, the human immunosurveillance system notably combats invading pathogens, during which acute phase proteins (CRP and cytokines are elevated markedly. However, the Pseudomonas aeruginosa is a persistent opportunistic pathogen prevalent at the site of local inflammation, and its acquisition of multiple antibiotic-resistance factors poses grave challenges to patient healthcare management. Using blood samples from infected patients, we demonstrate that P. aeruginosa is effectively killed in the plasma under defined local infection-inflammation condition, where slight acidosis and reduced calcium levels (pH 6.5, 2 mM calcium typically prevail. We showed that this powerful antimicrobial activity is provoked by crosstalk between two plasma proteins; CRPratioL-ficolin interaction led to communication between the complement classical and lectin pathways from which two amplification events emerged. Assays for C4 deposition, phagocytosis, and protein competition consistently proved the functional significance of the amplification pathways in boosting complement-mediated antimicrobial activity. The infection-inflammation condition induced a 100-fold increase in CRPratioL-ficolin interaction in a pH- and calcium-sensitive manner. We conclude that the infection-induced local inflammatory conditions trigger a strong interaction between CRPratioL-ficolin, eliciting complement-amplification pathways which are autonomous and which co-exist with and reinforce the classical and lectin pathways. Our findings provide new insights into the host immune response to P. aeruginosa infection under pathological conditions and the potential development of new therapeutic strategies against bacterial infection.

  2. Class A dioscorins of various yam species suppress ovalbumin-induced allergic reactions.

    Science.gov (United States)

    Yang, Ching-Chi; Lin, Kuo-Chih

    2014-06-01

    Dioscorins, the primary storage proteins in yam tubers, of different species exhibited varying immunomodulatory activities in mice. We inferred that this might be attributed to the various isoforms in the yam tubers. We aimed to investigate the antiallergic potential of the Class A dioscorins of various yam species using the ovalbumin (OVA)-induced murine allergy model. We purified the recombinant Class A dioscorins (rDioscorins) of various yam species from Escherichia coli and evaluated their antiallergic potential by enzyme-linked immunosorbent assay. The Class A rDioscorins of various yam species suppressed allergic reactions by significantly decreasing the serum IgE and histamine levels. The serum IFN-γ and IgG2a levels significantly increased in all rDioscorin-treated mice. The splenocytes of the rDioscorin-treated mice also exhibited upregulated IFN-γ secretion in response to ConA stimulation. By contrast, the serum IL-5 levels decreased to basal levels in mice treated with Class A rDioscorins and the amount of IL-5 produced by splenocytes decreased in response to ConA stimulation. The Class A rDioscorins suppress allergic reactions, possibly through modulating an imbalanced Th1/Th2 immune response to OVA by promoting Th1 cell responses. Furthermore, the Class A rDioscorins of various yam species exhibited similar immunomodulatory activities in OVA-sensitized mice, which were different from the activities demonstrated by native dioscorins, suggesting that distinct immunomodulatory effects of native dioscorins on mice were attributed to the various isoforms in the yam tubers. The Class A dioscorins of various yam species exhibit antiallergic activity and are potential immunotherapeutic agents for treating IgE-mediated hypersensitivity.

  3. Apigenin accelerates lipopolysaccharide induced apoptosis in mesenchymal stem cells through suppressing vitamin D receptor expression

    Institute of Scientific and Technical Information of China (English)

    ZHANG Huan-tian; ZHA Zhen-gang; CAOJia-hui; LIANG Zu-jian; WU Hao; HE Ming-tao; ZANG Xiao; YAO Ping; ZHANG Jia-qing

    2011-01-01

    5 μmol/L.Results from phase-contrast microscopy,MTT,Hoechst staining and AnnexinV/PI double stain FCM demonstrated that with the increasing concentrations of API and extension of administrating time,significant morphological changes of MSCs occurred,viability of cells was strongly inhibited,and meanwhile,apoptosis of LPS-administrated MSCs was exacerbated,compared with LPS individual group.In addition,API promoted caspase-3,Bad mRNA expression and inhibited Bcl-2 mRNA expression in a time-dependent and concentration- dependent manner.Further study found that pro-apoptosis effect of API was related to suppress VDR expression.Conclusions API could inhibit the expression of inducible inflammatory factors,therefore exert the strong anti-inflammatory function.However,API could not protect MSC apoptosis induced by LPS but amplified the apoptosis.The apoptosis is related to Bad/Bcl-2 increasing and caspase-3 activation,which is mediated through suppressing VDR expression.

  4. Telmisartan treatment targets inflammatory cytokines to suppress the pathogenesis of acute colitis induced by dextran sulphate sodium.

    Science.gov (United States)

    Arumugam, Somasundaram; Sreedhar, Remya; Thandavarayan, Rajarajan A; Giridharan, Vijayasree V; Karuppagounder, Vengadeshprabhu; Pitchaimani, Vigneshwaran; Afrin, Mst Rejina; Miyashita, Shizuka; Nomoto, Mayumi; Harima, Meilei; Suzuki, Hiroshi; Nakamura, Takashi; Nakamura, Masahiko; Suzuki, Kenji; Watanabe, Kenichi

    2015-08-01

    The renin angiotensin system (RAS) is essential for the regulation of cardiovascular and renal functions to maintain the fluid and electrolyte homeostasis. Recent studies have demonstrated a locally expressed RAS in various tissues of mammals, which is having pathophysiological roles in those organ system. Interestingly, local RAS has important role during the inflammatory bowel disease pathogenesis. Further to delineate its role and also to identify the potential effects of telmisartan, an angiotensin receptor blocker, we have used a mouse model of acute colitis induced by dextran sulphate sodium. We have used 0.01 and 5mg/kg body weight doses of telmisartan and administered as enema to facilitate the on-site action and to reduce the systemic adverse effects. Telmisartan high dose treatment significantly reduced the disease activity index score when compared with the colitis control mice. In addition, oxidative stress and endoplasmic reticulum stress markers expression were also significantly reduced when compared with the colitis control mice. Subsequent experiments were carried out to investigate some of the mechanisms underlying its anti-inflammatory effects and identified that the mRNA levels of pro-inflammatory cytokines such as tumour necrosis factor α, interleukin 1β, interleukin 6 and monocyte chemoattractant protein 1 as well as cellular DNA damage were significantly suppressed when compared with the colitis control mice. Similarly the apoptosis marker proteins such as cleaved caspase 3 and 7 levels were down-regulated and anti-apoptotic protein Bcl2 level was significantly upregulated by telmisartan treatment. These results indicate that blockade of RAS by telmisartan can be an effective therapeutic option against acute colitis.

  5. Andrographolide Inhibits Ovariectomy-Induced Bone Loss via the Suppression of RANKL Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Tao Wang

    2015-11-01

    Full Text Available Osteoporosis is a debilitating skeletal disorder with an increased risk of low-energy fracture, which commonly occurs among postmenopausal women. Andrographolide (AP, a natural product isolated from Andrographis paniculata, has been found to have anti-inflammatory, anti-cancer, anti-asthmatic, and neuro-protective properties. However, its therapeutic effect on osteoporosis is unknown. In this study, an ovariectomy (OVX mouse model was used to evaluate the therapeutic effects of AP on post-menopausal osteoporosis by using micro-computed tomography (micro-CT. Bone marrow-derived osteoclast culture was used to examine the inhibitory effect of AP on osteoclastogenesis. Real time PCR was employed to examine the effect of AP on the expression of osteoclast marker genes. The activities of transcriptional factors NF-κB and NFATc1 were evaluated using a luciferase reporter assay, and the IκBα protein level was analyzed by Western blot. We found that OVX mice treated with AP have greater bone volume (BV/TV, trabecular thickness (Tb.Th, and trabecular number (Tb.N compared to vehicle-treated OVX mice. AP inhibited RANKL-induced osteoclastogenesis, the expression of osteoclast marker genes including cathepsin K (Ctsk, TRACP (Acp5, and NFATc1, as well as the transcriptional activities of NF-κB and NFATc1. In conclusion, our results suggest that AP inhibits estrogen deficiency-induced bone loss in mice via the suppression of RANKL-induced osteoclastogensis and NF-κB and NFATc1 activities and, thus, might have therapeutic potential for osteoporosis.

  6. AKT inhibitor suppresses hyperthermia-induced Ndrg2 phosphorylation in gastric cancer cells

    Directory of Open Access Journals (Sweden)

    Yurong Tao

    2013-05-01

    Full Text Available Hyperthermia is one of the most effective adjuvant treatments for various cancers with few side effects. However, the underlying molecular mechanisms still are not known. N-myc downstream-regulated gene 2 (NDRG2, a tumor suppressor, has been shown to be involved in diverse cellular stresses including hypoxia, lipotoxicity, etc. In addition, Ndrg2 has been reported to be related to progression of gastric cancer. In the current study, our data showed that the apoptosis rate of MKN28 cells increased relatively rapidly to 13.4% by 24 h after treatment with hyperthermia (42°C for 1 h compared to 5.1% in control cells (P < 0.05. Nevertheless, there was no obvious change in the expression level of total Ndrg2 during this process. Further investigation demonstrated that the relative phosphorylation levels of Ndrg2 at Ser332, Thr348 increased up to 3.2- and 1.9-fold (hyperthermia group vs control group at 3 h in MKN28 cells, respectively (P < 0.05. We also found that heat treatment significantly increased AKT phosphorylation. AKT inhibitor VIII (10 µM decreased the phosphorylation level of Ndrg2 induced by hyperthermia. Accordingly, the apoptosis rate rose significantly in MKN28 cells (16.4% treated with a combination of AKT inhibitor VIII and hyperthermia compared to that (6.8% of cells treated with hyperthermia alone (P < 0.05. Taken together, these data demonstrated that Ndrg2 phosphorylation could be induced by hyperthermia in an AKT-dependent manner in gastric cancer cells. Furthermore, AKT inhibitor VIII suppressed Ndrg2 phosphorylation and rendered gastric cancer cells susceptible to apoptosis induced by hyperthermia.

  7. Phytic acid suppresses ischemia-induced hydroxyl radical generation in rat myocardium.

    Science.gov (United States)

    Obata, Toshio; Nakashima, Michiko

    2016-03-05

    The present study examined whether ischemia-reperfusion-induced hydroxyl radical (·OH) generation was attenuated by myo-inositol hexaphosphoric acid (phytic acid). A flexibly mounted microdialysis technique was used to detect the generation of ·OH in in vivo rat hearts. To measure the level of ·OH, sodium salicylate in Ringer's solution (0.5mM or 0.5 nmol/μl/min) was infused directly through a microdialysis probe to detect the generation of ·OH as reflected by the nonenzymatic formation of 2,3-dihydroxybenzoic acid (2,3-DHBA). To confirm the generation of ·OH by Fenton-type reaction, iron(II) was infused through a microdialysis probe. A positive linear correlation between iron(II) and the formation of 2,3-DHBA (R(2)=0.983) was observed. However, the level of 2,3-DHBA in norepinephrine (100 μM) plus phytic acid (100 μM) treated group were significantly lower than those observed in norepinephrine-only-treated group (n=6, *pphytic acid on ischemia-reperfusion-induced ·OH generation, the heart was subjected to myocardial ischemia for 15 min by occlusion of the left anterior descending coronary artery (LAD). When the heart was reperfused, the normal elevation of 2,3-DHBA in the heart dialysate was not observed in animals pretreated with phytic acid. These results suggest that phytic acid is associated with antioxidant effect due to the suppression of iron-induced ·OH generation.

  8. Identified Serotonin-Releasing Neurons Induce Behavioral Quiescence and Suppress Mating in Drosophila.

    Science.gov (United States)

    Pooryasin, Atefeh; Fiala, André

    2015-09-16

    Animals show different levels of activity that are reflected in sensory responsiveness and endogenously generated behaviors. Biogenic amines have been determined to be causal factors for these states of arousal. It is well established that, in Drosophila, dopamine and octopamine promote increased arousal. However, little is known about factors that regulate arousal negatively and induce states of quiescence. Moreover, it remains unclear whether global, diffuse modulatory systems comprehensively affecting brain activity determine general states of arousal. Alternatively, individual aminergic neurons might selectively modulate the animals' activity in a distinct behavioral context. Here, we show that artificially activating large populations of serotonin-releasing neurons induces behavioral quiescence and inhibits feeding and mating. We systematically narrowed down a role of serotonin in inhibiting endogenously generated locomotor activity to neurons located in the posterior medial protocerebrum. We identified neurons of this cell cluster that suppress mating, but not feeding behavior. These results suggest that serotonin does not uniformly act as global, negative modulator of general arousal. Rather, distinct serotoninergic neurons can act as inhibitory modulators of specific behaviors. An animal's responsiveness to external stimuli and its various types of endogenously generated, motivated behavior are highly dynamic and change between states of high activity and states of low activity. It remains unclear whether these states are mediated by unitary modulatory systems globally affecting brain activity, or whether distinct neurons modulate specific neuronal circuits underlying particular types of behavior. Using the model organism Drosophila melanogaster, we find that activating large proportions of serotonin-releasing neurons induces behavioral quiescence. Moreover, distinct serotonin-releasing neurons that we genetically isolated and identified negatively affect

  9. AKT inhibitor suppresses hyperthermia-induced Ndrg2 phosphorylation in gastric cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Tao, Yurong; Guo, Yan; Liu, Wenchao [Department of Oncology, State Key Discipline of Cell Biology, Xijing Hospital, The Fourth Military Medical University, Shaanxi, Xi' an (China); Zhang, Jian; Li, Xia; Shen, Lan; Ru, Yi [State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Shaanxi, Xi' an (China); Xue, Yan [Department of Oncology, State Key Discipline of Cell Biology, Xijing Hospital, The Fourth Military Medical University, Shaanxi, Xi' an (China); Zheng, Jin [Department of Traditional Chinese and Western Medicine of Oncology, Tangdu Hospital, The Fourth Military Medical University, Shaanxi, Xi' an (China); Liu, Xinping; Zhang, Jing; Yao, Libo [State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Shaanxi, Xi' an (China)

    2013-04-05

    Hyperthermia is one of the most effective adjuvant treatments for various cancers with few side effects. However, the underlying molecular mechanisms still are not known. N-myc downstream-regulated gene 2 (NDRG2), a tumor suppressor, has been shown to be involved in diverse cellular stresses including hypoxia, lipotoxicity, etc. In addition, Ndrg2 has been reported to be related to progression of gastric cancer. In the current study, our data showed that the apoptosis rate of MKN28 cells increased relatively rapidly to 13.4% by 24 h after treatment with hyperthermia (42°C for 1 h) compared to 5.1% in control cells (P < 0.05). Nevertheless, there was no obvious change in the expression level of total Ndrg2 during this process. Further investigation demonstrated that the relative phosphorylation levels of Ndrg2 at Ser332, Thr348 increased up to 3.2- and 1.9-fold (hyperthermia group vs control group) at 3 h in MKN28 cells, respectively (P < 0.05). We also found that heat treatment significantly increased AKT phosphorylation. AKT inhibitor VIII (10 µM) decreased the phosphorylation level of Ndrg2 induced by hyperthermia. Accordingly, the apoptosis rate rose significantly in MKN28 cells (16.4%) treated with a combination of AKT inhibitor VIII and hyperthermia compared to that (6.8%) of cells treated with hyperthermia alone (P < 0.05). Taken together, these data demonstrated that Ndrg2 phosphorylation could be induced by hyperthermia in an AKT-dependent manner in gastric cancer cells. Furthermore, AKT inhibitor VIII suppressed Ndrg2 phosphorylation and rendered gastric cancer cells susceptible to apoptosis induced by hyperthermia.

  10. Irsogladine maleate suppresses indomethacin-induced elevation of proinflammatory cytokines and gastric injury in rats

    Institute of Scientific and Technical Information of China (English)

    Xin Zhang; Koyuki Tajima; Kiyoto Kageyama; Takashi Kyoi

    2008-01-01

    AIM: To investigate the mucosal protective effect and the mechanisms of action of the anti-ulcer drug irsogladine maleate in gastric injury induced by indomethacin in rats.METHODS: Gastric mucosal injury was induced in male Hos:Donryu rats by oral administration of indomethacin at a dose of 48 mg/kg.One hour before indomethacin treatment,animals were orally pretreated with irsogladine maleate at doses of 1 mg/kg,3 mg/kg or 10 mg/kg.Four hours after indomethacin administration,the animals were sacrificed and their stomachs were rapidly removed and processed for the evaluation of gastric mucosal damage and the determination of the concentrations of tumor necrosis factor-α (TNF-α),interleukin-1β(IL-1β),IL-8 and myeloperoxidase (MPO) in mucosal tissues.RESULTS: Linear hemorrhagic mucosal lesions were observed primarily in the glandular stomach 4 h after oral administration of indomethacin.Pretreatment with irsogladine maleate markedly reduced the number and severity of these lesions in a dosedependent manner.The mucosal concentrations of proinflammatory cytokines (TNF-β,IL-1β,and IL-8)and MPO,which indicates the degree of mucosal infiltration by neutrophils,increased concomitantly with the occurrence of gastric injury in the indomethacintreated rats.Pretreatment with irsogladine maleate significantly decreased the levels of these inflammatory factors in gastric tissue elicited by indomethacin.CONCLUSION: The mucosal protective effects afforded by irsogladine maleate on gastric injury induced by indomethacin are mediated by inhibition of mucosal proinflammatory cytokine production and neutrophil infiltration,leading to suppression of mucosal inflammation and subsequent tissue destruction.

  11. Pharmacologic inhibition of Notch signaling suppresses food antigen-induced mucosal mast cell hyperplasia.

    Science.gov (United States)

    Honjo, Asuka; Nakano, Nobuhiro; Yamazaki, Susumu; Hara, Mutsuko; Uchida, Koichiro; Kitaura, Jiro; Nishiyama, Chiharu; Yagita, Hideo; Ohtsuka, Yoshikazu; Ogawa, Hideoki; Okumura, Ko; Shimizu, Toshiaki

    2017-03-01

    Mucosal mast cells (MMCs) play a central role in the development of symptoms associated with IgE-mediated food allergy. Recently, Notch2-mediated signaling was shown to be involved in proper MMC distribution in the intestinal tract. This study aimed to clarify the mechanism by which Notch signaling regulates MMC distribution in the intestinal mucosa. Furthermore, pharmacologic inhibition of Notch signaling was evaluated as a treatment for symptoms associated with experimental food allergy. Bone marrow-derived mast cells generated from mice were cultured with Notch ligands, and then expression of genes associated with MMCs was measured in the cells. In addition, the effect of an inhibitor of Notch signaling on food antigen-induced allergic reactions was examined in a mouse model of food allergy. Notch signaling induced MMC differentiation through upregulation of expression of genes characteristic of MMCs in the presence of IL-3. Some lamina propria cells isolated from the mouse small intestine expressed Notch ligands and were able to upregulate MMC markers in bone marrow-derived mast cells through Notch signaling. In a mouse model of food allergy, administration of a Notch signaling inhibitor led to suppression of food antigen-induced hyperplasia of intestinal MMCs, resulting in alleviation of allergic diarrhea and systemic anaphylaxis. Notch signaling contributes to differentiation and accumulation of MMCs in the intestinal mucosa. Thus inhibition of Notch signaling alleviates symptoms associated with experimental food allergy. These results raise the possibility that Notch signaling in mast cells is a novel target for therapy in patients with food allergy. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  12. Coriandrum sativum Suppresses Aβ42-Induced ROS Increases, Glial Cell Proliferation, and ERK Activation.

    Science.gov (United States)

    Liu, Quan Feng; Jeong, Haemin; Lee, Jang Ho; Hong, Yoon Ki; Oh, Youngje; Kim, Young-Mi; Suh, Yoon Seok; Bang, Semin; Yun, Hye Sup; Lee, Kyungho; Cho, Sung Man; Lee, Sung Bae; Jeon, Songhee; Chin, Young-Won; Koo, Byung-Soo; Cho, Kyoung Sang

    2016-01-01

    Alzheimer's disease (AD), the most common neurodegenerative disease, has a complex and widespread pathology that is characterized by the accumulation of amyloid [Formula: see text]-peptide (A[Formula: see text]) in the brain and various cellular abnormalities, including increased oxidative damage, an amplified inflammatory response, and altered mitogen-activated protein kinase signaling. Based on the complex etiology of AD, traditional medicinal plants with multiple effective components are alternative treatments for patients with AD. In the present study, we investigated the neuroprotective effects of an ethanol extract of Coriandrum sativum (C. sativum) leaves on A[Formula: see text] cytotoxicity and examined the molecular mechanisms underlying the beneficial effects. Although recent studies have shown the benefits of the inhalation of C. sativum oil in an animal model of AD, the detailed molecular mechanisms by which C. sativum exerts its neuroprotective effects are unclear. Here, we found that treatment with C. sativum extract increased the survival of both A[Formula: see text]-treated mammalian cells and [Formula: see text]42-expressing flies. Moreover, C. sativum extract intake suppressed [Formula: see text]-induced cell death in the larval imaginal disc and brain without affecting A[Formula: see text]42 expression and accumulation. Interestingly, the increases in reactive oxygen species levels and glial cell number in AD model flies were reduced by C. sativum extract intake. Additionally, C. sativum extract inhibited the epidermal growth factor receptor- and A[Formula: see text]-induced phosphorylation of extracellular signal-regulated kinase (ERK). The constitutively active form of ERK abolished the protective function of C. sativum extract against the [Formula: see text]-induced eye defect phenotype in Drosophila. Taken together, these results suggest that C. sativum leaves have antioxidant, anti-inflammatory, and ERK signaling inhibitory properties that

  13. Neotuberostemonine attenuates bleomycin-induced pulmonary fibrosis by suppressing the recruitment and activation of macrophages.

    Science.gov (United States)

    Xiang, Juan; Cheng, Si; Feng, Tianlong; Wu, Yan; Xie, Weina; Zhang, Mian; Xu, Xianghong; Zhang, Chaofeng

    2016-07-01

    Neotuberostemonine (NTS) is one of the main antitussive alkaloids in the root of Stemona tuberosa Lour. This study aimed to investigate the effects of NTS on bleomycin (BLM)-induced pulmonary fibrosis in mice and the underlying mechanism. After BLM administration, NTS were orally administered to mice at 20 and 40mg/kg per day from days 8 to 21, with nintedanib as a positive control. The effect of NTS on BLM-induced mice was assessed via histopathological examination by HE and Masson's trichrome staining, TGF-β1 level and macrophage recruitment by immunohistochemical staining, expression of profibrotic media and M1/M2 polarization by western blot. RAW 264.7 cells were used to evaluate whether NTS (1, 10, 100μM) directly affected macrophages. The results revealed that NTS treatment significantly ameliorated lung histopathological changes and decreased inflammatory cell counts in the bronchoalveolar lavage fluid. The over-expression of collagen, α-SMA and TGF-β1 was reduced by NTS. Furthermore, NTS markedly lowered the expression of MMP-2 and TIMP-1 while raised the expression of MMP-9. A further analysis showed that NTS was able to decrease the recruitment of macrophages and to inhibit the M2 polarization in mice lung tissues. The experiment in vitro showed that NTS significantly reduced the arginase-1 (marker for M2) expression in a dose-dependent manner but down-regulated the iNOS (marker for M1) expression only at 100μM. In conclusion, our study demonstrated for the first time that NTS has a significant protective effect on BLM-induced pulmonary fibrosis through suppressing the recruitment and M2 polarization of macrophages.

  14. MELATONIN-INDUCED SUPPRESSION OF PC12 CELL GROWTH IS MEDIATED BY ITS GI COUPLED TRANSMEMBRANE RECEPTORS. (R826248)

    Science.gov (United States)

    The effects of pertussis toxin, an uncoupler of Gi protein from adenylate cyclase, and luzindole, a competitive inhibitor of melatonin receptor binding, were examined for their ability to inhibit melatonin-induced suppression of PC12 cell growth. Both agents inhibited the mela...

  15. Kurarinol induces hepatocellular carcinoma cell apoptosis through suppressing cellular signal transducer and activator of transcription 3 signaling

    Energy Technology Data Exchange (ETDEWEB)

    Shu, Guangwen; Yang, Jing; Zhao, Wenhao; Xu, Chan; Hong, Zongguo; Mei, Zhinan; Yang, Xinzhou, E-mail: xinzhou_yang@hotmail.com

    2014-12-01

    Kurarinol is a flavonoid isolated from roots of the medical plant Sophora flavescens. However, its cytotoxic activity against hepatocellular carcinoma (HCC) cells and toxic effects on mammalians remain largely unexplored. Here, the pro-apoptotic activities of kurarinol on HCC cells and its toxic impacts on tumor-bearing mice were evaluated. The molecular mechanisms underlying kurarinol-induced HCC cell apoptosis were also investigated. We found that kurarinol dose-dependently provoked HepG2, Huh-7 and H22 HCC cell apoptosis. In addition, kurarinol gave rise to a considerable decrease in the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) in HCC cells. Suppression of STAT3 signaling is involved in kurarinol-induced HCC cell apoptosis. In vivo studies showed that kurarinol injection substantially induced transplanted H22 cell apoptosis with low toxic impacts on tumor-bearing mice. Similarly, the transcriptional activity of STAT3 in transplanted tumor tissues was significantly suppressed after kurarinol treatment. Collectively, our current research demonstrated that kurarinol has the capacity of inducing HCC cell apoptosis both in vitro and in vivo with undetectable toxic impacts on the host. Suppressing STAT3 signaling is implicated in kurarinol-mediated HCC cell apoptosis. - Highlights: • Kurarinol induces hepatocellular carcinoma (HCC) cell apoptosis. • Kurarinol induces HCC cell apoptosis via inhibiting STAT3. • Kurarinol exhibits low toxic effects on tumor-bearing animals.

  16. Tetrahydroxystilbene glucoside inhibits TNF-α-induced migration of vascular smooth muscle cells via suppression of vimentin.

    Science.gov (United States)

    Yao, Wenjuan; Sun, Qinju; Huang, Lei; Meng, Guoliang; Wang, Huiming; Jing, Xiang; Zhang, Wei

    2015-07-28

    Vascular smooth muscle cell (VSMC) migration triggered by TNF-α is an important event that occurs during the development of atherosclerosis. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-d-glucoside (TSG) has been proven to exhibit significant anti-atherosclerotic activity. Herein we investigate the inhibitory effect of TSG on TNF-α-induced VSMC migration and explore the underlying mechanisms. TSG pretreatment markedly inhibited TNF-α-induced cell migration. The inhibition of vimentin redistribution and expression was involved in the inhibitory effect of TSG on VSMC migration. The suppression of vimentin expression by shRNA in VSMCs significantly inhibited TNF-α-induced cell migration. Furthermore, TSG inhibited the TNF-α-induced expression of TGFβ1 and TGFβR1, and phosphorylation of TGFβR1 and Smad2/3. TSG also suppressed the nuclear translocation of Smad4 induced by TNF-α. These results suggest that TSG inhibits VSMC migration induced by TNF-α through inhibiting vimentin rearrangement and expression. The interruption of TGFβ/Smad pathway appears to be responsible for the suppression of TSG on vimentin expression.

  17. PGC-1β suppresses saturated fatty acid-induced macrophage inflammation by inhibiting TAK1 activation.

    Science.gov (United States)

    Chen, Hongen; Liu, Yan; Li, Di; Song, Jiayi; Xia, Min

    2016-02-01

    Inflammation of infiltrated macrophages in adipose tissue is a key contributor to the initiation of adipose insulin resistance. These macrophages are exposed to high local concentrations of free fatty acids (FFAs) and can be proinflammatory activated by saturated fatty acids (SFAs). However, the regulatory mechanisms on SFA-induced macrophage inflammation are still elusive. Peroxisome proliferator-activated receptor γ coactivator-1β (PGC-1β) is a member of the PGC-1 family of transcriptional coactivators and has been reported to play a key role in SFAs metabolism and in the regulation of inflammatory signaling. However, it remains unclear whether PGC-1β is involved in SFA-induced macrophage inflammation. In this study, we found that PGC-1β expression was significantly decreased in response to palmitic acid (PA) in macrophages in a dose dependent manner. PGC-1β inhibited PA induced TNFα, MCP-1, and IL-1β mRNA and protein expressions. Furthermore, PGC-1β significantly antagonized PA induced macrophage nuclear factor-κB (NF-κB) p65 and JUN N-terminal kinase activation. Mechanistically, we revealed that TGF-β-activated kinase 1 (TAK1) and its adaptor protein TAK1 binding protein 1 (TAB1) played a dominant role in the regulatory effects of PGC-1β. We confirmed that PGC-1β inhibited downstream inflammatory signals via binding with TAB1 and thus preventing TAB1/TAK1 binding and TAK1 activation. Finally, we showed that PGC-1β overexpression in PA treated macrophages improved adipocytes PI3K-Akt insulin signaling in a paracrine fashion. Collectively, our results uncovered a novel mechanism on how macrophage inflammation induced by SFAs was regulated and suggest a potential target in the treatment of obesity induced insulin resistance.

  18. Doxycycline Induces Mitophagy and Suppresses Production of Interferon-β in IPEC-J2 Cells

    Science.gov (United States)

    Xing, Yang; Liqi, Zhu; Jian, Lin; Qinghua, Yu; Qian, Yang

    2017-01-01

    Previous reports have demonstrated that the second-generation tetracycline derivative doxycycline (DOX) interrupts mitochondrial proteostasis and physiology, inhibits proliferation of many cell types, and induces apoptosis. However, the effects of DOX, which is widely used in porcine husbandry by feed, on the porcine intestinal epithelium are unclear. In this study, we demonstrated that DOX damaged mitochondrial morphology and induced the co-localization of mitochondria with autophagosomes, suggesting that DOX induces mitophagy in IPEC-J2 cells. We also found evidence that DOX increased intracellular levels of reactive oxygen species (ROS) or mitochondrial-specific ROS in a dose dependent manner. Moreover, 50 μg/ml DOX significantly decreased production of interferon-β and facilitated replication of transmissible gastroenteritis coronavirus in IPEC-J2 cells. These results demonstrated that DOX induced mitophagy and ROS production, which damaged the intestinal epithelium. As DOX is used extensively in pig husbandry, uncontrolled application poses a significant threat of viral infection, so stricter policies on its usage should be required. PMID:28203548

  19. Changes in cluster magnetism and suppression of local superconductivity in amorphous FeCrB alloy irradiated by Ar+ ions

    Science.gov (United States)

    Okunev, V. D.; Samoilenko, Z. A.; Szymczak, H.; Szewczyk, A.; Szymczak, R.; Lewandowski, S. J.; Aleshkevych, P.; Malinowski, A.; Gierłowski, P.; Więckowski, J.; Wolny-Marszałek, M.; Jeżabek, M.; Varyukhin, V. N.; Antoshina, I. A.

    2016-02-01

    We show that сluster magnetism in ferromagnetic amorphous Fe67Cr18B15 alloy is related to the presence of large, D=150-250 Å, α-(Fe Cr) clusters responsible for basic changes in cluster magnetism, small, D=30-100 Å, α-(Fe, Cr) and Fe3B clusters and subcluster atomic α-(Fe, Cr, B) groupings, D=10-20 Å, in disordered intercluster medium. For initial sample and irradiated one (Φ=1.5×1018 ions/cm2) superconductivity exists in the cluster shells of metallic α-(Fe, Cr) phase where ferromagnetism of iron is counterbalanced by antiferromagnetism of chromium. At Φ=3×1018 ions/cm2, the internal stresses intensify and the process of iron and chromium phase separation, favorable for mesoscopic superconductivity, changes for inverse one promoting more homogeneous distribution of iron and chromium in the clusters as well as gigantic (twice as much) increase in density of the samples. As a result, in the cluster shells ferromagnetism is restored leading to the increase in magnetization of the sample and suppression of local superconductivity. For initial samples, the temperature dependence of resistivity ρ(T) T2 is determined by the electron scattering on quantum defects. In strongly inhomogeneous samples, after irradiation by fluence Φ=1.5×1018 ions/cm2, the transition to a dependence ρ(T) T1/2 is caused by the effects of weak localization. In more homogeneous samples, at Φ=3×1018 ions/cm2, a return to the dependence ρ(T) T2 is observed.

  20. A nuclear localized protein ZCCHC9 is expressed in cerebral cortex and suppresses the MAPK signal pathway

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    The CCHC-type zinc finger motif has numerous biological activities (such as DNA binding and RNA binding) and can also mediate protein-protein interaction. This article gives a primary report about the human ZCCHC9 gene. Protein ZCCHC9 contains four CCHC motifs and is highly conserved in humans, mice, and rats. The whole cDNA sequence of the ZCCHC9 gene has been amplified by PCR and a number of plasmids have been constructed for further study. The results show that ZCCHC9 is localized in the nucleus, and especially concentrated in the nucleolus. It is highly expressed in the brain and testicles of the mouse. This has been confirmed by real-time reverse transcription polymerase chain reaction (RT-PCR). In situ hybridization of the mouse brain indicates that ZCCHC9 is mainly expressed in the cerebral cortex. Reporter gene assay shows that ZCCHC9 suppresses the transcription activities of NF-kappa B and SRE,and may play roles in the Mitogen-Activated Protein Kinase (MAPK) signaling transduction pathway.

  1. Differentially expressed genes in a flock of Chinese local-breed chickens infected with a subgroup J avian leukosis virus using suppression subtractive hybridization

    Directory of Open Access Journals (Sweden)

    Guiping Zhao

    2010-01-01

    Full Text Available Avian leukosis virus subgroup J (ALV-J is a new type of virus that mainly induces myeloid leukosis (ML in chickens. To further elucidate the pathogenesis of ALV-J infection and tumor development, expression profiles from the bone marrow tissue of 15 infected and 18 non-infected birds from a local-breed poultry-farm under naturally infected conditions, were analyzed by suppression-subtractive hybridization. The birds were diagnosed as ML+ (or ML- by specific ALV-J detection methods, involving serological tests for antigens and antibodies, and RT-PCR to detect viral RNA. A total of 59 partial gene sequences were revealed by differential screening of 496 forward and 384 reverse subtracted cDNA clones. Of these, 22 identified genes, including 8 up-regulated and 14 down-regulated, were related to immune functions, these genes being, MHC B-G antigen, translationally-controlled tumor protein (TPT1/TPTC, transferrin and ferritin, hemoglobin and Carbonic anhydrase. Four of the down-regulated genes were selected for further analysis, in view of their predicted roles in infection and immunity by real-time qRT-PCR, using RNA collected from the same birds as those used for SSH. The four genes were expressed at significantly lower levels (p < 0.001 in ALV-J infected birds than in non-infected ones.

  2. Differentially expressed genes in a flock of Chinese local-breed chickens infected with a subgroup J avian leukosis virus using suppression subtractive hybridization.

    Science.gov (United States)

    Zhao, Guiping; Zheng, Maiqing; Chen, Jilan; Wen, Jie; Wu, Chunmei; Li, Wenjuan; Liu, Libo; Zhang, Yuan

    2010-01-01

    Avian leukosis virus subgroup J (ALV-J) is a new type of virus that mainly induces myeloid leukosis (ML) in chickens. To further elucidate the pathogenesis of ALV-J infection and tumor development, expression profiles from the bone marrow tissue of 15 infected and 18 non-infected birds from a local-breed poultry-farm under naturally infected conditions, were analyzed by suppression-subtractive hybridization. The birds were diagnosed as ML+ (or ML-) by specific ALV-J detection methods, involving serological tests for antigens and antibodies, and RT-PCR to detect viral RNA. A total of 59 partial gene sequences were revealed by differential screening of 496 forward and 384 reverse subtracted cDNA clones. Of these, 22 identified genes, including 8 up-regulated and 14 down-regulated, were related to immune functions, these genes being, MHC B-G antigen, translationally-controlled tumor protein (TPT1/TPTC), transferrin and ferritin, hemoglobin and Carbonic anhydrase. Four of the down-regulated genes were selected for further analysis, in view of their predicted roles in infection and immunity by real-time qRT-PCR, using RNA collected from the same birds as those used for SSH. The four genes were expressed at significantly lower levels (p < 0.001) in ALV-J infected birds than in non-infected ones.

  3. Unified entropic measures of quantum correlations induced by local measurements

    Science.gov (United States)

    Bosyk, G. M.; Bellomo, G.; Zozor, S.; Portesi, M.; Lamberti, P. W.

    2016-11-01

    We introduce quantum correlation measures based on the minimal change in unified entropies induced by local rank-one projective measurements, divided by a factor that depends on the generalized purity of the system in the case of nonadditive entropies. In this way, we overcome the issue of the artificial increasing of the value of quantum correlation measures based on nonadditive entropies when an uncorrelated ancilla is appended to the system, without changing the computability of our entropic correlation measures with respect to the previous ones. Moreover, we recover as limiting cases the quantum correlation measures based on von Neumann and Rényi entropies (i.e., additive entropies), for which the adjustment factor becomes trivial. In addition, we distinguish between total and semiquantum correlations and obtain some inequalities between them. Finally, we obtain analytical expressions of the entropic correlation measures for typical quantum bipartite systems.

  4. Efficient and Selective Prevention of GVHD by Antigen-Specific Induced Tregs via Linked-Suppression in Mice

    OpenAIRE

    Semple, Kenrick; Yu, Yu; Wang, Dapeng; Anasetti, Claudio; Yu, Xue-Zhong

    2011-01-01

    Naturally occurring regulatory T cells (nTregs) suppress the development of GVHD and may spare graft-versus-leukemia (GVL) effect. Because nTreg is a rare population in a healthy individual, the limited source and the non-selective suppression are major hurdles towards the application of nTregs in the control of clinical GVHD after allogeneic HCT. An alternative approach is to generate induced Tregs (iTregs) from naïve CD4 precursors, but the effectiveness of iTregs in the control of GVHD is ...

  5. Protective effects of taurine on doxorubicin-induced acute hepatotoxicity through suppression of oxidative stress and apoptotic responses.

    Science.gov (United States)

    Nagai, Katsuhito; Fukuno, Shuhei; Oda, Ayano; Konishi, Hiroki

    2016-01-01

    The organ toxicity of doxorubicin (DOX), an anthracycline antineoplastic agent, narrows the therapeutic window despite its clinical usefulness. In the present study, we determined whether taurine protected against DOX-induced hepatic injury, and explored the molecular mechanisms underlying the suppressive effects of taurine in terms of alterations in oxidative stress and apoptotic responses. DOX-induced body weight loss was completely suppressed by taurine treatment. Elevations in the serum activity levels of lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase by DOX were also dose-dependently attenuated by a concurrent treatment with taurine. Superoxide dismutase activity and reduced glutathione content in the liver were decreased following the administration of DOX, whereas these changes were suppressed when 10 mg/kg taurine was given in combination with DOX. Taurine attenuated the increased expression of mRNAs for Fas and Bax after DOX exposure. Furthermore, the formation of cleaved caspase-3 protein in the group given DOX with taurine was lower than that in the group treated with DOX alone. Our results suggest that taurine can protect against DOX-induced acute hepatic damage, the underlying mechanism of which is attributable to the suppression of oxidative stress and apoptotic responses.

  6. Characterization of biocontrol bacterial strains isolated from a suppressiveness-induced soil after amendment with composted almond shells.

    Science.gov (United States)

    Vida, Carmen; Cazorla, Francisco M; de Vicente, Antonio

    The improvement in soil quality of avocado crops through organic amendments with composted almond shells has a positive effect on crop yield and plant health, and enhances soil suppressiveness against the phytopathogenic fungus Rosellinia necatrix. In previous studies, induced soil suppressiveness against this pathogen was related to stimulation of Gammaproteobacteria, especially some members of Pseudomonas spp. with biocontrol-related activities. In this work, we isolated bacteria from this suppressiveness-induced amended soil using a selective medium for Pseudomonas-like microorganisms. We characterized the obtained bacterial collection to aid in identification, including metabolic profiles, antagonistic responses, hybridization to biosynthetic genes of antifungal compounds, production of lytic exoenzymatic activities and plant growth-promotion-related traits, and sequenced and compared amplified 16S rDNA genes from representative bacteria. The final selection of representative strains mainly belonged to the genus Pseudomonas, but also included the genera Serratia and Stenotrophomonas. Their biocontrol-related activities were assayed using the experimental avocado model, and results showed that all selected strains protected the avocado roots against R. necatrix. This work confirmed the biocontrol activity of these Gammaproteobacteria-related members against R. necatrix following specific stimulation in a suppressiveness-induced soil after a composted almond shell application. Copyright © 2017 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  7. SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

    Science.gov (United States)

    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

  8. Chemokine CXCL16 Expression Suppresses Migration and Invasiveness and Induces Apoptosis in Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Yeying Fang

    2014-01-01

    Full Text Available Background. Increasing evidence argues that soluble CXCL16 promotes proliferation, migration, and invasion of cancer cells in vitro. However, the role of transmembrane or cellular CXCL16 in cancer remains relatively unknown. In this study, we determine the function of cellular CXCL16 as tumor suppressor in breast cancer cells. Methods. Expression of cellular CXCL16 in breast cancer cell lines was determined at both RNA and protein levels. In vitro and in vivo studies that overexpressed or downregulated CXCL16 were conducted in breast cancer cells. Results. We report differential expression of cellular CXCL16 in breast cancer cell lines that was negatively correlated with cell invasiveness and migration. Overexpression of CXCL16 in MDA-MB-231 cells led to a decrease in cell invasion and migration and induced apoptosis of the cells; downregulation of CXCL16 in MCF-7 cells increased cell migration and invasiveness. Consistent with the in vitro data, CXCL16 overexpression inhibited tumorigenesis in vivo. Conclusions. Cellular CXCL16 suppresses invasion and metastasis of breast cancer cells in vitro and inhibits tumorigenesis in vivo. Targeting of cellular CXCL16 expression is a potential therapeutic strategy for breast cancer.

  9. Prenatal Exposure to 1-Bromopropane Suppresses Kainate-Induced Wet Dog Shakes in Immature Rats.

    Science.gov (United States)

    Fueta, Yukiko; Kanemitsu, Masanari; Egawa, Sumie; Ishidao, Toru; Ueno, Susumu; Hori, Hajime

    2015-12-01

    1-Bromopropane (1-BP) is used in degreasing solvents and spray adhesives. The adverse effects of 1-BP have been reported in human cases and adult animal models, and its developmental toxicity has also been reported, but its effects on developmental neurotoxicity have not been investigated in detail. We evaluated the effects in rat pups of prenatal exposure to 1-BP on behaviors such as scratching and wet dog shakes (WDS), which were induced by injection of kainate (KA). Pregnant Wistar rats were exposed to vaporized 1-BP with 700 ppm from gestation day 1 to day 20 (6 h/day). KA at doses of 0.1, 0.5, and 2.0 mg/kg were intraperitoneally injected into a control group and a 1-BP-exposed group of pups on postnatal day 14. There was no significant difference in scratching between the control and the prenatally 1-BP-exposed groups, while suppression of the occurrence ratio of WDS was observed at the low dose of 0.1 mg/kg of KA in the prenatally 1-BP-exposed pups. Our results suggest that prenatal exposure to 1-BP affects neurobehavioral responses in the juvenile period.

  10. Numerical study on the suppression of shock induced separation on the non-adiabatic wall

    Science.gov (United States)

    Lee, Doug-Bong

    2000-12-01

    A numerical model is constructed to simulate the interaction of supersonic ( M=2.4) oblique shock wave / turbulent boundary layer on a strongly heated wall. The heated wall temperature is two times higher than the adiabatic wall temperature and the shock wave is strong enough to induce boundary layer separation. The turbulence model is Spalart-Allmaras model. The comparison of the wall pressure distribution with the experimental data ensures the validity of this numerical model. The effect of strong wall heating enlarges the separation region upstream and downstream. In order to eliminate the separation, wall bleeding is applied at the shock foot position. As a result of the parametric study, the best position of the bleeding slot is selected. The position of the bleeding is very important for the separation suppression. If the bleeding is applied upstream of shock foot, then separation reoccurs after the bleeding slot. If the bleeding is applied downstream of shock foot, the upstream boundary layer is little influenced and still separated. The bleeding vent width is about same as the upstream boundary layer thickness and suction mass flow is 20 to 80 % of the flow rate in the upstream boundary layer. The bleeding mass flow rate is very sensitive to the bleeding vent position if we fix the vent outlet pressure. The final configuration of the shock reflection pattern approaches to the non-viscous value when wall bleeding is applied at the shock impinging point.

  11. Identification of cadmium-induced Agaricus blazei genes through suppression subtractive hybridization.

    Science.gov (United States)

    Wang, Liling; Li, Haibo; Wei, Hailong; Wu, Xueqian; Ke, Leqin

    2014-01-01

    Cadmium (Cd) is one of the most serious environmental pollutants. Filamentous fungi are very promising organisms for controlling and reducing the amount of heavy metals released by human and industrial activities. However, the molecular mechanisms involved in Cd accumulation and tolerance of filamentous fungi are not fully understood. Agaricus blazei Murrill, an edible mushroom with medicinal properties, demonstrates high tolerance for heavy metals, especially Cd. To investigate the molecular mechanisms underlying the response of A. blazei after Cd exposure, we constructed a forward subtractive library that represents cadmium-induced genes in A. blazei under 4 ppm Cd stress for 14 days using suppression subtractive hybridization combined with mirror orientation selection. Differential screening allowed us to identify 39 upregulated genes, 26 of which are involved in metabolism, protein fate, cellular transport, transport facilitation and transport routes, cell rescue, defense and virulence, transcription, and the action of proteins with a binding function, and 13 are encoding hypothetical proteins with unknown functions. Induction of six A. blazei genes after Cd exposure was further confirmed by RT-qPCR. The cDNAs isolated in this study contribute to our understanding of genes involved in the biochemical pathways that participate in the response of filamentous fungi to Cd exposure.

  12. DIFFERENTIATION AND MALIGNANT SUPPRESSION INDUCED BY MOUSE ERYTHROID DIFFERENTIATION AND DENUCLEATION FACTOR ON MOUSE ERYTHROLEUKEMIA CELLS

    Institute of Scientific and Technical Information of China (English)

    韩代书; 赵青; 葛晔华; 周建平; 马静; 陈克铨; 薛社普

    2002-01-01

    Objective. To investigate the roles of mouse erythroid differentiation and denueleation factor (MEDDF), a novel factor cloned in our laboratory recently, in erythroid terminal differentiation.Methods. Mouse erythroleukemia (MEL) cells were transfected with eukaryotic expression plasmid pcD-NA-MEDDF. Then we investigated the changes on characteristics of cell growth by analyzing cells growth rate,mitotic index and colony-forming rate in semi-solid medium. The expressions of c-myc and β-globin genes were analysed by semi-quantitative RT-PCR.Results. MEL ceils transfected with pcDNA-MEDDF showed significant lower growth rate, mitotic index,and colony-forming rate in semi-solid medium ( P<0.01 ). The percentage of benzidine-positive cells was 32.8% after transfection. The expression of β-globin in cells transfected with pcDNA-MEDDF was 3.43 times higher than that of control (MEL transfected with blank vector, pcDNA3. 1 ), and the expression of c-myc decreased by 66.3%.Conclusions. MEDDF can induce differentiation of MEL cell and suppress its malignancy.

  13. Interleukin-12 suppresses filaria-induced pulmonary eosinophilia, deposition of major basic protein and airway hyperresponsiveness.

    Science.gov (United States)

    Mehlotra, R K; Hall, L R; Higgins, A W; Dreshaj, I A; Haxhiu, M A; Kazura, J W; Pearlman, E

    1998-10-01

    Tropical Pulmonary Eosinophilia (TPE) is a severe form of allergic asthma caused by the host inflammatory response to filarial helminths in the lung microvasculature, and is characterized by pulmonary eosinophilia, increased filarial-specific IgG and IgE antibodies, and airway hyperresponsiveness. The current study examined the effect of IL-12 on pulmonary eosinophilia, deposition of eosinophil major basic protein and airway hyperresponsiveness in mice inoculated i.v. with Brugia malayi microfilariae. Injection of recombinant murine IL-12 modulated the T helper (Th) response in the lungs from Th2- to Th1-like, with elevated IFN-gamma, and decreased IL-4 and IL-5 production. Consistent with this shift in cytokine response, antigen-specific IgG2a was elevated, and IgG1 and total serum IgE were decreased. In addition, eosinophils in BAL fluid from IL-12 treated mice were reduced from 56% to 11%, and there was no detectable MBP on respiratory epithelial cells. Importantly, IL-12 suppressed airway hyperresponsiveness compared with saline-injected control animals. Taken together, these data clearly demonstrate that by modulating Th associated cytokine production, IL-12 down-regulates filaria-induced lung immunopathology.

  14. Continous application of bioorganic fertilizer induced resilient culturable bacteria community associated with banana Fusarium wilt suppression

    Science.gov (United States)

    Fu, Lin; Ruan, Yunze; Tao, Chengyuan; Li, Rong; Shen, Qirong

    2016-06-01

    Fusarium wilt of banana always drives farmers to find new land for banana cultivation due to the comeback of the disease after a few cropping years. A novel idea for solving this problem is the continuous application of bioorganic fertilizer (BIO), which should be practiced from the beginning of banana planting. In this study, BIO was applied in newly reclaimed fields to pre-control banana Fusarium wilt and the culturable rhizobacteria community were evaluated using Biolog Ecoplates and culture-dependent denaturing gradient gel electrophoresis (CD-DGGE). The results showed that BIO application significantly reduced disease incidences and increased crop yields, respectivly. And the stabilized general bacterial metabolic potential, especially for the utilization of carbohydrates, carboxylic acids and phenolic compounds, was induced by BIO application. DGGE profiles demonstrated that resilient community structure of culturable rhizobacteria with higher richness and diversity were observed in BIO treated soils. Morever, enriched culturable bacteria affiliated with Firmicutes, Gammaproteobacteria and Actinobacteria were also detected. In total, continuous application of BIO effectively suppressed Fusarium wilt disease by stabilizing culturable bacterial metabolic potential and community structure. This study revealed a new method to control Fusarium wilt of banana for long term banana cultivation.

  15. Dibutyltin disrupts glucocorticoid receptor function and impairs glucocorticoid-induced suppression of cytokine production.

    Directory of Open Access Journals (Sweden)

    Christel Gumy

    Full Text Available BACKGROUND: Organotins are highly toxic and widely distributed environmental chemicals. Dibutyltin (DBT is used as stabilizer in the production of polyvinyl chloride plastics, and it is also the major metabolite formed from tributyltin (TBT in vivo. DBT is immunotoxic, however, the responsible targets remain to be defined. Due to the importance of glucocorticoids in immune-modulation, we investigated whether DBT could interfere with glucocorticoid receptor (GR function. METHODOLOGY: We used HEK-293 cells transiently transfected with human GR as well as rat H4IIE hepatoma cells and native human macrophages and human THP-1 macrophages expressing endogenous receptor to study organotin effects on GR function. Docking of organotins was used to investigate the binding mechanism. PRINCIPAL FINDINGS: We found that nanomolar concentrations of DBT, but not other organotins tested, inhibit ligand binding to GR and its transcriptional activity. Docking analysis indicated that DBT inhibits GR activation allosterically by inserting into a site close to the steroid-binding pocket, which disrupts a key interaction between the A-ring of the glucocorticoid and the GR. DBT inhibited glucocorticoid-induced expression of phosphoenolpyruvate carboxykinase (PEPCK and tyrosine-aminotransferase (TAT and abolished the glucocorticoid-mediated transrepression of TNF-alpha-induced NF-kappaB activity. Moreover, DBT abrogated the glucocorticoid-mediated suppression of interleukin-6 (IL-6 and TNF-alpha production in lipopolysaccharide (LPS-stimulated native human macrophages and human THP-1 macrophages. CONCLUSIONS: DBT inhibits ligand binding to GR and subsequent activation of the receptor. By blocking GR activation, DBT may disturb metabolic functions and modulation of the immune system, providing an explanation for some of the toxic effects of this organotin.

  16. Abrin P2 suppresses proliferation and induces apoptosis of colon cancer cells via mitochondrial membrane depolarization and caspase activation.

    Science.gov (United States)

    Yu, Ying; Yang, Runmei; Zhao, Xiuyun; Qin, Dandan; Liu, Zhaoyang; Liu, Fang; Song, Xin; Li, Liqin; Feng, Renqing; Gao, Nannan

    2016-05-01

    To explore the cytotoxic mechanism of abrin P2 on human colon cancer HCT-8 cells, abrin P2 was isolated from the seed of Abrus precatorius L. It was found that abrin P2 exhibited cytotoxicity toward 12 different human cancer cell lines. Our results demonstrated that abrin P2 suppressed the proliferation of human colon cancer cells (HCT-8 cells) and induced cell cycle arrest at the S and G2/M phases. The mechanism by which abrin P2 inhibited cell proliferation was via the down-regulation of cyclin B1, proliferating cell nuclear antigen and Ki67, as well as the up-regulation of P21. In addition, abrin P2 induced a dose- and time-dependent increase in the rate of HCT-8 cell apoptosis. Treatment with both Z-VAD-FMK, a broad-spectrum caspase inhibitor, and abrin P2 demonstrated that abrin P2 induced HCT-8 cell apoptosis via the activation of caspases. Together, our results revealed that abrin P2-induced apoptosis in HCT-8 cells was associated with the activation of caspases-3/-8/-9, the reduction in the Bcl-2/Bax ratio, the loss of mitochondrial membrane potential, and the increase in cytochrome c release. We further showed that abrin P2 administration effectively suppressed the growth of colon cancer xenografts in nude mice. This is the first report that abrin P2 effectively inhibits colon cancer cell growth in vivo and in vitro by suppressing proliferation and inducing apoptosis.

  17. Atorvastatin ameliorates contrast medium-induced renal tubular cell apoptosis in diabetic rats via suppression of Rho-kinase pathway.

    Science.gov (United States)

    Su, Jinzi; Zou, Wenbo; Cai, Wenqin; Chen, Xiuping; Wang, Fangbing; Li, Shuizhu; Ma, Wenwen; Cao, Yangming

    2014-01-15

    Contrast medium-induced acute kidney injury (CI-AKI) remains a leading cause of iatrogenic, drug-induced acute renal failure. This study aimed to investigate the protective effects of atorvastatin against renal tubular cell apoptosis in diabetic rats and the related mechanisms. CI-AKI was induced by intravenous administration of iopromide (12ml/kg) in streptozotocin-induced diabetic rats. Atorvastatin (ATO) was administered intragastrically at the dose of 5, 10 and 30mg/kg/d in different groups, respectively, for 5 days before iopromide injection. Renal function parameters, kidney histology, renal tubular cell apoptosis, the expression of apoptosis regulatory proteins, caspase-3 and Rho-associated protein kinase 1 (ROCK-1), and the phosphorylation of myosin phosphatase target subunit -1 (MYPT-1), were determined. Atorvastatin was shown to notably ameliorate contrast medium induced medullary damage, restore renal function, and suppress renal tubular apoptosis. Meanwhile, atorvastatin up-regulated the expression of Bcl-2, down-regulated the expression of Bax, caspase-3 and ROCK-1, restored the ratio of Bcl-2/Bax, and suppressed the phosphorylation of MYPT-1 in a dose-dependent manner. Thus, atorvastatin pretreatment could dose-dependently ameliorate the development of CI-AKI, which was partly attributed to its suppression of renal tubular cell apoptosis by inhibiting the Rho/ROCK pathway.

  18. Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction.

    Science.gov (United States)

    Alecu, Irina; Tedeschi, Andrea; Behler, Natascha; Wunderling, Klaus; Lamberz, Christian; Lauterbach, Mario A R; Gaebler, Anne; Ernst, Daniela; Van Veldhoven, Paul P; Al-Amoudi, Ashraf; Latz, Eicke; Othman, Alaa; Kuerschner, Lars; Hornemann, Thorsten; Bradke, Frank; Thiele, Christoph; Penno, Anke

    2017-01-01

    1-Deoxysphingolipids (deoxySLs) are atypical sphingolipids that are elevated in the plasma of patients with type 2 diabetes and hereditary sensory and autonomic neuropathy type 1 (HSAN1). Clinically, diabetic neuropathy and HSAN1 are very similar, suggesting the involvement of deoxySLs in the pathology of both diseases. However, very little is known about the biology of these lipids and the underlying pathomechanism. We synthesized an alkyne analog of 1-deoxysphinganine (doxSA), the metabolic precursor of all deoxySLs, to trace the metabolism and localization of deoxySLs. Our results indicate that the metabolism of these lipids is restricted to only some lipid species and that they are not converted to canonical sphingolipids or fatty acids. Furthermore, exogenously added alkyne-doxSA [(2S,3R)-2-aminooctadec-17-yn-3-ol] localized to mitochondria, causing mitochondrial fragmentation and dysfunction. The induced mitochondrial toxicity was also shown for natural doxSA, but not for sphinganine, and was rescued by inhibition of ceramide synthase activity. Our findings therefore indicate that mitochondrial enrichment of an N-acylated doxSA metabolite may contribute to the neurotoxicity seen in diabetic neuropathy and HSAN1. Hence, we provide a potential explanation for the characteristic vulnerability of peripheral nerves to elevated levels of deoxySLs.

  19. Localizing evoked and induced responses to faces using magnetoencephalography.

    Science.gov (United States)

    Perry, Gavin; Singh, Krish D

    2014-05-01

    A rich pattern of responses in frequency, time and space are known to be generated in the visual cortex in response to faces. Recently, a number of studies have used magnetoencephalography (MEG) to try to record these responses non-invasively - in many cases using source analysis techniques based on the beamforming method. Here we sought both to characterize best practice for measuring face-specific responses using MEG beamforming, and to determine whether the results produced by the beamformer match evidence from other modalities. We measured activity to visual presentation of face stimuli and phase-scrambled control stimuli, and performed source analyses of both induced and evoked responses using Synthetic Aperture Magnetometry. We localized the gamma-band response to bilateral lateral occipital cortex, and both the gamma-band response and the M170-evoked response to the right fusiform gyrus. Differences in the gamma-band response between faces and scrambled stimuli were confined to the frequency range 50-90 Hz; gamma-band activity at higher frequencies did not differ between the two stimulus categories. We additionally identified a component of the M220-evoked response - localized to the parieto-occipital sulcus - which was enhanced for scrambled vs. unscrambled faces. These findings help to establish that MEG beamforming can localize face-specific responses in time, frequency and space with good accuracy (when validated against established findings from functional magnetic resonance imaging and intracranial recordings), as well as contributing to the establishment of best methodological practice for the use of the beamformer method to measure face-specific responses.

  20. Classically induced suppression of energy growth in a chaotic quantum system

    Indian Academy of Sciences (India)

    Harinder Pal; M S Santhanam

    2011-11-01

    Recent experiments with Bose–Einstein condensates (BEC) in traps and speckle potentials have explored the dynamical regime in which the evolving BEC clouds localize due to the influence of classical dynamics. The growth of their mean energy is effectively arrested. This is in contrast with the well-known localization phenomena that originate due to quantum interferences. We show that classically induced localization can also be obtained in a classically chaotic, non-interacting system. In this work, we study the classical and quantum dynamics of non-interacting particles in a double-barrier structure. This is essentially a non-KAM system and, depending on the parameters, can display chaotic dynamics inside the finite well between the barriers. However, for the same set of parameters, it can display nearly regular dynamics above the barriers. We exploit this combination of two qualitatively different classical dynamical features to obtain saturation of energy growth. In the semiclassical regime, this classical mechanism strongly influences the quantum behaviour of the system.

  1. Chemotherapy-induced suppression to adenoma or complete suppression of the primary in patients with stage IV colorectal cancer: report of four cases.

    Science.gov (United States)

    Armbrust, Thomas; Sobotta, Michael; Füzesi, Laszlo; Grabbe, Eckhardt; Ramadori, Giuliano

    2007-11-01

    Although modern chemotherapy of stage IV advanced colorectal cancer (CRC) has impressively improved overall survival, the response of the primary tumor has not been studied because surgical resection of the primary continues to be the standard procedure in stage IV CRC. Long-term follow-up of the primary in patients with stage IV CRC under chemotherapy. Here we report on the histological changes in the primary tumor in four patients suffering from stage IV CRC. Systemic chemotherapy was started immediately after endoscopic tumor debulking in three cases. In one case no endoscopic intervention was performed before chemotherapy. Neither macroscopic nor histological evidence for malignant tumor growth was found at the former site of the primary after 6, 23, 26 or 48 months, respectively. Two patients had a complete suppression of the primary, two patients had an adenoma at the former site of the primary. To date, three patients have died because of progression of liver metastases and one patient is still alive with no signs of tumor growth. The four cases illustrate that today's chemotherapy may effectively induces suppression of the primary in CRC. The development of CRC may follow different pathways.

  2. Intranuclear interactomic inhibition of NF-κB suppresses LPS-induced severe sepsis

    Energy Technology Data Exchange (ETDEWEB)

    Park, Sung-Dong [Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Cheon, So Yeong [Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of); Park, Tae-Yoon; Shin, Bo-Young [Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Oh, Hyunju; Ghosh, Sankar [Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032 (United States); Koo, Bon-Nyeo, E-mail: koobn@yuhs.ac [Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of); Lee, Sang-Kyou, E-mail: sjrlee@yonsei.ac.kr [Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)

    2015-08-28

    Suppression of nuclear factor-κB (NF-κB) activation, which is best known as a major regulator of innate and adaptive immune responses, is a potent strategy for the treatment of endotoxic sepsis. To inhibit NF-κB functions, we designed the intra-nuclear transducible form of transcription modulation domain (TMD) of RelA (p65), called nt-p65-TMD, which can be delivered effectively into the nucleus without influencing the cell viability, and work as interactomic inhibitors via disruption of the endogenous p65-mediated transcription complex. nt-p65-TMD effectively inhibited the secretion of pro-inflammatory cytokines, including TNF-α, IL-1β, or IL-6 from BV2 microglia cells stimulated by lipopolysaccharide (LPS). nt-p65-TMD did not inhibit tyrosine phosphorylation of signaling mediators such as ZAP-70, p38, JNK, or ERK involved in T cell activation, but was capable of suppressing the transcriptional activity of NF-κB without the functional effect on that of NFAT upon T-cell receptor (TCR) stimulation. The transduced nt-p65-TMD in T cell did not affect the expression of CD69, however significantly inhibited the secretion of T cell-specific cytokines such as IL-2, IFN-γ, IL-4, IL-17A, or IL-10. Systemic administration of nt-p65-TMD showed a significant therapeutic effect on LPS-induced sepsis model by inhibiting pro-inflammatory cytokines secretion. Therefore, nt-p65-TMD can be a novel therapeutics for the treatment of various inflammatory diseases, including sepsis, where a transcription factor has a key role in pathogenesis, and further allows us to discover new functions of p65 under normal physiological condition without genetic alteration. - Highlights: • The nt-p65-TMD is intra-nuclear interactomic inhibitor of endogenous p65. • The nt-p65-TMD effectively inhibited the secretion of pro-inflammatory cytokines. • The excellent therapeutic potential of nt-p65-TMD was confirmed in sepsis model.

  3. Suppression of phase-induced intensity noise in fibre optic delay line signal processors using an optical phase modulation technique.

    Science.gov (United States)

    Chan, Erwin H W

    2010-10-11

    A technique that can suppress the dominant phase-induced intensity noise in fibre optic delay line signal processors is presented. It is based on phase modulation of the optical carrier to distribute the phase noise at the information band into a high frequency band which can be filtered out. This technique is suitable for suppressing the phase noise in various delay line structures and for integrating in the conventional fibre optic links. It can also suppress the coherent interference effect at the same time. A model for predicting the amount of phase noise reduction in various delay line structures using the optical phase modulation technique is presented for the first time and is experimentally verified. Experimental results demonstrate the technique can achieve a large phase noise reduction in various fibre optic delay line signal processors.

  4. Hydroxysafflor yellow A suppress oleic acid-induced acute lung injury via protein kinase A

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Chaoyun [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China); Huang, Qingxian [Department of Hepatobiliary Surgery, Yantai Yuhuangding Hospital, Yantai, Shandong 264000 (China); Wang, Chunhua; Zhu, Xiaoxi; Duan, Yunfeng; Yuan, Shuai [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China); Bai, Xianyong, E-mail: xybai2012@163.com [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China)

    2013-11-01

    Inflammation response and oxidative stress play important roles in acute lung injury (ALI). Activation of the cAMP/protein kinase A (PKA) signaling pathway may attenuate ALI by suppressing immune responses and inhibiting the generation of reactive oxygen species (ROS). Hydroxysafflor yellow A (HSYA) is a natural flavonoid compound that reduces oxidative stress and inflammatory cytokine-mediated damage. In this study, we examined whether HSYA could protect the lungs from oleic acid (OA)-induced injury, which was used to mimic ALI, and determined the role of the cAMP/PKA signaling pathway in this process. Arterial oxygen tension (PaO{sub 2}), carbon dioxide tension, pH, and the PaO{sub 2}/fraction of inspired oxygen ratio in the blood were detected using a blood gas analyzer. We measured wet/dry lung weight ratio and evaluated tissue morphology. The protein and inflammatory cytokine levels in the bronchoalveolar lavage fluid and serum were determined using enzyme-linked immunoassay. The activities of superoxide dismutase, glutathione peroxidase, PKA, and nicotinamide adenine dinucleotide phosphate oxidase, and the concentrations of cAMP and malondialdehyde in the lung tissue were detected using assay kits. Bcl-2, Bax, caspase 3, and p22{sup phox} levels in the lung tissue were analyzed using Western blotting. OA increased the inflammatory cytokine and ROS levels and caused lung dysfunction by decreasing cAMP synthesis, inhibiting PKA activity, stimulating caspase 3, and reducing the Bcl-2/Bax ratio. H-89 increased these effects. HSYA significantly increased the activities of antioxidant enzymes, inhibited the inflammatory response via cAMP/PKA pathway activation, and attenuated OA-induced lung injury. Our results show that the cAMP/PKA signaling pathway is required for the protective effect of HSYA against ALI. - Highlights: • Oleic acid (OA) cause acute lung injury (ALI) via inhibiting cAMP/PKA signal pathway. • Blocking protein kinase A (PKA) activation may

  5. 1-methylmalate from camu-camu (Myrciaria dubia) suppressed D-galactosamine-induced liver injury in rats.

    Science.gov (United States)

    Akachi, Toshiyuki; Shiina, Yasuyuki; Kawaguchi, Takumi; Kawagishi, Hirokazu; Morita, Tatsuya; Sugiyama, Kimio

    2010-01-01

    To evaluate the protective effects of fruit juices against D-galactosamine (GalN)-induced liver injury, lyophilized fruit juices (total 12 kinds) were fed to rats for 7 d, and then we evoked liver injury by injecting GalN. The juice of camu-camu (Myrciaria dubia) significantly suppressed GalN-induced liver injury when the magnitude of liver injury was assessed by plasma alanine aminotransferase and aspartate aminotransferase activities, although some other juices (acerola, dragon fruit, shekwasha, and star fruit) also tended to have suppressive effects. An active compound was isolated from camu-camu juice by solvent fractionation and silica gel column chromatography. The structure was determined to be 1-methylmalate. On the other hand, malate, 1,4-dimethylmalate, citrate, and tartrate had no significant effect on GalN-induced liver injury. It is suggested that 1-methylmalate might be a rather specific compound among organic acids and their derivatives in fruit juices in suppressing GalN-induced liver injury.

  6. Schisandrin B induces an Nrf2-mediated thioredoxin expression and suppresses the activation of inflammasome in vitro and in vivo.

    Science.gov (United States)

    Leong, Pou Kuan; Ko, Kam Ming

    2015-01-01

    Reactive oxygen species (ROS)-mediated activation of inflammasome is involved in the development of a wide spectrum of diseases. We aimed to investigate whether (-)schisandrin B [(-)Sch B], a phytochemical that can induce cellular antioxidant response, can suppress the inflammasome activation. Results showed that (-)Sch B can induce an nuclear factor erythroid 2-related factor 2-driven thioredoxin expression in primary peritoneal macrophages and cultured RAW264.7 macrophages. A 4-h priming of peritoneal macrophages with LPS followed by a 30-min incubation with ATP caused the activation of caspase 1 and the release of IL-1β, indicative of inflammasome activation. Although LPS/ATP did not activate inflammasome in RAW264.7 macrophages, it caused the ROS-dependent c-Jun N-terminal kinase1/2 (JNK1/2) activation and an associated lactate dehydrogenase (LDH) release in RAW264.7 macrophages, an indication of cytotoxicity. (-)Sch B suppressed the LPS/ATP-induced activation of caspase 1 and release of IL-1β in peritoneal macrophages. (-)Sch B also attenuated the LPS/ATP-induced ROS production, JNK1/2 activation and LDH release in RAW264.7 macrophages. The ability of (-)Sch B to suppress LPS/ATP-mediated inflammation in vitro was further confirmed by an animal study, in which schisandrin B treatment (2 mmol/kg p.o.) ameliorated the Imject Alum-induced peritonitis, as indicated by suppressions of caspase1 activation and plasma IL-1β level. The ensemble of results suggests that (-)Sch B may offer a promising prospect for preventing the inflammasome-mediated disorders.

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

    Science.gov (United States)

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

    2015-05-15

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

  8. Local delivery of siRNA using a biodegradable polymer application to enhance BMP-induced bone formation.

    Science.gov (United States)

    Manaka, Tomoya; Suzuki, Akinobu; Takayama, Kazushi; Imai, Yuuki; Nakamura, Hiroaki; Takaoka, Kunio

    2011-12-01

    Small interfering RNA (siRNA) is useful tool for specific and efficient knockdown of disease-related genes. However, in vivo applications of siRNA are limited due to difficulty in its efficient delivery to target cells. In this study, we investigated the efficacy of a biodegradable hydrogel, poly-d,l-lactic acid-p-dioxanone-polyethylene glycol block co-polymer (PLA-DX-PEG), as a siRNA carrier. PLA-DX-PEG pellets with or without fluorescein-labeled dsRNA were implanted into mouse dosal muscle pouches. The cellular uptake of dsRNA surround the polymer was confirmed by fluorescent microscopy. The fluorescence intensity was dose-dependent of the dsRNA, and exhibited a time-dependent decrease. To investigate its biological efficiency, noggin (antagonoist to BMPs) gene-silencing with siRNA (siRNA/Noggin) was examined by the amount of suppression of BMP-2-induced noggin expression and the level of performance of BMP, indicated by ectopic bone formation. Noggin gene expression induced by BMP-2 was suppressed by addition of siRNA/Noggin to the implant, and the ectopic bone formation induced by implants with both BMP-2 and siRNA/Noggin was significantly greater than those induced by implants with BMP-2 alone. These results indicate the efficacy of local delivery of siRNAs by PLA-DX-PEG polymer, which intensified bone-inducing effects of BMP and promoted new bone formation by suppressing gene expression of Noggin.

  9. The transcription factor EGR1 localizes to the nucleolus and is linked to suppression of ribosomal precursor synthesis.

    Directory of Open Access Journals (Sweden)

    Donatella Ponti

    Full Text Available EGR1 is an immediate early gene with a wide range of activities as transcription factor, spanning from regulation of cell growth to differentiation. Numerous studies show that EGR1 either promotes the proliferation of stimulated cells or suppresses the tumorigenic growth of transformed cells. Upon interaction with ARF, EGR1 is sumoylated and acquires the ability to bind to specific targets such as PTEN and in turn to regulate cell growth. ARF is mainly localized to the periphery of nucleolus where is able to negatively regulate ribosome biogenesis. Since EGR1 colocalizes with ARF under IGF-1 stimulation we asked the question of whether EGR1 also relocate to the nucleolus to interact with ARF. Here we show that EGR1 colocalizes with nucleolar markers such as fibrillarin and B23 in the presence of ARF. Western analysis of nucleolar extracts from HeLa cells was used to confirm the presence of EGR1 in the nucleolus mainly as the 100 kDa sumoylated form. We also show that the level of the ribosomal RNA precursor 47S is inversely correlated to the level of EGR1 transcripts. The EGR1 iseffective to regulate the synthesis of the 47S rRNA precursor. Then we demonstrated that EGR1 binds to the Upstream Binding Factor (UBF leading us to hypothesize that the regulating activity of EGR1 is mediated by its interaction within the transcriptional complex of RNA polymerase I. These results confirm the presence of EGR1 in the nucleolus and point to a role for EGR1 in the control of nucleolar metabolism.

  10. The transcription factor EGR1 localizes to the nucleolus and is linked to suppression of ribosomal precursor synthesis.

    Science.gov (United States)

    Ponti, Donatella; Bellenchi, Gian Carlo; Puca, Rosa; Bastianelli, Daniela; Maroder, Marella; Ragona, Giuseppe; Roussel, Pascal; Thiry, Marc; Mercola, Dan; Calogero, Antonella

    2014-01-01

    EGR1 is an immediate early gene with a wide range of activities as transcription factor, spanning from regulation of cell growth to differentiation. Numerous studies show that EGR1 either promotes the proliferation of stimulated cells or suppresses the tumorigenic growth of transformed cells. Upon interaction with ARF, EGR1 is sumoylated and acquires the ability to bind to specific targets such as PTEN and in turn to regulate cell growth. ARF is mainly localized to the periphery of nucleolus where is able to negatively regulate ribosome biogenesis. Since EGR1 colocalizes with ARF under IGF-1 stimulation we asked the question of whether EGR1 also relocate to the nucleolus to interact with ARF. Here we show that EGR1 colocalizes with nucleolar markers such as fibrillarin and B23 in the presence of ARF. Western analysis of nucleolar extracts from HeLa cells was used to confirm the presence of EGR1 in the nucleolus mainly as the 100 kDa sumoylated form. We also show that the level of the ribosomal RNA precursor 47S is inversely correlated to the level of EGR1 transcripts. The EGR1 iseffective to regulate the synthesis of the 47S rRNA precursor. Then we demonstrated that EGR1 binds to the Upstream Binding Factor (UBF) leading us to hypothesize that the regulating activity of EGR1 is mediated by its interaction within the transcriptional complex of RNA polymerase I. These results confirm the presence of EGR1 in the nucleolus and point to a role for EGR1 in the control of nucleolar metabolism.

  11. Numerical Study on the Suppression of Shock Induced Separation on the Non Adisbatic Wall

    Institute of Scientific and Technical Information of China (English)

    Doug-DongLEE

    2000-01-01

    A numerical model is constructued to simulate the interaction of supersonic(M=2.4) oblique shock wave/turbulent boundary layer on s trongly heated wall.The heated wall temperature is two times higher than the adiabatic wall temperature and the shock wave is strong enough to induce boundary layer sepqration.The turbulence model is Splanrt-Allmaras model.The comparison of the wall pressure distribution with the experimental data ensures the validity of this numerical model.The effect of strong wall heating enlarges the separation region upstream and downstream.In order to eliminate the separation.wall bleeding is appled at the shock foot position.As a result of the parametric study,the best position of the bleeding slot is selected.The position of the bleeding is very important for the separation suppression.If the bleeding is applied upstream of shock foot,then separation reoccurs after the bleeding slot.If the bleeding is applied downstream of shock foot,the upstream boundary layer is little influenced and still separated.The bleeding vent width is about same as the upstream boundary layer thickness and suction mass flow in 20 to 80% of the flow rate in the upstream boundary layer.The bleeding mass flow rate is very sensitive to the bleeding vent position if we fix the vent outlet pressure.The final configuration of the shock reflection pattern approaches to the non-viscous value when wall bleeding is applied at the shock impinging point.

  12. Rap1GAP interacts with RET and suppresses GDNF-induced neurite outgrowth

    Institute of Scientific and Technical Information of China (English)

    Li Jiao; Yong Zhang; Chun Hu; Yong-Gang Wang; Aijun Huang; Cheng He

    2011-01-01

    Glial cell line-derived neurotrophic factor(GDNF)was originally recognized for its ability to promote survival of midbrain dopaminergic neurons,but it has since been demonstrated to be crucial for the survival and differentiation of many neuronal subpopulations,including motor neurons,sympathetic neurons,sensory neurons and enteric neurons.To identify possible effectors or regulators of GDNF signaling,we performed a yeast two-hybrid screen using the intracellular domain of RET,the common signaling receptor of the GDNF family,as bait.Using this approach,we identified RaplGAP,a GTPase-activating protein(GAP)for Rap1,as a novel RET-binding protein.Endogenous RaplGAP co-immunoprecipitated with RET in neural tissues,and RET and RaplGAP were co-expressed in dopaminergic neurons of the mesencephalon,in addition,overexpression of RaplGAP attenuated GDNF-induced neurite outgrowth,whereas suppressing the expression of endogenous RaplGAP by RNAi enhanced neurite outgrowth.Furthermore,using co-immunoprecipitation analyses,we found that the interaction between RET and RaplGAP was enhanced following GDNF treatment.Mutagenesis analysis revealed that Tyr981 in the intracellular domain of RET was crucial for the interaction with RapiGAP.Moreover,we found that RaplGAP negatively regulatedGNDFinduced ERK activation and neurite outgrowth.Taken together,our results suggest the involvement of a novel interaction of RET with Rap l GAP in the regulation of GDNF-mediated neurite outgrowth.

  13. Transscleral sustained vasohibin-1 delivery by a novel device suppressed experimentally-induced choroidal neovascularization.

    Directory of Open Access Journals (Sweden)

    Hideyuki Onami

    Full Text Available We established a sustained vasohibin-1 (a 42-kDa protein, delivery device by a novel method using photopolymerization of a mixture of polyethylene glycol dimethacrylate, triethylene glycol dimethacrylate, and collagen microparticles. We evaluated its effects in a model of rat laser-induced choroidal neovascularization (CNV using a transscleral approach. We used variable concentrations of vasohibin-1 in the devices, and used an enzyme-linked immunosorbent assay and Western blotting to measure the released vasohibin-1 (0.31 nM/day when using the 10 μM vasohibin-1 delivery device [10VDD]. The released vasohibin-1 showed suppression activity comparable to native effects when evaluated using endothelial tube formation. We also used pelletized vasohibin-1 and fluorescein isothiocyanate-labeled 40 kDa dextran as controls. Strong fluorescein staining was observed on the sclera when the device was used for drug delivery, whereas pellet use produced strong staining in the conjunctiva and surrounding tissue, but not on the sclera. Vasohibin-1 was found in the sclera, choroid, retinal pigment epithelium (RPE, and neural retina after device implantation. Stronger immunoreactivity at the RPE and ganglion cell layers was observed than in other retinal regions. Significantly lower fluorescein angiography (FA scores and smaller CNV areas in the flat mounts of RPE-choroid-sclera were observed for the 10VDD, VDD (1 μM vasohibin-1 delivery device, and vasohibin-1 intravitreal direct injection (0.24 μM groups when compared to the pellet, non-vasohibin-1 delivery device, and intravitreal vehicle injection groups. Choroidal neovascularization can be treated with transscleral sustained protein delivery using our novel device. We offer a safer sustained protein release for treatment of retinal disease using the transscleral approach.

  14. Topically applied standardized aqueous extract of Curcuma longa Linn. suppresses endotoxin-induced uveal inflammation in rats.

    Science.gov (United States)

    Agarwal, Renu; Gupta, S K; Agarwal, Puneet; Srivastava, Sushma

    2013-10-01

    Aqueous extract of C. longa when administered 4 h after induction of E. coli lipopolysaccharide-induced uveitis in rats showed significantly suppressed inflammation with a significantly lower mean clinical grade, histopathological grade and aqueous humor (AH) protein level compared to vehicle treated group. Although, prednisolone group showed significantly lower clinical grade, histopathological grades and AH protein levels compared to C. longa group, TNF-alpha levels did not differ significantly. Moreover, when the aqueous extract was administered starting from 3 days before induction of uveitis, the mean clinical and histopathological grade as well as AH protein and TNF-alpha levels were comparable to C. longa group when treatment was administered 4 h after induction of uveitis. It is concluded that topically applied standardized aqueous extract of C. longa suppresses endotoxin-induced uveitis in rats by reducing TNF-alpha activity.

  15. Protective effect of melatonin against propoxur-induced oxidative stress and suppression of humoral immune response in rats.

    Science.gov (United States)

    Suke, Sanvidhan G; Kumar, Achint; Ahmed, Rafat S; Chakraborti, Ayanabha; Tripathi, A K; Mediratta, P K; Banerjee, B D

    2006-04-01

    Effect of melatonin in attenuation of propoxur induced oxidative stress and suppression of humoral immune response was studied in rats. Oral administration of propoxur (10 mg/kg) increased lipid peroxidation in serum after 28 days treatment. Superoxide dismutase, catalase and glutathione were also altered following propoxur exposure. In addition propoxur exposure markedly suppressed humoral immune response as assessed by antibody titre and plaque forming cell assay. Simultaneous treatment with melatonin (5 mg/kg, ip) markedly attenuated the effect of propoxur on (a) lipid peroxidation, (b) oxidative stress parameters and (c) immunotoxicity. Results have been discussed in the light of possible immunopotentiating and antioxidant effects of melatonin to understand the influence of oxidative stress on propoxur induced immunomodulation.

  16. An in-flight investigation of pilot-induced oscillation suppression filters during the fighter approach and landing task

    Science.gov (United States)

    Bailey, R. E.; Smith, R. E.

    1982-01-01

    An investigation of pilot-induced oscillation suppression (PIOS) filters was performed using the USAF/Flight Dynamics Laboratory variable stability NT-33 aircraft, modified and operated by Calspan. This program examined the effects of PIOS filtering on the longitudinal flying qualities of fighter aircraft during the visual approach and landing task. Forty evaluations were flown to test the effects of different PIOS filters. Although detailed analyses were not undertaken, the results indicate that PIOS filtering can improve the flying qualities of an otherwise unacceptable aircraft configuration (Level 3 flying qualities). However, the ability of the filters to suppress pilot-induced oscillations appears to be dependent upon the aircraft configuration characteristics. Further, the data show that the filters can adversely affect landing flying qualities if improperly designed. The data provide an excellent foundation from which detail analyses can be performed.

  17. Simvastatin suppresses cyclophosphamide-induced changes in urodynamics and bladder inflammation.

    Science.gov (United States)

    Hughes, Francis M; McKeithan, Paige; Ellett, Justin; Armeson, Kent E; Purves, J Todd

    2013-01-01

    To assess the ability of daily oral simvastatin administration to reduce the negative urodynamic changes associated with cyclophosphamide (CP)-induced cystitis and to prevent bladder inflammation. Patients undergoing CP chemotherapy frequently develop cystitis, leading to urinary dysfunction and hemorrhage. Recent studies have suggested statins possess anti-inflammatory properties and might be uroprotective. Urodynamic properties were analyzed in 4 groups of female Sprague-Dawley rats: group 1, vehicle (300 μL, 0.5% methylcellulose, orally for 7 days); group 2, simvastatin (1 mg/rat/d); group 3, vehicle plus CP (intraperitoneally 80 mg/kg, 24 h before cystometry); and group 4, simvastatin plus CP. The inflammation in the groups was assessed using Evans blue extravasation. CP stimulated significant increases in the number of nonvoiding contractions (0.83±0.26 vs 4.97±1.90; P=.03) and decreases in the peak voiding pressure (53.46±5.08 vs 33.34±4.37 cm H2O; P=.01). Simvastatin returned these parameters to the control levels of 1.62±0.73 (P=.70) and 45.98±7.78 cm H2O (P=.38). CP at this level caused a slight, but significant, increase in the voided volume (0.82±0.13 vs 1.16±0.14 mL; P=.04), which returned to control levels (0.74±0.12 mL; P=.65) with simvastatin. Other urodynamic parameters, such as the threshold pressure, were not affected by simvastatin or CP, or the combination of the 2. CP-induced inflammation in the bladder (Evans blue extravasation) was suppressed by simvastatin. Simvastatin was effective at ameliorating the negative urodynamic changes and inflammation in the bladder after CP administration and is a potential therapy for preventing side effects in patients undergoing this chemotherapy. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Resveratrol, but not EGCG, in the diet suppresses DMBA-induced mammary cancer in rats

    Directory of Open Access Journals (Sweden)

    Whitsett Timothy

    2006-05-01

    Full Text Available Abstract Despite the advent of new and aggressive therapeutics, breast cancer remains a leading killer among women; hence there is a need for the prevention of this disease. Several naturally occurring polyphenols have received much attention for their health benefits, including anti-carcinogenic properties. Two of these are resveratrol, a component of red grapes, and epigallocatechin-3-gallate (EGCG, the major catechin found in green tea. In this study, we tested the hypothesis that these two polyphenols protect against chemically-induced mammary cancer by modulating mammary gland architecture, cell proliferation, and apoptosis. Female Sprague-Dawley CD rats were exposed to either resveratrol (1 g/kg AIN-76A diet, EGCG (0.065% in the drinking water, or control diet (AIN-76A for the entirety of their life starting at birth. At 50 days postpartum, rats were treated with 60 mg dimethylbenz[a]anthracene (DMBA/kg body weight to induce mammary cancer. Resveratrol, but not EGCG, suppressed mammary carcinogenesis (fewer tumors per rat and longer tumor latency. Analysis of mammary whole mounts from 50-day-old rats revealed that resveratrol, but not EGCG, treatment resulted in more differentiated lobular structures. Bromodeoxyuridine (BrdU incorporation studies showed that resveratrol treatment caused a significant reduction in proliferative cells in mammary terminal ductal structures at 50 days postpartum, making them less susceptible to carcinogen insult. The epithelial cells of terminal end buds in the mammary glands of resveratrol-treated rats also showed an increase in apoptotic cells compared to the control or EGCG-treated rats as measured by a DNA fragmentation assay. At the given doses, resveratrol treatment resulted in a serum resveratrol concentration of 2.00 μM, while treatment with EGCG resulted in a serum EGCG concentration of 31.06 nM. 17β-Estradiol, progesterone, and prolactin concentrations in the serum were not significantly affected

  19. Buckwheat protein extract suppression of the growth depression in rats induced by feeding amaranth (Food Red No. 2).

    Science.gov (United States)

    Kayashita, J; Nagai, H; Kato, N

    1996-09-01

    Dietary fiber has an ameliorative effect on the toxicity of amaranth (Food Red No. 2). To test the possibility that a buckwheat protein extract (BWPE) has dietary fiber-like activity by virtue of its low digestibility, we examined the influence of BWPE on amaranth toxicity in rats. The results show that BWPE-containing diet suppressed the growth depression induced by the dietary addition of 5% amaranth.

  20. Hydrogen sulfide suppresses transforming growth factor-β1-induced differentiation of human cardiac fibroblasts into myofibroblasts.

    Science.gov (United States)

    Zhang, YouEn; Wang, JiaNing; Li, Hua; Yuan, LiangJun; Wang, Lei; Wu, Bing; Ge, JunBo

    2015-11-01

    In heart disease, transforming growth factor-β1 (TGF-β1) converts fibroblasts into myofibroblasts, which synthesize and secrete fibrillar type I and III collagens. The purpose of the present study was to investigate how hydrogen sulfide (H2S) suppresses TGF-β1-induced differentiation of human cardiac fibroblasts to myofibroblasts. Human cardiac fibroblasts were serum-starved in fibroblast medium for 16 h before exposure to TGF-β1 (10 ng mL(-1)) for 24 h with or without sodium hydrosulfide (NaHS, 100 µmol L(-1), 30 min pretreatment) treatment. NaHS, an exogenous H2S donor, potently inhibited the proliferation and migration of TGF-β1-induced human cardiac fibroblasts and regulated their cell cycle progression. Furthermore, NaHS treatment led to suppression of fibroblast differentiation into myofibroblasts, and reduced the levels of collagen, TGF-β1, and activated Smad3 in TGF-β1-induced human cardiac fibroblasts in vitro. We therefore conclude that H2S suppresses TGF-β1-stimulated conversion of fibroblasts to myofibroblasts by inhibiting the TGF-β1/Smad3 signaling pathway, as well as by inhibiting the proliferation, migration, and cell cycle progression of human cardiac myofibroblasts. These effects of H2S may play significant roles in cardiac remodeling associated with heart failure.

  1. TAT-mediated intracellular delivery of NPM-derived peptide induces apoptosis in leukemic cells and suppresses leukemogenesis in mice.

    Science.gov (United States)

    Zhou, Yun; Du, Wei; Koretsky, Tara; Bagby, Grover C; Pang, Qishen

    2008-09-15

    Nucleophosmin (NPM) is frequently overexpressed in leukemias and other tumors. NPM has been reported to suppress oncogene-induced senescence and apoptosis and may represent a therapeutic target for cancer. We fused a NPM-derived peptide to the HIV-TAT (TAT-NPMDeltaC) and found that the fusion peptide inhibited proliferation and induced apoptotic death of primary fibroblasts and preleukemic stem cells. TAT-NPMDeltaC down-regulated several NF-kappaB-controlled survival and inflammatory proteins and suppressed NF-kappaB-driven reporter gene activities. Using an inflammation-associated leukemia model, we demonstrate that TAT-NPMDeltaC induced proliferative suppression and apoptosis of preleukemic stem cells and significantly delayed leukemic development in mice. Mechanistically, TAT-NPMDeltaC associated with wild-type NPM proteins and formed complexes with endogenous NPM and p65 at promoters of several antiapoptotic and inflammatory genes and abrogated their transactivation by NF-kappaB in leu-kemic cells. Thus, TAT-delivered NPM peptide may provide a novel therapy for inflammation-associated tumors that require NF-kappaB signaling for survival.

  2. NBBA, a synthetic small molecule, inhibits TNF-{alpha}-induced angiogenesis by suppressing the NF-{kappa}B signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Nam Hee; Jung, Hye Jin [Chemical Genomics Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Shibasaki, Futoshi [Translation Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506 (Japan); Kwon, Ho Jeong, E-mail: kwonhj@yonsei.ac.kr [Chemical Genomics Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)

    2010-01-15

    Nuclear factor-{kappa}B (NF-{kappa}B) is a crucial transcription factor that contributes to cancer development by regulating a number of genes involved in angiogenesis and tumorigenesis. Here, we describe (Z)-N-(3-(7-nitro-3-oxobenzo[d][1,2]selenazol-2(3H)-yl)benzylidene) propan-2-amine oxide (NBBA) as a new anti-angiogenic small molecule that targets NF-{kappa}B activity. NBBA showed stronger growth inhibition on human umbilical vein endothelial cells (HUVECs) than on the cancer cell lines we tested. Moreover, NBBA inhibited tumor necrosis factor-alpha (TNF-{alpha})-induced tube formation and invasion of HUVECs. In addition, NBBA suppressed the neovascularization of chorioallantonic membrane from growing chick embryos in vivo. To address the mode of action of the compound, the effect of NBBA on TNF-{alpha}-induced NF-{kappa}B transcription activity was investigated. NBBA suppressed TNF-{alpha}-induced c-Jun N-terminal kinase phosphorylation, which resulted in suppression of transcription of NF-{kappa}B and its target genes, including interleukin-8, interleukin-1{alpha}, and epidermal growth factor. Collectively, these results demonstrated that NBBA is a new anti-angiogenic small molecule that targets the NF-{kappa}B signaling pathway.

  3. Oroxylin A inhibits hypoxia-induced invasion and migration of MCF-7 cells by suppressing the Notch pathway.

    Science.gov (United States)

    Cheng, Yao; Zhao, Kai; Li, Guojun; Yao, Jing; Dai, Qinsheng; Hui, Hui; Li, Zhiyu; Guo, Qinglong; Lu, Na

    2014-08-01

    Tumor invasion and migration obstructs the treatment and prognosis of cancer. In this research, we investigated the effect of oroxylin A, a natural compound extracted from Scutellaria radix, the root of Scutellaria baicalensis, on inhibition of the invasion and migration of three different tumor cell lines: MCF-7, DU145, and HepG2. The results suggested that oroxylin A could inhibit hypoxia-induced migration and invasion of the three cell lines mentioned above. To study the detailed mechanisms, studies were carried out on MCF-7 cells and it was found that oroxylin A could regulate the expression of related markers in MCF-7 cells including E-cadherin, N-cadherin, and Vimentin. It was also found that oroxylin A inhibited the hypoxia-induced invasion and migration of MCF-7 cells by suppressing the Notch pathway. Oroxylin A inhibited N1ICD translocating to the nucleus and binding to epithelial-mesenchymal transition-related transcription factor Snail, thus suppressing the invasion and migration of MCF-7 cells. Therefore, oroxylin A is expected to be a promising candidate for antimetastasis treatment through suppression of the hypoxia-induced Notch pathway.

  4. Andrographolide sensitizes cisplatin-induced apoptosis via suppression of autophagosome-lysosome fusion in human cancer cells.

    Science.gov (United States)

    Zhou, Jing; Hu, Shuai-Er; Tan, Shi-Hao; Cao, Ruoxi; Chen, Yiyang; Xia, Dajing; Zhu, Xinqiang; Yang, Xing-Fen; Ong, Choon-Nam; Shen, Han-Ming

    2012-03-01

    Suppression of autophagy has been increasingly recognized as a novel cancer therapeutic approach. Andrographolide (Andro), a diterpenoid lactone isolated from an herbal plant Andrographis paniculata, is known to possess anti-inflammatory and anticancer activity. In this study, we sought to examine the effect of Andro on autophagy, and to evaluate whether such effect is relevant to the sensitization effect of Andro on apoptosis induced by DNA damage agents in cancer cells. First, we found that Andro is able to significantly enhance autophagic markers in various cancer cell lines, including GFP-LC3 puncta and LC3-II level. Interestingly, Andro treatment also led to marked increase of p62 protein level and addition of chloroquine (CQ) failed to further enhance either LC3-II or p62 level, indicating that Andro is likely to suppress autophagic flux at the maturation and degradation stage. Next, we provided evidence that Andro inhibits autophagosome maturation not by affecting the lysosomal function, but by impairing autophagosome-lysosome fusion. Lastly, we demonstrated that treatment with cisplatin, a DNA damage agent, induces autophagy in cancer cells. Importantly, Andro is capable of sensitizing cisplatin-induced cell killing determined with both short-term apoptosis assays and long-term clonogenic test, via suppression of autophagy, a process independent of p53. In summary, these observations collectively suggest that Andro could be a promising anti-cancer agent in combination therapy via its potent inhibitory effect on autophagy by disrupting autophagosome-lysosome fusion.

  5. Roxatidine- and cimetidine-induced angiogenesis inhibition suppresses growth of colon cancer implants in syngeneic mice.

    Science.gov (United States)

    Tomita, Kazuyoshi; Izumi, Kazuki; Okabe, Susumu

    2003-11-01

    Cimetidine is known to suppress the growth of several tumors, including gastrointestinal cancer, in humans and animals. Nonetheless, whether other histamine H(2)-receptor antagonists exert such tumor suppressive effects remains unclear. The effect of roxatidine acetate hydrochloride (roxatidine), an H(2)-receptor antagonist, on the growth of colon cancer implanted in mice was examined and compared with that of cimetidine. Drugs were orally delivered for 26 - 29 days beginning before or after implantation of syngeneic colon cancer (Colon 38) in C57BL/6 mice. Tumor volume was determined throughout and histochemical analysis was also performed. Tumor tissue and serum vascular endothelial growth factor (VEGF) levels were measured. In vitro cell growth was assessed by the MTT assay. Both roxatidine and cimetidine significantly suppressed the growth of Colon 38 tumor implants. Histologic analysis revealed that such antagonists markedly increased necrotic areas and decreased the density of microvessels in tumor tissue. Both H(2)-receptor antagonists suppressed VEGF levels in tumor tissue and significantly decreased serum VEGF levels in Colon 38-bearing mice. Such drugs, however, failed to suppress in vitro growth of the cell line. In conclusion, both roxatidine and cimetidine were found to exert suppressive effects on the growth of colon cancer implants in mice by inhibiting angiogenesis via reducing VEGF expression.

  6. Detection of Amide and Aromatic Proton Resonances of Human Brain Metabolites Using Localized Correlated Spectroscopy Combined with Two Different Water Suppression Schemes

    Directory of Open Access Journals (Sweden)

    Rajakumar Nagarajan

    2010-06-01

    Full Text Available The purpose of the study was to demonstrate the J-coupling connectivity network between the amide, aliphatic, and aromatic proton resonances of metabolites in human brain using two-dimensional (2D localized correlated spectroscopy (L-COSY. Two different global water suppression techniques were combined with L-COSY, one before and another after localizing the volume of interest (VOI. Phantom solutions containing several cerebral metabolites at physiological concentrations were evaluated initially for sequence optimization. Nine healthy volunteers were scanned using a 3T whole body MRI scanner. The VOI for 2D L-COSY was placed in the right occipital white/gray matter region. The 2D cross and diagonal peak volumes were measured for several metabolites such as N-acetyl aspartate (NAA, creatine (Cr, free choline (Ch, glutamate/glutamine (Glx, aspartate (Asp, myo-inositol (mI, GABA, glutathione (GSH, phosphocholine (PCh, phosphoethanolamine (PE, tyrosine (Tyr, lactate (Lac, macromolecules (MM and homocarnosine (Car. Using the pre-water suppression technique with L-COSY, the above mentioned metabolites were clearly identifiable and the relative ratios of metabolites were calculated. In addition to detecting multitude of aliphatic resonances in the high field region, we have demonstrated that the amide and aromatic resonances can also be detected using 2D L-COSY by pre water suppression more reliably than the post-water suppression.

  7. Suppression of elliptic flow induced correlations in an observable of possible local parity violation

    CERN Document Server

    Bzdak, Adam

    2011-01-01

    It is shown that fluctuations in elliptic anisotropy in peripheral heavy ion collisions can be used to significantly reduce the contribution of transverse momentum conservation, and all background effects independent on the reaction plane orientation, from an observable of chiral magnetic effect. It is argued that at a given impact parameter the magnetic field is approximately independent on the fluctuating shape of the produced fireball.

  8. Rolipram and SP600125 suppress the early increase in PTP1B expression during cerulein-induced pancreatitis in rats.

    Science.gov (United States)

    Sarmiento, Nancy; Sánchez-Bernal, Carmen; Pérez, Nieves; Sardina, José L; Mangas, Arturo; Calvo, José J; Sánchez-Yagüe, Jesús

    2010-07-01

    To analyze the expression modulation of pancreatic protein tyrosine phosphatase (PTP)1B during the development of cerulein (Cer)-induced acute pancreatitis (AP) and the effect of inhibition of type 4 phosphodiesterase and c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2 on its expression levels. Acute pancreatitis was induced in rats by subcutaneous injections of 20 microg Cer per kilogram body weight at hourly intervals, and the animals were killed at 2, 4, or 9 hours after the first injection. Neutropenia was induced with vinblastine sulfate. Phosphodiesterase and the mitogen-activated protein kinases were inhibited with rolipram and SP600125, respectively, before the induction of AP. Protein tyrosine phosphatase 1B increases its expression at the levels of both protein and messenger RNA during the early phase of Cer-induced AP. The increase in protein expression persisted along the development of the disease, and neutrophil infiltration seemed to play a central role. Rolipram and SP600125 pretreatments mostly suppressed the increase in the expression of PTP1B during the early phase of AP. Cerulein-induced AP is associated with an increase in the expression of PTP1B in its early phase. An increase in cyclic adenosine monophosphate levels in inflammatory cells and the inhibition of c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2 are able to suppress the increase in PTP1B protein level.

  9. Afatinib induces apoptosis in NSCLC without EGFR mutation through Elk-1-mediated suppression of CIP2A.

    Science.gov (United States)

    Chao, Ting-Ting; Wang, Cheng-Yi; Chen, Yen-Lin; Lai, Chih-Cheng; Chang, Fang-Yu; Tsai, Yi-Ting; Chao, Chung-Hao H; Shiau, Chung-Wai; Huang, Yuh-Chin T; Yu, Chong-Jen; Chen, Kuen-Feng

    2015-02-10

    Afatinib has anti-tumor effect in non-small cell lung carcinoma (NSCLC) with epidermal growth factor receptor (EGFR) mutation. We found afatinib can also induce apoptosis in NSCLC cells without EGFR mutation through CIP2A pathway. Four NSCLC cell lines (H358 H441 H460 and A549) were treated with afatinib to determine their sensitivity to afatinib-induced cell death and apoptosis. The effects of CIP2A on afatinib-induced apoptosis were confirmed by overexpression and knockdown of CIP2A expression in the sensitive and resistant cells, respectively. Reduction of Elk-1 binding to the CIP2A promoter and suppression of CIP2A transcription were analyzed. In vivo efficacy of afatinib against H358 and H460 xenografts tumors were also determined in nude mice. Afatinib induced significant cell death and apoptosis in H358 and H441 cells, but not in H460 or A549 cells. The apoptotic effect of afatinib in sensitive cells was associated with downregulation of CIP2A, promotion of PP2A activity and decrease in AKT phosphorylation. Afatinib suppressed CIP2A at the gene transcription level by reducing the promoter binding activity of Elk-1. Clinical samples showed that higher CIP2A expression predicted a poor prognosis and Elk-1 and CIP2A expressions were highly correlated. In conclusion, afatinib induces apoptosis in NSCLC without EGFR mutations through Elk-1/CIP2A/PP2A/AKT pathway.

  10. The naphthoquinone plumbagin suppresses ADP-induced rat platelet aggregation through P2Y1-PLC signaling pathway.

    Science.gov (United States)

    Zhang, Qianrui; Liao, Xiaoyan; Wu, Fangjian

    2017-03-01

    Plumbagin (PLB) isolated from Plumbago zeylanica L (Plumbaginaceae) was evaluated for the suppressive effect and mechanism on ADP induced rat platelet aggregation. Adult male SD rats were randomly divided into control group, clopidogrel group, PLB 25mg/kg group and PLB 50mg/kg group. Clopidogrel (13.5mg/kg per day) and PLB (25 and 50mg/kg per day) were orally given to experimental rats by gavage for seven consecutive days. The antiplatelet properties were assessed by measuring the ADP-induced platelet aggregation rate (Aggmax). The level of cAMP in platelets before aggregation was determined by ELISA. The protein expression of pAkt, Akt, pPLC β3 and PLC β3 in platelets was measured by western blot. Our data indicated that PLB (25 and 50mg/kg) significantly inhibited ADP-induced rat platelet aggregation as well as clopidogrel (13.5mg/kg) in a dose dependent manner compared with the control group. PLB (25 and 50mg/kg) remarkably reduced the ADP-induced PLC β3 phosphorylation but not Akt in platelets as compared with the control group. The present study suggests that PLB exerts a suppressive effect on ADP-induced rat platelet aggregation, at least in part, through P2Y1-PLC signaling pathway.

  11. Propolis suppresses CdCl₂-induced cytotoxicity of COS7 cells through the prevention of intracellular reactive oxygen species accumulation.

    Science.gov (United States)

    Kamiya, Tetsuro; Izumi, Misato; Hara, Hirokazu; Adachi, Tetsuo

    2012-01-01

    Propolis is a natural product made by honeybees and contains various compounds, including flavonoids, amino acids and fatty acids. These compounds are considered to have antiviral, antibacterial and antioxidative properties. On the other hand, cadmium (Cd), an industrial and environmental pollutant, preferentially accumulates in the kidney and induces kidney injury. We previously reported that exposure to CdCl₂ induced cell death though intracellular reactive oxygen species (ROS) generation in kidney tubule epithelial COS7 cells. Here, we investigated whether propolis extracts suppress CdCl₂-induced cytotoxicity. Predictably, pretreatment with propolis extracts significantly suppressed CdCl₂-induced cytotoxicity and intracellular ROS generation. Propolis extracts not only showed superoxide dismutase and antioxidative activities, but also increased the expression of heme oxygenase-1 (HO-1), an antioxidative enzyme. Moreover, we determined the involvement of hypoxia inducible factor-1α in propolis extract-derived HO-1 induction. We demonstrate for the first time the utility of propolis for Cd-related COS7 cytotoxicity, and these novel findings are considered to contribute to the control of ROS-derived disorders.

  12. Protocatechuic aldehyde attenuates cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation

    Directory of Open Access Journals (Sweden)

    Li Gao

    2016-12-01

    Full Text Available Cisplatin is a classic chemotherapeutic agent widely used to treat different types of cancers including ovarian, head and neck, testicular and uterine cervical carcinomas. However, cisplatin induces acute kidney injury by directly triggering an excessive inflammatory response, oxidative stress and programmed cell death of renal tubular epithelial cells. All of which lead to higher mortality rates in patients. In this study we examined the protective effect of protocatechuic aldehyde (PA in vitro in cisplatin-treated tubular epithelial cells and in vivo in cisplatin nephropathy. PA is a monomer of Traditional Chinese Medicine isolated from the root of S. miltiorrhiza. Results show that PA prevented cisplatin-induced decline of renal function and histological damage, which was confirmed by attenuation of KIM1 in both mRNA and protein levels. Moreover, PA reduced renal inflammation by suppressing oxidative stress and programmed cell death in response to cisplatin, which was further evidenced by in vitro data. Of note, PA suppressed NAPDH oxidases, including Nox2 and Nox4, in a dosage-dependent manner. Moreover, silencing Nox4, but not Nox2, removed the inhibitory effect of PA on cisplatin-induced renal injury, indicating that Nox4 may play a pivotal role in mediating the protective effect of PA in cisplatin-induced acute kidney injury. Collectively, our data indicate that PA largely blocked cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation without compromising anti-tumor activity of cisplatin. These findings suggest that PA and its derivatives may serve as potential protective agents for cancer patients with cisplatin treatment.

  13. Sitagliptin, An Anti-diabetic Drug, Suppresses Estrogen Deficiency-Induced OsteoporosisIn Vivo and Inhibits RANKL-Induced Osteoclast Formation and Bone Resorption In Vitro

    Directory of Open Access Journals (Sweden)

    Chuandong Wang

    2017-06-01

    Full Text Available Postmenopausal osteoporosis is a disease characterized by excessive osteoclastic bone resorption. Some anti-diabetic drugs were demonstrated for anti-osteoclastic bone-loss effects. The present study investigated the skeletal effects of chronic administration of sitagliptin, a dipeptidyl peptidase IV (DPP IV inhibitor that is increasingly used for type 2 diabetes treatments, in an estrogen deficiency-induced osteoporosis and elucidated the associated mechanisms. This study indicated that sitagliptin effectively prevented ovariectomy-induced bone loss and reduced osteoclast numbers in vivo. It was also indicated that sitagliptin suppressed receptor activator of nuclear factor-κB ligand (RANKL-mediated osteoclast differentiation, bone resorption, and F-actin ring formation in a manner of dose-dependence. In addition, sitagliptin significantly reduced the expression of osteoclast-specific markers in mouse bone-marrow-derived macrophages, including calcitonin receptor (Calcr, dendrite cell-specific transmembrane protein (Dc-stamp, c-Fos, and nuclear factor of activated T-cells cytoplasmic 1 (Nfatc1. Further study indicated that sitagliptin inhibited osteoclastogenesis by suppressing AKT and ERK signaling pathways, scavenging ROS activity, and suppressing the Ca2+ oscillation that consequently affects the expression and/or activity of the osteoclast-specific transcription factors, c-Fos and NFATc1. Collectively, these findings suggest that sitagliptin possesses beneficial effects on bone and the suppression of osteoclast number implies that the effect is exerted directly on osteoclastogenesis.

  14. Measurement of the profiles of disorder-induced localized resonances by local tuning

    CERN Document Server

    Lian, J; Yüce, E; Combrié, S; De Rossi, A; Mosk, A P; .,

    2016-01-01

    Near the band edge of photonic crystal waveguides, localized modes appear due to disorder. We demonstrate a new method to elucidate spatial profile of the localized modes in such systems using precise local tuning. Using deconvolution with the known thermal profile, the spatial profile of a localized mode with quality factor ($Q$) $>10^5$ is successfully reconstructed with a resolution of $2.5 \\ \\mu $m.

  15. In vivo evidence for CD4+ and CD8+ suppressor T cells in vaccination-induced suppression of murine experimental autoimmune thyroiditis

    Energy Technology Data Exchange (ETDEWEB)

    Flynn, J.C.; Kong, Y.C. (Wayne State University School of Medicine, Detroit, Michigan (USA))

    1991-09-01

    In several experimental autoimmune diseases, including experimental autoimmune thyroiditis (EAT), vaccination with attenuated autoantigen-specific T cells has provided protection against subsequent induction of disease. However, the mechanism(s) of vaccination-induced suppression remains to be clarified. Since the authors have previously shown that suppression generated by pretreatment with mouse thyroglobulin (MTg) or thyroid-stimulating hormone in EAT is mediated by CD4+, not CD8+, suppressor T cells, they examined the role of T cell subsets in vaccination-induced suppression of EAT. Mice were vaccinated with irradiated, MTg-primed, and MTg-activated spleen cells and then challenged. Pretreatment with these cells suppressed EAT induced by immunization with MTg and adjuvant, but not by adoptive transfer of thyroiditogenic cells, suggesting a mechanism of afferent suppression. The activation of suppressor mechanisms did not require CD8+ cells, since mice depleted of CD8+ cells before vaccination showed reduced EAT comparable to control vaccinated mice. Furthermore, depletion of either the CD4+ or the CD8+ subset after vaccination did not significantly abrogate suppression. However, suppression was eliminated by the depletion of both CD4+ and CD8+ cells in vaccinated mice. These results provide evidence for the cooperative effects of CD4+ and CD8+ T cells in vaccination-induced suppression of EAT.

  16. Overexpression of glutaredoxin protects cardiomyocytes against nitric oxide-induced apoptosis with suppressing the S-nitrosylation of proteins and nuclear translocation of GAPDH

    Energy Technology Data Exchange (ETDEWEB)

    Inadomi, Chiaki, E-mail: inadomic@nagasaki-u.ac.jp [Department of Anesthesiology, Nagasaki University School of Medicine, Nagasaki 852-8501 (Japan); Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523 (Japan); Murata, Hiroaki [Department of Anesthesiology, Nagasaki University School of Medicine, Nagasaki 852-8501 (Japan); Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523 (Japan); Ihara, Yoshito [Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523 (Japan); Department of Biochemistry, Wakayama Medical University, Wakayama 641-8509 (Japan); Goto, Shinji; Urata, Yoshishige [Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523 (Japan); Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523 (Japan); Yodoi, Junji [Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507 (Japan); Kondo, Takahito [Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523 (Japan); Sumikawa, Koji [Department of Anesthesiology, Nagasaki University School of Medicine, Nagasaki 852-8501 (Japan)

    2012-08-31

    Highlights: Black-Right-Pointing-Pointer GRX1 overexpression protects myocardiac H9c2 cells against NO-induced apoptosis. Black-Right-Pointing-Pointer NO-induced nuclear translocation of GAPDH is suppressed in GRX overexpressors. Black-Right-Pointing-Pointer Oxidation of GAPDH by NO is less in GRX overexpressors than in controls. -- Abstract: There is increasing evidence demonstrating that glutaredoxin 1 (GRX1), a cytosolic enzyme responsible for the catalysis of protein deglutathionylation, plays distinct roles in inflammation and apoptosis by inducing changes in the cellular redox system. In this study, we investigated whether and how the overexpression of GRX1 protects cardiomyocytes against nitric oxide (NO)-induced apoptosis. Cardiomyocytes (H9c2 cells) were transfected with the expression vector for mouse GRX1 cDNA, and mock-transfected cells were used as a control. Compared with the mock-transfected cells, the GRX1-transfected cells were more resistant to NO-induced apoptosis. Stimulation with NO significantly increased the nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a pro-apoptotic protein, in the mock-transfected cells, but did not change GAPDH localization in the GRX1-transfected cells. Furthermore, we found that NO stimulation clearly induced the oxidative modification of GAPDH in the mock-transfected cells, whereas less modification of GAPDH was observed in the GRX1-transfected cells. These data suggest that the overexpression of GRX1 could protect cardiomyocytes against NO-induced apoptosis, likely through the inhibition of the oxidative modification and the nuclear translocation of GAPDH.

  17. Offset-Control Attenuates Context Conditioning Induced by US-unpredictability in a Human Conditioned Suppression Paradigm

    Directory of Open Access Journals (Sweden)

    Ann Meulders

    2013-03-01

    Full Text Available We investigated whether offset-control of the unconditioned stimulus (US reduces context conditioning induced by US-unpredictability within a human conditioned suppression preparation. We also examined lack of control 'vs'. loss of control. Three groups (No Controllability, NC; Controllability, C; Loss of Controllability, LC received unsignaled USs during two learning phases (ACQ1-2. The NC group, never had offset-control, whereas the C group, always had offset-control. The LC group, had offset-control during ACQ1, but not during ACQ2. Results indicated that US-unpredictability led to contextual conditioned suppression during ACQ1, only when participants did not have offset-control; when they did, no context conditioning was established. From ACQ1 to ACQ2, contextual conditioned suppression increased in the LC group, but it was not more pronounced than in the NC group. These data suggest that offset-control attenuates context conditioning induced by US-unpredictability and – at least in this paradigm – loss of control is not worse than lack of control.

  18. Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model.

    Directory of Open Access Journals (Sweden)

    Mimi Cushman-Nick

    Full Text Available There are no effective therapeutics that antagonize or reverse the protein-misfolding events underpinning polyglutamine (PolyQ disorders, including Spinocerebellar Ataxia Type-3 (SCA3. Here, we augment the proteostasis network of Drosophila SCA3 models with Hsp104, a powerful protein disaggregase from yeast, which is bafflingly absent from metazoa. Hsp104 suppressed eye degeneration caused by a C-terminal ataxin-3 (MJD fragment containing the pathogenic expanded PolyQ tract, but unexpectedly enhanced aggregation and toxicity of full-length pathogenic MJD. Hsp104 suppressed toxicity of MJD variants lacking a portion of the N-terminal deubiquitylase domain and full-length MJD variants unable to engage polyubiquitin, indicating that MJD-ubiquitin interactions hinder protective Hsp104 modalities. Importantly, in staging experiments, Hsp104 suppressed toxicity of a C-terminal MJD fragment when expressed after the onset of PolyQ-induced degeneration, whereas Hsp70 was ineffective. Thus, we establish the first disaggregase or chaperone treatment administered after the onset of pathogenic protein-induced degeneration that mitigates disease progression.

  19. Inhibition of Emodin on LPS-induced Nitric Oxide Generation by Suppressing PLC-γ Phosphorylation in Rat Peritoneal Macrophages

    Institute of Scientific and Technical Information of China (English)

    WANG Xin-yu; CAI Shou-guang; WU Yi-fen; LI Jun-ying; YANG Wen-xiu; HU Fen

    2010-01-01

    Objective To investigate the inhibitory mechanism of emodin on lipopolysaccharide(LPS)-induced nitric oxide(NO)generation in rat peritoneal macrophages.Methods NO production and iNOS expression were measured through nitrite assay and Western blotting assay,respectively.NF-kB activity and nuclei P65 expression were estimated by dual-luciferase and Western blotting assay,respectively.Intracellular free Ca2+([Ca2+]i)was detected using the ratiometric fluorescent calcium indicator dye,Fura-2,and a microspectrofluorometer.PLC-γphosporylation was analyzed by Western blotting assay.Results First,emodin was found playing active roles in suppressing LPS-induced NF-kB activation in rat peritoneal macrophages.Second,emodin down-regulated transient[Ca2*]i and could increase in NF-kB upstream signal.Finally,emodin suppressed phosphorylation of PLC-γ by LPS stimulation in the upstream of[Ca2+]i.Conclusion Suppression of PLC-γ phosphorylation is involved in emodin inhibiting NO generation by LPS stimulation in rat peritoneal macrophages.

  20. Quercetin Induces Antiproliferative Activity Against Human Hepatocellular Carcinoma (HepG2) Cells by Suppressing Specificity Protein 1 (Sp1).

    Science.gov (United States)

    Lee, Ra Ham; Cho, Jin Hyoung; Jeon, Young-Joo; Bang, Woong; Cho, Jung-Jae; Choi, Nag-Jin; Seo, Kang Seok; Shim, Jung-Hyun; Chae, Jung-Il

    2015-02-01

    Preclinical Research Quercetin, found in red onions and red apple skin can induce apoptosis insome malignant cells. However, the apoptotic effect of quercetin in hepatocellular carcinoma HepG2 cells via regulation of specificity protein 1 (Sp1) has not been studied. Here, we demonstrated that quercetin decreased cell growth and induce apoptosis in HepG2 cells via suppression of Sp1 using 3-(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay, 4',6-diamidino-2-phenylindole (DAPI) staining, Annexin V, and Western blot analysis, an effect that was dose- and time-dependent manner. Treatment of HepG2 cells with quercetin reduced cell growth and induced apoptosis, followed by regulation of Sp1 and Sp1 regulatory protein. Taken together, the results suggest that quercetin can induce apoptotic cell death by regulating cell cycle and suppressing antiapoptotic proteins. Therefore, quercetin may be useful for cancer prevention. Drug Dev Res 76 : 9-16, 2015. © 2015 Wiley Periodicals, Inc.

  1. Histone deacetylase inhibitor valproic acid promotes the induction of pluripotency in mouse fibroblasts by suppressing reprogramming-induced senescence stress

    Energy Technology Data Exchange (ETDEWEB)

    Zhai, Yingying; Chen, Xi; Yu, Dehai [Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061 (China); Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304 (United States); Li, Tao [Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304 (United States); Cui, Jiuwei; Wang, Guanjun [Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061 (China); Hu, Ji-Fan, E-mail: jifan@stanford.edu [Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061 (China); Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304 (United States); Li, Wei, E-mail: jdyylw@163.com [Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061 (China)

    2015-09-10

    Histone deacetylase inhibitor valproic acid (VPA) has been used to increase the reprogramming efficiency of induced pluripotent stem cell (iPSC) from somatic cells, yet the specific molecular mechanisms underlying this effect is unknown. Here, we demonstrate that reprogramming with lentiviruses carrying the iPSC-inducing factors (Oct4-Sox2-Klf4-cMyc, OSKM) caused senescence in mouse fibroblasts, establishing a stress barrier for cell reprogramming. Administration of VPA protected cells from reprogramming-induced senescent stress. Using an in vitro pre-mature senescence model, we found that VPA treatment increased cell proliferation and inhibited apoptosis through the suppression of the p16/p21 pathway. In addition, VPA also inhibited the G2/M phase blockage derived from the senescence stress. These findings highlight the role of VPA in breaking the cell senescence barrier required for the induction of pluripotency. - Highlights: • Histone deacetylase inhibitor valproic acid enhances iPSC induction. • Valproic acid suppresses reprogramming-induced senescence stress. • Valproic acid downregulates the p16/p21 pathway in reprogramming. • This study demonstrates a new mechanistic role of valproic acid in enhancing reprogramming.

  2. Relief of delayed oxidative stress by ascorbic acid can suppress radiation-induced cellular senescence in mammalian fibroblast cells.

    Science.gov (United States)

    Kobashigawa, Shinko; Kashino, Genro; Mori, Hiromu; Watanabe, Masami

    2015-03-01

    Ionizing radiation-induced cellular senescence is thought to be caused by nuclear DNA damage that cannot be repaired. However, here we found that radiation induces delayed increase of intracellular oxidative stress after irradiation. We investigated whether the relief of delayed oxidative stress by ascorbic acid would suppress the radiation-induced cellular senescence in Syrian golden hamster embryo (SHE) cells. We observed that the level of oxidative stress was drastically increased soon after irradiation, then declined to the level in non-irradiated cells, and increased again with a peak on day 3 after irradiation. We found that the inductions of cellular senescence after X-irradiation were reduced along with suppression of the delayed induction of oxidative stress by treatment with ascorbic acid, but not when oxidative stress occurred immediately after irradiation. Moreover, treatment of ascorbic acid inhibited p53 accumulation at 3 days after irradiation. Our data suggested a delayed increase of intracellular oxidative stress levels plays an important role in the process of radiation-induced cellular senescence by p53 accumulation.

  3. Lyapunov-Based Control for Suppression of Wind-Induced Galloping in Suspension Bridges

    Directory of Open Access Journals (Sweden)

    Naif B. Almutairi

    2011-01-01

    Full Text Available This paper investigates the suppression of galloping in a suspension bridge due to wind loads. The galloping phenomenon can be destructive due to the high-amplitude oscillations of the structure. Two controllers are proposed to generate the control force needed to suppress the vertical galloping in the suspended cables and in the bridge deck. SIMULINK software is used to simulate the controlled system. The simulation results indicate that the proposed controllers work well. In addition, the performance of the system with the proposed controllers is compared to the performance of the system controlled with a tuned mass damper.

  4. E2/ER β inhibit ISO-induced cardiac cellular hypertrophy by suppressing Ca2+-calcineurin signaling.

    Science.gov (United States)

    Tsai, Cheng-Yen; Kuo, Wei-Wen; Shibu, Marthandam Asokan; Lin, Yueh-Min; Liu, Chien-Nam; Chen, Yi-Hui; Day, Cecilia-Hsuan; Shen, Chia-Yao; Viswanadha, Vijaya Padma; Huang, Chih-Yang

    2017-01-01

    Cardiovascular incidences are markedly higher in men than in pre-menstrual women. However, this advantage in women declines with aging and therefore can be correlated with the sex hormone 17β-Estradiol (E2) which is reported to protect heart cells by acting though estrogen receptors (ERs). In this study we have determined the effect of E2/ERβ against ISO induced cellular hypertrophy in H9c2 cardiomyoblast cells. The results confirm that ISO induced cardiac-hypertrophy by elevating the levels of hypertrophy associated proteins, ANP and BNP and further by upregulating p-CaMKII, calcineurin, p-GATA4 and NFATc3 which was correlated with a significant enlargement of the H9c2 cardiomyoblast. However, overexpression of ERβ and/or administration of E2 inhibited ISO-induced hypertrophy in H9c2 cells. In addition, E2/ERβ also inhibited ISO-induced NFATc3 translocation, and reduced the protein level of downstream marker, BNP. Furthermore, by testing with the calcineurin inhibitor (CsA), it was confirmed that calcineurin acted as a key mediator for the anti-hypertrophic effect of E2/ERβ. In cells treated with calcium blocker (BATPA), the inhibitory effect of E2/ERβ on ISO-induced Ca2+ influx and hypertrophic effects were totally blocked suggesting that E2/ERβ inhibited calcineurin activity to activate I-1 protein and suppress PP1, then induce PLB protein phosphorylation and activation, resulting in Ca2+ reuptake into sarcoplasmic reticulum through SR Ca2+ cycling modification. In conclusion, E2/ERβ suppresses the Ca2+ influx and calcineurin activity induced by ISO to enhance the PLB protein activity and SR Ca2+ cycling.

  5. Purely nonlinear disorder-induced localizations and their parametric amplification

    CERN Document Server

    Folli, Viola; Conti, Claudio

    2013-01-01

    We investigate spatial localization in a quadratic nonlinear medium in the presence of randomness. By means of numerical simulations and theoretical analyses we show that, in the down conversion regime, the transverse random modulation of the nonlinear susceptibility generates localizations of the fundamental wave that grow exponentially in propagation. The localization length is optically controlled by the pump intensity which determines the amplification rate. The results also apply to cubic nonlinearities.

  6. Regulation of Wnt signaling activity for growth suppression induced by quercetin in 4T1 murine mammary cancer cells.

    Science.gov (United States)

    Kim, Haesung; Seo, Eun-Min; Sharma, Ashish R; Ganbold, Bilguun; Park, Jongbong; Sharma, Garima; Kang, Young-Hee; Song, Dong-Keun; Lee, Sang-Soo; Nam, Ju-Suk

    2013-10-01

    Quercetin is a promising chemopreventive agent against cancer that inhibits tumor progression by inducing cell cycle arrest and promoting apoptotic cell death. Recently, the Wnt/β-catenin signaling pathway has been implicated in mammary tumorigenesis, where its abnormal activation is associated with the development of breast cancer. Thus, the objective of this study was to examine the biological activities of quercetin against mammary cancer cells, and to determine whether quercetin could regulate the Wnt/β-catenin signaling pathway. Quercetin showed dose-dependent inhibition of cell growth and induced apoptosis in 4T1 cells. Treatment of 20 µM quercetin suppressed ~50% of basal TopFlash luciferase activity. Moreover, the inhibitory effect of quercetin on the Wnt/β-catenin signaling pathway was confirmed by the reduced stabilization of the β-catenin protein. Among various antagonists screened for the Wnt/β-catenin signaling pathway, the expression of DKK1, 2 and 3 was induced after treatment with 20 µM of quercetin. Stimulation with recombinant DKK1 protein, showed suppressive cell growth of mammary cancer cells instead of quercetin. When 4T1 cells were treated with recombinant Wnt3a or LiCl along with quercetin, both stimulators for the Wnt/β-catenin signaling pathway were able to restore the suppressed cell viability by quercetin. Thus, our data suggest that quercetin exerts its anticancer activity through the downregulation of Wnt/β-catenin signaling activity. These results indicate for the first time that quercetin decreases cell viability and induces apoptosis in murine mammary cancer cells, which is possibly mediated by DKK-dependent inhibition of the Wnt/β-catenin signaling pathway. In conclusion, our findings suggest that quercetin has great potential value as chemotherapeutic agent for cancer treatment, especially in breast cancer controlled by Wnt/β-catenin signaling activity.

  7. Leptin Induces Hippocampal Synaptogenesis via CREB-Regulated MicroRNA-132 Suppression of p250GAP

    Science.gov (United States)

    Dhar, Matasha; Zhu, Mingyan; Impey, Soren; Lambert, Talley J.; Bland, Tyler; Karatsoreos, Ilia N.; Nakazawa, Takanobu

    2014-01-01

    Leptin acts in the hippocampus to enhance cognition and reduce depression and anxiety. Cognitive and emotional disorders are associated with abnormal hippocampal dendritic spine formation and synaptogenesis. Although leptin has been shown to induce synaptogenesis in the hypothalamus, its effects on hippocampal synaptogenesis and the mechanism(s) involved are not well understood. Here we show that leptin receptors (LepRs) are critical for hippocampal dendritic spine formation in vivo because db/db mice lacking the long form of the leptin receptor (LepRb) have reduced spine density on CA1 and CA3 neurons. Leptin promotes the formation of mature spines and functional glutamate synapses on hippocampal pyramidal neurons in both dissociated and slice cultures. These effects are blocked by short hairpin RNAs specifically targeting the LepRb and are absent in cultures from db/db mice. Activation of the LepR leads to cAMP response element–binding protein (CREB) phosphorylation and initiation of CREB-dependent transcription via the MAPK kinase/Erk pathway. Furthermore, both Mek/Erk and CREB activation are required for leptin-induced synaptogenesis. Leptin also increases expression of microRNA-132 (miR132), a well-known CREB target, which is also required for leptin-induced synaptogenesis. Last, leptin suppresses the expression of p250GAP, a miR132 target, and this suppression is obligatory for leptin's effects as is the downstream target of p250GAP, Rac1. LepRs appear to be critical in vivo as db/db mice have lowered hippocampal miR132 levels and elevated p250GAP expression. In conclusion, we identify a novel signaling pathway by which leptin increases synaptogenesis through inducing CREB transcription and increasing microRNA-mediated suppression of p250GAP activity, thus removing a known inhibitor of Rac1-stimulated synaptogenesis. PMID:24877561

  8. Influenza A (H3N2-induced rhabdomyolysis complicating anterior compartment syndrome: Serial changes in muscle MRI T2 fat suppression imaging

    Directory of Open Access Journals (Sweden)

    Tadanori Hamano

    2017-06-01

    Conclusions: Muscle MRI T2 fat suppression imaging is a useful method to monitor influenza A induced rhabdomyolysis. We should keep in mind the possibilities of rhabdomyolysis and ACS in patients with influenza A infection presenting serious muscle pain.

  9. Suppression of a Brownian noise in a hole-type sensor due to induced-charge electro-osmosis

    Science.gov (United States)

    Sugioka, Hideyuki

    2016-03-01

    Noise reduction is essential for a single molecular sensor. Thus, we propose a novel noise reduction mechanism using a hydrodynamic force due to induced-charge electro-osmosis (ICEO) in a hole-type sensor and numerically examine the performance. By the boundary element method that considers both a Brownian motion and an ICEO flow of a polarizable particle, we find that the Brownian noise in a current signal is suppressed significantly in a converging channel because of the ICEO flow around the particle in the presence of an electric field. Further, we propose a simple model that explains a numerically obtained threshold voltage of the suppression of the Brownian noise due to ICEO. We believe that our findings contribute greatly to developments of a single molecular sensor.

  10. T cell subset distribution in HIV-1 infected patients after 12 years of treatment induced viraemic suppression

    DEFF Research Database (Denmark)

    Rönsholt, Frederikke F; Ullum, Henrik; Katzenstein, Terese L;

    2012-01-01

    OBJECTIVE:: Residual immune activation and skewed T cell maturation may contribute to excess comorbidity and mortality in successfully treated HIV infected patients and long term effects of combination antiretroviral therapy (cART) on immune reconstitution remain a debated issue. We investigated...... quantitative T cell reconstitution and activation and its association to residual viraemia in patients with 12 years of viraemic suppression. DESIGN:: Blood samples collected cross-sectionally from 71 HIV infected patients with cART induced viraemic suppression through 12 years were compared to samples from 16...... healthy controls. METHODS:: Several different subsets of naïve, memory and activated T cells were analyzed in fresh whole blood by 6-color flowcytometry and ultra sensitive quantification of HIV RNA was performed. RESULTS:: HIV-infected patients (HIV+) had lower absolute and relative CD4 T cell counts...

  11. Suppressive effect of mitragynine on the 5-methoxy-N,N-dimethyltryptamine-induced head-twitch response in mice.

    Science.gov (United States)

    Matsumoto, K; Mizowaki, M; Takayama, H; Sakai, S; Aimi, N; Watanabe, H

    1997-01-01

    We investigated the effects of mitragynine, a major alkaloid isolated from the leaves of Mitragyna speciosa Korth (Rubiaceae), on the 5-HT2A receptor-mediated head-twitch response in mice. Intraperitoneal injection of mitragynine (5-30 mg/kg), as well as intraperitoneal injection of 5-HT2A receptor antagonist ritanserin, inhibited the 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT: 16 mg/kg, IP)-induced head-twitch response in a dose-dependent manner. In contrast, mitragynine affected neither head-weaving caused by 5-MeO-DMT, nor drug-free spontaneous motor activity. Pretreatment of mice with reserpine (5 mg/kg, IP), p-chlorophenylalanine (p-CPA, 300 mg/kg x 3 times, IP), or 6-hydroxydopamine (6-OHDA, 50 micrograms/mouse, ICV) plus nomifensine (5 mg/kg, IP) did not change the suppressant effect of mitragynine on the head-twitch response caused by 5-MeO-DMT. On the other hand, the alpha 2-adrenoceptor antagonists yohimbine (0.5 mg/kg, IP), and idazoxan (0.2 mg/kg, IP), significantly attenuated the suppressant effect of mitragynine. Lesion of central noradrenergic systems by 6-OHDA plus nomifensine did not alter the effect of idazoxan (0.2 mg/kg) on mitragynine-induced suppression of the head-twitch response. These results indicate that stimulation of postsynaptic alpha 2-adrenoceptor, blockade of 5-HT2A receptors, or both, are involved in suppression of 5-HT2A receptor-mediated head-twitch response by mitragynine.

  12. Induced systemic resistance in Arabidopsis against Pseudomonas syringae pv. tomato by disease suppressive soils

    Science.gov (United States)

    Two-week-old Arabidopsis thaliana ecotype Col-0 seedlings were transferred into an autoclaved sand-soil mixture amended with 10% or 20% (weight/weight) soil that is suppressive to either take-all or Rhizoctonia root rot of wheat from fields in Washington State USA. These soils contain population siz...

  13. Mosquito and Drosophila entomobirnaviruses suppress dsRNA- and siRNA-induced RNAi

    NARCIS (Netherlands)

    Cleef, van K.W.R.; Mierlo, van J.T.; Miesen, P.; Overheul, G.J.; Fros, J.J.; Schuster, S.; Marklewitz, M.; Pijlman, G.P.; Junglen, S.; Rij, van R.P.

    2014-01-01

    RNA interference (RNAi) is a crucial antiviral defense mechanism in insects, including the major mosquito species that transmit important human viruses. To counteract the potent antiviral RNAi pathway, insect viruses encode RNAi suppressors. However, whether mosquito-specific viruses suppress RNAi r

  14. Identification by Suppression Subtractive Hybridization of Frankia Genes Induced under Nitrogen-Fixing Conditions▿ †

    OpenAIRE

    Yamaura, Masatoshi; UCHIUMI, Toshiki; Higashi, Shiro; Abe, Mikiko; Kucho, Ken-ichi

    2010-01-01

    Frankia is an actinobacterium that fixes nitrogen under both symbiotic and free-living conditions. We identified genes upregulated in free-living nitrogen-fixing cells by using suppression subtractive hybridization. They included genes with predicted functions related to nitrogen fixation, as well as with unknown function. Their upregulation was a novel finding in Frankia.

  15. Mosquito and Drosophila entomobirnaviruses suppress dsRNA- and siRNA-induced RNAi

    NARCIS (Netherlands)

    Cleef, K.W. van; Mierlo, J.T. van; Miesen, P.; Overheul, G.J.; Fros, J.J.; Schuster, S.; Marklewitz, M.; Pijlman, G.P.; Junglen, S.; Rij, R.P. van

    2014-01-01

    RNA interference (RNAi) is a crucial antiviral defense mechanism in insects, including the major mosquito species that transmit important human viruses. To counteract the potent antiviral RNAi pathway, insect viruses encode RNAi suppressors. However, whether mosquito-specific viruses suppress RNAi r

  16. Mitochondria localization and dimerization are required for CIDE-B to induce apoptosis.

    Science.gov (United States)

    Chen, Z; Guo, K; Toh, S Y; Zhou, Z; Li, P

    2000-07-28

    Cell death-inducing DFF45-like effector (CIDE)-B is a member of the novel family of apoptosis-inducing factors that share homology with the N-terminal region of DFF, the DNA fragmentation factor. The molecular mechanism of CIDE-B-induced apoptosis is unclear. We have shown here that CIDE-B protein is localized in mitochondria and forms homodimers and heterodimers with other family members. Serial deletion analyses suggest that the mitochondria localization signal and dimerization interface are overlapped and localized to the 30 amino acid residues at the C-terminal region of CIDE-B. Mitochondria localization and dimerization are both required for CIDE-B-induced apoptosis. Our study has thus revealed a mechanism for CIDE-B-induced apoptosis by localization to mitochondria and the formation of a high affinity homo- or heterodimeric complex.

  17. Cryptotanshinone inhibits TNF-α-induced LOX-1 expression by suppressing reactive oxygen species (ROS) formation in endothelial cells.

    Science.gov (United States)

    Ran, Xiaoli; Zhao, Wenwen; Li, Wenping; Shi, Jingshan; Chen, Xiuping

    2016-07-01

    Cryptotanshinone (CPT) is a natural compound isolated from traditional Chinese medicine Salvia miltiorrhiza Bunge. In the present study, the regulatory effect and potential mechanisms of CPT on tumor necrosis factor alpha (TNF-α) induced lectin-like receptor for oxidized low density lipoprotein (LOX-1) were investigated. Human umbilical vein endothelial cells (HUVECs) were cultured and the effect of TNF-α on LOX-1 expression at mRNA and protein levels was determined by Real-time PCR and Western blotting respectively. The formation of intracellular ROS was determined with fluorescence probe CM-DCFH2-DA. The endothelial ox-LDL uptake was evaluated with DiI-ox-LDL. The effect of CPT on LOX-1 expression was also evaluated with SD rats. TNF-α induced LOX-1 expression in a dose- and time-dependent manner in endothelial cells. TNF-α induced ROS formation, phosphorylation of NF-κB p65 and ERK, and LOX-1 expression, which were suppressed by rotenone, DPI, NAC, and CPT. NF-κB inhibitor BAY11-7082 and ERK inhibitor PD98059 inhibited TNF-α-induced LOX-1 expression. CPT and NAC suppressed TNF-α-induced LOX-1 expression and phosphorylation of NF-κB p65 and ERK in rat aorta. These data suggested that TNF-α induced LOX-1 expression via ROS activated NF-κB/ERK pathway, which could be inhibited by CPT. This study provides new insights for the anti-atherosclerotic effect of CPT.

  18. Discussion of dosimetric dependencies of experimental light-induced melatonin suppression studies; Diskussion dosimetrischer Aspekte bei experimentellen Studien zur lichtinduzierten Melatoninreduktion

    Energy Technology Data Exchange (ETDEWEB)

    Weber, M.; Schulmeister, K. [ARC Seibersdorf Research (Austria). Akkreditierte Pruefstelle fuer Laser und Optische Strahlung

    2004-07-01

    Based on a literature review, dosimetric dependencies of light-induced melatonin suppression are discussed. The quantity of light used to suppress melatonin in study trials is often given in terms of illuminance at the cornea, as this is easy to measure. The use of the term illuminance for such studies is critically discussed. A more appropriate measure would be effective irradiance. In our work we present a simplified model to estimate the photobiological effective irradiance and the spot size of the retinal image. Important issues which should ideally be considered in melatonin suppression study trials are pointed out. Another aim of this work is to derive from the literature data, up to what time frame the dosedependent relationship between time and melatonin suppression is valid. An evaluation is made of the situation on the workplace with regard to light-induced melatonin suppression. (orig.)

  19. An Allergic Lung Microenvironment Suppresses Carbon Nanotube-Induced Inflammasome Activation via STAT6-Dependent Inhibition of Caspase-1.

    Directory of Open Access Journals (Sweden)

    Kelly A Shipkowski

    Full Text Available Multi-walled carbon nanotubes (MWCNTs represent a human health risk as mice exposed by inhalation display pulmonary fibrosis. Production of IL-1β via inflammasome activation is a mechanism of MWCNT-induced acute inflammation and has been implicated in chronic fibrogenesis. Mice sensitized to allergens have elevated T-helper 2 (Th2 cytokines, IL-4 and IL-13, and are susceptible to MWCNT-induced airway fibrosis. We postulated that Th2 cytokines would modulate MWCNT-induced inflammasome activation and IL-1β release in vitro and in vivo during allergic inflammation.THP-1 macrophages were primed with LPS, exposed to MWCNTs and/or IL-4 or IL-13 for 24 hours, and analyzed for indicators of inflammasome activation. C57BL6 mice were sensitized to house dust mite (HDM allergen and MWCNTs were delivered to the lungs by oropharyngeal aspiration. Mice were euthanized 1 or 21 days post-MWCNT exposure and evaluated for lung inflammasome components and allergic inflammatory responses.Priming of THP-1 macrophages with LPS increased pro-IL-1β and subsequent exposure to MWCNTs induced IL-1β secretion. IL-4 or IL-13 decreased MWCNT-induced IL-1β secretion by THP-1 cells and reduced pro-caspase-1 but not pro-IL-1β. Treatment of THP-1 cells with STAT6 inhibitors, either Leflunomide or JAK I inhibitor, blocked suppression of caspase activity by IL-4 and IL-13. In vivo, MWCNTs alone caused neutrophilic infiltration into the lungs of mice 1 day post-exposure and increased IL-1β in bronchoalveolar lavage fluid (BALF and pro-caspase-1 immuno-staining in macrophages and airway epithelium. HDM sensitization alone caused eosinophilic inflammation with increased IL-13. MWCNT exposure after HDM sensitization increased total cell numbers in BALF, but decreased numbers of neutrophils and IL-1β in BALF as well as reduced pro-caspase-1 in lung tissue. Despite reduced IL-1β mice exposed to MWCNTs after HDM developed more severe airway fibrosis by 21 days and had increased

  20. An Allergic Lung Microenvironment Suppresses Carbon Nanotube-Induced Inflammasome Activation via STAT6-Dependent Inhibition of Caspase-1

    Science.gov (United States)

    Shipkowski, Kelly A.; Taylor, Alexia J.; Thompson, Elizabeth A.; Glista-Baker, Ellen E.; Sayers, Brian C.; Messenger, Zachary J.; Bauer, Rebecca N.; Jaspers, Ilona; Bonner, James C.

    2015-01-01

    Background Multi-walled carbon nanotubes (MWCNTs) represent a human health risk as mice exposed by inhalation display pulmonary fibrosis. Production of IL-1β via inflammasome activation is a mechanism of MWCNT-induced acute inflammation and has been implicated in chronic fibrogenesis. Mice sensitized to allergens have elevated T-helper 2 (Th2) cytokines, IL-4 and IL-13, and are susceptible to MWCNT-induced airway fibrosis. We postulated that Th2 cytokines would modulate MWCNT-induced inflammasome activation and IL-1β release in vitro and in vivo during allergic inflammation. Methods THP-1 macrophages were primed with LPS, exposed to MWCNTs and/or IL-4 or IL-13 for 24 hours, and analyzed for indicators of inflammasome activation. C57BL6 mice were sensitized to house dust mite (HDM) allergen and MWCNTs were delivered to the lungs by oropharyngeal aspiration. Mice were euthanized 1 or 21 days post-MWCNT exposure and evaluated for lung inflammasome components and allergic inflammatory responses. Results Priming of THP-1 macrophages with LPS increased pro-IL-1β and subsequent exposure to MWCNTs induced IL-1β secretion. IL-4 or IL-13 decreased MWCNT-induced IL-1β secretion by THP-1 cells and reduced pro-caspase-1 but not pro-IL-1β. Treatment of THP-1 cells with STAT6 inhibitors, either Leflunomide or JAK I inhibitor, blocked suppression of caspase activity by IL-4 and IL-13. In vivo, MWCNTs alone caused neutrophilic infiltration into the lungs of mice 1 day post-exposure and increased IL-1β in bronchoalveolar lavage fluid (BALF) and pro-caspase-1 immuno-staining in macrophages and airway epithelium. HDM sensitization alone caused eosinophilic inflammation with increased IL-13. MWCNT exposure after HDM sensitization increased total cell numbers in BALF, but decreased numbers of neutrophils and IL-1β in BALF as well as reduced pro-caspase-1 in lung tissue. Despite reduced IL-1β mice exposed to MWCNTs after HDM developed more severe airway fibrosis by 21 days and

  1. Dexamethasone but not tacrolimus suppresses TNF-α-induced thymic stromal lymphopoietin expression in lesional keratinocytes of atopic dermatitis model.

    Science.gov (United States)

    Mizuno, Kazuko; Morizane, Shin; Takiguchi, Tetsuya; Iwatsuki, Keiji

    2015-10-01

    Thymic stromal lymphopoietin (TSLP) initiates the Th2-type allergic inflammation, and is thought to play an important role in the pathogenesis of atopic dermatitis (AD). TNF-α is a key cytokine which is involved in the pathophysiology of various inflammatory diseases, and the expression level is elevated in the sera and skin of patients with AD. In addition, TNF-α has been reported to induce TSLP expression in epidermal keratinocytes. Topical glucocorticoids and calcineurin inhibitors are safe and effective agents for AD, but the effects of these agents on TNF-α-induced TSLP expression are not fully understood. To investigate whether the glucocorticosteroid dexamethasone and the calcineurin inhibitor tacrolimus could affect TSLP expression induced by TNF-α in lesional keratinocytes of AD. The effects of topical dexamethasone and tacrolimus on TSLP expression were evaluated in an AD mouse model induced by repeated 2,4,6-trinitro-1-chlorobenzene application. Co-immunostaining for TSLP and TNF-α was performed using skin samples from AD patients and the mouse model. Normal human epidermal keratinocytes (NHEKs) were cultured with dexamethasone or tacrolimus in the presence of TNF-α to analyze TSLP expression. Topical application of dexamethasone but not tacrolimus repressed TSLP expression in the mouse model. TSLP and TNF-α showed similar distribution pattern in epidermal keratinocytes of AD lesions and the mouse model. TSLP expression was induced by TNF-α via NF-κB in a dose-dependent and an autocrine and/or paracrine manner in NHEKs, which was significantly suppressed by dexamethasone but not by tacrolimus. Similarly to TSLP expression, IL-6, TNF-α, IL-8, and IL-36γ expression induced by TNF-α were significantly suppressed by dexamethasone but not by tacrolimus in NHEKs. Dexamethasone but not tacrolimus suppresses the TSLP expression induced by TNF-α in lesional keratinocytes of AD model. Our observations uncover the unreported functional difference

  2. Progesterone Receptor Membrane Component 1 Mediates Progesterone-Induced Suppression of Oocyte Meiotic Prophase I and Primordial Folliculogenesis.

    Science.gov (United States)

    Guo, Meng; Zhang, Cheng; Wang, Yan; Feng, Lizhao; Wang, Zhengpin; Niu, Wanbo; Du, Xiaoyan; Tang, Wang; Li, Yuna; Wang, Chao; Chen, Zhenwen

    2016-11-16

    Well-timed progression of primordial folliculogenesis is essential for mammalian female fertility. Progesterone (P4) inhibits primordial follicle formation under physiological conditions; however, P4 receptor that mediates this effect and its underlying mechanisms are unclear. In this study, we used an in vitro organ culture system to show that progesterone receptor membrane component 1 (PGRMC1) mediated P4-induced inhibition of oocyte meiotic prophase I and primordial follicle formation. We found that membrane-impermeable BSA-conjugated P4 inhibited primordial follicle formation similar to that by P4. Interestingly, PGRMC1 and its partner serpine1 mRNA-binding protein 1 were highly expressed in oocytes in perinatal ovaries. Inhibition or RNA interference of PGRMC1 abolished the suppressive effect of P4 on follicle formation. Furthermore, P4-PGRMC1 interaction blocked oocyte meiotic progression and decreased intra-oocyte cyclic AMP (cAMP) levels in perinatal ovaries. cAMP analog dibutyryl cAMP reversed P4-PGRMC1 interaction-induced inhibition of meiotic progression and follicle formation. Thus, our results indicated that PGRMC1 mediated P4-induced suppression of oocyte meiotic progression and primordial folliculogenesis by decreasing intra-oocyte cAMP levels.

  3. Harpagoside suppresses lipopolysaccharide-induced iNOS and COX-2 expression through inhibition of NF-kappa B activation.

    Science.gov (United States)

    Huang, Tom Hsun-Wei; Tran, Van H; Duke, Rujee K; Tan, Sharon; Chrubasik, Sigrun; Roufogalis, Basil D; Duke, Colin C

    2006-03-08

    Preparations of Harpagophytum procumbens, known as devil's claw, are used as an adjunctive therapy for the treatment of pain and osteoarthritis. Pharmacological evaluations have proven the effectiveness of this herbal drug as an anti-inflammatory and analgesic agent. The present study has investigated the mechanism of action of harpagoside, one of the major components of Harpagophytum procumbens, using human HepG2 hepatocarcinoma and RAW 264.7 macrophage cell lines. Harpagoside inhibited lipopolysaccharide-induced mRNA levels and protein expression of cyclooxygenase-2 and inducible nitric oxide in HepG2 cells. These inhibitions appeared to correlate with the suppression of NF-kappaB activation by harpagoside, as pre-treating cells with harpagoside blocked the translocation of NF-kappaB into the nuclear compartments and degradation of the inhibitory subunit IkappaB-alpha. Furthermore, harpagoside dose-dependently inhibited LPS-stimulated NF-kappaB promoter activity in a gene reporter assay in RAW 264.7 cells, indicating that harpagoside interfered with the activation of gene transcription. These results suggest that the inhibition of the expression of cyclooxygenase-2 and inducible nitric oxide by harpagoside involves suppression of NF-kappaB activation, thereby inhibiting downstream inflammation and subsequent pain events.

  4. Suppression of Aggrus/podoplanin-induced platelet aggregation and pulmonary metastasis by a single-chain antibody variable region fragment.

    Science.gov (United States)

    Miyata, Kenichi; Takagi, Satoshi; Sato, Shigeo; Morioka, Hiroshi; Shiba, Kiyotaka; Minamisawa, Tamiko; Takami, Miho; Fujita, Naoya

    2014-12-01

    Almost all highly metastatic tumor cells possess high platelet aggregating abilities, thereby form large tumor cell-platelet aggregates in the microvasculature. Embolization of tumor cells in the microvasculature is considered to be the first step in metastasis to distant organs. We previously identified the platelet aggregation-inducing factor expressed on the surfaces of highly metastatic tumor cells and named as Aggrus. Aggrus was observed to be identical to the marker protein podoplanin (alternative names, T1α, OTS-8, and others). Aggrus is frequently overexpressed in several types of tumors and enhances platelet aggregation by interacting with the platelet receptor C-type lectin-like receptor 2 (CLEC-2). Here, we generated a novel single-chain antibody variable region fragment (scFv) by linking the variable regions of heavy and light chains of the neutralizing anti-human Aggrus monoclonal antibody MS-1 with a flexible peptide linker. Unfortunately, the generated KM10 scFv failed to suppress Aggrus-induced platelet aggregation in vitro. Therefore, we performed phage display screening and finally obtained a high-affinity scFv, K-11. K-11 scFv was able to suppress Aggrus-induced platelet aggregation in vitro. Moreover, K-11 scFv prevented the formation of pulmonary metastasis in vivo. These results suggest that K-11 scFv may be useful as metastasis inhibitory scFv and is expected to aid in the development of preclinical and clinical examinations of Aggrus-targeted cancer therapies.

  5. Reversal of High dietary fructose-induced PPARα suppression by oral administration of lipoxygenase/cyclooxygenase inhibitors

    Directory of Open Access Journals (Sweden)

    Azhar Salman

    2005-08-01

    Full Text Available Abstract High fructose feeding causes diet-induced alterations of lipid metabolism and decreased insulin sensitivity, hallmark of which is a rapid and profound hypertriglyceridemia. One of the mechanisms that contribute to serum hypertriglyceridemia in this model is suppression of hepatic PPARα. HMG-CoA inhibitors, which reduce serum triglycerides in these animals, also elevate/restore hepatic PPARα. Previously we demonstrated that two known lipoxygenase/cyclooxygenase inhibitors reversed diet-induced hypertriglyceridemia in this model and that reversal of certain inflammatory markers in the liver correlated with the metabolic benefit. In this paper we extended these studies by examining the impact of these compounds on expression of PPARα, both at the level of transcription and expression. Our data show that diet-induced suppression of hepaic PPARα is reversed upon treatment with lipoxygenase/cyclooxygenase compounds. We then tested one of these compounds, BW-755c, over a range of doses from 10 mg/kg to 100 mg/kg to establish a dose-response relationship with the reduction of serum hypertriglyceridemia in this model. These experiments support the concept of using anti-inflammatory medications as one method to correct metabolic dysfunction.

  6. Localized microstructures induced by fluid flow in directional solidification.

    Science.gov (United States)

    Jamgotchian, H; Bergeon, N; Benielli, D; Voge, P; Billia, B; Guérin, R

    2001-10-15

    The dynamical process of microstructure localization by multiscale interaction between instabilities is uncovered in directional solidification of transparent alloy. As predicted by Chen and Davis, morphological instability of the interface is observed at inward flow-stagnation regions of the cellular convective field. Depending on the driving force of fluid flow, focus-type and honeycomb-type localized patterns form in the initial transient of solidification, that then evolves with time. In the case of solute-driven flow, the analysis of the onset of thermosolutal convection in initial transient of solidification enables a complete understanding of the dynamics and of the localization of morphological instability.

  7. Vasoconstriction Potency Induced by Aminoamide Local Anesthetics Correlates with Lipid Solubility

    Directory of Open Access Journals (Sweden)

    Hui-Jin Sung

    2012-01-01

    Full Text Available Aminoamide local anesthetics induce vasoconstriction in vivo and in vitro. The goals of this in vitro study were to investigate the potency of local anesthetic-induced vasoconstriction and to identify the physicochemical property (octanol/buffer partition coefficient, pKa, molecular weight, or potency of local anesthetics that determines their potency in inducing isolated rat aortic ring contraction. Cumulative concentration-response curves to local anesthetics (levobupivacaine, ropivacaine, lidocaine, and mepivacaine were obtained from isolated rat aorta. Regression analyses were performed to determine the relationship between the reported physicochemical properties of local anesthetics and the local anesthetic concentration that produced 50% (ED50 of the local anesthetic-induced maximum vasoconstriction. We determined the order of potency (ED50 of vasoconstriction among local anesthetics to be levobupivacaine > ropivacaine > lidocaine > mepivacaine. The relative importance of the independent variables that affect the vasoconstriction potency is octanol/buffer partition coefficient > potency > pKa > molecular weight. The ED50 in endothelium-denuded aorta negatively correlated with the octanol/buffer partition coefficient of local anesthetics (r2=0.9563; P<0.001. The potency of the vasoconstriction in the endothelium-denuded aorta induced by local anesthetics is determined primarily by lipid solubility and, in part, by other physicochemical properties including potency and pKa.

  8. Cyanidin Chloride Inhibits Ovariectomy-Induced Osteoporosis by Suppressing RANKL-mediated Osteoclastogenesis and Associated Signaling Pathways.

    Science.gov (United States)

    Cheng, Jianwen; Zhou, Lin; Liu, Qian; Tickner, Jennifer; Tan, Zhen; Li, Xiaofeng; Liu, Mei; Lin, Xixi; Wang, Tao; Pavlos, Nathan J; Zhao, Jinmin; Xu, Jiake

    2017-08-03

    Over-production and activation of osteoclasts is a common feature of osteolytic conditions such as osteoporosis, tumor-associated osteolysis, and inflammatory bone erosion. Cyanidin Chloride, a subclass of anthocyanin, displays antioxidant and anti-carcinogenesis properties, but its role in osteoclastic bone resorption and osteoporosis is not well understood. In this study, we showed that Cyanidin Chloride inhibits osteoclast formation, hydroxyapatite resorption, and receptor activator of NF-κB ligand (RANKL)-induced osteoclast marker gene expression; including ctr, ctsk and trap. Further investigation revealed that Cyanidin Chloride inhibits RANKL-induced NF-κB activation, suppresses the degradation of IκB-α and attenuates the phosphorylation of extracellular signal-regulated kinases (ERK). In addition, Cyanidin Chloride abrogated RANKL-induced calcium oscillations, the activation of nuclear factor of activated T cells calcineurin-dependent 1 (NFATc1), and the expression of c-Fos. Further, we showed that Cyanidin Chloride protects against ovariectomy-induced bone loss in vivo. Together our findings suggest that Cyanidin Chloride is capable of inhibiting osteoclast formation, hydroxyapatite resorption and RANKL-induced signal pathways in vitro and OVX-induced bone loss in vivo, and thus might have therapeutic potential for osteolytic diseases. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  9. Pentoxifylline Attenuates Methionine- and Choline-Deficient-Diet-Induced Steatohepatitis by Suppressing TNF-α Expression and Endoplasmic Reticulum Stress

    Directory of Open Access Journals (Sweden)

    Min Kyung Chae

    2012-01-01

    Full Text Available Background. Pentoxifylline (PTX anti-TNF properties are known to exert hepatoprotective effects in various liver injury models. The aim of this study was to investigate whether PTX has beneficial roles in the development of methionine- and choline-deficient-(MCD- diet-induced NAFLD SD rats in vivo and TNF-α-induced Hep3B cells in vitro. Methods. SD Rats were classified according to diet (chow or MCD diet and treatment (normal saline or PTX injection over a period of 4 weeks: group I (chow + saline, n=4, group II (chow + PTX, group III (MCD + saline, and group IV (MCD + PTX. Hep3B cells were treated with 100 ng/ml TNF-α (24 h in the absence or presence of PTX (1 mM. Results. PTX attenuated MCD-diet-induced serum ALT levels and hepatic steatosis. In real-time PCR and western blotting analysis, PTX decreased MCD-diet-induced TNF-alpha mRNA expression and proapoptotic unfolded protein response by ER stress (GRP78, p-eIF2, ATF4, IRE1α, CHOP, and p-JNK activation in vivo. PTX (1 mM reduced TNF-α-induced activation of GRP78, p-eIF2, ATF4, IRE1α, and CHOP in vitro. Conclusion. PTX has beneficial roles in the development of MCD-diet-induced steatohepatitis through partial suppression of TNF-α and ER stress.

  10. The Methanol Extract of Angelica sinensis Induces Cell Apoptosis and Suppresses Tumor Growth in Human Malignant Brain Tumors

    Directory of Open Access Journals (Sweden)

    Yu-Ling Lin

    2013-01-01

    Full Text Available Glioblastoma multiforme (GBM is a highly vascularized and invasive neoplasm. The methanol extract of Angelica sinensis (AS-M is commonly used in traditional Chinese medicine to treat several diseases, such as gastric mucosal damage, hepatic injury, menopausal symptoms, and chronic glomerulonephritis. AS-M also displays potency in suppressing the growth of malignant brain tumor cells. The growth suppression of malignant brain tumor cells by AS-M results from cell cycle arrest and apoptosis. AS-M upregulates expression of cyclin kinase inhibitors, including p16, to decrease the phosphorylation of Rb proteins, resulting in arrest at the G0-G1 phase. The expression of the p53 protein is increased by AS-M and correlates with activation of apoptosis-associated proteins. Therefore, the apoptosis of cancer cells induced by AS-M may be triggered through the p53 pathway. In in vivo studies, AS-M not only suppresses the growth of human malignant brain tumors but also significantly prolongs patient survival. In addition, AS-M has potent anticancer effects involving cell cycle arrest, apoptosis, and antiangiogenesis. The in vitro and in vivo anticancer effects of AS-M indicate that this extract warrants further investigation and potential development as a new antibrain tumor agent, providing new hope for the chemotherapy of malignant brain cancer.

  11. Unexpected events induce motor slowing via a brain mechanism for action-stopping with global suppressive effects.

    Science.gov (United States)

    Wessel, Jan R; Aron, Adam R

    2013-11-20

    When an unexpected event occurs in everyday life (e.g., a car honking), one experiences a slowing down of ongoing action (e.g., of walking into the street). Motor slowing following unexpected events is a ubiquitous phenomenon, both in laboratory experiments as well as such everyday situations, yet the underlying mechanism is unknown. We hypothesized that unexpected events recruit the same inhibition network in the brain as does complete cancellation of an action (i.e., action-stopping). Using electroencephalography and independent component analysis in humans, we show that a brain signature of successful outright action-stopping also exhibits activity following unexpected events, and more so in blocks with greater motor slowing. Further, using transcranial magnetic stimulation to measure corticospinal excitability, we show that an unexpected event has a global motor suppressive effect, just like outright action-stopping. Thus, unexpected events recruit a common mechanism with outright action-stopping, moreover with global suppressive effects. These findings imply that we can now leverage the considerable extant knowledge of the neural architecture and functional properties of the stopping system to better understand the processing of unexpected events, including perhaps how they induce distraction via global suppression.

  12. Arginine-aromatic interactions and their effects on arginine-induced solubilization of aromatic solutes and suppression of protein aggregation

    KAUST Repository

    Shah, Dhawal

    2011-09-21

    We examine the interaction of aromatic residues of proteins with arginine, an additive commonly used to suppress protein aggregation, using experiments and molecular dynamics simulations. An aromatic-rich peptide, FFYTP (a segment of insulin), and lysozyme and insulin are used as model systems. Mass spectrometry shows that arginine increases the solubility of FFYTP by binding to the peptide, with the simulations revealing the predominant association of arginine to be with the aromatic residues. The calculations further show a positive preferential interaction coefficient, Γ XP, contrary to conventional thinking that positive Γ XP\\'s indicate aggregation rather than suppression of aggregation. Simulations with lysozyme and insulin also show arginine\\'s preference for aromatic residues, in addition to acidic residues. We use these observations and earlier results reported by us and others to discuss the possible implications of arginine\\'s interactions with aromatic residues on the solubilization of aromatic moieties and proteins. Our results also highlight the fact that explanations based purely on Γ XP, which measures average affinity of an additive to a protein, could obscure or misinterpret the underlying molecular mechanisms behind additive-induced suppression of protein aggregation. © 2011 American Institute of Chemical Engineers (AIChE).

  13. RGS6 Suppresses Ras-induced Cellular Transformation by Facilitating Tip60-mediated Dnmt1 Degradation and Promoting Apoptosis

    Science.gov (United States)

    Huang, Jie; Stewart, Adele; Maity, Biswanath; Hagen, Jussara; Fagan, Rebecca L.; Yang, Jianqi; Quelle, Dawn E.; Brenner, Charles; Fisher, Rory A.

    2014-01-01

    The RAS protooncogene plays a central role in regulation of cell proliferation, and point mutations leading to oncogenic activation of Ras occur in a large number of human cancers. Silencing of tumor suppressor genes by DNA methyltransferase 1 (Dnmt1) is essential for oncogenic cellular transformation by Ras, and Dnmt1 is over-expressed in numerous human cancers. Here we provide new evidence that the pleiotropic Regulator of G protein Signaling (RGS) family member RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated degradation of Dmnt1 and promoting apoptosis. Employing mouse embryonic fibroblasts (MEFs) from wild type (WT) and RGS6−/− mice, we found that oncogenic Ras induced up-regulation of RGS6, which in turn blocked Ras-induced cellular transformation. RGS6 functions to suppress cellular transformation in response to oncogenic Ras by down regulating Dnmt1 protein expression leading to inhibition of Dnmt1-mediated anti-apoptotic activity. Further experiments showed that RGS6 functions as a scaffolding protein for both Dnmt1 and Tip60 and is required for Tip60-mediated acetylation of Dnmt1 and subsequent Dnmt1 ubiquitylation and degradation. The RGS domain of RGS6, known only for its GAP activity toward Gα subunits, was sufficient to mediate Tip60 association with RGS6. This work demonstrates a novel signaling action for RGS6 in negative regulation of oncogene-induced transformation and provides new insights into our understanding of the mechanisms underlying Ras-induced oncogenic transformation and regulation of Dnmt1 expression. Importantly, these findings identify RGS6 as an essential cellular defender against oncogenic stress and a potential therapeutic target for developing new cancer treatments. PMID:23995786

  14. Metformin Suppresses Lipopolysaccharide (LPS)-induced Inflammatory Response in Murine Macrophages via Activating Transcription Factor-3 (ATF-3) Induction*

    Science.gov (United States)

    Kim, Juyoung; Kwak, Hyun Jeong; Cha, Ji-Young; Jeong, Yun-Seung; Rhee, Sang Dahl; Kim, Kwang Rok; Cheon, Hyae Gyeong

    2014-01-01

    Metformin, a well known antidiabetic agent that improves peripheral insulin sensitivity, also elicits anti-inflammatory actions, but its mechanism is unclear. Here, we investigated the mechanism responsible for the anti-inflammatory effect of metformin action in lipopolysaccharide (LPS)-stimulated murine macrophages. Metformin inhibited LPS-induced production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in a concentration-dependent manner and in parallel induction of activating transcription factor-3 (ATF-3), a transcription factor and member of the cAMP-responsive element-binding protein family. ATF-3 knockdown abolished the inhibitory effects of metformin on LPS-induced proinflammatory cytokine production accompanied with reversal of metformin-induced suppression of mitogen-activated protein kinase (MAPK) phosphorylation. Conversely, AMP-activated protein kinase (AMPK) phosphorylation and NF-κB suppression by metformin were unaffected by ATF-3 knockdown. ChIP-PCR analysis revealed that LPS-induced NF-κB enrichments on the promoters of IL-6 and TNF-α were replaced by ATF-3 upon metformin treatment. AMPK knockdown blunted all the effects of metformin (ATF-3 induction, proinflammatory cytokine inhibition, and MAPK inactivation), suggesting that AMPK activation by metformin is required for and precedes ATF-3 induction. Oral administration of metformin to either mice with LPS-induced endotoxemia or ob/ob mice lowered the plasma and tissue levels of TNF-α and IL-6 and increased ATF-3 expression in spleen and lungs. These results suggest that metformin exhibits anti-inflammatory action in macrophages at least in part via pathways involving AMPK activation and ATF-3 induction. PMID:24973221

  15. Metformin suppresses lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages via activating transcription factor-3 (ATF-3) induction.

    Science.gov (United States)

    Kim, Juyoung; Kwak, Hyun Jeong; Cha, Ji-Young; Jeong, Yun-Seung; Rhee, Sang Dahl; Kim, Kwang Rok; Cheon, Hyae Gyeong

    2014-08-15

    Metformin, a well known antidiabetic agent that improves peripheral insulin sensitivity, also elicits anti-inflammatory actions, but its mechanism is unclear. Here, we investigated the mechanism responsible for the anti-inflammatory effect of metformin action in lipopolysaccharide (LPS)-stimulated murine macrophages. Metformin inhibited LPS-induced production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in a concentration-dependent manner and in parallel induction of activating transcription factor-3 (ATF-3), a transcription factor and member of the cAMP-responsive element-binding protein family. ATF-3 knockdown abolished the inhibitory effects of metformin on LPS-induced proinflammatory cytokine production accompanied with reversal of metformin-induced suppression of mitogen-activated protein kinase (MAPK) phosphorylation. Conversely, AMP-activated protein kinase (AMPK) phosphorylation and NF-κB suppression by metformin were unaffected by ATF-3 knockdown. ChIP-PCR analysis revealed that LPS-induced NF-κB enrichments on the promoters of IL-6 and TNF-α were replaced by ATF-3 upon metformin treatment. AMPK knockdown blunted all the effects of metformin (ATF-3 induction, proinflammatory cytokine inhibition, and MAPK inactivation), suggesting that AMPK activation by metformin is required for and precedes ATF-3 induction. Oral administration of metformin to either mice with LPS-induced endotoxemia or ob/ob mice lowered the plasma and tissue levels of TNF-α and IL-6 and increased ATF-3 expression in spleen and lungs. These results suggest that metformin exhibits anti-inflammatory action in macrophages at least in part via pathways involving AMPK activation and ATF-3 induction. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. The effects of diet and corticosteroid-induced immune suppression during infection by Haemonchus contortus in lambs.

    Science.gov (United States)

    Carvalho, Nadino; das Neves, José Henrique; Nazato, Carina; Louvandini, Helder; Amarante, Alessandro F T

    2015-12-15

    To evaluate the effects of Diet and corticosteroid-induced immune suppression during infection by Haemonchus contortus, 28 lambs were allocated to one of four groups treated as follows: Group Basal Diet - Normal; Group Basal Diet - Immune-Suppressed; Group Supplemented Diet - Normal; and Group Supplemented Diet - Immune-Suppressed. The Basal Diet contained Cynodon dactylon (cv. coast cross) hay with 82 g crude protein (CP)/kg dry matter (DM), which was provided to the lambs in all groups ad libitum. In addition, animals on the Supplemented Diet received daily a commercial concentrate containing 171 g CP/kg DM, which was offered in an amount corresponding to 3% of the animal's live weight. The Immune-Suppressed groups received treatments with the glucocorticoid methylprednisolone sodium succinate (1.33 mg/kg of body weight), administered weekly. All lambs received a single infection with 4000 H. contortus infective larvae (L3) and were euthanised 28 days post-infection. Differences in pH and in the short-chain fatty acid (SCFA) concentrations occurred in rumen as a result of the distinct Diets offered to lambs. Such changes, however, did not have any apparent effect on larvae exsheathment and/or larvae survival inside the rumen, with all groups presenting similar worm burdens. However, animals on the Supplemented Diet presented reductions in worm growth and faecal egg counts. There was a significant effect of the Diet on the IgG levels against total antigens of H. contortus L3 from 7 to 27 days post-infection, with supplemented animals showing higher overall mean values (PDiet; however, only the length of males was significantly affected (P<0.05). In conclusion, the changes caused in the rumen contents by supplementation with concentrate did not impair H. contortus establishment.

  17. Imperfect traveling chimera states induced by local synaptic gradient coupling

    Science.gov (United States)

    Bera, Bidesh K.; Ghosh, Dibakar; Banerjee, Tanmoy

    2016-07-01

    In this paper, we report the occurrence of chimera patterns in a network of neuronal oscillators, which are coupled through local, synaptic gradient coupling. We discover a new chimera pattern, namely the imperfect traveling chimera state, where the incoherent traveling domain spreads into the coherent domain of the network. Remarkably, we also find that chimera states arise even for one-way local coupling, which is in contrast to the earlier belief that only nonlocal, global, or nearest-neighbor local coupling can give rise to chimera state; this find further relaxes the essential connectivity requirement of getting a chimera state. We choose a network of identical bursting Hindmarsh-Rose neuronal oscillators, and we show that depending upon the relative strength of the synaptic and gradient coupling, several chimera patterns emerge. We map all the spatiotemporal behaviors in parameter space and identify the transitions among several chimera patterns, an in-phase synchronized state, and a global amplitude death state.

  18. Localizing an atom using electromagnetically induced transparency in three dimensions

    Science.gov (United States)

    Chen, Jinyu; Song, Fei; Ma, Yangcheng; Wang, Zhiping; Yu, Benli

    2017-09-01

    A new scheme for three-dimensional (3D) atom localization is proposed, in which the atomic system is driven by three orthogonal standing-wave lasers. Because of the space-dependent atom-field interaction, the position probability distribution of the atom can be directly determined by measuring the probe absorption. It is found that, by properly varying the parameters of the system, the probability of finding the atom in 3D space can be almost 100%. Our scheme opens a promising way to achieve high-precision and high-efficiency 3D atom localization, which provides some potential applications in laser cooling or atom nano-lithography via atom localization.

  19. Suppressing the formation of lipid raft-associated Rac1/PI3K/Akt signaling complexes by curcumin inhibits SDF-1α-induced invasion of human esophageal carcinoma cells.

    Science.gov (United States)

    Lin, Meng-Liang; Lu, Yao-Cheng; Chen, Hung-Yi; Lee, Chuan-Chun; Chung, Jing-Gung; Chen, Shih-Shun

    2014-05-01

    Stromal cell-derived factor-1α (SDF-1α) is a ligand for C-X-C chemokine receptor type 4 (CXCR4), which contributes to the metastasis of cancer cells by promoting cell migration. Here, we show that the SDF-1α/CXCR4 axis can significantly increase invasion of esophageal carcinoma (EC) cells. We accomplished this by examining the effects of CXCR4 knockdown as well as treatment with a CXCR4-neutralizing antibody and the CXCR4-specific inhibitor AMD3100. Curcumin suppressed SDF-1α-induced cell invasion and matrix metalloproteinase-2 (MMP-2) promoter activity, cell surface localization of CXCR4 at lipid rafts, and lipid raft-associated ras-related C3 botulinum toxin substrate 1 (Rac1)/phosphatidylinositol 3-kinase (PI3K) p85α/Akt signaling. Curcumin inhibited SDF-1α-induced cell invasion by suppressing the Rac1-PI3K signaling complex at lipid rafts but did not abrogate lipid raft formation. We further demonstrate that the attenuation of lipid raft-associated Rac1 activity by curcumin was critical for the inhibition of SDF-1α-induced PI3K/Akt/NF-κB activation, cell surface localization of CXCR4 at lipid rafts, MMP-2 promoter activity, and cell invasion. Collectively, our results indicate that curcumin inhibits SDF-1α-induced EC cell invasion by suppressing the formation of the lipid raft-associated Rac1-PI3K-Akt signaling complex, the localization of CXCR4 with lipid rafts at the cell surface, and MMP-2 promoter activity, likely through the inhibition of Rac1 activity.

  20. Electric field-induced suppression of PTEN drives epithelial-to-mesenchymal transition via mTORC1 activation.

    Science.gov (United States)

    Yan, Tiantian; Jiang, Xupin; Guo, Xiaowei; Chen, Wen; Tang, Di; Zhang, Junhui; Zhang, Xingyue; Zhang, Dongxia; Zhang, Qiong; Jia, Jiezhi; Huang, Yuesheng

    2017-02-01

    Naturally occurring electric fields (EFs) are an intrinsic property of wounds. Endogenous EFs in skin wounds play critical roles in the dynamic and well-ordered biological process of wound healing. The epithelial-to-mesenchymal transition (EMT) allows keratinocytes to transition from sedentary cells to motile cells, facilitating wound healing. However, EMT-related studies have been performed without considering endogenous EFs. Thus, the relationship between electrical signals and the EMT remain elusive. Phosphatase and tension homolog (PTEN) and mammalian target of rapamycin complex 1 (mTORC1) are key molecules in sensing electrical cues, and they play significant roles in cellular responses to EFs. In addition, these molecules are closely related to the occurrence of the EMT in other cells. We used primary human keratinocytes to investigate the influence of EFs on the EMT as well as the roles of PTEN and mTORC1 in this process. The effects of EFs on the EMT were investigated by analyzing the levels of specific proteins and transcription factors. The roles of mTORC1 and PTEN and their relationship with each other were studied via pharmacological inhibition or genetic knockdown. A Zeiss imaging system and scratch assays were used to study single-cell motility and monolayer cell migration. EFs induced a range of both biochemical changes (e.g., increased Snail, Slug, vimentin, and N-cadherin expression, decreased E-cadherin expression) and functional changes (e.g., enhanced migratory capacity) that are characteristic of the EMT. EF-stimulated cells exhibited suppressed PTEN expression, and further PTEN downregulation led to the acquisition of more mesenchymal features and the loss of epithelial characteristics, which was accompanied by increased migratory capacity. PTEN overexpression reversed the EF-induced EMT and inhibited the migratory capacity of keratinocytes. EF-induced mTORC1 activation was a required component of the causal relationship between PTEN

  1. Nicotine suppresses lipopolysaccharide-induced release of interleukin-6 in mixed glia and microglia-enriched cultures

    Institute of Scientific and Technical Information of China (English)

    Zhihua Li; Qingzan Zhao; Hua Zhang; Xiuhua Ren; Mingfu Zhou; Weidong Zang

    2011-01-01

    Inflammation plays an important role in the pathogenesis of Parkinson's disease (PD) through the over-activation of microglia.Epidemiological studies show that smoking is associated with a lower incidence of PD.This study hypothesized that the neuroprotective effect of nicotine is mediated by modulating the activation of microglia via cytokine release.This study found that nicotine pretreatment suppressed the lipopolysaccharide-induced inflammatory reaction in the nervous system, especially microglia activation and interleukin-6 production.The inhibitory effects of 100 pmol/L nicotine were stronger compared with 1 and 10 pmol/L nicotine.These findings indicate that nicotine significantly decreases the production of proinflammatory interleukin-6 in mixed glia or microglia-enriched cultures, and plays an inhibitory effect on the lipopolysaccharide-induced inflammatory reaction.

  2. Brugia malayi Microfilariae Induce a Regulatory Monocyte/Macrophage Phenotype That Suppresses Innate and Adaptive Immune Responses

    Science.gov (United States)

    Venugopal, Gopinath; Rao, Gopala B.; Lucius, Richard; Srikantam, Aparna; Hartmann, Susanne

    2014-01-01

    Background Monocytes and macrophages contribute to the dysfunction of immune responses in human filariasis. During patent infection monocytes encounter microfilariae in the blood, an event that occurs in asymptomatically infected filariasis patients that are immunologically hyporeactive. Aim To determine whether blood microfilariae directly act on blood monocytes and in vitro generated macrophages to induce a regulatory phenotype that interferes with innate and adaptive responses. Methodology and principal findings Monocytes and in vitro generated macrophages from filaria non-endemic normal donors were stimulated in vitro with Brugia malayi microfilarial (Mf) lysate. We could show that monocytes stimulated with Mf lysate develop a defined regulatory phenotype, characterised by expression of the immunoregulatory markers IL-10 and PD-L1. Significantly, this regulatory phenotype was recapitulated in monocytes from Wuchereria bancrofti asymptomatically infected patients but not patients with pathology or endemic normals. Monocytes from non-endemic donors stimulated with Mf lysate directly inhibited CD4+ T cell proliferation and cytokine production (IFN-γ, IL-13 and IL-10). IFN-γ responses were restored by neutralising IL-10 or PD-1. Furthermore, macrophages stimulated with Mf lysate expressed high levels of IL-10 and had suppressed phagocytic abilities. Finally Mf lysate applied during the differentiation of macrophages in vitro interfered with macrophage abilities to respond to subsequent LPS stimulation in a selective manner. Conclusions and significance Conclusively, our study demonstrates that Mf lysate stimulation of monocytes from healthy donors in vitro induces a regulatory phenotype, characterized by expression of PD-L1 and IL-10. This phenotype is directly reflected in monocytes from filarial patients with asymptomatic infection but not patients with pathology or endemic normals. We suggest that suppression of T cell functions typically seen in lymphatic

  3. Brugia malayi microfilariae induce a regulatory monocyte/macrophage phenotype that suppresses innate and adaptive immune responses.

    Directory of Open Access Journals (Sweden)

    Noëlle Louise O'Regan

    2014-10-01

    Full Text Available Monocytes and macrophages contribute to the dysfunction of immune responses in human filariasis. During patent infection monocytes encounter microfilariae in the blood, an event that occurs in asymptomatically infected filariasis patients that are immunologically hyporeactive.To determine whether blood microfilariae directly act on blood monocytes and in vitro generated macrophages to induce a regulatory phenotype that interferes with innate and adaptive responses.Monocytes and in vitro generated macrophages from filaria non-endemic normal donors were stimulated in vitro with Brugia malayi microfilarial (Mf lysate. We could show that monocytes stimulated with Mf lysate develop a defined regulatory phenotype, characterised by expression of the immunoregulatory markers IL-10 and PD-L1. Significantly, this regulatory phenotype was recapitulated in monocytes from Wuchereria bancrofti asymptomatically infected patients but not patients with pathology or endemic normals. Monocytes from non-endemic donors stimulated with Mf lysate directly inhibited CD4+ T cell proliferation and cytokine production (IFN-γ, IL-13 and IL-10. IFN-γ responses were restored by neutralising IL-10 or PD-1. Furthermore, macrophages stimulated with Mf lysate expressed high levels of IL-10 and had suppressed phagocytic abilities. Finally Mf lysate applied during the differentiation of macrophages in vitro interfered with macrophage abilities to respond to subsequent LPS stimulation in a selective manner.Conclusively, our study demonstrates that Mf lysate stimulation of monocytes from healthy donors in vitro induces a regulatory phenotype, characterized by expression of PD-L1 and IL-10. This phenotype is directly reflected in monocytes from filarial patients with asymptomatic infection but not patients with pathology or endemic normals. We suggest that suppression of T cell functions typically seen in lymphatic filariasis is caused by microfilaria-modulated monocytes in an IL

  4. Evodiamine suppresses capsaicin-induced thermal hyperalgesia through activation and subsequent desensitization of the transient receptor potential V1 channels.

    Science.gov (United States)

    Iwaoka, Emiko; Wang, Shenglan; Matsuyoshi, Nobuyuki; Kogure, Yoko; Aoki, Shunji; Yamamoto, Satoshi; Noguchi, Koichi; Dai, Yi

    2016-01-01

    Evodiae fructus (EF), a fruit of Evodia rutaecarpa Bentham, has long been used as an analgesic drug in traditional Chinese and Japanese medicine. However, the underlying molecular mechanism of its pharmacological action is unclear. Here, using calcium imaging, whole-cell patch-clamp recording, and behavioral analysis, we investigated the pharmacological action of EF and its principal compound, evodiamine, on the transient receptor potential (TRP) V1 channels. Dorsal root ganglion (DRG) neurons and TRPV1- or TRPA1-transfected human embryonic kidney-derived (HEK) 293 cells were used for calcium imaging or whole-cell patch-clamp recording. Twenty male adult Sprague-Dawley rats were used for the capsaicin-induced thermal hyperalgesia behavioral analyses. We found that evodiamine induced significant increases in intracellular calcium and robust inward currents in a subpopulation of isolated rat DRG neurons, most of which were also sensitive to capsaicin. The effect of evodiamine was completely blocked by capsazepine, a competitive antagonist of TRPV1. Evodiamine induced significant inward currents in TRPV1-, but not TRPA1-transfected HEK293 cells. Pretreatment with evodiamine reduced capsaicin-induced currents significantly. Furthermore, the in vivo pre-treatment of evodiamine suppressed thermal hyperalgesia induced by intraplantar injection of capsaicin in rats. These results identify that the analgesic effect of EF and evodiamine may be due to the activation and subsequent desensitization of TRPV1 in sensory neurons.

  5. The Methoxyflavonoid Isosakuranetin Suppresses UV-B-Induced Matrix Metalloproteinase-1 Expression and Collagen Degradation Relevant for Skin Photoaging

    Science.gov (United States)

    Jung, Hana; Lee, Eunjoo H.; Lee, Tae Hoon; Cho, Man-Ho

    2016-01-01

    Solar ultraviolet (UV) radiation is a main extrinsic factor for skin aging. Chronic exposure of the skin to UV radiation causes the induction of matrix metalloproteinases (MMPs), such as MMP-1, and consequently results in alterations of the extracellular matrix (ECM) and skin photoaging. Flavonoids are considered as potent anti-photoaging agents due to their UV-absorbing and antioxidant properties and inhibitory activity against UV-mediated MMP induction. To identify anti-photoaging agents, in the present study we examined the preventative effect of methoxyflavonoids, such as sakuranetin, isosakuranetin, homoeriodictyol, genkwanin, chrysoeriol and syringetin, on UV-B-induced skin photo-damage. Of the examined methoxyflavonoids, pretreatment with isosakuranetin strongly suppressed the UV-B-mediated induction of MMP-1 in human keratinocytes in a concentration-dependent manner. Isosakuranetin inhibited UV-B-induced phosphorylation of mitogen-activated protein kinase (MAPK) signaling components, ERK1/2, JNK1/2 and p38 proteins. This result suggests that the ERK1/2 kinase pathways likely contribute to the inhibitory effects of isosakuranetin on UV-induced MMP-1 production in human keratinocytes. Isosakuranetin also prevented UV-B-induced degradation of type-1 collagen in human dermal fibroblast cells. Taken together, our findings suggest that isosakuranetin has the potential for development as a protective agent for skin photoaging through the inhibition of UV-induced MMP-1 production and collagen degradation. PMID:27598131

  6. The Methoxyflavonoid Isosakuranetin Suppresses UV-B-Induced Matrix Metalloproteinase-1 Expression and Collagen Degradation Relevant for Skin Photoaging.

    Science.gov (United States)

    Jung, Hana; Lee, Eunjoo H; Lee, Tae Hoon; Cho, Man-Ho

    2016-09-01

    Solar ultraviolet (UV) radiation is a main extrinsic factor for skin aging. Chronic exposure of the skin to UV radiation causes the induction of matrix metalloproteinases (MMPs), such as MMP-1, and consequently results in alterations of the extracellular matrix (ECM) and skin photoaging. Flavonoids are considered as potent anti-photoaging agents due to their UV-absorbing and antioxidant properties and inhibitory activity against UV-mediated MMP induction. To identify anti-photoaging agents, in the present study we examined the preventative effect of methoxyflavonoids, such as sakuranetin, isosakuranetin, homoeriodictyol, genkwanin, chrysoeriol and syringetin, on UV-B-induced skin photo-damage. Of the examined methoxyflavonoids, pretreatment with isosakuranetin strongly suppressed the UV-B-mediated induction of MMP-1 in human keratinocytes in a concentration-dependent manner. Isosakuranetin inhibited UV-B-induced phosphorylation of mitogen-activated protein kinase (MAPK) signaling components, ERK1/2, JNK1/2 and p38 proteins. This result suggests that the ERK1/2 kinase pathways likely contribute to the inhibitory effects of isosakuranetin on UV-induced MMP-1 production in human keratinocytes. Isosakuranetin also prevented UV-B-induced degradation of type-1 collagen in human dermal fibroblast cells. Taken together, our findings suggest that isosakuranetin has the potential for development as a protective agent for skin photoaging through the inhibition of UV-induced MMP-1 production and collagen degradation.

  7. Prunella vulgaris Suppresses HG-Induced Vascular Inflammation via Nrf2/HO-1/eNOS Activation

    Directory of Open Access Journals (Sweden)

    Ho Sub Lee

    2012-01-01

    Full Text Available Vascular inflammation is an important factor which can promote diabetic complications. In this study, the inhibitory effects of aqueous extract from Prunella vulgaris (APV on high glucose (HG-induced expression of cell adhesion molecules in human umbilical vein endothelial cells (HUVEC are reported. APV decreased HG-induced expression of intercellular adhesion molecule-1 (ICAM-1, vascular cell adhesion molecule-1 (VCAM-1, and E-selectin. APV also dose-dependently inhibited HG-induced adhesion of HL-60 monocytic cells. APV suppressed p65 NF-κB activation in HG-treated cells. APV significantly inhibited the formation of intracellular reactive oxygen species (ROS. HG-stimulated HUVEC secreted gelatinases, however, APV inhibited it. APV induced Akt phosphorylation as well as activation of heme oxygenase-1 (HO-1, eNOS, and nuclear factor E2-related factor 2 (Nrf2, which may protect vascular inflammation caused by HG. In conclusion, APV exerts anti-inflammatory effect via inhibition of ROS/NF-κB pathway by inducing HO-1 and eNOS expression mediated by Nrf2, thereby suggesting that Prunella vulgaris may be a possible therapeutic approach to the inhibition of diabetic vascular diseases.

  8. The Methoxyflavonoid Isosakuranetin Suppresses UV-B-Induced Matrix Metalloproteinase-1 Expression and Collagen Degradation Relevant for Skin Photoaging

    Directory of Open Access Journals (Sweden)

    Hana Jung

    2016-09-01

    Full Text Available Solar ultraviolet (UV radiation is a main extrinsic factor for skin aging. Chronic exposure of the skin to UV radiation causes the induction of matrix metalloproteinases (MMPs, such as MMP-1, and consequently results in alterations of the extracellular matrix (ECM and skin photoaging. Flavonoids are considered as potent anti-photoaging agents due to their UV-absorbing and antioxidant properties and inhibitory activity against UV-mediated MMP induction. To identify anti-photoaging agents, in the present study we examined the preventative effect of methoxyflavonoids, such as sakuranetin, isosakuranetin, homoeriodictyol, genkwanin, chrysoeriol and syringetin, on UV-B-induced skin photo-damage. Of the examined methoxyflavonoids, pretreatment with isosakuranetin strongly suppressed the UV-B-mediated induction of MMP-1 in human keratinocytes in a concentration-dependent manner. Isosakuranetin inhibited UV-B-induced phosphorylation of mitogen-activated protein kinase (MAPK signaling components, ERK1/2, JNK1/2 and p38 proteins. This result suggests that the ERK1/2 kinase pathways likely contribute to the inhibitory effects of isosakuranetin on UV-induced MMP-1 production in human keratinocytes. Isosakuranetin also prevented UV-B-induced degradation of type-1 collagen in human dermal fibroblast cells. Taken together, our findings suggest that isosakuranetin has the potential for development as a protective agent for skin photoaging through the inhibition of UV-induced MMP-1 production and collagen degradation.

  9. Matrine derivate MASM suppresses LPS-induced phenotypic and functional maturation of murine bone marrow-derived dendritic cells.

    Science.gov (United States)

    Xu, Jing; Qi, Yang; Xu, Wei-Heng; Liu, Ying; Qiu, Lie; Wang, Ke-Qi; Hu, Hong-Gang; He, Zhi-Gao; Zhang, Jun-Ping

    2016-07-01

    Dendritic cell (DC) maturation process is a crucial step for the development of T cell immune responses and immune tolerance. In this study, we evaluated MASM, a novel derivative of the natural compound matrine that possesses a significant anti-inflammatory and immune-regulating property, for its efficacy to inhibit lipopolysaccharides (LPS)-induced maturation of murine bone marrow-derived dendritic cells. Here we show that MASM profoundly suppresses LPS-induced phenotypic and functional DC maturation. MASM inhibited LPS-induced expression of costimulatory molecules CD80 and CD86 in a concentration-dependent manner. MASM also attenuated LPS-induced IL-12p70, TNF-α, IL-6 and NO release of DCs. The MASM-treated DCs were highly efficient at antigen capture via mannose receptor-mediated endocytosis but showed weak stimulatory capacity for allogeneic T cell proliferation. Furthermore, MASM inhibited LPS-induced PI3K/Akt, MAPK and NF-κB pathways. These novel findings provide new insight into the immunopharmacological role of MASM in impacting on the DCs.

  10. Xanthohumol Improves Diet-induced Obesity and Fatty Liver by Suppressing Sterol Regulatory Element-binding Protein (SREBP) Activation.

    Science.gov (United States)

    Miyata, Shingo; Inoue, Jun; Shimizu, Makoto; Sato, Ryuichiro

    2015-08-14

    Sterol regulatory element-binding proteins (SREBPs) are key transcription factors that stimulate the expression of genes involved in fatty acid and cholesterol biosynthesis. Here, we demonstrate that a prenylated flavonoid in hops, xanthohumol (XN), is a novel SREBP inactivator that reduces the de novo synthesis of fatty acid and cholesterol. XN independently suppressed the maturation of SREBPs of insulin-induced genes in a manner different from sterols. Our results suggest that XN impairs the endoplasmic reticulum-to-Golgi translocation of the SREBP cleavage-activating protein (SCAP)-SREBP complex by binding to Sec23/24 and blocking SCAP/SREBP incorporation into common coated protein II vesicles. Furthermore, in diet-induced obese mice, dietary XN suppressed SREBP-1 target gene expression in the liver accompanied by a reduction of the mature form of hepatic SREBP-1, and it inhibited the development of obesity and hepatic steatosis. Altogether, our data suggest that XN attenuates the function of SREBP-1 by repressing its maturation and that it has the potential of becoming a nutraceutical food or pharmacological agent for improving metabolic syndrome.

  11. Xanthohumol Improves Diet-induced Obesity and Fatty Liver by Suppressing Sterol Regulatory Element-binding Protein (SREBP) Activation*

    Science.gov (United States)

    Miyata, Shingo; Inoue, Jun; Shimizu, Makoto; Sato, Ryuichiro

    2015-01-01

    Sterol regulatory element-binding proteins (SREBPs) are key transcription factors that stimulate the expression of genes involved in fatty acid and cholesterol biosynthesis. Here, we demonstrate that a prenylated flavonoid in hops, xanthohumol (XN), is a novel SREBP inactivator that reduces the de novo synthesis of fatty acid and cholesterol. XN independently suppressed the maturation of SREBPs of insulin-induced genes in a manner different from sterols. Our results suggest that XN impairs the endoplasmic reticulum-to-Golgi translocation of the SREBP cleavage-activating protein (SCAP)-SREBP complex by binding to Sec23/24 and blocking SCAP/SREBP incorporation into common coated protein II vesicles. Furthermore, in diet-induced obese mice, dietary XN suppressed SREBP-1 target gene expression in the liver accompanied by a reduction of the mature form of hepatic SREBP-1, and it inhibited the development of obesity and hepatic steatosis. Altogether, our data suggest that XN attenuates the function of SREBP-1 by repressing its maturation and that it has the potential of becoming a nutraceutical food or pharmacological agent for improving metabolic syndrome. PMID:26140926

  12. Unpredictable chronic stress-induced reproductive suppression associated with the decrease of kisspeptin immunoreactivity in male mice.

    Science.gov (United States)

    Hirano, Tetsushi; Kobayashi, Yoshihiro; Omotehara, Takuya; Tatsumi, Atsutoshi; Hashimoto, Rie; Umemura, Yuria; Nagahara, Daichi; Mantani, Youhei; Yokoyama, Toshifumi; Kitagawa, Hiroshi; Hoshi, Nobuhiko

    2014-09-01

    Environmental stress affects various parts of mammals typically through the circulation of stress hormones. It has been identified as one of the possible reasons for male reproductive difficulties, but the complex mechanisms responsible for stress-induced reproductive suppression are poorly understood. Here, we examined the relationship between chronic environmental stress and hypothalamic kisspeptin, a recently discovered upstream regulator of the reproductive endocrine feedback system. We studied male mice under an unpredictable chronic stress procedure to replicate the situation of animals under chronic stress. Histological and immunohistochemical analyses were performed focusing on kisspeptin neurons in the arcuate hypothalamic nucleus (ARC) and DNA fragmented cells in seminiferous tubules. Although the ARC was not morphologically altered in either the stressed or non-stressed group, granular kisspeptin immunoreactivities decreased slightly in the stress group. In the testes of the stress group, several signs of testicular degeneration were observed, including increased numbers of ssDNA-positive cells per seminiferous tubule, thinning, vacuoled seminiferous epithelia and multinucleated giant cells. The decreases in kisspeptin in the stress group might be due to other hypothalamic peptides, such as corticotropin-releasing hormone and leptin, whose receptors are known to coexpress in the ARC. In addition, environmental stress directly and indirectly affects testicular function through stress hormones and gonadotropins. In summary, our findings enhance the understanding of stress-induced reproductive suppression possibly mediated by kisspeptin in the ARC.

  13. Suppression of ovalbumin-induced airway inflammatory responses in a mouse model of asthma by Mimosa pudica extract.

    Science.gov (United States)

    Yang, Eun Ju; Lee, Ji-Sook; Yun, Chi-Young; Ryang, Yong Suk; Kim, Jong-Bae; Kim, In Sik

    2011-01-01

    Asthma is an inflammatory airway disease. The pathogenic mechanisms of asthma include the infiltration of leukocytes and release of cytokines. Mimosa pudica (Mp) has been used traditionally for the treatment of insomnia, diarrhea and inflammatory diseases. Although Mp extract has various therapeutic properties, the effect of this extract on asthma has not yet been reported. This study investigated the suppressive effects of Mp extract on asthmatic responses both in vitro and in vivo. Mp extract was acquired from dried and powdered whole plants of M. pudica using 80% ethanol. BALB/c mice were used for the mouse model of asthma induced by ovalbumin. Mp extract significantly inhibited the HMC-1 cell migration induced by stem cell factor and blocked the release of monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6) in EoL-1 cells. Leukocytosis, eosinophilia and mucus hypersecretion in asthmatic lung were significantly suppressed by Mp extract. The release of ovalbumin-specific IgE in bronchoalveolar lavage fluid and serum was also decreased. Mp extract treatment resulted in no liver cytotoxicity. The Mp extract has inhibitory properties on asthma and may be used as a potent therapeutic agent for allergic lung inflammation. Copyright © 2010 John Wiley & Sons, Ltd.

  14. Menadione Suppresses Benzo(α)pyrene-Induced Activation of Cytochromes P450 1A: Insights into a Possible Molecular Mechanism.

    Science.gov (United States)

    Sidorova, Yulia A; Perepechaeva, Maria L; Pivovarova, Elena N; Markel, Arkady L; Lyakhovich, Vyacheslav V; Grishanova, Alevtina Y

    2016-01-01

    Oxidative reactions that are catalyzed by cytochromes P450 1A (CYP1A) lead to formation of carcinogenic derivatives of arylamines and polycyclic aromatic hydrocarbons (PAHs), such as the widespread environmental pollutant benzo(α)pyrene (BP). These compounds upregulate CYP1A at the transcriptional level via an arylhydrocarbon receptor (AhR)-dependent signaling pathway. Because of the involvement of AhR-dependent genes in chemically induced carcinogenesis, suppression of this signaling pathway could prevent tumor formation and/or progression. Here we show that menadione (a water-soluble analog of vitamin K3) inhibits BP-induced expression and enzymatic activity of both CYP1A1 and CYP1A2 in vivo (in the rat liver) and BP-induced activity of CYP1A1 in vitro. Coadministration of BP and menadione reduced DNA-binding activity of AhR and increased DNA-binding activity of transcription factors Oct-1 and CCAAT/enhancer binding protein (C/EBP), which are known to be involved in negative regulation of AhR-dependent genes, in vivo. Expression of another factor involved in downregulation of CYP1A-pAhR repressor (AhRR)-was lower in the liver of the rats treated with BP and menadione, indicating that the inhibitory effect of menadione on CYP1A is not mediated by this protein. Furthermore, menadione was well tolerated by the animals: no signs of acute toxicity were detected by visual examination or by assessment of weight gain dynamics or liver function. Taken together, our results suggest that menadione can be used in further studies on animal models of chemically induced carcinogenesis because menadione may suppress tumor formation and possibly progression.

  15. Menadione Suppresses Benzo(αpyrene-Induced Activation of Cytochromes P450 1A: Insights into a Possible Molecular Mechanism.

    Directory of Open Access Journals (Sweden)

    Yulia A Sidorova

    Full Text Available Oxidative reactions that are catalyzed by cytochromes P450 1A (CYP1A lead to formation of carcinogenic derivatives of arylamines and polycyclic aromatic hydrocarbons (PAHs, such as the widespread environmental pollutant benzo(αpyrene (BP. These compounds upregulate CYP1A at the transcriptional level via an arylhydrocarbon receptor (AhR-dependent signaling pathway. Because of the involvement of AhR-dependent genes in chemically induced carcinogenesis, suppression of this signaling pathway could prevent tumor formation and/or progression. Here we show that menadione (a water-soluble analog of vitamin K3 inhibits BP-induced expression and enzymatic activity of both CYP1A1 and CYP1A2 in vivo (in the rat liver and BP-induced activity of CYP1A1 in vitro. Coadministration of BP and menadione reduced DNA-binding activity of AhR and increased DNA-binding activity of transcription factors Oct-1 and CCAAT/enhancer binding protein (C/EBP, which are known to be involved in negative regulation of AhR-dependent genes, in vivo. Expression of another factor involved in downregulation of CYP1A-pAhR repressor (AhRR-was lower in the liver of the rats treated with BP and menadione, indicating that the inhibitory effect of menadione on CYP1A is not mediated by this protein. Furthermore, menadione was well tolerated by the animals: no signs of acute toxicity were detected by visual examination or by assessment of weight gain dynamics or liver function. Taken together, our results suggest that menadione can be used in further studies on animal models of chemically induced carcinogenesis because menadione may suppress tumor formation and possibly progression.

  16. Pu-erh Tea Extract Ameliorates Ovariectomy-Induced Osteoporosis in Rats and Suppresses Osteoclastogenesis In Vitro

    Directory of Open Access Journals (Sweden)

    Titi Liu

    2017-05-01

    , PTE efficaciously suppressed the expression of key osteoclast-specific genes and proteins.Conclusion: PTE can ameliorate ovariectomy-induced osteoporosis in rats and suppress osteoclastogenesis in vitro.

  17. Trichostatin A Modulates Thiazolidinedione-Mediated Suppression of Tumor Necrosis Factor α-Induced Lipolysis in 3T3-L1 Adipocytes

    Science.gov (United States)

    Lu, Juu-Chin; Chang, Yu-Tzu; Wang, Chih-Tien; Lin, Yu-Chun; Lin, Chun-Ken; Wu, Zhong-Sheng

    2013-01-01

    In obesity, high levels of tumor necrosis factor α (TNFα) stimulate lipolysis in adipocytes, leading to hyperlipidemia and insulin resistance. Thiazolidinediones (TZDs), the insulin-sensitizing drugs, antagonize TNFα-induced lipolysis in adipocytes, thereby increasing insulin sensitivity in diabetes patients. The cellular target of TZDs is peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor that controls many adipocyte functions. As a transcription factor, PPARγ is closely modulated by coregulators, which include coactivators and corepressors. Previous studies have revealed that in macrophages, the insulin-sensitizing effect of PPARγ may involve suppression of proinflammatory gene expression by recruiting the corepressor complex that contains corepressors and histone deacetylases (HDACs). Therefore, we investigated whether the corepressor complex is involved in TZD-mediated suppression of TNFα-induced lipolysis in 3T3-L1 adipocytes. Trichostatin A (TSA), a pan HDAC inhibitor (HDACI) that inhibits class I and II HDACs, was used to examine the involvement of HDACs in the actions of TZDs. TSA alone increased basal lipolysis and attenuated TZD-mediated suppression of TNFα-induced lipolysis. Increased basal lipolysis may in part result from class I HDAC inhibition because selective class I HDACI treatment had similar results. However, attenuation of TZD-mediated TNFα antagonism may be specific to TSA and related hydroxamate-based HDACI rather than to HDAC inhibition. Consistently, corepressor depletion did not affect TZD-mediated suppression. Interestingly, TSA treatment greatly reduced PPARγ levels in differentiated adipocytes. Finally, extracellular signal-related kinase 1/2 (ERK1/2) mediated TNFα-induced lipolysis, and TZDs suppressed TNFα-induced ERK phosphorylation. We determined that TSA increased basal ERK phosphorylation, and attenuated TZD-mediated suppression of TNFα-induced ERK phosphorylation, consistent with TSA

  18. Trichostatin A modulates thiazolidinedione-mediated suppression of tumor necrosis factor α-induced lipolysis in 3T3-L1 adipocytes.

    Science.gov (United States)

    Lu, Juu-Chin; Chang, Yu-Tzu; Wang, Chih-Tien; Lin, Yu-Chun; Lin, Chun-Ken; Wu, Zhong-Sheng

    2013-01-01

    In obesity, high levels of tumor necrosis factor α (TNFα) stimulate lipolysis in adipocytes, leading to hyperlipidemia and insulin resistance. Thiazolidinediones (TZDs), the insulin-sensitizing drugs, antagonize TNFα-induced lipolysis in adipocytes, thereby increasing insulin sensitivity in diabetes patients. The cellular target of TZDs is peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor that controls many adipocyte functions. As a transcription factor, PPARγ is closely modulated by coregulators, which include coactivators and corepressors. Previous studies have revealed that in macrophages, the insulin-sensitizing effect of PPARγ may involve suppression of proinflammatory gene expression by recruiting the corepressor complex that contains corepressors and histone deacetylases (HDACs). Therefore, we investigated whether the corepressor complex is involved in TZD-mediated suppression of TNFα-induced lipolysis in 3T3-L1 adipocytes. Trichostatin A (TSA), a pan HDAC inhibitor (HDACI) that inhibits class I and II HDACs, was used to examine the involvement of HDACs in the actions of TZDs. TSA alone increased basal lipolysis and attenuated TZD-mediated suppression of TNFα-induced lipolysis. Increased basal lipolysis may in part result from class I HDAC inhibition because selective class I HDACI treatment had similar results. However, attenuation of TZD-mediated TNFα antagonism may be specific to TSA and related hydroxamate-based HDACI rather than to HDAC inhibition. Consistently, corepressor depletion did not affect TZD-mediated suppression. Interestingly, TSA treatment greatly reduced PPARγ levels in differentiated adipocytes. Finally, extracellular signal-related kinase 1/2 (ERK1/2) mediated TNFα-induced lipolysis, and TZDs suppressed TNFα-induced ERK phosphorylation. We determined that TSA increased basal ERK phosphorylation, and attenuated TZD-mediated suppression of TNFα-induced ERK phosphorylation, consistent with TSA's effects

  19. Trichostatin A modulates thiazolidinedione-mediated suppression of tumor necrosis factor α-induced lipolysis in 3T3-L1 adipocytes.

    Directory of Open Access Journals (Sweden)

    Juu-Chin Lu

    Full Text Available In obesity, high levels of tumor necrosis factor α (TNFα stimulate lipolysis in adipocytes, leading to hyperlipidemia and insulin resistance. Thiazolidinediones (TZDs, the insulin-sensitizing drugs, antagonize TNFα-induced lipolysis in adipocytes, thereby increasing insulin sensitivity in diabetes patients. The cellular target of TZDs is peroxisome proliferator-activated receptor γ (PPARγ, a nuclear receptor that controls many adipocyte functions. As a transcription factor, PPARγ is closely modulated by coregulators, which include coactivators and corepressors. Previous studies have revealed that in macrophages, the insulin-sensitizing effect of PPARγ may involve suppression of proinflammatory gene expression by recruiting the corepressor complex that contains corepressors and histone deacetylases (HDACs. Therefore, we investigated whether the corepressor complex is involved in TZD-mediated suppression of TNFα-induced lipolysis in 3T3-L1 adipocytes. Trichostatin A (TSA, a pan HDAC inhibitor (HDACI that inhibits class I and II HDACs, was used to examine the involvement of HDACs in the actions of TZDs. TSA alone increased basal lipolysis and attenuated TZD-mediated suppression of TNFα-induced lipolysis. Increased basal lipolysis may in part result from class I HDAC inhibition because selective class I HDACI treatment had similar results. However, attenuation of TZD-mediated TNFα antagonism may be specific to TSA and related hydroxamate-based HDACI rather than to HDAC inhibition. Consistently, corepressor depletion did not affect TZD-mediated suppression. Interestingly, TSA treatment greatly reduced PPARγ levels in differentiated adipocytes. Finally, extracellular signal-related kinase 1/2 (ERK1/2 mediated TNFα-induced lipolysis, and TZDs suppressed TNFα-induced ERK phosphorylation. We determined that TSA increased basal ERK phosphorylation, and attenuated TZD-mediated suppression of TNFα-induced ERK phosphorylation, consistent with

  20. Monitoring Locally Induced Hyperthermia with Magnetic Resonance Imaging

    NARCIS (Netherlands)

    M.W. Vogel (M.)

    2005-01-01

    markdownabstract__Abstract__ Magnetic resonance thermometry is a relatively new and unique technology for non-invasive monitoring of (local) therapeutic temperature changes that is not yet in common use. Temperature measurements using magnetic resonance heat thermometry can be performed in several

  1. Training-induced plasticity of auditory localization in adult mammals.

    Directory of Open Access Journals (Sweden)

    Oliver Kacelnik

    2006-04-01

    Full Text Available Accurate auditory localization relies on neural computations based on spatial cues present in the sound waves at each ear. The values of these cues depend on the size, shape, and separation of the two ears and can therefore vary from one individual to another. As with other perceptual skills, the neural circuits involved in spatial hearing are shaped by experience during development and retain some capacity for plasticity in later life. However, the factors that enable and promote plasticity of auditory localization in the adult brain are unknown. Here we show that mature ferrets can rapidly relearn to localize sounds after having their spatial cues altered by reversibly occluding one ear, but only if they are trained to use these cues in a behaviorally relevant task, with greater and more rapid improvement occurring with more frequent training. We also found that auditory adaptation is possible in the absence of vision or error feedback. Finally, we show that this process involves a shift in sensitivity away from the abnormal auditory spatial cues to other cues that are less affected by the earplug. The mature auditory system is therefore capable of adapting to abnormal spatial information by reweighting different localization cues. These results suggest that training should facilitate acclimatization to hearing aids in the hearing impaired.

  2. Self-induced suppression of collective neutrino oscillations in a supernova.

    Science.gov (United States)

    Duan, Huaiyu; Friedland, Alexander

    2011-03-04

    We investigate collective flavor oscillations of supernova neutrinos at late stages of the explosion. We first show that the frequently used single-angle (averaged coupling) approximation predicts oscillations close to, or perhaps even inside, the neutrinosphere, potentially invalidating the basic neutrino transport paradigm. Fortunately, we also find that the single-angle approximation breaks down in this regime; in the full multiangle calculation, the oscillations start safely outside the transport region. The new suppression effect is traced to the interplay between the dispersion in the neutrino-neutrino interactions and the vacuum oscillation term.

  3. Compact all-optical switches based on photon-induced suppression of mode interference

    Institute of Scientific and Technical Information of China (English)

    Longzhi Li; Yi Tang; Jianyi Yang; Minghua Wang; Xiaoqing Jiang

    2006-01-01

    @@ An optically activated optical switch based on suppression of mode interference (SMI) is presented. The imaging properties of multi-mode interference (MMI) section in the switch with Y-branch can be modified by a controlling light injection. The switch was simulated by finite difference beam propagation method(FD-BPM) and fabricated on GaAIAs/GaAs epitaxial materials. At the wavelength of 1.31 μm, the primary experiment showed an extinction ratio of about 8 dB with controlling light power density of 73.5W/mm2.

  4. Suppressive competition: how sounds may cheat sight.

    Science.gov (United States)

    Kayser, Christoph; Remedios, Ryan

    2012-02-23

    In this issue of Neuron, Iurilli et al. (2012) demonstrate that auditory cortex activation directly engages local GABAergic circuits in V1 to induce sound-driven hyperpolarizations in layer 2/3 and layer 6 pyramidal neurons. Thereby, sounds can directly suppress V1 activity and visual driven behavior. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. Aromatic Hydrocarbon Receptor Suppresses Prostate Cancer Bone Metastasis Cells-Induced Vasculogenesis of Endothelial Progenitor Cells under Hypoxia

    Directory of Open Access Journals (Sweden)

    Shuai Huang

    2016-07-01

    Full Text Available Background/Aims: Hypoxia leads to the development of neovascularization in solid tumor by regulating VEGF expression. Aromatic hydrocarbon receptor (AHR, a receptor for dioxin-like compounds, functions as a transcription factor through dimerization with hypoxia-inducible factors 1β (HIF-1β and inhibits the secretion of vascular endothelial growth factor (VEGF. The purpose of this study was to explore whether AHR can suppress hypoxia-induced VEGF production in prostate bone metastasis cells and repress neovascularization in endothelial progenitor cells (EPCs, and, if so, through what mechanisms. Methods: PC-3 or LNCaP cells induced angiogenesis was detected by Matrigel-based tube formation assay, mRNA expression levels was measured by qRT-PCR, VEGF secretion level was determined by ELISA assay, respectively. Results: AHR activation inhibits hypoxia-induced adhesiveness and vasculogenesis of EPCs induced by PC-3 or LNCaP cells under hypoxia. Moreover, AHR activation suppressed hypoxia-induced VEGF production in PC-3 and LNCaP cells (48 ± 14% in PC-3, p = 0.000; 41 ± 14% in LNCaP, p = 0.000 by attenuating HIF-1α and HIF-1β level that in turn diminished the angiogenic ability of EPCs in vitro. Furthermore, we found the mRNA level of hypoxia-inducible factors 1α (HIF-1α (1.54 ± 0.13 fold in PC-3, p = 0.002, 1.62 ± 0.12 fold in LNCaP, p = 0.001 and HIF-1β (1.67 ± 0.23 fold in PC-3, p = 0.007; 1.75 ± 0.26 fold in LNCaP, p=0.008 were upregulated in prostate cancer bone metastasis PC-3 and LNCaP cell lines in response to hypoxia, and revealed that the regulation of VEGF by HIF-1α and HIF-1β was possibly mediated by the activation of phosphatidylinositol 3-kinase pathway. Conclusion: By providing a mechanistic insight into the modulation of neovascularization by AHR ligand, we suggest that AHR ligand has a strong potential of being a new therapeutic agent with applications in the field of bone metastatic prostate cancer.

  6. Oncologic doses of zoledronic acid induce site specific suppression of bone modelling in rice rats.

    Science.gov (United States)

    Exposto, C R; Oz, U; Callard, J S; Allen, M J; Khurana, H; Atri, A D'; Mo, X; Fernandez, S A; Tatakis, D N; Edmonds, K; Westgate, P M; Huja, S S

    2017-06-01

    To examine the effect of zoledronic acid (ZOL) on cortical bone modelling and healing of extraction sockets in the jaw bones of a rodent model. We hypothesized ZOL suppresses both the bone formation in the modelling mode in the jaw bones and alters the extraction site healing. Rice rats were administered saline solution and two dose regimens of ZOL: 0.1 mg/kg, twice a week, for 4 weeks (n=17, saline=8 & ZOL=9) and a higher dose of 0.4 mg/kg, weekly, for 9 weeks (n=30, saline=15 & ZOL=15). Two pairs of fluorochrome bone labels were administered. Extraction of maxillary teeth was performed in maxilla. Mineral apposition rate, mineralizing surface and bone formation rate (BFR) were quantified on periodontal (PDL), alveolar and basal bone surfaces, and in the trabecular bone of proximal tibia. Bone volume (BV) was evaluated at extraction sockets. Multivariate Gaussian models were used to account for repeated measurements, and analyzes were conducted in SAS V9.3. ZOL suppressed bone modelling (BFR/BS) at the PDL surfaces in the mandible (Pmodelling mode in the jaws demonstrates the site specific effects of ZOL in rice rats. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Suppression of lipopolysaccharide-induced of inducible nitric oxide synthase and cyclooxygenase-2 by Sanguis Draconis, a dragon's blood resin, in RAW 264.7 cells.

    Science.gov (United States)

    Choy, Cheuk-Sing; Hu, Chien-Ming; Chiu, Wen-Ta; Lam, Carlos-Shu Kei; Ting, Yih; Tsai, Shin-Han; Wang, Tzu-Chien

    2008-02-12

    Sanguis Draconis (SD) is a kind of dragon's blood resin that is obtained from Daemomorops draco (Palmae). It is used in traditional medicine and has shown anti-inflammatory activity in some diseases. In this study, we examined the effects of Sanguis Dranonis ethanol extract (SDEE) on LPS-induced inflammation using RAW 264.7 cells. Our data indicated that SDEE inhibits LPS-stimulated NO, PGE2, IL-1 beta and TNF-alpha release, and iNOS and COX-2 expression. Furthermore, SDEE suppressed the LPS-induced p65 expression of NF-kappa B, which was associated with the inhibition of I kappa B-alpha degradation. We also found that the expression of HO-1 was significantly increased in RAW 264.7 cells by SDEE. These results suggest among possibilities of anti-inflammation that SDEE inhibits the production of NO and PGE2 by the down-regulation of iNOS and COX-2 gene expression via the suppression of NF-kappaB (p65) activation. SDEE can induce HO-1 over-expression in macrophage cells, which indicates that it may possess antioxidant properties. This result means that SEDD its anti-inflammatory effects in macrophages may be through a novel mechanism that involves the action of HO-1. Thus, SD could provide a potential therapeutic approach for inflammation-associated disorders.

  8. Pyrrolidinium fullerene induces apoptosis by activation of procaspase-9 via suppression of Akt in primary effusion lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Watanabe, Tadashi [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan); Nakamura, Shigeo [Department of Chemistry, Nippon Medical School, 1-7-1 Kyonan-cho, Musashino, Tokyo 180-0023 (Japan); Ono, Toshiya; Ui, Sadaharu [Department of Biotechnology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Kofu 400-8511 (Japan); Yagi, Syota; Kagawa, Hiroki [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan); Watanabe, Hisami [Center of Molecular Biosciences, Tropical Biosphere Research Center, University of the Ryukyus, 1 Senbaru, Nishihara-cho, Okinawa 903-0213 (Japan); Ohe, Tomoyuki; Mashino, Tadahiko [Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512 (Japan); Fujimuro, Masahiro, E-mail: fuji2@mb.kyoto-phu.ac.jp [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan)

    2014-08-15

    Highlights: • Seven fullerenes were evaluated in terms of their cytotoxic effects on B-lymphomas. • Pyrrolidinium fullerene induced apoptosis of KSHV-infected B-lymphoma PEL cells. • The activation of Akt is essential for PEL cell survival. • Pyrrolidinium fullerene activated caspase-9 by inactivating Akt in PEL cells. • Pyrrolidinium fullerene have potential as novel drugs for the treatment of PEL. - Abstract: Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin’s B-cell lymphoma and is an aggressive neoplasm caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients. In general, PEL cells are derived from post-germinal center B-cells and are infected with KSHV. To evaluate potential novel anti-tumor compounds against KSHV-associated PEL, seven water-soluble fullerene derivatives were evaluated as potential drug candidates for the treatment of PEL. Herein, we discovered a pyrrolidinium fullerene derivative, 1,1,1′,1′-tetramethyl [60]fullerenodipyrrolidinium diiodide, which induced apoptosis of PEL cells via a novel mechanism, the caspase-9 activation by suppressing the caspase-9 phosphorylation, causing caspase-9 inactivation. Pyrrolidinium fullerene treatment reduced significantly the viability of PEL cells compared with KSHV-uninfected lymphoma cells, and induced the apoptosis of PEL cells by activating caspase-9 via procaspase-9 cleavage. Pyrrolidinium fullerene additionally reduced the Ser473 phosphorylation of Akt and Ser196 of procaspase-9. Ser473-phosphorylated Akt (i.e., activated Akt) phosphorylates Ser196 in procaspase-9, causing inactivation of procaspase-9. We also demonstrated that Akt inhibitors suppressed the proliferation of PEL cells compared with KSHV-uninfected cells. Our data therefore suggest that Akt activation is essential for cell survival in PEL and a pyrrolidinium fullerene derivative induced apoptosis by activating caspase-9 via suppression of Akt in PEL cells. In addition, we evaluated

  9. Antidepressant indatraline induces autophagy and inhibits restenosis via suppression of mTOR/S6 kinase signaling pathway

    Science.gov (United States)

    Cho, Yoon Sun; Yen, Chih-na; Shim, Joong Sup; Kang, Dong Hoon; Kang, Sang Won; Liu, Jun O.; Kwon, Ho Jeong

    2016-01-01

    Indatraline is an antidepressive agent and a non-selective monoamine transporter inhibitor that blocks the reuptake of neurotransmitters (dopamine, serotonin, and norepinephrine). In this study, we report that indatraline induces autophagy via the suppression of mTOR/S6 kinase signaling. Autophagy induction was examined by a cell-based high content screening system using LysoTracker, which was followed by monodansylcadaverine staining and transmission electron microscope observation. Indatraline increased the number of EGFP-LC3 cells expressing autophagosomes in the cytoplasm. Conversion of LC3 was further validated by immunoblotting. Indatraline induced autophagy by affecting the AMPK/mTOR/S6K signaling axis and had no influence on the PI3K/AKT/ERK signaling. Moreover, indatraline induced autophagy in smooth muscle cells (SMCs); further, it exhibited therapeutic potential for restenosis by inhibiting SMC accumulation in a rat restenosis model. These results provide new insights into the role of monoamine transporters in autophagy regulation and identify indatraline as a novel agent for inducing autophagy. PMID:27694974

  10. Sodium orthovanadate suppresses palmitate-induced cardiomyocyte apoptosis by regulation of the JAK2/STAT3 signaling pathway.

    Science.gov (United States)

    Liu, Jing; Fu, Hui; Chang, Fen; Wang, Jinlan; Zhang, Shangli; Caudle, Yi; Zhao, Jing; Yin, Deling

    2016-05-01

    Elevated circulatory free fatty acids (FFAs) especially saturated FFAs, such as palmitate (PA), are detrimental to the heart. However, mechanisms responsible for this phenomenon remain unknown. Here, the role of JAK2/STAT3 in PA-induced cytotoxicity was investigated in cardiomyocytes. We demonstrate that PA suppressed the JAK2/STAT3 pathway by dephosphorylation of JAK2 (Y1007/1008) and STAT3 (Y705), and thus blocked the translocation of STAT3 into the nucleus. Conversely, phosphorylation of S727, another phosphorylated site of STAT3, was increased in response to PA treatment. Pretreatment of JNK inhibitor, but not p38 MAPK inhibitor, inhibited STAT3 (S727) activation induced by PA and rescued the phosphorylation of STAT3 (Y705). The data suggested that JNK may be another upstream factor regulating STAT3, and verified the important function of P-STAT3 (Y705) in PA-induced cardiomyocyte apoptosis. Sodium orthovanadate (SOV), a protein tyrosine phosphatase inhibitor, obviously inhibited PA-induced apoptosis by restoring JAK2/STAT3 pathways. This effect was diminished by STAT3 inhibitor Stattic. Collectively, our data suggested a novel mechanism that the inhibition of JAK2/STAT3 activation was responsible for palmitic lipotoxicity and SOV may act as a potential therapeutic agent by targeting JAK2/STAT3 in lipotoxic cardiomyopathy treatment.

  11. Aspirin-induced heat stress resistance in chicken myocardial cells can be suppressed by BAPTA-AM in vitro.

    Science.gov (United States)

    Wu, Di; Zhang, Miao; Lu, Yinjun; Tang, Shu; Kemper, N; Hartung, J; Bao, Endong

    2016-09-01

    Our recent studies have displayed the protective functions of aspirin against heat stress (HS) in chicken myocardial cells, and it may be associated with heat shock proteins (HSPs). In this study, we further investigated the potential role of HSPs in the aspirin-induced heat stress resistance. Four of the most important HSPs including HspB1 (Hsp27), Hsp60, Hsp70, and Hsp90 were induced by aspirin pretreatment and were suppressed by BAPTA-AM. When HSPs were induced by aspirin, much slighter HS injury was detected. But more serious damages were observed when HSPs were suppressed by BAPTA-AM than those cells exposed to HS without BAPTA-AM, even the myocardial cells have been treated with aspirin in prior. Comparing to other HSPs, HspB1 presented the largest increase after aspirin treatments, 86-fold higher than the baseline (the level before HS). These findings suggested that multiple HSPs participated in aspirin's anti-heat stress function but HspB1 may contribute the most. Interestingly, during the experiments, we also found that apoptosis rate as well as the oxidative stress indicators (T-SOD and MDA) was not consistently responding to heat stress injury as expected. By selecting from a series of candidates, myocardial cell damage-related enzymes (CK-MB and LDH), cytopathological tests, and necrosis rate (measured by flow cytometry assays) are believed to be reliable indicators to evaluate heat stress injury in chicken's myocardial cells and they will be used in our further investigations.

  12. Novel anti-apoptotic mechanism of A20 through targeting ASK1 to suppress TNF-induced JNK activation.

    Science.gov (United States)

    Won, M; Park, K A; Byun, H S; Sohn, K-C; Kim, Y-R; Jeon, J; Hong, J H; Park, J; Seok, J H; Kim, J M; Yoon, W-H; Jang, I-S; Shen, H M; Liu, Z G; Hur, G M

    2010-12-01

    The zinc-finger protein A20 has crucial physiological functions as a dual inhibitor of nuclear factor-κB (NF-κB) activation and apoptosis in tumor necrosis factor (TNF) receptor 1 signaling pathway. Although the molecular basis for the anti-NF-κB function of A20 has been well elucidated, the anti-apoptotic function of A20 is largely unknown. Here, we report a novel mechanism underlying the anti-apoptotic function of A20: A20 blocks TNF-induced apoptosis through suppression of c-jun N-terminal kinase (JNK) by targeting apoptosis signal-regulating kinase1 (ASK1). First, the ectopic expression of A20 drastically inhibits TNF-induced JNK activation and apoptosis in multiple cell types including those deficient of NF-κB activation. Unexpectedly, the blunting effect of A20 on TNF-induced JNK activation is not mediated by affecting the TNFR1 signaling complex formation. Instead, A20 interacts with ASK1, an important MAPKK kinase in the JNK signaling cascade. More importantly, overexpression of wild-type A20, but not of mutant A20 (ZnF4; C624A, C627A), promotes degradation of the ASK1 through the ubiquitin-proteasome system. Taken together, the results from this study reveal a novel anti-apoptotic mechanism of A20 in TNF signaling pathway: A20 binds to ASK1 and mediates ASK1 degradation, leading to suppression of JNK activation and eventually blockage of apoptosis.

  13. AA-PMe, a novel asiatic acid derivative, induces apoptosis and suppresses proliferation, migration, and invasion of gastric cancer cells.

    Science.gov (United States)

    Jing, Yue; Wang, Gang; Ge, Ying; Xu, Minjie; Tang, Shuainan; Gong, Zhunan

    2016-01-01

    Asiatic acid (AA; 2α,3β,23-trihydroxyurs-12-ene-28-oic acid) is widely used for medicinal purposes in many Asian countries due to its various bioactivities. A series of AA derivatives has been synthesized in attempts to improve its therapeutic potencies. Herein we investigated the anti-tumor activities of N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe), a novel AA derivative. AA-PMe exhibited a stronger anti-cancer activity than its parent compound AA. AA-PMe inhibited the proliferation of SGC7901 and HGC27 human gastric cancer cells in a dose-dependent manner but had no significant toxicity in human gastric mucosa epithelial cells (GES-1). AA-PMe induced cell cycle arrest in G0/G1 phase and blocked G1-S transition, which correlated well with marked decreases in levels of cyclin D1, cyclin-dependent kinase CKD4, and phosphorylated retinoblastoma protein, and increase in cyclin-dependent kinase inhibitor P15. Further, AA-PMe induced apoptosis of human gastric cancer cells by affecting Bcl-2, Bax, c-Myc, and caspase-3. Moreover, AA-PMe suppressed the migration and invasion of human gastric cancer cells (SGC7901 and HGC27) cells by downregulating the expression of MMP-2 and MMP-9. Overall, this study investigated the potential anti-cancer activities of AA-PMe including inducing apoptosis and suppressing proliferation, migration and invasion of gastric cancer cells, as well as the underlying mechanisms, suggesting that AA-PMe is a promising anti-cancer drug candidate in gastric cancer therapy.

  14. AA-PMe, a novel asiatic acid derivative, induces apoptosis and suppresses proliferation, migration, and invasion of gastric cancer cells

    Science.gov (United States)

    Jing, Yue; Wang, Gang; Ge, Ying; Xu, Minjie; Tang, Shuainan; Gong, Zhunan

    2016-01-01

    Asiatic acid (AA; 2α,3β,23-trihydroxyurs-12-ene-28-oic acid) is widely used for medicinal purposes in many Asian countries due to its various bioactivities. A series of AA derivatives has been synthesized in attempts to improve its therapeutic potencies. Herein we investigated the anti-tumor activities of N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe), a novel AA derivative. AA-PMe exhibited a stronger anti-cancer activity than its parent compound AA. AA-PMe inhibited the proliferation of SGC7901 and HGC27 human gastric cancer cells in a dose-dependent manner but had no significant toxicity in human gastric mucosa epithelial cells (GES-1). AA-PMe induced cell cycle arrest in G0/G1 phase and blocked G1-S transition, which correlated well with marked decreases in levels of cyclin D1, cyclin-dependent kinase CKD4, and phosphorylated retinoblastoma protein, and increase in cyclin-dependent kinase inhibitor P15. Further, AA-PMe induced apoptosis of human gastric cancer cells by affecting Bcl-2, Bax, c-Myc, and caspase-3. Moreover, AA-PMe suppressed the migration and invasion of human gastric cancer cells (SGC7901 and HGC27) cells by downregulating the expression of MMP-2 and MMP-9. Overall, this study investigated the potential anti-cancer activities of AA-PMe including inducing apoptosis and suppressing proliferation, migration and invasion of gastric cancer cells, as well as the underlying mechanisms, suggesting that AA-PMe is a promising anti-cancer drug candidate in gastric cancer therapy. PMID:27073325

  15. 1, 25(OH)2D3 protects β cell against high glucose-induced apoptosis through mTOR suppressing.

    Science.gov (United States)

    Yang, Zesong; Liu, Fang; Qu, Hua; Wang, Hang; Xiao, Xiaoqiu; Deng, Huacong

    2015-10-15

    Diabetes mellitus is a leading cause of death and disability worldwide, which presents a serious public health crisis in China nowadays. It has been well recognized that excessive β-cell apoptosis is the key pathogenesis of diabetes, of which the mammalian target of rapamycin (mTOR) serves as the critical signaling pathway. Emerging evidence indicates that vitamin D deficiency acts as a potential risk factor for diabetes. The present study aims to test the hypothesis that 1 alpha, 25-dihydroxyvitamin D(3) [1, 25(OH)2D3] can inhibit β-cell apoptosis via the suppression of mTOR signaling pathway. β-cells (INS-1) were cultured in the context of normal glucose or high glucose media with or without 1, 25(OH)2D3 treatment. β-cell apoptosis was evaluated by inverted fluorescence microscope, flow cytometry and electron microscope, respectively. Quantitative RT-PCR and Western blotting were performed to assess the possible perturbations in mTOR signaling pathway. High glucose significantly increased β-cell apoptosis. Of importance, RT-PCR and Western blotting demonstrated that high glucose inhibited DNA-damage-inducible transcript 4 (DDIT4) and TSC1/TSC2, up-regulated Rheb/mTOR/p70S6K and enhanced expression of the ap