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  1. Isosorbide delays gentamicin-induced vestibular sensory cell death.

    Science.gov (United States)

    Takumida, Masaya; Anniko, Matti

    2005-01-01

    The efficacy of isosorbide for protection from vestibular sensory cell damage was investigated. The effects of isosorbide on gentamicin-induced production of nitric oxide (NO) and reactive oxygen species (ROS) were studied by means of the fluorescence indicators 4,5-diaminofluorescein diacetate and dihydrotetramethylrosamine. The effect on gentamicin-induced vestibular sensory cell damage was examined by using an in vitro LIVE/DEAD system. Isosorbide inhibited the production of both NO and ROS. Isosorbide limited the vestibular sensory cell damage caused by gentamicin. It is, therefore, suggested that isosorbide may help to treat inner ear disorders.

  2. Delayed luminescence to monitor programmed cell death induced by berberine on thyroid cancer cells

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    Scordino, Agata; Campisi, Agata; Grasso, Rosaria; Bonfanti, Roberta; Gulino, Marisa; Iauk, Liliana; Parenti, Rosalba; Musumeci, Francesco

    2014-11-01

    Correlation between apoptosis and UVA-induced ultraweak photon emission delayed luminescence (DL) from tumor thyroid cell lines was investigated. In particular, the effects of berberine, an alkaloid that has been reported to have anticancer activities, on two cancer cell lines were studied. The FTC-133 and 8305C cell lines, as representative of follicular and anaplastic thyroid human cancer, respectively, were chosen. The results show that berberine is able to arrest cell cycle and activate apoptotic pathway as shown in both cell lines by deoxyribonucleic acid fragmentation, caspase-3 cleavage, p53 and p27 protein overexpression. In parallel, changes in DL spectral components after berberine treatment support the hypothesis that DL from human cells originates mainly from mitochondria, since berberine acts especially at the mitochondrial level. The decrease of DL blue component for both cell lines could be related to the decrease of intra-mitochondrial nicotinamide adenine dinucleotide and may be a hallmark of induced apoptosis. In contrast, the response in the red spectral range is different for the two cell lines and may be ascribed to a different iron homeostasis.

  3. The enteropathogenic Escherichia coli effector Cif induces delayed apoptosis in epithelial cells.

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    Samba-Louaka, Ascel; Nougayrède, Jean-Philippe; Watrin, Claude; Oswald, Eric; Taieb, Frédéric

    2009-12-01

    The cycle inhibiting factor (Cif) belongs to a family of bacterial toxins, the cyclomodulins, which modulate the host cell cycle. Upon injection into the host cell by the type III secretion system of enteropathogenic Escherichia coli (EPEC), Cif induces both G(2) and G(1) cell cycle arrests. The cell cycle arrests correlate with the accumulation of p21(waf1) and p27(kip1) proteins that inhibit CDK-cyclin complexes, whose activation is required for G(1)/S and G(2)/M transitions. Increases of p21 and p27 levels are independent of p53 transcriptional induction and result from protein stabilization through inhibition of the ubiquitin/proteasome degradation pathway. In this study, we show that Cif not only induces cell cycle arrest but also eventually provokes a delayed cell death. Indeed, 48 h after infection with EPEC expressing Cif, cultured IEC-6 intestinal cells were positive for extracellular binding of annexin V and exhibited high levels of cleaved caspase-3 and lactate dehydrogenase release, indicating evidence of apoptosis. Cif was necessary and sufficient for inducing this late apoptosis, and the cysteine residue of the catalytic site was required for Cif activity. These results highlight a more complex role of Cif than previously thought, as a cyclomodulin but also as an apoptosis inducer.

  4. Coronatine inhibits stomatal closure and delays hypersensitive response cell death induced by nonhost bacterial pathogens

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    Seonghee Lee

    2013-02-01

    Full Text Available Pseudomonas syringae is the most widespread bacterial pathogen in plants. Several strains of P. syringae produce a phytotoxin, coronatine (COR, which acts as a jasmonic acid mimic and inhibits plant defense responses and contributes to disease symptom development. In this study, we found that COR inhibits early defense responses during nonhost disease resistance. Stomatal closure induced by a nonhost pathogen, P. syringae pv. tabaci, was disrupted by COR in tomato epidermal peels. In addition, nonhost HR cell death triggered by P. syringae pv. tabaci on tomato was remarkably delayed when COR was supplemented along with P. syringae pv. tabaci inoculation. Using isochorismate synthase (ICS-silenced tomato plants and transcript profiles of genes in SA- and JA-related defense pathways, we show that COR suppresses SA-mediated defense during nonhost resistance.

  5. Staphylococcus aureus-induced G2/M phase transition delay in host epithelial cells increases bacterial infective efficiency.

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    Ludmila Alekseeva

    Full Text Available Staphylococcus aureus is a highly versatile, opportunistic pathogen and the etiological agent of a wide range of infections in humans and warm-blooded animals. The epithelial surface is its principal site of colonization and infection. In this work, we investigated the cytopathic effect of S. aureus strains from human and animal origins and their ability to affect the host cell cycle in human HeLa and bovine MAC-T epithelial cell lines. S. aureus invasion slowed down cell proliferation and induced a cytopathic effect, resulting in the enlargement of host cells. A dramatic decrease in the number of mitotic cells was observed in the infected cultures. Flow cytometry analysis revealed an S. aureus-induced delay in the G2/M phase transition in synchronous HeLa cells. This delay required the presence of live S. aureus since the addition of the heat-killed bacteria did not alter the cell cycle. The results of Western blot experiments showed that the G2/M transition delay was associated with the accumulation of inactive cyclin-dependent kinase Cdk1, a key inducer of mitosis entry, and with the accumulation of unphosphorylated histone H3, which was correlated with a reduction of the mitotic cell number. Analysis of S. aureus proliferation in asynchronous, G1- and G2-phase-enriched HeLa cells showed that the G2 phase was preferential for bacterial infective efficiency, suggesting that the G2 phase delay may be used by S. aureus for propagation within the host. Taken together, our results divulge the potential of S. aureus in the subversion of key cellular processes such as cell cycle progression, and shed light on the biological significance of S. aureus-induced host cell cycle alteration.

  6. Prenatal induced chronic dietary hypothyroidism delays but does not block adult-type Leydig cell development

    NARCIS (Netherlands)

    Rijntjes, E.; Teerds, K.J.; Swarts, H.J.

    2009-01-01

    Transient hypothyroidism induced by propyl-2-thiouracyl blocks postpartum Leydig cell development. In the present study, the effects of chronic hypothyroidism on the formation of this adult-type Leydig cell population were investigated, using a more physiological approach. Before mating, dams were

  7. Rhinovirus infection induces cytotoxicity and delays wound healing in bronchial epithelial cells

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    Constantopoulos Andreas G

    2005-10-01

    Full Text Available Abstract Background Human rhinoviruses (RV, the most common triggers of acute asthma exacerbations, are considered not cytotoxic to the bronchial epithelium. Recent observations, however, have questioned this knowledge. The aim of this study was to evaluate the ability of RV to induce epithelial cytotoxicity and affect epithelial repair in-vitro. Methods Monolayers of BEAS-2B bronchial epithelial cells, seeded at different densities were exposed to RV serotypes 1b, 5, 7, 9, 14, 16. Cytotoxicity was assessed chromatometrically. Epithelial monolayers were mechanically wounded, exposed or not to RV and the repopulation of the damaged area was assessed by image analysis. Finally epithelial cell proliferation was assessed by quantitation of proliferating cell nuclear antigen (PCNA by flow cytometry. Results RV1b, RV5, RV7, RV14 and RV16 were able to induce considerable epithelial cytotoxicity, more pronounced in less dense cultures, in a cell-density and dose-dependent manner. RV9 was not cytotoxic. Furthermore, RV infection diminished the self-repair capacity of bronchial epithelial cells and reduced cell proliferation. Conclusion RV-induced epithelial cytotoxicity may become considerable in already compromised epithelium, such as in the case of asthma. The RV-induced impairment on epithelial proliferation and self-repair capacity may contribute to the development of airway remodeling.

  8. Teriparatide Induced Delayed Persistent Hypercalcemia

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    Nirosshan Thiruchelvam

    2014-01-01

    Full Text Available Teriparatide, a recombinant PTH, is an anabolic treatment for osteoporosis that increases bone density. Transient hypercalcemia is a reported side effect of teriparatide that is seen few hours following administration of teriparatide and resolves usually within 16 hours of drug administration. Persistent hypercalcemia, although not observed in clinical trials, is rarely reported. The current case describes a rare complication of teriparatide induced delayed persistent hypercalcemia.

  9. Gastrointestinal dysfunction induced by early weaning is attenuated by delayed weaning and mast cell blockade in pigs.

    Science.gov (United States)

    Moeser, Adam J; Ryan, Kathleen A; Nighot, Prashant K; Blikslager, Anthony T

    2007-08-01

    Our previous work has demonstrated that weaning at 19 days of age has deleterious effects on mucosal barrier function in piglet intestine that are mediated through peripheral CRF receptor signaling pathways. The objectives of the present study were to assess the impact of piglet age on weaning-associated intestinal dysfunction and to determine the role that mast cells play in weaning-induced breakdown of mucosal barrier function. Nursing Yorkshire-cross piglets were either weaned at 19 days of age (early-weaned, n = 8) or 28 days of age (late-weaned, n = 8) and housed in nursery pens. Twenty-four hours postweaning, segments of midjejunum and ascending colon from piglets within each weaning age group were harvested and mounted on Ussing chambers for measurements of transepithelial electrical resistance and serosal-to-mucosal [(3)H]mannitol fluxes. Early weaning resulted in reductions in transepithelial electrical resistance and increases in mucosal permeability to [(3)H]mannitol in the jejunum and colon (P piglets weaned at 28 days of age. Early-weaned piglet intestinal mucosa had increased expression of CRF receptor 1 protein, increased mucosal mast cell tryptase levels, and evidence of enhanced mast cell degranulation compared with late-weaned intestinal mucosa. Pretreatment of piglets with the mast cell stabilizer drug cromolyn, injected intraperitoneally 30 min prior to weaning, abolished the early-weaning-induced intestinal barrier disturbances. Our results indicate that early-weaning stress induces mucosal dysfunction mediated by intestinal mast cell activation and can be prevented by delaying weaning.

  10. p53 dependent apoptosis and cell cycle delay induced by heteroleptic complexes in human cervical cancer cells.

    Science.gov (United States)

    Sharma, Gunjan; Rana, Nishant Kumar; Singh, Priya; Dubey, Pradeep; Pandey, Daya Shankar; Koch, Biplob

    2017-04-01

    We previously reported synthesis of novel arene ruthenium (Ru) complexes and evaluated their antitumor activity in murine lymphoma (DL) cells. In this present study we further investigated the mechanism of action of two ruthenium complexes [complex 1 (η6-arene)RuCl(2-pcdpm)] and complex 2 (η6-arene)RuCl(4-mtdpm)] in cervical cancer cell line (HeLa). Our studies demonstrate that anticancer property of these two complexes was due to induction of apoptosis through p53 mediated pathway as well as arrest of cells in G2/M phase of cell cycle. It is worth to note that the complexes did not cause any substantial cytotoxic effect on normal cells. Further in comprehensive studies, apoptosis inducing property of both complexes were established in accordance with array of morphological changes ranging from membrane blebbing to formation of apoptotic bodies and followed by DNA fragmentation assay. Furthermore, Flow cytometry by Annexin V/PI staining delineate that complex 1 and 2 have strident impact to induce apoptosis in HeLa cells. The complex 1 and 2 treated cells show increased level of intracellular ROS generation which was preceded by p53 activation. Apoptosis induced by 1 and 2 was preceded by mitochondrial aggregations which were monitored by mitotracker. In addition flow cytometry analysis showed that both complexes also effectively arrest cells at G2/M phase of cell cycle. Western blot, RT-PCR as well as Real Time analysis were used to further confirm that the complexes induced apoptosis in p53 dependent pathway. Thus, our promising results can contribute to the rational design of novel potential anticancer agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  11. Ectopic expression of Capsicum-specific cell wall protein Capsicum annuum senescence-delaying 1 (CaSD1) delays senescence and induces trichome formation in Nicotiana benthamiana.

    Science.gov (United States)

    Seo, Eunyoung; Yeom, Seon-In; Jo, Sunghwan; Jeong, Heejin; Kang, Byoung-Cheorl; Choi, Doil

    2012-04-01

    Secreted proteins are known to have multiple roles in plant development, metabolism, and stress response. In a previous study to understand the roles of secreted proteins, Capsicum annuum secreted proteins (CaS) were isolated by yeast secretion trap. Among the secreted proteins, we further characterized Capsicum annuum senescence-delaying 1 (CaSD1), a gene encoding a novel secreted protein that is present only in the genus Capsicum. The deduced CaSD1 contains multiple repeats of the amino acid sequence KPPIHNHKPTDYDRS. Interestingly, the number of repeats varied among cultivars and species in the Capsicum genus. CaSD1 is constitutively expressed in roots, and Agrobacterium-mediated transient overexpression of CaSD1 in Nicotiana benthamiana leaves resulted in delayed senescence with a dramatically increased number of trichomes and enlarged epidermal cells. Furthermore, senescence- and cell division-related genes were differentially regulated by CaSD1-overexpressing plants. These observations imply that the pepper-specific cell wall protein CaSD1 plays roles in plant growth and development by regulating cell division and differentiation.

  12. Delayed-type hypersensitivity reactions induced by proton pump inhibitors: A clinical and in vitro T-cell reactivity study.

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    Lin, C-Y; Wang, C-W; Hui, C-Y R; Chang, Y-C; Yang, C-H; Cheng, C-Y; Chen, W-W; Ke, W-M; Chung, W-H

    2017-06-28

    Proton pump inhibitors (PPIs) have been known to induce type I hypersensitivity reactions. However, severe delayed-type hypersensitivity reactions (DHR) induced by PPI, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS), are rarely reported. We conducted a study of a large series of PPI-related DHR, followed up their tolerability to alternative anti-ulcer agents, and investigated the T-cell reactivity to PPI in PPI-related DHR patients. We retrospectively analyzed patients with PPI-related DHR from multiple medical centers in Taiwan during the study period January 2003 to April 2016. We analyzed the causative PPI, clinical manifestations, organ involvement, treatment, and complications. We also followed up the potential risk of cross-hypersensitivity or tolerability to other PPI after their hypersensitivity episodes. Drug lymphocyte activation test (LAT) was conducted by measuring granulysin and interferon-γ to confirm the causalities. There were 69 cases of PPI-related DHR, including SJS/TEN (n=27) and DRESS (n=10). The LAT by measuring granulysin showed a sensitivity of 59.3% and specificity of 96.4%. Esomeprazole was the most commonly involved in PPI-related DHR (51%). Thirteen patients allergic to one kind of PPI could tolerate other structurally different PPI without cross-hypersensitivity reactions, whereas three patients developed cross-hypersensitivity reactions to alternative structurally similar PPI. The cross-reactivity to structurally similar PPI was also observed in LAT assay. PPIs have the potential to induce life-threatening DHR. In patients when PPI is necessary for treatment, switching to structurally different alternatives should be considered. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

  13. Delayed persistence of giant-nucleated cells induced by X-ray and proton irradiation in the progeny of replicating normal human f ibroblast cells

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    Almahwasi, A. A.; Jeynes, J. C.; Merchant, M. J.; Bradley, D. A.; Regan, P. H.

    2017-08-01

    Ionising radiation can induce giant-nucleated cells (GCs) in the progeny of irradiated populations, as demonstrated in various cellular systems. Most in vitro studies have utilised quiescent cancerous or normal cell lines but it is not clear whether radiation-induced GCs persist in the progeny of normal replicated cells. In the current work we show persistent induction of GCs in the progeny of normal human-diploid skin fibroblasts (AG1522). These cells were originally irradiated with a single equivalent clinical dose of 0.2, 1 or 2 Gy of either X-ray or proton irradiation and maintained in an active state for various post-irradiation incubation interval times before they were replated for GC analysis. The results demonstrate that the formation of GCs in the progeny of X-ray or proton irradiated cells was increased in a dose-dependent manner when measured 7 days after irradiation and this finding is in agreement with that reported for the AG1522 cells using other radiation qualities. For the 1 Gy X-ray doses it was found that the GC yield increased continually with time up to 21 days post-irradiation. These results can act as benchmark data for such work and may have important implications for studies aimed at evaluating the efficacy of radiation therapy and in determining the risk of delayed effects particularly when applying protons.

  14. Expression of orphan G-protein coupled receptor GPR174 in CHO cells induced morphological changes and proliferation delay via increasing intracellular cAMP

    Energy Technology Data Exchange (ETDEWEB)

    Sugita, Kazuya; Yamamura, Chiaki; Tabata, Ken-ichi [Laboratory of Pharmacoinformatics, Graduate School of Ritsumeikan University, Kusatsu, Shiga 525-8577 (Japan); Fujita, Norihisa, E-mail: nori@ph.ritsumei.ac.jp [Laboratory of Pharmacoinformatics, Graduate School of Ritsumeikan University, Kusatsu, Shiga 525-8577 (Japan); School of Pharmacy, Ristumeikan University, Kusatsu, Shiga 525-8577 (Japan)

    2013-01-04

    Highlights: Black-Right-Pointing-Pointer Expression of GPR174 in CHO cells induces morphological changes and proliferation delay. Black-Right-Pointing-Pointer These are due to increase in intracellular cAMP concentration. Black-Right-Pointing-Pointer Lysophosphatidylserine was identified to stimulate GPR174 leading to activate ACase. Black-Right-Pointing-Pointer The potencies of fatty acid moiety on LysoPS were oleoyl Greater-Than-Or-Slanted-Equal-To stearoyl > palmitoyl. Black-Right-Pointing-Pointer We propose that GPR174 is a lysophosphatidylserine receptor. -- Abstract: We established cell lines that stably express orphan GPCR GPR174 using CHO cells, and studied physiological and pharmacological features of the receptor. GPR174-expressing cells showed cell-cell adhesion with localization of actin filaments to cell membrane, and revealed significant delay of cell proliferation. Since the morphological changes of GPR174-cells were very similar to mock CHO cells treated with cholera toxin, we measured the concentration of intracellular cAMP. The results showed the concentration was significantly elevated in GPR174-cells. By measuring intracellular cAMP concentration in GPR174-cells, we screened lipids and nucleotides to identify ligands for GPR174. We found that lysophosphatidylserine (LysoPS) stimulated increase in intracellular cAMP in a dose-dependent manner. Moreover, phosphorylation of Erk was elevated by LysoPS in GPR174 cells. These LysoPS responses were inhibited by NF449, an inhibitor of G{alpha}{sub s} protein. These results suggested that GPR174 was a putative LysoPS receptor conjugating with G{alpha}{sub s}, and its expression induced morphological changes in CHO cells by constitutively activating adenylyl cycles accompanied with cell conjunctions and delay of proliferation.

  15. Thy-1 stimulation of mouse T cells induces a delayed T cell receptor-like signal that results in Ca2+‑independent cytotoxicity.

    Science.gov (United States)

    Furlong, Suzanne; Power Coombs, Melanie R; Hoskin, David W

    2017-10-01

    Antibody-mediated crosslinking of Thy-1 [also known as cluster of differentiation (CD)90], results in a T cell receptor (TcR)‑like signal; however, the impact of Thy‑1 stimulation in comparison to TcR stimulation on T cell activation and effector function has yet to be fully elucidated. In the present study, the outcome of Thy‑1‑ and TcR‑induced stimulation of T cells was investigated in mice, using fragment crystalizable (Fc) receptor‑bound antibodies and costimulatory signals provided by syngeneic lipopolysaccharide‑matured bone marrow‑derived dendritic cells. Compared with TcR signaling, Thy‑1 signaling initiated a less robust proliferative response in T cells, as determined by tritiated‑thymidine incorporation. In addition, enzyme‑linked immunosorbent assays revealed that interleukin‑2 production was reduced, and the expression of CD25 and cyclin D3 was weaker in Thy‑1‑stimulated cells, as determined by western blotting; however, the expression of cyclin‑dependent kinase 6 was similar to that in TcR‑inducedcells. Furthermore, western blotting demonstrated that the phosphorylation of ζ-chain‑associated protein kinase 70 and extracellular signal‑regulated kinase 1/2 was delayed following Thy‑1 stimulation. DNA fragmentation assays revealed that cytotoxic effector function was also slower to develop in Thy‑1‑stimulated T cells, required more time to be effective and was largely Ca2+‑independent; these findings suggested that Fas ligand rather than granule‑associated perforin was involved in T cell effector function. In conclusion, the present results suggested that Thy‑1 signaling may contribute to the regulation of T cell homeostasis and the development of non‑specific T cell‑mediated cytotoxicity. However, further studies are required to elucidate the exact physiological roles of TcR‑like signals that result from Thy‑1 crosslinking and to investigate the molecular mechanisms that are involved.

  16. Ectopic Expression of Capsicum-Specific Cell Wall Protein Capsicum annuum Senescence-Delaying 1 (CaSD1) Delays Senescence and Induces Trichome Formation in Nicotiana benthamiana

    OpenAIRE

    Seo, Eunyoung; Yeom, Seon-In; Jo, SungHwan; Jeong, Heejin; Kang, Byoung-Cheorl; Choi, Doil

    2012-01-01

    Secreted proteins are known to have multiple roles in plant development, metabolism, and stress response. In a previous study to understand the roles of secreted proteins, Capsicum annuum secreted proteins (CaS) were isolated by yeast secretion trap. Among the secreted proteins, we further characterized Capsicum annuum senescence-delaying 1 (CaSD1), a gene encoding a novel secreted protein that is present only in the genus Capsicum. The deduced CaSD1 contains multiple repeats of the amino aci...

  17. Isotype-like suppression of T cell-mediated immunity in vivo. I. Delayed-type hypersensitivity specificity of T cell suppression induced by antigen-binding T cell factors that initiate contact sensitivity.

    Science.gov (United States)

    Ptak, W; Bereta, M; Ptak, M; Askenase, P W

    1986-03-01

    A new form of immunoregulation is described that is based on the recent suggestion that the effector phase of delayed-type hypersensitivity (DTH) responses consists of a cascade of steps that are dependent on the sequential action of two types of antigen-specific Ly-1+ effector cells. According to this formulation, which is based on analysis of contact sensitivity (CS) in mice, DTH consists of at least two T cell-dependent steps that must occur in sequence. The first of these steps occurs within 2 hr of challenge and depends on DTH-initiating, antigen-binding, antigen-specific T cell factors that sensitize the tissues for an obligatory initial vasoactive step, which allows the antigen/major histocompatibility complex (MHC)-restricted, Ly-1+ effector T cells of classic 24 to 48 hr DTH responses to enter the tissues and produce chemoattractant lymphokines. We have now found that nonspecific suppression of CS responses can be induced by i.v. injection of these antigen-binding, CS-initiating T cell factors. Injection of the antigen-binding T cell factor induces Ly-2+, I-J-, cyclophosphamide sensitive, seemingly nonspecific suppressor T cells to inhibit initiation of CS responses. These suppressor cells do not affect the late-acting lymphokine-producing T cells, but probably act by preventing production of antigen-specific factors of the type that are required to initiate DTH responses. Furthermore, injection of CS-initiating antigen-binding T cell factors also induces suppression of sheep red blood cell (SRBC)-specific DTH, but does not affect classic anti-SRBC B cell responses, which are dependent on antigen/MHC-restricted Ly-1+ helper T cells; skin allograft rejection responses are also not affected. Thus, the suppression is DTH-specific. In addition, suppression induced by antigen-binding T cell factors is Igh and not MHC/H-2 restricted. These findings and data in the companion manuscript showing that these suppressor T cells act by production of soluble suppressor

  18. Cell-free antigens from precocious Paracoccidioides brasiliensis culture induce a typical delayed-type hypersensitivity reaction

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    Fecchio CJ

    2011-01-01

    Full Text Available Cell-free antigens (CFAg derived from Paracoccidioides brasiliensis have typically been used in immunodiffusion reactions for serodiagnosis or therapeutic follow-up of paracoccidioidomycosis patients. Thus, we investigated the usefulness of CFAg obtained from cultures at different ages, to evaluate cellular immunity by the footpad test, in experimental murine paracoccidioidomycosis. Male mice infected with P. brasiliensis 265 strain were challenged in the footpad with CFAg obtained from four- (4d CFAg or 11-day-old cultures (11d CFAg. The increase in footpad swelling provoked by 4d CFAg and 11d CFAg was similar and showed significant difference in relation to control groups. However, the infiltrate pattern was strikingly different: 4d CFAg induced a predominant mononuclear infiltrate whereas 11d CFAg provoked a predominant polymophonuclear infiltrate. These different inflammatory patterns were associated with distinct electrophoretic characteristics. By comparison with 11d CFAg, 4d CFAg showed more numerous and intense bands, including a strong one of 43 kDa (gp43. These results suggest that CFAg derived from Pb 265 isolate can be used as a reagent to evaluate cellular immunity; however, the culture's age is critical because only young cultures are able to induce a typical mononuclear infiltrate. The efficacy of this new paracoccidioidin to assay the cellular immunity in infections caused by other P. brasiliensis isolates is under investigation.

  19. Heme oxygenase-1 delays gibberellin-induced programmed cell death of rice aleurone layers subjected to drought stress by interacting with nitric oxide

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    Huangming eWu

    2016-01-01

    Full Text Available Cereal aleurone layers undergo a gibberellin (GA-regulated process of programmed cell death (PCD following germination. Heme oxygenase-1 (HO-1 is known as a rate-liming enzyme in the degradation of heme to biliverdin IXα (BV, carbon monoxide (CO, and free iron ions (Fe2+. It is a critical component in plant development and adaptation to environment stresses. Our previous studies confirmed that HO-1 inducer hematin (Ht promotes the germination of rice seeds in drought (20% polyethylene glycol-6000, PEG conditions, but the corresponding effects of HO-1 on the alleviation of germination-triggered PCD in GA-treated rice aleurone layers remain unknown. The present study has determined that GA co-treated with PEG results in lower HO-1 transcript levels and HO activity, which in turn results in the development of vacuoles in aleurone cells, followed by PCD. The pharmacology approach illustrated that up- or down-regulated HO-1 gene expression and HO activity delayed or accelerated GA-induced PCD. Furthermore, the application of the HO-1 inducer hematin and nitric oxide (NO donor sodium nitroprusside (SNP not only activated HO-1 gene expression, HO activity, and endogenous NO content, but also blocked GA-induced rapid vacuolation and accelerated aleurone layers PCD under drought stress. However, both HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX and NO scavenger 2-(4-carboxyphenyl0-4, 4, 5, 5-tetramethylimidazoline-l-oxyl-3-oxide potassium salt (cPTIO reserved the effects of hematin and SNP on rice aleurone layer PCD under drought stress by down-regulating endogenous HO-1 and NO, respectively. The inducible effects of hematin and SNP on HO-1 gene expression, HO activity, and NO content were blocked by cPTIO. Together, these results clearly suggest that HO-1 is involved in the alleviation of GA-induced PCD of drought-triggered rice aleurone layers by associating with NO.

  20. Delayed leaf senescence induces extreme drought tolerance in crop plants

    OpenAIRE

    Rivero, Rosa; Peleg, Zvi; Szczerba, Mark; Tumimbang, Ellen; Jauregui, Rosa N; Liu, Li; Blumwald, Eduardo

    2009-01-01

    Drought, the most prominent threat to agricultural production worldwide, accelerates leaf senescence, leading to a decrease in canopy size, loss in photosynthesis and reduced yields. On the basis of the assumption that senescence is a type of cell death program that could be inappropriately activated during drought, we hypothesized that it may be possible to enhance drought tolerance by delaying drought-induced leaf senescence through the stress-induced synthesis of cytokinins. We generated m...

  1. Delay estimation for CMOS functional cells

    DEFF Research Database (Denmark)

    Madsen, Jan

    1991-01-01

    Presents a new RC tree network model for delay estimation of CMOS functional cells. The model is able to reflect topological changes within a cell, which is of particular interest when doing performance driven layout synthesis. Further, a set of algorithms to perform worst case analysis on arbitr...... on arbitrary CMOS functional cells using the proposed delay model, is presented. Both model and algorithms have been implemented as a part of a cell compiler (CELLO) working in an experimental silicon compiler environment....

  2. Targeted cytosine deaminase-uracil phosphoribosyl transferase suicide gene therapy induces small cell lung cancer-specific cytotoxicity and tumor growth delay.

    Science.gov (United States)

    Christensen, Camilla L; Gjetting, Torben; Poulsen, Thomas T; Cramer, Frederik; Roth, Jack A; Poulsen, Hans S

    2010-04-15

    Small cell lung cancer (SCLC) is a highly malignant cancer for which there is no curable treatment. Novel therapies are therefore in great demand. In the present study we investigated the therapeutic effect of transcriptionally targeted suicide gene therapy for SCLC based on the yeast cytosine deaminase (YCD) gene alone or fused with the yeast uracil phosphoribosyl transferase (YUPRT) gene followed by administration of 5-fluorocytosine (5-FC) prodrug. The YCD gene or the YCD-YUPRT gene was placed under regulation of the SCLC-specific promoter insulinoma-associated 1 (INSM1). Therapeutic effect was evaluated in vitro in SCLC cell lines and in vivo in SCLC xenografted nude mice using the nonviral nanoparticle DOTAP/cholesterol for transgene delivery. INSM1-YCD/5-FC and INSM1-YCD-YUPRT/5-FC therapy induced high cytotoxicity in a range of SCLC cell lines. The highest therapeutic effect was obtained from the YCD-YUPRT fusion gene strategy. No cytotoxicity was induced after treatment of cell lines of other origin than SCLC. In addition the INSM1-YCD-YUPRT/5-FC therapy was superior to an established suicide gene system consisting of the herpes simplex virus thymidine kinase (HSVTK) gene and the prodrug ganciclovir. The superior effect was in part due to massive bystander cytotoxicity of YCD-YUPRT-produced toxins. Finally, INSM1-YCD-YUPRT/5-FC therapy induced significant tumor growth delay in SCLC xenografts compared with control-treated xenografts. The current study is the first to test cytosine deaminase-based suicide gene therapy for SCLC and the first to show an antitumor effect from the delivery of suicide gene therapeutics for SCLC in vivo.

  3. Targeted cytosine deaminase-uracil phosphoribosyl transferase suicide gene therapy induces small cell lung cancer specific cytotoxicity and tumor growth delay

    Science.gov (United States)

    Christensen, Camilla L.; Gjetting, Torben; Poulsen, Thomas T.; Cramer, Frederik; Roth, Jack A.; Poulsen, Hans S.

    2012-01-01

    Purpose Small cell lung cancer (SCLC) is a highly malignant cancer for which there is no curable treatment and novel therapies are therefore in high demand. In the present study we investigated the therapeutic effect of transcriptionally targeted suicide gene therapy for SCLC based on the yeast cytosine deaminase (YCD) gene alone or fused with the yeast uracil phosphoribosyl transferase (YUPRT) gene followed by administration of 5-fluorocytosine (5-FC) prodrug Experimental design The YCD gene or the YCD-YUPRT gene was placed under regulation of the SCLC-specific promoter Insulinoma-associated 1 (INSM1). Therapeutic effect was evaluated in vitro in SCLC cell lines and in vivo in SCLC xenografted nude mice using the non-viral nanoparticle, DOTAP:Cholesterol for transgene delivery. Results INSM1-YCD/5-FC and INSM1-YCD-YUPRT/5-FC therapy induced high cytotoxicity in a range of SCLC cell lines. The highest therapeutic effect was obtained from the YCD-YUPRT fusion gene strategy. No cytotoxicity was induced after treatment of cell lines of other origin than SCLC. In addition the INSM1-YCD-YUPRT/5-FC therapy was superior to an established suicide gene system consisting of the Herpes Simplex Virus Thymidine Kinase (HSVTK) gene and prodrug Ganciclovir (GCV). The superior effect was in part due to massive bystander cytotoxicity of YCD-YUPRT-produced toxins. Finally, INSM1-YCD-YUPRT/5-FC therapy induced significant tumor growth delay in SCLC xenografts compared to control treated xenografts. Conclusions The current study is the first to test cytosine deaminase-based suicide gene therapy for SCLC and the first to demonstrate an anti-tumor effect from the delivery of suicide gene therapeutics for SCLC in vivo. PMID:20371678

  4. Meiotic multivalent orientation and cell developmental delay.

    Science.gov (United States)

    Sybenga, J; Hsiao, C; de Vries, J M

    1989-01-01

    In the heterozygote for the combination of an interchange (662W;3R/6R) and a Robertsonian split (3R) of rye, one type of adjacent orientation leads to trisomy in the progeny. Pollen mother cells with adjacent orientation of the translocation quinquivalent or with a trivalent and a bivalent were delayed in their development and appeared at prometaphase and metaphase later than cells with alternate quinquivalents. Delay in cell development is ascribed to unfavorable (early) prophase positioning of chromosomes.

  5. [Ca2+]i Elevation and Oxidative Stress Induce KCNQ1 Protein Translocation from the Cytosol to the Cell Surface and Increase Slow Delayed Rectifier (IKs) in Cardiac Myocytes*

    Science.gov (United States)

    Wang, Yuhong; Zankov, Dimitar P.; Jiang, Min; Zhang, Mei; Henderson, Scott C.; Tseng, Gea-Ny

    2013-01-01

    Our goals are to simultaneously determine the three-dimensional distribution patterns of KCNQ1 and KCNE1 in cardiac myocytes and to study the mechanism and functional implications for variations in KCNQ1/KCNE1 colocalization in myocytes. We monitored the distribution patterns of KCNQ1, KCNE1, and markers for subcellular compartments/organelles using immunofluorescence/confocal microscopy and confirmed the findings in ventricular myocytes by directly observing fluorescently tagged KCNQ1-GFP and KCNE1-dsRed expressed in these cells. We also monitored the effects of stress on KCNQ1-GFP and endoplasmic reticulum (ER) remodeling during live cell imaging. The data showed that 1) KCNE1 maintained a stable cell surface localization, whereas KCNQ1 exhibited variations in the cytosolic compartment (striations versus vesicles) and the degree of presence on the cell surface; 2) the degree of cell surface KCNQ1/KCNE1 colocalization was positively correlated with slow delayed rectifier (IKs) current density; 3) KCNQ1 and calnexin (an ER marker) shared a cytosolic compartment; and 4) in response to stress ([Ca2+]i elevation, oxidative overload, or AT1R stimulation), KCNQ1 exited the cytosolic compartment and trafficked to the cell periphery in vesicles. This was accompanied by partial ER fragmentation. We conclude that the cellular milieu regulates KCNQ1 distribution in cardiac myocytes and that stressful conditions can increase IKs by inducing KCNQ1 movement to the cell surface. This represents a hitherto unrecognized mechanism by which IKs fulfills its function as a repolarization reserve in ventricular myocytes. PMID:24142691

  6. [Ca2+]i elevation and oxidative stress induce KCNQ1 protein translocation from the cytosol to the cell surface and increase slow delayed rectifier (IKs) in cardiac myocytes.

    Science.gov (United States)

    Wang, Yuhong; Zankov, Dimitar P; Jiang, Min; Zhang, Mei; Henderson, Scott C; Tseng, Gea-Ny

    2013-12-06

    Our goals are to simultaneously determine the three-dimensional distribution patterns of KCNQ1 and KCNE1 in cardiac myocytes and to study the mechanism and functional implications for variations in KCNQ1/KCNE1 colocalization in myocytes. We monitored the distribution patterns of KCNQ1, KCNE1, and markers for subcellular compartments/organelles using immunofluorescence/confocal microscopy and confirmed the findings in ventricular myocytes by directly observing fluorescently tagged KCNQ1-GFP and KCNE1-dsRed expressed in these cells. We also monitored the effects of stress on KCNQ1-GFP and endoplasmic reticulum (ER) remodeling during live cell imaging. The data showed that 1) KCNE1 maintained a stable cell surface localization, whereas KCNQ1 exhibited variations in the cytosolic compartment (striations versus vesicles) and the degree of presence on the cell surface; 2) the degree of cell surface KCNQ1/KCNE1 colocalization was positively correlated with slow delayed rectifier (IKs) current density; 3) KCNQ1 and calnexin (an ER marker) shared a cytosolic compartment; and 4) in response to stress ([Ca(2+)]i elevation, oxidative overload, or AT1R stimulation), KCNQ1 exited the cytosolic compartment and trafficked to the cell periphery in vesicles. This was accompanied by partial ER fragmentation. We conclude that the cellular milieu regulates KCNQ1 distribution in cardiac myocytes and that stressful conditions can increase IKs by inducing KCNQ1 movement to the cell surface. This represents a hitherto unrecognized mechanism by which IKs fulfills its function as a repolarization reserve in ventricular myocytes.

  7. Carbon monoxide-induced delayed amnesia, delayed neuronal death and change in acetylcholine concentration in mice

    Energy Technology Data Exchange (ETDEWEB)

    Nabeshima, T.; Katoh, A.; Ishimaru, H.; Yoneda, Y.; Ogita, K.; Murase, K.; Ohtsuka, H.; Inari, K.; Fukuta, T.; Kameyama, T. (Meijo Univ., Nagoya (Japan))

    1991-01-01

    We investigated the interrelationship of delayed amnesia, delayed neuronal death and changes in acetylcholine concentration induced by carbon monoxide (CO)-exposure in mice. In the test for retention of the passive avoidance task, amnesia was observed 5 and 7 days after CO-exposure when the mice were exposed to CO 1 day after training; in the case when the mice were exposed to CO 5 and 7 days before training, amnesia was also observed in a retention test given 1 day after training. The number of pyramidal cells in the hippocampal CA1 subfield was lower than that of the control 3, 5 and 7 days after CO-exposure. But the neurodegeneration in the parietal cortex, area 1, was not observed until 7 days after CO-exposure. The findings indicated that the amnesia and the neuronal death were produced after a delay when the mice were exposed to CO. In addition, the delayed amnesia was closely related to the delayed neuronal death in the hippocampal CA1 subfield. Moreover, (3H)glutamate and (3H)glycine binding sites did not change after CO-exposure but, 7 days after CO-exposure, the concentration of acetylcholine and the binding of (3H)quinuclidinyl benzilate in the frontal cortex and the striatum were found to have significantly changed, but those in the hippocampus did not show significant change. Therefore, we suggest that delayed amnesia induced by CO-exposure may result from delayed neuronal death in the hippocampal CA1 subfield and dysfunction in the acetylcholinergic neurons, in the frontal cortex, the striatum and/or the hippocampus.

  8. Optogenetics reveal delayed afferent synaptogenesis on grafted human-induced pluripotent stem cell-derived neural progenitors

    DEFF Research Database (Denmark)

    Avaliani, Natalia; Sørensen, Andreas Toft; Ledri, Marco

    2014-01-01

    properties such as tetrodotoxin-sensitive sodium currents and action potentials (APs), as well as both spontaneous and evoked postsynaptic currents, indicating functional afferent synaptic inputs. The grafted cells had a distinct electrophysiological profile compared to host cells in the OHSCs with higher...... input resistance, lower resting membrane potential, and APs with lower amplitude and longer duration. To investigate the origin of synaptic afferents to the grafted lt-NES cell-derived neurons, the host neurons were transduced with Channelrhodopsin-2 (ChR2) and optogenetically activated by blue light...

  9. A newly synthesized Ligustrazine stilbene derivative inhibits PDGF-BB induced vascular smooth muscle cell phenotypic switch and proliferation via delaying cell cycle progression.

    Science.gov (United States)

    Peng, Chunlian; Zhang, Siming; Liu, Haixin; Jiao, Yanxiao; Su, Guifa; Zhu, Yan

    2017-11-05

    Vascular Smooth muscle cells (VSMCs) possess remarkable phenotype plasticity that allows it to rapidly adapt to fluctuating environmental cues, including the period of development and progression of vascular diseases such as atherosclerosis and restenosis subsequent to vein grafting or coronary intervention. Although VSMC phenotypic switch is an attractive target, there is no effective drug so far. Using rat aortic VSMCs, we investigate the effects of Ligustrazine and its synthetic derivatives on platelet-derived growth factor-BB (PDGF-BB) induced proliferation and phenotypic switch by a cell image-based screening of 60 Ligustrazine stilbene derivatives. We showed that one of the Ligustrazine stilbene derivatives TMP-C4a markedly inhibited PDGF-BB-induced VSMCs proliferation in a time and dose-dependent manner, which is more potent than Ligustrazine. Stimulation of contractile VSMCs with PDGF-BB significantly reduced the contractile marker protein α-smooth muscle actin expression and increased the synthetic marker proteins osteopontin expression. However, TMP-C4a effectively reversed this phenotypic switch, which was accompanied by a decreased expression of Matrix metalloproteinase 2 and 9 (MMP2 and MMP9) and cell cycle related proteins, including cyclin D1 and CDK4. In conclusion, the present study showed that a new Ligustrazine stilbene derivative TMP-C4a suppressed PDGF-induced VSMC proliferation and phenotypic switch, indicating that it has a potential to become a promising therapeutic agent for treating VSMC-related atherosclerosis and restenosis. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Precocious centriole disengagement and centrosome fragmentation induced by mitotic delay

    OpenAIRE

    Karki, Menuka; Keyhaninejad, Neda; Shuster, Charles B.

    2017-01-01

    The spindle assembly checkpoint (SAC) delays mitotic progression until all sister chromatid pairs achieve bi-orientation, and while the SAC can maintain mitotic arrest for extended periods, moderate delays in mitotic progression have significant effects on the resulting daughter cells. Here we show that when retinal-pigmented epithelial (RPE1) cells experience mitotic delay, there is a time-dependent increase in centrosome fragmentation and centriole disengagement. While most cells with disen...

  11. PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53

    DEFF Research Database (Denmark)

    Zandi, Roza; Selivanova, Galina; Christensen, Camilla Laulund

    2011-01-01

    Small cell lung cancer (SCLC) is a highly malignant disease with poor prognosis, necessitating the need to develop new and efficient treatment modalities. PRIMA-1(Met) (p53-dependent reactivation of massive apoptosis), also known as APR-246, is a small molecule, which restores tumor suppressor fu...... function to mutant p53 and induces cancer cell death in various cancer types. Since p53 is mutated in more than 90% of SCLC, we investigated the ability of PRIMA-1(Met) to induce apoptosis and inhibit tumor growth in SCLC with different p53 mutations....

  12. Dietary Indoles Suppress Delayed-Type Hypersensitivity by Inducing a Switch from Proinflammatory Th17 Cells to Anti-Inflammatory Regulatory T Cells through Regulation of MicroRNA.

    Science.gov (United States)

    Singh, Narendra P; Singh, Udai P; Rouse, Michael; Zhang, Jiajia; Chatterjee, Saurabh; Nagarkatti, Prakash S; Nagarkatti, Mitzi

    2016-02-01

    Aryl hydrocarbon receptor (AhR) has been shown to have profound influence on T cell differentiation, and use of distinct AhR ligands has shown that whereas some ligands induce regulatory T cells (Tregs), others induce Th17 cells. In the present study, we tested the ability of dietary AhR ligands (indole-3-carbinol [I3C] and 3,3'-diindolylmethane [DIM]) and an endogenous AhR ligand, 6-formylindolo(3,2-b)carbazole (FICZ), on the differentiation and functions of Tregs and Th17 cells. Treatment of C57BL/6 mice with indoles (I3C or DIM) attenuated delayed-type hypersensitivity (DTH) response to methylated BSA and generation of Th17 cells while promoting Tregs. In contrast, FICZ exacerbated the DTH response and promoted Th17 cells. Indoles decreased the induction of IL-17 but promoted IL-10 and Foxp3 expression. Also, indoles caused reciprocal induction of Tregs and Th17 cells only in wild-type (AhR(+/+)) but not in AhR knockout (AhR(-/-)) mice. Upon analysis of microRNA (miR) profile in draining lymph nodes of mice with DTH, treatment with I3C and DIM decreased the expression of several miRs (miR-31, miR-219, and miR-490) that targeted Foxp3, whereas it increased the expression of miR-495 and miR-1192 that were specific to IL-17. Interestingly, treatment with FICZ had precisely the opposite effects on these miRs. Transfection studies using mature miR mimics of miR-490 and miR-1192 that target Foxp3 and IL-17, respectively, or scrambled miR (mock) or inhibitors confirmed that these miRs specifically targeted Foxp3 and IL-17 genes. Our studies demonstrate, to our knowledge for the first time, that the ability of AhR ligands to regulate the differentiation of Tregs versus Th17 cells may depend on miR signature profile. Copyright © 2016 by The American Association of Immunologists, Inc.

  13. Controlling flow time delays in flexible manufacturing cells

    NARCIS (Netherlands)

    Slomp, J.; Caprihan, R.; Bokhorst, J. A. C.

    2009-01-01

    Flow time delays in Flexible Manufacturing Cells (FMCs) are caused by transport and clamping/reclamping activities. This paper shows how dynamic scheduling parameters may control the flow times of jobs and the available task windows for flow time delays.

  14. Precocious centriole disengagement and centrosome fragmentation induced by mitotic delay.

    Science.gov (United States)

    Karki, Menuka; Keyhaninejad, Neda; Shuster, Charles B

    2017-06-13

    The spindle assembly checkpoint (SAC) delays mitotic progression until all sister chromatid pairs achieve bi-orientation, and while the SAC can maintain mitotic arrest for extended periods, moderate delays in mitotic progression have significant effects on the resulting daughter cells. Here we show that when retinal-pigmented epithelial (RPE1) cells experience mitotic delay, there is a time-dependent increase in centrosome fragmentation and centriole disengagement. While most cells with disengaged centrioles maintain spindle bipolarity, clustering of disengaged centrioles requires the kinesin-14, HSET. Centrosome fragmentation and precocious centriole disengagement depend on separase and anaphase-promoting complex/cyclosome (APC/C) activity, which also triggers the acquisition of distal appendage markers on daughter centrioles and the loss of procentriolar markers. Together, these results suggest that moderate delays in mitotic progression trigger the initiation of centriole licensing through centriole disengagement, at which point the ability to maintain spindle bipolarity becomes a function of HSET-mediated spindle pole clustering.

  15. Modification of radiation-induced division delay by caffeine analogues and dibutyryl cyclic AMP

    Energy Technology Data Exchange (ETDEWEB)

    Kimler, B.F.; Leeper, D.B.; Snyder, M.H.; Rowley, R.; Schneiderman, M.H. (Thomas Jefferson Univ., Philadelphia, PA (USA). Hospital)

    1982-01-01

    The mitotic selection procedure for cell cycle analysis was utilized to investigate the concentration-dependent modification of x-radiation-induced division delay in Chinese hamster ovary (CHO) cells by methyl xanthines (caffeine, theophylline, and theobromine) and by dibutyryl cyclic AMP. The methyl xanthines (concentrations from 0.5 to 1000 ..mu..g/ml) all reduced radiation-induced division delay with the effect being linear between approximately 100 and 1000 ..mu..g/ml. After doses of 100-300 rad, delay was reduced by 75, 94 or 83 per cent at 1000 ..mu..g/ml for each drug, respectively. However, the addition of dibutyryl cyclic AMP had an opposite effect: radiation-induced delay was increased by the concentration range of 0.3 to 300 ..mu..g/ml. These results indicate that in mammalian cells the control of cell cycle progression and the modification of radiation-induced division delay are not simply related to intracellular levels of cyclic AMP. Rather, there appear to be at least two competing mechanisms which are differentially affected by caffeine analogues or by direct addition of dibutyryl cyclic AMP. The direct effect of caffeine and the methyl xanthines on membrane calcium permeability is considered.

  16. Role of Ku80-dependent end-joining in delayed genomic instability in mammalian cells surviving ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Suzuki, Keiji, E-mail: kzsuzuki@nagasaki-u.ac.jp [Course of Life Sciences and Radiation Research, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Kodama, Seiji [Research Institute for Advanced Science and Technology, Osaka Prefecture University, 1-2 Gakuen-machi, Sakai 599-8570 (Japan); Watanabe, Masami [Kyoto University Research Reactor Institute, Kumatori-cho Sennan-gun, Osaka 590-0494 (Japan)

    2010-01-05

    Ionizing radiation induces delayed destabilization of the genome in the progenies of surviving cells. This phenomenon, which is called radiation-induced genomic instability, is manifested by delayed induction of radiation effects, such as cell death, chromosome aberration, and mutation in the progeny of cells surviving radiation exposure. Previously, there was a report showing that delayed cell death was absent in Ku80-deficient Chinese hamster ovary (CHO) cells, however, the mechanism of their defect has not been determined. We found that delayed induction of DNA double strand breaks and chromosomal breaks were intact in Ku80-deficient cells surviving X-irradiation, whereas there was no sign for the production of chromosome bridges between divided daughter cells. Moreover, delayed induction of dicentric chromosomes was significantly compromised in those cells compared to the wild-type CHO cells. Reintroduction of the human Ku86 gene complimented the defective DNA repair and recovered delayed induction of dicentric chromosomes and delayed cell death, indicating that defective Ku80-dependent dicentric induction was the cause of the absence of delayed cell death. Since DNA-PKcs-defective cells showed delayed phenotypes, Ku80-dependent illegitimate rejoining is involved in delayed impairment of the integrity of the genome in radiation-survived cells.

  17. Ultrasound v. sham ultrasound for experimentally induced delayed ...

    African Journals Online (AJOL)

    In a double-blind controlled trial, delayed-onset muscle soreness (DOMS) was experimentally induced in both bicep muscles of 15 females. Sham US was applied to one bicep (n=15 biceps) and pulsed active US to the other bicep (n=15 biceps) of each participant, 48 and 72 h after induction of DOMS. Primary and ...

  18. Interleukin 1 β-induced SMAD2/3 linker modifications are TAK1 dependent and delay TGFβ signaling in primary human mesenchymal stem cells.

    Science.gov (United States)

    van den Akker, Guus G; van Beuningen, Henk M; Vitters, Elly L; Koenders, Marije I; van de Loo, Fons A; van Lent, Peter L; Blaney Davidson, Esmeralda N; van der Kraan, Peter M

    2017-12-01

    Chondrogenic differentiation of mesenchymal stem cells (MSC) requires transforming growth factor beta (TGFβ) signaling. TGFβ binds to the type I receptor activin-like kinase (ALK)5 and results in C-terminal SMAD2/3 phosphorylation (pSMAD2/3C). In turn pSMAD2/3C translocates to the nucleus and regulates target gene expression. Inflammatory mediators are known to exert an inhibitory effect on MSC differentiation. In this study we investigated the effect of interleukin 1 β (IL1β) on SMAD2/3 signaling dynamics and post-translational modifications. Co-stimulation of MSC with TGFβ and IL1β did not affect peak pSMAD2C levels at 1h post-stimulation. Surprisingly, SMAD3 transcriptional activity, as determined by the CAGA12-luciferase reporter construct, was enhanced by co-stimulation of TGFβ and IL1β compared to TGFβ alone. Furthermore, IL1β stimulation induced CAGA12-luciferase activity in a SMAD dependent way. As SMAD function can be modulated independent of canonical TGFβ signaling through the SMAD linker domain, we studied SMAD2 linker phosphorylation at specific threonine and serine residues. SMAD2 linker threonine and serine modifications were observed within 1h following TGFβ, IL1β or TGFβ and IL1β stimulation. Upon co-stimulation linker modified SMAD2 accumulated in the cytoplasm and SMAD2/3 target gene transcription (ID1, JUNB) at 2-4h was inhibited. A detailed time course analysis of IL1β-induced SMAD2 linker modifications revealed a distinct temperospatial pattern compared to TGFβ. Co-stimulation with both factors resulted in a similar kinetic profile as TGFβ alone. Nevertheless, IL1β did subtly alter TGFβ-induced pSMAD2C levels between 8 and 24h post-stimulation, which was reflected by TGFβ target gene expression (PAI1, JUNB). Direct evidence for the importance of SMAD3 linker modifications for the effect of IL1β on TGFβ signaling was obtained by over-expression of SMAD3 or a SMAD3 linker phospho-mutant. Finally, an inhibitor screening was

  19. Bystander effects in UV-induced genomic instability: Antioxidants inhibit delayed mutagenesis induced by ultraviolet A and B radiation

    Directory of Open Access Journals (Sweden)

    Dahle Jostein

    2005-01-01

    Full Text Available Abstract Background Genomic instability is characteristic of many types of human cancer. Recently, we reported that ultraviolet radiation induced elevated mutation rates and chromosomal instability for many cell generations after ultraviolet irradiation. The increased mutation rates of unstable cells may allow them to accumulate aberrations that subsequently lead to cancer. Ultraviolet A radiation, which primarily acts by oxidative stress, and ultraviolet B radiation, which initially acts by absorption in DNA and direct damage to DNA, both produced genomically unstable cell clones. In this study, we have determined the effect of antioxidants on induction of delayed mutations by ultraviolet radiation. Delayed mutations are indicative of genomic instability. Methods Delayed mutations in the hypoxanthine phosphoribosyl transferase (hprt gene were detected by incubating the cells in medium selectively killing hprt mutants for 8 days after irradiation, followed by a 5 day period in normal medium before determining mutation frequencies. Results The UVB-induced delayed hprt mutations were strongly inhibited by the antioxidants catalase, reduced glutathione and superoxide dismutase, while only reduced glutathione had a significant effect on UVA-induced delayed mutations. Treatment with antioxidants had only minor effects on early mutation frequenies, except that reduced glutathione decreased the UVB-induced early mutation frequency by 24 %. Incubation with reduced glutathione was shown to significantly increase the intracellular amount of reduced glutathione. Conclusion The strong effects of these antioxidants indicate that genomic instability, which is induced by the fundamentally different ultraviolet A and ultraviolet B radiation, is mediated by reactive oxygen species, including hydrogen peroxide and downstream products. However, cells take up neither catalase nor SOD, while incubation with glutathione resulted in increased intracellular levels of

  20. Targeted cytosine deaminase-uracil phosphoribosyl transferase suicide gene therapy induces small cell lung cancer-specific cytotoxicity and tumor growth delay

    DEFF Research Database (Denmark)

    Christensen, Camilla L; Gjetting, Torben; Poulsen, Thomas Tuxen

    2010-01-01

    Small cell lung cancer (SCLC) is a highly malignant cancer for which there is no curable treatment. Novel therapies are therefore in great demand. In the present study we investigated the therapeutic effect of transcriptionally targeted suicide gene therapy for SCLC based on the yeast cytosine...

  1. Lercanidipine Rescues Hippocampus Pyramidal Neurons from Mild Ischemia-Induced Delayed Neuronal Death in SHRSP.

    OpenAIRE

    Sakurai-Yamashita, Yasuko; Harada, Noboru; Niwa, Masami

    2011-01-01

    Stroke-prone spontaneously hypertensive rats (SHRSPs) are vulnerable to ischemia and delayed neuronal death (DND) of hippocampus pyramidal cells when bilateral carotid arteries are occluded for only 10 min. Since this occlusion induces just mild ischemia, the resulting DND may be an appropriate animal model for dementia in patient with essential hypertension exposed to small ischemic insults. This study was designed to compare the effects of the antihypertensive drugs lercanidipine, nicardipi...

  2. Delayed haemolytic transfusion reactions in patients with sickle cell disease.

    OpenAIRE

    Cummins, D; Webb, G.; Shah, N; Davies, S C

    1991-01-01

    We describe two cases which illustrate the difficult diagnostic and therapeutic problems posed by delayed haemolytic transfusion reactions in patients with sickle-cell disease. The cases emphasize the need for meticulous phenotypic and serological assessment of sickle-cell patients prior to transfusion therapy.

  3. Targeted cytosine deaminase-uracil phosphoribosyl transferase suicide gene therapy induces small cell lung cancer-specific cytotoxicity and tumor growth delay

    DEFF Research Database (Denmark)

    Christensen, Camilla L; Gjetting, Torben; Poulsen, Thomas Tuxen

    2010-01-01

    Small cell lung cancer (SCLC) is a highly malignant cancer for which there is no curable treatment. Novel therapies are therefore in great demand. In the present study we investigated the therapeutic effect of transcriptionally targeted suicide gene therapy for SCLC based on the yeast cytosine...... deaminase (YCD) gene alone or fused with the yeast uracil phosphoribosyl transferase (YUPRT) gene followed by administration of 5-fluorocytosine (5-FC) prodrug. Experimental design: The YCD gene or the YCD-YUPRT gene was placed under regulation of the SCLC-specific promoter insulinoma-associated 1 (INSM1...

  4. Propylthiouracil-induced hypothyroidism delays apoptosis during the first wave of spermatogenesis

    Directory of Open Access Journals (Sweden)

    Doris Silva

    2011-01-01

    Full Text Available Mammalian germ cell apoptosis plays a key role in controlling the correct number of germ cells supported by Sertoli cells during the first wave of spermatogenesis in mammalian puberty. However, little is known about hormonal factors that could influence the rate of germ cell apoptosis during puberty or adulthood. In this work we evaluate germ cell apoptosis under hypothyroidism induced by goitrogen propylthiouracil (PTU during the first wave of spermatogenesis. Neonatally administered PTU promoted a delay in the differentiation of Sertoli cells as evaluated by the expression of clusterin using immunohistochemistry and RT-PCR. Clusterin had different expression levels in control and PTU-treated animals, but under both conditions the highest levels were found in 35-day-old rats. In addition, clusterin displayed a cytoplasmic localization in control testes, but appeared located in the nucleus in PTU-treated animals. The wave of apoptosis (determined by caspase activity and quantification of apoptotic cells characteristic of the first round of spermatogenesis was delayed by at least 10 days in these animals. The expression levels of proapoptotic genes like BAX or BAD were different between control and PTU-treated rats; although in both groups the highest level was found at the same age (days. Thus our results indicate that the characteristic pubertal apoptotic wave during rat spermatogenesis is delayed in neonatal hypothyroid rats.

  5. Dynamics of an HBV/HCV infection model with intracellular delay and cell proliferation

    Science.gov (United States)

    Zhang, Fengqin; Li, Jianquan; Zheng, Chongwu; Wang, Lin

    2017-01-01

    A new mathematical model of hepatitis B/C virus (HBV/HCV) infection which incorporates the proliferation of healthy hepatocyte cells and the latent period of infected hepatocyte cells is proposed and studied. The dynamics is analyzed via Pontryagin's method and a newly proposed alternative geometric stability switch criterion. Sharp conditions ensuring stability of the infection persistent equilibrium are derived by applying Pontryagin's method. Using the intracellular delay as the bifurcation parameter and applying an alternative geometric stability switch criterion, we show that the HBV/HCV infection model undergoes stability switches. Furthermore, numerical simulations illustrate that the intracellular delay can induce complex dynamics such as persistence bubbles and chaos.

  6. 8-Modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription.

    Directory of Open Access Journals (Sweden)

    Valérie Vivet-Boudou

    Full Text Available The occurrence of resistant viruses to any of the anti-HIV-1 compounds used in the current therapies against AIDS underlies the urge for the development of new drug targets and/or new drugs acting through novel mechanisms. While all anti-HIV-1 nucleoside analogues in clinical use and in clinical trials rely on ribose modifications for activity, we designed nucleosides with a natural deoxyribose moiety and modifications of position 8 of the adenine base. Such modifications might induce a steric clash with helix αH in the thumb domain of the p66 subunit of HIV-1 RT at a distance from the catalytic site, causing delayed chain termination. Eleven new 2'-deoxyadenosine analogues modified on position 8 of the purine base were synthesized and tested in vitro and in cell-based assays. In this paper we demonstrate for the first time that chemical modifications on position 8 of 2'-deoxyadenosine induce delayed chain termination in vitro, and also inhibit DNA synthesis when incorporated in a DNA template strand. Furthermore, one of them had moderate anti-HIV-1 activity in cell-culture. Our results constitute a proof of concept indicating that modification on the base moiety of nucleosides can induce delayed polymerization arrest and inhibit HIV-1 replication.

  7. The Enteropathogenic Escherichia coli Effector Cif Induces Delayed Apoptosis in Epithelial Cells▿

    Science.gov (United States)

    Samba-Louaka, Ascel; Nougayrède, Jean-Philippe; Watrin, Claude; Oswald, Eric; Taieb, Frédéric

    2009-01-01

    The cycle inhibiting factor (Cif) belongs to a family of bacterial toxins, the cyclomodulins, which modulate the host cell cycle. Upon injection into the host cell by the type III secretion system of enteropathogenic Escherichia coli (EPEC), Cif induces both G2 and G1 cell cycle arrests. The cell cycle arrests correlate with the accumulation of p21waf1 and p27kip1 proteins that inhibit CDK-cyclin complexes, whose activation is required for G1/S and G2/M transitions. Increases of p21 and p27 levels are independent of p53 transcriptional induction and result from protein stabilization through inhibition of the ubiquitin/proteasome degradation pathway. In this study, we show that Cif not only induces cell cycle arrest but also eventually provokes a delayed cell death. Indeed, 48 h after infection with EPEC expressing Cif, cultured IEC-6 intestinal cells were positive for extracellular binding of annexin V and exhibited high levels of cleaved caspase-3 and lactate dehydrogenase release, indicating evidence of apoptosis. Cif was necessary and sufficient for inducing this late apoptosis, and the cysteine residue of the catalytic site was required for Cif activity. These results highlight a more complex role of Cif than previously thought, as a cyclomodulin but also as an apoptosis inducer. PMID:19786559

  8. Ranitidine prevents postoperative transfusion-induced depression of delayed hypersensitivity

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Hammer, J H; Moesgaard, F

    1989-01-01

    The influence of perioperative blood transfusion on postoperative depression of cell-mediated immunity (CMI) and the effect of ranitidine on transfusion-induced changes in postoperative CMI were investigated. CMI was assessed preoperatively and postoperatively by skin testing with seven common...

  9. Modularity Induced Gating and Delays in Neuronal Networks

    Science.gov (United States)

    Shein-Idelson, Mark; Cohen, Gilad; Hanein, Yael

    2016-01-01

    Neural networks, despite their highly interconnected nature, exhibit distinctly localized and gated activation. Modularity, a distinctive feature of neural networks, has been recently proposed as an important parameter determining the manner by which networks support activity propagation. Here we use an engineered biological model, consisting of engineered rat cortical neurons, to study the role of modular topology in gating the activity between cell populations. We show that pairs of connected modules support conditional propagation (transmitting stronger bursts with higher probability), long delays and propagation asymmetry. Moreover, large modular networks manifest diverse patterns of both local and global activation. Blocking inhibition decreased activity diversity and replaced it with highly consistent transmission patterns. By independently controlling modularity and disinhibition, experimentally and in a model, we pose that modular topology is an important parameter affecting activation localization and is instrumental for population-level gating by disinhibition. PMID:27104350

  10. Distant, delayed and ancient earthquake-induced landslides

    Science.gov (United States)

    Havenith, Hans-Balder; Torgoev, Almaz; Braun, Anika; Schlögel, Romy; Micu, Mihai

    2016-04-01

    On the basis of a new classification of seismically induced landslides we outline particular effects related to the delayed and distant triggering of landslides. Those cannot be predicted by state-of-the-art methods. First, for about a dozen events the 'predicted' extension of the affected area is clearly underestimated. The most problematic cases are those for which far-distant triggering of landslides had been reported, such as for the 1988 Saguenay earthquake. In Central Asia reports for such cases are known for areas marked by a thick cover of loess. One possible contributing effect could be a low-frequency resonance of the thick soils induced by distant earthquakes, especially those in the Pamir - Hindu Kush seismic region. Such deep focal and high magnitude (>>7) earthquakes are also found in Europe, first of all in the Vrancea region (Romania). For this area and others in Central Asia we computed landslide event sizes related to scenario earthquakes with M>7.5. The second particular and challenging type of triggering is the one delayed with respect to the main earthquake event: case histories have been reported for the Racha earthquake in 1991 when several larger landslides only started moving 2 or 3 days after the main shock. Similar observations were also made after other earthquake events in the U.S., such as after the 1906 San Francisco, the 1949 Tacoma, the 1959 Hebgen Lake and the 1983 Bora Peak earthquakes. Here, we will present a series of detailed examples of (partly monitored) mass movements in Central Asia that mainly developed after earthquakes, some even several weeks after the main shock: e.g. the Tektonik and Kainama landslides triggered in 1992 and 2004, respectively. We believe that the development of the massive failures is a consequence of the opening of tension cracks during the seismic shaking and their filling up with water during precipitations that followed the earthquakes. The third particular aspect analysed here is the use of large

  11. Induction of delayed-type hypersensitivity by the T cell line specific to bacterial peptidoglycans

    Energy Technology Data Exchange (ETDEWEB)

    Katsuki, M.; Kakimoto, K.; Kawata, S.; Kotani, S.; Koga, T.

    1987-12-01

    A T cell line specific for the chemically well-defined peptidoglycan of bacterial cell wall, disaccharide tetrapeptide, was established from Lewis rats immunized with the antigen covalently linked to the autologous rat serum albumin. The antigen specificity was examined with various analogues or derivatives of the peptidoglycan. The cell line was reactive to analogues with the COOH-terminal D-amino acid, but least reactive to those with L-amino acid as COOH terminus. Transferring of the T cell line into X-irradiated normal Lewis rats induced delayed-type hypersensitivity in an antigen specific manner.

  12. Delayed menopause due to granulosa cell tumor of the ovary

    Directory of Open Access Journals (Sweden)

    Bhushan Murkey

    2011-01-01

    Full Text Available A 52-year-old patient presented with complaints of menorrhagia. Endometrial biopsy revealed simple hyperplasia of the endometrium. Total abdominal hysterectomy with bilateral oophorectomy was carried out. The ovaries looked grossly normal, but histopathology reported granulosa cell tumor of the right ovary. Granulosa cell tumors belong to the sexcord stromal category and account for approximately 2% of all ovarian tumors. We review the features and treatment of granulosa cell tumors and the importance of screening for ovarian tumors in a case of endometrial hyperplasia and delayed menopause.

  13. Delay-induced cluster patterns in coupled Cayley tree networks

    Science.gov (United States)

    Singh, A.; Jalan, S.

    2013-07-01

    We study effects of delay in diffusively coupled logistic maps on the Cayley tree networks. We find that smaller coupling values exhibit sensitiveness to value of delay, and lead to different cluster patterns of self-organized and driven types. Whereas larger coupling strengths exhibit robustness against change in delay values, and lead to stable driven clusters comprising nodes from last generation of the Cayley tree. Furthermore, introduction of delay exhibits suppression as well as enhancement of synchronization depending upon coupling strength values. To the end we discuss the importance of results to understand conflicts and cooperations observed in family business.

  14. Delay-induced wave instabilities in single-species reaction-diffusion systems

    Science.gov (United States)

    Otto, Andereas; Wang, Jian; Radons, Günter

    2017-11-01

    The Turing (wave) instability is only possible in reaction-diffusion systems with more than one (two) components. Motivated by the fact that a time delay increases the dimension of a system, we investigate the presence of diffusion-driven instabilities in single-species reaction-diffusion systems with delay. The stability of arbitrary one-component systems with a single discrete delay, with distributed delay, or with a variable delay is systematically analyzed. We show that a wave instability can appear from an equilibrium of single-species reaction-diffusion systems with fluctuating or distributed delay, which is not possible in similar systems with constant discrete delay or without delay. More precisely, we show by basic analytic arguments and by numerical simulations that fast asymmetric delay fluctuations or asymmetrically distributed delays can lead to wave instabilities in these systems. Examples, for the resulting traveling waves are shown for a Fisher-KPP equation with distributed delay in the reaction term. In addition, we have studied diffusion-induced instabilities from homogeneous periodic orbits in the same systems with variable delay, where the homogeneous periodic orbits are attracting resonant periodic solutions of the system without diffusion, i.e., periodic orbits of the Hutchinson equation with time-varying delay. If diffusion is introduced, standing waves can emerge whose temporal period is equal to the period of the variable delay.

  15. Reduced ultraviolet irradiation delays subsequent squamous cell carcinomas in hairless mice

    DEFF Research Database (Denmark)

    Togsverd-Bo, Katrine; Lerche, Catharina M; Poulsen, Thomas

    2009-01-01

    BACKGROUND: Ultraviolet (UV) radiation induces non-melanoma skin cancer (NMSC), and UV prophylaxis is essential to prevent skin cancer. It is unclear whether patients diagnosed with squamous cell carcinomas (SCC) may benefit from reduced UV exposures in terms of delaying the development of new...... tumors. The objective was to evaluate the significance of discontinued or reduced UV exposure for the development of subsequent skin tumors. METHODS: Seven groups of mice (n = 175) were irradiated with UV doses of 2 and 4 standard erythema doses (SED) that were continued, reduced or discontinued...... at the time of appearance of the first skin tumor. RESULTS: The development of new tumors was delayed, corresponding to the degree of reductions in UV dose in an inversely linear manner. Discontinuation of UV doses delayed the median times to the second tumor by 24 days (2 SED, P = 0.0549) and 33.5 days (4...

  16. Ranitidine prevents postoperative transfusion-induced depression of delayed hypersensitivity

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Hammer, J H; Moesgaard, F

    1989-01-01

    The influence of perioperative blood transfusion on postoperative depression of cell-mediated immunity (CMI) and the effect of ranitidine on transfusion-induced changes in postoperative CMI were investigated. CMI was assessed preoperatively and postoperatively by skin testing with seven common...... ranitidine therapy, and whole blood transfusion was given to 24 of these patients. Postoperative skin test response was more reduced in transfused vs nontransfused patients (-57% vs -38%, p less than 0.0001). Fourteen of the 24 patients receiving blood transfusion could be exactly matched to 14 patients...

  17. Stochastic Simulation of Delay-Induced Circadian Rhythms in Drosophila

    Directory of Open Access Journals (Sweden)

    Xu Zhouyi

    2009-01-01

    Full Text Available Circadian rhythms are ubiquitous in all eukaryotes and some prokaryotes. Several computational models with or without time delays have been developed for circadian rhythms. Exact stochastic simulations have been carried out for several models without time delays, but no exact stochastic simulation has been done for models with delays. In this paper, we proposed a detailed and a reduced stochastic model with delays for circadian rhythms in Drosophila based on two deterministic models of Smolen et al. and employed exact stochastic simulation to simulate circadian oscillations. Our simulations showed that both models can produce sustained oscillations and that the oscillation is robust to noise in the sense that there is very little variability in oscillation period although there are significant random fluctuations in oscillation peeks. Moreover, although average time delays are essential to simulation of oscillation, random changes in time delays within certain range around fixed average time delay cause little variability in the oscillation period. Our simulation results also showed that both models are robust to parameter variations and that oscillation can be entrained by light/dark circles. Our simulations further demonstrated that within a reasonable range around the experimental result, the rates that dclock and per promoters switch back and forth between activated and repressed sites have little impact on oscillation period.

  18. Hopf Bifurcation and Delay-Induced Turing Instability in a Diffusive lac Operon Model

    Science.gov (United States)

    Cao, Xin; Song, Yongli; Zhang, Tonghua

    In this paper, we investigate the dynamics of a lac operon model with delayed feedback and diffusion effect. If the system is without delay or the delay is small, the positive equilibrium is stable so that there are no spatial patterns formed; while the time delay is large enough the equilibrium becomes unstable so that rich spatiotemporal dynamics may occur. We have found that time delay can not only incur temporal oscillations but also induce imbalance in space. With different initial values, the system may have different spatial patterns, for instance, spirals with one head, four heads, nine heads, and even microspirals.

  19. An attempt to induce transient immunosuppression pre-erythrocytapheresis in a girl with sickle cell disease, a history of severe delayed hemolytic transfusion reactions and need for hip prosthesis

    Directory of Open Access Journals (Sweden)

    Alessandro Cattoni

    2013-06-01

    Full Text Available We report on a case of delayed hemolytic transfusion reaction (DHTR occurred 7 days after an erythrocytapheresis or eritroexchange procedure (EEX treated with rituximab and glucocorticoids in a 15-years old patient with sickle cell disease. EEX was performed despite a previous diagnosis of alloimmunization, in order to reduce hemoglobin S rate before a major surgery for avascular necrosis of the femoral head. A first dose of rituximab was administered before EEX. However, rituximab couldn’t prevent DHTR that occurred with acute hemolysis, hemoglobinuria and hyper-bilirubinemia. A further dose of rituximab and three boli of methylprednisolone were given after the onset of the reaction. It is likely that the combined use of rituximab and steroids managed to gradually improve both patient’s general conditions and hemoglobin levels. Nor early or late side effects were registered in a 33-months follow-up period. This report suggests the potential effectiveness and safety of rituximab in combination with steroids in managing and mitigating the symptoms of delayed post-transfusional hemolytic reactions in alloimmunized patients affected by sickle cell disease with absolute need for erythrocytapheresis.

  20. Prevention of ultraviolet radiation-induced immunosuppression by sunscreen in Candida albicans-induced delayed-type hypersensitivity

    OpenAIRE

    Chen, Quan; LI, RUNXIANG; Zhao, Xiaoxia; LIANG, BIHUA; MA, SHAOYIN; Li, Zhenjie; ZHU, HUILAN

    2016-01-01

    Ultraviolet (UV) radiation-induced immunosuppression leading to skin cancer has received increased attention in previous years. The present study aimed to investigate the immunoprotection offered by Anthelios sunscreen in a mouse model of Candida albicans-induced delayed-type hypersensitivity. Anthelios sunscreen was applied to the skin on the dorsal skin of BALB/c mice treated with a sub-erythema dose of solar-simulated radiation. Delayed-type hypersensitivity was induced by immunization wit...

  1. Noise-and delay-induced phase transitions of the dimer-monomer surface reaction model

    Energy Technology Data Exchange (ETDEWEB)

    Zeng Chunhua, E-mail: zchh2009@126.com [Faculty of Science, Kunming University of Science and Technology, Kunming 650093 (China) and Center of Metallurgical Energy Conservation and Emission Reduction, Ministry of Education, Kunming University of Science and Technology, Kunming 650093 (China); Wang Hua, E-mail: wanghuaheat@hotmail.com [Center of Metallurgical Energy Conservation and Emission Reduction, Ministry of Education, Kunming University of Science and Technology, Kunming 650093 (China)

    2012-06-19

    Highlights: Black-Right-Pointing-Pointer We study the dimer-monomer surface reaction model. Black-Right-Pointing-Pointer We show that noise induces first-order irreversible phase transition (IPT). Black-Right-Pointing-Pointer Combination of noise and time-delayed feedback induce first- and second-order IPT. Black-Right-Pointing-Pointer First- and second-order IPT is viewed as noise-and delay-induced phase transitions. - Abstract: The effects of noise and time-delayed feedback in the dimer-monomer (DM) surface reaction model are investigated. Applying small delay approximation, we construct a stochastic delayed differential equation and its Fokker-Planck equation to describe the state evolution of the DM reaction model. We show that the noise can only induce first-order irreversible phase transition (IPT) characteristic of the DM model, however the combination of the noise and time-delayed feedback can simultaneously induce first- and second-order IPT characteristics of the DM model. Therefore, it is shown that the well-known first- and second-order IPT characteristics of the DM model may be viewed as noise-and delay-induced phase transitions.

  2. A Delayed Virus Infection Model with Cell-to-Cell Transmission and CTL Immune Response

    Science.gov (United States)

    Yang, Yu; Zhang, Tonghua; Xu, Yancong; Zhou, Jinling

    In this paper, a delayed virus infection model with cell-to-cell transmission and CTL immune response is investigated. In the model, time delay is incorporated into the CTL response. By constructing Lyapunov functionals, global dynamical properties of the two boundary equilibria are established. Our results show that time delay in the CTL response process may lead to sustained oscillation. To further investigate the nature of the oscillation, we apply the method of multiple time scales to calculate the normal form on the center manifold of the model. At the end of the paper, numerical simulations are carried out, which support our theoretical results.

  3. Delayed neutron yield from fast neutron induced fission of sup 2 sup 3 sup 8 U

    CERN Document Server

    Piksaikin, V M; Isaev, S G; Kazakov, L E; Roshchenko, V A; Tertytchnyi, R G

    2001-01-01

    The measurements of the total delayed neutron yield from fast neutron induced fission of sup 2 sup 3 sup 8 U were made. The experimental method based on the periodic irradiation of the fissionable sample by neutrons from a suitable nuclear reaction had been employed. The preliminary results on the energy dependence of the total delayed neutron yield from fission of sup 2 sup 3 sup 8 U are obtained. According to the comparison of experimental data with our prediction based on correlation properties of delayed neutron characteristics, it is concluded that the value of the total delayed neutron yield near the threshold of (n,f) reaction is not a constant.

  4. Delayed Chemotherapy-Induced Nausea and Vomiting: Pathogenesis, Incidence, and Current Management.

    Science.gov (United States)

    Rapoport, Bernardo L

    2017-01-01

    Even when chemotherapy-induced nausea and vomiting (CINV) can be effectively controlled in the acute phase, it may still occur in the delayed phase. Identifying at-risk patients is complex and requires consideration of clinical, personal, demographic, and behavioral factors. Delayed CINV has a significant detrimental effect on patients' daily life and is responsible for significant healthcare resource utilization. Patients who do not experience acute CINV are not necessarily exempt from delayed CINV, and healthcare professionals have been shown to underestimate the incidence of delayed CINV. Failure to protect against CINV during the first cycle of chemotherapy is the most significant independent risk factor for delayed CINV during subsequent cycles. Addition of a neurokinin-1 receptor antagonist to antiemetic prophylactic regimens involving a 5-hydroxytryptamine type 3 receptor antagonist and a corticosteroid helps to ameliorate delayed CINV, particularly vomiting. Netupitant and rolapitant are second-generation neurokinin-1 receptor antagonists that provide effective prophylaxis against delayed chemotherapy-induced vomiting and also have an antinausea benefit. All of the neurokinin-1 receptor antagonists with the exception of rolapitant inhibit or induce cytochrome P450 3A4 (CYP3A4), and a reduced dose of dexamethasone (a CYP3A4 substrate) should be administered with aprepitant or netupitant; by contrast, this is not necessary with rolapitant. Here we review specific challenges associated with delayed CINV, its pathophysiology, epidemiology, treatment, and outcomes relative to acute CINV, and its management within the larger context of overall CINV.

  5. Ethanol exposure induces a delay in the reacquisition of function during head regeneration in Schmidtea mediterranea.

    Science.gov (United States)

    Lowe, Jesse R; Mahool, Tyler D; Staehle, Mary M

    2015-01-01

    Prenatal exposure to ethanol affects neurodevelopmental processes, leading to a variety of physical and cognitive impairments collectively termed Fetal Alcohol Spectrum Disorders (FASD). The molecular level ethanol-induced alterations that underlie FASD are poorly understood and are difficult to study in mammals. Ethanol exposure has been shown to affect regulation and differentiation of embryonic stem cells in vitro, suggesting that in vivo effects such as FASD could arise from similar alterations of stem cells. In this study, we hypothesize that ethanol exposure affects head regeneration and neuroregeneration in the Schmidtea mediterranea planarian. S. mediterranea freshwater flatworms have remarkable regenerative abilities arising from an abundant population of pluripotent adult somatic stem cells known as neoblasts. Here, we evaluated the mobility-normalized photophobic behavior of ethanol-exposed planaria as an indicator of cognitive function in intact and head-regenerating worms. Our studies show that exposure to 1% ethanol induces a delay in the reacquisition of behavior during head regeneration that cannot be attributed to the effect of ethanol on intact worms. This suggests that the S. mediterranea planarian could provide insight into conserved neurodevelopmental processes that are affected by ethanol and that lead to FASD in humans. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Correlation between induction of meiotic delay and aneuploidy in male mouse germ cells

    Energy Technology Data Exchange (ETDEWEB)

    Adler, I.D.; Gassner, P.; Schriever-Schwemmer, G.; Min, Zhou Ru [Institut fuer Sauugetiergenetik, Neuherberg (Germany)

    1993-12-31

    No aneuploidy assays are prescribed in any international guidelines for chemical safety testing up to now. The CEC-sponsored Aneuploidy Project has the aim to validate test methods for aneuploidy induction which could be used as screening tests. Furthermore, one of the major goals is to develop an understanding of mechanisms by which aneuploidy is induced. The present paper describes the investigation of meiotic delay and aneuploidy induction with the drug diazepam (DZ), the environmentally important mutagen acrylamide (AA) and the spindle poison colchicine (COL), which is used as a positive control. The time course of events was investigated. It is concluded that the assessment of meiotic delay can be used to preselect chemicals which require evaluation of aneuploidy induction during MMI in male germ cells.

  7. Reduction theories elucidate the origins of complex biological rhythms generated by interacting delay-induced oscillations.

    Directory of Open Access Journals (Sweden)

    Ikuhiro Yamaguchi

    Full Text Available Time delay is known to induce sustained oscillations in many biological systems such as electroencephalogram (EEG activities and gene regulations. Furthermore, interactions among delay-induced oscillations can generate complex collective rhythms, which play important functional roles. However, due to their intrinsic infinite dimensionality, theoretical analysis of interacting delay-induced oscillations has been limited. Here, we show that the two primary methods for finite-dimensional limit cycles, namely, the center manifold reduction in the vicinity of the Hopf bifurcation and the phase reduction for weak interactions, can successfully be applied to interacting infinite-dimensional delay-induced oscillations. We systematically derive the complex Ginzburg-Landau equation and the phase equation without delay for general interaction networks. Based on the reduced low-dimensional equations, we demonstrate that diffusive (linearly attractive coupling between a pair of delay-induced oscillations can exhibit nontrivial amplitude death and multimodal phase locking. Our analysis provides unique insights into experimentally observed EEG activities such as sudden transitions among different phase-locked states and occurrence of epileptic seizures.

  8. Carrageenan delays cell cycle progression in human cancer cells in vitro demonstrated by FUCCI imaging.

    Science.gov (United States)

    Prasedya, Eka Sunarwidhi; Miyake, Masao; Kobayashi, Daisuke; Hazama, Akihiro

    2016-08-04

    Carrageenan is a sulfated polysaccharide that exists in red seaweeds recently shown to have anticancer properties. Previous findings show various effects of carrageenan suppressing tumor cell growth. One of the hallmarks of cancer is uncontrolled proliferation, a consequence of loss of normal cell-cycle control, that underlies tumor growth. Recently there is an increasing interest in potential anticancer agents that affect cell cycle in cancer cells. Thus, in this study we investigated the effects of carrageenan on the tumor cell cycle. Using human cervical carcinoma cells (HeLa) cells as and human umbilical vein endothelial cells (HUVEC), the cytotoxic effects of kappa carrageenan (k-CO) and lambda carrageenan (λ-CO) at the concentrations of 250-2500 μg/mL were observed. Cell viability was determined using the MTT assay while cell death rates were determined using staining with calcein-AM/propidium iodide. Cell-cycle profile and progression were demonstrated with HeLa cells expressing FUCCI (fluorescence ubiquitination-based cell-cycle indicator) probes (HeLa-FUCCI). Carrageenan had no significant effect on HUVEC (normal cells). In contrast both forms of carrageenan were cytotoxic towards HeLa cells (cancer cells). Furthermore, according to cell-cycle analysis with FUCCI cells, the cell cycle of HeLa cells was delayed in specific phases due to different carrageenan treatments. Considering these results, it could be suggested that carrageenan affects the cell-cycle of HeLa cells not only by arresting the cell cycle in specific phases but also by delaying the time needed for the cell to progress through the cell cycle. Additionally, different types of carrageenans have different effects on cell cycle progression. This effect of carrageenan towards cancer cells could possibly be developed into a tumor cell-specific anticancer agent.

  9. Telomerase inhibition effectively targets mouse and human AML stem cells and delays relapse following chemotherapy

    DEFF Research Database (Denmark)

    Bruedigam, Claudia; Bagger, Frederik Otzen; Heidel, Florian H.

    2014-01-01

    priority. Here, we show that targeting telomerase activity eradicates AML LSCs. Genetic deletion of the telomerase subunit Terc in a retroviral mouse AML model induces cell-cycle arrest and apoptosis of LSCs, and depletion of telomerase-deficient LSCs is partially rescued by p53 knockdown. Murine Terc......(-/-) LSCs express a specific gene expression signature that can be identified in human AML patient cohorts and is positively correlated with patient survival following chemotherapy. In xenografts of primary human AML, genetic or pharmacological inhibition of telomerase targets LSCs, impairs leukemia...... progression, and delays relapse following chemotherapy. Altogether, these results establish telomerase inhibition as an effective strategy for eliminating AML LSCs....

  10. Modeling a snap-action, variable-delay switch controlling extrinsic cell death.

    Directory of Open Access Journals (Sweden)

    John G Albeck

    2008-12-01

    Full Text Available When exposed to tumor necrosis factor (TNF or TNF-related apoptosis-inducing ligand (TRAIL, a closely related death ligand and investigational therapeutic, cells enter a protracted period of variable duration in which only upstream initiator caspases are active. A subsequent and sudden transition marks activation of the downstream effector caspases that rapidly dismantle the cell. Thus, extrinsic apoptosis is controlled by an unusual variable-delay, snap-action switch that enforces an unambiguous choice between life and death. To understand how the extrinsic apoptosis switch functions in quantitative terms, we constructed a mathematical model based on a mass-action representation of known reaction pathways. The model was trained against experimental data obtained by live-cell imaging, flow cytometry, and immunoblotting of cells perturbed by protein depletion and overexpression. The trained model accurately reproduces the behavior of normal and perturbed cells exposed to TRAIL, making it possible to study switching mechanisms in detail. Model analysis shows, and experiments confirm, that the duration of the delay prior to effector caspase activation is determined by initiator caspase-8 activity and the rates of other reactions lying immediately downstream of the TRAIL receptor. Sudden activation of effector caspases is achieved downstream by reactions involved in permeabilization of the mitochondrial membrane and relocalization of proteins such as Smac. We find that the pattern of interactions among Bcl-2 family members, the partitioning of Smac from its binding partner XIAP, and the mechanics of pore assembly are all critical for snap-action control.

  11. Waves of seed propagation induced by delayed animal dispersion.

    Science.gov (United States)

    Kazimierski, Laila D; Kuperman, Marcelo N; Wio, Horacio S; Abramson, Guillermo

    2018-01-07

    We study a model of seed dispersal that considers the inclusion of an animal disperser moving diffusively, feeding on fruits and transporting the seeds, which are later deposited and capable of germination. The dynamics depends on several population parameters of growth, decay, harvesting, transport, digestion and germination. In particular, the deposition of transported seeds at places away from their collection sites produces a delay in the dynamics, whose effects are the focus of this work. Analytical and numerical solutions of different simplified scenarios show the existence of travelling waves. The effect of zoochory is apparent in the increase of the velocity of these waves. The results support the hypothesis of the relevance of animal mediated seed dispersion when trying to understand the origin of the high rates of vegetable invasion observed in real systems. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Visible light induced ocular delayed bioluminescence as a possible origin of negative afterimage

    CERN Document Server

    Bokkon, I; Wang, C; Dai, J; Salari, V; Grass, F; Antal, I

    2011-01-01

    The delayed luminescence of biological tissues is an ultraweak reemission of absorbed photons after exposure to external monochromatic or white light illumination. Recently, Wang, B\\'okkon, Dai and Antal (Brain Res. 2011) presented the first experimental proof of the existence of spontaneous ultraweak biophoton emission and visible light induced delayed ultraweak photon emission from in vitro freshly isolated rat's whole eye, lens, vitreous humor and retina. Here, we suggest that the photobiophysical source of negative afterimage can also occur within the eye by delayed bioluminescent photons. In other words, when we stare at a colored (or white) image for few seconds, external photons can induce excited electronic states within different parts of the eye that is followed by a delayed reemission of absorbed photons for several seconds. Finally, these reemitted photons can be absorbed by nonbleached photoreceptors that produce a negative afterimage. Although this suggests the photobiophysical source of negativ...

  13. Design of coupling parameters for inducing amplitude death in Cartesian product networks of delayed coupled oscillators

    Science.gov (United States)

    Sugitani, Yoshiki; Konishi, Keiji

    2017-10-01

    The present study investigates amplitude death in Cartesian product networks of two subnetworks, where each subnetwork has a different coupling delay. The property of the Cartesian product helps us to analyze the stability of amplitude death. Our analysis reveals that amplitude death can occur for long coupling delays if there is a suitable difference in the coupling delays in the two subnetworks. Furthermore, based on the edge theorem in robust control theory, we propose two design procedures of coupling parameters for inducing amplitude death in the Cartesian product networks. Our procedures do not require any information of topologies of the subnetworks. The validity of these procedures is numerically confirmed.

  14. Equine herpesvirus type 1 replication is delayed in CD172a+ monocytic cells and controlled by histone deacetylases.

    Science.gov (United States)

    Laval, Kathlyn; Favoreel, Herman W; Nauwynck, Hans J

    2015-01-01

    Equine herpesvirus type 1 (EHV-1) replicates in the epithelial cells of the upper respiratory tract and disseminates through the body via a cell-associated viraemia in monocytic cells, despite the presence of neutralizing antibodies. However, the mechanism by which EHV-1 hijacks immune cells and uses them as 'Trojan horses' in order to disseminate inside its host is still unclear. Here, we hypothesize that EHV-1 delays its replication in monocytic cells in order to avoid recognition by the immune system. We compared replication kinetics in vitro of EHV-1 in RK-13, a cell line fully susceptible to EHV-1 infection, and primary horse cells from the myeloid lineage (CD172a(+)). We found that EHV-1 replication was restricted to 4 % of CD172a(+) cells compared with 100 % in RK-13 cells. In susceptible CD172a(+) cells, the expression of immediate-early (IEP) and early (EICP22) proteins was delayed in the cell nuclei by 2-3 h post-infection (p.i.) compared with RK-13, and the formation of replicative compartments by 15 h p.i. Virus production in CD172a(+) cells was significantly lower (from 10(1.7) to 10(3.1) TCID50 per 10(5) inoculated cells) than in RK-13 (from 10(5) to 10(5.7) TCID50 per 10(5) inoculated cells). Less than 0.02 % of inoculated CD172a(+) cells produced and transmitted infectious virus to neighbouring cells. Pre-treatment of CD172a(+) cells with inhibitors of histone deacetylase activity increased and accelerated viral protein expression at very early times of infection and induced productive infection in CD172a(+) cells. Our results demonstrated that the restriction and delay of EHV-1 replication in CD172a(+) cells are part of an immune evasive strategy and involve silencing of EHV-1 gene expression associated with histone deacetylases. © 2015 The Authors.

  15. Carbonate fuel cell and components thereof for in-situ delayed addition of carbonate electrolyte

    Energy Technology Data Exchange (ETDEWEB)

    Johnsen, Richard [Waterbury, CT; Yuh, Chao-Yi [New Milford, CT; Farooque, Mohammad [Danbury, CT

    2011-05-10

    An apparatus and method in which a delayed carbonate electrolyte is stored in the storage areas of a non-electrolyte matrix fuel cell component and is of a preselected content so as to obtain a delayed time release of the electrolyte in the storage areas in the operating temperature range of the fuel cell.

  16. Temporal recalibration in vocalization induced by adaptation of delayed auditory feedback.

    Directory of Open Access Journals (Sweden)

    Kosuke Yamamoto

    Full Text Available BACKGROUND: We ordinarily perceive our voice sound as occurring simultaneously with vocal production, but the sense of simultaneity in vocalization can be easily interrupted by delayed auditory feedback (DAF. DAF causes normal people to have difficulty speaking fluently but helps people with stuttering to improve speech fluency. However, the underlying temporal mechanism for integrating the motor production of voice and the auditory perception of vocal sound remains unclear. In this study, we investigated the temporal tuning mechanism integrating vocal sensory and voice sounds under DAF with an adaptation technique. METHODS AND FINDINGS: Participants produced a single voice sound repeatedly with specific delay times of DAF (0, 66, 133 ms during three minutes to induce 'Lag Adaptation'. They then judged the simultaneity between motor sensation and vocal sound given feedback. We found that lag adaptation induced a shift in simultaneity responses toward the adapted auditory delays. This indicates that the temporal tuning mechanism in vocalization can be temporally recalibrated after prolonged exposure to delayed vocal sounds. Furthermore, we found that the temporal recalibration in vocalization can be affected by averaging delay times in the adaptation phase. CONCLUSIONS: These findings suggest vocalization is finely tuned by the temporal recalibration mechanism, which acutely monitors the integration of temporal delays between motor sensation and vocal sound.

  17. Compound ICA-105574 prevents arrhythmias induced by cardiac delayed repolarization.

    Science.gov (United States)

    Meng, Jing; Shi, Chenxia; Li, Lin; Du, Yumin; Xu, Yanfang

    2013-10-15

    Impaired ventricular repolarization can lead to long QT syndrome (LQT), a proarrhythmic disease with high risk of developing lethal ventricular tachyarrhythmias. The compound ICA-105574 is a recently developed hERG activator and it enhances IKr current with very high potency by removing the channel inactivation. The present study was designed to investigate antiarrhythmic properties of ICA-105574. For comparison, the effects of another compound NS1643 was in-parallel assessed, which also acts primarily to attenuate channel inactivation with moderate potency. We found that both ICA-105574 and NS1643 concentration-dependently shortened action potential duration (APD) in ventricular myocytes, and QT/QTc intervals in isolated guinea-pig hearts. ICA-105574, but not NS1643, completely prevented ventricular arrhythmias in intact guinea-pig hearts caused by IKr and IKs inhibitors, although both ICA-105574 and NS1643 could reverse the drug-induced prolongation of APD in ventricular myocytes. Reversing prolongation of QT/QTc intervals and antagonizing the increases in transmural dispersion of repolarization and instability of the QT interval induced by IKr and IKs inhibitors contributed to antiarrhythmic effect of ICA-105574. Meanwhile, ICA-105574 at higher concentrations showed a potential proarrhythmic risk in normal hearts. Our results suggest that ICA-105574 has more efficient antiarrhythmic activity than NS1643. However, its potential proarrhythmic risk implies that benefits and risks should be seriously taken into consideration for further developing this type of hERG activators. © 2013 Elsevier B.V. All rights reserved.

  18. Telomerase Inhibition Effectively Targets Mouse and Human AML Stem Cells and Delays Relapse Following Chemotherapy

    Science.gov (United States)

    Bruedigam, Claudia; Bagger, Frederik O.; Heidel, Florian H.; Kuhn, Catherine Paine; Guignes, Solene; Song, Axia; Austin, Rebecca; Vu, Therese; Lee, Erwin; Riyat, Sarbjit; Moore, Andrew S.; Lock, Richard B.; Bullinger, Lars; Hill, Geoffrey R.; Armstrong, Scott A.; Williams, David A.; Lane, Steven W.

    2014-01-01

    SUMMARY Acute myeloid leukemia (AML) is an aggressive and lethal blood cancer maintained by rare populations of leukemia stem cells (LSCs). Selective targeting of LSCs is a promising approach for treating AML and preventing relapse following chemotherapy, and developing such therapeutic modalities is a key priority. Here, we show that targeting telomerase activity eradicates AML LSCs. Genetic deletion of the telomerase subunit Terc in a retroviral mouse AML model induces cell cycle arrest and apoptosis of LSCs, and depletion of telomerase-deficient LSCs is partially rescued by p53 knockdown. Murine Terc−/− LSCs express a specific gene expression signature that can be identified in human AML patient cohorts and is positively correlated with patient survival following chemotherapy. In xenografts of primary human AML, genetic or pharmacological inhibition of telomerase targets LSCs, impairs leukemia progression, and delays relapse following chemotherapy. Together, these results establish telomerase inhibition as an effective strategy for eliminating AML LSCs. PMID:25479751

  19. Neutralization of interleukin-17A delays progression of silica-induced lung inflammation and fibrosis in C57BL/6 mice

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Ying; Li, Cuiying [Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, Liaoning (China); Weng, Dong [Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, Liaoning (China); Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai (China); Song, Laiyu; Tang, Wen; Dai, Wujing; Yu, Ye; Liu, Fangwei; Zhao, Ming; Lu, Chunwei [Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, Liaoning (China); Chen, Jie, E-mail: chenjie@mail.cmu.edu.cn [Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, Liaoning (China)

    2014-02-15

    Silica exposure can cause lung inflammation and fibrosis, known as silicosis. Interleukin-17A (IL-17A) and Th17 cells play a pivotal role in controlling inflammatory diseases. However, the roles of IL-17A and Th17 cells in the progress of silica-induced inflammation and fibrosis are poorly understood. This study explored the effects of IL-17A on silica-induced inflammation and fibrosis. We used an anti-mouse IL-17A antibody to establish an IL-17A-neutralized mice model, and mice were exposed to silica to establish an experimental silicosis model. We showed that IL-17A neutralization delayed neutrophil accumulation and progression of silica-induced lung inflammation and fibrosis. IL-17A neutralization reduced the percentage of Th17 in CD4 + T cells, decreased IL-6 and IL-1β expression, and increased Tregs at an early phase of silica-induced inflammation. Neutralization of IL-17A delayed silica-induced Th1/Th2 immune and autoimmune responses. These results suggest that IL-17A neutralization alleviates early stage silica-induced lung inflammation and delays progression of silica-induced lung inflammation and fibrosis. Neutralization of IL-17A suppressed Th17 cell development by decreasing IL-6 and/or IL-1β and increased Tregs at an early phase of silica-induced inflammation. Neutralization of IL-17A also delayed the Th1/Th2 immune response during silica-induced lung inflammation and fibrosis. IL-17A may play a pivotal role in the early phase of silica-induced inflammation and may mediate the Th immune response to influence silica-induced lung inflammation and fibrosis in mice. - Highlights: • Neutralization of IL-17A alleviated silica-induced lung inflammation of early stage. • Neutralization of IL-17A decreased Th17 cells and increased Tregs. • IL-17A mediated the reciprocal relationship of Th17/Tregs by IL-6 and/or IL-1β. • Neutralization of IL-17A delayed silica-induced Th1/Th2 immune response. • Neutralization of IL-17A delayed silica-induced lung

  20. Rapid and durable response to intravenous immunoglobulin in delayed heparin-induced thrombocytopenia: a case report.

    Science.gov (United States)

    Lei, Brandon Z; Shatzel, Joseph J; Sendowski, Merav

    2017-04-01

    Heparin-induced thrombocytopenia (HIT) results in platelet consumption and a virulent thrombotic state, which generally responds to cessation of heparin and initiation of anticoagulation. Rarely, delayed HIT can occur and/or persist after heparin is discontinued. A 47-year-old male developed delayed HIT with severe thrombocytopenia and thrombosis after cardiac surgery. Thrombocytopenia developed and persisted after heparin cessation and did not improve despite sequential use of argatroban followed by bivalirudin. Treatment with intravenous immunoglobulin (IVIg) was well tolerated and resulted in rapid resolution of thrombocytopenia. There are few case reports on the management of delayed HIT with severe and prolonged thrombocytopenia. The risk for thrombosis and bleeding in the setting of an undefined time course increases uncertainty in management. This case, along with others accumulating in the literature, suggest that IVIg may be effective in treating delayed HIT with persistent thrombocytopenia. © 2016 AABB.

  1. Instability in time-delayed switched systems induced by fast and random switching

    Science.gov (United States)

    Guo, Yao; Lin, Wei; Chen, Yuming; Wu, Jianhong

    2017-07-01

    In this paper, we consider a switched system comprising finitely or infinitely many subsystems described by linear time-delayed differential equations and a rule that orchestrates the system switching randomly among these subsystems, where the switching times are also randomly chosen. We first construct a counterintuitive example where even though all the time-delayed subsystems are exponentially stable, the behaviors of the randomly switched system change from stable dynamics to unstable dynamics with a decrease of the dwell time. Then by using the theories of stochastic processes and delay differential equations, we present a general result on when this fast and random switching induced instability should occur and we extend this to the case of nonlinear time-delayed switched systems as well.

  2. Overexpression of PCNA Attenuates Oxidative Stress-Caused Delay of Gap-Filling during Repair of UV-Induced DNA Damage

    Directory of Open Access Journals (Sweden)

    Yi-Chih Tsai

    2017-01-01

    Full Text Available UVC irradiation-caused DNA lesions are repaired in mammalian cells solely by nucleotide excision repair (NER, which consists of sequential events including initial damage recognition, dual incision of damage site, gap-filling, and ligation. We have previously shown that gap-filling during the repair of UV-induced DNA lesions may be delayed by a subsequent treatment of oxidants or prooxidants such as hydrogen peroxide, flavonoids, and colcemid. We considered the delay as a result of competition for limiting protein/enzyme factor(s during repair synthesis between NER and base excision repair (BER induced by the oxidative chemicals. In this report, using colcemid as oxidative stress inducer, we showed that colcemid-caused delay of gap-filling during the repair of UV-induced DNA lesions was attenuated by overexpression of PCNA but not ligase-I. PCNA knockdown, as expected, delayed the gap-filling of NER but also impaired the repair of oxidative DNA damage. Fen-1 knockdown, however, did not affect the repair of oxidative DNA damage, suggesting repair of oxidative DNA damage is not of long patch BER. Furthermore, overexpression of XRCC1 delayed the gap-filling, and presumably increase of XRCC1 pulls PCNA away from gap-filling of NER for BER, consistent with our hypothesis that delay of gap-filling of NER attributes the competition between NER and BER.

  3. Environmental Enrichment Decreases Asphyxia-Induced Neurobehavioral Developmental Delay in Neonatal Rats

    Directory of Open Access Journals (Sweden)

    Peter Kiss

    2013-11-01

    Full Text Available Perinatal asphyxia during delivery produces long-term disability and represents a major problem in neonatal and pediatric care. Numerous neuroprotective approaches have been described to decrease the effects of perinatal asphyxia. Enriched environment is a popular strategy to counteract nervous system injuries. The aim of the present study was to investigate whether enriched environment is able to decrease the asphyxia-induced neurobehavioral developmental delay in neonatal rats. Asphyxia was induced in ready-to-deliver mothers by removing the pups by caesarian section after 15 min of asphyxia. Somatic and neurobehavioral development was tested daily and motor coordination weekly. Our results show that rats undergoing perinatal asphyxia had a marked developmental delay and worse performance in motor coordination tests. However, pups kept in enriched environment showed a decrease in the developmental delay observed in control asphyctic pups. Rats growing up in enriched environment did not show decrease in weight gain after the first week and the delay in reflex appearance was not as marked as in control rats. In addition, the development of motor coordination was not as strikingly delayed as in the control group. Short-term neurofunctional outcome are known to correlate with long-term deficits. Our results thus show that enriched environment could be a powerful strategy to decrease the deleterious developmental effects of perinatal asphyxia.

  4. Adaptation to Delayed Speech Feedback Induces Temporal Recalibration between Vocal Sensory and Auditory Modalities

    Directory of Open Access Journals (Sweden)

    Kosuke Yamamoto

    2011-10-01

    Full Text Available We ordinarily perceive our voice sound as occurring simultaneously with vocal production, but the sense of simultaneity in vocalization can be easily interrupted by delayed auditory feedback (DAF. DAF causes normal people to have difficulty speaking fluently but helps people with stuttering to improve speech fluency. However, the underlying temporal mechanism for integrating the motor production of voice and the auditory perception of vocal sound remains unclear. In this study, we investigated the temporal tuning mechanism integrating vocal sensory and voice sounds under DAF with an adaptation technique. Participants read some sentences with specific delay times of DAF (0, 30, 75, 120 ms during three minutes to induce ‘Lag Adaptation’. After the adaptation, they then judged the simultaneity between motor sensation and vocal sound given feedback in producing simple voice but not speech. We found that speech production with lag adaptation induced a shift in simultaneity responses toward the adapted auditory delays. This indicates that the temporal tuning mechanism in vocalization can be temporally recalibrated after prolonged exposure to delayed vocal sounds. These findings suggest vocalization is finely tuned by the temporal recalibration mechanism, which acutely monitors the integration of temporal delays between motor sensation and vocal sound.

  5. Inhibition of Bim enhances replication of varicella-zoster virus and delays plaque formation in virus-infected cells.

    Science.gov (United States)

    Liu, Xueqiao; Cohen, Jeffrey I

    2014-01-01

    Programmed cell death (apoptosis) is an important host defense mechanism against intracellular pathogens, such as viruses. Accordingly, viruses have evolved multiple mechanisms to modulate apoptosis to enhance replication. Varicella-zoster virus (VZV) induces apoptosis in human fibroblasts and melanoma cells. We found that VZV triggered the phosphorylation of the proapoptotic proteins Bim and BAD but had little or no effect on other Bcl-2 family members. Since phosphorylation of Bim and BAD reduces their proapoptotic activity, this may prevent or delay apoptosis in VZV-infected cells. Phosphorylation of Bim but not BAD in VZV-infected cells was dependent on activation of the MEK/extracellular signal-regulated kinase (ERK) pathway. Cells knocked down for Bim showed delayed VZV plaque formation, resulting in longer survival of VZV-infected cells and increased replication of virus, compared with wild-type cells infected with virus. Conversely, overexpression of Bim resulted in earlier plaque formation, smaller plaques, reduced virus replication, and increased caspase 3 activity. Inhibition of caspase activity in VZV-infected cells overexpressing Bim restored levels of virus production similar to those seen with virus-infected wild-type cells. Previously we showed that VZV ORF12 activates ERK and inhibits apoptosis in virus-infected cells. Here we found that VZV ORF12 contributes to Bim and BAD phosphorylation. In summary, VZV triggers Bim phosphorylation; reduction of Bim levels results in longer survival of VZV-infected cells and increased VZV replication.

  6. Improved tumor tissue penetration and tumor cell uptake achieved by delayed charge reversal nanoparticles.

    Science.gov (United States)

    Gou, Jingxin; Liang, Yuheng; Miao, Linlin; Guo, Wei; Chao, Yanhui; He, Haibing; Zhang, Yu; Yang, Jingyu; Wu, Chunfu; Yin, Tian; Wang, Yanjiao; Tang, Xing

    2017-10-15

    The high affinity of positively charged nanoparticles to biological interfaces makes them easily taken up by tumor cells but limits their tumor permeation due to non-specific electrostatic interactions. In this study, polyion complex coated nanoparticles with different charge reversal profiles were developed to study the influence of charge reversal profile on tumor penetration. The system was constructed by polyion complex coating using micelles composed of poly (lysine)-b-polycaprolactone (PLys-b-PCL) as the cationic core and poly (glutamic acid)-g- methoxyl poly (ethylene glycol) (PGlu-g-mPEG) as the anionic coating material. Manipulation of charge reversal profile was achieved by controlling the polymer chain entanglement and electrostatic interaction in the polyion complex layer through glutaraldehyde-induced shell-crosslinking. The delayed charge reversal nanoparticles (CTCL30) could maintain negatively charged in pH 6.5 PBS for at least 2h and exhibit pH-responsive cytotoxicity and cellular uptake in an extended time scale. Compared with a faster charge reversal counterpart (CTCL70) with similar pharmacokinetic profile, CTCL30 showed deeper penetration, higher in vivo tumor cell uptake and stronger antitumor activity in vivo (tumor inhibition rate: 72.3% vs 60.2%, compared with CTCL70). These results indicate that the delayed charge reversal strategy could improve therapeutic effect via facilitating tumor penetration. Here, the high tumor penetration capability of PEG-coated nanoparticles and the high cellular uptake of cationic nanoparticles were combined by a delayed charge reversal drug delivery system. This drug delivery system was composed of a drug-loading cationic inner core and a polyion complex coating. Manipulation of charge reversal profile was realized by varying the crosslinking degree of the shell of the cationic inner core, through which changed the strength of the polyion complex layer. Nanoparticles with delayed charge reversal profile

  7. Dynamics of a stochastic cell-to-cell HIV-1 model with distributed delay

    Science.gov (United States)

    Ji, Chunyan; Liu, Qun; Jiang, Daqing

    2018-02-01

    In this paper, we consider a stochastic cell-to-cell HIV-1 model with distributed delay. Firstly, we show that there is a global positive solution of this model before exploring its long-time behavior. Then sufficient conditions for extinction of the disease are established. Moreover, we obtain sufficient conditions for the existence of an ergodic stationary distribution of the model by constructing a suitable stochastic Lyapunov function. The stationary distribution implies that the disease is persistent in the mean. Finally, we provide some numerical examples to illustrate theoretical results.

  8. Diagnostic delay in oral squamous cell carcinoma: the role of cognitive and psychological variables.

    Science.gov (United States)

    Panzarella, Vera; Pizzo, Giuseppe; Calvino, Francesco; Compilato, Domenico; Colella, Giuseppe; Campisi, Giuseppina

    2014-03-01

    This retrospective study investigated, in two cohorts of subjects living in Southern Italy and awaiting treatment for oral squamous cell carcinoma (OSCC), the variables related to diagnostic delay ascribable to the patient, with particular reference to the cognitive and psychological ones. A total of 156 patients with OSCC (mean age: 62 years, M/F: 2.39∶1) were recruited at the Universities of Palermo and Naples. Risk factors related to patient delay included: sociodemographic, health-related, cognitive and psychological variables. The analysis was conducted by considering two different delay ranges: dichotomous (≤1 month vs. >1 month) and polytomous (3 months) delay. Data were investigated by univariate and multivariate analyses and a P value ≤0.05 was considered statistically significant. For both delay measurements, the most relevant variables were: 'Personal experience of cancer' (dichotomous delay: P=0.05, odds ratio (OR)=0.33, 95% confidence interval (CI)=0.11-0.99; polytomous delay: P=0.006, Chi-square=10.224) and 'Unawareness' (dichotomous delay: Pdichotomous and for polytomous categorization of delay, respectively. The findings of this study indicated that, in the investigated cohorts, the knowledge about cancer issues is strongly linked to the patient delay. Educational interventions on the Mediterranean population are necessary in order to increase the patient awareness and to emphasize his/her key role in early diagnosis of OSCC.

  9. Methimazole Induced Total Myeloid Aplasia with Delayed Recovery Despite Granulocyte Colony Stimulating Factor (G-CSF): Marrow Progenitor Recovery Kinetics.

    Science.gov (United States)

    Sarker, Tania; Özgönenel, Bülent; Gadgeel, Manisha; Buck, Steven; Adhikari, Amita; Ravindranath, Yaddanapudi

    2016-06-01

    An eighteen-year-old female with Graves thyrotoxicosis presented with methimazole-induced agranulocytosis and total myeloid aplasia. The bone marrow at presentation showed complete absence of myeloid precursors and striking plasmacytosis. 16 days later, myeloid precursors were still absent morphologically; however bone marrow flow cytometry and cell culture detected an improvement in myelogenesis, which was soon followed by clinical recovery of agranulocytosis. Neutrophil recovery was delayed until day 22 after cessation of methimazole despite G-CSF use, consistent with a direct toxic effect on committed myeloid cells. Our findings suggest that cell culture and flow cytometric evaluation of bone marrow myeloid progenitors can be used as a guide to anticipate neutrophil recovery.

  10. Effect of Nb on hydrogen-induced delayed fracture in high strength hot stamping steels

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Shiqi [School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing 100083 (China); College of Mechanical Engineering, Yangtze University, Jingzhou 434023 (China); Huang, Yunhua, E-mail: huangyh@mater.ustb.edu.cn [School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing 100083 (China); Sun, Bintang, E-mail: bingtangsun@ustb.edu.cn [School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing 100083 (China); Liao, Qingliang [School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing 100083 (China); Lu, Hongzhou [CITIC Metal Co. Ltd., Room 1901, Capital Mansion 6, Xin Yuan Nanlu, Chaoyang District, Beijing 100004 (China); The School of Resources and Environmental Engineering, East China University of Science and Technology, Meilong road 130, Xujiahui District, Shanghai 200237 (China); Jian, Bian [Niobium Tech Asia, 068898 Singapore (Singapore); Mohrbacher, Hardy [NiobelCon bvba, 2970 Schilde (Belgium); Zhang, Wei; Guo, Aimin [CITIC Metal Co. Ltd., Room 1901, Capital Mansion 6, Xin Yuan Nanlu, Chaoyang District, Beijing 100004 (China); Zhang, Yue [School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing 100083 (China); The State Key Laboratory for Advanced Metals and Materials, University of Science and Technology Beijing, Beijing 100083 (China)

    2015-02-25

    The effect of Nb addition (0.022, 0.053, 0.078 wt%) on the hydrogen-induced delayed fracture resistance of 22MnB5 was studied by constant load test and electrochemical hydrogen permeation method. It is shown that the appropriate addition of Nb is beneficial to the improvement of the delayed fracture resistance of tested steel, especially when the steel contains high concentration of hydrogen, and the maximum delayed fracture resistance is obtained at a Nb content of 0.053%.The result of hydrogen permeation test shows that the diffusion coefficient of hydrogen in the steel containing niobium is lower than that in steel without niobium, which indicates that it is harder for hydrogen in the steels containing niobium to diffuse and aggregate. In addition, the reason for Nb improving the delayed fracture resistance of steels is discussed from two aspects: hydrogen trap effect and grain refinement effect. The analysis shows that the main reason leading to the improvement of the delayed fracture resistance is the hydrogen trapping effect of NbC while the grain refinement effect of Nb(C,N) secondary.

  11. Importance of cell damage causing growth delay for high pressure inactivation of Saccharomyces cerevisiae

    Science.gov (United States)

    Nanba, Masaru; Nomura, Kazuki; Nasuhara, Yusuke; Hayashi, Manabu; Kido, Miyuki; Hayashi, Mayumi; Iguchi, Akinori; Shigematsu, Toru; Hirayama, Masao; Ueno, Shigeaki; Fujii, Tomoyuki

    2013-06-01

    A high pressure (HP) tolerant (barotolerant) mutant a2568D8 and a variably barotolerant mutant a1210H12 were generated from Saccharomyces cerevisiae using ultra-violet mutagenesis. The two mutants, a barosensitive mutant a924E1 and the wild-type strain, were pressurized (225 MPa), and pressure inactivation behavior was analyzed. In the wild-type strain, a proportion of the growth-delayed cells were detected after exposure to HP. In a924E1, the proportion of growth-delayed cells significantly decreased compared with the wild-type. In a2568D8, the proportion of growth-delayed cells increased and the proportion of inactivated cells decreased compared with the wild-type. In a1210H12, the growth-delayed cells could not be detected within 120 s of exposure to HP. The proportion of growth-delayed cells, which incurred the damage, would affect the survival ratio by HP. These results suggested that cellular changes in barotolerance caused by mutations are remarkably affected by the ability to recover from cellular damage, which results in a growth delay.

  12. Delayed auditory conduction in diabetes: is metformin-induced vitamin B12 deficiency responsible?

    OpenAIRE

    Khattar, Deepti; Khaliq, Farah; Vaney, Neelam; Madhu, Sri Venkata

    2016-01-01

    The present study aims to evaluate the functional integrity of the auditory pathway in patients with diabetes taking metformin. A further aim is to assess its association with vitamin B12 deficiency induced by metformin. Thirty diabetics taking metformin and 30 age-matched non-diabetic controls were enrolled. Stimulus-related potentials and vitamin B12 levels were evaluated in all the subjects. The diabetics showed deficient vitamin B12 levels and delayed wave III latency and III–V interpeak ...

  13. Montelukast Induces Apoptosis-Inducing Factor-Mediated Cell Death of Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Ming-Ju Tsai

    2017-06-01

    Full Text Available Developing novel chemo-prevention techniques and advancing treatment are key elements to beating lung cancer, the most common cause of cancer mortality worldwide. Our previous cohort study showed that cysteinyl leukotriene receptor antagonists, mainly montelukast, decreased the lung cancer risk in asthma patients. In the current study, we conducted in vivo and in vitro experiments to demonstrate the inhibiting effect of montelukast on lung cancer and to investigate the underlying mechanisms. Using Lewis lung carcinoma-bearing mice, we showed that feeding montelukast significantly delayed the tumor growth in mice (p < 0.0001. Montelukast inhibited cell proliferation and colony formation and induced the cell death of lung cancer cells. Further investigation showed the down-regulation of B-cell lymphoma 2 (Bcl-2, up-regulation of Bcl-2 homologous antagonist/killer (Bak, and nuclear translocation of apoptosis-inducing factor (AIF in montelukast-treated lung cancer cells. Montelukast also markedly decreased the phosphorylation of several proteins, such as with no lysine 1 (WNK1, protein kinase B (Akt, extracellular signal-regulated kinase 1/2 (Erk1/2, MAPK/Erk kinase (MEK, and proline-rich Akt substrate of 40-kDa (PRAS40, which might contribute to cell death. In conclusion, montelukast induced lung cancer cell death via the nuclear translocation of AIF. This study confirmed the chemo-preventive effect of montelukast shown in our previous cohort study. The utility of montelukast in cancer prevention and treatment thus deserves further studies.

  14. Montelukast Induces Apoptosis-Inducing Factor-Mediated Cell Death of Lung Cancer Cells.

    Science.gov (United States)

    Tsai, Ming-Ju; Chang, Wei-An; Tsai, Pei-Hsun; Wu, Cheng-Ying; Ho, Ya-Wen; Yen, Meng-Chi; Lin, Yi-Shiuan; Kuo, Po-Lin; Hsu, Ya-Ling

    2017-06-24

    Developing novel chemo-prevention techniques and advancing treatment are key elements to beating lung cancer, the most common cause of cancer mortality worldwide. Our previous cohort study showed that cysteinyl leukotriene receptor antagonists, mainly montelukast, decreased the lung cancer risk in asthma patients. In the current study, we conducted in vivo and in vitro experiments to demonstrate the inhibiting effect of montelukast on lung cancer and to investigate the underlying mechanisms. Using Lewis lung carcinoma-bearing mice, we showed that feeding montelukast significantly delayed the tumor growth in mice (p Montelukast inhibited cell proliferation and colony formation and induced the cell death of lung cancer cells. Further investigation showed the down-regulation of B-cell lymphoma 2 (Bcl-2), up-regulation of Bcl-2 homologous antagonist/killer (Bak), and nuclear translocation of apoptosis-inducing factor (AIF) in montelukast-treated lung cancer cells. Montelukast also markedly decreased the phosphorylation of several proteins, such as with no lysine 1 (WNK1), protein kinase B (Akt), extracellular signal-regulated kinase 1/2 (Erk1/2), MAPK/Erk kinase (MEK), and proline-rich Akt substrate of 40-kDa (PRAS40), which might contribute to cell death. In conclusion, montelukast induced lung cancer cell death via the nuclear translocation of AIF. This study confirmed the chemo-preventive effect of montelukast shown in our previous cohort study. The utility of montelukast in cancer prevention and treatment thus deserves further studies.

  15. An investigation of dendritic delay in octopus cells of the mammalian cochlear nucleus

    Science.gov (United States)

    Spencer, Martin J.; Grayden, David B.; Bruce, Ian C.; Meffin, Hamish; Burkitt, Anthony N.

    2012-01-01

    Octopus cells, located in the mammalian auditory brainstem, receive their excitatory synaptic input exclusively from auditory nerve fibers (ANFs). They respond with accurately timed spikes but are broadly tuned for sound frequency. Since the representation of information in the auditory nerve is well understood, it is possible to pose a number of questions about the relationship between the intrinsic electrophysiology, dendritic morphology, synaptic connectivity, and the ultimate functional role of octopus cells in the brainstem. This study employed a multi-compartmental Hodgkin-Huxley model to determine whether dendritic delay in octopus cells improves synaptic input coincidence detection in octopus cells by compensating for the cochlear traveling wave delay. The propagation time of post-synaptic potentials from synapse to soma was investigated. We found that the total dendritic delay was approximately 0.275 ms. It was observed that low-threshold potassium channels in the dendrites reduce the amplitude dependence of the dendritic delay of post-synaptic potentials. As our hypothesis predicted, the model was most sensitive to acoustic onset events, such as the glottal pulses in speech when the synaptic inputs were arranged such that the model's dendritic delay compensated for the cochlear traveling wave delay across the ANFs. The range of sound frequency input from ANFs was also investigated. The results suggested that input to octopus cells is dominated by high frequency ANFs. PMID:23125831

  16. Adaptation to delayed auditory feedback induces the temporal recalibration effect in both speech perception and production.

    Science.gov (United States)

    Yamamoto, Kosuke; Kawabata, Hideaki

    2014-12-01

    We ordinarily speak fluently, even though our perceptions of our own voices are disrupted by various environmental acoustic properties. The underlying mechanism of speech is supposed to monitor the temporal relationship between speech production and the perception of auditory feedback, as suggested by a reduction in speech fluency when the speaker is exposed to delayed auditory feedback (DAF). While many studies have reported that DAF influences speech motor processing, its relationship to the temporal tuning effect on multimodal integration, or temporal recalibration, remains unclear. We investigated whether the temporal aspects of both speech perception and production change due to adaptation to the delay between the motor sensation and the auditory feedback. This is a well-used method of inducing temporal recalibration. Participants continually read texts with specific DAF times in order to adapt to the delay. Then, they judged the simultaneity between the motor sensation and the vocal feedback. We measured the rates of speech with which participants read the texts in both the exposure and re-exposure phases. We found that exposure to DAF changed both the rate of speech and the simultaneity judgment, that is, participants' speech gained fluency. Although we also found that a delay of 200 ms appeared to be most effective in decreasing the rates of speech and shifting the distribution on the simultaneity judgment, there was no correlation between these measurements. These findings suggest that both speech motor production and multimodal perception are adaptive to temporal lag but are processed in distinct ways.

  17. Systemic alkalinisation delays prostate cancer cell progression in TRAMP mice.

    Science.gov (United States)

    Astigiano, Simonetta; Puglisi, Andrea; Mastracci, Luca; Fais, Stefano; Barbieri, Ottavia

    2017-12-01

    The microenvironment of solid tumours is extremely acidic and this condition arises since the precancerous stage. This acidic milieu could therefore provide a useful target for both prophylactic and therapeutic approaches. In TRAMP transgenic mice, an in vivo model of prostate adenocarcinoma (AC), oral administration of alkaline water was devoid of unwanted side effects, and when started from an early age was as effective as NaHCO3 in significantly delaying tumour progression, while when started when prostate tumours were already present, a nonstatistically significant trend in the same direction was detected. These findings indicate that the use of alkalinizing drugs should be considered for chemoprevention and, in association with standard chemotherapy, for treatment of human prostate AC.

  18. Artemisinin-induced delayed hemolysis after administration of artesunate and artesunate-amodiaquine in malaria-free Wistar rats

    Directory of Open Access Journals (Sweden)

    Titilope M. Dokunmu

    2017-04-01

    Full Text Available Background: Hemolysis is common in malaria infection and during the course of treatment. Previous studies have reported delayed post-artemisinin hemolysis occurring in naïve and immune individuals treated with parenteral or oral artemisinin-derivatives. This study aims to understand if delayed hemolysis occurs in the absence of malaria parasites and the underlying mechanisms for the hemolytic effects after administration of two antimalarial drugs to malaria-free Wistar rats. Methods: Forty animals were randomized into 5 groups of eight animals each; they received 4 mg/kg artesunate for 7 days (AS, 4 mg/kg artesunate plus 10mg/kg amodiaquine for 3 days (ASQ, 10mg/kg amodiaquine for 3 days (AQ, distilled water [normal control], (Control and 1mg/kg phenylhydrazine for 1 day to induce hemolysis (PHZ groups respectively. Packed cell volume (PCV, white blood cell differential count and serum haptoglobin (Hpt levels were determined in all groups on day 4 and 18 to detect hemolysis. Mean values were compared using t-test and ANOVA with p values <0.05 taken to be significantly different. Results: Post-treatment mean PCV on day 4 was significantly lower than day 18 in all groups except AS group which had similar PCV all through evaluation. Although AQ had lowest mean PCV on day 4, by day 18, mean PCV returned to normal and hpt levels was significantly higher than AS and ASQ groups (p<0.001. Hpt level (mean ± sem for AS, ASQ, AQ, and control on day 18 were: 18.67 ± 0.004, 50.66 ± 0.014, 73.06 ± 0.003, and 74.13 ± 0.032 mg/dl respectively (p < 0.0001. On day 18, AS and ASQ had significantly lower Hpt level compared to day 4 (p <0.001. No neutropenia was observed during the study. Conclusion: Artesunate induces delayed hemolysis in malaria-free animals possibly through an oxidative toxic effect on the red blood cell membrane. Delayed post-treatment hemolysis was not observed with artesunate-amodiaquine or amodiaquine alone.

  19. Bronchoconstriction induced by inhaled methacholine delays desflurane uptake and elimination in a piglet model.

    Science.gov (United States)

    Kretzschmar, Moritz; Kozian, Alf; Baumgardner, James E; Schreiber, Jens; Hedenstierna, Göran; Larsson, Anders; Hachenberg, Thomas; Schilling, Thomas

    2016-01-01

    Bronchoconstriction is a hallmark of asthma and impairs gas exchange. We hypothesized that pharmacokinetics of volatile anesthetics would be affected by bronchoconstriction. Ventilation/perfusion (VA/Q) ratios and pharmacokinetics of desflurane in both healthy state and during inhalational administration of methacholine (MCh) to double peak airway pressure were studied in a piglet model. In piglets, MCh administration by inhalation (100 μg/ml, n=6) increased respiratory resistance, impaired VA/Q distribution, increased shunt, and decreased paO2 in all animals. The uptake and elimination of desflurane in arterial blood was delayed by nebulization of MCh, as determined by Micropore Membrane Inlet Mass Spectrometry (wash-in time to P50, healthy vs. inhalation: 0.5 min vs. 1.1 min, to P90: 4.0 min vs. 14.8 min). Volatile elimination was accordingly delayed. Inhaled methacholine induced severe bronchoconstriction and marked inhomogeneous VA/Q distribution in pigs, which is similar to findings in human asthma exacerbation. Furthermore, MCh-induced bronchoconstriction delayed both uptake and elimination of desflurane. These findings might be considered when administering inhalational anesthesia to asthmatic patients. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Delayed phase of hematoporphyrin-induced phototoxicity: modulation by complement, leukocytes, and antihistamines

    Energy Technology Data Exchange (ETDEWEB)

    Lim, H.W.; Young, L.; Hagan, M.; Gigli, I.

    1985-02-01

    The role of complement, leukocytes, and histamine was investigated in the delayed phase of hematoporphyrin-induced phototoxicity in guinea pigs. The phototoxic response was quantified by the accumulation of intravenously injected (/sup 125/I)bovine serum albumin in the skin. There was a greater than 6-fold increase in the vascular response at the completion of irradiation, which subsided partially to reach a plateau of twice the preirradiation level between 0.5 h and 12 h. At 18 h, the vascular responsiveness returned to the baseline value. The 7 h timepoint was selected in this study to evaluate the modulation of the delayed phase. In complement-depleted guinea pigs, as well as in leukopenic animals, the enhancement in the vascular response was significantly suppressed (p vs control, less than 0.0001 and 0.0022, respectively). Cimetidine, when administered prior to irradiation, significantly suppressed the phototoxic response (p vs control, 0.0365). The combination of diphenhydramine and cimetidine, administered 6 h after the induction of phototoxicity, also suppressed the vascular response (p vs control, less than 0.0001). These data indicate that the expression of the delayed phase of hematoporphyrin-induced phototoxicity, similar to the early phase, requires the presence of an intact complement system, leukocytes, and histamine.

  1. Delayed Activation Kinetics of Th2- and Th17 Cells Compared to Th1 Cells.

    Science.gov (United States)

    Duechting, Andrea; Przybyla, Anna; Kuerten, Stefanie; Lehmann, Paul V

    2017-09-12

    During immune responses, different classes of T cells arise: Th1, Th2, and Th17. Mobilizing the right class plays a critical role in successful host defense and therefore defining the ratios of Th1/Th2/Th17 cells within the antigen-specific T cell repertoire is critical for immune monitoring purposes. Antigen-specific Th1, Th2, and Th17 cells can be detected by challenging peripheral blood mononuclear cells (PBMC) with antigen, and establishing the numbers of T cells producing the respective lead cytokine, IFN-γ and IL-2 for Th1 cells, IL-4 and IL-5 for Th2, and IL-17 for Th-17 cells, respectively. Traditionally, these cytokines are measured within 6 h in flow cytometry. We show here that 6 h of stimulation is sufficient to detect peptide-induced production of IFN-γ, but 24 h are required to reveal the full frequency of protein antigen-specific Th1 cells. Also the detection of IL-2 producing Th1 cells requires 24 h stimulation cultures. Measurements of IL-4 producing Th2 cells requires 48-h cultures and 96 h are required for frequency measurements of IL-5 and IL-17 secreting T cells. Therefore, accounting for the differential secretion kinetics of these cytokines is critical for the accurate determination of the frequencies and ratios of antigen-specific Th1, Th2, and Th17 cells.

  2. A low-power DCO using inverter interlaced cascaded delay cell

    Science.gov (United States)

    Qiang, Huang; Tao, Fan; Xiangming, Dai; Guoshun, Yuan

    2014-11-01

    This paper presents a low-power small-area digitally controlled oscillator (DCO) using an inverters interlaced cascaded delay cell (IICDC). It uses a coarse-fine architecture with binary-weighted delay stages for the delay range and resolution. The coarse-tuning stage of the DCO uses IICDC, which is power and area efficient with low phase noise, as compared with conventional delay cells. The ADPLL with a DCO is fabricated in the UMC 180-nm CMOS process with an active area of 0.071 mm2. The output frequency range is 140-600 MHz at the power supply of 1.8 V. The power consumption is 2.34 mW @ a 200 MHz output.

  3. Nadroparin carries a potentially high risk of inducing cutaneous delayed-type hypersensitivity responses.

    Science.gov (United States)

    Schindewolf, Marc; Recke, Andreas; Zillikens, Detlef; Lindhoff-Last, Edelgard; Ludwig, Ralf J

    2017-07-01

    Heparins are widely used for the prophylaxis/treatment of thromboembolic events. As adverse effects, heparin-induced skin lesions occur frequently (in 7.5-39% of patients). Skin lesions may be the only clinical manifestation of life-threatening immune-mediated heparin-induced thrombocytopenia, but are commonly caused by a delayed-type hypersensitivity response [heparin-induced delayed-type hypersensitivity (HIHS)]. Risk factors have not been prospectively identified. To identify possible risk factors for heparin-induced skin lesions from three independent clinical trials in a combined analysis. A pooled analysis from prospective studies was performed, and possible risk factors were included in a multiple logistic regression analysis. Obesity (body mass index of > 25), prolonged anticoagulant therapy, prior heparin exposure and younger age (< 55 years) were confirmed as independent risk factors for HIHS. The choice of anticoagulant preparation had the greatest influence. On comparison of dalteparin, enoxaparin, fondaparinux, unfractionated heparin, and nadroparin, the latter was associated with the highest risk of eliciting HIHS (odds ratio of 30.2, 95%CI: 11.7-77.9). The high risk associated with nadroparin has been validated in controlled trials, and this emphasizes the singularity of each heparin preparation in terms of allergenicity and that individualized anticoagulation is required. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. 4-1BB signaling activates the t cell factor 1 effector/β-catenin pathway with delayed kinetics via ERK signaling and delayed PI3K/AKT activation to promote the proliferation of CD8+ T Cells.

    Science.gov (United States)

    Lee, Do Y; Choi, Beom K; Lee, Don G; Kim, Young H; Kim, Chang H; Lee, Seung J; Kwon, Byoung S

    2013-01-01

    4-1BB (CD137), an inducible costimulatory molecule, strongly enhances the proliferation and effector function of CD8(+) T cells. Since the serine/threonine kinase, glycogen synthase kinase-3 (GSK-3), is involved in a variety of signaling pathways of cellular proliferation, migration, immune responses, and apoptosis, we examined whether 4-1BB signaling activates GSK-3/β-catenin signaling and downstream transcription factors to enhance the proliferation of CD8(+) T cells. 4-1BB signaling induces rapid activation of ERK and IκB degradation, and shows delayed activation of AKT at 24 h post 4-1BB stimulation on anti-CD3 activated T cells. ERK and AKT signals were required for sustained β-catenin levels by inactivating GSK-3, which was also observed with delayed kinetics after 4-1BB stimulation. As a transcriptional partner of β-catenin, 4-1BB signaling decreased levels of FOXO1 and increased levels of stimulatory TCF1 in CD8(+) T cells at 2-3 days but not at early time points after 4-1BB engagement. The enhanced proliferation of CD8(+) T cells due to 4-1BB signaling was completely abolished by treatment with the TCF1/β-catenin inhibitor quercetin. These results show that 4-1BB signaling enhances the proliferation of activated CD8(+) T cells by activating the TCF1/β-catenin axis via the PI3K/AKT/ERK pathway. As effects of 4-1BB on AKT, FOXO1, β-catenin and GSK-3β showed delayed kinetics it is likely that an intervening molecule induced by 4-1BB and ERK signaling in activated T cells is responsible for these effects. These effects were observed on CD8(+) but not on CD4(+) T cells. Moreover, 4-1BB appeared to be unique among several TNFRs tested in inducing increase in stimulatory over inhibitory TCF-1.

  5. Preventive Effects of a Chinese Herbal Formula, Shengjiang Xiexin Decoction, on Irinotecan-Induced Delayed-Onset Diarrhea in Rats.

    Science.gov (United States)

    Deng, Chao; Deng, Bo; Jia, Liqun; Tan, Huangying; Zhang, Pan; Liu, Sida; Zhang, Yanan; Song, Aiping; Pan, Lin

    2017-01-01

    Irinotecan is a well-known chemotherapy drug for the treatment of various cancers. However, delayed-onset diarrhea is a common adverse reaction, limiting the application of the drug. The study presented was designed to evaluate the preventive effects of Shengjiang Xiexin decoction (SXD) on irinotecan-induced diarrhea and to explore the possible mechanisms of this action. We established a diarrhea rat model. The condition of the rats was observed. The proliferation and apoptosis of intestinal cells were measured using immunohistochemical assays and a caspase-3 activity assay, respectively. The expression of Lgr5 and CD44 staining were used to observe intestinal stem cells (ISCs). In addition, the activity of β-glucuronidase in the rats' feces was measured. Our results showed that the number of proliferating intestinal cells in the SXD groups was obviously higher, while the activity of caspase-3 was lower. The expression of Lgr5 and the integrated option density (IOD) of CD44 stain were increased significantly by SXD. Additionally, SXD decreased the activity of β-glucuronidase after irinotecan administration. In conclusion, SXD exhibited preventive effects on irinotecan-induced diarrhea, and this action was associated with an inhibitory effect on intestinal apoptosis and β-glucuronidase and a promotive effect on intestinal cell proliferation due to increased maintenance of ISCs.

  6. Preventive Effects of a Chinese Herbal Formula, Shengjiang Xiexin Decoction, on Irinotecan-Induced Delayed-Onset Diarrhea in Rats

    Directory of Open Access Journals (Sweden)

    Chao Deng

    2017-01-01

    Full Text Available Irinotecan is a well-known chemotherapy drug for the treatment of various cancers. However, delayed-onset diarrhea is a common adverse reaction, limiting the application of the drug. The study presented was designed to evaluate the preventive effects of Shengjiang Xiexin decoction (SXD on irinotecan-induced diarrhea and to explore the possible mechanisms of this action. We established a diarrhea rat model. The condition of the rats was observed. The proliferation and apoptosis of intestinal cells were measured using immunohistochemical assays and a caspase-3 activity assay, respectively. The expression of Lgr5 and CD44 staining were used to observe intestinal stem cells (ISCs. In addition, the activity of β-glucuronidase in the rats’ feces was measured. Our results showed that the number of proliferating intestinal cells in the SXD groups was obviously higher, while the activity of caspase-3 was lower. The expression of Lgr5 and the integrated option density (IOD of CD44 stain were increased significantly by SXD. Additionally, SXD decreased the activity of β-glucuronidase after irinotecan administration. In conclusion, SXD exhibited preventive effects on irinotecan-induced diarrhea, and this action was associated with an inhibitory effect on intestinal apoptosis and β-glucuronidase and a promotive effect on intestinal cell proliferation due to increased maintenance of ISCs.

  7. Delayed effects of cold atmospheric plasma on vascular cells

    NARCIS (Netherlands)

    Stoffels, Eva; Roks, Anton J. M.; Deelmm, Leo E.

    2008-01-01

    We investigated the long-term behaviour of vascular cells (endothelial and smooth muscle) after exposure to a cold atmospheric plasma source. The cells were treated through a gas-permeable membrane, in order to simulate intravenous treatment with a gas plasma-filled catheter. Such indirect treatment

  8. Delayed auditory conduction in diabetes: is metformin-induced vitamin B12 deficiency responsible?

    Science.gov (United States)

    Khattar, D; Khaliq, F; Vaney, N; Madhu, S V

    2016-01-01

    The present study aims to evaluate the functional integrity of the auditory pathway in patients with diabetes taking metformin. A further aim is to assess its association with vitamin B12 deficiency induced by metformin. Thirty diabetics taking metformin and 30 age-matched non-diabetic controls were enrolled. Stimulus-related potentials and vitamin B12 levels were evaluated in all the subjects. The diabetics showed deficient vitamin B12 levels and delayed wave III latency and III-V interpeak latency in the right ear and delayed Na and Pa wave latencies in the left ear compared with the controls. The dose and duration of metformin showed no association with the stimulusrelated potentials. Therefore, although vitamin B12 levels were deficient and auditory conduction impairment was present in the diabetics on metformin, this impairment cannot be attributed to the vitamin B12 deficiency.

  9. Chronological changes of delayed-type hypersensitivity in mice immunised with testicular germ cells alone.

    Science.gov (United States)

    Qu, N; Naito, M; Terayama, H; Hirai, S; Musha, M; Itoh, M

    2014-06-01

    Experimental autoimmune orchitis (EAO), comprising a breakdown of the testicular immune privilege, is one of the models of immunological male infertility. EAO is characterised by CD4 + T-cell-dependent lymphocytic inflammation and augmented delayed-type hypersensitivity (DTH) against testicular antigens. We previously established an EAO model in mice by immunisation with viable syngeneic testicular germ cells (TGC) alone. However, the sequential change of DTH during development of this EAO has not been analysed yet. In this study, the DTH response during TGC-induced EAO was investigated by the injection of syngeneic TGC protein into the ears of mice. The results showed that a significant DTH response was observed on injection of 20 μg TGC protein, but not on that of 0.2 or 2 μg TGC protein. Also, the level of the DTH response to 20 μg TGC protein was highly relevant to the pathology of EAO development. These results indicate that the DTH response on injection of 20 μg TGC protein into the ears of mice is effective for predicting the pathology of EAO development. © 2013 Blackwell Verlag GmbH.

  10. Mechanisms of Broad-Spectrum Antiemetic Efficacy of Cannabinoids against Chemotherapy-Induced Acute and Delayed Vomiting

    Directory of Open Access Journals (Sweden)

    Nissar A. Darmani

    2010-09-01

    Full Text Available Chemotherapy-induced nausea and vomiting (CINV is a complex pathophysiological condition and consists of two phases. The conventional CINV neurotransmitter hypothesis suggests that the immediate phase is mainly due to release of serotonin (5-HT from the enterochromaffin cells in the gastrointestinal tract (GIT, while the delayed phase is a consequence of release of substance P (SP in the brainstem. However, more recent findings argue against this simplistic neurotransmitter and anatomical view of CINV. Revision of the hypothesis advocates a more complex, differential and overlapping involvement of several emetic neurotransmitters/modulators (e.g. dopamine, serotonin, substance P, prostaglandins and related arachidonic acid derived metabolites in both phases of emesis occurring concomitantly in the brainstem and in the GIT enteric nervous system (ENS [1]. No single antiemetic is currently available to completely prevent both phases of CINV. The standard antiemetic regimens include a 5-HT3 antagonist plus dexamethasone for the prevention of acute emetic phase, combined with an NK1 receptor antagonist (e.g. aprepitant for the delayed phase. Although NK1 antagonists behave in animals as broad-spectrum antiemetics against different emetogens including cisplatin-induced acute and delayed vomiting, by themselves they are not very effective against CINV in cancer patients. Cannabinoids such as D9-THC also behave as broad-spectrum antiemetics against diverse emetic stimuli as well as being effective against both phases of CINV in animals and patients. Potential side effects may limit the clinical utility of direct-acting cannabinoid agonists which could be avoided by the use of corresponding indirect-acting agonists. Cannabinoids (both phyto-derived and synthetic behave as agonist antiemetics via the activation of cannabinoid CB1 receptors in both the brainstem and the ENS emetic loci. An endocannabinoid antiemetic tone may exist since inverse CB1

  11. Organophosphate-induced delayed neuropathy: case report Neuropatia tardia por organofosforado: relato de caso

    Directory of Open Access Journals (Sweden)

    Luiz Felipe R Vasconcellos

    2002-12-01

    Full Text Available Organophosphate induced delayed neuropathy (OPIDN is an uncommon clinical condition. It occurs in association with the ingestion of great amounts of organophosphate after the stimulation of cholinergic receptor. The clinical picture is characterized by a distal paresis in lower limbs associated with sensitive symptoms. Electrodiagnostic studies show a motor axonal neuropathy. Involvement of the central nervous system may occur. We describe a 39 years-old female patient who developed hyperesthesia associated with lower limbs paresis, fourteen days after she had ingested a Dichlorvos-based insecticide. Electrophysiological study was characterized by an axonal polyneuropathy pattern. Pyramidal tract dysfunction was observed later in upper limbs. Considering that both peripheral and central nervous systems are involved we believe that the more appropriated term would be organophosphate induced delayed neuropathy (OPIDN instead of organophosphate induced delayed polyneuropathy (OPIDP.A neuropatia tardia dos organofosforados (NTOF é condição clinica incomum. Geralmente ocorre após a intoxicação aguda por organofosforados, seguindo-se a fase de hiperestimulação colinérgica. O quadro clínico é caracterizado por déficit motor distal nos membros inferiores associado a sintomas sensitivos. O estudo eletroneuromiográfico tem demonstrado padrão axonal motor na maioria dos casos. Podem ocorrer sinais de comprometimento do sistema nervoso central. Descrevemos o caso de uma paciente de 39 anos que ingeriu inseticida a base de Dichlorvos e quatorze dias após apresentou quadro de hiperestesia associado a paresia distal nos membros inferiores. Realizou eletroneuromiografia que se caracterizou por padrão compatível com polineuropatia axonal. Sinais piramidais, de aparecimento mais tardio, foram observados nos membros superiores. Diante do comprometimento do sistema nervoso periférico e central, também consideramos o termo neuropatia tardia por

  12. Effect of the GABA B agonist baclofen on dipyrone-induced delayed gastric emptying in rats

    Directory of Open Access Journals (Sweden)

    E.F. Collares

    2005-01-01

    Full Text Available Dipyrone administered intravenously (iv or intracerebroventricularly (icv delays gastric emptying (GE in rats. Gamma-aminobutyric acid (GABA is the most potent inhibitory neurotransmitter of the central nervous system. The objective of the present study was to determine the effect of icv baclofen, a GABA B receptor agonist, on delayed GE induced by dipyrone. Adult male Wistar rats received a saline test meal containing phenol red as a marker. GE was indirectly evaluated by determining the percent of gastric retention (%GR of the meal 10 min after orogastric administration. In the first experiment, the animals were injected iv with vehicle (Civ or 80 mg/kg (240 µmol/kg dipyrone (Dp iv, followed by icv injection of 10 µl vehicle (bac0, or 0.5 (bac0.5, 1 (bac1 or 2 µg (bac2 baclofen. In the second experiment, the animals were injected icv with 5 µl vehicle (Cicv or an equal volume of a solution containing 4 µmol (1333.2 µg dipyrone (Dp icv, followed by 5 µl vehicle (bac0 or 1 µg baclofen (bac1. GE was determined 10 min after icv injection. There was no significant difference between control animals from one experiment to another concerning GR values. Baclofen at the doses of 1 and 2 µg significantly reduced mean %GR induced by iv dipyrone (Dp iv bac1 = 35.9% and Dp iv bac2 = 26.9% vs Dp iv bac0 = 51.8%. Similarly, baclofen significantly reduced the effect of dipyrone injected icv (mean %GR: Dp icv bac1 = 30.4% vs Dp icv bac0 = 54.2%. The present results suggest that dipyrone induces delayed GE through a route in the central nervous system that is blocked by the activation of GABA B receptors.

  13. Benzothiadiazole-Mediated Induced Resistance to Colletotrichum musae and Delayed Ripening of Harvested Banana Fruit.

    Science.gov (United States)

    Zhu, Xiaoyang; Lin, Huanzhang; Si, Zhenwei; Xia, Yihua; Chen, Weixin; Li, Xueping

    2016-02-24

    Benzothiadiazole (BTH) works as a plant activator. The effects of different BTH treatments and fungicides SPORGON on fruit ripening and disease incidence were investigated. The results showed that BTH treatment significantly delayed fruit ripening, maintained fruit firmness, color, and good fruit quality, and dramatically reduced the incidence of disease. BTH effectively inhibited the invasion and development of pathogenic bacteria and controlled the occurrence of disease. BTH treatment enhanced the activities of defense-related enzymes, including chitinase, phenylalanine ammonia-lyase, peroxidase, and polyphenol oxidase, increased the content of hydrogen peroxide and total antioxidant capacity, and reduced malondialdehyde content. Cellular structure analysis after inoculation confirmed that BTH treatment effectively maintained the cell structural integrity. SPORGON did not provide benefits for delaying fruit ripening or for the resistance system, while it can control the disease only during the earlier stage and not at later stages.

  14. Opioid-induced delay in gastric emptying: a peripheral mechanism in humans.

    LENUS (Irish Health Repository)

    Murphy, D B

    2012-02-03

    BACKGROUND: Opioids delay gastric emptying, which in turn may increase the risk of vomiting and pulmonary aspiration. Naloxone reverses this opiate action on gastric emptying, but it is not known whether this effect in humans is mediated by central or peripheral opiate antagonism. The importance of peripheral opioid receptor antagonism in modulating opioid-induced delay in gastric emptying was evaluated using methylnaltrexone, a quaternary derivative of the opiate antagonist naltrexone, which does not cross the blood-brain barrier. METHODS: In a randomized, double-blind, crossover placebo-controlled study, 11 healthy volunteers were given either placebo (saline), 0.09 mg\\/kg morphine, or 0.09 mg\\/kg morphine plus 0.3 mg\\/kg methylnaltrexone on three separate occasions before ingesting 500 ml deionized water. The rate of gastric emptying was measured by two methods: a noninvasive epigastric bioimpedance technique and the acetaminophen absorption test. RESULTS: The epigastric bioimpedance technique was sufficiently sensitive to detect opioid-induced changes in the rate of gastric emptying. The mean +\\/- SD time taken for the gastric volume to decrease to 50% (t0.5) after placebo was 5.5 +\\/- 2.1 min. Morphine prolonged gastric emptying to (t0.5) of 21 +\\/- 9.0 min (P < 0.03). Methylnaltrexone given concomitantly with morphine reversed the morphine-induced delay in gastric emptying to a t0.5 of 7.4 +\\/- 3.0 (P < 0.04). Maximum concentrations and area under the concentration curve from 0 to 90 min of serum acetaminophen concentrations after morphine were significantly different from placebo and morphine administered concomitantly with methylnaltrexone (P < 0.05). No difference in maximum concentration or area under the concentration curve from 0 to 90 min was noted between placebo and methylnaltrexone coadministered with morphine. CONCLUSIONS: The attenuation of morphine-induced delay in gastric emptying by methylnaltrexone suggests that the opioid effect is

  15. Secretory phospholipase A(2) induces delayed neuronal COX-2 expression compared with glutamate

    DEFF Research Database (Denmark)

    Kolko, Miriam; Nielsen, Marianne; Bazan, Nicolas G

    2002-01-01

    Agonists of the binding site for secretory phospholipase A(2) (sPLA(2)) potentiate glutamate-induced neuronal cell death in primary cell cultures and in vivo (Kolko et al. [1996] J. Biol. Chem. 271:32722; Kolko et al. [1999] Neurosci. Lett. 274:167]. Here, we tested the hypothesis that COX-2...

  16. Staphylococcus aureus Lpl Lipoproteins Delay G2/M Phase Transition in HeLa Cells.

    Science.gov (United States)

    Nguyen, Minh-Thu; Deplanche, Martine; Nega, Mulugeta; Le Loir, Yves; Peisl, Loulou; Götz, Friedrich; Berkova, Nadia

    2016-01-01

    The cell cycle is an ordered set of events, leading to cell growth and division into two daughter cells. The eukaryotic cell cycle consists of interphase (G1, S, and G2 phases), followed by the mitotic phase and G0 phase. Many bacterial pathogens secrete cyclomodulins that interfere with the host cell cycle. In Staphylococcus aureus four cyclomodulins have been described so far that all represent toxins and are secreted into the culture supernatant. Here we show that the membrane-anchored lipoprotein-like proteins (Lpl), encoded on a genomic island called νSaα, interact with the cell cycle of HeLa cells. By comparing wild type and lpl deletion mutant it turned out that the lpl cluster is causative for the G2/M phase transition delay and also contributes to increased invasion frequency. The lipoprotein Lpl1, a representative of the lpl cluster, also caused G2/M phase transition delay. Interestingly, the lipid modification, which is essential for TLR2 signaling and activation of the immune system, is not necessary for cyclomodulin activity. Unlike the other staphylococcal cyclomodulins Lpl1 shows no cytotoxicity even at high concentrations. As all Lpl proteins are highly conserved there might be a common function that is accentuated by their multiplicity in a tandem gene cluster. The cell surface localized Lpls' suggests a correlation between G2/M phase transition delay and host cell invasion.

  17. Silent Crooke's cell corticotroph adenoma of the pituitary gland presenting as delayed puberty.

    Science.gov (United States)

    Giri, Dinesh; Roncaroli, Federico; Sinha, Ajay; Didi, Mohammed; Senniappan, Senthil

    2017-01-01

    Corticotroph adenomas are extremely rare in children and adolescents. We present a 15-year-old boy who was investigated for delayed puberty (A1P2G1, bilateral testicular volumes of 3 mL each). There was no clinical or laboratory evidence suggestive of chronic illness, and the initial clinical impression was constitutional delay in puberty. Subsequently, MRI scan of the brain revealed the presence of a mixed cystic and solid pituitary lesion slightly displacing the optic chiasma. The lesion was removed by transphenoidal surgery and the biopsy confirmed the lesion to be pituitary adenoma. Furthermore, the adenoma cells also had Crooke's hyaline changes and were intensely positive for ACTH. However there was no clinical/biochemical evidence of ACTH excess. There was a spontaneous pubertal progression twelve months after the surgery (A2P4G4, with bilateral testicular volume of 8 mL). Crooke's cell adenoma is an extremely rare and aggressive variant of corticotroph adenoma that can uncommonly present as a silent corticotroph adenoma in adults. We report for the first time Crooke's cell adenoma in an adolescent boy presenting with delayed puberty. Constitutional delay of growth and puberty (CDGP) is a diagnosis of exclusion; hence a systematic and careful review should be undertaken while assessing boys with delayed puberty.Crooke's cell adenomas are a group of corticotroph adenomas that can rarely present in childhood and adolescence with delayed puberty.Crooke's cell adenomas can be clinically silent but are potentially aggressive tumours that require careful monitoring.

  18. Induced Hypertension for Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: A Randomized Clinical Trial.

    Science.gov (United States)

    Gathier, Celine S; van den Bergh, Walter M; van der Jagt, Mathieu; Verweij, Bon H; Dankbaar, Jan Willem; Müller, Marcella C; Oldenbeuving, Annemarie W; Rinkel, Gabriel J E; Slooter, Arjen J C

    2018-01-01

    Induced hypertension is widely used to treat delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage, but a literature review shows that its presumed effectiveness is based on uncontrolled case-series only. We here report clinical outcome of aneurysmal subarachnoid hemorrhage patients with DCI included in a randomized trial on the effectiveness of induced hypertension. Aneurysmal subarachnoid hemorrhage patients with clinical symptoms of DCI were randomized to induced hypertension or no induced hypertension. Risk ratios for poor outcome (modified Rankin Scale score >3) at 3 months, with 95% confidence intervals, were calculated and adjusted for age, clinical condition at admission and at time of DCI, and amount of blood on initial computed tomographic scan with Poisson regression analysis. The trial aiming to include 240 patients was ended, based on lack of effect on cerebral perfusion and slow recruitment, when 21 patients had been randomized to induced hypertension, and 20 patients to no hypertension. With induced hypertension, the adjusted risk ratio for poor outcome was 1.0 (95% confidence interval, 0.6-1.8) and the risk ratio for serious adverse events 2.1 (95% confidence interval, 0.9-5.0). Before this trial, the effectiveness of induced hypertension for DCI in aneurysmal subarachnoid hemorrhage patients was unknown because current literature consists only of uncontrolled case series. The results from our premature halted trial do not add any evidence to support induced hypertension and show that this treatment can lead to serious adverse events. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01613235. © 2017 American Heart Association, Inc.

  19. Delayed Diagnosis: Giant Basal Cell Carcinoma of Scalp

    Directory of Open Access Journals (Sweden)

    Didem Didar Balcı,

    2008-07-01

    Full Text Available Although basal cell carcinoma (BCC is the most common form of skin cancer, the scalp lesions of BCC have been rarely reported. Giant BCC is defined as a tumor larger than 5 cm in diameter and only 0.5-1 % of all BCCs achieve this size. We report a case of giant BCC on the scalp that was treated with topical coticosteroids and antifungal shampoo for five years. BCC should be considered in the differential diagnosis in erythematous plaque type lesions resistant to therapy with long duration localized on the scalp.

  20. Increased susceptibility to delayed genetic effects of low dose X-irradiation in DNA repair deficient cells.

    Science.gov (United States)

    Kashino, Genro; Suzuki, Keiji; Kodama, Seiji; Watanabe, Masami; Prise, Kevin M

    2013-04-01

    To examine whether the levels of micronuclei induction, as a marker for genomic instability in the progeny of X-irradiated cells, correlates with DNA repair function. Two repair deficient cell lines (X-ray repair cross-complementing 1 [XRCC1] deficient cell line [EM9] and X-ray repair cross complementing 5 [XRCC5; Ku80] deficient X-ray sensitive Chinese hamster ovary [CHO] cell line [xrs5]) were used in addition to wild-type CHO cells. These cells were irradiated with low doses of X-rays (up to 1 Gy). Seven days after irradiation, micronuclei formed in binucleated cells were counted. To assess the contribution of the bystander effect micronuclei induction was measured in progeny of non-irradiated cells co-cultured with cells that had been irradiated with 1Gy. The delayed induction of micronuclei in 1 Gy-irradiated cells was observed in normal CHO and EM9 but not in xrs5. In the clone analysis, progenies of xrs5 under bystander conditions showed significantly higher levels of micronuclei, while CHO and EM9 did not. Genomic instability induced by X-irradiation is associated with DSB (double-strand break) repair, even at low doses. It is also suggested that bystander signals, which lead to genomic instability, may be enhanced when DSB repair is compromised.

  1. [Epicutaneous patch testing in delayed drug hypersensitivity reactions induced by antiepileptic drugs].

    Science.gov (United States)

    Ben Mahmoud, Lobna; Bahloul, Najla; Ghozzi, Hanen; Kammoun, Brahim; Hakim, Ahmed; Sahnoun, Zouheir; Kammoun, Sami; Zeghal, Khaled

    2017-10-01

    Antiepileptic drugs are widely used and are associated with numerous side effects including skin eruptions. Epicutaneous tests have been used with variable success in skin drug reactions. The purpose of this study was to evaluate the profitability of epicutaneous tests in delayed hypersensitivity reactions induced by antiepileptic drugs. We analyzed all cases of allergic skin reactions to antiepileptic drugs notified in regional pharmacovigilance center of Sfax (Tunisia) between June 1, 2014 and April 30, 2016. The imputation score, determined using the French imputation method, should be at least doubtful. Patch-tests were performed in accordance with the general Europen network on Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) guidelines. Patch-tests were read according to the generally accepted criteria of the International contact dermatitis research group (ICDRG). In our study, 20 patients were included, among which 23 events were observed. The drug involved in delayed hypersensitivity reactions was carbamazepine in 11 cases, phenobarbital in 10 cases and valproic acid in 4 cases. The clinical reactions caused by the drug were classified as maculopapular exanthema (11 cases), DRESS syndrome (6 cases), Stevens-Johnson syndrome (2 cases), fixed drug eruption (2 cases) and erythroderma (2 cases). Patch-tests were positive in 19 patients (95 %). Cross-reactivity between antiepileptic drugs was observed in 4 cases: between valproic acid and carbamazepine in 2 cases between valproic acid and phenobarbital in 1 case and between phenobarbital and carbamazepine in 1 case. In this study, patch testing was a safe and useful method in confirming the culprit drug in delayed hypersensitivity reactions induced by antiepileptic drugs. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

  2. Food-grade micro-encapsulation systems that may induce satiety via delayed lipolysis: A review.

    Science.gov (United States)

    Corstens, Meinou N; Berton-Carabin, Claire C; de Vries, Renko; Troost, Freddy J; Masclee, Ad A M; Schroën, Karin

    2017-07-03

    The increasing prevalence of overweight and obesity requires new, effective prevention and treatment strategies. One approach to reduce energy intake is by developing novel foods with increased satiating properties, which may be accomplished by slowing down lipolysis to deliver substrates to the ileum, thereby enhancing natural gut-brain signaling pathways of satiety that are normally induced by meal intake. To develop slow release food additives, their processing in the gastrointestinal tract has to be understood; therefore, we start from a general description of the digestive system and relate that to in vitro modeling, satiety, and lipolytic mechanisms. The effects of physicochemical lipid composition, encapsulation matrix, and interfacial structure on lipolysis are emphasized. We give an overview of techniques and materials used, and discuss partitioning, which may be a key factor for encapsulation performance. Targeted release capsules that delay lipolysis form a real challenge because of the high efficiency of the digestive system; hardly any proof was found that intact orally ingested lipids can be released in the ileum and thereby induce satiety. We expect that this challenge could be tackled with structured o/w-emulsion-based systems that have some protection against lipase, e.g., by hindering bile salt adsorption and/or delaying lipase diffusion.

  3. Experimental colitis delays and reduces the severity of collagen-induced arthritis in mice.

    Science.gov (United States)

    Hablot, Julie; Peyrin-Biroulet, Laurent; Kokten, Tunay; El Omar, Reine; Netter, Patrick; Bastien, Claire; Jouzeau, Jean-Yves; Sokol, Harry; Moulin, David

    2017-01-01

    Amongst extraintestinal manifestations (EIM) occurring in IBD patients, rheumatologic manifestations are the most frequent. Understanding the relationships between arthritis and colitis is a prerequisite to improving the management of these patients. Microbiota of patients with IBD or rheumatologic diseases, like spondyloarthritis (SpA) is modified compared to healthy individual. Thus, we have evaluated the impact of colitis in the development of arthritis in mice and we have analyzed microbiota changes. Collagen-induced arthritis (CIA) was induced at day 0 in DBA1 mice exposed or not to Dextran Sodium Sulfate (DSS) to induce colitis between day 14 and day 21. Animals were monitored regularly for arthritis and colitis severity (clinical score, hindpaw edema). Fecal microbiota was studied by 16S rRNA deep sequencing at critical time points (D14, D14, D21 & D41). At day 41, histological scoring of the intestines and ankles were performed at the end of experiment. Induction of colitis slightly delayed arthritis onset (2 ± 1 days of delay) and reduced its severity (5.75 ± 1.62 in arthritis only group vs 4.00 ± 1.48 in arthritis + colitis group (p = 0.02 at day 28) macroscopically and histologically. In contrast, colitis severity was not influenced by arthritis development. Induction of colitis promoted a modification of microbiota composition and a decrease of α-diversity. Fecal microbiota composition was different between "colitis" and "arthritis+colitis" groups during colitis development. Interestingly a milder decrease of bacterial diversity in the "arthritis+colitis" group was observed. Concomitant experimental colitis protects mice against collagen-induced arthritis and this is associated with changes in gut microbiome composition.

  4. Experimental colitis delays and reduces the severity of collagen-induced arthritis in mice

    Science.gov (United States)

    Hablot, Julie; Peyrin-Biroulet, Laurent; Kokten, Tunay; El Omar, Reine; Netter, Patrick; Bastien, Claire; Jouzeau, Jean-Yves; Sokol, Harry

    2017-01-01

    Amongst extraintestinal manifestations (EIM) occurring in IBD patients, rheumatologic manifestations are the most frequent. Understanding the relationships between arthritis and colitis is a prerequisite to improving the management of these patients. Microbiota of patients with IBD or rheumatologic diseases, like spondyloarthritis (SpA) is modified compared to healthy individual. Thus, we have evaluated the impact of colitis in the development of arthritis in mice and we have analyzed microbiota changes. Collagen-induced arthritis (CIA) was induced at day 0 in DBA1 mice exposed or not to Dextran Sodium Sulfate (DSS) to induce colitis between day 14 and day 21. Animals were monitored regularly for arthritis and colitis severity (clinical score, hindpaw edema). Fecal microbiota was studied by 16S rRNA deep sequencing at critical time points (D14, D14, D21 & D41). At day 41, histological scoring of the intestines and ankles were performed at the end of experiment. Induction of colitis slightly delayed arthritis onset (2 ± 1 days of delay) and reduced its severity (5.75 ± 1.62 in arthritis only group vs 4.00 ± 1.48 in arthritis + colitis group (p = 0.02 at day 28) macroscopically and histologically. In contrast, colitis severity was not influenced by arthritis development. Induction of colitis promoted a modification of microbiota composition and a decrease of α-diversity. Fecal microbiota composition was different between “colitis” and “arthritis+colitis” groups during colitis development. Interestingly a milder decrease of bacterial diversity in the “arthritis+colitis” group was observed. Concomitant experimental colitis protects mice against collagen-induced arthritis and this is associated with changes in gut microbiome composition. PMID:28926599

  5. Checkpoint genes required to delay cell division in response to nocodazole respond to impaired kinetochore function in the yeast Saccharomyces cerevisiae

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yanchang; Burke, D.J. [Univ. of Virginia, Charlottesville, VA (United States)

    1995-12-01

    This report describes the effects of antimitotic drugs on cell cycle when administered in quantities which maintain the spindle structure of microtubules. This research was carried out using the yeast Saccharomyces cerevisiae and the antimitotic drug nocodazole. Results show that a low concentration of nocodazole induces a cell cycle delay that is sensitive to impaired kinetochore function under the control of previously identified mitotic checkpoint genes. 40 refs., 6 figs., 4 tabs.

  6. Delayed Treatment with Lidocaine Reduces Mouse Microglial Cell Injury and Cytokine Production After Stimulation with Lipopolysaccharide and Interferon γ

    Science.gov (United States)

    Jeong, Hae-Jeong; Lin, Daowei; Li, Liaoliao; Zuo, Zhiyi

    2012-01-01

    Background Neuroinflammation is an important pathological process for almost all acquired neurological diseases. Microglial cells play a critical role in neuroinflammation. We determined whether lidocaine, a local anesthetic with antiinflammatory property, protected microglial cells and attenuated cytokine production from activated microglial cells. Methods Mouse microglial cultures were incubated with or without 1 µg/ml lipopolysaccharide and 10 U/ml interferon γ (IFNγ) for 24 h in the presence or absence of lidocaine for 1 h started at 2, 3 or 4 h after the onset of lipopolysaccharide and IFNγ stimulation. Lactate dehydrogenase release and cytokine production were determined after the cells were stimulated by lipopolysaccharide and IFNγ for 24 h. Results Lidocaine dose-dependently reduced lipopolysaccharide and IFNγ-induced microglial cell injury as measured by lactate dehydrogenase release. This effect was apparent with lidocaine at 2 µg/ml (30.3 ± 5.8 and 23.1 ± 9.7%, respectively, for stimulation alone and the stimulation in the presence of lidocaine, n = 18, P = 0.025). Lidocaine applied at 2, 3 or 4 h after the onset of lipopolysaccharide and IFNγ stimulation reduced the cell injury. This lidocaine effect was not affected by the mitochondrial KATP channel inhibitor 5-hydroxydecanoate. Similar to lidocaine, QX314, a permanently charged lidocaine analog that usually does not permeate through the plasma membrane, reduced lipopolysaccharide and IFNγ-induced microglial cell injury. QX314 also attenuated the stimulation-induced interleukin-1β production. Conclusions Delayed treatment with lidocaine protects microglial cells and reduces cytokine production from these cells. These effects may involve action site(s) on the cell surface. PMID:22253275

  7. Hydrogen-Induced Delayed Cracking in TRIP-Aided Lean-Alloyed Ferritic-Austenitic Stainless Steels.

    Science.gov (United States)

    Papula, Suvi; Sarikka, Teemu; Anttila, Severi; Talonen, Juho; Virkkunen, Iikka; Hänninen, Hannu

    2017-06-03

    Susceptibility of three lean-alloyed ferritic-austenitic stainless steels to hydrogen-induced delayed cracking was examined, concentrating on internal hydrogen contained in the materials after production operations. The aim was to study the role of strain-induced austenite to martensite transformation in the delayed cracking susceptibility. According to the conducted deep drawing tests and constant load tensile testing, the studied materials seem not to be particularly susceptible to delayed cracking. Delayed cracks were only occasionally initiated in two of the materials at high local stress levels. However, if a delayed crack initiated in a highly stressed location, strain-induced martensite transformation decreased the crack arrest tendency of the austenite phase in a duplex microstructure. According to electron microscopy examination and electron backscattering diffraction analysis, the fracture mode was predominantly cleavage, and cracks propagated along the body-centered cubic (BCC) phases ferrite and α'-martensite. The BCC crystal structure enables fast diffusion of hydrogen to the crack tip area. No delayed cracking was observed in the stainless steel that had high austenite stability. Thus, it can be concluded that the presence of α'-martensite increases the hydrogen-induced cracking susceptibility.

  8. Hydrogen-Induced Delayed Cracking in TRIP-Aided Lean-Alloyed Ferritic-Austenitic Stainless Steels

    Directory of Open Access Journals (Sweden)

    Suvi Papula

    2017-06-01

    Full Text Available Susceptibility of three lean-alloyed ferritic-austenitic stainless steels to hydrogen-induced delayed cracking was examined, concentrating on internal hydrogen contained in the materials after production operations. The aim was to study the role of strain-induced austenite to martensite transformation in the delayed cracking susceptibility. According to the conducted deep drawing tests and constant load tensile testing, the studied materials seem not to be particularly susceptible to delayed cracking. Delayed cracks were only occasionally initiated in two of the materials at high local stress levels. However, if a delayed crack initiated in a highly stressed location, strain-induced martensite transformation decreased the crack arrest tendency of the austenite phase in a duplex microstructure. According to electron microscopy examination and electron backscattering diffraction analysis, the fracture mode was predominantly cleavage, and cracks propagated along the body-centered cubic (BCC phases ferrite and α’-martensite. The BCC crystal structure enables fast diffusion of hydrogen to the crack tip area. No delayed cracking was observed in the stainless steel that had high austenite stability. Thus, it can be concluded that the presence of α’-martensite increases the hydrogen-induced cracking susceptibility.

  9. [Mechanisms of delay endothelial cell replicative senescence by extracts from Panax ginseng, Panax notoginseng and Ligusticum chuanxiong].

    Science.gov (United States)

    Yang, Jing; Lei, Yan; Cui, Wei; Fang, Suping; Chen, Keji

    2009-06-01

    To explore effect of extracts from Panax ginseng, P. notoginseng and Ligusticum chuanxiong on human umbilical endothelial cells (HUVECs) replicative senescence. HUVECs were induced to aging by generation cultivating to the eighth cells in order to establish a model of endothelial cells replicative senescence. The cultured HUVECs in vitro were divided into 4 groups, the eighth generation cell-senescence untreated group, Vitamin E group, herbal treated high dose and low dose groups. Changes of HUVECs aging were observed by method of SA-beta-gal stained HUVECs and cells cycle were analyzed. Contents of ROS in cells, the levels of anti-superoxide (O2-) and nitric oxide (NO) in cell mediums were examined. Western blot were used to analyse protein expression of NADPH oxidase p47phox, angiotensin type 1 and 2 receptor (AT1R, AT2R). Compared with Vitamin E group, the positive cell numbers of beta-gal stained HUVECs were enhanced, cell proliferation was depressed, and the fluorescence intensity of ROS was increased, at the same time, less NO and more O2- in cells were produced in the eighth generation cell-senescence untreated group. Protein expression of p47phox, AT1R and AT2R in cells increased compared with Vit E group. Chinese herbs of high dose and low dose could improve condutions of HUVECs aging. Chinese herbs of high dose and low dose could reduce the positive cell numbers of beta-gal stained HUVEC, increase cell proliferation and decrease fluorescence intensity of ROS in cells, at the same time, cells secreting more NO and less O2-. Protein expression of p47phox, AT1R and AT2R in cells treated with Chinese herbs of high dose and low dose were decreased compared with Vit E group. The study indicated that extracts from P. ginseng, P. notoginseng and L. chuanxiong could delay endothelial cell replicative senescence. Herbal extracts downregulate the expression of NAD (P) H oxidase subunit-p47phox by means of ROS, hence decrease O2- production and ultimately delay

  10. Generation of time delays: simplified models of intracellular signaling in cerebellar Purkinje cells

    NARCIS (Netherlands)

    Steuber, V.; Willshaw, D.; van Ooyen, A.

    2006-01-01

    In many neuronal systems, information is encoded in temporal spike patterns. The recognition and storage of temporal patterns requires the generation and modulation of time delays between inputs and outputs. In cerebellar Purkinje cells, stimulation of metabotropic glutamate receptors (mGluRs)

  11. O-antigen delays lipopolysaccharide recognition and impairs antibacterial host defense in murine intestinal epithelial cells.

    Directory of Open Access Journals (Sweden)

    Claudia U Duerr

    2009-09-01

    Full Text Available Although Toll-like receptor (TLR 4 signals from the cell surface of myeloid cells, it is restricted to an intracellular compartment and requires ligand internalization in intestinal epithelial cells (IECs. Yet, the functional consequence of cell-type specific receptor localization and uptake-dependent lipopolysaccharide (LPS recognition is unknown. Here, we demonstrate a strikingly delayed activation of IECs but not macrophages by wildtype Salmonella enterica subsp. enterica sv. (S. Typhimurium as compared to isogenic O-antigen deficient mutants. Delayed epithelial activation is associated with impaired LPS internalization and retarded TLR4-mediated immune recognition. The O-antigen-mediated evasion from early epithelial innate immune activation significantly enhances intraepithelial bacterial survival in vitro and in vivo following oral challenge. These data identify O-antigen expression as an innate immune evasion mechanism during apical intestinal epithelial invasion and illustrate the importance of early innate immune recognition for efficient host defense against invading Salmonella.

  12. Delayed ossification in Wistar rats induced by Morinda citrifolia L. exposure during pregnancy.

    Science.gov (United States)

    Marques, Nelson Fernando Quallio; Marques, Ana Paula Bombonatto Mariano; Iwano, Ana Lívia; Golin, Munisa; De-Carvalho, Rosangela Ribeiro; Paumgartten, Francisco José Roma; Dalsenter, Paulo Roberto

    2010-03-02

    Different products of plant Morinda citrifolia L. (noni) have been marketed and used around the world based on properties described by Polynesian people that use them for more than 2000 years. Marketing of these products is based on their presumptive phytotherapic properties. However there is little scientific evidence about their safety, especially when used during pregnancy. Evaluate the possible developmental toxicity of the noni fruit aqueous extract and commercial product of TAHITIAN NONI juice in rats exposed during pregnancy. Pregnant Wistar rats were exposed by gavage to 7, 30 and 300 mg/kg bw (body weight) of noni aqueous extract or to 0.4, 2 and 20 mL/kg bw (body weight) of noni juice between day 7 and day 15 of pregnancy. Caesarean sections were performed on day 20 of pregnancy and reproductive parameters were evaluated. Implantations sites and postimplantation losses were recorded. Fetuses were weighted and examined for externally visible anomalies. After, the fetuses were cleared with KOH and the bones stained with alizarin red. Skeletal alterations of the skull, vertebral column, ribs, forelimbs, hindlimbs, sternum, sings of delayed ossification and variations were examined in accordance with pre-defined criteria and identified using harmonized and internationally accepted nomenclature recommended by the International Federation of Teratology Societies. Exposure with extract and juice of Morinda citrifolia did not induce maternal toxicity at the tested doses, but induced delayed ossification in fetuses. The exposure of pregnant rats to aqueous extract or juice Morinda citrifolia during organogenesis period may induce adverse effects on the normal development of fetuses. These findings indicate the need for further studies with noni derivates preceding their use in pregnant women. Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.

  13. Non-targeted and delayed effects of exposure to ionizing radiation: I. Radiation-induced genomic instability and bystander effects in vitro

    Science.gov (United States)

    Morgan, William F.

    2003-01-01

    A long-standing dogma in the radiation sciences is that energy from radiation must be deposited in the cell nucleus to elicit a biological effect. A number of non-targeted, delayed effects of ionizing radiation have been described that challenge this dogma and pose new challenges to evaluating potential hazards associated with radiation exposure. These effects include induced genomic instability and non-targeted bystander effects. The in vitro evidence for non-targeted effects in radiation biology will be reviewed, but the question as to how one extrapolates from these in vitro observations to the risk of radiation-induced adverse health effects such as cancer remains open.

  14. Evidence for factors modulating radiation-induced G2-delay: potential application as radioprotectors

    Science.gov (United States)

    Cheong, N.; Zeng, Z. C.; Wang, Y.; Iliakis, G.

    2001-01-01

    Manipulation of checkpoint response to DNA damage can be developed as a means for protecting astronauts from the adverse effects of unexpected, or background exposures to ionizing radiation. To achieve this goal reagents need to be developed that protect cells from radiation injury by prolonging checkpoint response, thus promoting repair. We present evidence for a low molecular weight substance excreted by cells that dramatically increases the duration of the G2-delay. This compound is termed G2-Arrest Modulating Activity (GAMA). A rat cell line (A1-5) generated by transforming rat embryo fibroblasts with a temperature sensitive form of p53 plus H-ras demonstrates a dramatic increase in radiation resistance after exposure to low LET radiation that is not associated with an increase in the efficiency of rejoining of DNA double strand breaks. Radioresistance in this cell line correlates with a dramatic increase in the duration of the G2 arrest that is modulated by a GAMA produced by actively growing cells. The properties of GAMA suggest that it is a low molecular weight heat-stable peptide. Further characterization of this substance and elucidation of its mechanism of action may allow the development of a biological response modifier with potential applications as a radioprotector. GAMA may be useful for protecting astronauts from radiation injury as preliminary evidence suggests that it is able to modulate the response of cells exposed to heavy ion radiation, similar to that encountered in outer space.

  15. Delayed animal aging through the recovery of stem cell senescence by platelet rich plasma.

    Science.gov (United States)

    Liu, Hen-Yu; Huang, Chiung-Fang; Lin, Tzu-Chieh; Tsai, Ching-Yu; Tina Chen, Szu-Yu; Liu, Alice; Chen, Wei-Hong; Wei, Hong-Jian; Wang, Ming-Fu; Williams, David F; Deng, Win-Ping

    2014-12-01

    Aging is related to loss of functional stem cell accompanying loss of tissue and organ regeneration potentials. Previously, we demonstrated that the life span of ovariectomy-senescence accelerated mice (OVX-SAMP8) was significantly prolonged and similar to that of the congenic senescence-resistant strain of mice after platelet rich plasma (PRP)/embryonic fibroblast transplantation. The aim of this study is to investigate the potential of PRP for recovering cellular potential from senescence and then delaying animal aging. We first examined whether stem cells would be senescent in aged mice compared to young mice. Primary adipose derived stem cells (ADSCs) and bone marrow derived stem cells (BMSCs) were harvested from young and aged mice, and found that cell senescence was strongly correlated to animal aging. Subsequently, we demonstrated that PRP could recover cell potential from senescence, such as promote cell growth (cell proliferation and colony formation), increase osteogenesis, decrease adipogenesis, restore cell senescence related markers and resist the oxidative stress in stem cells from aged mice. The results also showed that PRP treatment in aged mice could delay mice aging as indicated by survival, body weight and aging phenotypes (behavior and gross morphology) in term of recovering the cellular potential of their stem cells compared to the results on aged control mice. In conclusion these findings showed that PRP has potential to delay aging through the recovery of stem cell senescence and could be used as an alternative medicine for tissue regeneration and future rejuvenation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Successful Treatment of T Cell-Mediated Acute Rejection with Delayed CTLA4-Ig in Mice

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    James S. Young

    2017-09-01

    Full Text Available Clinical observations that kidney transplant recipients receiving belatacept who experienced T cell-mediated acute rejection can be successfully treated and subsequently maintained on belatacept-based immunosuppression suggest that belatacept is able to control memory T cells. We recently reported that treatment with CTLA4-Ig from day 6 posttransplantation successfully rescues allografts from acute rejection in a BALB/c to C57BL/6 heart transplant model, in part, by abolishing B cell germinal centers and reducing alloantibody titers. Here, we show that CTLA4-Ig is additionally able to inhibit established T cell responses independently of B cells. CTLA4-Ig inhibited the in vivo cytolytic activity of donor-specific CD8+ T cells, and the production of IFNγ by graft-infiltrating T cells. Delayed CTLA4-Ig treatment did not reduce the numbers of graft-infiltrating T cells nor prevented the accumulation of antigen-experienced donor-specific memory T cells in the spleen. Nevertheless, delayed CTLA4-Ig treatment successfully maintained long-term graft acceptance in the majority of recipients that had experienced a rejection crisis, and enabled the acceptance of secondary BALB/c heart grafts transplanted 30 days after the first transplantation. In summary, we conclude that delayed CTLA4-Ig treatment is able to partially halt ongoing T cell-mediated acute rejection. These findings extend the functional efficacy of CTLA4-Ig therapy to effector T cells and provide an explanation for why CTLA4-Ig-based immunosuppression in the clinic successfully maintains long-term graft survival after T cell-mediated rejection.

  17. Gas6 Delays Senescence in Vascular Smooth Muscle Cells through the PI3K/ Akt/FoxO Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Cheng-wei Jin

    2015-02-01

    Full Text Available Background/Aims: Growth arrest-specific protein 6 (Gas6 is a cytokine that can be synthesized by a variety of cell types and secreted into the extracellular matrix. Previous studies have confirmed that Gas6 is involved in certain pathophysiological processes of the cardiovascular system through binding to its receptor, Axl. In the present study, we investigated the role of Gas6 in cellular senescence and explored the mechanisms underlying its activity. Methods: We used vascular smooth muscle cells (VSMCs to create two cellular senescence models, one for replicative senescence (RS and one for induced senescence (IS, to test the hypothesis that Gas6 delays senescence. Results: Gas6-treated cells appear relatively younger compared with non-Gas6-treated cells. In particular, Gas6-treated cells displayed decreased staining for SA-β-Gal, fewer G1 phase cells, and decreased levels of p16INK4a and p21Cip1 expression; conversely, Gas6-treated cells displayed more S phase cells and significantly increased proliferation indexes. Furthermore, in both the IS and RS models with Gas6 treatment, the levels of PI3K, p-Akt, and p-FoxO3a decreased following Axl inhibition by R428; similarly, the levels of p-Akt and p-FoxO3a also decreased following PI3K inhibition by LY294002. Conclusion: Gas6/Axl signaling is essential for delaying the cellular senescence process regulated by the PI3K/Akt/FoxO signaling pathway.

  18. Mini-review: Discovery of GnIH and its role in hypothyroidism-induced delayed puberty.

    Science.gov (United States)

    Tsutsui, Kazuyoshi; Son, You Lee; Kiyohara, Mika; Miyata, Ichiro

    2017-09-18

    It is known that hypothyroidism delays puberty in mammals. Interaction between the hypothalamo-pituitary-thyroid (HPT) and hypothalamo-pituitary-gonadal (HPG) axes may be important processes in delayed puberty. Gonadotropin-inhibitory hormone (GnIH) is a newly discovered hypothalamic neuropeptide inhibiting gonadotropin synthesis and release in quail. It now apperas that GnIH is conserved across various mammals and primates including humans and inhibits reproduction. We have further demonstrated that GnIH is involved in pubertal delay induced by thyroid dysfunction in female mice. Hypothyroidism delays pubertal onset with the increase in hypothalamic GnIH expression and the decrease in circulating gonadotropin and estradiol levels. Thyroid status regulates GnIH expression by epigenetic modification of the GnIH promoter region. Furthermore, knockout of GnIH gene abolishes the effect of hypothyroidism on delayed pubertal onset. Accordingly, it is considered that GnIH is a mediator of pubertal disorder induced by thyroid dysfunction. This is a novel function of GnIH that interacts between the HPT-HPG axes in pubertal onset delay. This mini-review summarizes the structure, expression and function of GnIH and highlights the action of GnIH in pubertal disorder induced by thyroid dysfunction. Copyright © 2017 Endocrine Society.

  19. Partial hepatectomy induces delayed hepatocyte proliferation and normal liver regeneration in ovariectomized mice

    Directory of Open Access Journals (Sweden)

    Umeda M

    2015-07-01

    Full Text Available Makoto Umeda,1 Masaki Hiramoto,1,2 Takeshi Imai1 1Department of Aging Intervention, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; 2Department of Biochemistry, Tokyo Medical University, Tokyo, Japan Abstract: Estrogens play central roles in sexual development, reproduction, and hepatocyte proliferation. The ovaries are one of the main organs for estradiol (E2 production. Ovariectomies (OVXs were performed on the female mice, and hepatocyte proliferation was analyzed. The ovariectomized mice exhibited delayed hepatocyte proliferation after partial hepatectomy (PH and also exhibited delayed and reduced E2 induction. Both E2 administration and PH induced the gene expression of estrogen receptor α (ERα. The transcripts of ERα were detected specifically in periportal hepatocytes after E2 administration and PH. Moreover, the E2 concentrations and hepatocyte proliferation rates were highest in the proestrus period of the estrous cycle. Taken together, these findings indicate that E2 accelerated ERα expression in periportal hepatocytes and hepatocyte proliferation in the female mice.Keywords: estrogen, ER, estrous cycle, hepatocyte proliferation, liver regeneration

  20. Test Generation for Crosstalk-Induced Delay Faults in VLSI Circuits Using Modified FAN Algorithm

    Directory of Open Access Journals (Sweden)

    S. Jayanthy

    2012-01-01

    Full Text Available As design trends move toward nanometer technology, new problems due to noise effects lead to a decrease in reliability and performance of VLSI circuits. Crosstalk is one such noise effect which affects the timing behaviour of circuits. In this paper, an efficient Automatic Test Pattern Generation (ATPG method based on a modified Fanout Oriented (FAN to detect crosstalk-induced delay faults in VLSI circuits is presented. Tests are generated for ISCAS_85 and enhanced scan version of ISCAS_89 benchmark circuits. Experimental results demonstrate that the test program gives better fault coverage, less number of backtracks, and hence reduced test generation time for most of the benchmark circuits when compared to modified Path-Oriented Decision Making (PODEM based ATPG. The number of transitions is also reduced thus reducing the power dissipation of the circuit.

  1. Stability and Hopf bifurcation in a delayed model for HIV infection of CD4{sup +}T cells

    Energy Technology Data Exchange (ETDEWEB)

    Cai Liming [Department of Mathematics, Xinyang Normal University, Xinyang, 464000 Henan (China); Beijing Institute of Information Control, Beijing 100037 (China)], E-mail: lmcai06@yahoo.com.cn; Li Xuezhi [Department of Mathematics, Xinyang Normal University, Xinyang, 464000 Henan (China)

    2009-10-15

    In this paper, we consider a delayed mathematical model for the interactions of HIV infection and CD4{sup +}T cells. We first investigate the existence and stability of the Equilibria. We then study the effect of the time delay on the stability of the infected equilibrium. Criteria are given to ensure that the infected equilibrium is asymptotically stable for all delay. Moreover, by applying Nyquist criterion, the length of delay is estimated for which stability continues to hold. Finally by using a delay {tau} as a bifurcation parameter, the existence of Hopf bifurcation is also investigated. Numerical simulations are presented to illustrate the analytical results.

  2. Transplantation of Bone Marrow-Derived Mesenchymal Stem Cells Promotes Delayed Wound Healing in Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Jiangbo Wan

    2013-01-01

    Full Text Available In this paper, we established a delayed wound healing model on diabetic rat to mimic the pathophysiology of clinical patients who suffered from diabetic foot ulcers. We also evaluated if transplantation of allogeneic bone marrow-derived mesenchymal stem cells could promote the delayed wound healing and investigated the possible underlying biological mechanisms and stem cell behavior involved in this process. The results showed that bone marrow-derived mesenchymal stem cells had a positive effect on delayed wound healing in diabetic rats. Intramuscular transplantation demonstrated the best efficacy. This effect is associated with granulation tissue formation, angiogenesis, cellular proliferation, and high vascular endothelial growth factor expression in wound tissues. In addition, bone marrow-derived mesenchymal stem cells have been shown to mobilize and find home for ischemic and wounded tissues to participate in the process of wound healing. Intramuscular transplantation of exogenous isogeneic stem cells may be suitable for clinical application in the treatment of diabetic foot ulcers although the safety of this therapy should be considered.

  3. Stability analysis and compensation of network-induced delays in communication-based power system control: A survey.

    Science.gov (United States)

    Liu, Shichao; Liu, Peter Xiaoping; Wang, Xiaoyu

    2017-01-01

    This survey is to summarize and compare existing and recently emerging approaches for the analysis and compensation of the effects of network-induced delays on the stability and performance of communication-based power control systems. Several important communication-based power control systems are briefly introduced. The deterministic and stochastic methodologies of analyzing the impacts of network-induced delays on the stability of the communication-based power control systems are summarized and compared. A variety of control approaches are reviewed and compared for mitigating the effects of network-induced delays, depending on several design requirements, such as model dependence and design difficulty. The summary and comparison of these control approaches in this survey provide researchers and utilities valuable guidance for designing advanced communication-based power control systems in the future. Copyright © 2016 ISA. Published by Elsevier Ltd. All rights reserved.

  4. [Proteomics analysis of adenosine A1 receptor agonist-induced delayed myocardial protection in rabbits].

    Science.gov (United States)

    Zhou, Jianmei; Zou, Dingquan; Ran, Ke; Chang, Yetian

    2011-10-01

    To investigate the changes of myocardial protein expression profiles in 2-chloro-N6-cyclopentyladenosine (CCPA), an adenosine A1 receptor agonist-induced delayed myocardial protection in New Zealand rabbits . A total of 8 rabbits were randomly divided into a CCPA group (CCPA group) and a normal saline group (NS group). CCPA and NS were infused into rabbits in the CCPA group and the NS group respectively. Twenty-four hours later, the rabbits were subjected to 30 min left anterior descending coronary artery occlusion and were reperfused for 2 hours, then the ischemic zone tissues of left ventricle were sampled for proteomic analysis.A total of 12 other New Zeland rabbits were divided into a sham group (Sham group), a normal saline group (NS group) and a CCPA group (CCPA group). The expression of αB-crystalline, one of the differential proteins, was confirmed by Western blot. Analysis of two dimensional gel electrophoresis showed that the expression of 55 protein spots were different between the two groups, 17 protein spots were preliminarily identified with the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and Mascot and Expasy bioinformatics software. These proteins included stress proteins, metabolism-associated proteins, signal transduction pathway-related proteins, ionophorous proteins, immunity-associated proteins, and so on. Western blot showed that the expression of αB-crystalline was significantly up-regulated in the CCPA group. The myocardial protein expression profiles are changed markedly in the preconditioning late phase of CCPA .The differential proteins might be involved in the delayed cardioprotection induced by CCPA.

  5. Pharmacological Characterization of the Mechanisms Involved in Delayed Calcium Deregulation in SH-SY5Y Cells Challenged with Methadone

    Science.gov (United States)

    Perez-Alvarez, Sergio; Solesio, Maria E.; Cuenca-Lopez, Maria D.; Melero-Fernández de Mera, Raquel M.; Villalobos, Carlos; Kmita, Hanna; Galindo, Maria F.; Jordán, Joaquin

    2012-01-01

    Previously, we have shown that SH-SY5Y cells exposed to high concentrations of methadone died due to a necrotic-like cell death mechanism related to delayed calcium deregulation (DCD). In this study, we show that, in terms of their Ca2+ responses to 0.5 mM methadone, SH-SY5Y cells can be pooled into four different groups. In a broad pharmacological survey, the relevance of different Ca2+-related mechanisms on methadone-induced DCD was investigated including extracellular calcium, L-type Ca2+ channels, μ-opioid receptor, mitochondrial inner membrane potential, mitochondrial ATP synthesis, mitochondrial Ca2+/2Na+-exchanger, reactive oxygen species, and mitochondrial permeability transition. Only those compounds targeting mitochondria such as oligomycin, FCCP, CGP 37157, and cyclosporine A were able to amend methadone-induced Ca2+ dyshomeostasis suggesting that methadone induces DCD by modulating the ability of mitochondria to handle Ca2+. Consistently, mitochondria became dramatically shorter and rounder in the presence of methadone. Furthermore, analysis of oxygen uptake by isolated rat liver mitochondria suggested that methadone affected mitochondrial Ca2+ uptake in a respiratory substrate-dependent way. We conclude that methadone causes failure of intracellular Ca2+ homeostasis, and this effect is associated with morphological and functional changes of mitochondria. Likely, this mechanism contributes to degenerative side effects associated with methadone treatment. PMID:22778742

  6. Regulation of action potential delays via voltage-gated potassium Kv1.1 channels in dentate granule cells during hippocampal epilepsy

    Directory of Open Access Journals (Sweden)

    Florian eKirchheim

    2013-12-01

    Full Text Available Action potential (AP responses of dentate gyrus granule (DG cells have to be tightly regulated to maintain hippocampal function. However, which ion channels control the response delay of DG cells is not known. In some neuron types, spike latency is influenced by a dendrotoxin (DTX-sensitive delay current (ID mediated by unidentified combinations of voltage-gated K+ (Kv channels of the Kv1 family Kv1.1-6. In DG cells, the ID has not been characterized and its molecular basis is unknown. The response phenotype of mature DG cells is usually considered homogenous but intrinsic adaptations likely occur in particular in conditions of hyperexcitability, for example during temporal lobe epilepsy (TLE. In this study, we examined response delays of DG cells and underlying ion channel molecules by employing a new combination of gramicidin-perforated patch-clamp recordings in acute brain slices and single-cell reverse transcriptase quantitative polymerase chain reaction (SC RT-qPCR experiments. An in vivo mouse model of TLE consisting of intrahippocampal kainate (KA injection was used to examine epilepsy-related plasticity. Response delays of DG cells were DTX-sensitive and strongly increased in KA-injected hippocampi; Kv1.1 mRNA was elevated 10-fold, and the response delays correlated with Kv1.1 mRNA abundance on the single cell level. Other Kv1 subunits did not show overt changes in mRNA levels. Kv1.1 immunolabeling was enhanced in KA DG cells. The biophysical properties of ID and the delay heterogeneity between inner and outer DG cell layer were characterized. Using organotypic hippocampal slice cultures (OHCs, where KA incubation also induced ID upregulation, reversibility and neuroprotective potential for DG cells were tested. In summary, the AP timing of DG cells is effectively controlled via scaling of Kv1.1 subunit transcription. With this antiepileptic mechanism, DG cells delay their

  7. NF-κB inhibition delays DNA damage–induced senescence and aging in mice

    Science.gov (United States)

    Tilstra, Jeremy S.; Robinson, Andria R.; Wang, Jin; Gregg, Siobhán Q.; Clauson, Cheryl L.; Reay, Daniel P.; Nasto, Luigi A.; St Croix, Claudette M.; Usas, Arvydas; Vo, Nam; Huard, Johnny; Clemens, Paula R.; Stolz, Donna B.; Guttridge, Denis C.; Watkins, Simon C.; Garinis, George A.; Wang, Yinsheng; Niedernhofer, Laura J.; Robbins, Paul D.

    2012-01-01

    The accumulation of cellular damage, including DNA damage, is thought to contribute to aging-related degenerative changes, but how damage drives aging is unknown. XFE progeroid syndrome is a disease of accelerated aging caused by a defect in DNA repair. NF-κB, a transcription factor activated by cellular damage and stress, has increased activity with aging and aging-related chronic diseases. To determine whether NF-κB drives aging in response to the accumulation of spontaneous, endogenous DNA damage, we measured the activation of NF-κB in WT and progeroid model mice. As both WT and progeroid mice aged, NF-κB was activated stochastically in a variety of cell types. Genetic depletion of one allele of the p65 subunit of NF-κB or treatment with a pharmacological inhibitor of the NF-κB–activating kinase, IKK, delayed the age-related symptoms and pathologies of progeroid mice. Additionally, inhibition of NF-κB reduced oxidative DNA damage and stress and delayed cellular senescence. These results indicate that the mechanism by which DNA damage drives aging is due in part to NF-κB activation. IKK/NF-κB inhibitors are sufficient to attenuate this damage and could provide clinical benefit for degenerative changes associated with accelerated aging disorders and normal aging. PMID:22706308

  8. Inducible CTCF insulator delays the IgH 3' regulatory region-mediated activation of germline promoters and alters class switching.

    Science.gov (United States)

    Braikia, Fatima-Zohra; Oudinet, Chloé; Haddad, Dania; Oruc, Zeliha; Orlando, Domenico; Dauba, Audrey; Le Bert, Marc; Khamlichi, Ahmed Amine

    2017-06-06

    Class switch recombination (CSR) plays an important role in adaptive immune response by enabling mature B cells to switch from IgM expression to the expression of downstream isotypes. CSR is preceded by inducible germline (GL) transcription of the constant genes and is controlled by the 3' regulatory region (3'RR) in a stimulus-dependent manner. Why the 3'RR-mediated up-regulation of GL transcription is delayed to the mature B-cell stage is presently unknown. Here we show that mice devoid of an inducible CTCF binding element, located in the α constant gene, display a marked isotype-specific increase of GL transcription in developing and resting splenic B cells and altered CSR in activated B cells. Moreover, insertion of a GL promoter downstream of the CTCF insulator led to premature activation of the ectopic promoter. This study provides functional evidence that the 3'RR has a developmentally controlled potential to constitutively activate GL promoters but that this activity is delayed, at least in part, by the CTCF insulator, which borders a transcriptionally active domain established by the 3'RR in developing B cells.

  9. Transplantation of Aire-overexpressing bone marrow-derived dendritic cells delays the onset of type 1 diabetes.

    Science.gov (United States)

    Li, Dongbei; Zhao, Bo; Luo, Yadong; Limbara, Steven; Zhao, Bingjie; Zou, Xueyang; Yang, Wei; Li, Yi

    2017-08-01

    Autoimmune regulator (Aire) plays an indispensable role in maintaining central immune tolerance by promoting the ectopic expression of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), which lead to the deletion of autoreactive T cells or the induction of Tregs and consequently prevent autoimmune disease development. Curing autoimmune diseases has always been a challenge. DC-based immunotherapy represents a new and effective method to establish tolerance. We attempted to transplant Aire-overexpressing bone marrow-derived DCs (Aire-BMDCs) to treat type 1 diabetes (T1D) and to explore a new strategy for autoimmune disease treatment. We observed that the onset of T1D in recipient mice was delayed; insulin autoantibody (IAA) production was significantly decreased; the structure of islets was protected; and the degree of inflammatory infiltration was lower. Furthermore, we found that Aire-BMDCs can promote apoptosis and induce autoreactive CD4 + T cell clonal anergy, inhibit Th1 and Th17 production, and induce Treg production. These results suggest that transplantation of Aire-BMDCs will be a manipulation and effective method for preventing or treating T1D. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. p53 Suppresses Metabolic Stress-Induced Ferroptosis in Cancer Cells

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    Amy Tarangelo

    2018-01-01

    Full Text Available How cancer cells respond to nutrient deprivation remains poorly understood. In certain cancer cells, deprivation of cystine induces a non-apoptotic, iron-dependent form of cell death termed ferroptosis. Recent evidence suggests that ferroptosis sensitivity may be modulated by the stress-responsive transcription factor and canonical tumor suppressor protein p53. Using CRISPR/Cas9 genome editing, small-molecule probes, and high-resolution, time-lapse imaging, we find that stabilization of wild-type p53 delays the onset of ferroptosis in response to cystine deprivation. This delay requires the p53 transcriptional target CDKN1A (encoding p21 and is associated with both slower depletion of intracellular glutathione and a reduced accumulation of toxic lipid-reactive oxygen species (ROS. Thus, the p53-p21 axis may help cancer cells cope with metabolic stress induced by cystine deprivation by delaying the onset of non-apoptotic cell death.

  11. 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.

  12. Synchronization transitions induced by the fluctuation of adaptive coupling strength in delayed Newman-Watts neuronal networks.

    Science.gov (United States)

    Wang, Qi; Gong, Yubing; Wu, Yanan

    2015-11-01

    Introducing adaptive coupling in delayed neuronal networks and regulating the dissipative parameter (DP) of adaptive coupling by noise, we study the effect of fluctuations of the changing rate of adaptive coupling on the synchronization of the neuronal networks. It is found that time delay can induce synchronization transitions for intermediate DP values, and the synchronization transitions become strongest when DP is optimal. As the intensity of DP noise is varied, the neurons can also exhibit synchronization transitions, and the phenomenon is delay-dependent and is enhanced for certain time delays. Moreover, the synchronization transitions change with the change of DP and become strongest when DP is optimal. These results show that randomly changing adaptive coupling can considerably change the synchronization of the neuronal networks, and hence could play a crucial role in the information processing and transmission in neural systems. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  13. Stabilizing nanocellulose-nonionic surfactant composite foams by delayed Ca-induced gelation.

    Science.gov (United States)

    Gordeyeva, Korneliya S; Fall, Andreas B; Hall, Stephen; Wicklein, Bernd; Bergström, Lennart

    2016-06-15

    Aggregation of dispersed rod-like particles like nanocellulose can improve the strength and rigidity of percolated networks but may also have a detrimental effect on the foamability. However, it should be possible to improve the strength of nanocellulose foams by multivalent ion-induced aggregation if the aggregation occurs after the foam has been formed. Lightweight and highly porous foams based on TEMPO-mediated oxidized cellulose nanofibrils (CNF) were formulated with the addition of a non-ionic surfactant, pluronic P123, and CaCO3 nanoparticles. Foam volume measurements show that addition of the non-ionic surfactant generates wet CNF/P123 foams with a high foamability. Foam bubble size studies show that delayed Ca-induced aggregation of CNF by gluconic acid-triggered dissolution of the CaCO3 nanoparticles significantly improves the long-term stability of the wet composite foams. Drying the Ca-reinforced foam at 60 °C results in a moderate shrinkage and electron microscopy and X-ray tomography studies show that the pores became slightly oblate after drying but the overall microstructure and pore/foam bubble size distribution is preserved after drying. The elastic modulus (0.9-1.4 MPa) of Ca-reinforced composite foams with a density of 9-15 kg/m(3) is significantly higher than commercially available polyurethane foams used for thermal insulation. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Cesium blockade of delayed outward currents and electrically induced pacemaker activity in mammalian ventricular myocardium.

    Science.gov (United States)

    Meier, C F; Katzung, B G

    1981-05-01

    The effects of Cs+, 5-25 mM, were studied in cat and guinea pig papillary muscles using voltage clamp and current clamp techniques. In solutions containing normal K+, the major effects of Cs+ were depolarization of the resting potential and reduction of the delayed outward current (ixl) between -80 and -20 mV. Both inward and outward portions of the isochronal current voltage relation (l-s clamps) were reduced by extracellular Cs+. This resulted in a substantial reduction of inward rectification and, by subtraction from the normal I-V relationship, the definition of a Cs+-sensitive component of current. Under current clamp conditions, 5-10 mM Cs+ produced a dose-dependent slowing of repetitive firing induced by depolarization. At higher concentrations (25 mM) the resting potential was depolarized and repetitive activity could not be induced by further depolarization. However, release of hyperpolarizing pulses was followed by prolonged bursts of repetitive action potentials, suggesting partial reversal of blockade or participation of another pacemaker process. The experimental results and a numerical simulation show that under readily attainable conditions, reduction in an outward pacemaker current may slow pacemaker activity.

  15. bFGF-Regulating MAPKs Are Involved in High Glucose-Mediated ROS Production and Delay of Vascular Endothelial Cell Migration.

    Directory of Open Access Journals (Sweden)

    Zhong Xin Zhu

    Full Text Available High blood sugar is a symptom of diabetes mellitus (DM. Vascular endothelial cells (VECs directly contact the blood and are damaged when blood sugar levels are high. However, the molecular mechanism underlying this process remains elusive. To analyze the effects of DM on migration, we simulated DM by applying high glucose (HG to the human VEC. HG delayed cell migration and induced phosphorylation of MAPKs (JNK and ERK. By contrast, in presence of bFGF, cell migration was promoted and MAPK phosphorylation levels were reduced. Furthermore, treatment with JNK and ERK inhibitors rescued HG-mediated delay of cell migration. Molecular and cell biological studies demonstrated that HG increased ROS production, whereas treatment with bFGF or JNK/ERK inhibitors blocked HG-induced ROS accumulation. Addition of MnTMPyP, a ROS scavenger, reduced HG-induced ROS production and accelerated cell migration, suggesting that the influence of HG on bFGF-MAPK signaling causes accumulation of ROS, which in turn regulate cell migration. This is the first study to elucidate the molecular mechanism of HG-mediated VEC migration; these findings could facilitate the development of novel therapies for DM.

  16. Neural Mechanisms and Delayed Gastric Emptying of Liquid Induced Through Acute Myocardial Infarction in Rats

    Energy Technology Data Exchange (ETDEWEB)

    Nunez, Wilson Ranu Ramirez; Ozaki, Michiko Regina; Vinagre, Adriana Mendes; Collares, Edgard Ferro; Almeida, Eros Antonio de, E-mail: erosaa@cardiol.br [Universidade Estadual de Campinas, Campinas, SP (Brazil)

    2015-02-15

    In pathological situations, such as acute myocardial infarction, disorders of motility of the proximal gut can trigger symptoms like nausea and vomiting. Acute myocardial infarction delays gastric emptying (GE) of liquid in rats. Investigate the involvement of the vagus nerve, α 1-adrenoceptors, central nervous system GABA{sub B} receptors and also participation of paraventricular nucleus (PVN) of the hypothalamus in GE and gastric compliance (GC) in infarcted rats. Wistar rats, N = 8-15 in each group, were divided as INF group and sham (SH) group and subdivided. The infarction was performed through ligation of the left anterior descending coronary artery. GC was estimated with pressure-volume curves. Vagotomy was performed by sectioning the dorsal and ventral branches. To verify the action of GABA{sub B} receptors, baclofen was injected via icv (intracerebroventricular). Intravenous prazosin was used to produce chemical sympathectomy. The lesion in the PVN of the hypothalamus was performed using a 1mA/10s electrical current and GE was determined by measuring the percentage of gastric retention (% GR) of a saline meal. No significant differences were observed regarding GC between groups; vagotomy significantly reduced % GR in INF group; icv treatment with baclofen significantly reduced %GR. GABA{sub B} receptors were not conclusively involved in delaying GE; intravenous treatment with prazosin significantly reduced GR% in INF group. PVN lesion abolished the effect of myocardial infarction on GE. Gastric emptying of liquids induced through acute myocardial infarction in rats showed the involvement of the vagus nerve, alpha1- adrenergic receptors and PVN.

  17. Human placenta-derived adherent cells induce tolerogenic immune responses

    Science.gov (United States)

    Liu, Wei; Morschauser, Andrew; Zhang, Xin; Lu, Xiaohua; Gleason, Joseph; He, Shuyang; Chen, Hong-Jung; Jankovic, Vladimir; Ye, Qian; Labazzo, Kristen; Herzberg, Uri; Albert, Vivian R; Abbot, Stewart E; Liang, Bitao; Hariri, Robert

    2014-01-01

    Human placenta-derived adherent cells (PDAC cells) are a culture expanded, undifferentiated mesenchymal-like population derived from full-term placental tissue, with immunomodulatory and anti-inflammatory properties. PDA-001 (cenplacel-L), an intravenous formulation of PDAC cells, is in clinical development for the treatment of autoimmune and inflammatory diseases. To elucidate the mechanisms underlying the immunoregulatory properties of PDAC cells, we investigated their effects on immune cell populations, including T cells and dendritic cells (DC) in vitro and in vivo. PDAC cells suppressed T-cell proliferation in an OT-II T-cell adoptive transfer model, reduced the severity of myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis and ameliorated inflammation in a delayed type hypersensitivity response model. In vitro, PDAC cells suppressed T-cell proliferation and inhibited Th1 and Th17 differentiation. Analysis of tissues derived from PDAC cell-treated animals revealed diminished CD86 expression on splenic DC, suggesting that they can also modulate DC populations. Furthermore, PDAC cells modulate the differentiation and maturation of mouse bone marrow-derived DC. Similarly, human DC differentiated from CD14+ monocytes in the presence of PDAC cells acquired a tolerogenic phenotype. These tolerogenic DC failed to induce allogeneic T-cell proliferation and differentiation toward Th1, but skewed T-cell differentiation toward Th2. Inhibition of cyclo-oxygenase-2 activity resulted in a significant, but not complete, abrogation of PDAC cells' effects on DC phenotype and function, implying a role for prostaglandin E2 in PDAC-mediated immunomodulation. This study identifies modulation of DC differentiation toward immune tolerance as a key mechanism underlying the immunomodulatory activities of PDAC cells. PMID:25505962

  18. Influence of distributed delays on the dynamics of a generalized immune system cancerous cells interactions model

    Science.gov (United States)

    Piotrowska, M. J.; Bodnar, M.

    2018-01-01

    We present a generalisation of the mathematical models describing the interactions between the immune system and tumour cells which takes into account distributed time delays. For the analytical study we do not assume any particular form of the stimulus function describing the immune system reaction to presence of tumour cells but we only postulate its general properties. We analyse basic mathematical properties of the considered model such as existence and uniqueness of the solutions. Next, we discuss the existence of the stationary solutions and analytically investigate their stability depending on the forms of considered probability densities that is: Erlang, triangular and uniform probability densities separated or not from zero. Particular instability results are obtained for a general type of probability densities. Our results are compared with those for the model with discrete delays know from the literature. In addition, for each considered type of probability density, the model is fitted to the experimental data for the mice B-cell lymphoma showing mean square errors at the same comparable level. For estimated sets of parameters we discuss possibility of stabilisation of the tumour dormant steady state. Instability of this steady state results in uncontrolled tumour growth. In order to perform numerical simulation, following the idea of linear chain trick, we derive numerical procedures that allow us to solve systems with considered probability densities using standard algorithm for ordinary differential equations or differential equations with discrete delays.

  19. Silent Crooke’s cell corticotroph adenoma of the pituitary gland presenting as delayed puberty

    Directory of Open Access Journals (Sweden)

    Dinesh Giri

    2017-03-01

    Full Text Available Corticotroph adenomas are extremely rare in children and adolescents. We present a 15-year-old boy who was investigated for delayed puberty (A1P2G1, bilateral testicular volumes of 3 mL each. There was no clinical or laboratory evidence suggestive of chronic illness, and the initial clinical impression was constitutional delay in puberty. Subsequently, MRI scan of the brain revealed the presence of a mixed cystic and solid pituitary lesion slightly displacing the optic chiasma. The lesion was removed by transphenoidal surgery and the biopsy confirmed the lesion to be pituitary adenoma. Furthermore, the adenoma cells also had Crooke’s hyaline changes and were intensely positive for ACTH. However there was no clinical/biochemical evidence of ACTH excess. There was a spontaneous pubertal progression twelve months after the surgery (A2P4G4, with bilateral testicular volume of 8 mL. Crooke’s cell adenoma is an extremely rare and aggressive variant of corticotroph adenoma that can uncommonly present as a silent corticotroph adenoma in adults. We report for the first time Crooke’s cell adenoma in an adolescent boy presenting with delayed puberty.

  20. Local intra-articular injection of resveratrol delays cartilage degeneration in C57BL/6 mice by inducing autophagy via AMPK/mTOR pathway.

    Science.gov (United States)

    Qin, Na; Wei, Liwei; Li, Wuyin; Yang, Wei; Cai, Litao; Qian, Zhuang; Wu, Shufang

    2017-07-01

    Autophagy is an essential cellular homeostasis mechanism that was found to be compromised in aging and osteoarthritis (OA) cartilage. Previous studies showed that resveratrol can effectively regulate autophagy in other cells. The purpose of this study was to determine whether the chondroprotective effect of resveratrol was related to chondrocyte autophagy and to elucidate underlying mechanisms. OA model was induced by destabilization of the medial meniscus (DMM) in 10-week-old male mice. OA mice were treated with resveratrol with/without 3-MA for 8 weeks beginning 4 weeks after surgery. The local intra-articular injection of resveratrol delayed articular cartilage degradation in DMM-induced OA by OARSI scoring systems and Safranin O-fast green. Resveratrol treatment increased Unc-51-like kinase1, Beclin1, microtubule-associated protein light chain 3, hypoxia inducible factor-1α, phosphorylated AMPK, collagen-2A1, Aggrecan expressions, but decreased hypoxia inducible factor-2α, phosphorylated mTOR, matrix metalloproteinases13 and a disintegrin and metalloproteinase with thrombospondin motifs 5 expressions. The effects of resveratrol were obviously blunted by 3-MA except HIF and AMPK. These findings indicate that resveratrol intra-articular injection delayed articular cartilage degeneration and promoted chondrocyte autophagy in an experimental model of surgical DMM-induced OA, in part via balancing HIF-1α and HIF-2α expressions and thereby regulating AMPK/mTOR signaling pathway. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  1. Local intra-articular injection of resveratrol delays cartilage degeneration in C57BL/6 mice by inducing autophagy via AMPK/mTOR pathway

    Directory of Open Access Journals (Sweden)

    Na Qin

    2017-07-01

    Full Text Available Autophagy is an essential cellular homeostasis mechanism that was found to be compromised in aging and osteoarthritis (OA cartilage. Previous studies showed that resveratrol can effectively regulate autophagy in other cells. The purpose of this study was to determine whether the chondroprotective effect of resveratrol was related to chondrocyte autophagy and to elucidate underlying mechanisms. OA model was induced by destabilization of the medial meniscus (DMM in 10-week-old male mice. OA mice were treated with resveratrol with/without 3-MA for 8 weeks beginning 4 weeks after surgery. The local intra-articular injection of resveratrol delayed articular cartilage degradation in DMM-induced OA by OARSI scoring systems and Safranin O-fast green. Resveratrol treatment increased Unc-51-like kinase1, Beclin1, microtubule-associated protein light chain 3, hypoxia inducible factor-1α, phosphorylated AMPK, collagen-2A1, Aggrecan expressions, but decreased hypoxia inducible factor-2α, phosphorylated mTOR, matrix metalloproteinases13 and a disintegrin and metalloproteinase with thrombospondin motifs 5 expressions. The effects of resveratrol were obviously blunted by 3-MA except HIF and AMPK. These findings indicate that resveratrol intra-articular injection delayed articular cartilage degeneration and promoted chondrocyte autophagy in an experimental model of surgical DMM-induced OA, in part via balancing HIF-1α and HIF-2α expressions and thereby regulating AMPK/mTOR signaling pathway.

  2. Blood Brain Barrier Dysfunction and Delayed Neurological Deficits in Mild Traumatic Brain Injury Induced by Blast Shock Waves

    Directory of Open Access Journals (Sweden)

    Ashok K Shetty

    2014-08-01

    Full Text Available Mild traumatic brain injury (mTBI resulting from exposure to blast shock waves (BSWs is one of the most predominant causes of illnesses among veterans who served in the recent Iraq and Afghanistan wars. Such mTBI can also happen to civilians if exposed to shock waves of bomb attacks by terrorists. While cognitive problems, memory dysfunction, depression, anxiety and diffuse white matter injury have been observed at both early and/or delayed time-points, an initial brain pathology resulting from exposure to BSWs appears to be the dysfunction or disruption of the blood-brain barrier (BBB. Studies in animal models suggest that exposure to relatively milder BSWs (123 kPa initially induces free radical generating enzymes in and around brain capillaries, which enhances oxidative stress resulting in loss of tight junction proteins, edema formation, and leakiness of BBB with disruption or loss of its components pericytes and astrocyte end-feet. On the other hand, exposure to more intense BSWs (145-323 kPa causes acute disruption of the BBB with vascular lesions in the brain. Both of these scenarios lead to apoptosis of endothelial and neural cells and neuroinflammation in and around capillaries, which may progress into chronic traumatic encephalopathy and/or a variety of neurological impairments, depending on brain regions that are afflicted with such lesions. This review discusses studies that examined alterations in the brain milieu causing dysfunction or disruption of the BBB and neuroinflammation following exposure to different intensities of BSWs. Furthermore, potential of early intervention strategies capable of easing oxidative stress, repairing the BBB or blocking inflammation for minimizing delayed neurological deficits resulting from exposure to BSWs is conferred.

  3. Blood brain barrier dysfunction and delayed neurological deficits in mild traumatic brain injury induced by blast shock waves.

    Science.gov (United States)

    Shetty, Ashok K; Mishra, Vikas; Kodali, Maheedhar; Hattiangady, Bharathi

    2014-01-01

    Mild traumatic brain injury (mTBI) resulting from exposure to blast shock waves (BSWs) is one of the most predominant causes of illnesses among veterans who served in the recent Iraq and Afghanistan wars. Such mTBI can also happen to civilians if exposed to shock waves of bomb attacks by terrorists. While cognitive problems, memory dysfunction, depression, anxiety and diffuse white matter injury have been observed at both early and/or delayed time-points, an initial brain pathology resulting from exposure to BSWs appears to be the dysfunction or disruption of the blood-brain barrier (BBB). Studies in animal models suggest that exposure to relatively milder BSWs (123 kPa) initially induces free radical generating enzymes in and around brain capillaries, which enhances oxidative stress resulting in loss of tight junction (TJ) proteins, edema formation, and leakiness of BBB with disruption or loss of its components pericytes and astrocyte end-feet. On the other hand, exposure to more intense BSWs (145-323 kPa) causes acute disruption of the BBB with vascular lesions in the brain. Both of these scenarios lead to apoptosis of endothelial and neural cells and neuroinflammation in and around capillaries, which may progress into chronic traumatic encephalopathy (CTE) and/or a variety of neurological impairments, depending on brain regions that are afflicted with such lesions. This review discusses studies that examined alterations in the brain milieu causing dysfunction or disruption of the BBB and neuroinflammation following exposure to different intensities of BSWs. Furthermore, potential of early intervention strategies capable of easing oxidative stress, repairing the BBB or blocking inflammation for minimizing delayed neurological deficits resulting from exposure to BSWs is conferred.

  4. CALCULUS FROM THE PAST: MULTIPLE DELAY SYSTEMS ARISING IN CANCER CELL MODELLING

    KAUST Repository

    WAKE, G. C.

    2013-01-01

    Nonlocal calculus is often overlooked in the mathematics curriculum. In this paper we present an interesting new class of nonlocal problems that arise from modelling the growth and division of cells, especially cancer cells, as they progress through the cell cycle. The cellular biomass is assumed to be unstructured in size or position, and its evolution governed by a time-dependent system of ordinary differential equations with multiple time delays. The system is linear and taken to be autonomous. As a result, it is possible to reduce its solution to that of a nonlinear matrix eigenvalue problem. This method is illustrated by considering case studies, including a model of the cell cycle developed recently by Simms, Bean and Koeber. The paper concludes by explaining how asymptotic expressions for the distribution of cells across the compartments can be determined and used to assess the impact of different chemotherapeutic agents. Copyright © 2013 Australian Mathematical Society.

  5. Effect of ranitidine on postoperative suppression of natural killer cell activity and delayed hypersensitivity

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Pedersen, B K; Moesgaard, F

    1989-01-01

    In a randomized study of patients undergoing major elective abdominal surgery, 12 received i.v. ranitidine (50 mg every 6 hours for 72 hours from the skin incision) and 12 had no ranitidine. Cell-mediated immunity was assessed pre- and postoperatively by skin testing with seven common delayed type...... hypersensitivity (DTH) antigens, and blood drawn immediately before and 24 hours after skin incision was analyzed for spontaneous and in vitro stimulated (IL-2, IFN-alpha or indomethacin) natural killer (NK) cell activity and PHA and PPD-stimulated lymphocyte proliferation. Lymphocyte subsets (helper...

  6. Hippocampal lesions facilitate instrumental learning with delayed reinforcement but induce impulsive choice in rats

    Directory of Open Access Journals (Sweden)

    Cheung Timothy HC

    2005-05-01

    Full Text Available Abstract Background Animals must frequently act to influence the world even when the reinforcing outcomes of their actions are delayed. Learning with action-outcome delays is a complex problem, and little is known of the neural mechanisms that bridge such delays. When outcomes are delayed, they may be attributed to (or associated with the action that caused them, or mistakenly attributed to other stimuli, such as the environmental context. Consequently, animals that are poor at forming context-outcome associations might learn action-outcome associations better with delayed reinforcement than normal animals. The hippocampus contributes to the representation of environmental context, being required for aspects of contextual conditioning. We therefore hypothesized that animals with hippocampal lesions would be better than normal animals at learning to act on the basis of delayed reinforcement. We tested the ability of hippocampal-lesioned rats to learn a free-operant instrumental response using delayed reinforcement, and what is potentially a related ability – the ability to exhibit self-controlled choice, or to sacrifice an immediate, small reward in order to obtain a delayed but larger reward. Results Rats with sham or excitotoxic hippocampal lesions acquired an instrumental response with different delays (0, 10, or 20 s between the response and reinforcer delivery. These delays retarded learning in normal rats. Hippocampal-lesioned rats responded slightly less than sham-operated controls in the absence of delays, but they became better at learning (relative to shams as the delays increased; delays impaired learning less in hippocampal-lesioned rats than in shams. In contrast, lesioned rats exhibited impulsive choice, preferring an immediate, small reward to a delayed, larger reward, even though they preferred the large reward when it was not delayed. Conclusion These results support the view that the hippocampus hinders action-outcome learning

  7. Time Delay and Long-Range Connection Induced Synchronization Transitions in Newman-Watts Small-World Neuronal Networks

    Science.gov (United States)

    Qian, Yu

    2014-01-01

    The synchronization transitions in Newman-Watts small-world neuronal networks (SWNNs) induced by time delay and long-range connection (LRC) probability have been investigated by synchronization parameter and space-time plots. Four distinct parameter regions, that is, asynchronous region, transition region, synchronous region, and oscillatory region have been discovered at certain LRC probability as time delay is increased. Interestingly, desynchronization is observed in oscillatory region. More importantly, we consider the spatiotemporal patterns obtained in delayed Newman-Watts SWNNs are the competition results between long-range drivings (LRDs) and neighboring interactions. In addition, for moderate time delay, the synchronization of neuronal network can be enhanced remarkably by increasing LRC probability. Furthermore, lag synchronization has been found between weak synchronization and complete synchronization as LRC probability is a little less than 1.0. Finally, the two necessary conditions, moderate time delay and large numbers of LRCs, are exposed explicitly for synchronization in delayed Newman-Watts SWNNs. PMID:24810595

  8. Non-targeted and delayed effects of exposure to ionizing radiation: II. Radiation-induced genomic instability and bystander effects in vivo, clastogenic factors and transgenerational effects

    Science.gov (United States)

    Morgan, William F.

    2003-01-01

    The goal of this review is to summarize the evidence for non-targeted and delayed effects of exposure to ionizing radiation in vivo. Currently, human health risks associated with radiation exposures are based primarily on the assumption that the detrimental effects of radiation occur in irradiated cells. Over the years a number of non-targeted effects of radiation exposure in vivo have been described that challenge this concept. These include radiation-induced genomic instability, bystander effects, clastogenic factors produced in plasma from irradiated individuals that can cause chromosomal damage when cultured with nonirradiated cells, and transgenerational effects of parental irradiation that can manifest in the progeny. These effects pose new challenges to evaluating the risk(s) associated with radiation exposure and understanding radiation-induced carcinogenesis.

  9. Topical cooling (icing) delays recovery from eccentric exercise-induced muscle damage.

    Science.gov (United States)

    Tseng, Ching-Yu; Lee, Jo-Ping; Tsai, Yung-Shen; Lee, Shin-Da; Kao, Chung-Lan; Liu, Te-Chih; Lai, Cheng- Hsiu; Harris, M Brennan; Kuo, Chia-Hua

    2013-05-01

    It is generally thought that topical cooling can interfere with blood perfusion and may have positive effects on recovery from a traumatic challenge. This study examined the influence of topical cooling on muscle damage markers and hemodynamic changes during recovery from eccentric exercise. Eleven male subjects (age 20.2 ± 0.3 years) performed 6 sets of elbow extension at 85% maximum voluntary load and randomly assigned to topical cooling or sham groups during recovery in a randomized crossover fashion. Cold packs were applied to exercised muscle for 15 minutes at 0, 3, 24, 48, and 72 hours after exercise. The exercise significantly elevated circulating creatine kinase-MB isoform (CK-MB) and myoglobin levels. Unexpectedly, greater elevations in circulating CK-MB and myoglobin above the control level were noted in the cooling trial during 48-72 hours of the post-exercise recovery period. Subjective fatigue feeling was greater at 72 hours after topical cooling compared with controls. Removal of the cold pack also led to a protracted rebound in muscle hemoglobin concentration compared with controls. Measures of interleukin (IL)-8, IL-10, IL-1β, and muscle strength during recovery were not influenced by cooling. A peak shift in IL-12p70 was noted during recovery with topical cooling. These data suggest that topical cooling, a commonly used clinical intervention, seems to not improve but rather delay recovery from eccentric exercise-induced muscle damage.

  10. Direct formation of millisecond pulsars from rotationally delayed accretion-induced collapse of massive white dwarfs

    Science.gov (United States)

    Freire, Paulo C. C.; Tauris, Thomas M.

    2014-02-01

    Millisecond pulsars (MSPs) are believed to be old neutron stars, formed via Type Ib/c core-collapse supernovae, which have subsequently been spun up to high rotation rates via accretion from a companion star in a highly circularized low-mass X-ray binary. The recent discoveries of Galactic field binary MSPs in eccentric orbits, and mass functions compatible with that expected for helium white dwarf companions, PSR J2234+06 and PSR J1946+3417, therefore challenge this picture. Here, we present a hypothesis for producing this new class of systems, where the MSPs are formed directly from a rotationally delayed accretion-induced collapse of a super-Chandrasekhar mass white dwarf. We compute the orbital properties of the MSPs formed in such events and demonstrate that our hypothesis can reproduce the observed eccentricities, masses and orbital periods of the white dwarfs, as well as forecasting the pulsar masses and velocities. Finally, we compare this hypothesis to a triple-star scenario.

  11. Methadone-Induced Delayed Posthypoxic Encephalopathy: Clinical, Radiological, and Pathological Findings

    Directory of Open Access Journals (Sweden)

    Manoj Mittal

    2010-01-01

    Full Text Available Objective. To describe the clinical, radiological and pathological findings in a patient with methadone-induced delayed posthypoxic encephalopathy (DPHE. Case Report. A Thirty-eight-year-old man was found unconscious for an unknown duration after methadone and diazepam ingestion. His initial vitals were temperature 104 degree Fahrenheit, heart rate 148/minute, respiratory rate 50/minute, and blood pressure 107/72 mmhg. He developed renal failure, rhabdomyolysis, and elevated liver enzymes which resolved completely in 6 days. After 2 weeks from discharge he had progressive deterioration of his cognitive, behavioral and neurological function. Brain MRI showed diffuse abnormal T2 signal in the corona radiata, centrum semiovale, and subcortical white matter throughout all lobes. Extensive work up was negative for any metabolic, infectious or autoimmune disorder. Brain biopsy showed significant axonal injury in the white matter. He was treated successfully with combination of steroids and antioxidants. Follow up at 2 year showed no residual deficits. Conclusion. Our observation suggests that patients on methadone therapy should be monitored for any neurological or psychiatric symptoms, and in suspected cases MRI brain may help to make the diagnosis of DPHE. A trial of steroids and antioxidants may be considered in these patients.

  12. Stability and bifurcation analysis in hematopoietic stem cell dynamics with multiple delays

    Science.gov (United States)

    Qu, Ying; Wei, Junjie; Ruan, Shigui

    2010-10-01

    This paper is devoted to the analysis of a maturity structured system of hematopoietic stem cell (HSC) populations in the bone marrow. The model is a system of differential equations with several time delays. We discuss the stability of equilibria and perform the analysis of Hopf bifurcation. More precisely, we first obtain a set of improved sufficient conditions ensuring the global asymptotical stability of the zero solution using the Lyapunov method and the embedding technique of asymptotically autonomous semiflows. Then we prove that there exists at least one positive periodic solution for the n-dimensional system as a time delay varies in some region. This result is established by combining Hopf bifurcation theory, the global Hopf bifurcation theorem due to Wu [J. Wu, Symmetric functional differential equations and neural networks with memory, Trans. Amer. Math. Soc. 350 (1998) 4799-4838], and a continuation theorem of coincidence degree theory. Some numerical simulations are also presented to illustrate the analytic results.

  13. 1090 nm infrared radiation at close to threshold dose induces cataract with a time delay.

    Science.gov (United States)

    Yu, Zhaohua; Schulmeister, Karl; Talebizadeh, Nooshin; Kronschläger, Martin; Söderberg, Per G

    2015-03-01

    To investigate whether infrared radiation (IRR)-induced cataract is instant or is associated with a time delay between the exposure and the onset of lens light scattering after an exposure to just above threshold dose. Six-weeks-old albino Sprague-Dawley female rats were unilaterally exposed to 197 W/cm2 IRR at 1090 nm within the dilated pupil. In the first experiment, the animals were exposed with four exposure times of 5, 8, 13 and 20 second, respectively. At 24 hr after exposure, the light scattering in both exposed and contralateral not exposed lenses was measured. Based on the first experiment, four postexposure time groups were exposed unilaterally to 1090 nm IRR of 197 W/cm2 for 8 second. At 6, 18, 55 and 168 hr after exposure, the light scattering in both lenses was measured. A 197 W/cm2 IRR-induced light scattering in the lens with exposures of at least 8 second. Further, after exposure to IRR of 197 W/cm2 for 8 second, the light-scattering increase in the lens was delayed approximately 16 hr after the exposure. There is a time delay between the exposure and the onset of cataract after exposure to close to threshold dose implicating that either near IRR cataract is photochemical or there is a time delay in the biological expression of thermally induced damage. © 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  14. A Small Molecule Polyamine Oxidase Inhibitor Blocks Androgen-Induced Oxidative Stress and Delays Prostate Cancer Progression in the TRAMP Mouse Model

    Science.gov (United States)

    Basu, Hirak S.; Thompson, Todd A.; Church, Dawn R.; Clower, Cynthia C.; Mehraein-Ghomi, Farideh; Amlong, Corey A.; Martin, Christopher T.; Woster, Patrick M.; Lindstrom, Mary J.; Wilding, George

    2009-01-01

    High levels of reactive oxygen species (ROS) present in human prostate epithelia are an important etiological factor in prostate cancer (CaP) occurrence, recurrence and progression. Androgen induces ROS production in the prostate by a yet unknown mechanism. Here, to the best of our knowledge, we report for the first time that androgen induces an overexpression of spermidine/spermine N1-acetyltransferase (SSAT), the rate-limiting enzyme in the polyamine oxidation pathway. As prostatic epithelia produce a large excess of polyamines, the androgen-induced polyamine oxidation that produces H2O2 could be a major reason for the high ROS levels in the prostate epithelia. A small molecule polyamine oxidase inhibitor N,N'-butanedienyl butanediamine (MDL 72,527 or CPC-200) effectively blocks androgen-induced ROS production in human CaP cells as well as significantly delays CaP progression and death in animals developing spontaneous CaP. These data demonstrate that polyamine oxidation is not only a major pathway for ROS production in prostate, but inhibiting this pathway also successfully delays prostate cancer progression. PMID:19773450

  15. A small molecule polyamine oxidase inhibitor blocks androgen-induced oxidative stress and delays prostate cancer progression in the transgenic adenocarcinoma of the mouse prostate model.

    Science.gov (United States)

    Basu, Hirak S; Thompson, Todd A; Church, Dawn R; Clower, Cynthia C; Mehraein-Ghomi, Farideh; Amlong, Corey A; Martin, Christopher T; Woster, Patrick M; Lindstrom, Mary J; Wilding, George

    2009-10-01

    High levels of reactive oxygen species (ROS) present in human prostate epithelia are an important etiologic factor in prostate cancer (CaP) occurrence, recurrence, and progression. Androgen induces ROS production in the prostate by a yet unknown mechanism. Here, to the best of our knowledge, we report for the first time that androgen induces an overexpression of spermidine/spermine N1-acetyltransferase, the rate-limiting enzyme in the polyamine oxidation pathway. As prostatic epithelia produce a large excess of polyamines, the androgen-induced polyamine oxidation that produces H2O2 could be a major reason for the high ROS levels in the prostate epithelia. A small molecule polyamine oxidase inhibitor N,N'-butanedienyl butanediamine (MDL 72,527 or CPC-200) effectively blocks androgen-induced ROS production in human CaP cells, as well as significantly delays CaP progression and death in animals developing spontaneous CaP. These data show that polyamine oxidation is not only a major pathway for ROS production in prostate, but inhibiting this pathway also successfully delays CaP progression.

  16. [Increase in cell metabolism in normal, diploid human glial cells in stationary cell cultures induced by meclofenoxate].

    Science.gov (United States)

    Ludwig-Festl, M; Gräter, B; Bayreuther, K

    1983-01-01

    Quantitative biochemical studies were undertaken in order to examine the influence of the accumulation of lipofuscin in secondary lysosomes on cell metabolic activities of normal diploid human glia cells in a stationary cell culture system. Glia cells accumulate lipofuscin as a function of the duration of the stationary cultivation in vitro. The accumulation of lipofuscin can be decreased by the long-term treatment with the pharmacon meclofenoxate (centrophenoxine, Helfergin). Concomitant with the reduction of the accumulated lipofuscin, meclofenoxate-treated glia cells show enhanced rates of RNA synthesis, protein synthesis and glucose uptake. Most likely, in meclofenoxate-treated normal diploid human glia cells in vitro, the utilisation of glucose is shifted from glycolysis to the pentose phosphate pathway. The data suggest that the meclofenoxate-induced reduction of lipofuscin accumulation has a positive effect on cell metabolic functions and causes a delay of the cellular aging of the human glia cells in vitro.

  17. HIV transcription is induced in dying cells

    Energy Technology Data Exchange (ETDEWEB)

    Woloschak, G.E.; Chang-Liu, Chin-Mei [Argonne National Lab., IL (United States); Schreck, S. [Argonne National Lab., IL (United States)]|[Univ. of South Carolina, Columbia, SC (United States). Dept. of Chemistry; Panozzo, J. [Loyola Univ. Medical Center, Maywood, IL (United States); Libertin, C.R. [Loyola Univ. Medical Center, Maywood, IL (United States)

    1996-02-01

    Using HeLa cells stably transfected with an HIV-LTR-CAT construct, we demonstrated a peak in CAT induction that occurs in viable (but not necessarily cell-division-competent) cells 24 h following exposure to some cell-killing agents. {gamma} rays were the only cell-killing agent which did not induce HIV transcription; this can be attributed to the fact that {gamma}-ray-induced apoptotic death requires functional p53, which is not present in HeLa cells. For all other agents, HIV-LTR induction was dose-dependent and correlated with the amount of cell killing that occurred in the culture. Doses which caused over 99% cell killing induced HIV-LTR transcription maximally, demonstrating that cells that will go on to die by 14 days are the cells expressing HIV-LTR-CAT.

  18. Colony stimulating factor 1 receptor inhibition delays recurrence of glioblastoma after radiation by altering myeloid cell recruitment and polarization.

    Science.gov (United States)

    Stafford, Jason H; Hirai, Takahisa; Deng, Lei; Chernikova, Sophia B; Urata, Kimiko; West, Brian L; Brown, J Martin

    2016-06-01

    Glioblastoma (GBM) may initially respond to treatment with ionizing radiation (IR), but the prognosis remains extremely poor because the tumors invariably recur. Using animal models, we previously showed that inhibiting stromal cell-derived factor 1 signaling can prevent or delay GBM recurrence by blocking IR-induced recruitment of myeloid cells, specifically monocytes that give rise to tumor-associated macrophages. The present study was aimed at determining if inhibiting colony stimulating factor 1 (CSF-1) signaling could be used as an alternative strategy to target pro-tumorigenic myeloid cells recruited to irradiated GBM. To inhibit CSF-1 signaling in myeloid cells, we used PLX3397, a small molecule that potently inhibits the tyrosine kinase activity of the CSF-1 receptor (CSF-1R). Combined IR and PLX3397 therapy was compared with IR alone using 2 different human GBM intracranial xenograft models. GBM xenografts treated with IR upregulated CSF-1R ligand expression and increased the number of CD11b+ myeloid-derived cells in the tumors. Treatment with PLX3397 both depleted CD11b+ cells and potentiated the response of the intracranial tumors to IR. Median survival was significantly longer for mice receiving combined therapy versus IR alone. Analysis of myeloid cell differentiation markers indicated that CSF-1R inhibition prevented IR-recruited monocyte cells from differentiating into immunosuppressive, pro-angiogenic tumor-associated macrophages. CSF-1R inhibition may be a promising strategy to improve GBM response to radiotherapy. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  19. Targeting Senescent Cells : Possible Implications for Delaying Skin Aging: A Mini-Review

    NARCIS (Netherlands)

    Velarde, Michael C.; Demaria, Marco

    2016-01-01

    Senescent cells are induced by a wide variety of stimuli. They accumulate in several tissues during aging, including the skin. Senescent cells secrete proinflammatory cytokines, chemokines, growth factors, and proteases, a phenomenon called senescence-associated secretory phenotype (SASP), which are

  20. A novel mechanism of immune regulation: interferon-γ regulates retention of CD4+ T cells during delayed type hypersensitivity

    Science.gov (United States)

    Seabrook, Tim J; Borron, Paul J; Dudler, Lisbeth; Hay, John B; Young, Alan J

    2005-01-01

    The local immune response is characterized by an increase in the rate of entry of lymphocytes from the blood into regional lymph nodes and changes in the output of cells in lymph. While significant data are available regarding the role of inflammation-induced vascular adhesion processes in regulating lymphocyte entry into inflamed tissues and lymph nodes, relatively little is known about the molecular processes governing lymphocyte exit into efferent lymph. We have defined a novel role for lymphatic endothelial cells in the regulation of lymphocyte exit during a delayed type hypersensitivity (DTH) response to mycobacterial purified protein derivative (PPD). Soluble, pro-adhesive factors were identified in efferent lymph concomitant with reduced lymphocyte output in lymph, which significantly increased lymphocyte binding to lymphatic endothelial cells. While all lymphocyte subsets were retained, CD4+ T cells appeared less susceptible than others. Among a panel of cytokines in inflammatory lymph plasma, interferon (IFN)-γ alone appeared responsible for this retention. In vitro adhesion assays using physiological levels of IFN-γ confirmed the interaction between recirculating lymphocytes and lymphatic endothelium. These data demonstrate a new level of immune regulation, whereby the exit of recirculating lymphocytes from lymph nodes is selectively and sequentially regulated by cytokines in a manner equally as complex as lymphocyte recruitment. PMID:16162267

  1. Dichloroacetate induces tumor-specific radiosensitivity in vitro but attenuates radiation-induced tumor growth delay in vivo.

    Science.gov (United States)

    Zwicker, F; Kirsner, A; Peschke, P; Roeder, F; Debus, J; Huber, P E; Weber, K J

    2013-08-01

    Inhibition of pyruvate dehydrogenase kinase (PDK) by dichloroacetate (DCA) can shift tumor cell metabolism from anaerobic glycolysis to glucose oxidation, with activation of mitochondrial activity and chemotherapy-dependent apoptosis. In radiotherapy, DCA could thus potentially enhance the frequently moderate apoptotic response of cancer cells that results from their mitochondrial dysfunction. The aim of this study was to investigate tumor-specific radiosensitization by DCA in vitro and in a human tumor xenograft mouse model in vivo. The interaction of DCA with photon beam radiation was investigated in the human tumor cell lines WIDR (colorectal) and LN18 (glioma), as well as in the human normal tissue cell lines HUVEC (endothelial), MRC5 (lung fibroblasts) and TK6 (lymphoblastoid). Apoptosis induction in vitro was assessed by DAPI staining and sub-G1 flow cytometry; cell survival was quantified by clonogenic assay. The effect of DCA in vivo was investigated in WIDR xenograft tumors growing subcutaneously on BALB/c-nu/nu mice, with and without fractionated irradiation. Histological examination included TUNEL and Ki67 staining for apoptosis and proliferation, respectively, as well as pinomidazole labeling for hypoxia. DCA treatment led to decreased clonogenic survival and increased specific apoptosis rates in tumor cell lines (LN18, WIDR) but not in normal tissue cells (HUVEC, MRC5, TK6). However, this significant tumor-specific radiosensitization by DCA in vitro was not reflected by the situation in vivo: The growth suppression of WIDR xenograft tumors after irradiation was reduced upon additional DCA treatment (reflected by Ki67 expression levels), although early tumor cell apoptosis rates were significantly increased by DCA. This apparently paradoxical effect was accompanied by a marked DCA-dependent induction of hypoxia in tumor-tissue. DCA induced tumor-specific radiosensitization in vitro but not in vivo. DCA also induced development of hypoxia in tumor tissue

  2. Artesunate induces necrotic cell death in schwannoma cells.

    Science.gov (United States)

    Button, R W; Lin, F; Ercolano, E; Vincent, J H; Hu, B; Hanemann, C O; Luo, S

    2014-10-16

    Established as a potent anti-malaria medicine, artemisinin-based drugs have been suggested to have anti-tumour activity in some cancers. Although the mechanism is poorly understood, it has been suggested that artemisinin induces apoptotic cell death. Here, we show that the artemisinin analogue artesunate (ART) effectively induces cell death in RT4 schwannoma cells and human primary schwannoma cells. Interestingly, our data indicate for first time that the cell death induced by ART is largely dependent on necroptosis. ART appears to inhibit autophagy, which may also contribute to the cell death. Our data in human schwannoma cells show that ART can be combined with the autophagy inhibitor chloroquine (CQ) to potentiate the cell death. Thus, this study suggests that artemisinin-based drugs may be used in certain tumours where cells are necroptosis competent, and the drugs may act in synergy with apoptosis inducers or autophagy inhibitors to enhance their anti-tumour activity.

  3. Chaotic spiking induced by variable delayed optoelectronic feedback in a model of class B laser

    Science.gov (United States)

    Grigorieva, E. V.; Kaschenko, S. A.

    2018-01-01

    We analyze the dynamics of a class B laser with optoelectronic delayed feedback and periodic modulation of the delay time. For the delay-differential model, we describe asymptotically spike regimes with various properties, namely, with inter-spikes intervals greater than delay, less delay, and a mixed type. Sets of initial conditions in an infinite-dimensional phase space are determined for each type of pulsed solutions. The dynamics of each regime is described by the dynamics of a certain finite-dimensional mapping. By computing the maps we obtain the modulation parameters at which the chaotic spiking of desired structure is realized. We demonstrate bistability of chaotic spiking, their intermittence and merge.

  4. Inhibition of STAT3 activity delays obesity-induced thyroid carcinogenesis in a mouse model.

    Science.gov (United States)

    Park, Jeong Won; Han, Cho Rong; Zhao, Li; Willingham, Mark C; Cheng, Sheue-yann

    2016-01-01

    Compelling epidemiologic studies indicate that obesity is a risk factor for many human cancers, including thyroid cancer. In recent decades, the incidence of thyroid cancer has dramatically increased along with a marked rise in obesity prevalence. We previously demonstrated that a high fat diet (HFD) effectively induced the obese phenotype in a mouse model of thyroid cancer (Thrb(PV/PV)Pten(+/-) mice). Moreover, HFD activates the STAT3 signal pathway to promote more aggressive tumor phenotypes. The aim of the present study was to evaluate the effect of S3I-201, a specific inhibitor of STAT3 activity, on HFD-induced aggressive cancer progression in the mouse model of thyroid cancer. WT and Thrb(PV/PV)Pten(+/-) mice were treated with HFD together with S3I-201 or vehicle-only as controls. We assessed the effects of S3I-201 on HFD-induced thyroid cancer progression, the leptin-JAK2-STAT3 signaling pathway, and key regulators of epithelial-mesenchymal transition (EMT). S3I-201 effectively inhibited HFD-induced aberrant activation of STAT3 and its downstream targets to markedly inhibit thyroid tumor growth and to prolong survival. Decreased protein levels of cyclins D1 and B1, cyclin dependent kinase 4 (CDK4), CDK6, and phosphorylated retinoblastoma protein led to the inhibition of tumor cell proliferation in S3I-201-treated Thrb(PV/PV)Pten(+/-) mice. Reduced occurrence of vascular invasion and blocking of anaplasia and lung metastasis in thyroid tumors of S3I-201-treated Thrb(PV/PV)Pten(+/-) mice were mediated via decreased expression of vimentin and matrix metalloproteinases, two key effectors of EMT. The present findings suggest that inhibition of the STAT3 activity would be a novel treatment strategy for obesity-induced thyroid cancer. © 2016 Society for Endocrinology.

  5. Maintenance of Manganese Superoxide Dismutase (SOD2)-Mediated Delayed Radioprotection Induced by Repeated Administration of the Free Thiol Form of Amifostine

    Science.gov (United States)

    Murley, Jeffrey S.; Nantajit, Danupon; Baker, Kenneth L.; Kataoka, Yasushi; Li, Jian Jian; Grdina, David J.

    2008-01-01

    Thiol-containing drugs such as WR1065, the free thiol form of amifostine, have been shown to induce a delayed radioprotective effect in both malignant and non-malignant cells. In mammalian cells exposed to a dose as low as 40 μM WR1065, the redox-sensitive nuclear transcription factor κB (NFκB) is activated, leading to an elevation in the expression of the antioxidant gene manganese superoxide dismutase (SOD2) and a concomitant increase in active SOD2 enzyme levels that peaks 24 to 32 h later. Exposure of cells to ionizing radiation during the period of elevated SOD2 enzymatic activity results in an enhanced radiation resistance. This is seen as an increase in surviving fraction as determined by standard colony formation assays. To determine whether this delayed radioprotection can be maintained over a prolonged period in cells of either malignant or non-malignant origin, both human microvascular endothelial cells (HMEC) and SA-NH mouse sarcoma cells were grown to confluence and exposed to 40 μM WR1065 using three administration protocols: (1) daily drug exposure for 10 days followed each day by irradiation with 2 Gy; (2) drug exposure once every 48 h followed by irradiation with 2 Gy 48 h later for 14 days; and (3) drug exposure every 72 h followed by irradiation with 2 Gy 72 h later for 12 days. As a function of each experimental condition, cell numbers and associated SOD2 enzymatic activities were measured at the time of each irradiation. None of the treatment conditions were toxic to either HMEC or SA-NH cells. SOD2 activity was elevated 5.3- and 1.8-fold over background on average for HMEC exposed to 40 μM WR1065 every 24 or 48 h, respectively. Likewise, SOD2 activity was elevated in SA-NH mouse sarcoma cells 7.8- and 4.9-fold after daily exposure to WR1065 or exposure to WR1065 once every 48 h, respectively. Both HMEC and SA-NH cells exhibited enhanced radiation resistance that correlated with the increase in SOD2 activity. The average respective

  6. Delayed progression of diabetic cataractogenesis and retinopathy by Litchi chinensis in STZ-induced diabetic rats.

    Science.gov (United States)

    Kilari, Eswar Kumar; Putta, Swathi

    2017-03-01

    The study was carried out to evaluate the effect of the aqueous fruit pericarp extract of Litchi chinensis (APLC) on parameters which leads to diabetic cataractogenesis and retinopathy in the streptozotocin-induced diabetic rats. The objective of the study is to evaluate the APLC for in vivo antioxidant activity and its role in inhibiting the polyol pathway and formation of advanced glycation end products (AGEs). The diabetic animals were treated with L. chinensis for a period of 12 weeks. At the end of 12 weeks, the animals were killed and the biochemical pathways involved in the pathogenesis of cataract such as oxidative stress by protein content, superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and polyolpathway by aldose reductase (AR) in lens homogenates, alterations in protein carbonyl content (PCO) and AGEs in both serum and lens the APLC-treated diabetic rats were compared against diabetic control rats. Cataract progression due to hyperglycemia was monitored by slit lamp bio microscope and classified into four stages. Fundoscope test and retinal histopathology were done for assessing retinopathy. Statistically significant reduction in glucose, and elevation of protein content, SOD, CAT, and GSH levels and decreased levels of AR and PCO in lens homogenate and significant reduction in AGEs serum and lens homogenate were observed. Slit lamp examination, fundoscope, and histopathology showed improvement in retinal changes in APLC-treated rats compared to diabetic control animals. The treatment with APLC found to delay the progression of diabetic cataractogenesis and retinopathy, which might be due to its antioxidant activity, because of the presence of active phytochemicals in APLC.

  7. Central Autonomic Dysfunction Delays Recovery of Fingolimod Induced Heart Rate Slowing.

    Directory of Open Access Journals (Sweden)

    Max J Hilz

    Full Text Available In multiple sclerosis (MS patients, Fingolimod may induce prolonged heart-rate slowing which might be caused by MS-related central autonomic lesions.To evaluate whether MS-patients with prolonged heart-rate slowing (> six hours upon Fingolimod show cardiovascular-autonomic dysfunction before Fingolimod-initiation.Before Fingolimod-initiation, we recorded electrocardiographic RR-intervals (RRIs and blood-pressure (BP at rest, upon standing-up, during metronomic deep-breathing, Valsalva-maneuver, and "sustained-handgrip-exercise" in 21 patients with relapsing-remitting MS, and 20 healthy persons. We calculated sympathetic and parasympathetic cardiovascular parameters, including low- (LF and high-frequency (HF powers of RRI- and BP-oscillations, RRI-RMSSDs, RRI- and BP-changes during handgrip-exercise, parasympathetic heart-rate-slowing in relation to BP-overshoot after Valsalva-strain-release. We compared values of healthy persons and patients with and without prolonged heart-rate slowing after Fingolimod-initiation (ANOVA; significance: p<0.05.Upon Fingolimod-initiation, 7/21 patients had prolonged HR-slowing. Before Fingolimod, these patients had higher resting BP and higher BP increase during handgrip-exercise than had the other participants (p<0.05. They did not reduce parasympathetic HR-parameters upon standing-up. After Valsalva-strain-release, their parasympathetic HR-slowing in response to BP-overshoot was four times higher than in the other participants (p<0.05.The autonomic cardiovascular dysfunction in MS-patients with delayed HR-re-acceleration upon Fingolimod-initiation suggests that MS-related central autonomic lesions compromise HR-re-acceleration upon Fingolimod.German Clinical Trial Register DRKS00004548 http://drks-neu.uniklinik-freiburg.de/drks_web/setLocale_EN.do.

  8. Noise-induced decline and propagation of population in the delayed Malthus-Verhulst model

    Energy Technology Data Exchange (ETDEWEB)

    Cai Jianchun; Mei Dongcheng, E-mail: meidch@ynu.edu.c [Department of Physics, Yunnan University, Kunming 650091 (China)

    2010-06-01

    The effects of multiplicative and additive colored noises on decline and propagation processes of population in the delayed stochastic Malthus-Verhulst model are investigated by numerically computing and stochastically simulating. From the biological point of view, our results indicate that: the increasing correlation time of multiplicative noise strengthens the stability of population, and the correlation time of additive noise does not affect it. The increasing correlation time of multiplicative noise slows down the replacement of old individuals with young ones, while the increasing correlation time of additive noise with short delay time and the optimal correlation time of additive noise with long delay time quicken it.

  9. GAS1 induces cell death through an intrinsic apoptotic pathway.

    Science.gov (United States)

    Zarco, Natanael; González-Ramírez, Ricardo; González, Rosa O; Segovia, José

    2012-06-01

    Growth Arrest Specific 1 (GAS1) is a protein expressed when cells are arrested and during development. When ectopically expressed, GAS1 induces cell arrest and apoptosis of different cell lines, and we have previously demonstrated that the apoptotic process set off by GAS1 is caused by its capacity inhibiting the GDNF-mediated intracellular survival signaling. In the present work, we have dissected the molecular pathway leading to cell death. We employed the SH-SY5Y human neuroblastoma cell line that expresses GAS1 when deprived of serum. We observed, as we have previously described, that the presence of GAS1 reduces RET phosphorylation and inhibits the activation of AKT. We have now determined that the presence of GAS1 also triggers the dephosphorylation of BAD, which, in turn, provokes the release of Cytochrome-c from the mitochondria to the cytosol activating caspase-9, prompting the activity of caspase-3 and resulting in apoptosis of the cells. The apoptotic process is intrinsic, because there is no activation of caspase-8, thus this is consistent with apoptosis induced by the lack of trophic support. Interestingly, in cells where GAS1 has been silenced there is a significant delay in the onset of apoptosis.

  10. Delayed Treatment with Sodium Hydrosulfide Improves Regional Blood Flow and Alleviates Cecal Ligation and Puncture (CLP)-Induced Septic Shock.

    Science.gov (United States)

    Ahmad, Akbar; Druzhyna, Nadiya; Szabo, Csaba

    2016-08-01

    Cecal ligation and puncture (CLP)-induced sepsis is a serious medical condition, caused by a severe systemic infection resulting in a systemic inflammatory response. Recent studies have suggested the therapeutic potential of donors of hydrogen sulfide (H2S), a novel endogenous gasotransmitter and biological mediator in various diseases. The aim of the present study was to assess the effect of H2S supplementation in sepsis, with special reference to its effect on the modulation of regional blood flow. We infused sodium hydrosulfide (NaHS), a compound that produces H2S in aqueous solution (1, 3, or 10 mg/kg/h, for 1 h at each dose level) in control rats or rats 24 h after CLP, and measured blood flow using fluorescent microspheres. In normal control animals, NaHS induced a characteristic redistribution of blood flow, and reduced cardiac, hepatic, and renal blood flow in a dose-dependent fashion. In contrast, in rats subjected to CLP, cardiac, hepatic, and renal blood flow was significantly reduced; infusion of NaHS (1 mg/kg/h and 3 mg/kg/h) significantly increased organ blood flow. In other words, the effect of H2S on regional blood flow is dependent on the status of the animals (i.e., a decrease in blood flow in normal controls, but an increase in blood flow in CLP). We have also evaluated the effect of delayed treatment with NaHS on organ dysfunction and the inflammatory response by treating the animals with NaHS (3 mg/kg) intraperitoneally (i.p.) at 24 h after the start of the CLP procedure; plasma levels of various cytokines and tissue indicators of inflammatory cell infiltration and oxidative stress were measured 6 h later. After 24 h of CLP, glomerular function was significantly impaired, as evidenced by markedly increased (over 4-fold over baseline) blood urea nitrogen and creatinine levels; this increase was also significantly reduced by treatment with NaHS. NaHS also attenuated the CLP-induced increases in malondialdehyde levels (an index of

  11. Human umbilical cord blood mononuclear cell transplantation for delayed encephalopathy after carbon monoxide intoxication

    Directory of Open Access Journals (Sweden)

    Gong D

    2013-08-01

    Full Text Available Dianrong Gong,1 Haiyan Yu,1 Weihua Wang,2 Haixin Yang,1 Fabin Han1,21Department of Neurology, 2Centre for Stem Cells and Regenerative Medicine, Liaocheng People's Hospital, The Affiliated Liaocheng Hospital, Taishan Medical University, Shandong, People's Republic of ChinaAbstract: Stem cell transplantation is one of the potential treatments for neurological disorders. Since human umbilical cord stem cells have been shown to provide neuroprotection and promote neural regeneration, we have attempted to transplant the human umbilical cord blood mononuclear cells (hUCB-MNCs to treat patients with delayed encephalopathy after carbon monoxide intoxication (DEACOI. The hUCB-MNCs were isolated from fresh umbilical cord blood and were given to patients subarachnoidally. Physical examinations, mini-mental state examination scores, and computed tomography scans were used to evaluate the improvement of symptoms, signs, and pathological changes of the patient's brain before and after hUCB-MNC transplantation. A total of 12 patients with DEACOI were treated with hUCB-MNCs in this study. We found that most of the patients have shown significant improvements in movement, behavior, and cognitive function, and improved brain images in 1–4 months from the first transplantation of hUCB-MNCs. None of these patients have been observed to have any severe adverse effects. Our study suggests that the hUCB-MNC transplantation may be a safe and effective treatment for DEACOI. Further studies and clinical trials with more cases, using more systematic scoring methods, are needed to evaluate brain structural and functional improvements in patients with DEACOI after hUCB-MNC therapy.Keywords: human umbilical cord blood mononuclear cells, transplantation, delayed encephalopathy after carbon monoxide intoxication, MMSE

  12. MIF inhibition interferes with the inflammatory and T cell-stimulatory capacity of NOD macrophages and delays autoimmune diabetes onset.

    Directory of Open Access Journals (Sweden)

    Hannelie Korf

    Full Text Available Macrophages contribute in the initiation and progression of insulitis during type 1 diabetes (T1D. However, the mechanisms governing their recruitment into the islets as well as the manner of retention and activation are incompletely understood. Here, we investigated a role for macrophage migration inhibitory factor (MIF and its transmembrane receptor, CD74, in the progression of T1D. Our data indicated elevated MIF concentrations especially in long-standing T1D patients and mice. Additionally, NOD mice featured increased MIF gene expression and CD74+ leukocyte frequencies in the pancreas. We identified F4/80+ macrophages as the main immune cells in the pancreas expressing CD74 and showed that MIF antagonism of NOD macrophages prevented their activation-induced cytokine production. The physiological importance was highlighted by the fact that inhibition of MIF delayed the onset of autoimmune diabetes in two different diabetogenic T cell transfer models. Mechanistically, macrophages pre-conditioned with the MIF inhibitor featured a refractory capacity to trigger T cell activation by keeping them in a naïve state. This study underlines a possible role for MIF/CD74 signaling pathways in promoting macrophage-mediated inflammation in T1D. As therapies directed at the MIF/CD74 pathway are in clinical development, new opportunities may be proposed for arresting T1D progression.

  13. Premature ejaculation and serotonergic antidepressants-induced delayed ejaculation : the involvement of the serotonergic system

    NARCIS (Netherlands)

    Waldinger, MD; Berendsen, HHG; Blok, BFM; Olivier, B; Holstege, G

    Premature ejaculation has generally been considered a psychosexual disorder with psychogenic aetiology. Although still mainly treated by behavioural therapy, in recent years double-blind studies have indicated the beneficial effects of some of the serotonergic antidepressants (SSRIs) in delaying

  14. Red cell exchange to mitigate a delayed hemolytic transfusion reaction in a patient transfused with incompatible red blood cells.

    Science.gov (United States)

    Irani, Mehraboon S; Karafin, Matthew S; Ernster, Luke

    2017-02-01

    A red cell exchange was performed to prevent a potentially fatal hemolytic transfusion reaction in a patient with anti-e who was transfused with e-antigen unscreened red blood cells during liver transplant surgery. A 64-year-old woman with cirrhosis due to hepatitis C was scheduled to receive a liver transplant. She had a previously documented anti-e, an antibody to the Rh(e)-antigen that is known to cause delayed hemolytic transfusion reactions. Pre-operatively and intra-operatively, she had massive hemorrhage which required transfusion of 34 e-antigen unscreened red blood cells (RBCs) most of which were incompatible. The hemoglobin dropped from 9.1 g/dL on post-operative day (POD)1 to 6.6 g/dL on POD6, with no evidence of blood loss. The bilirubin also increased from 5.0 mg/dL on POD 1 to 11.0 mg/dL on POD 6. As she was also becoming more hemodynamically unstable, a red cell exchange with 10 units of e-negative RBCs was performed on POD 6. She improved clinically and was extubated the following day. A few residual transfused e-positive red cells were detected after the red cell exchange until POD 13. This case illustrates how a red cell exchange can mitigate the potentially harmful effects of a delayed hemolytic transfusion reaction caused by red cell antibodies. With massive intraoperative blood loss it may not be possible to have antigen-negative RBCs immediately available, particularly for the e-antigen, which is present in 98% of the donor population. The ability to perform such a procedure may be life-saving in such patients. J. Clin. Apheresis 32:59-61, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  15. Activation delay-induced mechanical dyssynchrony in single-ventricle heart disease

    DEFF Research Database (Denmark)

    Forsha, Daniel; Risum, Niels; Barker, Piers

    2017-01-01

    We present the case of an infant with a single functional ventricle who developed ventricular dysfunction and heart failure due to an electrical activation delay and dyssynchrony. Earlier recognition of this potentially reversible aetiology may have changed her poor outcome.......We present the case of an infant with a single functional ventricle who developed ventricular dysfunction and heart failure due to an electrical activation delay and dyssynchrony. Earlier recognition of this potentially reversible aetiology may have changed her poor outcome....

  16. Interaction between the Cardiac Rapidly (IKr) and Slowly (IKs) Activating Delayed Rectifier Potassium Channels Revealed by Low K+-induced hERG Endocytic Degradation*

    Science.gov (United States)

    Guo, Jun; Wang, Tingzhong; Yang, Tonghua; Xu, Jianmin; Li, Wentao; Fridman, Michael D.; Fisher, John T.; Zhang, Shetuan

    2011-01-01

    Cardiac repolarization is controlled by the rapidly (IKr) and slowly (IKs) activating delayed rectifier potassium channels. The human ether-a-go-go-related gene (hERG) encodes IKr, whereas KCNQ1 and KCNE1 together encode IKs. Decreases in IKr or IKs cause long QT syndrome (LQTS), a cardiac disorder with a high risk of sudden death. A reduction in extracellular K+ concentration ([K+]o) induces LQTS and selectively causes endocytic degradation of mature hERG channels from the plasma membrane. In the present study, we investigated whether IKs compensates for the reduced IKr under low K+ conditions. Our data show that when hERG and KCNQ1 were expressed separately in human embryonic kidney (HEK) cells, exposure to 0 mm K+ for 6 h completely eliminated the mature hERG channel expression but had no effect on KCNQ1. When hERG and KCNQ1 were co-expressed, KCNQ1 significantly delayed 0 mm K+-induced hERG reduction. Also, hERG degradation led to a significant reduction in KCNQ1 in 0 mm K+ conditions. An interaction between hERG and KCNQ1 was identified in hERG+KCNQ1-expressing HEK cells. Furthermore, KCNQ1 preferentially co-immunoprecipitated with mature hERG channels that are localized in the plasma membrane. Biophysical and pharmacological analyses indicate that although hERG and KCNQ1 closely interact with each other, they form distinct hERG and KCNQ1 channels. These data extend our understanding of delayed rectifier potassium channel trafficking and regulation, as well as the pathology of LQTS. PMID:21844197

  17. Global metabolic profiling of Arabidopsis Polyamine Oxidase 4 (AtPAO4 loss-of-function mutants exhibiting delayed dark-induced senescence

    Directory of Open Access Journals (Sweden)

    Miren Iranzu Sequera-Mutiozabal

    2016-02-01

    Full Text Available Early and more recent studies have suggested that some polyamines (PAs, and particularly spermine (Spm, exhibit anti-senescence properties in plants. In this work, we have investigated the role of Arabidopsis Polyamine Oxidase 4 (PAO4, encoding a PA back-conversion oxidase, during dark-induced senescence. Two independent PAO4 (pao4-1 and pao4-2 loss-of-function mutants have been found that accumulate 10-fold higher Spm, and this associated with delayed entry into senescence under dark conditions. Mechanisms underlying pao4 delayed senescence have been studied using global metabolic profiling by GC-TOF/MS. pao4 mutants exhibit constitutively higher levels of important metabolites involved in redox regulation, central metabolism and signaling that support a priming status against oxidative stress. During senescence, interactions between PAs and oxidative, sugar and nitrogen metabolism have been detected that additively contribute to delayed entry into senescence. Our results indicate the occurrence of metabolic interactions between PAs, particularly Spm, with cell oxidative balance and transport/biosynthesis of amino acids as a strategy to cope with oxidative damage produced during senescence.

  18. Small interfering RNA targeted to IGF-IR delays tumor growth and induces proinflammatory cytokines in a mouse breast cancer model.

    Directory of Open Access Journals (Sweden)

    Tiphanie Durfort

    Full Text Available Insulin-like growth factor I (IGF-I and its type I receptor (IGF-IR play significant roles in tumorigenesis and in immune response. Here, we wanted to know whether an RNA interference approach targeted to IGF-IR could be used for specific antitumor immunostimulation in a breast cancer model. For that, we evaluated short interfering RNA (siRNAs for inhibition of in vivo tumor growth and immunological stimulation in immunocompetent mice. We designed 2'-O-methyl-modified siRNAs to inhibit expression of IGF-IR in two murine breast cancer cell lines (EMT6, C4HD. Cell transfection of IGF-IR siRNAs decreased proliferation, diminished phosphorylation of downstream signaling pathway proteins, AKT and ERK, and caused a G0/G1 cell cycle block. The IGF-IR silencing also induced secretion of two proinflammatory cytokines, TNF- α and IFN-γ. When we transfected C4HD cells with siRNAs targeting IGF-IR, mammary tumor growth was strongly delayed in syngenic mice. Histology of developing tumors in mice grafted with IGF-IR siRNA treated C4HD cells revealed a low mitotic index, and infiltration of lymphocytes and polymorphonuclear neutrophils, suggesting activation of an antitumor immune response. When we used C4HD cells treated with siRNA as an immunogen, we observed an increase in delayed-type hypersensitivity and the presence of cytotoxic splenocytes against wild-type C4HD cells, indicative of evolving immune response. Our findings show that silencing IGF-IR using synthetic siRNA bearing 2'-O-methyl nucleotides may offer a new clinical approach for treatment of mammary tumors expressing IGF-IR. Interestingly, our work also suggests that crosstalk between IGF-I axis and antitumor immune response can mobilize proinflammatory cytokines.

  19. Adipose-derived stromal cells inhibit prostate cancer cell proliferation inducing apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Takahara, Kiyoshi [Department of Urology, Faculty of Medicine, Osaka Medical College, Osaka (Japan); Ii, Masaaki, E-mail: masaii@art.osaka-med.ac.jp [Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Osaka (Japan); Inamoto, Teruo; Komura, Kazumasa; Ibuki, Naokazu; Minami, Koichiro; Uehara, Hirofumi; Hirano, Hajime; Nomi, Hayahito; Kiyama, Satoshi [Department of Urology, Faculty of Medicine, Osaka Medical College, Osaka (Japan); Asahi, Michio [Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Osaka (Japan); Azuma, Haruhito [Department of Urology, Faculty of Medicine, Osaka Medical College, Osaka (Japan)

    2014-04-18

    Highlights: • AdSC transplantation exhibits inhibitory effect on tumor progressions of PCa cells. • AdSC-induced PCa cell apoptosis may occur via the TGF-β signaling pathway. • High expression of the TGF-β1 gene in AdSCs. - Abstract: Mesenchymal stem cells (MSCs) have generated a great deal of interest in the field of regenerative medicine. Adipose-derived stromal cells (AdSCs) are known to exhibit extensive proliferation potential and can undergo multilineage differentiation, sharing similar characteristics to bone marrow-derived MSCs. However, as the effect of AdSCs on tumor growth has not been studied sufficiently, we assessed the degree to which AdSCs affect the proliferation of prostate cancer (PCa) cell. Human AdSCs exerted an inhibitory effect on the proliferation of androgen-responsive (LNCaP) and androgen-nonresponsive (PC3) human PCa cells, while normal human dermal fibroblasts (NHDFs) did not, and in fact promoted PCa cell proliferation to a degree. Moreover, AdSCs induced apoptosis of LNCaP cells and PC3 cells, activating the caspase3/7 signaling pathway. cDNA microarray analysis suggested that AdSC-induced apoptosis in both LNCaP and PC3 cells was related to the TGF-β signaling pathway. Consistent with our in vitro observations, local transplantation of AdSCs delayed the growth of tumors derived from both LNCaP- and PC3-xenografts in immunodeficient mice. This is the first preclinical study to have directly demonstrated that AdSC-induced PCa cell apoptosis may occur via the TGF-β signaling pathway, irrespective of androgen-responsiveness. Since autologous AdSCs can be easily isolated from adipose tissue without any ethical concerns, we suggest that therapy with these cells could be a novel approach for patients with PCa.

  20. Loss of PACS-2 delays regeneration in DSS-induced colitis but does not affect the ApcMin model of colorectal cancer

    DEFF Research Database (Denmark)

    Dombernowsky, Sarah L.; Schwarz, Jeanette; Samsøe-Petersen, Jacob

    2017-01-01

    PACS-2 is a multifunctional sorting protein that mediates cell homeostasis. We recently identified PACS-2 in a functional genome-wide siRNA screen for novel regulators of the metalloproteinase ADAM17, the main sheddase for ligands of the ErbB receptor family. Of note, we showed that Pacs2-/- mice...... have significantly reduced EGFR activity and proliferative index in the intestinal epithelium. As EGFR signaling is highly mitogenic for intestinal epithelial stem cells, and plays essential roles in intestinal epithelial regeneration and tumor development, we have now examined the role of PACS-2...... in these processes. Specifically, we analyzed the role of Pacs2- deficiency in a DSS-induced colitis model as well as in the genetic ApcMin colon cancer model. We now report that loss of PACS-2 delays tissue regeneration after colonic injury with little effect on key inflammatory parameters. We did however...

  1. The role of ERK-1/2 in the N/OFQ-induced inhibition of delayed rectifier potassium currents

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Wei [Laboratory of Neural Electrophysiology, Department of Physiology, Harbin Medical University, Harbin 150081 (China); Cui, Qingbo [Department of Pediatric Surgery, The 2nd Hospital of Harbin Medical University, Harbin 150081 (China); Li, Yurong [Laboratory of Neural Electrophysiology, Department of Physiology, Harbin Medical University, Harbin 150081 (China); Li, Baoxin [Institute of Pharmacology, Harbin Medical University, Harbin 150081 (China); Yang, Xu; Cui, Lanwei; Jin, Hongbo [Laboratory of Neural Electrophysiology, Department of Physiology, Harbin Medical University, Harbin 150081 (China); Qu, Lihui, E-mail: lihui_qu@yahoo.com.cn [Laboratory of Neural Electrophysiology, Department of Physiology, Harbin Medical University, Harbin 150081 (China)

    2010-04-16

    Nociceptin/orphanin FQ (N/OFQ) is an endogenous opioid-like heptadecapeptide involved in many neurocognitive functions, including learning and memory. Our previous report showed that N/OFQ inhibits the delayed rectifier potassium current (I{sub K}), and this effect is associated with protein kinase C (PKC) activation. Therefore, we wanted to determine if extracellular signal-regulated kinase-1/2 (ERK-1/2) signaling is regulated by N/OFQ and associated with the effect of N/OFQ on the I{sub K}. In the current study, we tested if N/OFQ and two PKC activators [phorbol 12,13-dibutyrate (PDBu) and ingenol 3,20-dibenzoate (IDB)] affected the phosphorylation level of ERK-1/2 and its nuclear substrate, ETS-like transcription factor-1 (Elk-1), using western blots. In addition, we tested if ERK-1/2 affected the N/OFQ-induced inhibition of the I{sub K} by using whole-cell patch-clamp recordings in acutely dissociated rat parietal cortical neurons. We found that N/OFQ, PDBu, and IDB increased the amount of phosphorylated ERK-1/2 and Elk-1; U0126, a specific inhibitor for ERK-1/2, attenuated the inhibitory effect of N/OFQ on the I{sub K}. These data suggest that the ERK-1/2 pathway, at least in part, mediates the inhibitory effect of N/OFQ on the I{sub K} in acutely dissociated rat cerebral parietal cortical neurons.

  2. Timing of xenon-induced delayed postconditioning to protect against spinal cord ischaemia-reperfusion injury in rats.

    Science.gov (United States)

    Yang, Y W; Cheng, W P; Lu, J K; Dong, X H; Wang, C B; Zhang, J; Zhao, L Y; Gao, Z F

    2014-07-01

    This study was designed to assess the neuroprotective effect of xenon-induced delayed postconditioning on spinal cord ischaemia-reperfusion injury (IRI) and to determine the time of administration for best neuroprotection in a rat model of spinal cord IRI. Fifty male rats were randomly divided equally into a sham group, control group, and three xenon postconditioning groups (n=10 per group). The control group underwent spinal cord IRI and immediately inhaled 50% nitrogen/50% oxygen for 3 h at the initiation of reperfusion. The three xenon postconditioning groups underwent the same surgical procedure and immediately inhaled 50% xenon/50% oxygen for 3 h at the initiation of reperfusion or 1 and 2 h after reperfusion. The sham operation group underwent the same surgical procedure without aortic occlusion, and inhaled 50% nitrogen/50% oxygen. Neurological function was assessed using the Basso, Beattie, and Bresnahan score at 4, 24, and 48 h of reperfusion. Histological examination was performed using Nissl staining and immunohistochemistry, and apoptosis was detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling staining. Compared with the control group, the three xenon postconditioning groups showed improvements in neurological outcomes, and had more morphologically normal neurones at 48 h of reperfusion. Apoptotic cell death was reduced and the ratio of Bcl-2/Bax immunoreactivity increased in xenon-treated rats compared with controls. Xenon postconditioning up to 2 h after reperfusion provided protection against spinal cord IRI in rats, but the greatest neuroprotection occurred with administration of xenon for 1 h at reperfusion. © The Author [2013]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. Aire-Overexpressing Dendritic Cells Induce Peripheral CD4+ T Cell Tolerance

    Science.gov (United States)

    Li, Dongbei; Li, Haijun; Fu, Haiying; Niu, Kunwei; Guo, Yantong; Guo, Chuan; Sun, Jitong; Li, Yi; Yang, Wei

    2015-01-01

    Autoimmune regulator (Aire) can promote the ectopic expression of peripheral tissue-restricted antigens (TRAs) in thymic medullary epithelial cells (mTECs), which leads to the deletion of autoreactive T cells and consequently prevents autoimmune diseases. However, the functions of Aire in the periphery, such as in dendritic cells (DCs), remain unclear. This study’s aim was to investigate the effect of Aire-overexpressing DCs (Aire cells) on the functions of CD4+ T cells and the treatment of type 1 diabetes (T1D). We demonstrated that Aire cells upregulated the mRNA levels of the tolerance-related molecules CD73, Lag3, and FR4 and the apoptosis of CD4+ T cells in STZ-T1D mouse-derived splenocytes. Furthermore, following insulin stimulation, Aire cells decreased the number of CD4+ IFN-γ+ T cells in both STZ-T1D and WT mouse-derived splenocytes and reduced the expression levels of TCR signaling molecules (Ca2+ and p-ERK) in CD4+ T cells. We observed that Aire cells-induced CD4+ T cells could delay the development of T1D. In summary, Aire-expressing DCs inhibited TCR signaling pathways and decreased the quantity of CD4+IFN-γ+ autoreactive T cells. These data suggest a mechanism for Aire in the maintenance of peripheral immune tolerance and provide a potential method to control autoimmunity by targeting Aire. PMID:26729097

  4. Aire-Overexpressing Dendritic Cells Induce Peripheral CD4+ T Cell Tolerance

    Directory of Open Access Journals (Sweden)

    Dongbei Li

    2015-12-01

    Full Text Available Autoimmune regulator (Aire can promote the ectopic expression of peripheral tissue-restricted antigens (TRAs in thymic medullary epithelial cells (mTECs, which leads to the deletion of autoreactive T cells and consequently prevents autoimmune diseases. However, the functions of Aire in the periphery, such as in dendritic cells (DCs, remain unclear. This study’s aim was to investigate the effect of Aire-overexpressing DCs (Aire cells on the functions of CD4+ T cells and the treatment of type 1 diabetes (T1D. We demonstrated that Aire cells upregulated the mRNA levels of the tolerance-related molecules CD73, Lag3, and FR4 and the apoptosis of CD4+ T cells in STZ-T1D mouse-derived splenocytes. Furthermore, following insulin stimulation, Aire cells decreased the number of CD4+ IFN-γ+ T cells in both STZ-T1D and WT mouse-derived splenocytes and reduced the expression levels of TCR signaling molecules (Ca2+ and p-ERK in CD4+ T cells. We observed that Aire cells-induced CD4+ T cells could delay the development of T1D. In summary, Aire-expressing DCs inhibited TCR signaling pathways and decreased the quantity of CD4+IFN-γ+ autoreactive T cells. These data suggest a mechanism for Aire in the maintenance of peripheral immune tolerance and provide a potential method to control autoimmunity by targeting Aire.

  5. Local and global synchronization transitions induced by time delays in small-world neuronal networks with chemical synapses.

    Science.gov (United States)

    Yu, Haitao; Wang, Jiang; Du, Jiwei; Deng, Bin; Wei, Xile

    2015-02-01

    Effects of time delay on the local and global synchronization in small-world neuronal networks with chemical synapses are investigated in this paper. Numerical results show that, for both excitatory and inhibitory coupling types, the information transmission delay can always induce synchronization transitions of spiking neurons in small-world networks. In particular, regions of in-phase and out-of-phase synchronization of connected neurons emerge intermittently as the synaptic delay increases. For excitatory coupling, all transitions to spiking synchronization occur approximately at integer multiples of the firing period of individual neurons; while for inhibitory coupling, these transitions appear at the odd multiples of the half of the firing period of neurons. More importantly, the local synchronization transition is more profound than the global synchronization transition, depending on the type of coupling synapse. For excitatory synapses, the local in-phase synchronization observed for some values of the delay also occur at a global scale; while for inhibitory ones, this synchronization, observed at the local scale, disappears at a global scale. Furthermore, the small-world structure can also affect the phase synchronization of neuronal networks. It is demonstrated that increasing the rewiring probability can always improve the global synchronization of neuronal activity, but has little effect on the local synchronization of neighboring neurons.

  6. Aloin induces apoptosis in Jurkat cells.

    Science.gov (United States)

    Buenz, Eric J

    2008-03-01

    Aloe is widely used as a dietary supplement. However, there are continuing concerns over the toxicity and the purity of aloe-based products. The primary class of compounds responsible for aloe-induced toxicity are anthraquinones. One of these, aloe-emodin, has been extensively investigated for apoptosis inducing effects. Conversely, the precursor to aloe-emodin, aloin, has been subjected to only minimal investigation of any cytotoxic effects. Jurkat T cells, an established model for the study of compound toxicity, were used to evaluate the effect of aloin on cell viability. Cells were analyzed using flow cytometry and microscopy for cell size and granularity, cell membrane integrity, mitochondrial membrane potential, and cell cycle profile. Treatment with aloin resulted in a reduction in cell size, compromised membrane integrity, and loss of mitochondrial membrane potential in a dose-dependent manner. Additionally, treatment with aloin resulted in alteration of the cell cycle, specifically a block at G2/M phase. Importantly, the loss of cell membrane integrity was preceded by a loss of mitochondrial membrane potential, suggesting a mitochondrial-dependent pathway for aloin-induced apoptosis. These observations provide insight into the potential mechanisms of aloin-induced toxicity and thus, perhaps, aloe preparation-induced toxicity. Furthermore, because of the concern over the safety of aloe-based supplements, this work suggests that aloe supplements not containing aloin may be safer than aloe supplements containing aloin, and that aloin should be considered in addition to concentrations of aloe-emodin.

  7. Evidence for Inhibitory Effects of Flupirtine, a Centrally Acting Analgesic, on Delayed Rectifier K+ Currents in Motor Neuron-Like Cells

    Directory of Open Access Journals (Sweden)

    Sheng-Nan Wu

    2012-01-01

    Full Text Available Flupirtine (Flu, a triaminopyridine derivative, is a centrally acting, non-opiate analgesic agent. In this study, effects of Flu on K+ currents were explored in two types of motor neuron-like cells. Cell exposure to Flu decreased the amplitude of delayed rectifier K+ current (IK(DR with a concomitant raise in current inactivation in NSC-34 neuronal cells. The dissociation constant for Flu-mediated increase of IK(DR inactivation rate was about 9.8 μM. Neither linopirdine (10 μM, NMDA (30 μM, nor gabazine (10 μM reversed Flu-induced changes in IK(DR inactivation. Addition of Flu shifted the inactivation curve of IK(DR to a hyperpolarized potential. Cumulative inactivation for IK(DR was elevated in the presence of this compound. Flu increased the amplitude of M-type K+ current (IK(M and produced a leftward shift in the activation curve of IK(M. In another neuronal cells (NG108-15, Flu reduced IK(DR amplitude and enhanced the inactivation rate of IK(DR. The results suggest that Flu acts as an open-channel blocker of delayed-rectifier K+ channels in motor neurons. Flu-induced block of IK(DR is unlinked to binding to NMDA or GABA receptors and the effects of this agent on K+ channels are not limited to its action on M-type K+ channels.

  8. Amygdalin delays cell cycle progression and blocks growth of prostate cancer cells in vitro.

    Science.gov (United States)

    Makarević, Jasmina; Tsaur, Igor; Juengel, Eva; Borgmann, Hendrik; Nelson, Karen; Thomas, Christian; Bartsch, Georg; Haferkamp, Axel; Blaheta, Roman A

    2016-02-15

    Despite impressive survival benefits from new agents to treat metastasized prostate cancer (PCa), progressive drug resistance hinders long-term response and restricts the efficacy of subsequent therapy. Due to reported antitumor activity of amygdalin and growing popularity for complementary and alternative medicine the potential of this natural, widely used substance to exert antineoplastic effects on prostate cancer cells has been assessed. LNCaP (castration-sensitive), DU-145 and PC3 cells (castration-resistant) were exposed to different concentrations of amygdalin for 24h or 2weeks. Cell growth was measured by the MTT test, clonal formation by the clonogenic assay. Flow cytometry served to investigate apoptosis and cell cycle phases. Cell cycle regulating proteins and the mTOR-akt signaling axis were analyzed by western blotting. Amygdalin dose-dependently diminished tumor cell growth with maximum effects at 10mg/ml. Apoptosis of PC3 and LNCaP but not of DU-145 cells was reduced, whereas colony formation was suppressed in all cell lines. A decrease in the number of G2/M- and S-phase cells along with an elevated number of G0/G1-phase cells was recorded. The cell cycle proteins cdk 1, cdk 2 and cdk 4 as well as cyclin A, cyclin B and cyclin D3 were modulated by amygdalin after both 24h and 2weeks. Distinct effects on p19 and p27 expression and on Akt, Rictor and Raptor activation became evident only after 2weeks. Amygdalin exhibits significant antitumor activity in both castration-sensitive and castration-resistant PCa cell lines and merits further evaluation for therapeutic purposes. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Delayed cell cycle pathway modulation facilitates recovery after spinal cord injury

    Science.gov (United States)

    Wu, Junfang; Stoica, Bogdan A.; Dinizo, Michael; Pajoohesh-Ganji, Ahdeah; Piao, Chunshu; Faden, Alan I.

    2012-01-01

    Traumatic spinal cord injury (SCI) causes tissue loss and associated neurological dysfunction through mechanical damage and secondary biochemical and physiological responses. We have previously described the pathobiological role of cell cycle pathways following rat contusion SCI by examining the effects of early intrathecal cell cycle inhibitor treatment initiation or gene knockout on secondary injury. Here, we delineate changes in cell cycle pathway activation following SCI and examine the effects of delayed (24 h) systemic administration of flavopiridol, an inhibitor of major cyclin-dependent kinases (CDKs), on functional recovery and histopathology in a rat SCI contusion model. Immunoblot analysis demonstrated a marked upregulation of cell cycle-related proteins, including pRb, cyclin D1, CDK4, E2F1 and PCNA, at various time points following SCI, along with downregulation of the endogenous CDK inhibitor p27. Treatment with flavopiridol reduced induction of cell cycle proteins and increased p27 expression in the injured spinal cord. Functional recovery was significantly improved after SCI from day 7 through day 28. Treatment significantly reduced lesion volume and the number of Iba-1+ microglia in the preserved tissue and increased the myelinated area of spared white matter as well as the number of CC1+ oligodendrocytes. Furthermore, flavopiridol attenuated expression of Iba-1 and glactin-3, associated with microglial activation and astrocytic reactivity by reduction of GFAP, NG2, and CHL1 expression. Our current study supports the role of cell cycle activation in the pathophysiology of SCI and by using a clinically relevant treatment model, provides further support for the therapeutic potential of cell cycle inhibitors in the treatment of human SCI. PMID:22510563

  10. Tumor Regression and Delayed Onset Toxicity Following B7-H4 CAR T Cell Therapy

    Science.gov (United States)

    Smith, Jenessa B; Lanitis, Evripidis; Dangaj, Denarda; Buza, Elizabeth; Poussin, Mathilde; Stashwick, Caitlin; Scholler, Nathalie; Powell, Daniel J

    2016-01-01

    B7-H4 protein is frequently overexpressed in ovarian cancer. Here, we engineered T cells with novel B7-H4-specific chimeric antigen receptors (CARs) that recognized both human and murine B7-H4 to test the hypothesis that B7-H4 CAR T cell therapy can be applied safely in preclinical models. B7-H4 CAR T cells specifically secreted IFN-γ and lysed B7-H4(+) targets. In vivo, B7-H4 CAR T cells displayed antitumor reactivity against B7-H4(+) human ovarian tumor xenografts. Unexpectedly, B7-H4 CAR T cell treatment reproducibly showed delayed, lethal toxicity 6–8 weeks after therapy. Comprehensive assessment of murine B7-H4 protein distribution uncovered expression in ductal and mucosal epithelial cells in normal tissues. Postmortem analysis revealed the presence of widespread histologic lesions that correlated with B7-H4(+) expression, and were inconsistent with graft versus host disease. Lastly, expression patterns of B7-H4 protein in normal human tissue were comparable to distribution in mice, advancing our understanding of B7-H4. We conclude that B7-H4 CAR therapy mediates control of cancer outgrowth. However, long-term engraftment of B7-H4 CAR T cells mediates lethal, off-tumor toxicity that is likely due to wide expression of B7-H4 in healthy mouse organs. This model system provides a unique opportunity for preclinical evaluation of safety approaches that limit CAR-mediated toxicity after tumor destruction in vivo. PMID:27439899

  11. Detection of Special Nuclear Material from Delayed Neutron Emission Induced by a Dual-Particle Monoenergetic Source

    Energy Technology Data Exchange (ETDEWEB)

    Mayer, Michael F.; Nattress, J.; Jovanovic, I

    2016-06-30

    Detection of unique signatures of special nuclear materials is critical for their interdiction in a variety of nuclear security and nonproliferation scenarios. We report on the observation of delayed neutrons from fission of uranium induced in dual-particle active interrogation based on the 11B(d,n gamma)12C nuclear reaction. Majority of the fissions are attributed to fast fission induced by the incident quasi-monoenergetic neutrons. A Li-doped glass–polymer composite scintillation neutron detector, which displays excellent neutron/γ discrimination at low energies, was used in the measurements, along with a recoil-based liquid scintillation detector. Time- dependent buildup and decay of delayed neutron emission from 238U were measured between the interrogating beam pulses and after the interrogating beam was turned off, respectively. Characteristic buildup and decay time profiles were compared to the common parametrization into six delayed neutron groups, finding a good agreement between the measurement and nuclear data. This method is promising for detecting fissile and fissionable materials in cargo scanning applications and can be readily integrated with transmission radiography using low-energy nuclear reaction sources.

  12. Detection of special nuclear material from delayed neutron emission induced by a dual-particle monoenergetic source

    Energy Technology Data Exchange (ETDEWEB)

    Mayer, M. [Department of Mechanical and Nuclear Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802 (United States); Nattress, J.; Jovanovic, I., E-mail: ijov@umich.edu [Department of Nuclear Engineering and Radiological Sciences, University of Michigan, Ann Arbor, Michigan 48109 (United States)

    2016-06-27

    Detection of unique signatures of special nuclear materials is critical for their interdiction in a variety of nuclear security and nonproliferation scenarios. We report on the observation of delayed neutrons from fission of uranium induced in dual-particle active interrogation based on the {sup 11}B(d,n γ){sup 12}C nuclear reaction. Majority of the fissions are attributed to fast fission induced by the incident quasi-monoenergetic neutrons. A Li-doped glass–polymer composite scintillation neutron detector, which displays excellent neutron/γ discrimination at low energies, was used in the measurements, along with a recoil-based liquid scintillation detector. Time-dependent buildup and decay of delayed neutron emission from {sup 238}U were measured between the interrogating beam pulses and after the interrogating beam was turned off, respectively. Characteristic buildup and decay time profiles were compared to the common parametrization into six delayed neutron groups, finding a good agreement between the measurement and nuclear data. This method is promising for detecting fissile and fissionable materials in cargo scanning applications and can be readily integrated with transmission radiography using low-energy nuclear reaction sources.

  13. The singlet-oxygen-sensitized delayed fluorescence in mammalian cells: a time-resolved microscopy approach.

    Science.gov (United States)

    Scholz, Marek; Biehl, Anna-Louisa; Dědic, Roman; Hála, Jan

    2015-04-01

    The present work provides a proof-of-concept that the singlet oxygen-sensitized delayed fluorescence (SOSDF) can be detected from individual living mammalian cells in a time-resolved microscopy experiment. To this end, 3T3 mouse fibroblasts incubated with 100 μM TPPS4 or TMPyP were used and the microsecond kinetics of the delayed fluorescence (DF) were recorded. The analysis revealed that SOSDF is the major component of the overall DF signal. The microscopy approach enables precise control of experimental conditions - the DF kinetics are clearly influenced by the presence of the (1)O2 quencher (sodium azide), H2O/D2O exchange, and the oxygen concentration. Analysis of SOSDF kinetics, which was reconstructed as a difference DF kinetics between the unquenched and the NaN3-quenched samples, provides a cellular (1)O2 lifetime of τΔ = 1-2 μs and a TPPS4 triplet lifetime of τT = 22 ± 5 μs in agreement with previously published values. The short SOSDF acquisition times, typically in the range of tens of seconds, enable us to study the dynamic cellular processes. It is shown that SOSDF lifetimes increase during PDT-like treatment, which may provide valuable information about changes of the intracellular microenvironment. SOSDF is proposed and evaluated as an alternative tool for (1)O2 detection in biological systems.

  14. Impaired immune evasion in HIV through intracellular delays and multiple infection of cells

    Science.gov (United States)

    Althaus, Christian L.; De Boer, Rob J.

    2012-01-01

    With its high mutation rate, HIV is capable of escape from recognition, suppression and/or killing by CD8+ cytotoxic T lymphocytes (CTLs). The rate at which escape variants replace each other can give insights into the selective pressure imposed by single CTL clones. We investigate the effects of specific characteristics of the HIV life cycle on the dynamics of immune escape. First, it has been found that cells in HIV-infected patients can carry multiple copies of proviruses. To investigate how this process affects the emergence of immune escape, we develop a mathematical model of HIV dynamics with multiple infections of cells. Increasing the frequency of multiple-infected cells delays the appearance of immune escape variants, slows down the rate at which they replace the wild-type variant and can even prevent escape variants from taking over the quasi-species. Second, we study the effect of the intracellular eclipse phase on the rate of escape and show that escape rates are expected to be slower than previously anticipated. In summary, slow escape rates do not necessarily imply inefficient CTL-mediated killing of HIV-infected cells, but are at least partly a result of the specific characteristics of the viral life cycle. PMID:22492063

  15. Induced pluripotent stem cell lines derived from human somatic cells.

    Science.gov (United States)

    Yu, Junying; Vodyanik, Maxim A; Smuga-Otto, Kim; Antosiewicz-Bourget, Jessica; Frane, Jennifer L; Tian, Shulan; Nie, Jeff; Jonsdottir, Gudrun A; Ruotti, Victor; Stewart, Ron; Slukvin, Igor I; Thomson, James A

    2007-12-21

    Somatic cell nuclear transfer allows trans-acting factors present in the mammalian oocyte to reprogram somatic cell nuclei to an undifferentiated state. We show that four factors (OCT4, SOX2, NANOG, and LIN28) are sufficient to reprogram human somatic cells to pluripotent stem cells that exhibit the essential characteristics of embryonic stem (ES) cells. These induced pluripotent human stem cells have normal karyotypes, express telomerase activity, express cell surface markers and genes that characterize human ES cells, and maintain the developmental potential to differentiate into advanced derivatives of all three primary germ layers. Such induced pluripotent human cell lines should be useful in the production of new disease models and in drug development, as well as for applications in transplantation medicine, once technical limitations (for example, mutation through viral integration) are eliminated.

  16. Involvement of substance P in the development of cisplatin-induced acute and delayed pica in rats.

    Science.gov (United States)

    Yamamoto, Kouichi; Asano, Keiko; Tasaka, Ayana; Ogura, Yuko; Kim, Seikou; Ito, Yui; Yamatodani, Atsushi

    2014-06-01

    Although substance P (SP) and neurokinin NK1 receptors have been reported to be involved in cisplatin-induced acute and delayed emesis, their precise roles remain unclear. Pica, the consumption of non-nutrient materials such as kaolin in rats, can be used as a model of nausea in humans. We investigated the time-dependent changes in cisplatin-induced pica and the involvement of SP and NK1 receptors in this behaviour. Rats were administered cisplatin with or without a daily injection of a 5-HT3 receptor antagonist (granisetron) or an NK1 receptor antagonist (aprepitant), and kaolin intake was then monitored for 5 days. The effects of granisetron on the cisplatin-induced expression of preprotachykinin-A (PPT-A) mRNA, which encodes mainly for SP, and on SP release in the medulla, measured by in vivo brain microdialysis, were also investigated. Cisplatin induced pica within 8 h of its administration that continued for 5 days. Granisetron inhibited the acute phase (day 1), but not the delayed phase (days 2-5), of pica, whereas aprepitant abolished both phases. Within 24 h of the injection of cisplatin, PPT-A mRNA expression and SP release in the medulla were significantly increased; these findings lasted during the observation period and were inhibited by granisetron for up to 24 h. The profiles of cisplatin-induced pica in rats are similar to clinical findings for cisplatin-induced emesis in humans, and we showed that SP production in the medulla and activation of NK1 receptors are involved in this cisplatin-induced pica. © 2014 The British Pharmacological Society.

  17. Small margin (2 mm) excision of peri-ocular basal cell carcinoma with delayed repair.

    Science.gov (United States)

    David, D B.; Gimblett, M L.; Potts, M J.; Harrad, R A.

    1999-03-01

    Successful surgical treatment of peri-ocular basal cell carcinomas requires complete excision. Mohs' micrographic surgery achieves this, but is not readily available in all hospitals. The standard 3-4 mm margin does not guarantee complete excision and histology is often not available until after a repair has been undertaken. The 3-4 mm margin has evolved to deal with all forms of BCC. In our opinion, this margin is unnecessarily large for nodular/ulcerative BCC. We report our interim results of excision of localised BCCs using a 2 mm margin in conjunction with a delayed repair following confirmation of histological clearance. Thirty-one patients were treated in this manner; there have been no recurrences after an average follow-up period of 36 months (range 24-57 months).

  18. Can Full Duplex Boost Throughput and Delay of 5G Ultra-Dense Small Cell Networks?

    DEFF Research Database (Denmark)

    Gatnau, Marta; Berardinelli, Gilberto; Mahmood, Nurul Huda

    2016-01-01

    Given the recent advances in system and antenna design, practical implementation of full duplex (FD) communication is becoming increasingly feasible. In this paper, the potential of FD in enhancing the performance of 5th generation (5G) ultra-dense small cell networks is investigated. The goal...... is to understand whether FD is able to boost the system performance from a throughput and delay perspective. The impact of having symmetric and asymmetric finite buffer traffic is studied for two types of FD: when only the base station is FD capable, and when both the user equipment and base station are FD nodes....... System level results indicate that there is a trade-off between multiple-input multiple-output (MIMO) spatial multiplexing and FD in achieving the optimal system performance. Moreover, results show that FD may be useful for asymmetric traffic applications where the lightly loaded link requires high level...

  19. HIV transcription is induced in dying cells

    Energy Technology Data Exchange (ETDEWEB)

    Woloschak, G.E.; Chang-Liu, Chin-Mei [Argonne National Lab., IL (United States); Schreck, S. [Argonne National Lab., IL (United States)]|[Univ. of South Carolina, Columbia, SC (United States). Dept. of Chemistry

    1995-06-01

    Using HeLa cells stably transfected with an HIV-LTR-CAT construct, we demonstrated a peak in CAT induction that occurs in viable (but not necessarily cell-division-competent) cells 24 h following exposure to some cell-killing agents. {gamma} rays were the only cell-killing agent which did not induce HIV transcription; this can be attributed to the fact that {gamma}-ray-induced apoptotic death requires functional p53, which is not present in HeLa cells. For all other agents, HIV-LTR induction was dose-dependent and correlated with the amount of cell killing that occurred in the culture. 14 refs., 4 figs., 1 tab.

  20. Luteal cell steroidogenesis in relation to delayed embryonic development in the Indian short-nosed fruit bat, Cynopterus sphinx.

    Science.gov (United States)

    Meenakumari, Karukayil J; Banerjee, Arnab; Krishna, Amitabh

    2009-01-01

    The primary aim of this study was to determine the possible cause of slow or delayed embryonic development in Cynopterus sphinx by investigating morphological and steroidogenic changes in the corpus luteum (CL) and circulating hormone concentrations during two pregnancies of a year. This species showed delayed post-implantational embryonic development during gastrulation of the first pregnancy. Morphological features of the CL showed normal luteinization during both pregnancies. The CL did not change significantly in luteal cell size during the delay period of the first pregnancy as compared with the second pregnancy. The circulating progesterone and 17beta-estradiol concentrations were significantly lower during the period of delayed embryonic development as compared with the same stage of embryonic development during the second pregnancy. We also showed a marked decline in the activity of 3beta-hydroxysteroid dehydrogenase, P450 side chain cleavage enzyme, and steroidogenic acute regulatory peptide in the CL during the delay period. This may cause low circulating progesterone and estradiol synthesis and consequently delay embryonic development. What causes the decrease in steroidogenic factors in the CL during the period of delayed development in C. sphinx is under investigation.

  1. Hematopoietic cell differentiation from embryonic and induced pluripotent stem cells

    Science.gov (United States)

    2013-01-01

    Pluripotent stem cells, both embryonic stem cells and induced pluripotent stem cells, are undifferentiated cells that can self-renew and potentially differentiate into all hematopoietic lineages, such as hematopoietic stem cells (HSCs), hematopoietic progenitor cells and mature hematopoietic cells in the presence of a suitable culture system. Establishment of pluripotent stem cells provides a comprehensive model to study early hematopoietic development and has emerged as a powerful research tool to explore regenerative medicine. Nowadays, HSC transplantation and hematopoietic cell transfusion have successfully cured some patients, especially in malignant hematological diseases. Owing to a shortage of donors and a limited number of the cells, hematopoietic cell induction from pluripotent stem cells has been regarded as an alternative source of HSCs and mature hematopoietic cells for intended therapeutic purposes. Pluripotent stem cells are therefore extensively utilized to facilitate better understanding in hematopoietic development by recapitulating embryonic development in vivo, in which efficient strategies can be easily designed and deployed for the generation of hematopoietic lineages in vitro. We hereby review the current progress of hematopoietic cell induction from embryonic stem/induced pluripotent stem cells. PMID:23796405

  2. Cell penetrable-mouse forkhead box P3 suppresses type 1 T helper cell-mediated immunity in a murine model of delayed-type hypersensitivity.

    Science.gov (United States)

    Liu, Xia; Wang, Jun; Wang, Hui; Zhou, Chen; Yu, Qihong; Yin, Lei; Wu, Weijiang; Xia, Sheng; Shao, Qixiang

    2017-02-01

    Forkhead box P3 (FOXP3), which is a transcription factor, has a primary role in the development and function of regulatory T cells, and thus contributes to homeostasis of the immune system. A previous study generated a cell-permeable fusion protein of mouse FOXP3 conjugated to a protein transduction domain (PTD-mFOXP3) that successfully blocked differentiation of type 17 T helper cells in vitro and alleviated experimental arthritis in mice. In the present study, the role of PTD-mFOXP3 in type 1 T helper (Th1) cell-mediated immunity was investigated and the possible mechanisms for its effects were explored. Under Th1 polarization conditions, cluster of differentiation 4(+) T cells were treated with PTD-mFOXP3 and analyzed by flow cytometry in vitro, which revealed that PTD-mFOXP3 blocked Th1 differentiation in vitro. Mice models of delayed type hypersensitivity (DTH) reactions were generated by subcutaneous sensitization and challenge with ovalbumin (OVA) to the ears of mice. PTD-mFOXP3, which was administered via local subcutaneous injection, significantly reduced DTH-induced inflammation, including ear swelling (ear swelling, P<0.001; pinnae weight, P<0.05 or P<0.01 with 0.25 and 1.25 mg/kg PTD-mFOXP3, respectively), infiltration of T cells, and expression of interferon-γ at local inflammatory sites (mRNA level P<0.05) compared with the DTH group. The results of the present study demonstrated that PTD-mFOXP3 may attenuate DTH reactions by suppressing the infiltration and activity of Th1 cells.

  3. High pressure processing treatment prevents embryonation of eggs of Trichuris vulpis and Ascaris suum and induces delay in development of eggs.

    Science.gov (United States)

    Rosypal, Alexa C; Zajac, Anne M; Flick, George J; Bowman, Dwight D; Lindsay, David S

    2011-09-27

    High hydrostatic pressure processing (HPP) is an effective non-thermal treatment used to inactivate pathogens from a variety of food and food products. It has been extensively examined using prokaryotic organisms and protozoan's but has had limited study on metazoans. Treatment using HPP has been shown to be effective in inactivating nematode larvae in food and preventing embryonation of Ascaris suum eggs. We conducted experiments using eggs of the canine whipworm Trichuris vulpis collected from naturally infected dogs and A. suum eggs from naturally infected pigs. We observed a delay in development of eggs of T. vulpis in a preliminary experiment and conducted 2 experiments to test the hypothesis that appropriate HPP levels can induce a delay in embryonation of nematode eggs. In experiment 1, nonembryonated T. vulpis eggs in tap water were packaged in sealable bags and exposed to 138-600 megapascals (MPa; 1 MPa=10 atm=147 psi) for 60s in a commercial HPP unit. In a second experiment, nonembryonated eggs of A. suum were exposed to 138-600 MPa and treated for 60s in the same commercial HPP unit. Embyronation of T. vulpis eggs was delayed by 4 and 5 days for eggs treated with 207 and 241 MPa but eventually eggs developed and the numbers of embryonated eggs was similar to controls on day 55. Embryonation of T. vulpis eggs treated with 345 or 350 MPa was delayed by 9 days and never reached more than 5% of eggs embryonated. On day 55 post treatment, 95% of control nontreated T. vulpis eggs were embryonated, 100-65% of eggs treated with 138-276 MPa were embryonated, a maximum of 5% of eggs treated with 345-350 MPa were embryonated, and 0% of eggs treated with ≥ 400 MPa were embryonated. T. vulpis eggs treated with ≥ 400 MPa did not undergo cell division. Embryrnation of A. suum eggs was delayed by 4, 10, and 16 days for eggs treated with 207, 241, and 250MPa, respectively, compared to nontreated control eggs. A. suum eggs treated with 207 MPa eventually embryonated

  4. Detailed Analysis of Apoptosis and Delayed Luminescence of Human Leukemia Jurkat T Cells after Proton Irradiation and Treatments with Oxidant Agents and Flavonoids

    Science.gov (United States)

    Baran, Irina; Ganea, Constanta; Privitera, Simona; Scordino, Agata; Barresi, Vincenza; Musumeci, Francesco; Mocanu, Maria Magdalena; Condorelli, Daniele F.; Ursu, Ioan; Grasso, Rosaria; Gulino, Marisa; Garaiman, Alexandru; Musso, Nicolò; Cirrone, Giuseppe A. Pablo; Cuttone, Giacomo

    2012-01-01

    Following previous work, we investigated in more detail the relationship between apoptosis and delayed luminescence (DL) in human leukemia Jurkat T cells under a wide variety of treatments. We used menadione and hydrogen peroxide to induce oxidative stress and two flavonoids, quercetin, and epigallocatechin gallate, applied alone or in combination with menadione or H2O2. 62 MeV proton beams were used to irradiate cells under a uniform dose of 2 or 10 Gy, respectively. We assessed apoptosis, cell cycle distributions, and DL. Menadione, H2O2 and quercetin were potent inducers of apoptosis and DL inhibitors. Quercetin decreased clonogenic survival and the NAD(P)H level in a dose-dependent manner. Proton irradiation with 2 Gy but not 10 Gy increased the apoptotic rate. However, both doses induced a substantial G2/M arrest. Quercetin reduced apoptosis and prolonged the G2/M arrest induced by radiation. DL spectroscopy indicated that proton irradiation disrupted the electron flow within Complex I of the mitochondrial respiratory chain, thus explaining the massive necrosis induced by 10 Gy of protons and also suggested an equivalent action of menadione and quercetin at the level of the Fe/S center N2, which may be mediated by their binding to a common site within Complex I, probably the rotenone-binding site. PMID:22829956

  5. Detailed Analysis of Apoptosis and Delayed Luminescence of Human Leukemia Jurkat T Cells after Proton Irradiation and Treatments with Oxidant Agents and Flavonoids

    Directory of Open Access Journals (Sweden)

    Irina Baran

    2012-01-01

    Full Text Available Following previous work, we investigated in more detail the relationship between apoptosis and delayed luminescence (DL in human leukemia Jurkat T cells under a wide variety of treatments. We used menadione and hydrogen peroxide to induce oxidative stress and two flavonoids, quercetin, and epigallocatechin gallate, applied alone or in combination with menadione or H2O2. 62 MeV proton beams were used to irradiate cells under a uniform dose of 2 or 10 Gy, respectively. We assessed apoptosis, cell cycle distributions, and DL. Menadione, H2O2 and quercetin were potent inducers of apoptosis and DL inhibitors. Quercetin decreased clonogenic survival and the NAD(PH level in a dose-dependent manner. Proton irradiation with 2 Gy but not 10 Gy increased the apoptotic rate. However, both doses induced a substantial G2/M arrest. Quercetin reduced apoptosis and prolonged the G2/M arrest induced by radiation. DL spectroscopy indicated that proton irradiation disrupted the electron flow within Complex I of the mitochondrial respiratory chain, thus explaining the massive necrosis induced by 10 Gy of protons and also suggested an equivalent action of menadione and quercetin at the level of the Fe/S center N2, which may be mediated by their binding to a common site within Complex I, probably the rotenone-binding site.

  6. Induced Pluripotent Stem Cells from Nonhuman Primates.

    Science.gov (United States)

    Mishra, Anuja; Qiu, Zhifang; Farnsworth, Steven L; Hemmi, Jacob J; Li, Miao; Pickering, Alexander V; Hornsby, Peter J

    2016-01-01

    Induced pluripotent stem cells from nonhuman primates (NHPs) have unique roles in cell biology and regenerative medicine. Because of the relatedness of NHPs to humans, NHP iPS cells can serve as a source of differentiated derivatives that can be used to address important questions in the comparative biology of primates. Additionally, when used as a source of cells for regenerative medicine, NHP iPS cells serve an invaluable role in translational experiments in cell therapy. Reprogramming of NHP somatic cells requires the same conditions as previously established for human cells. However, throughout the process, a variety of modifications to the human cell protocols must be made to accommodate significant species differences.

  7. Radiation-induced cleavage delay in mouse zygotes fertilized in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Yamada, T.; Takiuchi, H.; Okuyama, K.; Ohyama, H.

    1986-05-01

    Recently a complete culture system for the in vitro fertilized mouse eggs to the expanded blastocyst. With such an in vitro fertilization system, zygotes can be selected at a known stage, irradiated at a precise time after fertilization and their development observed periodically through the expanded blastocyst stage. In the present study, the authors examined the quantitative correlation between the first cleavage delay and the radiation dose using the same experimental system. The mouse zygotes fertilized in vitro (BC3F/sub 1/ eggs x ICR sperm) were irradiated with X-rays (10-100 R) at the pronuclear stage (4 hr after insemination). The zygotes were observed periodically at 30 min intervals from 16 to 24 hr after insemination. The results show that the first cleavage was delayed depending linearly on the X-ray dose.

  8. Multi-walled carbon nanotubes impair Kv4.2/4.3 channel activities, delay membrane repolarization and induce bradyarrhythmias in the rat.

    Directory of Open Access Journals (Sweden)

    Xiao-Qiu Tan

    Full Text Available PURPOSE: The potential hazardous effects of multi-walled carbon nanotubes (MWCNTs on cardiac electrophysiology are seldom evaluated. This study aimed to investigate the impacts of MWCNTs on the Kv4/Ito channel, action potential and heart rhythm and the underlying mechanisms. METHODS: HEK293 cells were engineered to express Kv4.2 or Kv4.3 with or without KChIP2 expression. A series of approaches were introduced to analyze the effects of MWCNTs on Kv4/Ito channel kinetics, current densities, expression and trafficking. Transmission electron microscopy was performed to observe the internalization of MWCNTs in HEK293 cells and rat cardiomyocytes. Current clamp was employed to record the action potentials of isolated rat cardiomyocytes. Surface ECG and epicardial monophasic action potentials were recorded to monitor heart rhythm in rats in vivo. Vagal nerve discharge monitoring and H&E staining were also performed. RESULTS: Induction of MWCNTs into the cytosole through pipette solution soon accelerated the decay of IKv4 in HEK293 cells expressing Kv4.2/4.3 and KChIP2, and promoted the recovery from inactivation when Kv4.2 or Kv4.3 was expressed alone. Longer exposure (6 h to MWCNTs decreased the IKv4.2 density, Kv4.2/Kv4.3 (but not KChIP2 expression and trafficking towards the plasma membrane in HEK293 cells. In acutely isolated rat ventricular myocytes, pipette MWCNTs also quickly accelerated the decay of IKv4 and prolonged the action potential duration (APD. Intravenous infusion of MWCNTs (2 mg/rat induced atrioventricular (AV block and even cardiac asystole. No tachyarrhythmia was observed after MWCNTs administration. MWCNTs did not cause coronary clot but induced myocardial inflammation and increased vagus discharge. CONCLUSIONS: MWCNTs suppress Kv4/Ito channel activities likely at the intracellular side of plasma membrane, delay membrane repolarization and induce bradyarrhythmia. The delayed repolarization, increased vagus output and focal

  9. Emergent bimodality and switch induced by time delays and noises in a synthetic gene circuit

    Science.gov (United States)

    Zhang, Chun; Du, Liping; Xie, Qingshuang; Wang, Tonghuan; Zeng, Chunhua; Nie, Linru; Duan, Weilong; Jia, Zhenglin; Wang, Canjun

    2017-10-01

    Based on the kinetic model for obtaining emergent bistability proposed by Tan et al. (2009), the effects of the fluctuations of protein synthesis rate and maximum dilution rate, the cross-correlation between two noises, and the time delay and the strength of the feedback loop in the synthetic gene circuit have been investigated through theoretical analysis and numerical simulation. Our results show that: (i) the fluctuations of protein synthesis rate and maximum dilution rate enhance the emergent bimodality of the probability distribution phenomenon, while the cross-correlation between two noises(λ), the time delay(τ) and the strength of the feedback loop(K) cause it to disappear; and (ii) the mean first passage time(MFPT) as functions of the noise strengths exhibits a maximum, this maximum is called noise-delayed switching (NDS) of the high concentration state. The NDS phenomenon shows that the noise can modify the stability of a metastable system in a counterintuitive way, the system remains in the metastable state for a longer time compared to the deterministic case. And the τ and the K enhances the stability of the ON state. The physical mechanisms for the switch between the ON and OFF states can be explained from the point of view of the effective potential.

  10. Angular momentum-induced delays in solid-state photoemission enhanced by intra-atomic interactions.

    Science.gov (United States)

    Siek, Fabian; Neb, Sergej; Bartz, Peter; Hensen, Matthias; Strüber, Christian; Fiechter, Sebastian; Torrent-Sucarrat, Miquel; Silkin, Vyacheslav M; Krasovskii, Eugene E; Kabachnik, Nikolay M; Fritzsche, Stephan; Muiño, Ricardo Díez; Echenique, Pedro M; Kazansky, Andrey K; Müller, Norbert; Pfeiffer, Walter; Heinzmann, Ulrich

    2017-09-22

    Attosecond time-resolved photoemission spectroscopy reveals that photoemission from solids is not yet fully understood. The relative emission delays between four photoemission channels measured for the van der Waals crystal tungsten diselenide (WSe 2 ) can only be explained by accounting for both propagation and intra-atomic delays. The intra-atomic delay depends on the angular momentum of the initial localized state and is determined by intra-atomic interactions. For the studied case of WSe 2 , the photoemission events are time ordered with rising initial-state angular momentum. Including intra-atomic electron-electron interaction and angular momentum of the initial localized state yields excellent agreement between theory and experiment. This has required a revision of existing models for solid-state photoemission, and thus, attosecond time-resolved photoemission from solids provides important benchmarks for improved future photoemission models. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  11. HDAC8 Inhibition Blocks SMC3 Deacetylation and Delays Cell Cycle Progression without Affecting Cohesin-dependent Transcription in MCF7 Cancer Cells.

    Science.gov (United States)

    Dasgupta, Tanushree; Antony, Jisha; Braithwaite, Antony W; Horsfield, Julia A

    2016-06-10

    Cohesin, a multi-subunit protein complex involved in chromosome organization, is frequently mutated or aberrantly expressed in cancer. Multiple functions of cohesin, including cell division and gene expression, highlight its potential as a novel therapeutic target. The SMC3 subunit of cohesin is acetylated (ac) during S phase to establish cohesion between replicated chromosomes. Following anaphase, ac-SMC3 is deacetylated by HDAC8. Reversal of SMC3 acetylation is imperative for recycling cohesin so that it can be reloaded in interphase for both non-mitotic and mitotic functions. We blocked deacetylation of ac-SMC3 using an HDAC8-specific inhibitor PCI-34051 in MCF7 breast cancer cells, and examined the effects on transcription of cohesin-dependent genes that respond to estrogen. HDAC8 inhibition led to accumulation of ac-SMC3 as expected, but surprisingly, had no influence on the transcription of estrogen-responsive genes that are altered by siRNA targeting of RAD21 or SMC3. Knockdown of RAD21 altered estrogen receptor α (ER) recruitment at SOX4 and IL20, and affected transcription of these genes, while HDAC8 inhibition did not. Rather, inhibition of HDAC8 delayed cell cycle progression, suppressed proliferation and induced apoptosis in a concentration-dependent manner. We conclude that HDAC8 inhibition does not change the estrogen-specific transcriptional role of cohesin in MCF7 cells, but instead, compromises cell cycle progression and cell survival. Our results argue that candidate inhibitors of cohesin function may differ in their effects depending on the cellular genotype and should be thoroughly tested for predicted effects on cohesin's mechanistic roles. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. The business of exploiting induced pluripotent stem cells.

    Science.gov (United States)

    Prescott, Catherine

    2011-08-12

    Induced pluripotent stem cells (iPS cells) can be exploited for both research and clinical applications. The first part of this review seeks to provide an understanding of the financial drivers and key elements of a successful business strategy that underpin a company focused on developing iPS-related products and services targeted at the research market. The latter part of the review highlights some of the reasons as to why the reprogramming of somatic cells is currently being used to develop cell-based models to screen for small molecules with drug-like properties rather than to develop cell-based regenerative medicines per se. The latter may be used to repair or replace a patient's damaged cells and thereby have the potential to 'cure' a disease and, in doing so, prevent or delay the onset of associated medical conditions. However, the cost of an expensive regenerative medicine and time to accrue any benefit linked to a decrease in co-morbidity expenditure may not outweigh the benefit for a healthcare community that has finite resources. The implications of this are discussed together with evidence that the UK National Institute for Health and Clinical Excellence (NICE) and the National Health Service (NHS) have established a precedent for a cost-sharing strategy with the pharmaceutical industry.

  13. Delayed IFN response differentiates replication of West Nile virus and Japanese encephalitis virus in human neuroblastoma and glioblastoma cells.

    Science.gov (United States)

    Takamatsu, Yuki; Uchida, Leo; Morita, Kouichi

    2015-08-01

    West Nile virus (WNV) and Japanese encephalitis virus (JEV) are important causes of human encephalitis cases, which result in a high mortality ratio and neurological sequelae after recovery. Understanding the mechanism of neuropathogenicity in these viral infections is important for the development of specific antiviral therapy. Here, we focused on human-derived neuronal and glial cells to understand the cellular responses against WNV and JEV infection. It was demonstrated that early IFN-β induction regulated virus replication in glioblastoma tbl98G cells, whereas delayed IFN-β induction resulted in efficient virus replication in neuroblastoma SK-N-SH cells. Moreover, the concealing of viral dsRNA in the intracellular membrane resulted in the delayed IFN response in SK-N-SH cells. These results, which showed different IFN responses between human neuronal and glial cells after WNV or JEV infection, are expected to contribute to our understanding of the molecular mechanisms for neuropathology in these viral infections.

  14. To prevent the occurrence of black water agglomerate through delaying decomposition of cyanobacterial bloom biomass by sediment microbial fuel cell.

    Science.gov (United States)

    Zhou, Yan-Li; Jiang, He-Long; Cai, Hai-Yuan

    2015-04-28

    Settlement of cyanobacterial bloom biomass (CBB) into sediments in eutrophic lakes often induced the occurrence of black water agglomerate and then water quality deterioration. This study investigated the effect of sediment microbial fuel cell (SMFC) on CBB removal in sediments and related water pollution. Sediment bulking and subsequent black water from decomposition of settled CBB happened without SMFC, but were not observed over 100-day experiments with SMFC employment. While CBB in sediments improved power production from SMFC, the removal efficiency of organic matters in CBB-amended sediments with SMFC was significantly lower than that without SMFC. Pyrosequencing analysis showed higher abundances of the fermentative Clostridium and acetoclastic methanogen in CBB-amended bulk sediments without SMFC than with SMFC at the end of experiments. Obviously, SMFC operation changed the microbial community in CBB-amended sediments, and delayed the CBB degradation against sediment bulking. Thus, SMFC could be potentially applied as pollution prevention in CBB-settled and sensitive zones in shallow lakes. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Delayed neuronal cell death in brainstem after transient brainstem ischemia in gerbils

    Directory of Open Access Journals (Sweden)

    Hakuba Nobuhiro

    2010-09-01

    Full Text Available Abstract Background Because of the lack of reproducible brainstem ischemia models in rodents, the temporal profile of ischemic lesions in the brainstem after transient brainstem ischemia has not been evaluated intensively. Previously, we produced a reproducible brainstem ischemia model of Mongolian gerbils. Here, we showed the temporal profile of ischemic lesions after transient brainstem ischemia. Results Brainstem ischemia was produced by occlusion of the bilateral vertebral arteries just before their entry into the transverse foramina of the cervical vertebrae of Mongolian gerbils. Animals were subjected to brainstem ischemia for 15 min, and then reperfused for 0 d (just after ischemia, 1 d, 3 d and 7 d (n = 4 in each group. Sham-operated animals (n = 4 were used as control. After deep anesthesia, the gerbils were perfused with fixative for immunohistochemical investigation. Ischemic lesions were detected by immunostaining for microtubule-associated protein 2 (MAP2. Just after 15-min brainstem ischemia, ischemic lesions were detected in the lateral vestibular nucleus and the ventral part of the spinal trigeminal nucleus, and these ischemic lesions disappeared one day after reperfusion in all animals examined. However, 3 days and 7 days after reperfusion, ischemic lesions appeared again and clusters of ionized calcium-binding adapter molecule-1(IBA-1-positive cells were detected in the same areas in all animals. Conclusion These results suggest that delayed neuronal cell death took place in the brainstem after transient brainstem ischemia in gerbils.

  16. Lck is involved in interleukin-2 induced proliferation but not cell survival in human T cells through a MAP kinase-independent pathway

    DEFF Research Database (Denmark)

    Brockdorff, J; Nielsen, M; Kaltoft, K

    2000-01-01

    The role of Lck in IL-2-induced proliferation and cell survival is still controversial. Here, we show that the Src family kinase inhibitor, PP1, reduced the IL-2-induced proliferation of human T cells significantly without inhibiting the anti-apoptotic effect of IL-2. As Lck is the only Src family...... kinase activated upon IL-2 stimulation in T cells, this indicates that Lck is involved in IL-2-induced proliferation but not survival. IL-2-induced MAP kinase activation was only slightly inhibited by PP1, suggesting that Lck is not essential for IL-2-induced MAP kinase activation in human T cells. We...... found that an IL-2-sensitive, human mycosis fungoides-derived tumor T cell line is Lck negative, and that the IL-2-induced MAP kinase activation is comparable to non-cancerous T cells, although a little delayed in kinetics. An Lck expressing clone was established by transfecting Lck into mycosis...

  17. Plasma Rich in Growth Factors Induces Cell Proliferation, Migration, Differentiation, and Cell Survival of Adipose-Derived Stem Cells

    Directory of Open Access Journals (Sweden)

    Maravillas Mellado-López

    2017-01-01

    Full Text Available Adipose-derived stem cells (ASCs are a promising therapeutic alternative for tissue repair in various clinical applications. However, restrictive cell survival, differential tissue integration, and undirected cell differentiation after transplantation in a hostile microenvironment are complications that require refinement. Plasma rich in growth factors (PRGF from platelet-rich plasma favors human and canine ASC survival, proliferation, and delaying human ASC senescence and autophagocytosis in comparison with serum-containing cultures. In addition, canine and human-derived ASCs efficiently differentiate into osteocytes, adipocytes, or chondrocytes in the presence of PRGF. PRGF treatment induces phosphorylation of AKT preventing ASC death induced by lethal concentrations of hydrogen peroxide. Indeed, AKT inhibition abolished the PRGF apoptosis prevention in ASC exposed to 100 μM of hydrogen peroxide. Here, we show that canine ASCs respond to PRGF stimulus similarly to the human cells regarding cell survival and differentiation postulating the use of dogs as a suitable translational model. Overall, PRGF would be employed as a serum substitute for mesenchymal stem cell amplification to improve cell differentiation and as a preconditioning agent to prevent oxidative cell death.

  18. TNF-TNFR2/p75 Signaling Inhibits Early and Increases Delayed Nontargeted Effects in Bone Marrow-derived Endothelial Progenitor Cells*

    Science.gov (United States)

    Sasi, Sharath P.; Song, Jin; Park, Daniel; Enderling, Heiko; McDonald, J. Tyson; Gee, Hannah; Garrity, Brittany; Shtifman, Alexander; Yan, Xinhua; Walsh, Kenneth; Natarajan, Mohan; Kishore, Raj; Goukassian, David A.

    2014-01-01

    TNF-α, a pro-inflammatory cytokine, is highly expressed after being irradiated (IR) and is implicated in mediating radiobiological bystander responses (RBRs). Little is known about specific TNF receptors in regulating TNF-induced RBR in bone marrow-derived endothelial progenitor cells (BM-EPCs). Full body γ-IR WT BM-EPCs showed a biphasic response: slow decay of p-H2AX foci during the initial 24 h and increase between 24 h and 7 days post-IR, indicating a significant RBR in BM-EPCs in vivo. Individual TNF receptor (TNFR) signaling in RBR was evaluated in BM-EPCs from WT, TNFR1/p55KO, and TNFR2/p75KO mice, in vitro. Compared with WT, early RBR (1–5 h) were inhibited in p55KO and p75KO EPCs, whereas delayed RBR (3–5 days) were amplified in p55KO EPCs, suggesting a possible role for TNFR2/p75 signaling in delayed RBR. Neutralizing TNF in γ-IR conditioned media (CM) of WT and p55KO BM-EPCs largely abolished RBR in both cell types. ELISA protein profiling of WT and p55KO EPC γ-IR-CM over 5 days showed significant increases in several pro-inflammatory cytokines, including TNF-α, IL-1α (Interleukin-1 alpha), RANTES (regulated on activation, normal T cell expressed and secreted), and MCP-1. In vitro treatments with murine recombinant (rm) TNF-α and rmIL-1α, but not rmMCP-1 or rmRANTES, increased the formation of p-H2AX foci in nonirradiated p55KO EPCs. We conclude that TNF-TNFR2 signaling may induce RBR in naïve BM-EPCs and that blocking TNF-TNFR2 signaling may prevent delayed RBR in BM-EPCs, conceivably, in bone marrow milieu in general. PMID:24711449

  19. Vaccinium myrtillus extract prevents or delays the onset of diabetes--induced blood-retinal barrier breakdown.

    Science.gov (United States)

    Kim, Junghyun; Kim, Chan-Sik; Lee, Yun Mi; Sohn, Eunjin; Jo, Kyuhyung; Kim, Jin Sook

    2015-03-01

    Many dietary supplements have been sold through advertising their large number of beneficial effects. The aim of this study was to determine whether bilberries (Vaccinium myrtillus) help to prevent diabetes-induced retinal vascular dysfunction in vivo. V. myrtillus extract (VME; 100 mg/kg) was orally administered to streptozotocin-induced diabetic rats for 6 weeks. All diabetic rats exhibited hyperglycemia, and VME did not affect the blood glucose levels and body weight during the experiments. In the fluorescein-dextran angiography, the fluorescein leakage was significantly reduced in diabetic rats treated with VME. VME treatment also decreased markers of diabetic retinopathy, such as retinal vascular endothelial growth factor (VEGF) expression and degradation of zonula occludens-1, occludin and claudin-5 in diabetic rats. In conclusion, VME may prevent or delay the onset of early diabetic retinopathy. These findings have important implications for prevention of diabetic retinopathy using a dietary bilberry supplement.

  20. Inhibitory effect of ramosetron on corticotropin releasing factor- and soybean oil-induced delays in gastric emptying in rats.

    Science.gov (United States)

    Hirata, Takuya; Keto, Yoshihiro; Yamano, Mayumi; Yokoyama, Toshihide; Sengoku, Takanori; Seki, Nobuo

    2012-09-01

    Symptoms of functional dyspepsia (FD) are highly prevalent in patients with irritable bowel syndrome (IBS). However, the effects of therapeutic agents for IBS on the pathophysiology of FD are unclear. In this study, therefore, we examined the effects of ramosetron, a serotonin 5-HT(3) receptor antagonist, on corticotropin releasing factor (CRF)- and soybean oil-induced delays in gastric emptying of rats, in comparison with anti-diarrheal agent and spasmolytics. The involvement of 5-HT and the 5-HT(3) receptor in delayed gastric emptying was also evaluated. Corticotropin releasing factor was administered intravenously to rats 10min before oral administration of 0.05% phenol red solution, and the amount remaining in the stomach was measured after 30min. Soybean oil was administered orally with glass beads, and the number of residual beads in the stomach was counted 1h later. Both CRF and soybean oil inhibited gastric emptying dose-dependently. Ramosetron and itopride, a gastro-prokinetic agent, significantly reduced both CRF- and soybean oil-induced delays in gastric emptying, while an anti-diarrheal agent and spasmolytics aggravated them. Pretreatment with p-chlorophenylalanine for 2days to reduced the synthesis of endogenous 5-HT diminished the effects of both CRF and soybean oil on gastric emptying. A 5-HT(3) receptor agonist m-chlorophenylbiguanide suppressed gastric emptying of both phenol red and glass beads, and those effects were reversed by ramosetron. These results suggest that CRF and soybean oil suppress gastric emptying in rats by activating 5-HT(3) receptors, and that by antagonizing these receptors, ramosetron may ameliorate symptoms of FD in clinical settings. © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

  1. Cisplatin induces differentiation of breast cancer cells.

    Science.gov (United States)

    Prabhakaran, Praseetha; Hassiotou, Foteini; Blancafort, Pilar; Filgueira, Luis

    2013-01-01

    Breast tumors are heterogeneous including cells with stem cell properties and more differentiated cells. This heterogeneity is reflected into the molecular breast cancer subtypes. Breast cancer stem cells are resistant to chemotherapy, thus recent efforts are focusing on identifying treatments that shift them toward a more differentiated phenotype, making them more susceptible to chemotherapy. We examined whether the drug cisplatin induces differentiation in breast cancer cell lines that represent different breast cancer subtypes. We used three cell lines representing triple-negative breast cancers, BT-549 and MDA-MB-231 (claudin-low), and MDA-MB-468 (basal-like), along with estrogen and progesterone receptor positive MCF-7 cells (luminal). Cisplatin was applied at 2.5, 5, 10, and 20 μM, and cell viability and proliferation were measured using MTS and BrdU assays, respectively. The effect of cisplatin on the cellular hierarchy was examined by flow cytometry, immunofluorescence and qRT-PCR. Cisplatin treatment of 10 and 20 μM reduced cell viability by 36-51% and proliferation capacity by 36-67%. Treatment with cisplatin resulted in 12-67% down-regulation of stem cell markers (CD49f, SSEA4) and 10-130% up-regulation of differentiation markers (CK18, SMA, β-tubulin). At the mRNA level, CD49f was down-regulated whilst β-tubulin was up-regulated in the claudin-low cell lines. SSEA4 protein expression decreased upon cisplatin treatment, but SSEA4 mRNA expression increased indicating a differential regulation of cisplatin at the post-transcriptional level. It is concluded that cisplatin reduces breast cancer cell survival and induces differentiation of stem/progenitor cell subpopulations within breast cancer cell lines. These effects indicate the potential of this drug to target specific chemotherapy-resistant cells within a tumor.

  2. Phenylbutazone prevents the endotoxin-induced delay in gastric emptying in horses.

    Science.gov (United States)

    Valk, N; Doherty, T J; Blackford, J T; Abraha, T W; Frazier, D L

    1998-01-01

    The effect of phenylbutazone on gastric emptying in horses was determined by measuring serum concentrations of acetaminophen. Gastric emptying was determined in normal fasted horses (n = 6), horses given endotoxin intravenously (n = 6), horses given intravenous phenylbutazone (n = 6), and horses given intravenous phenylbutazone plus endotoxin (n = 6). The mean time to reach maximum serum acetaminophen concentration (Tmax), the maximum serum concentration (Cmax), and the area under the serum acetaminophen concentration versus time curve (AUC) were compared among treatment groups. Phenylbutazone did not alter gastric emptying in normal horses. Endotoxin caused a profound delay in gastric emptying, and pretreatment with phenylbutazone abolished this effect. PMID:9684051

  3. Stability and Hopf bifurcation on a model for HIV infection of CD4{sup +} T cells with delay

    Energy Technology Data Exchange (ETDEWEB)

    Wang Xia [College of Mathematics and Information Science, Xinyang Normal University, Xinyang, Henan 464000 (China)], E-mail: xywangxia@163.com; Tao Youde [College of Mathematics and Information Science, Xinyang Normal University, Xinyang, Henan 464000 (China); Beijing Institute of Information Control, Beijing 100037 (China); Song Xinyu [College of Mathematics and Information Science, Xinyang Normal University, Xinyang, Henan 464000 (China) and Research Institute of Forest Resource Information Techniques, Chinese Academy of Forestry, Beijing 100091 (China)], E-mail: xysong88@163.com

    2009-11-15

    In this paper, a delayed differential equation model that describes HIV infection of CD4{sup +} T cells is considered. The stability of the positive equilibrium and the existence of Hopf bifurcation are investigated. In succession, using the normal form theory and center manifold argument, we derive the explicit formulas which determine the stability, direction and other properties of bifurcating periodic solutions.

  4. Anandamide attenuates Th-17 cell-mediated delayed-type hypersensitivity response by triggering IL-10 production and consequent microRNA induction.

    Directory of Open Access Journals (Sweden)

    Austin R Jackson

    Full Text Available Endogenous cannabinoids [endocannabinoids] are lipid signaling molecules that have been shown to modulate immune functions. However, their role in the regulation of Th17 cells has not been studied previously. In the current study, we used methylated Bovine Serum Albumin [mBSA]-induced delayed type hypersensitivity [DTH] response in C57BL/6 mice, mediated by Th17 cells, as a model to test the anti-inflammatory effects of endocannabinoids. Administration of anandamide [AEA], a member of the endocannabinoid family, into mice resulted in significant mitigation of mBSA-induced inflammation, including foot pad swelling, cell infiltration, and cell proliferation in the draining lymph nodes [LN]. AEA treatment significantly reduced IL-17 and IFN-γ production, as well as decreased RORγt expression while causing significant induction of IL-10 in the draining LNs. IL-10 was critical for the AEA-induced mitigation of DTH response inasmuch as neutralization of IL-10 reversed the effects of AEA. We next analyzed miRNA from the LN cells and found that 100 out of 609 miRNA species were differentially regulated in AEA-treated mice when compared to controls. Several of these miRNAs targeted proinflammatory mediators. Interestingly, many of these miRNA were also upregulated upon in vitro treatment of LN cells with IL-10. Together, the current study demonstrates that AEA may suppress Th-17 cell-mediated DTH response by inducing IL-10 which in turn triggers miRNA that target proinflammatory pathways.

  5. Mechanisms of tolvaptan-induced toxicity in HepG2 cells.

    Science.gov (United States)

    Wu, Yuanfeng; Beland, Frederick A; Chen, Si; Liu, Fang; Guo, Lei; Fang, Jia-Long

    2015-06-15

    Tolvaptan, a vasopressin receptor 2 antagonist used to treat hyponatremia, has recently been reported to be associated with an increased risk of liver injury. In this study, we explored the underlying mechanisms of hepatotoxicity of tolvaptan using human HepG2 cells. Tolvaptan inhibited cell growth and caused cell death in a concentration- and time-dependent manner. Tolvaptan treatment led to delayed cell cycle progression, accompanied by decreased levels of several cyclins and cyclin-dependent kinases. Tolvaptan was found to cause DNA damage, as assessed by alkaline comet assays; this was confirmed by increased levels of 8-oxoguanine and phosphorylation of histone H2AX. Exposure of HepG2 cells to tolvaptan enhanced cytochrome C release and triggered apoptosis by modulating Bcl-2 family members. The activation of p38 contributed to tolvaptan-mediated apoptosis via down-regulation of Bcl-2. Proteasome inhibition altered tolvaptan-induced cell cycle deregulation and enhanced tolvaptan-induced apoptosis and cytotoxicity. Moreover, tolvaptan treatment induced autophagy. Inhibition of autophagy by knocking-down an autophagy-related gene increased tolvaptan-induced apoptosis and cytotoxicity. Taken together, our findings suggest that the cytotoxicity of tolvaptan results from delayed cell cycle progression, the induction of DNA damage, and the execution of apoptosis. In addition, a number of signaling pathways were perturbed by tolvaptan and played an important role in its cytotoxicity. Published by Elsevier Inc.

  6. Sodium Valproate Induces Cell Senescence in Human Hepatocarcinoma Cells

    Directory of Open Access Journals (Sweden)

    Hong-Mei An

    2013-12-01

    Full Text Available Hepatocarcinogenesis is associated with epigenetic changes, including histone deacetylases (HDACs. Epigenetic modulation by HDAC inhibition is a potentially valuable approach for hepatocellular carcinoma treatment. In present study, we evaluated the anticancer effects of sodium valproate (SVP, a known HDAC inhibitor, in human hepatocarcinoma cells. The results showed SVP inhibited the proliferation of Bel-7402 cells in a dose-dependent manner. Low dose SVP treatment caused a large and flat morphology change, positive SA-β-gal staining, and G0/G1 phase cell cycle arrest in human hepatocarcinoma cells. Low dose SVP treatment also increased acetylation of histone H3 and H4 on p21 promoter, accompanied by up-regulation of p21 and down-regulation of RB phosphorylation. These observations suggested that a low dose of SVP could induce cell senescence in hepatocarcinoma cells, which might correlate with hyperacetylation of histone H3 and H4, up-regulation of p21, and inhibition of RB phosphorylation. Since the effective concentration inducing cell senescence in hepatocarcinoma cells is clinically available, whether a clinical dose of SVP could induce cell senescence in clinical hepatocarcinoma is worthy of further study.

  7. Knockdown of Cs-Spook induces delayed larval molting in rice striped stem borer Chilo suppressalis.

    Science.gov (United States)

    Shahzad, Muhammad Faisal; Li, Yao; Ge, Chang; Sun, Yang; Yang, Qiupu; Li, Fei

    2015-03-01

    Spook has essential roles in the biogenesis of the molting hormone 20-hydroxyecdysone (20-E). The function of spook in the rice striped stem borer (SSB) Chilo suppressalis remains unclear, prompting our hypothesis that it exerts actions similar to those reported for other insect species. Here we amplified the full-length transcript of spook (Cs-Spook) in SSB by 5' and 3' rapid amplification of cDNA ends. Cs-Spook has conserved P450 motifs such as Helix-C, Helix-I, Helix-K, and PERF motif (PxxFxPxRF). It was highly expressed in late instar larvae but less so in newly molted larvae. Cs-Spook was highly expressed in prothoracic glands. Cs-Spook was knocked down by dsRNA treatments. Compared with controls, the gene expression level was reduced to 9% at 24 h post injection (PI), 33% at 48 h PI, and 24% at 72 h PI. The ecdysteroid titer decreased significantly in the dsRNA-treated group (P < 0.05), resulting in delayed larval development. The delayed development in dsRNA-treatment group was rescued by treating with 20-E. Our work demonstrates that Cs-Spook participates in the biogenesis of 20-E and regulates the molt of SSB, as seen in other species. © 2014 Wiley Periodicals, Inc.

  8. SKF-96365 activates cytoprotective autophagy to delay apoptosis in colorectal cancer cells through inhibition of the calcium/CaMKIIγ/AKT-mediated pathway.

    Science.gov (United States)

    Jing, Zhao; Sui, Xinbing; Yao, Junlin; Xie, Jiansheng; Jiang, Liming; Zhou, Yubin; Pan, Hongming; Han, Weidong

    2016-03-28

    Store-operated Ca(2+) entry (SOCE) inhibitors are emerging as an attractive new generation of anti-cancer drugs. Here, we report that SKF-96365, an SOCE inhibitor, exhibits potent anti-neoplastic activity by inducing cell-cycle arrest and apoptosis in colorectal cancer cells. In the meantime, SKF-96365 also induces cytoprotective autophagy to delay apoptosis by preventing the release of cytochrome c (cyt c) from the mitochondria into the cytoplasm. Mechanistically, SKF-96365 treatment inhibited the calcium/calmodulin-dependent protein kinase IIγ (CaMKIIγ)/AKT signaling cascade in vitro and in vivo. Overexpression of CaMKIIγ or AKT abolished the effects of SKF-96365 on cancer cells, suggesting a critical role of the CaMKIIγ/AKT signaling pathway in SFK-96365-induced biological effects. Moreover, Hydroxychloroquine (HCQ), an FDA-approved drug used to inhibit autophagy, could significantly augment the anti-cancer effect of SFK-96365 in a mouse xenograft model. To our best knowledge, this is the first report to demonstrate that calcium/CaMKIIγ/AKT signaling can regulate apoptosis and autophagy simultaneously in cancer cells, and the combination of the SOCE inhibitor SKF-96365 with autophagy inhibitors represents a promising strategy for treating patients with colorectal cancer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Selected Activities of Citrus Maxima Merr. Fruits on Human Endothelial Cells: Enhancing Cell Migration and Delaying Cellular Aging

    Directory of Open Access Journals (Sweden)

    Paiwan Buachan

    2014-04-01

    Full Text Available Endothelial injury and damage as well as accumulated reactive oxygen species (ROS in aging play a significant role in the development of cardiovascular disease (CVD. Recent studies show an association of high citrus fruit intake with a lower risk of CVD and stroke but the mechanisms involved are not fully understood. This study investigated the effects of pummelo (Citrus maxima Merr. var. Tubtim Siam, CM fruit extract on human umbilical vein endothelial cell (HUVECs migration and aging. The freeze-dried powder of fruit extract was characterized for antioxidant capacity (FRAP assay and certain natural antioxidants, including ascorbic acid, gallic acid, hesperidin, and naringin (HPLC. Short-term (48 h co-cultivation of HUVECs with CM enhanced cell migration as evaluated by a scratch wound assay and Boyden chamber assay. A long-term treatment with CM for 35 days significantly increased HUVEC proliferation capability as indicated by population doubling level (PDL. CM also delayed the onset of aging phenotype shown by senescence-associated β-galactosidase (SA-β-gal staining. Furthermore, CM was able to attenuate increased ROS levels in aged cells when determined by 2′,7′-dichlorodihydrofluorescein diacetate (DCDHF while eNOS mRNA expression was increased but the eNOS protein level was not changed. Thus, further in vivo and clinical studies are warranted to support the use of pummelo as a functional fruit for endothelial health and CVD risk reduction.

  10. Understanding delayed T-cell priming, lung recruitment, and airway luminal T-cell responses in host defense against pulmonary tuberculosis.

    Science.gov (United States)

    Shaler, Christopher R; Horvath, Carly; Lai, Rocky; Xing, Zhou

    2012-01-01

    Mycobacterium tuberculosis (M.tb), the causative bacterium of pulmonary tuberculosis (TB), is a serious global health concern. Central to M.tb effective immune avoidance is its ability to modulate the early innate inflammatory response and prevent the establishment of adaptive T-cell immunity for nearly three weeks. When compared with other intracellular bacterial lung pathogens, such as Legionella pneumophila, or even closely related mycobacterial species such as M. smegmatis, this delay is astonishing. Customarily, the alveolar macrophage (AM) acts as a sentinel, detecting and alerting surrounding cells to the presence of an invader. However, in the case of M.tb, this may be impaired, thus delaying the recruitment of antigen-presenting cells (APCs) to the lung. Upon uptake by APC populations, M.tb is able to subvert and delay the processing of antigen, MHC class II loading, and the priming of effector T cell populations. This delay ultimately results in the deferred recruitment of effector T cells to not only the lung interstitium but also the airway lumen. Therefore, it is of upmost importance to dissect the mechanisms that contribute to the delayed onset of immune responses following M.tb infection. Such knowledge will help design the most effective vaccination strategies against pulmonary TB.

  11. Production of endocannabinoids by activated T cells and B cells modulates inflammation associated with delayed-type hypersensitivity.

    Science.gov (United States)

    Sido, Jessica M; Nagarkatti, Prakash S; Nagarkatti, Mitzi

    2016-06-01

    Endocannabinoids are endogenous ligands for the cannabinoid (CB) receptors which include anandamide (AEA) and 2-arachidonyl glycerol (2-AG). 2-AG has been linked to inflammation due to its elevated expression in animal models of autoimmunity and hypersensitivity. However, administration of exogenous 2-AG has been shown to suppress inflammation making its precise role unclear. In the current study, we investigated the role of 2-AG following immunization of C57BL/6 (BL6) mice with methylated BSA (mBSA) antigen, which triggers both delayed-type hypersensitivity (DTH) and antibody response. We found that while naïve T cells and B cells expressed low levels of 2-AG, expression significantly increased upon activation. Furthermore, mBSA-immunized mice exhibited higher 2-AG concentration than naïve mice. Exogenous 2-AG treatment (40 mg/kg) in mBSA-immunized mice led to reduced DTH response, and decreased Th1 and Th17-associated cytokines including IL-6, IL-2, TNF-α, and the IgG response. Addition of 2-AG to activated popliteal lymph node (PopLN) cell cultures also inhibited lymphocyte proliferation. Together, these data show for the first time that activated T and B cells produce 2-AG, which plays a negative regulatory role to decrease DTH via inhibition of T-cell activation and proliferation. Moreover, these findings suggest that exogenous 2-AG treatment can be used therapeutically in Th1- or Th17-driven disease. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Chromate-induced epimutations in mammalian cells.

    Science.gov (United States)

    Klein, Catherine B; Su, Lin; Bowser, Darlene; Leszczynska, Joanna

    2002-10-01

    Epigenetic gene silencing by aberrant DNA methylation of gene promoter regions is a nonmutagenic but heritable epigenetic mechanism that may mistakenly cause the silencing of important cancer-related tumor suppressor genes. Using a transgenic, V79-derived, mammalian cell line (G12) that contains a bacterial gpt reporter gene in its DNA, we can study carcinogen-induced gene inactivation by mutagenic as well as epigenetic DNA methylation mechanisms. Whereas numerous carcinogens have previously been shown to be mutagenic in these cells, a few carcinogens, including nickel, diethylstilbestrol, and X-rays, are also capable of silencing the G12 cell gpt transgene by aberrant DNA methylation. Here we report for the first time that carcinogenic potassium chromate salts can also induce aberrant DNA methylation in this system. In contrast insoluble barium chromate produced significant level of mutations in these cells but did not cause DNA methylation changes associated with transgene expression.

  13. Deficiency of inducible and endothelial nitric oxide synthase results in diminished bone formation and delayed union and nonunion development.

    Science.gov (United States)

    Meesters, D M; Neubert, S; Wijnands, K A P; Heyer, F L; Zeiter, S; Ito, K; Brink, P R G; Poeze, M

    2016-02-01

    Between 5% and 10% of all fractures fail to heal adequately resulting in nonunion of the fracture fragments. This can significantly decrease a patient's quality of life and create associated psychosocial and socio-economic problems. Nitric oxide (NO) and nitric oxide synthases (NOS) have been found to be involved in fracture healing, but until now it is not known if disturbances in these mechanisms play a role in nonunion and delayed union development. In this study, we explored the role of endothelial and inducible NOS deficiency in a delayed union model in mice. A 0.45mm femur osteotomy with periosteal cauterization followed by plate-screw osteosynthesis was performed in the left leg of 20-24week old wild type, Nos2(-/-) and Nos3(-/-) mice. Contralateral unfractured legs were used as a control. Callus volume was measured using micro-computed tomography (μCT) after 28 and 42days of fracture healing. Immuno histochemical myeloperoxidase (MPO) staining was performed on paraffin embedded sections to assess neutrophil influx in callus tissue and surrounding proximal and distal marrow cavities of the femur. After 7 and 28days of fracture healing, femurs were collected for amino acid and RNA analysis to study arginine-NO metabolism. With μCT, delayed union was observed in wild type animals, whereas in both Nos2(-/-) and Nos3(-/-) mice nonunion development was evident. Both knock-out strains also showed a significantly increased influx of MPO when compared with wild type mice. Concentrations of amino acids and expression of enzymes related to the arginine-NO metabolism were aberrant in NOS deficient mice when compared to contralateral control femurs and wild type samples. In the present study we show for the first time that the absence of nitric oxide synthases results in a disturbed arginine-NO metabolism and inadequate fracture healing with the transition of delayed union into a nonunion in mice after a femur osteotomy. Based on these data we suggest that the

  14. DNA damage enhanced by the attenuation of SLD5 delays cell cycle restoration in normal cells but not in cancer cells.

    Directory of Open Access Journals (Sweden)

    Zhi-Yuan Gong

    Full Text Available SLD5 is a member of the GINS complex composed of PSF1, PSF2, PSF3 and SLD5, playing a critical role in the formation of the DNA replication fork with CDC45 in yeast. Previously, we had isolated a PSF1 orthologue from a murine hematopoietic stem cell DNA library and were then able to identify orthologues of all the other GINS members by the yeast two hybrid approach using PSF1 as the bait. These GINS orthologues may also function in DNA replication in mammalian cells because they form tetrameric complexes as observed in yeast, and gene deletion mutants of both PSF1 and SLD5 result in a lack of epiblast proliferation and early embryonic lethality. However, we found that PSF1 is also involved in chromosomal segregation in M phase, consistent with recent suggestions that homologues of genes associated with DNA replication in lower organisms also regulate cellular events other than DNA replication in mammalian cells. Here we analyzed the function of SLD5 other than DNA replication and found that it is active in DNA damage and repair. Attenuation of SLD5 expression results in marked DNA damage in both normal cells and cancer cells, suggesting that it protects against DNA damage. Attenuation of SLD5 delays the DNA repair response and cell cycle restoration in normal cells but not in cancer cells. These findings suggest that SLD5 might represent a therapeutic target molecule acting at the level of tumor stromal cells rather than the cancerous cells themselves, because development of the tumor microenvironment could be delayed or disrupted by the suppression of its expression in the normal cell types within the tumor.

  15. Delayed fertilization of anuran amphibian (Xenopus) eggs leads to reduced numbers of primordial germ cells

    Science.gov (United States)

    Wakahara, M.; Neff, A. W.; Malacinski, G. M.

    1984-01-01

    Several media were tested for the extent to which they promoted high fertilization efficiencies in ovulated, stripped Xenopus eggs. One medium was selected for maintaining eggs in a 'delayed fertilization' (DelF) condition. DelF eggs displayed several unusual characteristics, including shift of the center of gravity, prominent sperm entrance site, and occasional polyspermy. The frequency of normal pattern formation varied according to the length of time eggs were maintained in the DelF condition. Various developmental abnormalities were observed during gastrulation, neurulation, and organogenesis. Most abnormalities appeared, however, to be related to morphogenesis of the endoderm. Primordial germ cell (PGC) development was examined in DelF eggs which displayed normal external morphological features at the swimming tadpole stage. PGC counts were usually normal in short-duration (eg, 5 hr) DelF eggs, but frequently substantially reduced or completely diminished in longer-duration (eg, 25h) tadpoles. Six spawnings were compared and shown to exhibit considerable variability in fertility, morphogenesis, and PGC development. Yolk platelet shifts and developmental parameters were examined in two additional spawnings. The subcortical cytoplasm in which the germ plasm is normally localized appeared to be disrupted in longer duration DelF eggs. That observation may account for low PGC counts in DelF tadpoles.

  16. BCG vaccination induces HIV target cell activation in HIV-exposed infants in a randomized trial.

    Science.gov (United States)

    Gasper, Melanie A; Hesseling, Anneke C; Mohar, Isaac; Myer, Landon; Azenkot, Tali; Passmore, Jo-Ann S; Hanekom, Willem; Cotton, Mark F; Crispe, I Nicholas; Sodora, Donald L; Jaspan, Heather B

    2017-04-06

    BACKGROUND. Bacillus Calmette-Guérin (BCG) vaccine is administered at birth to protect infants against tuberculosis throughout Africa, where most perinatal HIV-1 transmission occurs. We examined whether BCG vaccination alters the levels of activated HIV target T cells in HIV-exposed South African infants. METHODS. HIV-exposed infants were randomized to receive routine (at birth) or delayed (at 8 weeks) BCG vaccination. Activated and CCR5-expressing peripheral blood CD4+ T cell, monocyte, and NK cell frequencies were evaluated by flow cytometry and immune gene expression via PCR using Biomark (Fluidigm). RESULTS. Of 149 infants randomized, 92% (n = 137) were retained at 6 weeks: 71 in the routine BCG arm and 66 in the delayed arm. Routine BCG vaccination led to a 3-fold increase in systemic activation of HIV target CD4+CCR5+ T cells (HLA-DR+CD38+) at 6 weeks (0.25% at birth versus 0.08% in delayed vaccination groups; P = 0.029), which persisted until 8 weeks of age when the delayed arm was vaccinated. Vaccination of the infants in the delayed arm at 8 weeks resulted in a similar increase in activated CD4+CCR5+ T cells. The increase in activated T cells was associated with increased levels of MHC class II transactivator (CIITA), IL12RB1, and IFN-α1 transcripts within peripheral blood mononuclear cells but minimal changes in innate cells. CONCLUSION. BCG vaccination induces immune changes in HIV-exposed infants, including an increase in the proportion of activated CCR5+CD4+ HIV target cells. These findings provide insight into optimal BCG vaccine timing to minimize the risks of HIV transmissions to exposed infants while preserving potential benefits conferred by BCG vaccination. TRIAL REGISTRATION. ClinicalTrials.gov NCT02062580. FUNDING. This trial was sponsored by the Elizabeth Glaser Pediatric AIDS Foundation (MV-00-9-900-01871-0-00) and the Thrasher Foundation (NR-0095); for details, see Acknowledgments.

  17. Hyperbaric oxygen for carbon monoxide poisoning-induced delayed neuropsychiatric sequelae.

    Science.gov (United States)

    Lee, H F; Mak, S C; Chi, C S; Hung, D Z

    2001-05-01

    The clinical manifestations of delayed neuropsychiatric sequelae after carbon monoxide (CO) intoxication are variable. In addition, there is no specific therapy for these complications. Fortunately, these complications have occurred less frequently in recent years, probably due to the usage of hyperbaric oxygen (HBO) therapy. We report an 8-year-old boy who developed late psychiatric disturbances 2 days after full recovery of consciousness from initial CO intoxication. His neuropsychiatric symptoms included consciousness disturbance, motor dysfunction, chorea, aphasia and agnosias. He received HBO therapy at 2.0 barr for 60 minutes once a day for 7 consecutive days. Three weeks later, he was functioning normally with no neuropsychiatric symptoms. A literature review concluded that HBO may be effective in treating neuropsychiatric sequelae. Moreover, immediate administration of HBO during acute CO intoxication may prevent these complications.

  18. Polarization-resolved time-delay signatures of chaos induced by FBG-feedback in VCSEL.

    Science.gov (United States)

    Zhong, Zhu-Qiang; Li, Song-Sui; Chan, Sze-Chun; Xia, Guang-Qiong; Wu, Zheng-Mao

    2015-06-15

    Polarization-resolved chaotic emission intensities from a vertical-cavity surface-emitting laser (VCSEL) subject to feedback from a fiber Bragg grating (FBG) are numerically investigated. Time-delay (TD) signatures of the feedback are examined through various means including self-correlations of intensity time-series of individual polarizations, cross-correlation of intensities time-series between both polarizations, and permutation entropies calculated for the individual polarizations. The results show that the TD signatures can be clearly suppressed by selecting suitable operation parameters such as the feedback strength, FBG bandwidth, and Bragg frequency. Also, in the operational parameter space, numerical maps of TD signatures and effective bandwidths are obtained, which show regions of chaotic signals with both wide bandwidths and weak TD signatures. Finally, by comparing with a VCSEL subject to feedback from a mirror, the VCSEL subject to feedback from the FBG generally shows better concealment of the TD signatures with similar, or even wider, bandwidths.

  19. Delayed methicillin-resistant Staphylococcus aureus-induced osteomyelitis of the tibia after pin tract infection: two case reports.

    Science.gov (United States)

    Hamahashi, Kosuke; Uchiyama, Yoshiyasu; Kobayashi, Yuka; Watanabe, Masahiko

    2017-01-31

    Pin tract infection is a common complication of external fixation. It usually heals after treatment with debridement, antibiotics, and/or pin removal, only rarely developing into delayed osteomyelitis. We treated two patients with delayed methicillin-resistant Staphylococcus aureus-induced osteomyelitis of the tibia following pin tract infection. One patient, a diabetic 60-year-old Japanese man, underwent definitive external fixation using an Ilizarov fixator for postoperative osteomyelitis of an open fracture of his left ankle. One year after removing the external fixator, he developed methicillin-resistant Staphylococcus aureus-induced osteomyelitis of the tibial pin site. He underwent surgical debridement four times. No recurrence was seen 2 years 8 months after the last debridement. Another patient, a healthy 38-year-old Japanese man, underwent bilateral temporary external fixation for a right ankle open fracture and a comminuted fracture of the left tibial plateau. Three months after removal of the external fixator, he was diagnosed with methicillin-resistant Staphylococcus aureus-induced osteomyelitis of the bilateral tibial pin sites. He underwent surgical debridement three times, but the infection of his right tibia persisted. Finally, a gastrocnemius muscle flap was placed. No recurrence was seen 2 years after this last surgery. Pin tract infection should not be considered a minor complication because osteomyelitis may develop, requiring treatment that is more aggressive than curettage of the pin tract. A gastrocnemius flap is a useful treatment option for refractory osteomyelitis because flap harvest causes less functional disturbance and is a relatively easy surgical technique.

  20. Low-Dose Formaldehyde Delays DNA Damage Recognition and DNA Excision Repair in Human Cells

    Science.gov (United States)

    Luch, Andreas; Frey, Flurina C. Clement; Meier, Regula; Fei, Jia; Naegeli, Hanspeter

    2014-01-01

    Objective Formaldehyde is still widely employed as a universal crosslinking agent, preservative and disinfectant, despite its proven carcinogenicity in occupationally exposed workers. Therefore, it is of paramount importance to understand the possible impact of low-dose formaldehyde exposures in the general population. Due to the concomitant occurrence of multiple indoor and outdoor toxicants, we tested how formaldehyde, at micromolar concentrations, interferes with general DNA damage recognition and excision processes that remove some of the most frequently inflicted DNA lesions. Methodology/Principal Findings The overall mobility of the DNA damage sensors UV-DDB (ultraviolet-damaged DNA-binding) and XPC (xeroderma pigmentosum group C) was analyzed by assessing real-time protein dynamics in the nucleus of cultured human cells exposed to non-cytotoxic (formaldehyde concentrations. The DNA lesion-specific recruitment of these damage sensors was tested by monitoring their accumulation at local irradiation spots. DNA repair activity was determined in host-cell reactivation assays and, more directly, by measuring the excision of DNA lesions from chromosomes. Taken together, these assays demonstrated that formaldehyde obstructs the rapid nuclear trafficking of DNA damage sensors and, consequently, slows down their relocation to DNA damage sites thus delaying the excision repair of target lesions. A concentration-dependent effect relationship established a threshold concentration of as low as 25 micromolar for the inhibition of DNA excision repair. Conclusions/Significance A main implication of the retarded repair activity is that low-dose formaldehyde may exert an adjuvant role in carcinogenesis by impeding the excision of multiple mutagenic base lesions. In view of this generally disruptive effect on DNA repair, we propose that formaldehyde exposures in the general population should be further decreased to help reducing cancer risks. PMID:24722772

  1. Trophoblast lineage cells derived from human induced pluripotent stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Ying, E-mail: ying.chen@hc.msu.edu [Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, 333 Bostwick NE, Grand Rapids, MI 49503 (United States); Wang, Kai; Chandramouli, Gadisetti V.R. [Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, 333 Bostwick NE, Grand Rapids, MI 49503 (United States); Knott, Jason G. [Developmental Epigenetics Laboratory, Department of Animal Science, Michigan State University (United States); Leach, Richard, E-mail: Richard.leach@hc.msu.edu [Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, 333 Bostwick NE, Grand Rapids, MI 49503 (United States); Department of Obstetrics, Gynecology and Women’s Health, Spectrum Health Medical Group (United States)

    2013-07-12

    Highlights: •Epithelial-like phenotype of trophoblast lineage cells derived from human iPS cells. •Trophoblast lineage cells derived from human iPS cells exhibit trophoblast function. •Trophoblasts from iPS cells provides a proof-of-concept in regenerative medicine. -- Abstract: Background: During implantation, the blastocyst trophectoderm attaches to the endometrial epithelium and continues to differentiate into all trophoblast subtypes, which are the major components of a placenta. Aberrant trophoblast proliferation and differentiation are associated with placental diseases. However, due to ethical and practical issues, there is almost no available cell or tissue source to study the molecular mechanism of human trophoblast differentiation, which further becomes a barrier to the study of the pathogenesis of trophoblast-associated diseases of pregnancy. In this study, our goal was to generate a proof-of-concept model for deriving trophoblast lineage cells from induced pluripotency stem (iPS) cells from human fibroblasts. In future studies the generation of trophoblast lineage cells from iPS cells established from patient’s placenta will be extremely useful for studying the pathogenesis of individual trophoblast-associated diseases and for drug testing. Methods and results: Combining iPS cell technology with BMP4 induction, we derived trophoblast lineage cells from human iPS cells. The gene expression profile of these trophoblast lineage cells was distinct from fibroblasts and iPS cells. These cells expressed markers of human trophoblasts. Furthermore, when these cells were differentiated they exhibited invasive capacity and placental hormone secretive capacity, suggesting extravillous trophoblasts and syncytiotrophoblasts. Conclusion: Trophoblast lineage cells can be successfully derived from human iPS cells, which provide a proof-of-concept tool to recapitulate pathogenesis of patient placental trophoblasts in vitro.

  2. Absence of a p53 allele delays nitrogen mustard-induced early apoptosis and inflammation of murine skin.

    Science.gov (United States)

    Inturi, Swetha; Tewari-Singh, Neera; Jain, Anil K; Roy, Srirupa; White, Carl W; Agarwal, Rajesh

    2013-09-15

    Bifunctional alkylating agent sulfur mustard (SM) and its analog nitrogen mustard (NM) cause DNA damage leading to cell death, and potentially activating inflammation. Transcription factor p53 plays a critical role in DNA damage by regulating cell cycle progression and apoptosis. Earlier studies by our laboratory demonstrated phosphorylation of p53 at Ser15 and an increase in total p53 in epidermal cells both in vitro and in vivo following NM exposure. To elucidate the role of p53 in NM-induced skin toxicity, we employed SKH-1 hairless mice harboring wild type (WT) or heterozygous p53 (p53+/-). Exposure to NM (3.2mg) caused a more profound increase in epidermal thickness and apoptotic cell death in WT relative to p53+/- mice at 24h. However, by 72h after exposure, there was a comparable increase in NM-induced epidermal cell death in both WT and p53+/- mice. Myeloperoxidase activity data showed that neutrophil infiltration was strongly enhanced in NM-exposed WT mice at 24h persisting through 72h of exposure. Conversely, robust NM-induced neutrophil infiltration (comparable to WT mice) was seen only at 72h after exposure in p53+/- mice. Similarly, NM-exposure strongly induced macrophage and mast cell infiltration in WT, but not p53+/- mice. Together, these data indicate that early apoptosis and inflammation induced by NM in mouse skin are p53-dependent. Thus, targeting this pathway could be a novel strategy for developing countermeasures against vesicants-induced skin injury. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  3. UV-B induces DNA damage and DNA synthesis delay in the marine diatom Cyclotella sp.

    NARCIS (Netherlands)

    Buma, A.G.J.; van Hannen, E.J; Veldhuis, M.J W; Gieskes, W.W C

    The effect of UV-B on the occurrence of DNA damage and consequences for the cell cycle were studied in the marine diatom Cyclotella sp. DNA damage was quantified by immunofluorescent detection of thymine dimers in nuclear DNA of single cells using flow cytometry. A total UV-B dose (biologically

  4. UV-B induces DNA damage and DNA synthesis delay in the marine diatom Cyclotella sp

    NARCIS (Netherlands)

    Buma, A.G.J.; Van Hannen, E.J.; Veldhuis, M.; Gieskes, W.W.C.

    1996-01-01

    The effect of UV-B on the occurrence of DNA damage and consequences for the cell cycle were studied in the marine diatom Cyclotella sp. DNA damage was quantified by immunofluorescent detection of thymine dimers in nuclear DNA of single cells using flow cytometry. A total UV-B dose (biologically

  5. 8-group relative delayed neutron yields for epithermal neutron induced fission of sup 2 sup 3 sup 5 U and sup 2 sup 3 sup 9 Pu

    CERN Document Server

    Piksaikin, V M; Kazakov, L E; Korolev, G G; Roshchenko, V A; Tertychnyj, R G

    2001-01-01

    An 8-group representation of relative delayed neutron yields was obtained for epithermal neutron induced fission of sup 2 sup 3 sup 5 U and sup 2 sup 3 sup 9 Pu. These data were compared with ENDF/B-VI data in terms of the average half- life of the delayed neutron precursors and on the basis of the dependence of reactivity on the asymptotic period.

  6. Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol-induced hepatotoxicity

    Science.gov (United States)

    Craig, Darren G N; Bates, Caroline M; Davidson, Janice S; Martin, Kirsty G; Hayes, Peter C; Simpson, Kenneth J

    2012-01-01

    AIMS Paracetamol (acetaminophen) poisoning remains the major cause of severe acute hepatotoxicity in the UK. In this large single centre cohort study we examined the clinical impact of staggered overdoses and delayed presentation following paracetamol overdose. RESULTS Between 1992 and 2008, 663 patients were admitted with paracetamol-induced severe liver injury, of whom 161 (24.3%) had taken a staggered overdose. Staggered overdose patients were significantly older and more likely to abuse alcohol than single time point overdose patients. Relief of pain (58.2%) was the commonest rationale for repeated supratherapeutic ingestion. Despite lower total ingested paracetamol doses and lower admission serum alanine aminotransferase concentrations, staggered overdose patients were more likely to be encephalopathic on admission, require renal replacement therapy or mechanical ventilation and had higher mortality rates compared with single time point overdoses (37.3% vs. 27.8%, P = 0.025), although this overdose pattern did not independently predict death. The King's College poor prognostic criteria had reduced sensitivity (77.6, 95% CI 70.8, 81.5) for this pattern of overdose. Of the 396/450 (88.0%) single time point overdoses in whom accurate timings could be obtained, 178 (44.9%) presented to medical services >24 h following overdose. Delayed presentation beyond 24 h post overdose was independently associated with death/liver transplantation (OR 2.25, 95% CI 1.23, 4.12, P = 0.009). CONCLUSIONS Both delayed presentation and staggered overdose pattern are associated with adverse outcomes following paracetamol overdose. These patients are at increased risk of developing multi-organ failure and should be considered for early transfer to specialist liver centres. PMID:22106945

  7. Heat induces gene amplification in cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Yan, Bin, E-mail: yanbin@mercyhealth.com [Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS 39213 (United States); Mercy Cancer Center, Mercy Medical Center-North Iowa, Mason City, IA 50401 (United States); Ouyang, Ruoyun [Department of Respiratory Medicine, The Second Xiangya Hospital, Xinagya School of Medicine, Central South University, Changsha 410011 (China); Huang, Chenghui [Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS 39213 (United States); Department of Oncology, The Third Xiangya Hospital, Xinagya School of Medicine, Central South University, Changsha 410013 (China); Liu, Franklin [Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710 (United States); Neill, Daniel [Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS 39213 (United States); Li, Chuanyuan [Dermatology, Duke University Medical Center, Durham, NC 27710 (United States); Dewhirst, Mark [Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710 (United States)

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer This study discovered that heat exposure (hyperthermia) results in gene amplification in cancer cells. Black-Right-Pointing-Pointer Hyperthermia induces DNA double strand breaks. Black-Right-Pointing-Pointer DNA double strand breaks are considered to be required for the initiation of gene amplification. Black-Right-Pointing-Pointer The underlying mechanism of heat-induced gene amplification is generation of DNA double strand breaks. -- Abstract: Background: Hyperthermia plays an important role in cancer therapy. However, as with radiation, it can cause DNA damage and therefore genetic instability. We studied whether hyperthermia can induce gene amplification in cancer cells and explored potential underlying molecular mechanisms. Materials and methods: (1) Hyperthermia: HCT116 colon cancer cells received water-submerged heating treatment at 42 or 44 Degree-Sign C for 30 min; (2) gene amplification assay using N-(phosphoacetyl)-L-aspartate (PALA) selection of cabamyl-P-synthetase, aspartate transcarbarmylase, dihydro-orotase (cad) gene amplified cells; (3) southern blotting for confirmation of increased cad gene copies in PALA-resistant cells; (4) {gamma}H2AX immunostaining to detect {gamma}H2AX foci as an indication for DNA double strand breaks. Results: (1) Heat exposure at 42 or 44 Degree-Sign C for 30 min induces gene amplification. The frequency of cad gene amplification increased by 2.8 and 6.5 folds respectively; (2) heat exposure at both 42 and 44 Degree-Sign C for 30 min induces DNA double strand breaks in HCT116 cells as shown by {gamma}H2AX immunostaining. Conclusion: This study shows that heat exposure can induce gene amplification in cancer cells, likely through the generation of DNA double strand breaks, which are believed to be required for the initiation of gene amplification. This process may be promoted by heat when cellular proteins that are responsible for checkpoints, DNA replication, DNA repair and

  8. 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...... hydrate anaesthesia. Repeated episodes of 1 min of ischemia were induced by transiently clamping the carotid arteries in a 'four-vessel occlusion' model. We devised an automatic method of T(ES) estimation based on the decay of the root mean square of two-channel electrocorticographic recordings...... in vitro....

  9. Aire-Overexpressing Dendritic Cells Induce Peripheral CD4⁺ T Cell Tolerance.

    Science.gov (United States)

    Li, Dongbei; Li, Haijun; Fu, Haiying; Niu, Kunwei; Guo, Yantong; Guo, Chuan; Sun, Jitong; Li, Yi; Yang, Wei

    2015-12-29

    Autoimmune regulator (Aire) can promote the ectopic expression of peripheral tissue-restricted antigens (TRAs) in thymic medullary epithelial cells (mTECs), which leads to the deletion of autoreactive T cells and consequently prevents autoimmune diseases. However, the functions of Aire in the periphery, such as in dendritic cells (DCs), remain unclear. This study's aim was to investigate the effect of Aire-overexpressing DCs (Aire cells) on the functions of CD4⁺ T cells and the treatment of type 1 diabetes (T1D). We demonstrated that Aire cells upregulated the mRNA levels of the tolerance-related molecules CD73, Lag3, and FR4 and the apoptosis of CD4⁺ T cells in STZ-T1D mouse-derived splenocytes. Furthermore, following insulin stimulation, Aire cells decreased the number of CD4⁺ IFN-γ⁺ T cells in both STZ-T1D and WT mouse-derived splenocytes and reduced the expression levels of TCR signaling molecules (Ca(2+) and p-ERK) in CD4⁺ T cells. We observed that Aire cells-induced CD4⁺ T cells could delay the development of T1D. In summary, Aire-expressing DCs inhibited TCR signaling pathways and decreased the quantity of CD4⁺IFN-γ⁺ autoreactive T cells. These data suggest a mechanism for Aire in the maintenance of peripheral immune tolerance and provide a potential method to control autoimmunity by targeting Aire.

  10. Age-related effects of triphenyl phosphite-induced delayed neuropathy on central visual pathways in the European ferret (Mustela putorius furo).

    Science.gov (United States)

    Tanaka, D; Bursian, S J; Aulerich, R J

    1994-05-01

    The objective of this study was to investigate the relationship between the maturation of visual system neurons and the onset of their susceptibility to triphenyl phosphite (TPP)-induced delayed neurotoxicity in the European ferret. We administered single subcutaneous doses of TPP (1184 mg/kg body wt) to 1- to 10-week-old ferret kits to assess the effects on connections and neurons of the developing lateral geniculate thalamic nucleus (LGN) and primary visual cortex. Brains were processed with a modified Fink-Heimer silver-impregnation method. Axonal and terminal degeneration were first noted in the LGN of kits injected at 5 weeks of age. The severity of the degeneration increased in kits injected at later ages and reached adult densities and configurations in ferrets injected at 10 weeks of age. Degenerating neuronal cell bodies were also present in the LGN of kits injected at 7 weeks of age and older. In the visual cortex, axonal and terminal degeneration were consistently present in kits injected at 8 weeks of age and attained adult-like densities in kits injected at 10 weeks of age. Previous studies have reported that the ferret visual system appears to reach anatomical maturity (as defined by mature LGN lamination patterns, the location and density of axon terminals originating from neurons in the retina and LGN, and the migration and synaptic connections of cortical neurons) by 4-5 weeks of age. A temporal comparison of these normal developmental data with the degeneration data obtained in the present study suggests that immature neurons in the visual system of the ferret are not susceptible to TPP-induced delayed neurotoxicity but only become so after they have achieved some degree of maturity. Whether the LGN neurons undergoing degeneration are directly affected by TPP or are showing a transneuronal response to loss of afferent input remains unresolved.

  11. Inhibition of Mitochondrial Cytochrome c Release and Suppression of Caspases by Gamma-Tocotrienol Prevent Apoptosis and Delay Aging in Stress-Induced Premature Senescence of Skin Fibroblasts

    Directory of Open Access Journals (Sweden)

    Suzana Makpol

    2012-01-01

    Full Text Available In this study, we determined the molecular mechanism of γ-tocotrienol (GTT in preventing cellular aging by focusing on its anti-apoptotic effect in stress-induced premature senescence (SIPS model of human diploid fibroblasts (HDFs. Results obtained showed that SIPS exhibited senescent-phenotypic characteristic, increased expression of senescence-associated β-galactosidase (SA β-gal and promoted G0/G1 cell cycle arrest accompanied by shortening of telomere length with decreased telomerase activity. Both SIPS and senescent HDFs shared similar apoptotic changes such as increased Annexin V-FITC positive cells, increased cytochrome c release and increased activation of caspase-9 and caspase-3 (P<0.05. GTT treatment resulted in a significant reduction of Annexin V-FITC positive cells, inhibited cytochrome c release and decreased activation of caspase-9 and caspase-3 (P<0.05. Gene expression analysis showed that GTT treatment down regulated BAX mRNA, up-regulated BCL2A1 mRNA and decreased the ratio of Bax/Bcl-2 protein expression (P<0.05 in SIPS. These findings suggested that GTT inhibits apoptosis by modulating the upstream apoptosis cascade, causing the inhibition of cytochrome c release from the mitochondria with concomitant suppression of caspase-9 and caspase-3 activation. In conclusion, GTT delays cellular senescence of human diploid fibroblasts through the inhibition of intrinsic mitochondria-mediated pathway which involved the regulation of pro- and anti-apoptotic genes and proteins.

  12. Prevention of cisplatin-based chemotherapy-induced delayed nausea and vomiting using triple antiemetic regimens: a mixed treatment comparison.

    Science.gov (United States)

    Shi, Qi; Li, Wen; Li, Hongjia; Le, Qiqi; Liu, Shanshan; Zong, Shaoqi; Zheng, Leizhen; Hou, Fenggang

    2016-04-26

    A variety of triple antiemetic regimens are being used to prevent cisplatin-based chemotherapy induced delayed emesis and nausea in cancer patients. We performed a network meta-analysis to compare the efficacies of the different regimens. Electronic searches of the PubMed, Cochrane Library and MEDLINE databases were performed to identify randomized controlled trials, and data were analyzed using JAGS, Stata 14.0 and R project. The primary outcome was a complete response (CR). The secondary outcomes were no vomiting (NV) and no nausea (NN). Among the 398 studies identified, 10 were eligible and included, providing data on nine regimens. In the CR analysis, the absolute rank of netupitant + palonosetron + dexamethasone (NEPA) was 0.8579. In the NV and NN analyses, NEPA's absolute ranks were 0.8631 and 0.7902, respectively. The compliance of patients treated with rolapitant + granisetron + dexamethasone (RGD) was the best due to a low incidence of adverse events, and good compliance was also observed with NEPA. It was difficult to achieve good compliance with aprepitant + granisetron + dexamethasone (AGD). Overall, NEPA was the best regimen, and aprepitant + ondansetron + dexamethasone (AOD) is also worthy of recommendation because of its low cost and good effect. For patients with severe constipation, hiccups, asthenia and/or delayed nausea, RGD is worthy of consideration.

  13. Sucrose delays membrane deterioration of chrysanthemum flowers induced by gamma-rays

    Science.gov (United States)

    Kikuchi, O. K.; Todoriki, S.; Hayashi, T.

    1998-06-01

    Fluidity of the flower membranes of cut chrysanthemums ( Dendranthema grandiflorum Kitamura) decreased soon after gamma-irradiation at 750Gy and continued to decrease during storage following irradiation. Holding chrysanthemum cut inflorescence in 2% sucrose suppressed the decrease. The results suggest that sugars reduce radiation-induced physiological deterioration of chrysanthemum flower membranes.

  14. Sucrose delays membrane deterioration of chrysanthemum flowers induced by gamma-rays

    Energy Technology Data Exchange (ETDEWEB)

    Kikuchi, O.K.; Todoriki, S.; Hayashi, T

    1998-06-01

    Fluidity of the flower membranes of cut chrysanthemums (Dendranthema grandiflorum Kitamura) decreased soon after gamma-irradiation at 750Gy and continued to decrease during storage following irradiation. Holding chrysanthemum cut inflorescence in 2% sucrose suppressed the decrease. The results suggest that sugars reduce radiation-induced physiological deterioration of chrysanthemum flower membranes.

  15. Menstruum induces changes in mesothelial cell morphology.

    Science.gov (United States)

    Koks, C A; Demir Weusten, A Y; Groothuis, P G; Dunselman, G A; de Goeij, A F; Evers, J L

    2000-01-01

    In previous studies, we have shown that menstrual endometrium preferentially adheres to the subepithelial lining of the peritoneum. It remains to be elucidated, however, whether this damage is preexisting or inflicted by the menstrual tissue itself. We hypothesized that the menstrual tissue itself damages the peritoneum. To investigate this, the viability of menstrual endometrial tissue in peritoneal fluid (PF) was evaluated and the morphologic changes in the mesothelial cells were studied by in vitro cocultures of menstruum with mesothelial cell monolayers. Menstruum was collected with a menstrual cup. Endometrial tissue was isolated from the menstruum, resuspended in culture medium or in the cell-free fraction of PF and cultured for 24, 48 or 72 h. A 3(4, 5-dimethylthiazolyl-2)-2,5-diphenyl tetrazolium bromide (MTT) assay was performed to obtain a relative measure of viable adhered endometrial cells. Mesothelial cells isolated from human omental tissue were cultured on Matrigel or uncoated plastic. At confluence, overnight cocultures were performed and scanning electron microscopy was used to evaluate the morphologic changes. The viability of endometrial fragments was 84% (n = 36, p Menstrual endometrial fragments or menstrual serum added to and cocultured with mesothelial cells induced severe morphologic alterations of the latter, including retraction, shrinking and gap formation. Similar morphologic changes were observed when mesothelial cells were cocultured with menstrual endometrial fragments in PF or in culture inserts. Incubation with conditioned medium from cultured menstrual endometrium induced similar but less pronounced changes in morphology. In conclusion, menstrual endometrial fragments remain viable in PF in vitro for at least 72 h. Antegradely shed menstruum induces changes in mesothelial cell morphology, including retraction and shrinking with exposure of the underlying surface. These findings suggest that menstruum is harmful to the peritoneal

  16. Direct imaging of delayed magneto-dynamic modes induced by surface acoustic waves.

    Science.gov (United States)

    Foerster, Michael; Macià, Ferran; Statuto, Nahuel; Finizio, Simone; Hernández-Mínguez, Alberto; Lendínez, Sergi; Santos, Paulo V; Fontcuberta, Josep; Hernàndez, Joan Manel; Kläui, Mathias; Aballe, Lucia

    2017-09-01

    The magnetoelastic effect-the change of magnetic properties caused by the elastic deformation of a magnetic material-has been proposed as an alternative approach to magnetic fields for the low-power control of magnetization states of nanoelements since it avoids charge currents, which entail ohmic losses. Here, we have studied the effect of dynamic strain accompanying a surface acoustic wave on magnetic nanostructures in thermal equilibrium. We have developed an experimental technique based on stroboscopic X-ray microscopy that provides a pathway to the quantitative study of strain waves and magnetization at the nanoscale. We have simultaneously imaged the evolution of both strain and magnetization dynamics of nanostructures at the picosecond time scale and found that magnetization modes have a delayed response to the strain modes, adjustable by the magnetic domain configuration. Our results provide fundamental insight into magnetoelastic coupling in nanostructures and have implications for the design of strain-controlled magnetostrictive nano-devices.Understanding the effects of local dynamic strain on magnetization may help the development of magnetic devices. Foerster et al. demonstrate stroboscopic imaging that allows the observation of both strain and magnetization dynamics in nickel when surface acoustic waves are driven in the substrate.

  17. Inflammatory cytokine-mediated evasion of virus-induced tumors from NK cell control.

    Science.gov (United States)

    Mishra, Rabinarayan; Polic, Bojan; Welsh, Raymond M; Szomolanyi-Tsuda, Eva

    2013-07-15

    Infections with DNA tumor viruses, including members of the polyomavirus family, often result in tumor formation in immune-deficient hosts. The complex control involved in antiviral and antitumor immune responses during these infections can be studied in murine polyomavirus (PyV)-infected mice as a model. We found that NK cells efficiently kill cells derived from PyV-induced salivary gland tumors in vitro in an NKG2D (effector cell)-RAE-1 (target cell)-dependent manner; but in T cell-deficient mice, NK cells only delay but do not prevent the development of PyV-induced tumors. In this article, we show that the PyV-induced tumors have infiltrating functional NK cells. The freshly removed tumors, however, lack surface RAE-1 expression, and the tumor tissues produce soluble factors that downregulate RAE-1. These factors include the proinflammatory cytokines IL-1α, IL-1β, IL-33, and TNF. Each of these cytokines downregulates RAE-1 expression and susceptibility to NK cell-mediated cytotoxicity. CD11b(+)F4/80(+) macrophages infiltrating the PyV-induced tumors produce high amounts of IL-1β and TNF. Thus, our data suggest a new mechanism whereby inflammatory cytokines generated in the tumor environment lead to evasion of NK cell-mediated control of virus-induced tumors.

  18. LPS-induced delayed preconditioning is mediated by Hsp90 and involves the heat shock response in mouse kidney.

    Directory of Open Access Journals (Sweden)

    Tamás Kaucsár

    Full Text Available We and others demonstrated previously that preconditioning with endotoxin (LPS protected from a subsequent lethal LPS challenge or from renal ischemia-reperfusion injury (IRI. LPS is effective in evoking the heat shock response, an ancient and essential cellular defense mechanism, which plays a role in resistance to, and recovery from diseases. Here, by using the pharmacological Hsp90 inhibitor novobiocin (NB, we investigated the role of Hsp90 and the heat shock response in LPS-induced delayed renal preconditioning.Male C57BL/6 mice were treated with preconditioning (P: 2 mg/kg, i.p. and subsequent lethal (L: 10 mg/kg, i.p. doses of LPS alone or in combination with NB (100 mg/kg, i.p.. Controls received saline (C or NB.Preconditioning LPS conferred protection from a subsequent lethal LPS treatment. Importantly, the protective effect of LPS preconditioning was completely abolished by a concomitant treatment with NB. LPS induced a marked heat shock protein increase as demonstrated by Western blots of Hsp70 and Hsp90. NB alone also stimulated Hsp70 and Hsp90 mRNA but not protein expression. However, Hsp70 and Hsp90 protein induction in LPS-treated mice was abolished by a concomitant NB treatment, demonstrating a NB-induced impairment of the heat shock response to LPS preconditioning.LPS-induced heat shock protein induction and tolerance to a subsequent lethal LPS treatment was prevented by the Hsp90 inhibitor, novobiocin. Our findings demonstrate a critical role of Hsp90 in LPS signaling, and a potential involvement of the heat shock response in LPS-induced preconditioning.

  19. FACT prevents the accumulation of free histones evicted from transcribed chromatin and a subsequent cell cycle delay in G1.

    Directory of Open Access Journals (Sweden)

    Macarena Morillo-Huesca

    2010-05-01

    Full Text Available The FACT complex participates in chromatin assembly and disassembly during transcription elongation. The yeast mutants affected in the SPT16 gene, which encodes one of the FACT subunits, alter the expression of G1 cyclins and exhibit defects in the G1/S transition. Here we show that the dysfunction of chromatin reassembly factors, like FACT or Spt6, down-regulates the expression of the gene encoding the cyclin that modulates the G1 length (CLN3 in START by specifically triggering the repression of its promoter. The G1 delay undergone by spt16 mutants is not mediated by the DNA-damage checkpoint, although the mutation of RAD53, which is otherwise involved in histone degradation, enhances the cell-cycle defects of spt16-197. We reveal how FACT dysfunction triggers an accumulation of free histones evicted from transcribed chromatin. This accumulation is enhanced in a rad53 background and leads to a delay in G1. Consistently, we show that the overexpression of histones in wild-type cells down-regulates CLN3 in START and causes a delay in G1. Our work shows that chromatin reassembly factors are essential players in controlling the free histones potentially released from transcribed chromatin and describes a new cell cycle phenomenon that allows cells to respond to excess histones before starting DNA replication.

  20. SWCNTs induced autophagic cell death in human bronchial epithelial cells.

    Science.gov (United States)

    Park, Eun-Jung; Zahari, Nur Elida M; Lee, Eun-Woo; Song, Jaewhan; Lee, Jae-Hyeok; Cho, Myung-Haing; Kim, Jae-Ho

    2014-04-01

    Carbon nanotubes are being actively introduced in electronics, computer science, aerospace, and other industries. Thus, the urgent need for toxicological studies on CNTs is mounting. In this study, we investigated the alterations in cellular response with morphological changes induced by single-walled carbon nanotubes (SWCNTs) in BEAS-2B cells, a human bronchial epithelial cell line. At 24h after exposure, SWCNTs rapidly decreased ATP production and cell viability as well a slight increase in the number of cells in the subG1 and G1 phases. In addition, SWCNTs increased the expression of superoxide dismutase (SOD)-1, but not SOD-2, and the number of cells generating ROS. The concentration of Cu and Zn ions also increased in a dose-dependent manner in cells exposed to SWCNTs. SWCNTs significantly enhanced the release of nitric oxide, interleukin (IL)-6, and IL-8 and up-regulated the expression of chemokine- and cytokine-related genes. Furthermore, the levels of autophagy-related genes, especially the DRAM1 gene, and the autophagosome formation-related proteins, were clearly up-regulated together with an increase of autophagosome-like vacuoles. Based on these results, we suggest that SWCNTs induce autophagic cell death through mitochondrial dysfunction and cytosolic damage in human bronchial epithelial cells. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Direct Yaw-Moment Control of All-Wheel-Independent-Drive Electric Vehicles with Network-Induced Delays through Parameter-Dependent Fuzzy SMC Approach

    Directory of Open Access Journals (Sweden)

    Wanke Cao

    2017-01-01

    Full Text Available This paper investigates the robust direct yaw-moment control (DYC through parameter-dependent fuzzy sliding mode control (SMC approach for all-wheel-independent-drive electric vehicles (AWID-EVs subject to network-induced delays. AWID-EVs have obvious advantages in terms of DYC over the traditional centralized-drive vehicles. However it is one of the most principal issues for AWID-EVs to ensure the robustness of DYC. Furthermore, the network-induced delays would also reduce control performance of DYC and even deteriorate the EV system. To ensure robustness of DYC and deal with network-induced delays, a parameter-dependent fuzzy sliding mode control (FSMC method based on the real-time information of vehicle states and delays is proposed in this paper. The results of cosimulations with Simulink® and CarSim® demonstrate the effectiveness of the proposed controller. Moreover, the results of comparison with a conventional FSMC controller illustrate the strength of explicitly dealing with network-induced delays.

  2. Early and Delayed Antiretroviral Therapy Results in Comparable Reductions in CD8+T Cell Exhaustion Marker Expression.

    Science.gov (United States)

    Rutishauser, Rachel Lena; Hartogensis, Wendy; Deguit, Christian Deo; Krone, Melissa; Hoh, Rebecca; Hecht, Frederick M; Pilcher, Christopher D; Bacchetti, Peter; Deeks, Steven G; Hunt, Peter W; McCune, Joseph M

    2017-07-01

    In untreated HIV infection, CD8 + T cell exhaustion (i.e., decreased proliferative and effector capacity) is associated with high levels of expression of coinhibitory receptors, including PD-1, T cell immunoreceptor with Ig and ITIM domains (TIGIT), CD160, and 2B4. This is evident for both HIV-specific and non-HIV-specific CD8 + T cells. Antiretroviral therapy (ART) initiated during chronic infection decreases but may not completely normalize the expression of such "exhaustion markers." Compared to initiation of ART later in the course of disease, initiation soon after infection reduces some parameters of chronic inflammation and adaptive immune dysfunction. However, it is not known if Early ART (e.g., initiated within the first 6 months after HIV infection) versus Delayed ART (e.g., initiated during chronic infection) preferentially reduces expression of exhaustion markers. We evaluated exhaustion marker expression on subsets of circulating effector and memory CD8 + T cells at longitudinal pre- and post-ART (2 and 5 years on ART) time points from n = 19 (Early ART) and n = 23 (Delayed ART) individuals. Before ART, TIGIT and CD160 were expressed on a statistically significantly higher proportion of effector and transitional memory cells from individuals in the Delayed ART group: the timing of ART initiation, however, did not consistently affect the expression of the exhaustion markers once viral suppression was achieved. Understanding which factors do and do not regulate aspects of CD8 + T cell exhaustion, including the expression of exhaustion markers, is critical to inform the rational design of CD8 + T cell-based therapies to treat HIV, for which CD8 + T cell exhaustion remains an important barrier to efficacy.

  3. Moderately delayed post-insult treatment with normobaric hyperoxia reduces excitotoxin-induced neuronal degeneration but increases ischemia-induced brain damage

    Directory of Open Access Journals (Sweden)

    Haelewyn Benoit

    2011-04-01

    Full Text Available Abstract Background The use and benefits of normobaric oxygen (NBO in patients suffering acute ischemic stroke is still controversial. Results Here we show for the first time to the best of our knowledge that NBO reduces both NMDA-induced calcium influxes in vitro and NMDA-induced neuronal degeneration in vivo, but increases oxygen and glucose deprivation-induced cell injury in vitro and ischemia-induced brain damage produced by middle cerebral artery occlusion in vivo. Conclusions Taken together, these results indicate that NBO reduces excitotoxin-induced calcium influx and subsequent neuronal degeneration but favors ischemia-induced brain damage and neuronal death. These findings highlight the complexity of the mechanisms involved by the use of NBO in patients suffering acute ischemic stroke.

  4. IGF Binding Protein-5 Induces Cell Senescence

    Directory of Open Access Journals (Sweden)

    Fumihiro Sanada

    2018-02-01

    Full Text Available Cellular senescence is the complex process of deterioration that drives the aging of an organism, resulting in the progressive loss of organ function and eventually phenotypic aging. Senescent cells undergo irreversible growth arrest, usually by inducing telomere shortening. Alternatively, senescence may also occur prematurely in response to various stress stimuli, such as oxidative stress, DNA damage, or activated oncogenes. Recently, it has been shown that IGF binding protein-5 (IGFBP-5 with the induction of the tumor suppressor p53 is upregulated during cellular senescence. This mechanism mediates interleukin-6/gp130-induced premature senescence in human fibroblasts, irradiation-induced premature senescence in human endothelial cells (ECs, and replicative senescence in human ECs independent of insulin-like growth factor I (IGF-I and IGF-II. Additionally, a link between IGFBP-5, hyper-coagulation, and inflammation, which occur with age, has been implicated. Thus, IGFBP-5 seems to play decisive roles in controlling cell senescence and cell inflammation. In this review, we describe the accumulating evidence for this role of IGFBP-5 including our new finding.

  5. Dietary heme induces acute oxidative stress, but delayed cytotoxicity and compensatory hyperproliferation in mouse colon

    NARCIS (Netherlands)

    IJssenagger, N.; Rijnierse, A.; Wit, de N.J.W.; Boekschoten, M.V.; Dekker, J.; Schonewille, A.; Müller, M.R.; Meer, van der M.

    2013-01-01

    Red meat consumption is associated with an increased colon cancer risk. Heme, present in red meat, injures the colon surface epithelium by generating cytotoxic and oxidative stress. Recently, we found that this surface injury is compensated by hyperproliferation and hyperplasia of crypt cells, which

  6. Delayed effects of accelerated heavy ions on the induction of HPRT mutations in V79 hamster cells.

    Science.gov (United States)

    Bláha, Pavel; Koshlan, Nataliya A; Koshlan, Igor V; Petrova, Daria V; Bogdanova, Yulia V; Govorun, Raisa D; Múčka, Viliam; Krasavin, Evgeny A

    2017-10-01

    Fundamental research on the harmful effects of ionizing radiation on living cells continues to be of great interest. Recently, priority has been given to the study of high-charge and high-energy (HZE) ions that comprise a substantial part of the galactic cosmic ray (GCR) spectra that would be encountered during long-term space flights. Moreover, predictions of the delayed genetic effects of high linear energy transfer (LET) exposure is becoming more important as heavy ion therapy use is increasing. This work focuses mainly on the basic research on the delayed effects of HZE ions on V79 Chinese hamster cells, with emphasis on the induction of HPRT mutations after prolonged expression times (ET). The research was conducted under various irradiation conditions with accelerated ions 18 O (E=35.2MeV/n), 20 Ne (E=47.7MeV/n and 51.8MeV/n), and 11 B (E=32.4MeV/n), with LET in the range from 49 to 149 keV/μm and with 60 Co γ-rays. The HPRT mutant fractions (MF) were detected in irradiated cells in regular intervals during every cell culture recultivation (every 3days) up to approximately 40days (70-80 generations) after irradiation. The MF maximum was reached at different ET depending on ionizing radiation characteristics. The position of the maximum was shifting towards longer ET with increasing LET. We speculate that the delayed mutations are created de novo and that they are the manifestation of genomic instability. Although the exact mechanisms involved in genomic instability initiation are yet to be identified, we hypothesize that differences in induction of delayed mutations by radiations with various LET values are related to variations in energy deposition along the particle track. A dose dependence of mutation yield is discussed as well. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Alpha-toxin induces programmed cell death of human T cells, B cells, and monocytes during USA300 infection.

    Directory of Open Access Journals (Sweden)

    Tyler K Nygaard

    Full Text Available This investigation examines the influence of alpha-toxin (Hla during USA300 infection of human leukocytes. Survival of an USA300 isogenic deletion mutant of hla (USA300Δhla in human blood was comparable to the parental wild-type strain and polymorphonuclear leukocyte (PMN plasma membrane permeability caused by USA300 did not require Hla. Flow cytometry analysis of peripheral blood mononuclear cells (PBMCs following infection by USA300, USA300Δhla, and USA300Δhla transformed with a plasmid over-expressing Hla (USA300Δhla Comp demonstrated this toxin plays a significant role inducing plasma membrane permeability of CD14(+, CD3(+, and CD19(+ PBMCs. Rapid plasma membrane permeability independent of Hla was observed for PMNs, CD14(+ and CD19(+ PBMCs following intoxication with USA300 supernatant while the majority of CD3(+ PBMC plasma membrane permeability induced by USA300 required Hla. Addition of recombinant Hla to USA300Δhla supernatant rescued CD3(+ and CD19(+ PBMC plasma membrane permeability generated by USA300 supernatant. An observed delay in plasma membrane permeability caused by Hla in conjunction with Annexin V binding and ApoBrdU Tunel assays examining PBMCs intoxicated with recombinant Hla or infected with USA300, USA300Δhla, USA300Δhla Comp, and USA300ΔsaeR/S suggest Hla induces programmed cell death of monocytes, B cells, and T cells that results in plasma membrane permeability. Together these findings underscore the importance of Hla during S. aureus infection of human tissue and specifically demonstrate Hla activity during USA300 infection triggers programmed cell death of human monocytes, T cells and B cells that leads to plasma membrane permeability.

  8. Inducible cell death in plant immunity

    DEFF Research Database (Denmark)

    Hofius, Daniel; Tsitsigiannis, Dimitrios I; Jones, Jonathan D G

    2006-01-01

    Programmed cell death (PCD) occurs during vegetative and reproductive plant growth, as typified by autumnal leaf senescence and the terminal differentiation of the endosperm of cereals which provide our major source of food. PCD also occurs in response to environmental stress and pathogen attack......, and these inducible PCD forms are intensively studied due their experimental tractability. In general, evidence exists for plant cell death pathways which have similarities to the apoptotic, autophagic and necrotic forms described in yeast and metazoans. Recent research aiming to understand these pathways...

  9. Adenovirus vectors can induce activation of endothelial cells: CD40 ...

    African Journals Online (AJOL)

    Adenovirus vectors can induce activation of endothelial cells: CD40-CD40L interactions partly participate in the endothelial cells activation induced by adenovirus vectors in an NF-kappaB-dependent manner.

  10. Chromate-induced epimutations in mammalian cells.

    OpenAIRE

    Klein, Catherine B.; Su, Lin; Bowser, Darlene; Leszczynska, Joanna

    2002-01-01

    Epigenetic gene silencing by aberrant DNA methylation of gene promoter regions is a nonmutagenic but heritable epigenetic mechanism that may mistakenly cause the silencing of important cancer-related tumor suppressor genes. Using a transgenic, V79-derived, mammalian cell line (G12) that contains a bacterial gpt reporter gene in its DNA, we can study carcinogen-induced gene inactivation by mutagenic as well as epigenetic DNA methylation mechanisms. Whereas numerous carcinogens have previously ...

  11. Low concentrations of salicylic acid delay methyl jasmonate-induced leaf senescence by up-regulating nitric oxide synthase activity.

    Science.gov (United States)

    Ji, Yingbin; Liu, Jian; Xing, Da

    2016-09-01

    In plants, extensive efforts have been devoted to understanding the crosstalk between salicylic acid (SA) and jasmonic acid (JA) signaling in pathogen defenses, but this crosstalk has scarcely been addressed during senescence. In this study, the effect of SA application on methyl jasmonate (MeJA)-induced leaf senescence was assessed. We found that low concentrations of SA (1-50 μM) played a delayed role against the senescence promoted by MeJA. Furthermore, low concentrations of SA enhanced plant antioxidant defenses and restricted reactive oxygen species (ROS) accumulation in MeJA-treated leaves. When applied simultaneously with MeJA, low concentrations of SA triggered a nitric oxide (NO) burst, and the elevated NO levels were linked to the nitric oxide associated 1 (NOA1)-dependent pathway via nitric oxide synthase (NOS) activity. The ability of SA to up-regulate plant antioxidant defenses, reduce ROS accumulation, and suppress leaf senescence was lost in NO-deficient Atnoa1 plants. In a converse manner, exogenous addition of NO donors increased the plant antioxidant capacity and lowered the ROS levels in MeJA-treated leaves. Taken together, the results indicate that SA at low concentrations counteracts MeJA-induced leaf senescence through NOA1-dependent NO signaling and strengthening of the antioxidant defense. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  12. Acute and delayed peripheral and central neuromuscular alterations induced by a short and intense downhill trail run.

    Science.gov (United States)

    Giandolini, M; Horvais, N; Rossi, J; Millet, G Y; Morin, J-B; Samozino, P

    2016-11-01

    Downhill sections are highly strenuous likely contributing to the development of neuromuscular fatigue in trail running. Our purpose was to investigate the consequences of an intense downhill trail run (DTR) on peripheral and central neuromuscular fatigue at knee extensors (KE) and plantar flexors (PF). Twenty-three runners performed a 6.5-km DTR (1264-m altitude drop) as fast as possible. The electromyographic activity of vastus lateralis (VL) and gastrocnemius lateralis (GL) was continuously recorded. Neuromuscular functions were assessed Pre-, Post-, and 2-day Post-DTR (Post2d). Maximal voluntary torques decreased Post (∼ -19% for KE, ∼ -25% for PF) and Post2d (∼ -9% for KE, ∼ -10% for PF). Both central and peripheral dysfunctions were observed. Decreased KE and PF voluntary activation (VA), evoked forces, VL M-wave amplitude, and KE low-frequency fatigue were observed at Post. Changes in VL M-wave amplitude were negatively correlated to VL activity during DTR. Changes in PF twitch force and VA were negatively correlated to GL activity during DTR. The acute KE VA deficit was about a third of that reported after ultramarathons, although peripheral alterations were similar. The prolonged force loss seems to be mainly associated to VA deficit likely induced by the delayed inflammatory response to DTR-induced ultrastructural muscle damage. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Determinantes del retraso de la interrupción voluntaria del embarazo Determinants of induced abortion delay

    Directory of Open Access Journals (Sweden)

    Laia Font-Ribera

    2009-10-01

    Full Text Available Antecedentes: El momento de la gestación en que se induce una interrupción voluntaria del embarazo (IVE determina el método, el riesgo de complicaciones y el coste económico de la intervención. El objetivo de nuestro estudio fue describir los determinantes del retraso de la IVE hasta el segundo trimestre de gestación en Barcelona. Métodos: Estudio transversal de las IVE por motivos de salud física o mental de la mujer (Barcelona, 2004-2005; N=9.175. El registro de IVE de la ciudad proporcionó el tiempo de gestación (variable dependiente, el nivel de estudios, la edad, la convivencia en pareja, el número de hijos, IVE anteriores y tipo de centro. Se calcularon razones de prevalencia ajustadas (RPa mediante modelos de regresión log-binomial. Resultados: El 7,7% de las IVE fueron de segundo trimestre y el 99,3% se realizaron en centros privados. En comparación con las mujeres con estudios universitarios, las que tienen educación primaria o menos tienen una RPa de 1,8 (intervalo de confianza del 95% [IC95%]: 1,4-2,2 de IVE de segundo trimestre. También se registran más IVE de segundo trimestre en las menores de 18 años (RPa=2,6; IC95%: 2,0-3,4, las que no conviven en pareja (RPa=1,4; IC95%: 1,2-1,6 y en los centros públicos (RPa=2,8; IC95%: 2,2-3,7. No hay diferencias en el retraso de la IVE entre las mujeres que han tenido IVE anteriores y las que no. Conclusión: El retraso de la IVE hasta el segundo trimestre se asoció a niveles educativos más bajos, edades jóvenes, no convivencia en pareja y centros públicos, y se demuestra la existencia de desigualdades socioeconómicas en las condiciones de acceso a la IVE.Background: In induced abortion, the method, the risk of complications and the economic cost of the abortion are determined by gestational age. The aim of this study was to describe the determinants of induced abortion delay until the second trimester of pregnancy in Barcelona. Methods: We performed a cross

  14. Cell death induced by endoplasmic reticulum stress.

    Science.gov (United States)

    Iurlaro, Raffaella; Muñoz-Pinedo, Cristina

    2016-07-01

    The endoplasmic reticulum is an organelle with multiple functions. The synthesis of transmembrane proteins and proteins that are to be secreted occurs in this organelle. Many conditions that impose stress on cells, including hypoxia, starvation, infections and changes in secretory needs, challenge the folding capacity of the cell and promote endoplasmic reticulum stress. The cellular response involves the activation of sensors that transduce signaling cascades with the aim of restoring homeostasis. This is known as the unfolded protein response, which also intersects with the integrated stress response that reduces protein synthesis through inactivation of the initiation factor eIF2α. Central to the unfolded protein response are the sensors PERK, IRE1 and ATF6, as well as other signaling nodes such as c-Jun N-terminal kinase 1 (JNK) and the downstream transcription factors XBP1, ATF4 and CHOP. These proteins aim to restore homeostasis, but they can also induce cell death, which has been shown to occur by necroptosis and, more commonly, through the regulation of Bcl-2 family proteins (Bim, Noxa and Puma) that leads to mitochondrial apoptosis. In addition, endoplasmic reticulum stress and proteotoxic stress have been shown to induce TRAIL receptors and activation of caspase-8. Endoplasmic reticulum stress is a common feature in the pathology of numerous diseases because it plays a role in neurodegeneration, stroke, cancer, metabolic diseases and inflammation. Understanding how cells react to endoplasmic reticulum stress can accelerate discovery of drugs against these diseases. © 2015 FEBS.

  15. Loss of the Inducible Hsp70 Delays the Inflammatory Response to Skeletal Muscle Injury and Severely Impairs Muscle Regeneration

    Science.gov (United States)

    Howard, Travis M.; Ahn, Bumsoo; Ferreira, Leonardo F.

    2013-01-01

    Skeletal muscle regeneration following injury is a highly coordinated process that involves transient muscle inflammation, removal of necrotic cellular debris and subsequent replacement of damaged myofibers through secondary myogenesis. However, the molecular mechanisms which coordinate these events are only beginning to be defined. In the current study we demonstrate that Heat shock protein 70 (Hsp70) is increased following muscle injury, and is necessary for the normal sequence of events following severe injury induced by cardiotoxin, and physiological injury induced by modified muscle use. Indeed, Hsp70 ablated mice showed a significantly delayed inflammatory response to muscle injury induced by cardiotoxin, with nearly undetected levels of both neutrophil and macrophage markers 24 hours post-injury. At later time points, Hsp70 ablated mice showed sustained muscle inflammation and necrosis, calcium deposition and impaired fiber regeneration that persisted several weeks post-injury. Through rescue experiments reintroducing Hsp70 intracellular expression plasmids into muscles of Hsp70 ablated mice either prior to injury or post-injury, we confirm that Hsp70 optimally promotes muscle regeneration when expressed during both the inflammatory phase that predominates in the first four days following severe injury and the regenerative phase that predominates thereafter. Additional rescue experiments reintroducing Hsp70 protein into the extracellular microenvironment of injured muscles at the onset of injury provides further evidence that Hsp70 released from damaged muscle may drive the early inflammatory response to injury. Importantly, following induction of physiological injury through muscle reloading following a period of muscle disuse, reduced inflammation in 3-day reloaded muscles of Hsp70 ablated mice was associated with preservation of myofibers, and increased muscle force production at later time points compared to WT. Collectively our findings indicate that

  16. Chemical -induced apoptotic cell death in tomato cells : involvement of caspase-like proteases

    NARCIS (Netherlands)

    Jong, de A.J.; Hoeberichts, F.A.; Yakimova, E.T.; Maximova, E.; Woltering, E.J.

    2000-01-01

    A new system to study programmed cell death in plants is described. Tomato (Lycopersicon esculentum Mill.) suspension cells were induced to undergo programmed cell death by treatment with known inducers of apoptosis in mammalian cells. This chemical-induced cell death was accompanied by the

  17. Inhibition of veratridine-induced delayed inactivation of the voltage-sensitive sodium channel by synthetic analogs of crambescin B.

    Science.gov (United States)

    Tsukamoto, Tadaaki; Chiba, Yukie; Nakazaki, Atsuo; Ishikawa, Yuki; Nakane, Yoshiki; Cho, Yuko; Yotsu-Yamashita, Mari; Nishikawa, Toshio; Wakamori, Minoru; Konoki, Keiichi

    2017-03-01

    Crambescin B carboxylic acid, a synthetic analog of crambescin B, was recently found to inhibit the voltage-sensitive sodium channels (VSSC) in a cell-based assay using neuroblastoma Neuro 2A cells. In the present study, whole-cell patch-clamp recordings were conducted with three heterologously expressed VSSC subtypes, Na v 1.2, Na v 1.6 and Na v 1.7, in a human embryonic kidney cell line HEK293T to further characterize the inhibition of VSSC by crambescin B carboxylic acid. Contrary to the previous observation, crambescin B carboxylic acid did not inhibit peak current evoked by depolarization from the holding potential of -100mV to the test potential of -10mV in the absence or presence of veratridine (VTD). In the presence of VTD, however, crambescin B carboxylic acid diminished VTD-induced sustained and tail currents through the three VSSC subtypes in a dose-dependent manner, whereas TTX inhibited both the peak current and the VTD-induced sustained and tail currents through all subtypes of VSSC tested. We thus concluded that crambescin B carboxylic acid does not block VSSC in a similar manner to TTX but modulate the action of VTD, thereby causing an apparent block of VSSC in the cell-based assay. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Increased mammogram-induced DNA damage in mammary epithelial cells aged in vitro.

    Directory of Open Access Journals (Sweden)

    Laia Hernández

    Full Text Available Concerned about the risks of mammography screening in the adult population, we analyzed the ability of human mammary epithelial cells to cope with mammogram-induced DNA damage. Our study shows that an X-ray dose of 20 mGy, which is the standard dose received by the breast surface per two-view mammogram X-ray exploration, induces increased frequencies of DNA double-strand breaks to in vitro aged-but not to young-human mammary epithelial cells. We provide evidence that aged epithelial breast cells are more radiosensitive than younger ones. Our studies point to an inefficient damage response of aged cells to low-dose radiation, this being due to both delayed and incomplete mobilization of repair proteins to DNA strand breaks. This inefficient damage response is translated into an important delay in double-strand break disappearance and consequent accumulation of unrepaired DNA breaks. The result of this is a significant increase in micronuclei frequency in the in vitro aged mammary epithelial cells exposed to doses equivalent to a single mammogram X-ray exploration. Since our experiments were carried out in primary epithelial cell cultures in which cells age at the same time as they undergo replication-dependent telomere shortening, we needed to determine the contribution of these two factors to their phenotype. In this paper, we report that the exogenous expression of human telomerase retrotranscriptase in late population doubling epithelial cells does not rescue its delayed repair phenotype. Therefore, retarded DNA break repair is a direct consequence of cellular aging itself, rather than a consequence of the presence of dysfunctional telomeres. Our findings of long-lasting double strand breaks and incomplete DNA break repair in the in vitro aged epithelial cells are in line with the increased carcinogenic risks of radiation exposures at older ages revealed by epidemiologic studies.

  19. Increased Mammogram-Induced DNA Damage in Mammary Epithelial Cells Aged In Vitro

    Science.gov (United States)

    Hernández, Laia; Terradas, Mariona; Martín, Marta; Feijoo, Purificación; Soler, David; Tusell, Laura; Genescà, Anna

    2013-01-01

    Concerned about the risks of mammography screening in the adult population, we analyzed the ability of human mammary epithelial cells to cope with mammogram-induced DNA damage. Our study shows that an X-ray dose of 20 mGy, which is the standard dose received by the breast surface per two-view mammogram X-ray exploration, induces increased frequencies of DNA double-strand breaks to in vitro aged–but not to young–human mammary epithelial cells. We provide evidence that aged epithelial breast cells are more radiosensitive than younger ones. Our studies point to an inefficient damage response of aged cells to low-dose radiation, this being due to both delayed and incomplete mobilization of repair proteins to DNA strand breaks. This inefficient damage response is translated into an important delay in double-strand break disappearance and consequent accumulation of unrepaired DNA breaks. The result of this is a significant increase in micronuclei frequency in the in vitro aged mammary epithelial cells exposed to doses equivalent to a single mammogram X-ray exploration. Since our experiments were carried out in primary epithelial cell cultures in which cells age at the same time as they undergo replication-dependent telomere shortening, we needed to determine the contribution of these two factors to their phenotype. In this paper, we report that the exogenous expression of human telomerase retrotranscriptase in late population doubling epithelial cells does not rescue its delayed repair phenotype. Therefore, retarded DNA break repair is a direct consequence of cellular aging itself, rather than a consequence of the presence of dysfunctional telomeres. Our findings of long-lasting double strand breaks and incomplete DNA break repair in the in vitro aged epithelial cells are in line with the increased carcinogenic risks of radiation exposures at older ages revealed by epidemiologic studies. PMID:23667571

  20. Uranium induces apoptosis in lung epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Periyakaruppan, Adaikkappan; Sarkar, Shubhashish; Sadanandan, Bindu; Thomas, Renard; Wilson, Bobby L. [Texas Southern University, Environmental Toxicology Program, Department of Chemistry, Houston, TX (United States); Ravichandran, Prabakaran; Sharma, Chidananda S.; Ramesh, Vani; Hall, Joseph C.; Ramesh, Govindarajan T. [Norfolk State University, Molecular Toxicology Laboratory, Department of Biology, Center for Biotechnology and Biomedical Sciences, Norfolk, VA (United States)

    2009-06-15

    Uranium is a naturally occurring radioactive material present everywhere in the environment. It is toxic because of its chemical or radioactive properties. Uranium enters environment mainly from mines and industry and cause threat to human health by accumulating in lungs as a result of inhalation. In our previous study, we have shown the effectiveness of antioxidant system response to the oxidative stress induced by uranyl acetate (UA) in rat lung epithelial (LE) cells. As part of our continuing studies; here, we investigated the mechanism underlying when LE cells are exposed to different concentration of UA. Oxidative stress may lead to apoptotic signaling pathways. LE cells treated with 0.25, 0.5 and 1 mM of UA results in dose and time-dependent increase in activity of both caspases-3 and -8. Increase in the concentration of cytochrome-c oxidase in cytosol was seen in LE cells treated with 1 mM UA as a result of mitochondria membrane permeability. The cytochrome-c leakage may trigger the apoptotic pathway. TUNEL assay performed in LE cells treated with 1 mM of UA showed significant incorporation of dNTPs in the nucleus after 24 h. In the presence of the caspase inhibitors, we observed the significant decrease in the activity of caspases-8 and -3 in 0.5 and 1 mM UA-treated LE cells. (orig.)

  1. Involvement of the p38 MAPK pathway in IL-13-induced mucous cell metaplasia in mouse tracheal epithelial cells.

    Science.gov (United States)

    Fujisawa, Tomoyuki; Ide, Kyotaro; Holtzman, Michael J; Suda, Takafumi; Suzuki, Kenichiro; Kuroishi, Shigeki; Chida, Kingo; Nakamura, Hirotoshi

    2008-03-01

    IL-13 has been shown to play a pivotal role in mucous cell metaplasia, which is an important feature of the pathogenesis of asthma. However, the signalling pathways evoked by IL-13 in airway epithelial cells remain unclear. This study investigated the signalling mechanism of IL-13-induced mucous cell metaplasia in primary cultures of mouse tracheal epithelial cells (mTEC). mTEC were cultured in an air-liquid interface system in the presence or absence of IL-13. Goblet cell hyperplasia was evaluated quantitatively by immunofluorescent staining for MUC5AC, which is a major component of airway mucins. Western blotting was used to assess activation of the signalling molecules, signal transducer and activator of transcription 6 (STAT6), p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) 1/2. MUC5AC gene expression was measured by RT-PCR. IL-13 induced mucous cell metaplasia for 7-14 days in mTEC. IL-13 phosphorylated STAT6 within 20 min, whereas it induced delayed phosphorylation of p38 MAPK 36-48 h after stimulation. In contrast, ERK1/2 was constantly activated and was not enhanced by IL-13. An inhibitor of p38 MAPK (SB202190) suppressed mucous cell differentiation in a concentration-dependent manner. In STAT6 knockout mice, IL-13 failed to induce mucous cell metaplasia and activate p38 MAPK. Cycloheximide also diminished activation of p38 MAPK and induction of MUC5AC mRNA expression by IL-13. The p38 MAPK pathway is involved in IL-13-induced mucous cell metaplasia and MUC5AC mRNA regulation in mTEC. In addition, p38 MAPK phosphorylation may require STAT6-dependent de novo protein synthesis induced by IL-13.

  2. H2O2 INDUCES DELAYED HYPEREXCITABILITY IN NUCLEUS TRACTUS SOLITARII NEURONS

    Science.gov (United States)

    Ostrowski, Tim D.; Hasser, Eileen M.; Heesch, Cheryl M.; Kline, David D.

    2014-01-01

    Hydrogen peroxide (H2O2) is a stable reactive oxygen species and potent neuromodulator of cellular and synaptic activity. Centrally, endogenous H2O2 is elevated during bouts of hypoxia-reoxygenation, a variety of disease states, and aging. The nucleus tractus solitarii (nTS) is the central termination site of visceral afferents for homeostatic reflexes and contributes to reflex alterations during these conditions. We determined the extent to which H2O2 modulates synaptic and membrane properties in nTS neurons in rat brainstem slices. Stimulation of the tractus solitarii (which contains the sensory afferent fibers) evoked synaptic currents that were not altered by 10 – 500 μM H2O2. However, 500 μM H2O2 modulated several intrinsic membrane properties of nTS neurons, including a decrease in input resistance, hyperpolarization of resting membrane potential (RMP) and action potential (AP) threshold (THR), and an initial reduction in AP discharge to depolarizing current. H2O2 increased conductance of barium-sensitive potassium currents, and block of these currents ablated H2O2-induced changes in RMP, input resistance and AP discharge. Following washout of H2O2 AP discharge was enhanced due to depolarization of RMP and a partially maintained hyperpolarization of THR. Hyperexcitability persisted with repeated H2O2 exposure. H2O2 effects on RMP and THR were ablated by intracellular administration of the antioxidant catalase, which was immunohistochemically identified in neurons throughout the nTS. Thus, H2O2 initially reduces excitability of nTS neurons that is followed by sustained hyperexcitability, which may play a profound role in cardiorespiratory reflexes. PMID:24397952

  3. Serotonin Transporter Promoter Region (5-HTTLPR) Polymorphism Is Not Associated With Paroxetine-Induced Ejaculation Delay in Dutch Men With Lifelong Premature Ejaculation

    NARCIS (Netherlands)

    Janssen, Paddy K C; Zwinderman, Aeilko H; Olivier, Berend; Waldinger, Marcel D

    PURPOSE: To investigate the association between the 5-HT-transporter-gene-linked promoter region (5-HTTLPR) polymorphism and 20-mg paroxetine-induced ejaculation delay in men with lifelong premature ejaculation (LPE). MATERIALS AND METHODS: This was a prospective study of 10 weeks of paroxetine

  4. A specific inhibitor of protein kinase CK2 delays gamma-H2Ax foci removal and reduces clonogenic survival of irradiated mammalian cells

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    Huber Peter E

    2011-02-01

    Full Text Available Abstract Background The protein kinase CK2 sustains multiple pro-survival functions in cellular DNA damage response and its level is tightly regulated in normal cells but elevated in cancers. Because CK2 is thus considered as potential therapeutic target, DNA double-strand break (DSB formation and rejoining, apoptosis induction and clonogenic survival was assessed in irradiated mammalian cells upon chemical inhibition of CK2. Methods MRC5 human fibroblasts and WIDR human colon carcinoma cells were incubated with highly specific CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB, or mock-treated, 2 hours prior to irradiation. DSB was measured by pulsed-field electrophoresis (PFGE as well as gamma-H2AX foci formation and removal. Apoptosis induction was tested by DAPI staining and sub-G1 flow cytometry, survival was quantified by clonogenic assay. Results TBB treatment did not affect initial DNA fragmention (PFGE; up to 80 Gy or foci formation (1 Gy. While DNA fragment rejoining (PFGE was not inhibited by the drug, TBB clearly delayed gamma-H2AX foci disappearence during postirradiation incubation. No apoptosis induction could be detected for up to 38 hours for both cell lines and exposure conditions (monotherapies or combination, but TBB treatment at this moderately toxic concentration of 20 μM (about 40% survival enhanced radiation-induced cell killing in the clonogenic assay. Conclusions The data imply a role of CK2 in gamma-H2AX dephosporylation, most likely through its known ability to stimulate PP2A phosphatase, rather than DSB rejoining. The slight but definite clonogenic radiosensitization by TBB does apparently not result from interference with an apoptosis suppression function of CK2 in these cells but could reflect inhibitor-induced uncoupling of DNA damage response decay from break ligation.

  5. TNF-TNFR2/p75 signaling inhibits early and increases delayed nontargeted effects in bone marrow-derived endothelial progenitor cells.

    Science.gov (United States)

    Sasi, Sharath P; Song, Jin; Park, Daniel; Enderling, Heiko; McDonald, J Tyson; Gee, Hannah; Garrity, Brittany; Shtifman, Alexander; Yan, Xinhua; Walsh, Kenneth; Natarajan, Mohan; Kishore, Raj; Goukassian, David A

    2014-05-16

    TNF-α, a pro-inflammatory cytokine, is highly expressed after being irradiated (IR) and is implicated in mediating radiobiological bystander responses (RBRs). Little is known about specific TNF receptors in regulating TNF-induced RBR in bone marrow-derived endothelial progenitor cells (BM-EPCs). Full body γ-IR WT BM-EPCs showed a biphasic response: slow decay of p-H2AX foci during the initial 24 h and increase between 24 h and 7 days post-IR, indicating a significant RBR in BM-EPCs in vivo. Individual TNF receptor (TNFR) signaling in RBR was evaluated in BM-EPCs from WT, TNFR1/p55KO, and TNFR2/p75KO mice, in vitro. Compared with WT, early RBR (1-5 h) were inhibited in p55KO and p75KO EPCs, whereas delayed RBR (3-5 days) were amplified in p55KO EPCs, suggesting a possible role for TNFR2/p75 signaling in delayed RBR. Neutralizing TNF in γ-IR conditioned media (CM) of WT and p55KO BM-EPCs largely abolished RBR in both cell types. ELISA protein profiling of WT and p55KO EPC γ-IR-CM over 5 days showed significant increases in several pro-inflammatory cytokines, including TNF-α, IL-1α (Interleukin-1 alpha), RANTES (regulated on activation, normal T cell expressed and secreted), and MCP-1. In vitro treatments with murine recombinant (rm) TNF-α and rmIL-1α, but not rmMCP-1 or rmRANTES, increased the formation of p-H2AX foci in nonirradiated p55KO EPCs. We conclude that TNF-TNFR2 signaling may induce RBR in naïve BM-EPCs and that blocking TNF-TNFR2 signaling may prevent delayed RBR in BM-EPCs, conceivably, in bone marrow milieu in general. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Oocyte-like cells induced from mouse spermatogonial stem cells

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    Wang Lu

    2012-08-01

    Full Text Available Abstract Background During normal development primordial germ cells (PGCs derived from the epiblast are the precursors of spermatogonia and oogonia. In culture, PGCs can be induced to dedifferentiate to pluripotent embryonic germ (EG cells in the presence of various growth factors. Several recent studies have now demonstrated that spermatogonial stem cells (SSCs can also revert back to pluripotency as embryonic stem (ES-like cells under certain culture conditions. However, the potential dedifferentiation of SSCs into PGCs or the potential generation of oocytes from SSCs has not been demonstrated before. Results We report that mouse male SSCs can be converted into oocyte-like cells in culture. These SSCs-derived oocytes (SSC-Oocs were similar in size to normal mouse mature oocytes. They expressed oocyte-specific markers and gave rise to embryos through parthenogenesis. Interestingly, the Y- and X-linked testis-specific genes in these SSC-Oocs were significantly down-regulated or turned off, while oocyte-specific X-linked genes were activated. The gene expression profile appeared to switch to that of the oocyte across the X chromosome. Furthermore, these oocyte-like cells lost paternal imprinting but acquired maternal imprinting. Conclusions Our data demonstrate that SSCs might maintain the potential to be reprogrammed into oocytes with corresponding epigenetic reversals. This study provides not only further evidence for the remarkable plasticity of SSCs but also a potential system for dissecting molecular and epigenetic regulations in germ cell fate determination and imprinting establishment during gametogenesis.

  7. Silencing of the CaCP Gene Delays Salt- and Osmotic-Induced Leaf Senescence in Capsicum annuum L.

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    Huai-Juan Xiao

    2014-05-01

    Full Text Available Cysteine proteinases have been known to participate in developmental processes and in response to stress in plants. Our present research reported that a novel CP gene, CaCP, was involved in leaf senescence in pepper (Capsicum annuum L.. The full-length CaCP cDNA is comprised of 1316 bp, contains 1044 nucleotides in open reading frame (ORF, and encodes a 347 amino acid protein. The deduced protein belongs to the papain-like cysteine proteases (CPs superfamily, containing a highly conserved ERFNIN motif, a GCNGG motif and a conserved catalytic triad. This protein localized to the vacuole of plant cells. Real-time quantitative PCR analysis revealed that the expression level of CaCP gene was dramatically higher in leaves and flowers than that in roots, stems and fruits. Moreover, CaCP transcripts were induced upon during leaf senescence. CaCP expression was upregulated by plant hormones, especially salicylic acid. CaCP was also significantly induced by abiotic and biotic stress treatments, including high salinity, mannitol and Phytophthora capsici. Loss of function of CaCP using the virus-induced gene-silencing technique in pepper plants led to enhanced tolerance to salt- and osmotic-induced stress. Taken together, these results suggest that CaCP is a senescence-associated gene, which is involved in developmental senescence and regulates salt- and osmotic-induced leaf senescence in pepper.

  8. Mucosal B Cells Are Associated with Delayed SIV Acquisition in Vaccinated Female but Not Male Rhesus Macaques Following SIVmac251 Rectal Challenge.

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    Iskra Tuero

    2015-08-01

    Full Text Available Many viral infections, including HIV, exhibit sex-based pathogenic differences. However, few studies have examined vaccine-related sex differences. We compared immunogenicity and protective efficacy of monomeric SIV gp120 with oligomeric SIV gp140 in a pre-clinical rhesus macaque study and explored a subsequent sex bias in vaccine outcome. Each immunization group (16 females, 8 males was primed twice mucosally with replication-competent Ad-recombinants encoding SIVsmH4env/rev, SIV239gag and SIV239nefΔ1-13 and boosted twice intramuscularly with SIVmac239 monomeric gp120 or oligomeric gp140 in MF59 adjuvant. Controls (7 females, 5 males received empty Ad and MF59. Up to 9 weekly intrarectal challenges with low-dose SIVmac251 were administered until macaques became infected. We assessed vaccine-induced binding, neutralizing, and non-neutralizing antibodies, Env-specific memory B cells and plasmablasts/plasma cells (PB/PC in bone marrow and rectal tissue, mucosal Env-specific antibodies, and Env-specific T-cells. Post-challenge, only one macaque (gp140-immunized remained uninfected. However, SIV acquisition was significantly delayed in vaccinated females but not males, correlated with Env-specific IgA in rectal secretions, rectal Env-specific memory B cells, and PC in rectal tissue. These results extend previous correlations of mucosal antibodies and memory B cells with protective efficacy. The gp140 regimen was more immunogenic, stimulating elevated gp140 and cyclic V2 binding antibodies, ADCC and ADCP activities, bone marrow Env-specific PB/PC, and rectal gp140-specific IgG. However, immunization with gp120, the form of envelope immunogen used in RV144, the only vaccine trial to show some efficacy, provided more significant acquisition delay. Further over 40 weeks of follow-up, no gp120 immunized macaques met euthanasia criteria in contrast to 7 gp140-immunized and 2 control animals. Although males had higher binding antibodies than females, ADCC

  9. Is Low Non-Lethal Concentration of Methylmercury Really Safe? A Report on Genotoxicity with Delayed Cell Proliferation

    Science.gov (United States)

    Crespo-Lopez, María Elena; Costa-Malaquias, Allan; Oliveira, Edivaldo H. C.; Miranda, Moysés S.; Arrifano, Gabriela P. F.; Souza-Monteiro, José R.; Sagica, Fernanda Espirito-Santo; Fontes-Junior, Enéas A.; Maia, Cristiane S. F.; Macchi, Barbarella M.; do Nascimento, José Luiz M.

    2016-01-01

    Human exposure to relatively low levels of methylmercury is worrying, especially in terms of its genotoxicity. It is currently unknown as to whether exposure to low levels of mercury (below established limits) is safe. Genotoxicity was already shown in lymphocytes, but studies with cells of the CNS (as the main target organ) are scarce. Moreover, disturbances in the cell cycle and cellular proliferation have previously been observed in neuronal cells, but no data are presently available for glial cells. Interestingly, cells of glial origin accumulate higher concentrations of methylmercury than those of neuronal origin. Thus, the aim of this work was to analyze the possible genotoxicity and alterations in the cell cycle and cell proliferation of a glioma cell line (C6) exposed to a low, non-lethal and non-apoptotic methylmercury concentration. Biochemical (mitochondrial activity) and morphological (integrity of the membrane) assessments confirmed the absence of cell death after exposure to 3 μM methylmercury for 24 hours. Even without promoting cell death, this treatment significantly increased genotoxicity markers (DNA fragmentation, micronuclei, nucleoplasmic bridges and nuclear buds). Changes in the cell cycle profile (increased mitotic index and cell populations in the S and G2/M phases) were observed, suggesting arrest of the cycle. This delay in the cycle was followed, 24 hours after methylmercury withdrawal, by a decrease number of viable cells, reduced cellular confluence and increased doubling time of the culture. Our work demonstrates that exposure to a low sublethal concentration of MeHg considered relatively safe according to current limits promotes genotoxicity and disturbances in the proliferation of cells of glial origin with sustained consequences after methylmercury withdrawal. This fact becomes especially important, since this cellular type accumulates more methylmercury than neurons and displays a vital role protecting the CNS, especially in

  10. Dendritic cells derived from TBP-2-deficient mice are defective in inducing T cell responses.

    Science.gov (United States)

    Son, Aoi; Nakamura, Hajime; Okuyama, Hiroaki; Oka, Shin-ichi; Yoshihara, Eiji; Liu, Wenrui; Matsuo, Yoshiyuki; Kondo, Norihiko; Masutani, Hiroshi; Ishii, Yasuyuki; Iyoda, Tomonori; Inaba, Kayo; Yodoi, Junji

    2008-05-01

    Thioredoxin-binding protein-2 (TBP-2), also known as vitamin D3-up-regulated protein 1 (VDUP1), was identified as an endogenous molecule interacting with thioredoxin (TRX). Here, we show that dendritic cells (DC) derived from TBP-2-deficient mice are defective in the function of T cell activation. To compare TBP-2(-/-) DC function with wild-type (WT) DC, we stimulated DC with lipopolysaccharide (LPS). Although TBP-2(-/-) DC and WT DC expressed comparable levels of MHC class II and costimulatory molecules such as CD40, CD80 and CD86, the IL-12p40, IL-12p70 and IL-6 productions of TBP-2(-/-) DC were attenuated. In a mixed leukocyte reaction (MLR), the concentrations of IL-2, IFN-gamma, IL-4 and IL-10 in the culture supernatant of MLR with TBP-2(-/-) DC were significantly lower than those in the cultures with WT DC. In MLR also, as with LPS stimulation, IL-12p40 and IL-12p70 production from TBP-2(-/-) DC was less than that from WT DC. Proliferation of T cells cultured with TBP-2(-/-) DC was poorer than that with WT DC. In vivo delayed-type hypersensitivity responses in TBP-2(-/-) mice immunized with ovalbumin were significantly reduced compared to WT mice. These results indicate that TBP-2 plays a crucial role in DC to induce T cell responses.

  11. Reprogramming T cell Lymphocytes to Induced Pluripotent Stem Cells

    Science.gov (United States)

    Bared, Kalia

    The discovery of induced pluripotent stem cells (iPSC) provided a novel technology for the study of development and pharmacology and complement embryonic stem cells (ES) for cell therapy applications. Though iPSC are derived from adult tissue they are comparable to ES cells in their behavior; multi-lineage differentiation and self-renewal. This makes iPSC research appealing because they can be studied in great detail and expanded in culture broadly. Fibroblasts were the first cell type reprogrammed to an iPSC using a retrovirus vector, since then alternative cell types including lymphocytes have been used to generate iPSC. Different types of vectors have also been developed to enhance iPSC formation and quality. However, specific T lymphocyte subsets have not been shown to reprogram to a pluripotent state to date. Here, we proposed to derive iPSC from peripheral blood effector and central memory T cells, reasoning that the resultant iPSC will maintain the epigenetic memory of a T lymphocyte, including the T cell receptor (TCR) gene rearrangement. This epigenetic memory will enable the differentiation and expansion of T cell iPSC into professional T cells containing a specific TCR. These could then be used for cell therapy to target specific antigens, as well as to improve culture techniques to expand T cells in vitro. We studied different gene delivery methods to derive iPSC from different types of T lymphocytes. We assessed the viability of viral transduction using flow cytometry to detect green fluorescent marker contained in the viral construct and quantitative real time polymerase chain reaction (qRT-PCR) to detect Oct4, Klf4, Sox2, and c-Myc gene expression. Our results demonstrate that the Sendai virus construct is the most feasible platform to reprogram T lymphocytes. We anticipate that this platform will provide an efficient and safe approach to derive iPSC from different T cell subsets, including memory T cells.

  12. Management of acute and delayed chemotherapy-induced nausea and vomiting: role of netupitant-palonosetron combination.

    Science.gov (United States)

    Janicki, Piotr K

    2016-01-01

    The purpose of this review is to summarize and discuss the recently published data (both original studies and reviews) on the oral medication NEPA, consisting of netupitant (a neurokinin-1 receptor antagonist [NK1RA], 300 mg dose) and palonosetron (5-hydroxytryptamine [serotonin or 5HT] type 3 receptor antagonist [5HT3RA], 0.5 mg dose), in the prevention of the acute and delayed nausea and vomiting in patients receiving highly or moderately emetogenic chemotherapy. This review was based on the very limited number of available published trials consisting of two Phase III studies and one Phase II dose-selecting trial. These studies demonstrated some therapeutic benefits of NEPA over related chemotherapy-induced nausea and vomiting (CINV) prophylaxis management, as well as its beneficial safety profile. In particular, compared with single-dose 0.5 mg palonosetron, the complete response rates for all phases of CINV for the first cycle of highly emetogenic chemotherapy (with cisplatin), as well as anthracycline-cyclophosphamide-based moderately emetogenic chemotherapy, were significantly higher for single-dose NEPA. The high efficacy of NEPA in terms of prevention of CINV continued throughout repeated cycles of highly and moderately emetogenic therapies. It is currently recommended that patients who are administered highly emetogenic chemotherapy regimens should obtain a three-drug combination consisting of NK1RA, 5HT3RA, and dexamethasone. The recently available oral combination of NEPA plus dexamethasone provides an additional pharmacological management option that could be considered in this scenario.

  13. Salivary glucose oxidase from caterpillars mediates the induction of rapid and delayed-induced defenses in the tomato plant.

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    Donglan Tian

    Full Text Available Caterpillars produce oral secretions that may serve as cues to elicit plant defenses, but in other cases these secretions have been shown to suppress plant defenses. Ongoing work in our laboratory has focused on the salivary secretions of the tomato fruitworm, Helicoverpa zea. In previous studies we have shown that saliva and its principal component glucose oxidase acts as an effector by suppressing defenses in tobacco. In this current study, we report that saliva elicits a burst of jasmonic acid (JA and the induction of late responding defense genes such as proteinase inhibitor 2 (Pin2. Transcripts encoding early response genes associated with the JA pathway were not affected by saliva. We also observed a delayed response to saliva with increased densities of Type VI glandular trichomes in newly emerged leaves. Proteomic analysis of saliva revealed glucose oxidase (GOX was the most abundant protein identified and we confirmed that it plays a primary role in the induction of defenses in tomato. These results suggest that the recognition of GOX in tomato may represent a case for effector-triggered immunity. Examination of saliva from other caterpillar species indicates that saliva from the noctuids Spodoptera exigua and Heliothis virescens also induced Pin2 transcripts.

  14. Salivary glucose oxidase from caterpillars mediates the induction of rapid and delayed-induced defenses in the tomato plant.

    Science.gov (United States)

    Tian, Donglan; Peiffer, Michelle; Shoemaker, Erica; Tooker, John; Haubruge, Eric; Francis, Frederic; Luthe, Dawn S; Felton, Gary W

    2012-01-01

    Caterpillars produce oral secretions that may serve as cues to elicit plant defenses, but in other cases these secretions have been shown to suppress plant defenses. Ongoing work in our laboratory has focused on the salivary secretions of the tomato fruitworm, Helicoverpa zea. In previous studies we have shown that saliva and its principal component glucose oxidase acts as an effector by suppressing defenses in tobacco. In this current study, we report that saliva elicits a burst of jasmonic acid (JA) and the induction of late responding defense genes such as proteinase inhibitor 2 (Pin2). Transcripts encoding early response genes associated with the JA pathway were not affected by saliva. We also observed a delayed response to saliva with increased densities of Type VI glandular trichomes in newly emerged leaves. Proteomic analysis of saliva revealed glucose oxidase (GOX) was the most abundant protein identified and we confirmed that it plays a primary role in the induction of defenses in tomato. These results suggest that the recognition of GOX in tomato may represent a case for effector-triggered immunity. Examination of saliva from other caterpillar species indicates that saliva from the noctuids Spodoptera exigua and Heliothis virescens also induced Pin2 transcripts.

  15. Effect of Nigella sativa L. seed extract on cisplatin-induced delay in gastric emptying in Sprague-Dawley rats.

    Science.gov (United States)

    Riyaz, Ambreena; Nazir, Shahid; Khushtar, Mohammad; Mishra, Anuradha; Jahan, Yasmeen; Ahmad, Asad

    2017-03-01

    The aim of this study was focused on investigating the possible protective effect of Nigella sativa L. seed extract against cisplatin-induced delay in gastric emptying, in a rat model. Twenty-five male Sprague-Dawley rats were divided into five equal groups as follows: Group I or control group, Group II (cisplatin 10 mg/kg, i.p at day 5), Group III (N. sativa L. 250 mg/kg for 5 days + cisplatin 10 mg/kg, i.p on day 5), Group IV (N. sativa L. 500 mg/kg for 5 days + cisplatin 10 mg/kg, i.p on day 5) and Group V (ondansetron 3 mg/kg/day, per os + cisplatin 10 mg/kg, i.p on day 5). Phenol red meal was adopted to estimate gastric emptying in different groups of the rats. Gastric emptying was significantly increased (p cisplatin treatment alone (Group II). However, ondansetron produced significantly (p < 0.01) better reversal than N. sativa L. seed extract.

  16. Warm preconditioning protects against acute heat-induced respiratory dysfunction and delays bleaching in a symbiotic sea anemone.

    Science.gov (United States)

    Hawkins, Thomas D; Warner, Mark E

    2017-03-15

    Preconditioning to non-stressful warming can protect some symbiotic cnidarians against the high temperature-induced collapse of their mutualistic endosymbiosis with photosynthetic dinoflagellates (Symbiodinium spp.), a process known as bleaching. Here, we sought to determine whether such preconditioning is underpinned by differential regulation of aerobic respiration. We quantified in vivo metabolism and mitochondrial respiratory enzyme activity in the naturally symbiotic sea anemone Exaiptasia pallida preconditioned to 30°C for >7 weeks as well as anemones kept at 26°C. Preconditioning resulted in increased Symbiodinium photosynthetic activity and holobiont (host+symbiont) respiration rates. Biomass-normalised activities of host respiratory enzymes [citrate synthase and the mitochondrial electron transport chain (mETC) complexes I and IV] were higher in preconditioned animals, suggesting that increased holobiont respiration may have been due to host mitochondrial biogenesis and/or enlargement. Subsequent acute heating of preconditioned and 'thermally naive' animals to 33°C induced dramatic increases in host mETC complex I and Symbiodinium mETC complex II activities only in thermally naive E. pallida These changes were not reflected in the activities of other respiratory enzymes. Furthermore, bleaching in preconditioned E. pallida (defined as the significant loss of symbionts) was delayed by several days relative to the thermally naive group. These findings suggest that changes to mitochondrial biogenesis and/or function in symbiotic cnidarians during warm preconditioning might play a protective role during periods of exposure to stressful heating. © 2017. Published by The Company of Biologists Ltd.

  17. Management of acute and delayed chemotherapy-induced nausea and vomiting: role of netupitant–palonosetron combination

    Directory of Open Access Journals (Sweden)

    Janicki PK

    2016-05-01

    Full Text Available Piotr K JanickiDepartment of Anesthesiology and Perioperative Medicine, Milton S Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, PA, USAPurpose: The purpose of this review is to summarize and discuss the recently published data (both original studies and reviews on the oral medication NEPA, consisting of netupitant (a neurokinin-1 receptor antagonist [NK1RA], 300 mg dose and palonosetron (5-hydroxytryptamine [serotonin or 5HT] type 3 receptor antagonist [5HT3RA], 0.5 mg dose, in the prevention of the acute and delayed nausea and vomiting in patients receiving highly or moderately emetogenic chemotherapy.Methods: This review was based on the very limited number of available published trials consisting of two Phase III studies and one Phase II dose-selecting trial.Results: These studies demonstrated some therapeutic benefits of NEPA over related chemotherapy-induced nausea and vomiting (CINV prophylaxis management, as well as its beneficial safety profile. In particular, compared with single-dose 0.5 mg palonosetron, the complete response rates for all phases of CINV for the first cycle of highly emetogenic chemotherapy (with cisplatin, as well as anthracycline–cyclophosphamide-based moderately emetogenic chemotherapy, were significantly higher for single-dose NEPA. The high efficacy of NEPA in terms of prevention of CINV continued throughout repeated cycles of highly and moderately emetogenic therapies.Conclusion: It is currently recommended that patients who are administered highly emetogenic chemotherapy regimens should obtain a three-drug combination consisting of NK1RA, 5HT3RA, and dexamethasone. The recently available oral combination of NEPA plus dexa­methasone provides an additional pharmacological management option that could be considered in this scenario.Keywords: chemotherapy-induced nausea and vomiting, palonosetron, netupitant, NEPA, safety, pharmacology, outcomes

  18. Role of Bax in resveratrol-induced apoptosis of colorectal carcinoma cells

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    Roemer Klaus

    2002-10-01

    Full Text Available Abstract Background The natural plant polyphenol resveratrol present in some foods including grapes, wine, and peanuts, has been implicated in the inhibition, delay, and reversion of cellular events associated with heart diseases and tumorigenesis. Recent work has suggested that the cancer chemoprotective effect of the compound is primarily linked to its ability to induce cell division cycle arrest and apoptosis, the latter possibly through the activation of pro-apoptotic proteins such as Bax. Methods The expression, subcellular localization, and importance of Bax for resveratrol-provoked apoptosis were assessed in human HCT116 colon carcinoma cells and derivatives with both bax alleles inactivated. Results Low to moderate concentrations of resveratrol induced co-localization of cellular Bax protein with mitochondria, collapse of the mitochondrial membrane potential, activation of caspases 3 and 9, and finally, apoptosis. In the absence of Bax, membrane potential collapse was delayed, and apoptosis was reduced but not absent. Resveratrol inhibited the formation of colonies by both HCT116 and HCT116 bax -/- cells. Conclusion Resveratrol at physiological doses can induce a Bax-mediated and a Bax-independent mitochondrial apoptosis. Both can limit the ability of the cells to form colonies.

  19. True-time delay line with separate carrier tuning using dual-parallel MZM and stimulated Brillouin scattering-induced slow light.

    Science.gov (United States)

    Li, Wei; Zhu, Ning Hua; Wang, Li Xian; Wang, Jia Sheng; Liu, Jian Guo; Liu, Yu; Qi, Xiao Qiong; Xie, Liang; Chen, Wei; Wang, Xin; Han, Wei

    2011-06-20

    We experimentally demonstrate a novel tunable true-time delay line with separate carrier tuning using dual-parallel Mach-Zehnder modulator and stimulated Brillouin scattering-induced slow light. The phase of the optical carrier can be continuously and precisely controlled by simply adjusting the dc bias of the dual-parallel Mach-Zehnder modulator. In addition, both the slow light and single-sideband modulation can be simultaneously achieved in the stimulated Brillouin scattering process with three types of configuration. Finally, the true-time delay technique is clearly verified by a two-tap incoherent microwave photonic filter as the free spectral range of the filter is changed.

  20. Oral administration of apple condensed tannins delays rheumatoid arthritis development in mice via downregulation of T helper 17 (Th17) cell responses.

    Science.gov (United States)

    Nakamura, Kosuke; Matsuoka, Hideki; Nakashima, Syohei; Kanda, Tomomasa; Nishimaki-Mogami, Tomoko; Akiyama, Hiroshi

    2015-07-01

    Apples are known to contain high concentrations of phenolic compounds such as condensed tannins. Consumption of condensed tannins has been reported to reduce the risk of many types of chronic diseases including allergies. However, their therapeutic effectiveness and potential in treating autoimmune disease remain controversial. Here, the effect of oral administration of apple condensed tannins (ACT) prepared from apples (Malus pumila cv. Fuji) on bovine type II collagen (CII)-induced arthritis in DBA1/J mice, a well-established murine model of human rheumatoid arthritis (RA), was evaluated. As compared to the control (without ACT administration) group, RA development was delayed and a significant reduction in the RA clinical score was observed in the ACT-administered group. Using cultured splenocytes isolated from CII-immunized mice, ACT-administration was shown to decrease the CII-induced increases in IL-17 expression and production in vitro. We propose that downregulation of T helper (Th) 17 cells is responsible for the ACT-induced RA suppression. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Endotoxin induces a delayed loss of TH-IR neurons in substantia nigra and motor behavioral deficits.

    Science.gov (United States)

    Liu, Yuxin; Qin, Liya; Wilson, Belinda; Wu, Xuefei; Qian, Li; Granholm, Ann-Charlotte; Crews, Fulton T; Hong, Jau-Shyong

    2008-09-01

    We have previously reported that a single injection of endotoxin, lipopolysaccharide (LPS, 5mg/kg, i.p.), causes a delayed and progressive loss of TH-IR neurons in the substantia nigra (SN) in C57BL/six male mice. In this study, we determined sex differences and behavioral deficits accompanying the loss of TH-IR neurons in response to peripheral LPS injection. A single injection of LPS (5mg/kg, i.p.) failed to produce any loss of TH-IR neurons in the SN of female mice over a 12-month period. To determine if multiple-injections were required, female mice received five injections of LPS (5mg/kg, i.p.) at either weekly or monthly intervals. Behavioral motor ability and TH-IR neuronal loss were determined after the first injection of LPS. We found significant differences in both behavioral activities and neuronal loss between these two injection paradigms. Between 7 and 20 months after the first injection of LPS, progressive behavioral changes, measured by rotor-rod and open-field activities, and neuronal loss in SN were observed in monthly injected, but not in weekly injected mice. In addition, reduced rotor-rod ability in monthly injected mice were restored following treatment of l-dopa/carbidopa (30 mg/3mg/kg), i.p.). Approximately 40 and 50% loss of TH-IR neurons at 9 and 20 months, respectively, was observed after exposure to LPS, suggesting that the behavioral deficit is related to loss of dopamine function in the nigra-striatal pathway. More intense immuno-staining of alpha-synuclein and inflammatory markers were detected in brain sections exposed to LPS. In conclusion, these results show that multi-LPS monthly injections can induce a delayed and progressive loss of TH-IR neurons and motor deficits which resemble the progressive nature of Parkinson's disease. Further, the present study reveals a clear sex difference: female mice are more resistant to LPS than male mice. Repeated monthly LPS injections are required to cause both motor behavioral deficits and DA

  2. Regulatory T cells ameliorate tissue plasminogen activator-induced brain haemorrhage after stroke.

    Science.gov (United States)

    Mao, Leilei; Li, Peiying; Zhu, Wen; Cai, Wei; Liu, Zongjian; Wang, Yanling; Luo, Wenli; Stetler, Ruth A; Leak, Rehana K; Yu, Weifeng; Gao, Yanqin; Chen, Jun; Chen, Gang; Hu, Xiaoming

    2017-07-01

    Delayed thrombolytic treatment with recombinant tissue plasminogen activator (tPA) may exacerbate blood-brain barrier breakdown after ischaemic stroke and lead to lethal haemorrhagic transformation. The immune system is a dynamic modulator of stroke response, and excessive immune cell accumulation in the cerebral vasculature is associated with compromised integrity of the blood-brain barrier. We previously reported that regulatory T cells, which function to suppress excessive immune responses, ameliorated blood-brain barrier damage after cerebral ischaemia. This study assessed the impact of regulatory T cells in the context of tPA-induced brain haemorrhage and investigated the underlying mechanisms of action. The number of circulating regulatory T cells in stroke patients was dramatically reduced soon after stroke onset (84 acute ischaemic stroke patients with or without intravenous tPA treatment, compared to 115 age and gender-matched healthy controls). Although stroke patients without tPA treatment gradually repopulated the numbers of circulating regulatory T cells within the first 7 days after stroke, post-ischaemic tPA treatment led to sustained suppression of regulatory T cells in the blood. We then used the murine suture and embolic middle cerebral artery occlusion models of stroke to investigate the therapeutic potential of adoptive regulatory T cell transfer against tPA-induced haemorrhagic transformation. Delayed administration of tPA (10 mg/kg) resulted in haemorrhagic transformation in the ischaemic territory 1 day after ischaemia. When regulatory T cells (2 × 106/mouse) were intravenously administered immediately after delayed tPA treatment in ischaemic mice, haemorrhagic transformation was significantly decreased, and this was associated with improved sensorimotor functions. Blood-brain barrier disruption and tight junction damages were observed in the presence of delayed tPA after stroke, but were mitigated by regulatory T cell transfer. Mechanistic

  3. Prior attenuation of KiSS1/GPR54 signaling in the anteroventral periventricular nucleus is a trigger for the delayed effect induced by neonatal exposure to 17alpha-ethynylestradiol in female rats.

    Science.gov (United States)

    Ichimura, Ryohei; Takahashi, Miwa; Morikawa, Tomomi; Inoue, Kaoru; Maeda, Jun; Usuda, Kento; Yokosuka, Makoto; Watanabe, Gen; Yoshida, Midori

    2015-01-01

    Neonatal exposure to 17alpha-ethynylestradiol (EE) causes delayed effect, a late-occurring irreversible damage to reproductive functions characterized by the early onset of age-matched abnormal estrous cycling. To clarify the involvement of a hypothalamic key cycling regulator KiSS1/GPR54 in the delayed effect, we investigated artificially induced LH surges and KiSS1 mRNA expression in the anteroventral periventricular nucleus (AVPV) of cycling young adult rats neonatally exposed to EE, and compared these parameters to those in about 5 months old middle-aged rats. KiSS1 mRNA expression, the number of KiSS1-positive cells and KiSS1/ERα co-expressing cells in the AVPV decreased in both EE-exposed and middle-aged rats. The peak area and levels of LH surge dose-dependently decreased in EE-exposed rats, and reduction was more evident in middle-aged rats. These results indicate that the prior attenuation of KiSS1 and consequent depression of LH surges plays a key role in the onset of abnormal estrous cycling in the delayed effect. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Capacitive water release and internal leaf water relocation delay drought-induced cavitation in African Maesopsis eminii.

    Science.gov (United States)

    Epila, Jackie; De Baerdemaeker, Niels J F; Vergeynst, Lidewei L; Maes, Wouter H; Beeckman, Hans; Steppe, Kathy

    2017-04-01

    The impact of drought on the hydraulic functioning of important African tree species, like Maesopsis eminii Engl., is poorly understood. To map the hydraulic response to drought-induced cavitation, sole reliance on the water potential at which 50% loss of xylem hydraulic conductivity (ψ50) occurs might be limiting and at times misleading as the value alone does not give a comprehensive overview of strategies evoked by M. eminii to cope with drought. This article therefore uses a methodological framework to study the different aspects of drought-induced cavitation and water relations in M. eminii. Hydraulic functioning of whole-branch segments was investigated during bench-top dehydration. Cumulative acoustic emissions and continuous weight measurements were used to quantify M. eminii's vulnerability to drought-induced cavitation and hydraulic capacitance. Wood structural traits, including wood density, vessel area, diameter and wall thickness, vessel grouping index, solitary vessel index and vessel wall reinforcement, were used to underpin observed physiological responses. On average, M. eminii's ψ50 (±SE) was -1.9 ± 0.1 MPa, portraying its xylem as drought vulnerable, just as one would expect for a common tropical pioneer. However, M. eminii additionally employed an interesting desiccation delay strategy, fuelled by internal relocation of leaf water, hydraulic capacitance and the presence of parenchyma around the xylem vessels. Our findings suggest that exclusive dependence on ψ50 would have misdirected our assessments of M. eminii's drought stress vulnerability. Hydraulic capacitance linked to anatomy and leaf-water relocation behaviour was equally important to better understand M. eminii's drought survival strategies. Because our study was conducted on branches of 3-year-old greenhouse-grown M. eminii seedlings, the findings cannot be simply extrapolated to adult M. eminii trees or their mature wood, because structural and physiological plant properties

  5. Toxicant induced changes on delayed fluorescence decay kinetics of cyanobacteria and green algae: a rapid and sensitive biotest.

    Directory of Open Access Journals (Sweden)

    Franziska Leunert

    Full Text Available Algal tests have developed into routine tools for testing toxicity of pollutants in aquatic environments. Meanwhile, in addition to algal growth rates, an increasing number of fluorescence based methods are used for rapid and sensitive toxicity measures. The present study stresses the suitability of delayed fluorescence (DF as a promising parameter for biotests. DF is based on the recombination fluorescence at the reaction centre of photosystem II, which is emitted only by photosynthetically active cells. We analyzed the effects of three chemicals (3-(3,4-dichlorophenyl-1,1-dimethylurea (DCMU, 3,5 Dichlorophenol (3,5 DCP and copper on the shape of the DF decay kinetics for potential use in phytoplankton toxicity tests. The short incubation tests were done with four phytoplankton species, with special emphasis on the cyanobacterium Microcystis aeruginosa. All species exhibited a high sensitivity to DCMU, but cyanobacteria were more affected by copper and less by 3,5 DCP than the tested green algae. Analyses of changes in the DF decay curve in response to the added chemicals indicated the feasibility of the DF decay approach as a rapid and sensitive testing tool.

  6. Metformin Induces Growth Inhibition and Cell Cycle Arrest by Upregulating MicroRNA34a in Renal Cancer Cells.

    Science.gov (United States)

    Xie, Wei; Wang, Lei; Sheng, Halei; Qiu, Jing; Zhang, Di; Zhang, Le; Yang, Fan; Tang, Dahai; Zhang, Kebin

    2017-01-03

    BACKGROUND Metformin is a widely used biguanide drug for the treatment of type 2 diabetes. It has been revaluated as a potential anti-cancer drug with promising activity in various tumors. However, the precise mechanisms underlying the suppression of cancer cells by metformin remain not well understood. MATERIAL AND METHODS In this study, human renal cell carcinoma cell line ACHN was used to investigate the anti-proliferation effect of metformin. A cell counting kit-8 assay was used to detect the cell viability. The cell cycle distribution and apoptosis were analyzed by flow cytometry. The expression of cyclin D1 and p27KIP1 was detected by Western blot. The underlying mechanism involving miRNA34a was further investigated by quantitative RT-PCR and transfection with miRNA inhibitor specific for miRNA34a in ACHN, 769-P, and A498 cells. RESULTS Metformin could significantly inhibit the proliferation of ACHN cells in a dose- and time-dependent manner. In addition, the results showed that metformin induced G0/G1 phase arrest and delayed entry into S phase in ACHN cells. It was shown that metformin downregulates the expression of cyclin D1 and increases the p27KIP1 level. Furthermore, metformin increased ACHN cell death. Lastly, miRNA34a was found to be upregulated by metformin in ACHN, 769-P, and A498 cells. Subsequently, it was demonstrated that inhibition of miRNA34a could partially attenuate the suppressive effect of metformin on renal cancer cell proliferation. CONCLUSIONS The study data revealed that metformin induced cell growth inhibition and cell cycle arrest partially by upregulating miRNA34a in renal cancer cells.

  7. Induced Accelerated Aging in Induced Pluripotent Stem Cell Lines from Patients with Parkinson’s Disease

    Science.gov (United States)

    2014-07-01

    Induced Pluripotent Stem Cell Lines from Patients with Parkinson’s Disease PRINCIPAL INVESTIGATOR: Dr. Birgitt Schuele CONTRACTING...Aging in Induced Pluripotent Stem Cell Lines from Patients with Parkinson’s Disease 5b. GRANT NUMBER W81XWH-12-1-0003 5c. PROGRAM ELEMENT NUMBER...for grant W81XWH-12-1-0003 Title: “Induced accelerated aging in induced pluripotent stem cell lines from patients with

  8. Human-induced pluripotent stem cell-derived cardiomyocytes from cardiac progenitor cells: effects of selective ion channel blockade.

    Science.gov (United States)

    Altomare, Claudia; Pianezzi, Enea; Cervio, Elisabetta; Bolis, Sara; Biemmi, Vanessa; Benzoni, Patrizia; Camici, Giovanni G; Moccetti, Tiziano; Barile, Lucio; Vassalli, Giuseppe

    2016-12-01

    Human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes are likely to revolutionize electrophysiological approaches to arrhythmias. Recent evidence suggests the somatic cell origin of hiPSCs may influence their differentiation potential. Owing to their cardiomyogenic potential, cardiac-stromal progenitor cells (CPCs) are an interesting cellular source for generation of hiPSC-derived cardiomyocytes. The effect of ionic current blockade in hiPSC-derived cardiomyocytes generated from CPCs has not been characterized yet. Human-induced pluripotent stem cell-derived cardiomyocytes were generated from adult CPCs and skin fibroblasts from the same individuals. The effect of selective ionic current blockade on spontaneously beating hiPSC-derived cardiomyocytes was assessed using multi-electrode arrays. Cardiac-stromal progenitor cells could be reprogrammed into hiPSCs, then differentiated into hiPSC-derived cardiomyocytes. Human-induced pluripotent stem cell-derived cardiomyocytes of cardiac origin showed higher upregulation of cardiac-specific genes compared with those of fibroblastic origin. Human-induced pluripotent stem cell-derived cardiomyocytes of both somatic cell origins exhibited sensitivity to tetrodotoxin, a blocker of Na(+ )current (INa), nifedipine, a blocker of L-type Ca(2+ )current (ICaL), and E4031, a blocker of the rapid component of delayed rectifier K(+ )current (IKr). Human-induced pluripotent stem cell-derived cardiomyocytes of cardiac origin exhibited sensitivity to JNJ303, a blocker of the slow component of delayed rectifier K(+ )current (IKs). In hiPSC-derived cardiomyocytes of cardiac origin, INa, ICaL, IKr, and IKs were present as tetrodotoxin-, nifedipine-, E4031-, and JNJ303-sensitive currents, respectively. Although cardiac differentiation efficiency was improved in hiPSCs of cardiac vs. non-cardiac origin, no major functional differences were observed between hiPSC-derived cardiomyocytes of different somatic cell origins

  9. Delayed intranasal delivery of hypoxic-preconditioned bone marrow mesenchymal stem cells enhanced cell homing and therapeutic benefits after ischemic stroke in mice.

    Science.gov (United States)

    Wei, Ning; Yu, Shan Ping; Gu, Xiaohuan; Taylor, Tammi M; Song, Denise; Liu, Xin-Feng; Wei, Ling

    2013-01-01

    Stem cell transplantation therapy has emerged as a potential treatment for ischemic stroke and other neurodegenerative diseases. Effective delivery of exogenous cells and homing of these cells to the lesion region, however, have been challenging issues that hinder the efficacy and efficiency of cell-based therapy. In the present investigation, we tested a delayed treatment of noninvasive and brain-targeted intranasal delivery of bone marrow mesenchymal stem cells (BMSCs) in a mouse focal cerebral ischemia model. The investigation tested the feasibility and effectiveness of intranasal delivery of BMSCs to the ischemic cortex. Hypoxia preconditioning (HP) of BMSCs was performed before transplantation in order to promote their survival, migration, and homing to the ischemic brain region after intranasal transplantation. Hoechst dye-labeled normoxic- or hypoxic-pretreated BMSCs (1 × 10(6) cells/animal) were delivered intranasally 24 h after stroke. Cells reached the ischemic cortex and deposited outside of vasculatures as early as 1.5 h after administration. HP-treated BMSCs (HP-BMSCs) showed a higher level of expression of proteins associated with migration, including CXC chemokine receptor type 4 (CXCR4), matrix metalloproteinase 2 (MMP-2), and MMP-9. HP-BMSCs exhibited enhanced migratory capacities in vitro and dramatically enhanced homing efficiency to the infarct cortex when compared with normoxic cultured BMSCs (N-BMSCs). Three days after transplantation and 4 days after stroke, both N-BMSCs and HP-BMSCs decreased cell death in the peri-infarct region; significant neuroprotection of reduced infarct volume was seen in mice that received HP-BMSCs. In adhesive removal test of sensorimotor functional assay performed 3 days after transplantation, HP-BMSC-treated mice performed significantly better than N-BMSC- and vehicle-treated animals. These data suggest that delayed intranasal administration of stem cells is feasible in the treatment of stroke and hypoxic

  10. Induced pluripotent stem cells for retinal degenerative diseases: a ...

    Indian Academy of Sciences (India)

    2009-12-31

    Dec 31, 2009 ... Frane J. L., Tian S. et al. 2007 Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920. Yu J., Hu K., Smuga-Otto K., Tian S., Stewart R., Slukvin II et al. 2009 Human induced pluripotent stem cells free of vector and transgene sequences. Science 324, 797–801.

  11. In vitro megakaryocyte expansion in patients with delayed platelet engraftment after autologous stem cell transplantation

    NARCIS (Netherlands)

    Drayer, AL; Sibinga, CTS; Esselink, MT; de Wolf, JTM; Vellenga, E

    Increasing the number of megakaryocytic cells in stem cell transplants by ex vivo expansion culture may provide an approach to accelerate platelet engraftment after high-dose chemotherapy. However, it is unknown if a relationship exists between the expansion potential of progenitor cells and the

  12. The combination of valproic acid and lithium delays hematopoietic stem/progenitor cell differentiation

    NARCIS (Netherlands)

    Walasek, Marta A.; Bystrykh, Leonid; van den Boom, Vincent; Olthof, Sandra; Ausema, Albertina; Ritsema, Martha; Huls, Gerwin; de Haan, Gerald; van Os, Ronald

    2012-01-01

    Despite increasing knowledge on the regulation of hematopoietic stem/progenitor cell (HSPC) self-renewal and differentiation, in vitro control of stem cell fate decisions has been difficult. The ability to inhibit HSPC commitment in culture may be of benefit to cell therapy protocols. Small

  13. The combination of valproic acid and lithium delays hematopoietic stem/progenitor cell differentiation.

    NARCIS (Netherlands)

    Walasek, M.A.; Bystrykh, L.; Boom, V. van den; Olthof, S.; Ausema, A.; Ritsema, M.; Huls, G.A.; Haan, G. de; Os, R. van

    2012-01-01

    Despite increasing knowledge on the regulation of hematopoietic stem/progenitor cell (HSPC) self-renewal and differentiation, in vitro control of stem cell fate decisions has been difficult. The ability to inhibit HSPC commitment in culture may be of benefit to cell therapy protocols. Small

  14. Immediate and delayed transplantation of mesenchymal stem cells improve muscle force after skeletal muscle injury in rats.

    Science.gov (United States)

    Winkler, Tobias; von Roth, Philipp; Radojewski, Piotr; Urbanski, Alexander; Hahn, Sebastian; Preininger, Bernd; Duda, Georg N; Perka, Carsten

    2012-12-01

    Mesenchymal stem cell (MSC) therapy is a promising approach for regaining muscle function after trauma. Prior to clinical application, the ideal time of transplantation has to be determined. We investigated the effects of immediate and delayed transplantation. Sprague-Dawley rats received a crush trauma to the left soleus muscle. Treatment groups were transplanted locally with 2 × 10(6) autologous MSCs, either immediately or 7 days after trauma. Saline was used as sham therapy. Contraction force tests and histological analyses were performed 4 weeks after injury. GFP-labelled MSCs were followed after transplantation. The traumatized soleus muscles of the sham group displayed a reduction of twitch forces to 36 ± 17% and of tetanic forces to 29 ± 11% of the non-injured right control side, respectively. Delayed MSC transplantation resulted in a significant improvement of contraction maxima in both stimulation modes (twitch, p = 0.011; tetany, p = 0.014). Immediate transplantation showed a significant increase in twitch forces to 59 ± 17% (p = 0.043). There was no significant difference in contraction forces between muscles treated by immediate and delayed cell transplantation. We were able to identify MSCs in the interstitium of the injured muscles up to 4 weeks after transplantation. Despite the fundamental differences of the local environment, which MSCs encounter after transplantation, similar results could be obtained with respect to functional muscle regeneration. We believe that transplanted MSCs residing in the interstitial compartment evolve their regenerative capabilities through paracrine pathways. Our data suggest a large time window of the therapeutical measures. Copyright © 2012 John Wiley & Sons, Ltd.

  15. Prophylactic treatment for delayed chemotherapy-induced nausea and vomiting after non-AC based moderately emetogenic chemotherapy: a systematic review of randomized controlled trials.

    Science.gov (United States)

    van der Vorst, Maurice J D L; Neefjes, Elisabeth C W; Konings, Inge R H M; Verheul, Henk M W

    2015-08-01

    Delayed chemotherapy-induced nausea and vomiting (CINV) remains an important adverse effect of moderately emetogenic chemotherapy not containing anthracyclines and cyclophosphamide (non-AC MEC). In this review, we summarize current literature to update recommendations for delayed CINV prophylaxis after non-AC MEC. We conducted a systematic search in PubMed and conference proceedings from ASCO, ESMO, and MASCC. Included randomized controlled trials (RCTs) aimed to prospectively evaluate the efficacy of two or more antiemetic strategies in the prevention of delayed CINV after the administration of non-AC MEC. At least one of the following endpoints was used: complete response, complete control, no nausea, no vomiting, and/or no use of rescue medication. Our search provided 247 publications. Nine met the predefined criteria. Included RCTs reported outcomes on palonosetron, aprepitant, casopitant, netupitant/palonosetron (NEPA), olanzapine, and megestrol acetate. Superiority of palonosetron over first-generation 5-HT3 receptor antagonists for the prevention of acute and delayed CINV after non-AC MEC has not been proven. The addition of an NK1 receptor antagonist to first-generation 5-HT3 receptor antagonists does not significantly improve the incidence of delayed CINV after non-AC MEC. The efficacy of a single-day regimen of dexamethasone with palonosetron is non-inferior to multiday dexamethasone. NEPA, olanzapine, and megestrol acetate show highly effective complete response (CR) rates.

  16. M867, a novel selective inhibitor of caspase-3 enhances cell death and extends tumor growth delay in irradiated lung cancer models.

    Directory of Open Access Journals (Sweden)

    Kwang Woon Kim

    Full Text Available BACKGROUND: Lung cancer remains the leading cause of cancer death worldwide. Radioresistance of lung cancer cells results in unacceptable rate of loco-regional failure. Although radiation is known to induce apoptosis, our recent study showed that knockdown of pro-apoptotic proteins Bak and Bax resulted in an increase in autophagic cell death and lung cancer radiosensitivity in vitro. To further explore the potential of apoptosis inhibition as a way to sensitize lung cancer for therapy, we tested M867, a novel chemical and reversible caspase-3 inhibitor, in combination with ionizing radiation in vivo and in vitro. METHODS AND FINDINGS: M867 reduced clonogenic survival in H460 lung cancer cells (DER = 1.27, p = 0.007 compared to the vehicle-treated treated cells. We found that administration of M867 with ionizing radiation in an in vivo mouse hind limb lung cancer model was well tolerated, and produced a significant tumor growth delay compared to radiation alone. A dramatic decrease in tumor vasculature was observed with M867 and radiation using von Willebrand factor staining. In addition, Ki67 index showed >5-fold reduction of tumor proliferation in the combination therapy group, despite the reduced levels of apoptosis observed with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. Radiosensitizing effect of M867 through inhibiting caspases was validated using caspase-3/-7 double-knockout (DKO mouse embryonic fibroblasts (MEF cell model. Consistent with our previous study, autophagy contributed to the mechanism of increased cell death, following inhibition of apoptosis. In addition, matrigel assay showed a decrease in in vitro endothelial tubule formation during the M867/radiation combination treatment. CONCLUSIONS: M867 enhances the cytotoxic effects of radiation on lung cancer and its vasculature both in vitro and in vivo. M867 has the potential to prolong tumor growth delay by inhibiting tumor proliferation

  17. Artesunate induces AIF-dependent apoptosis in A549 cells

    Science.gov (United States)

    Zhou, Chen-juan; Chen, Tong-Sheng

    2012-03-01

    Artesunate (ART), a semi-synthetic derivative of the sesquiterpene artemisinin extracted from the Chinese herb Artemisia annua, exerts a broad spectrum of clinical activity against human cancers. It has been shown that ART induces cancer cells death through apoptosis pathway. This study investigated whether ART treatment induced reactive oxygen species (ROS)-dependent cell death in the apoptosis fashion in human lung adenocarconoma A549 cell line and the proapoptotic protein apoptosis inducing factor (AIF) is involved in ART-induced apoptosis. Cells treated with ART exhibited typical apoptotic morphology as chromatin condensation, margination and shrunken nucleus. ART treatment also induced a loss of mitochondrial membrane potential and AIF release from mitochondria. Silencing AIF can remarkable attenuated ART-induced apoptosis. Collectively, ART induces apoptosis by caspase-independent intrinsic pathway in A549 cells.

  18. Management of acute and delayed chemotherapy-induced nausea and vomiting: role of netupitant–palonosetron combination

    Science.gov (United States)

    Janicki, Piotr K

    2016-01-01

    Purpose The purpose of this review is to summarize and discuss the recently published data (both original studies and reviews) on the oral medication NEPA, consisting of netupitant (a neurokinin-1 receptor antagonist [NK1RA], 300 mg dose) and palonosetron (5-hydroxytryptamine [serotonin or 5HT] type 3 receptor antagonist [5HT3RA], 0.5 mg dose), in the prevention of the acute and delayed nausea and vomiting in patients receiving highly or moderately emetogenic chemotherapy. Methods This review was based on the very limited number of available published trials consisting of two Phase III studies and one Phase II dose-selecting trial. Results These studies demonstrated some therapeutic benefits of NEPA over related chemotherapy-induced nausea and vomiting (CINV) prophylaxis management, as well as its beneficial safety profile. In particular, compared with single-dose 0.5 mg palonosetron, the complete response rates for all phases of CINV for the first cycle of highly emetogenic chemotherapy (with cisplatin), as well as anthracycline–cyclophosphamide-based moderately emetogenic chemotherapy, were significantly higher for single-dose NEPA. The high efficacy of NEPA in terms of prevention of CINV continued throughout repeated cycles of highly and moderately emetogenic therapies. Conclusion It is currently recommended that patients who are administered highly emetogenic chemotherapy regimens should obtain a three-drug combination consisting of NK1RA, 5HT3RA, and dexamethasone. The recently available oral combination of NEPA plus dexamethasone provides an additional pharmacological management option that could be considered in this scenario. PMID:27194913

  19. A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD).

    Science.gov (United States)

    Wiseman, Daniel H; May, Alison; Jolles, Stephen; Connor, Philip; Powell, Colin; Heeney, Matthew M; Giardina, Patricia J; Klaassen, Robert J; Chakraborty, Pranesh; Geraghty, Michael T; Major-Cook, Nathalie; Kannengiesser, Caroline; Thuret, Isabelle; Thompson, Alexis A; Marques, Laura; Hughes, Stephen; Bonney, Denise K; Bottomley, Sylvia S; Fleming, Mark D; Wynn, Robert F

    2013-07-04

    Congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited disorders identified by pathological erythroid precursors with perinuclear mitochondrial iron deposition in bone marrow. An international collaborative group of physicians and laboratory scientists collated clinical information on cases of CSA lacking known causative mutations, identifying a clinical subgroup of CSA associated with B immunodeficiency, periodic fevers, and development delay. Twelve cases from 10 families were identified. Median age at presentation was 2 months. Anemia at diagnosis was sideroblastic, typically severe (median hemoglobin, 7.1 g/dL) and markedly microcytic (median mean corpuscular volume, 62.0 fL). Clinical course involved recurrent febrile illness and gastrointestinal disturbance, lacking an infective cause. Investigation revealed B-cell lymphopenia (CD19⁺ range, 0.016-0.22 × 10⁹/L) and panhypogammaglobulinemia in most cases. Children displayed developmental delay alongside variable neurodegeneration, seizures, cerebellar abnormalities, sensorineural deafness, and other multisystem features. Most required regular blood transfusion, iron chelation, and intravenous immunoglobulin replacement. Median survival was 48 months, with 7 deaths caused by cardiac or multiorgan failure. One child underwent bone marrow transplantation aged 9 months, with apparent cure of the hematologic and immunologic manifestations. We describe and define a novel CSA and B-cell immunodeficiency syndrome with additional features resembling a mitochondrial cytopathy. The molecular etiology is under investigation.

  20. A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD)

    Science.gov (United States)

    May, Alison; Jolles, Stephen; Connor, Philip; Powell, Colin; Heeney, Matthew M.; Giardina, Patricia J.; Klaassen, Robert J.; Chakraborty, Pranesh; Geraghty, Michael T.; Major-Cook, Nathalie; Kannengiesser, Caroline; Thuret, Isabelle; Thompson, Alexis A.; Marques, Laura; Hughes, Stephen; Bonney, Denise K.; Bottomley, Sylvia S.; Fleming, Mark D.; Wynn, Robert F.

    2013-01-01

    Congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited disorders identified by pathological erythroid precursors with perinuclear mitochondrial iron deposition in bone marrow. An international collaborative group of physicians and laboratory scientists collated clinical information on cases of CSA lacking known causative mutations, identifying a clinical subgroup of CSA associated with B immunodeficiency, periodic fevers, and development delay. Twelve cases from 10 families were identified. Median age at presentation was 2 months. Anemia at diagnosis was sideroblastic, typically severe (median hemoglobin, 7.1 g/dL) and markedly microcytic (median mean corpuscular volume, 62.0 fL). Clinical course involved recurrent febrile illness and gastrointestinal disturbance, lacking an infective cause. Investigation revealed B-cell lymphopenia (CD19+ range, 0.016-0.22 × 109/L) and panhypogammaglobulinemia in most cases. Children displayed developmental delay alongside variable neurodegeneration, seizures, cerebellar abnormalities, sensorineural deafness, and other multisystem features. Most required regular blood transfusion, iron chelation, and intravenous immunoglobulin replacement. Median survival was 48 months, with 7 deaths caused by cardiac or multiorgan failure. One child underwent bone marrow transplantation aged 9 months, with apparent cure of the hematologic and immunologic manifestations. We describe and define a novel CSA and B-cell immunodeficiency syndrome with additional features resembling a mitochondrial cytopathy. The molecular etiology is under investigation. PMID:23553769

  1. Defining the optimal window for cranial transplantation of human induced pluripotent stem cell-derived cells to ameliorate radiation-induced cognitive impairment.

    Science.gov (United States)

    Acharya, Munjal M; Martirosian, Vahan; Christie, Lori-Ann; Riparip, Lara; Strnadel, Jan; Parihar, Vipan K; Limoli, Charles L

    2015-01-01

    Past preclinical studies have demonstrated the capability of using human stem cell transplantation in the irradiated brain to ameliorate radiation-induced cognitive dysfunction. Intrahippocampal transplantation of human embryonic stem cells and human neural stem cells (hNSCs) was found to functionally restore cognition in rats 1 and 4 months after cranial irradiation. To optimize the potential therapeutic benefits of human stem cell transplantation, we have further defined optimal transplantation windows for maximizing cognitive benefits after irradiation and used induced pluripotent stem cell-derived hNSCs (iPSC-hNSCs) that may eventually help minimize graft rejection in the host brain. For these studies, animals given an acute head-only dose of 10 Gy were grafted with iPSC-hNSCs at 2 days, 2 weeks, or 4 weeks following irradiation. Animals receiving stem cell grafts showed improved hippocampal spatial memory and contextual fear-conditioning performance compared with irradiated sham-surgery controls when analyzed 1 month after transplantation surgery. Importantly, superior performance was evident when stem cell grafting was delayed by 4 weeks following irradiation compared with animals grafted at earlier times. Analysis of the 4-week cohort showed that the surviving grafted cells migrated throughout the CA1 and CA3 subfields of the host hippocampus and differentiated into neuronal (∼39%) and astroglial (∼14%) subtypes. Furthermore, radiation-induced inflammation was significantly attenuated across multiple hippocampal subfields in animals receiving iPSC-hNSCs at 4 weeks after irradiation. These studies expand our prior findings to demonstrate that protracted stem cell grafting provides improved cognitive benefits following irradiation that are associated with reduced neuroinflammation. ©AlphaMed Press.

  2. Inflammatory responses are not sufficient to cause delayed neuronal death in ATP-induced acute brain injury.

    Directory of Open Access Journals (Sweden)

    Hey-Kyeong Jeong

    Full Text Available BACKGROUND: Brain inflammation is accompanied by brain injury. However, it is controversial whether inflammatory responses are harmful or beneficial to neurons. Because many studies have been performed using cultured microglia and neurons, it has not been possible to assess the influence of multiple cell types and diverse factors that dynamically and continuously change in vivo. Furthermore, behavior of microglia and other inflammatory cells could have been overlooked since most studies have focused on neuronal death. Therefore, it is essential to analyze the precise roles of microglia and brain inflammation in the injured brain, and determine their contribution to neuronal damage in vivo from the onset of injury. METHODS AND FINDINGS: Acute neuronal damage was induced by stereotaxic injection of ATP into the substantia nigra pars compacta (SNpc and the cortex of the rat brain. Inflammatory responses and their effects on neuronal damage were investigated by immunohistochemistry, electron microscopy, quantitative RT-PCR, and stereological counting, etc. ATP acutely caused death of microglia as well as neurons in a similar area within 3 h. We defined as the core region the area where both TH(+ and Iba-1(+ cells acutely died, and as the penumbra the area surrounding the core where Iba-1(+ cells showed activated morphology. In the penumbra region, morphologically activated microglia arranged around the injury sites. Monocytes filled the damaged core after neurons and microglia died. Interestingly, neither activated microglia nor monocytes expressed iNOS, a major neurotoxic inflammatory mediator. Monocytes rather expressed CD68, a marker of phagocytic activity. Importantly, the total number of dopaminergic neurons in the SNpc at 3 h (∼80% of that in the contralateral side did not decrease further at 7 d. Similarly, in the cortex, ATP-induced neuron-damage area detected at 3 h did not increase for up to 7 d. CONCLUSIONS: Different cellular

  3. α-Mangostin Induces Apoptosis and Cell Cycle Arrest in Oral Squamous Cell Carcinoma Cell

    Directory of Open Access Journals (Sweden)

    Hyun-Ho Kwak

    2016-01-01

    Full Text Available Mangosteen has long been used as a traditional medicine and is known to have antibacterial, antioxidant, and anticancer effects. Although the effects of α-mangostin, a natural compound extracted from the pericarp of mangosteen, have been investigated in many studies, there is limited data on the effects of the compound in human oral squamous cell carcinoma (OSCC. In this study, α-mangostin was assessed as a potential anticancer agent against human OSCC cells. α-Mangostin inhibited cell proliferation and induced cell death in OSCC cells in a dose- and time-dependent manner with little to no effect on normal human PDLF cells. α-Mangostin treatment clearly showed apoptotic evidences such as nuclear fragmentation and accumulation of annexin V and PI-positive cells on OSCC cells. α-Mangostin treatment also caused the collapse of mitochondrial membrane potential and the translocation of cytochrome c from the mitochondria into the cytosol. The expressions of the mitochondria-related proteins were activated by α-mangostin. Treatment with α-mangostin also induced G1 phase arrest and downregulated cell cycle-related proteins (CDK/cyclin. Hence, α-mangostin specifically induces cell death and inhibits proliferation in OSCC cells via the intrinsic apoptosis pathway and cell cycle arrest at the G1 phase, suggesting that α-mangostin may be an effective agent for the treatment of OSCC.

  4. [The mechanisms of p21WAF1/Cip-1 expression in MOLT-4 cell line induced by TSA].

    Science.gov (United States)

    Song, Yi; Liu, Mei-Ju; Zhao, Guo-Wei; Qian, Jun-Jie; Dong, Yan; Liu, Hua; Sun, Guo-Jing; Mei, Zhu-Zhong; Liu, Bin; Tian, Bao-Lei; Sun, Zhi-Xian

    2005-04-01

    To investigate the function and molecular mechanism of p21(WAF1/Cip-1) expression in MOLT-4 cells induced by HDAC inhibitor TSA, the expression pattern of p21(WAF1/Cip-1) and the distribution of cell cycle in TSA treated cells were analyzed. The results showed that TSA could effectively induce G(2)/M arrest and apoptosis of MOLT-4 cells. Kinetic experiments demonstrated that p21(WAF1/Cip-1) were upregulated quickly before cell arrested in G(2)/M and began decreasing at the early stage of apoptosis. Meanwhile, the proteasome inhibitor MG-132 could inhibit the decrease of p21(WAF1/Cip-1) at the early stage of apoptosis, which showed that proteasome pathway involved in p21(WAF1/Cip-1) degradation during the TSA induced G(2)/M arrest and apoptosis responses. This study also identified that the protein level of p21(WAF1/Cip-1) was highly associated with the cell cycle change induced by TSA. Compared to cells treated by TSA only, exposure MOLT-4 cells to TSA meanwhile treatment with MG-132 increased the protein level of p21(WAF1/Cip-1) and increased the numbers of cell in G(2)/M-phase, whereas the cell apoptosis were delayed. It is concluded that p21(WAF1/Cip-1) plays a significant role in G(2)/M arrest and apoptosis signaling induced by TSA in MOLT-4 cells.

  5. The use of cell phones and radio communication systems to reduce delays in getting help for pregnant women in low- and middle-income countries: a scoping review

    Directory of Open Access Journals (Sweden)

    Sunday O. Oyeyemi

    2015-09-01

    Full Text Available Background: Delays in getting medical help are important factors in the deaths of many pregnant women and unborn children in the low- and middle-income countries (LMIC. Studies have suggested that the use of cell phones and radio communication systems might reduce such delays. Objectives: We review the literature regarding the impact of cell phones and radio communication systems on delays in getting medical help by pregnant women in the LMIC. Design: Cochrane Library, PubMed, Maternity and Infant care (Ovid, Web of Science (ISI, and Google Scholar were searched for studies relating to the use of cell phones for maternal and child health services, supplemented with hand searches. We included studies in LMIC and in English involving the simple use of cell phones (or radio communication to either make calls or send text messages. Results: Fifteen studies met the inclusion criteria. All the studies, while of various designs, demonstrated positive contributory effects of cell phones or radio communication systems in reducing delays experienced by pregnant women in getting medical help. Conclusions: While the results suggested that cell phones could contribute in reducing delays, more studies of a longer duration are needed to strengthen the finding.

  6. The use of cell phones and radio communication systems to reduce delays in getting help for pregnant women in low- and middle-income countries: a scoping review.

    Science.gov (United States)

    Oyeyemi, Sunday O; Wynn, Rolf

    2015-01-01

    Delays in getting medical help are important factors in the deaths of many pregnant women and unborn children in the low- and middle-income countries (LMIC). Studies have suggested that the use of cell phones and radio communication systems might reduce such delays. We review the literature regarding the impact of cell phones and radio communication systems on delays in getting medical help by pregnant women in the LMIC. Cochrane Library, PubMed, Maternity and Infant care (Ovid), Web of Science (ISI), and Google Scholar were searched for studies relating to the use of cell phones for maternal and child health services, supplemented with hand searches. We included studies in LMIC and in English involving the simple use of cell phones (or radio communication) to either make calls or send text messages. Fifteen studies met the inclusion criteria. All the studies, while of various designs, demonstrated positive contributory effects of cell phones or radio communication systems in reducing delays experienced by pregnant women in getting medical help. While the results suggested that cell phones could contribute in reducing delays, more studies of a longer duration are needed to strengthen the finding.

  7. The association of treatment delay and prognosis in head and neck squamous cell carcinoma (HNSCC) patients in a Dutch comprehensive cancer center.

    Science.gov (United States)

    van Harten, Michel C; de Ridder, Mischa; Hamming-Vrieze, Olga; Smeele, Ludi E; Balm, Alfons J M; van den Brekel, Michiel W M

    2014-04-01

    The increasing volume of head and neck squamous cell carcinoma (HNSCC) patients can lead to longer intervals between histopathological diagnosis and primary treatment. This could cause psychological distress to the patient, but more importantly could possibly lead to tumor progression and decreased survival. Accordingly, this study investigates these relationships. The correlation of professional delay and clinical characteristics of 2493 patients, treated between 1990 and 2011 with oral, oropharyngeal, hypopharyngeal and laryngeal SCC, was investigated. Patients were divided in two groups based on treatment delay, defined as the interval between histopathological diagnosis and initial treatment. Univariate and multivariate proportional hazards models were used to assess disease specific survival (DSS) and disease free survival (DFS). Year of diagnosis, tumor site and therapy were significantly related to treatment delay. Tumor stage was not related to treatment delay. Multivariate regression models revealed that the group with a delay of more than 30 days had a better DSS (HR .838, CI .697-.922, p=.041) and DFS (HR .816, CI .702-.947), p=.007) than the group treated within 30 days. In our study, treatment delay up to 90 days is not related to impaired survival. This argument can be used extremely cautiously to comfort patients who have to wait several weeks for treatment. Although, possible tumor progression during treatment delay could have led to increased morbidity subsequent to more extensive treatment. Also, possible negative psychological impact of delay in treatment should not be underestimated. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Immunogenic cell death of human ovarian cancer cells induced by cytosolic poly(I:C) leads to myeloid cell maturation and activates NK cells.

    Science.gov (United States)

    Kübler, Kirsten; tho Pesch, Carola; Gehrke, Nadine; Riemann, Soheila; Dassler, Juliane; Coch, Christoph; Landsberg, Jennifer; Wimmenauer, Vera; Pölcher, Martin; Rudlowski, Christian; Tüting, Thomas; Kuhn, Walther; Hartmann, Gunther; Barchet, Winfried

    2011-10-01

    Owing to high rates of tumor relapse, ovarian cancer remains a fatal disease for which new therapeutic approaches are urgently needed. Accumulating evidence indicates that immune stimulation may delay or even prevent disease recurrence in ovarian cancer. In order to elicit proinflammatory signals that induce or amplify antitumor immune reactivity, we mimicked viral infection in ascites-derived ovarian cancer cells. By transfection or electroporation we targeted the synthetic double-stranded RNA poly(I:C) intracellularly in order to activate melanoma differentiation-associated gene-5 (MDA-5), a sensor of viral RNA in the cytosol of somatic cells. Cancer cells reacted with enhanced expression of HLA-class I, release of CXCL10, IL-6, and type I IFN as well as tumor cell apoptosis. Monocytes and monocyte-derived DCs (MoDCs) engulfed MDA-5-activated cancer cells, and subsequently upregulated HLA-class I/II and costimulatory molecules, and secreted CXCL10 and IFN-α. Further, this proinflammatory milieu promoted cytolytic activity and IFN-γ secretion of NK cells. Thus, our data suggest that the engagement of MDA-5 in a whole tumor cell vaccine is a promising approach for the immunotherapy of ovarian cancer. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Measurements of periods, relative abundances and absolute yields of delayed neutrons from fast neutron induced fission of {sup 237}Np

    Energy Technology Data Exchange (ETDEWEB)

    Piksaikine, V. [Institute of Physics and Power Engineering, Obninsk (Russian Federation)

    1997-03-01

    The experimental method for measurements of the delayed neutron yields and period is presented. The preliminary results of the total yield, relative abundances and periods are shown comparing with the previously reported values. (J.P.N.)

  10. Channel noise-induced temporal coherence transitions and synchronization transitions in adaptive neuronal networks with time delay

    Science.gov (United States)

    Gong, Yubing; Xie, Huijuan

    2017-09-01

    Using spike-timing-dependent plasticity (STDP), we study the effect of channel noise on temporal coherence and synchronization of adaptive scale-free Hodgkin-Huxley neuronal networks with time delay. It is found that the spiking regularity and spatial synchronization of the neurons intermittently increase and decrease as channel noise intensity is varied, exhibiting transitions of temporal coherence and synchronization. Moreover, this phenomenon depends on time delay, STDP, and network average degree. As time delay increases, the phenomenon is weakened, however, there are optimal STDP and network average degree by which the phenomenon becomes strongest. These results show that channel noise can intermittently enhance the temporal coherence and synchronization of the delayed adaptive neuronal networks. These findings provide a new insight into channel noise for the information processing and transmission in neural systems.

  11. Delay-induced Turing-like waves for one-species reaction-diffusion model on a network

    Science.gov (United States)

    Petit, Julien; Carletti, Timoteo; Asllani, Malbor; Fanelli, Duccio

    2015-09-01

    A one-species time-delay reaction-diffusion system defined on a complex network is studied. Traveling waves are predicted to occur following a symmetry-breaking instability of a homogeneous stationary stable solution, subject to an external nonhomogeneous perturbation. These are generalized Turing-like waves that materialize in a single-species populations dynamics model, as the unexpected byproduct of the imposed delay in the diffusion part. Sufficient conditions for the onset of the instability are mathematically provided by performing a linear stability analysis adapted to time-delayed differential equations. The method here developed exploits the properties of the Lambert W-function. The prediction of the theory are confirmed by direct numerical simulation carried out for a modified version of the classical Fisher model, defined on a Watts-Strogatz network and with the inclusion of the delay.

  12. Human retinal pigment epithelial cell-induced apoptosis in activated T cells

    DEFF Research Database (Denmark)

    Jørgensen, A; Wiencke, A K; la Cour, M

    1998-01-01

    human retinal pigment epithelial (RPE) cells can induce apoptosis in activated T cells. METHODS: Fas ligand (FasL) expression was detected by flow cytometry and immunohistochemistry. Cultured RPE cells were cocultured with T-cell lines and peripheral blood lymphocytes for 6 hours to 2 days. Induction...... of apoptosis was detected by 7-amino-actinomycin D and annexin V staining. RESULTS: Retinal pigment epithelial cells expressed FasL and induced apoptosis in activated Fas+ T cells. Blocking of Fas-FasL interaction with antibody strongly inhibited RPE-mediated T-cell apoptosis. Retinal pigment epithelial cells...... induced apoptosis in several activated T-cell populations and T-cell lines, including T-cell antigen receptor (TCR)-CD3-negative T-cell lines. In contrast, RPE cells induced little or no apoptosis in resting peripheral T cells. Major histocompatibility complex (MHC) class II monoclonal antibodies, which...

  13. Analysis of stability and Hopf bifurcation for a delay-differential equation model of HIV infection of CD4{sup +} T-cells

    Energy Technology Data Exchange (ETDEWEB)

    Jiang Xiaowu [Department of Mathematics, Xinyang Normal University, Xinyang 464000, Henan (China); Zhou Xueyong [Department of Mathematics, Xinyang Normal University, Xinyang 464000, Henan (China)], E-mail: xueyongzhou@126.com; Shi Xiangyun [Department of Mathematics, Xinyang Normal University, Xinyang 464000, Henan (China); Song Xinyu [Department of Mathematics, Xinyang Normal University, Xinyang 464000, Henan (China)], E-mail: xysong88@163.com

    2008-10-15

    A delay differential mathematical model that described HIV infection of CD4{sup +} T-cells is analyzed. The stability of the non-negative equilibria and the existence of Hopf bifurcation are investigated. A stability switch in the system due to variation of delay parameter has been observed, so is the phenomena of Hopf bifurcation and stable limit cycle. The estimation of the length of delay to preserve stability has been calculated. Using the normal form theory and center manifold argument, the explicit formulaes which determine the stability, the direction and the periodic of bifurcating period solutions are derived. Numerical simulations are carried out to explain the mathematical conclusions.

  14. Nucleolar re-activation is delayed in mouse embryos cloned from two different cell lines

    DEFF Research Database (Denmark)

    Svarcova, Olga; Dinnyes, A.; Polgar, Z.

    2009-01-01

    Aim of this study was to evaluate and compare embryonic genome activation (EGA) in mouse embryos of different origin using nucleolus as a marker. Early and late 2-cell and late 4-cell stage embryos, prepared by in vitro fertilization (IVF), parthenogenetic activation (PG), and nuclear transfer of...

  15. Delayed protection by ESAT-6–specific effector CD4+ T cells after airborne M. tuberculosis infection

    Science.gov (United States)

    Gallegos, Alena M.; Pamer, Eric G.; Glickman, Michael S.

    2008-01-01

    Mycobacterium tuberculosis infection induces complex CD4 T cell responses that include T helper type 1 (Th1) cells and regulatory T cells. Although Th1 cells control infection, they are unable to fully eliminate M. tuberculosis, suggesting that Th1-mediated immunity is restrained from its full sterilizing potential. Investigation into T cell–mediated defense is hindered by difficulties in expanding M. tuberculosis–specific T cells. To circumvent this problem, we cloned CD4+ T cells from M. tuberculosis–infected B6 mice and generated transgenic mice expressing a T cell receptor specific for the immunodominant antigen early secreted antigenic target 6 (ESAT-6). Adoptively transferred naive ESAT-6–specific CD4+ T cells are activated in pulmonary lymph nodes between 7 and 10 d after aerosol infection and undergo robust expansion before trafficking to the lung. Adoptive transfer of activated ESAT-6–specific Th1 cells into naive recipients before aerosol M. tuberculosis infection dramatically enhances resistance, resulting in 100-fold fewer bacteria in infected lungs. However, despite large numbers of Th1 cells in the lungs of mice at the time of M. tuberculosis challenge, protection was not manifested until after 7 d following infection. Our results demonstrate that pathogen-specific Th1 cells can provide protection against inhaled M. tuberculosis, but only after the first week of infection. PMID:18779346

  16. Centering Single Cells in Microgels via Delayed Crosslinking Supports Long-Term 3D Culture by Preventing Cell Escape

    NARCIS (Netherlands)

    Kamperman, Tom; Henke, Sieger; Visser, Claas Willem; Karperien, Marcel; Leijten, Jeroen

    2017-01-01

    Single-cell-laden microgels support physiological 3D culture conditions while enabling straightforward handling and high-resolution readouts of individual cells. However, their widespread adoption for long-term cultures is limited by cell escape. In this work, it is demonstrated that cell escape is

  17. Functional Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells

    National Research Council Canada - National Science Library

    Zhang, Jianhua; Wilson, Gisela F; Soerens, Andrew G; Koonce, Chad H; Yu, Junying; Palecek, Sean P; Thomson, James A; Kamp, Timothy J

    2009-01-01

    Human induced pluripotent stem (iPS) cells hold great promise for cardiovascular research and therapeutic applications, but the ability of human iPS cells to differentiate into functional cardiomyocytes has not yet been demonstrated...

  18. MC1R and cAMP signaling inhibit cdc25B activity and delay cell cycle progression in melanoma cells.

    Science.gov (United States)

    Lyons, Jesse; Bastian, Boris C; McCormick, Frank

    2013-08-20

    The melanocortin 1 receptor (MC1R) mediates the tanning response through induction of cAMP and downstream pigmentary enzymes. Diminished function alleles of MC1R are associated with decreased tanning and increased melanoma risk, which has been attributed to increased rates of mutation. We have found that MC1R or cAMP signaling also directly decreases proliferation in melanoma cell lines. MC1R overexpression, treatment with the MC1R ligand, or treatment with small-molecule activators of cAMP signaling causes delayed progression from G2 into mitosis. This delay is caused by phosphorylation and inhibition of cdc25B, a cyclin dependent kinase 1-activating phosphatase, and is rescued by expression of a cdc25B mutant that cannot be phosphorylated at the serine 323 residue. These results show that MC1R and cAMP signaling can directly inhibit melanoma growth through regulation of the G2/M checkpoint.

  19. The Hydrogen Sulfide Donor NaHS Delays Programmed Cell Death in Barley Aleurone Layers by Acting as an Antioxidant

    Directory of Open Access Journals (Sweden)

    Ying-Xin Zhang

    2015-01-01

    Full Text Available H2S is a signaling molecule in plants and animals. Here we investigated the effects of H2S on programmed cell death (PCD in barley (Hordeum vulgare L. aleurone layers. The H2S donor NaHS significantly delayed PCD in aleurone layers isolated from imbibed embryoless barley grain. NaHS at 0.25 mM effectively reduced the accumulation of superoxide anion (·O2-, hydrogen peroxide (H2O2, and malondialdehyde (MDA, promoted the activity of superoxide dismutase (SOD, guaiacol peroxidase (POD, catalase (CAT, and ascorbate peroxidase (APX, and decreased those of lipoxygenase (LOX in isolated aleurone layers. Quantitative-PCR showed that NaHS treatment of aleurone tissue led to enhanced transcript levels of the antioxidant genes HvSOD1, HvAPX, HvCAT1, and HvCAT2 and repressed transcript levels of HvLOX (lipoxygenase gene and of two cysteine protease genes HvEPA and HvCP3-31. NaHS treatment in gibberellic acid- (GA- treated aleurone layers also delayed the PCD process, reduced the content of ·O2-, and increased POD activity while decreasing LOX activity. Furthermore, α-amylase secretion in barley aleurone layers was enhanced by NaHS treatment regardless of the presence or absence of GA. These data imply that H2S acted as an antioxidant in delaying PCD and enhances α-amylase secretion regardless of the presence of GA in barley aleurone layers.

  20. HIV transcription is induced with some forms of cell killing

    Energy Technology Data Exchange (ETDEWEB)

    Woloschak, G.E. [Argonne National Lab., IL (United States); Schreck, S. [Argonne National Lab., IL (United States)][South Carolina Univ., Columbia, SC (United States). Dept. of Chemistry; Panozzo, J. [Loyola Univ. Medical Center, Maywood, IL (United States); Chang-Liu, C.-M. [Argonne National Lab., IL (United States); Libertin, C.R. [Loyola Univ. Medical Center, Maywood, IL (United States)

    1996-11-01

    Using HeLa cells stably transfected with an HIV-LTR-CAT construct`, we demonstrated a peak in CAT induction that occurs in viable (but not necessarily cell-division-competent) cells 24 h following exposure to some cell-killing agents. {Gamma} rays were the only cell-killing agent which did not induce HIV transcription; this can be attributed to the fact that {gamma}-ray-induced apoptotic death requires function p53, which is missing in HeLa cells. For all other agents, HIV-LTR induction was dose-dependent and correlated with the amount of cell killing that occurred in the culture.

  1. Cannabinoids induce incomplete maturation of cultured human leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Murison, G.; Chubb, C.B.H.; Maeda, S.; Gemmell, M.A.; Huberman, E.

    1987-08-01

    Monocyte maturation markers were induced in cultured human myeloblastic ML-2 leukemia cells after treatment for 1-6 days with 0.03-30 ..mu..M ..delta../sup 9/-tetrahydrocannabinol (THC), the major psychoactive component of marijuana. After a 2-day or longer treatment, 2- to 5-fold increases were found in the percentages of cells exhibiting reactivity with either the murine OKM1 monoclonal antibody of the Leu-M5 monoclonal antibody, staining positively for nonspecific esterase activity, and displaying a promonocyte morphology. The increases in these differentiation markers after treatment with 0.03-1 ..mu..M THC were dose dependent. At this dose range, THC did not cause an inhibition of cell growth. The THC-induced cell maturation was also characterized by specific changes in the patterns of newly synthesized proteins. The THC-induced differentiation did not, however, result in cells with a highly developed mature monocyte phenotype. However, treatment of these incompletely matured cells with either phorbol 12-myristate 13-acetate of 1..cap alpha..,25-dihydroxycholecalciferol, which are inducers of differentiation in myeloid leukemia cells (including ML-2 cells), produced cells with a mature monocyte morphology. The ML-2 cell system described here may be a useful tool for deciphering critical biochemical events that lead to the cannabinoid-induced incomplete cell differentiation of ML-2 cells and other related cell types. Findings obtained from this system may have important implications for studies of cannabinoid effects on normal human bone-marrow progenitor cells.

  2. Delayed Mesoderm and Erythroid Differentiation of Murine Embryonic Stem Cells in the Absence of the Transcriptional Regulator FUBP1

    Directory of Open Access Journals (Sweden)

    Josephine Wesely

    2017-01-01

    Full Text Available The transcriptional regulator far upstream binding protein 1 (FUBP1 is essential for fetal and adult hematopoietic stem cell (HSC self-renewal, and the constitutive absence of FUBP1 activity during early development leads to embryonic lethality in homozygous mutant mice. To investigate the role of FUBP1 in murine embryonic stem cells (ESCs and in particular during differentiation into hematopoietic lineages, we generated Fubp1 knockout (KO ESC clones using CRISPR/Cas9 technology. Although FUBP1 is expressed in undifferentiated ESCs and during spontaneous differentiation following aggregation into embryoid bodies (EBs, absence of FUBP1 did not affect ESC maintenance. Interestingly, we observed a delayed differentiation of FUBP1-deficient ESCs into the mesoderm germ layer, as indicated by impaired expression of several mesoderm markers including Brachyury at an early time point of ESC differentiation upon aggregation to EBs. Coculture experiments with OP9 cells in the presence of erythropoietin revealed a diminished differentiation capacity of Fubp1 KO ESCs into the erythroid lineage. Our data showed that FUBP1 is important for the onset of mesoderm differentiation and maturation of hematopoietic progenitor cells into the erythroid lineage, a finding that is supported by the phenotype of FUBP1-deficient mice.

  3. Induced pluripotent stem cells for retinal degenerative diseases: a ...

    Indian Academy of Sciences (India)

    Induced pluripotent stem (iPS) cells are an innovative technology that turns somatic cells into embryonic stem (ES)-like cells with pluripotent potential via the exogenous expression of several key genes. It can be used as an unlimited source for cell differentiation or tissue engineering, either of which is a promising therapy ...

  4. Green tea polyphenol induces significant cell death in human lung ...

    African Journals Online (AJOL)

    Green tea polyphenol induces significant cell death in human lung cancer cells. ... Tropical Journal of Pharmaceutical Research ... (8-OHdG), and apoptosis based on 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were evaluated in non-small cell lung cancer (NSCLC) cell lines, namely, H1155, ...

  5. Piroxicam fails to reduce myocellular enzyme leakage and delayed onset muscle soreness induced by isokinetic eccentric exercise

    Directory of Open Access Journals (Sweden)

    J-L. Croisier

    1996-01-01

    Full Text Available To test the hypothesis that delayed onset muscular soreness (DOMS following intense eccentric muscle contraction could be due to increased production of prostaglandin E2 (PGE2, ten healthy male subjects were studied. Using a double-blind randomized crossover design, each subject performed two isokinetic tests separated by a period of at least 6 weeks: once with placebo, and once with piroxicam (Feldene®. They were given one capsule containing either placebo or piroxicam (20 mg per day for 6 days with initial doses given starting 3 days prior to isokinetic testing. Exercise consisted of eight stages of five maximal contractions of the knee extensor and flexor muscle groups of both legs separated by 1 min rest phases, on a Kin Trex device at 60°/s angular velocity. The subjective presence and intensity of DOMS were evaluated using a visual analogue scale immediately after, and 24 and 48 h after each test. The mean plasma concentration of PGE2 measured at rest and after exercise was significantly lower in the group treated with piroxicam (p < 0.05. However, statistical analysis (two-way ANOVA test revealed that exercise did not cause any significant change of mean plasma PGE2 over time in either of the two groups. Eccentric work was followed by severe muscle pain in extensor and flexor muscle groups. Maximal soreness was noted 48 h postexercise. Serum creatine kinase activity and the serum concentration of myoglobin increased significantly, and reached peak values 48 h after exercise in both experimental conditions (p < 0.001. By paired t-test, it appeared that there were no significant differences in the serum levels of these two markers of muscle damage between the two groups at any time point. We conclude that: (1 oral administration of piroxicam fails to reduce muscle damage and DOMS caused by strenuous eccentric exercise; and (2 the hypothetical role of increased PGE2 production in eccentric exercise-induced muscle damage, DOMS, and reduced

  6. Cadmium-induced programmed cell death signaling in tomato suspension cells

    NARCIS (Netherlands)

    Yakimova, E.T.; Woltering, E.J.; Kapchina-Toteva, V.M.

    2009-01-01

    Here we present a summary of our study on cadmium-induced cell death signaling in a model system of suspension-cultured tomato cells. Exposure of the cells to CdSO4 induced typical for PCD (cytoplasm shrinkage and nuclear condensation) morphological changes of the dead cells. Ethylene and hydrogen

  7. Mesenchymal Stem Cells Protect Nucleus Pulposus Cells from Compression-Induced Apoptosis by Inhibiting the Mitochondrial Pathway

    Directory of Open Access Journals (Sweden)

    Sheng Chen

    2017-01-01

    Full Text Available Objective. Excessive apoptosis of nucleus pulposus cells (NPCs induced by various stresses, including compression, contributes to the development of intervertebral disc degeneration (IVDD. Mesenchymal stem cells (MSCs can benefit the regeneration of NPCs and delay IVDD, but the underlying molecular mechanism is poorly understood. This study aimed to evaluate the antiapoptosis effects of bone marrow-derived MSC (BMSC on rat NPCs exposed to compression and investigate whether the mitochondrial pathway was involved. Methods. BMSCs and NPCs were cocultured in the compression apparatus at 1.0 MPa for 36 h. Cell viability, apoptosis, mitochondrial function, and the expression of apoptosis-related proteins were evaluated. Results. The results showed that coculturing with BMSCs increased the cell viability and reduced apoptosis of NPCs exposed to compression. Meanwhile, BMSCs could relieve the compression-induced mitochondrial damage of NPCs by decreasing reactive oxygen species level and maintaining mitochondrial membrane potential as well as mitochondrial integrity. Furthermore, coculturing with BMSCs suppressed the activated caspase-3 and activated caspase-9, decreased the expressions of cytosolic cytochrome c and Bax, and increased the expression of Bcl-2. Conclusions. Our results suggest that BMSCs can protect against compression-induced apoptosis of NPCs by inhibiting the mitochondrial pathway and thus enhance our understanding on the MSC-based therapy for IVDD.

  8. Dearth and Delayed Maturation of Testicular Germ Cells in Fanconi Anemia E Mutant Male Mice.

    Directory of Open Access Journals (Sweden)

    Chun Fu

    Full Text Available After using a self-inactivating lentivirus for non-targeted insertional mutagenesis in mice, we identified a transgenic family with a recessive mutation that resulted in reduced fertility in homozygous transgenic mice. The lentiviral integration site was amplified by inverse PCR. Sequencing revealed that integration had occurred in intron 8 of the mouse Fance gene, which encodes the Fanconi anemia E (Fance protein. Fanconi anemia (FA proteins play pivotal roles in cellular responses to DNA damage and Fance acts as a molecular bridge between the FA core complex and Fancd2. To investigate the reduced fertility in the mutant males, we analyzed postnatal development of testicular germ cells. At one week after birth, most tubules in the mutant testes contained few or no germ cells. Over the next 2-3 weeks, germ cells accumulated in a limited number of tubules, so that some tubules contained germ cells around the full periphery of the tubule. Once sufficient numbers of germ cells had accumulated, they began to undergo the later stages of spermatogenesis. Immunoassays revealed that the Fancd2 protein accumulated around the periphery of the nucleus in normal developing spermatocytes, but we did not detect a similar localization of Fancd2 in the Fance mutant testes. Our assays indicate that although Fance mutant males are germ cell deficient at birth, the extant germ cells can proliferate and, if they reach a threshold density, can differentiate into mature sperm. Analogous to previous studies of FA genes in mice, our results show that the Fance protein plays an important, but not absolutely essential, role in the initial developmental expansion of the male germ line.

  9. Exposure of Endothelial Cells to Physiological Levels of Myeloperoxidase-Modified LDL Delays Pericellular Fibrinolysis

    Science.gov (United States)

    Moguilevsky, Nicole; Delree, Paul; Ducobu, Jean; Raes, Martine; Badran, Bassam; Vanhaeverbeek, Michel; Brohee, Dany; Remacle, Claude; Vanhamme, Luc

    2012-01-01

    Background Blood fluidity is maintained by a delicate balance between coagulation and fibrinolysis. The endothelial cell surface is a key player in this equilibrium and cell surface disruptions can upset the balance. We investigated the role of pericellular myeloperoxidase oxidized LDLs (Mox-LDLs) in this balance. Methods and Results We designed a technical device that enabled us to monitor fibrinolysis in real-time at the surface of an endothelial cell line (EA.hy926), and showed that Mox-LDL decreased pericellular fibrinolysis. There were no changes in fibrinolysis when EA.hy926 endothelial cells were exposed to native LDL (24 hours) at doses of 10, 50, 100 and up to 1250 µg/ml. However, treatment of EA.hy926 endothelial cells with 10 and 50 µg/ml of Mox-LDL (physiological serum concentrations) increased the lysis time by 15 and 13%, respectively (p<0.001), although this effect was not present at higher concentrations of 100 µg/ml. This effect was not correlated with any changes in PAI-1 or t-PA or PA Receptor (PAR) expression. No effect was observed at the surface of smooth muscle cells used as controls. Conclusion Our data link the current favorite hypothesis that modified LDL has a causal role in atheroma plaque formation with an old suggestion that fibrin may also play a causal role. Our data help complete the paradigm of atherosclerosis: Modified LDL locally enhances fibrin deposition (present work); fibrin deposits enhance endothelial permeability; this effect allows subendothelial accumulation of lipid and foam cells. PMID:22723891

  10. Clozapine Induces Autophagic Cell Death in Non-Small Cell Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Yu-Chun Yin

    2015-02-01

    Full Text Available Background/Aims: Previous studies have shown that patients with schizophrenia have a lower incidence of cancer than the general population, and several antipsychotics have been demonstrated to have cytotoxic effects on cancer cells. However, the mechanisms underlying these results remain unclear. The present study aimed to investigate the effect of clozapine, which is often used to treat patients with refractory schizophrenia, on the growth of non-small cell lung carcinoma cell lines and to examine whether autophagy contributes to its effects. Methods: A549 and H1299 cells were treated with clozapine, and cell cytotoxicity, cell cycle and autophagy were then assessed. The autophagy inhibitor bafilomycin A1 and siRNA-targeted Atg7 were used to determine the role of autophagy in the effect of clozapine. Results: Clozapine inhibited A549 and H1299 proliferation and increased p21 and p27 expression levels, leading to cell cycle arrest. Clozapine also induced a high level of autophagy, but not apoptosis, in both cell lines, and the growth inhibitory effect of clozapine was blunted by treatment with the autophagy inhibitor bafilomycin A1 or with an siRNA targeting atg7. Conclusions: Clozapine inhibits cell proliferation by inducing autophagic cell death in two non-small cell lung carcinoma cell lines. These findings may provide insights into the relationship between clozapine use and the lower incidence of lung cancer among patients with schizophrenia.

  11. Tangeretin sensitises human lung cancer cells to TRAIL- induced ...

    African Journals Online (AJOL)

    necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells. (H1299 and H1975). Methods: ... Western blotting was performed to assess the expression of death receptors, apoptosis pathway proteins, JNK and ERK1/2. ...... upregulation in hepatocellular carcinoma cells. World J.

  12. Delayed postoperative radiation therapy in local control of squamous cell carcinoma of the tongue and floor of the mouth

    Energy Technology Data Exchange (ETDEWEB)

    Amar, Ali; Chedid, Helma Maria; Curioni, Otavio Alberto; Rapoport, Abrao, E-mail: arapoport@uol.com.br [Universidade de Sao Paulo (USP), Sao Paulo, SP (Brazil); Dedivitis, Rogerio Aparecido; Cernea, Claudio Roberto; Brandao, Lenine Garcia [Hospital Heliopolis, Sao aulo, SP (Brazil)

    2014-10-15

    Objective: to evaluate the effect of time between surgery and postoperative radiation therapy on local recurrence of squamous cell carcinoma of the tongue and floor of the mouth. Methods: a total of 154 patients treated between 1996 and 2007 were selected considering local recurrence rate and time of the adjuvant radiotherapy. Results: local recurrence was diagnosed in 54 (35%) patients. Radiation therapy reduced the rate of local recurrences, although with no statistical significance. The time between surgery and initiation of postoperative radiotherapy did not significantly influence the risk of local recurrence in patients referred to adjuvant treatment (p=0.49). Conclusion: in the presence of risk factors for local recurrence, a short delay in starting the adjuvant radiation therapy does not contraindicate its performance. (author)

  13. Entamoeba histolytica induces cell death of HT29 colonic epithelial cells via NOX1-derived ROS.

    Science.gov (United States)

    Kim, Kyeong Ah; Kim, Ju Young; Lee, Young Ah; Min, Arim; Bahk, Young Yil; Shin, Myeong Heon

    2013-02-01

    Entamoeba histolytica, which causes amoebic colitis and occasionally liver abscess in humans, is able to induce host cell death. However, signaling mechanisms of colon cell death induced by E. histolytica are not fully elucidated. In this study, we investigated the signaling role of NOX in cell death of HT29 colonic epithelial cells induced by E. histolytica. Incubation of HT29 cells with amoebic trophozoites resulted in DNA fragmentation that is a hallmark of apoptotic cell death. In addition, E. histolytica generate intracellular reactive oxygen species (ROS) in a contact-dependent manner. Inhibition of intracellular ROS level with treatment with DPI, an inhibitor of NADPH oxidases (NOXs), decreased Entamoeba-induced ROS generation and cell death in HT29 cells. However, pan-caspase inhibitor did not affect E. histolytica-induced HT29 cell death. In HT29 cells, catalytic subunit NOX1 and regulatory subunit Rac1 for NOX1 activation were highly expressed. We next investigated whether NADPH oxidase 1 (NOX1)-derived ROS is closely associated with HT29 cell death induced by E. histolytica. Suppression of Rac1 by siRNA significantly inhibited Entamoeba-induced cell death. Moreover, knockdown of NOX1 by siRNA, effectively inhibited E. histolytica-triggered DNA fragmentation in HT29 cells. These results suggest that NOX1-derived ROS is required for apoptotic cell death in HT29 colon epithelial cells induced by E. histolytica.

  14. Alpha-particles induce autophagy in multiple myeloma cells

    Directory of Open Access Journals (Sweden)

    Joelle Marcelle Gaschet

    2015-10-01

    Full Text Available Objectives: Radiations emitted by the radionuclides in radioimmunotherapy (RIT approaches induce direct killing of the targeted cells as well as indirect killing through bystander effect. Our research group is dedicated to the development of α-RIT, i.e RIT using α-particles especially for the treatment of multiple myeloma (MM. γ-irradiation and β-irradiation have been shown to trigger apoptosis in tumor cells. Cell death mode induced by 213Bi α-irradiation appears more controversial. We therefore decided to investigate the effects of 213Bi on MM cell radiobiology, notably cell death mechanisms as well as tumor cell immunogenicity after irradiation.Methods: Murine 5T33 and human LP-1 multiple myeloma (MM cell lines were used to study the effects of such α-particles. We first examined the effects of 213Bi on proliferation rate, double strand DNA breaks, cell cycle and cell death. Then, we investigated autophagy after 213Bi irradiation. Finally, a co-culture of dendritic cells (DC with irradiated tumour cells or their culture media was performed to test whether it would induce DC activation.Results: We showed that 213Bi induces DNA double strand breaks, cell cycle arrest and autophagy in both cell lines but we detected only slight levels of early apoptosis within the 120 hours following irradiation in 5T33 and LP-1. Inhibition of autophagy prevented 213Bi induced inhibition of proliferation in LP-1 suggesting that this mechanism is involved in cell death after irradiation. We then assessed the immunogenicity of irradiated cells and found that irradiated LP-1 can activate DC through the secretion of soluble factor(s, however no increase in membrane or extracellular expression of danger associated molecular patterns (DAMPs was observed after irradiation.Conclusion: This study demonstrates that 213Bi induces mainly necrosis in MM cells, low levels of apoptosis and also autophagy that might be involved in tumor cell death.

  15. Intravitreal implantation of TPP1-transduced stem cells delays retinal degeneration in canine CLN2 neuronal ceroid lipofuscinosis.

    Science.gov (United States)

    Tracy, Christopher J; Whiting, Rebecca E H; Pearce, Jacqueline W; Williamson, Baye G; Vansteenkiste, Daniella P; Gillespie, Lauren E; Castaner, Leilani J; Bryan, Jeffrey N; Coates, Joan R; Jensen, Cheryl A; Katz, Martin L

    2016-11-01

    The CLN2 form of neuronal ceroid lipofuscinosis is a neurodegenerative disease that results from mutations in the TPP1 gene. Affected children exhibit progressive declines in most neurological functions including vision. Functional declines are accompanied by progressive brain and retinal atrophy. TPP1 encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Dachshunds with a TPP1 null mutation exhibit a disorder very similar to human CLN2 disease. Periodic infusion of recombinant TPP1 protein or a single injection of a TPP1 gene therapy vector into the cerebrospinal fluid of affected dogs significantly delays the onset and progression of neurological signs but does not slow vision loss or retinal degeneration. Studies were conducted to determine whether intravitreal implantation of autologous bone marrow derived stem cells transduced with a TPP1 expression construct would inhibit retinal degeneration in the canine model. A single injection of the transduced cells at an early stage in the disease progression substantially inhibited the development of disease-related retinal function deficits and structural changes. No adverse effects of the treatment were detected. These findings indicate that ex vivo gene therapy using autologous stem cells is an effective means of achieving sustained delivery of therapeutic compounds to tissues such as the retina for which systemic administration would be ineffective. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  16. Chemical Methods to Induce Beta-Cell Proliferation

    Directory of Open Access Journals (Sweden)

    Amedeo Vetere

    2012-01-01

    Full Text Available Pancreatic beta-cell regeneration, for example, by inducing proliferation, remains an important goal in developing effective treatments for diabetes. However, beta cells have mainly been considered quiescent. This “static” view has recently been challenged by observations of relevant physiological conditions in which metabolic stress is compensated by an increase in beta-cell mass. Understanding the molecular mechanisms underlining these process could open the possibility of developing novel small molecules to increase beta-cell mass. Several cellular cell-cycle and signaling proteins provide attractive targets for high throughput screening, and recent advances in cell culture have enabled phenotypic screening for small molecule-induced beta-cell proliferation. We present here an overview of the current trends involving small-molecule approaches to induce beta-cell regeneration by proliferation.

  17. 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.

  18. Osteoblasts Protect AML Cells from SDF-1-Induced Apoptosis

    Science.gov (United States)

    Kremer, Kimberly N.; Dudakovic, Amel; McGee-Lawrence, Meghan E.; Philips, Rachael L.; Hess, Allan D.; Smith, B. Douglas; van Wijnen, Andre J.; Karp, Judith E.; Kaufmann, Scott H.; Westendorf, Jennifer J.; Hedin, Karen E.

    2014-01-01

    The bone marrow provides a protective environment for acute myeloid leukemia (AML) cells that often allows leukemic stem cells to survive standard chemotherapeutic regimens. Targeting these leukemic stem cells within the bone marrow is critical for preventing relapse. We recently demonstrated that SDF-1, a chemokine abundant in the bone marrow, induces apoptosis in AML cell lines and in patient samples expressing high levels of its receptor, CXCR4. Here we show that a subset of osteoblast lineage cells within the bone marrow can protect AML cells from undergoing apoptosis in response to the SDF-1 naturally present in that location. In co-culture systems, osteoblasts at various stages of differentiation protected AML cell lines and patient isolates from SDF-1-induced apoptosis. The differentiation of the osteoblast cell lines, MC3T3 and W-20-17, mediated this protection via a cell contact-independent mechanism. In contrast, bone marrow-derived mesenchymal cells, the precursors of osteoblasts, induced apoptosis in AML cells via a CXCR4-dependent mechanism and failed to protect AML cells from exogenously added SDF-1. These results indicate that osteoblasts in the process of differentiation potently inhibit the SDF-1-driven apoptotic pathway of CXCR4-expressing AML cells residing in the bone marrow. Drugs targeting this protective mechanism could potentially provide a new approach to treating AML by enhancing the SDF-1-induced apoptosis of AML cells residing within the bone marrow microenvironment. PMID:24851270

  19. Pulsed Radiation Therapy With Concurrent Cisplatin Results in Superior Tumor Growth Delay in a Head and Neck Squamous Cell Carcinoma Murine Model

    Energy Technology Data Exchange (ETDEWEB)

    Meyer, Kurt; Krueger, Sarah A.; Kane, Jonathan L.; Wilson, Thomas G.; Hanna, Alaa; Dabjan, Mohamad; Hege, Katie M.; Wilson, George D.; Grills, Inga; Marples, Brian, E-mail: brian.marples@beaumont.edu

    2016-09-01

    Purpose: To assess the efficacy of 3-week schedules of low-dose pulsed radiation treatment (PRT) and standard radiation therapy (SRT), with concurrent cisplatin (CDDP) in a head and neck squamous cell carcinoma xenograft model. Methods and Materials: Subcutaneous UT-SCC-14 tumors were established in athymic NIH III HO female mice. A total of 30 Gy was administered as 2 Gy/d, 5 d/wk for 3 weeks, either by PRT (10 × 0.2 Gy/d, with a 3-minute break between each 0.2-Gy dose) or SRT (2 Gy/d, uninterrupted delivery) in combination with concurrent 2 mg/kg CDDP 3 times per week in the final 2 weeks of radiation therapy. Treatment-induced growth delays were defined from twice-weekly tumor volume measurements. Tumor hypoxia was assessed by {sup 18}F-fluoromisonidazole positron emission tomography imaging, and calculated maximum standardized uptake values compared with tumor histology. Tumor vessel density and hypoxia were measured by quantitative immunohistochemistry. Normal tissues effects were evaluated in gut and skin. Results: Untreated tumors grew to 1000 mm{sup 3} in 25.4 days (±1.2), compared with delays of 62.3 days (±3.5) for SRT + CDDP and 80.2 days (±5.0) for PRT + CDDP. Time to reach 2× pretreatment volume ranged from 8.2 days (±1.8) for untreated tumors to 67.1 days (±4.7) after PRT + CDDP. Significant differences in tumor growth delay were observed for SRT versus SRT + CDDP (P=.04), PRT versus PRT + CDDP (P=.035), and SRT + CDDP versus PRT + CDDP (P=.033), and for survival between PRT versus PRT + CDDP (P=.017) and SRT + CDDP versus PRT + CDDP (P=.008). Differences in tumor hypoxia were evident by {sup 18}F-fluoromisonidazole positron emission tomography imaging between SRT and PRT (P=.025), although not with concurrent CDDP. Tumor vessel density differed between SRT + CDDP and PRT + CDDP (P=.011). No differences in normal tissue parameters were seen. Conclusions: Concurrent CDDP was more effective in combination PRT than SRT at

  20. Polyphosphate induces matrix metalloproteinase-3-mediated proliferation of odontoblast-like cells derived from induced pluripotent stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Ozeki, Nobuaki; Hase, Naoko; Yamaguchi, Hideyuki; Hiyama, Taiki; Kawai, Rie [Department of Endodontics, School of Dentistry, Aichi Gakuin University, 2-11 Suemori-dori, Chikusa-ku, Nagoya, Aichi 464-8651 (Japan); Kondo, Ayami [Department of Medicinal Biochemistry, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto, Chikusa-ku, Nagoya 464-8650 (Japan); Nakata, Kazuhiko [Department of Endodontics, School of Dentistry, Aichi Gakuin University, 2-11 Suemori-dori, Chikusa-ku, Nagoya, Aichi 464-8651 (Japan); Mogi, Makio, E-mail: makio@dpc.agu.ac.jp [Department of Medicinal Biochemistry, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto, Chikusa-ku, Nagoya 464-8650 (Japan)

    2015-05-01

    Inorganic polyphosphate [Poly(P)] may represent a physiological source of phosphate and has the ability to induce bone differentiation in osteoblasts. We previously reported that cytokine-induced matrix metalloproteinase (MMP)-3 accelerates the proliferation of purified odontoblast-like cells. In this study, MMP-3 small interfering RNA (siRNA) was transfected into odontoblast-like cells derived from induced pluripotent stem cells to investigate whether MMP-3 activity is induced by Poly(P) and/or is associated with cell proliferation and differentiation into odontoblast-like cells. Treatment with Poly(P) led to an increase in both cell proliferation and additional odontoblastic differentiation. Poly(P)-treated cells showed a small but significant increase in dentin sialophosphoprotein (DSPP) and dentin matrix protein-1 (DMP-1) mRNA expression, which are markers of mature odontoblasts. The cells also acquired additional odontoblast-specific properties including adoption of an odontoblastic phenotype typified by high alkaline phosphatase (ALP) activity and a calcification capacity. In addition, Poly(P) induced expression of MMP-3 mRNA and protein, and increased MMP-3 activity. MMP-3 siRNA-mediated disruption of the expression of these effectors potently suppressed the expression of odontoblastic biomarkers ALP, DSPP, and DMP-1, and blocked calcification. Interestingly, upon siRNA-mediated silencing of MMP-3, we noted a potent and significant decrease in cell proliferation. Using specific siRNAs, we revealed that a unique signaling cascade, Poly(P)→MMP-3→DSPP and/or DMP-1, was intimately involved in the proliferation of odontoblast-like cells. - Highlights: • Polyphosphate increases proliferation of iPS cell-derived odontoblast-like cells. • Polyphosphate-induced MMP-3 results in an increase of cell proliferation. • Induced cell proliferation involves MMP-3, DSPP, and/or DMP-1 sequentially. • Induced MMP-3 also results in an increase of odontoblastic

  1. Impaired immune evasion in HIV through intracellular delays and multiple infection of cells

    OpenAIRE

    Althaus, Christian; de Boer, Rob J

    2012-01-01

    With its high mutation rate, HIV is capable of escape from recognition, suppression and/or killing by CD8(+) cytotoxic T lymphocytes (CTLs). The rate at which escape variants replace each other can give insights into the selective pressure imposed by single CTL clones. We investigate the effects of specific characteristics of the HIV life cycle on the dynamics of immune escape. First, it has been found that cells in HIV-infected patients can carry multiple copies of proviruses. To investigate...

  2. Chalcones Enhance TRAIL-Induced Apoptosis in Prostate Cancer Cells

    OpenAIRE

    Ewelina Szliszka; Zenon P. Czuba; Bogdan Mazur; Lukasz Sedek; Andrzej Paradysz; Wojciech Krol

    2009-01-01

    Chalcones exhibit chemopreventive and antitumor effects. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a naturally occurring anticancer agent that induces apoptosis in cancer cells and is not toxic to normal cells. We examined the cytotoxic and apoptotic effect of five chalcones in combination with TRAIL on prostate cancer cells. The cytotoxicity was evaluated by the MTT and LDH assays. The apoptosis was determined using flow cytometry with annexin V-FITC. Our study showe...

  3. Continuous cytokine exposure of colonic epithelial cells induces DNA damage

    DEFF Research Database (Denmark)

    Seidelin, Jakob B; Nielsen, Ole Haagen

    2005-01-01

    by inducible nitrogen oxide synthase (iNOS). NO as well as other ROS are potential DNA damaging agents. The aim was to determine the effect of long-term cytokine exposure on NO formation and DNA damage in epithelial cells. METHODS: A colonic cell line (HT29) was stimulated for 1-10 weeks with interferon...... stimulated cells had increased DNA instability (Pcytokine exposure induces an iNOS dependent up-regulation of ROS production and DNA instability. This mechanism...

  4. Cell death induced by endoplasmic reticulum stress

    National Research Council Canada - National Science Library

    Iurlaro, Raffaella; Muñoz‐Pinedo, Cristina

    2016-01-01

    .... Many conditions that impose stress on cells, including hypoxia, starvation, infections and changes in secretory needs, challenge the folding capacity of the cell and promote endoplasmic reticulum stress...

  5. Canthin-6-one induces cell death, cell cycle arrest and differentiation in human myeloid leukemia cells.

    Science.gov (United States)

    Vieira Torquato, Heron F; Ribeiro-Filho, Antonio C; Buri, Marcus V; Araújo Júnior, Roberto T; Pimenta, Renata; de Oliveira, José Salvador R; Filho, Valdir C; Macho, Antonio; Paredes-Gamero, Edgar J; de Oliveira Martins, Domingos T

    2017-04-01

    Canthin-6-one is a natural product isolated from various plant genera and from fungi with potential antitumor activity. In the present study, we evaluate the antitumor effects of canthin-6-one in human myeloid leukemia lineages. Kasumi-1 lineage was used as a model for acute myeloid leukemia. Cells were treated with canthin-6-one and cell death, cell cycle and differentiation were evaluated in both total cells (Lin+) and leukemia stem cell population (CD34+CD38-Lin-/low). Among the human lineages tested, Kasumi-1 was the most sensitive to canthin-6-one. Canthin-6-one induced cell death with apoptotic (caspase activation, decrease of mitochondrial potential) and necrotic (lysosomal permeabilization, double labeling of annexin V/propidium iodide) characteristics. Moreover, canthin-6-one induced cell cycle arrest at G0/G1 (7μM) and G2 (45μM) evidenced by DNA content, BrdU incorporation and cyclin B1/histone 3 quantification. Canthin-6-one also promoted differentiation of Kasumi-1, evidenced by an increase in the expression of myeloid markers (CD11b and CD15) and the transcription factor PU.1. Furthermore, a reduction of the leukemic stem cell population and clonogenic capability of stem cells were observed. These results show that canthin-6-one can affect Kasumi-1 cells by promoting cell death, cell cycle arrest and cell differentiation depending on concentration used. Canthin-6-one presents an interesting cytotoxic activity against leukemic cells and represents a promising scaffold for the development of molecules for anti-leukemic applications, especially by its anti-leukemic stem cell activity. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Pineapple bromelain induces autophagy, facilitating apoptotic response in mammary carcinoma cells.

    Science.gov (United States)

    Bhui, Kulpreet; Tyagi, Shilpa; Prakash, Bharti; Shukla, Yogeshwer

    2010-01-01

    Bromelain, from pineapple, possesses potent anticancer effects. We investigated autophagic phenomenon in mammary carcinoma cells (estrogen receptor positive and negative) under bromelain treatment and also illustrated the relationship between autophagy and apoptosis in MCF-7 cells. MCF-7 cells exposed to bromelain showed delayed growth inhibitory response and induction of autophagy, identified by monodansylcadaverine localization. It was succeeded by apoptotic cell death, evident by sub-G1 cell fraction and apoptotic features like chromatin condensation and nuclear cleavage. 3-Methyladenine (MA, autophagy inhibitor) pretreatment reduced the bromelain-induced autophagic level, also leading to decline in apoptotic population, indicating that here autophagy facilitates apoptosis. However, addition of caspase-9 inhibitor Z-LEHD-FMK augmented the autophagy levels, inhibited morphological apoptosis but did not prevent cell death. Next, we found that bromelain downregulated the phosphorylation of extracellular signal-regulated kinase ½ (ERK½), whereas that of c-jun N-terminal kinase (JNK) and p38 kinase were upregulated. Also, MA had no influence on bromelain-suppressed ERK½ activation, yet, it downregulated JNK and p38 activation. Also, addition of mitogen-activated protein kinase (MAPK) inhibitors enhanced the autophagic ratios, which suggested the role of MAP kinases in bromelain-induced autophagy. All three MAPKs were seen to be constantly activated over the time. Bromelain was seen to induce the expressions of autophagy-related proteins, light chain 3 protein B II (LC3BII), and beclin-1. Using ERK½ inhibitor, expressions of LC3BII and beclin-1 increased, whereas p38 and JNK inhibitors decreased this protein expression, indicating that bromelain-induced autophagy was positively regulated by p38 and JNK but negatively regulated by ERK½. Autophagy-inducing property of bromelain can be further exploited in breast cancer therapy. Copyright © 2010 International Union

  7. Protection of neuroblastoma Neuro2A cells from hypoxia-induced apoptosis by cyclic phosphatidic acid (cPA.

    Directory of Open Access Journals (Sweden)

    Mari Gotoh

    Full Text Available Cyclic phosphatidic acid (cPA is a naturally occurring phospholipid mediator with a unique cyclic phosphate ring at the sn-2 and sn-3 positions of its glycerol backbone. We have previously shown that cPA significantly suppresses ischemia-induced delayed neuronal death and the accumulation of glial fibrillary acidic protein in the CA1 region of the rat hippocampus. These results indicated that the systemic administration of cPA can protect hippocampal neurons against ischemia-induced delayed neuronal cell death. In the current study, we investigated the effects of cPA on neuronal cell death caused by hypoxia in vitro and the molecular mechanisms underlying these effects. We used cobalt chloride (CoCl(2 to expose cells to hypoxic conditions in vitro. Treating mouse neuroblastoma (Neuro2A cells with CoCl(2 induced nuclear DNA condensation and phosphatidylserine exposure. However, adding cPA led to the suppression of CoCl(2-induced apoptosis in a cPA dose-dependent manner and attenuated the increase in the Bax/Bcl-2 ratio caused by CoCl(2. Quantitative PCR analysis showed that Neuro2A cells strongly express the LPA(1, LPA(2, and LPA(6, which are G-protein coupled receptors that can be activated by cPA. To date, LPA(1 and LPA(2 have been reported to exhibit antiapoptotic activity. Therefore, to assess the roles of LPA(1 and LPA(2 on cPA-induced neuroprotective functions, Ki16425, a selective LPA(1 and LPA(3 antagonist, was adopted to know the LPA(1 function and siRNA was used to knockdown the expression of LPA(2. On the basis of our results, we propose that cPA-induced protection of Neuro2A cells from CoCl(2-induced hypoxia damage is mediated via LPA(2.

  8. Hyperthermia: an effective strategy to induce apoptosis in cancer cells.

    Science.gov (United States)

    Ahmed, Kanwal; Tabuchi, Yoshiaki; Kondo, Takashi

    2015-11-01

    Heat has been used as a medicinal and healing modality throughout human history. The combination of hyperthermia (HT) with radiation and anticancer agents has been used clinically and has shown positive results to a certain extent. However, the clinical results of HT treatment alone have been only partially satisfactory. Cell death following HT treatment is a function of both temperature and treatment duration. HT induces cancer cell death through apoptosis; the degree of apoptosis and the apoptotic pathway vary in different cancer cell types. HT-induced reactive oxygen species production are responsible for apoptosis in various cell types. However, the underlying mechanism of signal transduction and the genes related to this process still need to be elucidated. In this review, we summarize the molecular mechanism of apoptosis induced by HT, enhancement of heat-induced apoptosis, and the genetic network involved in HT-induced apoptosis.

  9. Delayed Cystectomy for T1G3 Transitional Cell Carcinoma (TCC) of the Urinary Bladder, NCI Retrospective Case Series.

    Science.gov (United States)

    Fakhr, Ibrahim; El-Hossieny, Hesham; Salama, Asmaa

    2008-12-01

    We aim to evaluate the National Cancer Institute (NCI) treatment protocol and its outcome regarding recurrence, progression and survival in patients with T1G3 urinary bladder transitional cell carcinoma. In a retrospective study, between January 2001 and December 2007, all 34 patients with T1G3 bladder transitional cell carcinoma (TCC), after complete transurethral resection (TURBT), received intravesical BCG as adjuvant therapy. A conservative approach was adopted, whereby those with superficial recurrences were eligible to TURBT, with delayed cystectomy for progression to muscle invasion. Overall, recurrence, and progression-free survival were analyzed. Thirty-three patients were included, 29 were males and 4 were females. The mean age was 61 years (range 35-89 years). Final analysis was made at median follow-up of 15 months (Range of 3-68 months, mean 18 months) for survival. Eleven (33.3%) patients had multifocal tumors. Associated schistosomiasis was present in 12 (36.6%) patients. Twenty-two (66.67%) patients showed recurrence. Eleven out of these 22 (50.0%) patients progressed to muscle invasion and underwent radical cystectomy. Ten out of 34 (30.3%) patients received postcystectomy radiotherapy. Two (20.0%) of them, were staged as TNM stage II, 6 (60.0%) as TNM stage III and 2 (20.0%) patients were TNM stage IV. Eight (72.7%) of these 11 patients had post-cystectomy radiotherapy alone; while the 2 (6.0%) other patients with stage IV had adjuvant concomitant Cisplatin and Gemcitabine chemotherapy. Five (14%) patients of those cystectomy patients died of TCC. Three (60%) patients died from metastatic disease (to lung, liver and bone), one patient died from advanced locoregional disease and another patient died from postoperative complications. Among those patients who received radiotherapy alone, 62.5% are alive. Although, we report a biologically more aggressive behavior of T1G3 than that reported by some authors, for this conservative approach, the overall

  10. Characterization of renal cell carcinoma, oncocytoma, and lipid-poor angiomyolipoma by unenhanced, nephrographic, and delayed phase contrast-enhanced computed tomography.

    Science.gov (United States)

    Ishigami, Kousei; Pakalniskis, Marius G; Leite, Leandro V; Lee, Daniel K; Holanda, Danniele G; Rajput, Maheen

    2015-01-01

    The purpose of this study was to assess the characterization of renal cell carcinoma (RCC) and benign renal tumors by unenhanced, nephrographic, and delayed phase computed tomography (CT). The study group consisted of 129 renal tumors including 79 clear cell RCCs, 17 papillary RCCs, 6 chromophobe RCCs, 21 oncocytoma, and 6 lipid-poor angiomyolipomas (AMLs). CT studies were retrospectively reviewed. Our results suggested that it was possible to discriminate clear cell RCC from papillary RCC, chromophobe RCC, and lipid-poor AML. CT findings of oncocytoma overlapped with both clear cell and non-clear cell RCCs, although oncocytoma more commonly became homogeneous in the delayed phase. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Human retinal pigment epithelial cell-induced apoptosis in activated T cells

    DEFF Research Database (Denmark)

    Jørgensen, A; Wiencke, A K; la Cour, M

    1998-01-01

    human retinal pigment epithelial (RPE) cells can induce apoptosis in activated T cells. METHODS: Fas ligand (FasL) expression was detected by flow cytometry and immunohistochemistry. Cultured RPE cells were cocultured with T-cell lines and peripheral blood lymphocytes for 6 hours to 2 days. Induction...... of apoptosis was detected by 7-amino-actinomycin D and annexin V staining. RESULTS: Retinal pigment epithelial cells expressed FasL and induced apoptosis in activated Fas+ T cells. Blocking of Fas-FasL interaction with antibody strongly inhibited RPE-mediated T-cell apoptosis. Retinal pigment epithelial cells...... block alloactivation, had no inhibitory effect on RPE-mediated T-cell apoptotic responses in MHC class II-specific CD4+ T-cell lines. CONCLUSIONS: Retinal pigment epithelial cells express FasL and induce TCR-independent apoptosis in activated human T cells through Fas-FasL interaction. Retinal pigment...

  12. Human retinal pigment epithelial cell-induced apoptosis in activated T cells

    DEFF Research Database (Denmark)

    Jørgensen, A; Wiencke, A K; la Cour, M

    1998-01-01

    block alloactivation, had no inhibitory effect on RPE-mediated T-cell apoptotic responses in MHC class II-specific CD4+ T-cell lines. CONCLUSIONS: Retinal pigment epithelial cells express FasL and induce TCR-independent apoptosis in activated human T cells through Fas-FasL interaction. Retinal pigment...... human retinal pigment epithelial (RPE) cells can induce apoptosis in activated T cells. METHODS: Fas ligand (FasL) expression was detected by flow cytometry and immunohistochemistry. Cultured RPE cells were cocultured with T-cell lines and peripheral blood lymphocytes for 6 hours to 2 days. Induction...... of apoptosis was detected by 7-amino-actinomycin D and annexin V staining. RESULTS: Retinal pigment epithelial cells expressed FasL and induced apoptosis in activated Fas+ T cells. Blocking of Fas-FasL interaction with antibody strongly inhibited RPE-mediated T-cell apoptosis. Retinal pigment epithelial cells...

  13. Cryptotanshinone Induces Apoptosis of HL-60 Cells via ...

    African Journals Online (AJOL)

    Furthermore, increased Bax expression, decreased Bcl-2 expression, loss of mitochondria membrane potential .... obtained from HL-60 cells indicated that the. CPT-induced arrest in G0/G1 phase was paralleled by the accumulation of p53 and p21 proteins (Figure 4C). ... cells (MCF-7) and hepatocellular carcinoma cells.

  14. Duramycin-induced calcium release in cancer cells.

    Science.gov (United States)

    Broughton, Laura J; Crow, Chris; Maraveyas, Anthony; Madden, Leigh A

    2016-03-01

    Duramycin, through binding with phosphatidylethanolamine (PE), has shown potential to be an effective antitumour agent. However, its mode of action in relation to tumour cells is not fully understood. PE expression on the surface of a panel of cancer cell lines was analysed using duramycin and subsequent antibody labelling, and then analysed by flow cytometry. Cell viability was also assessed by flow cytometry using annexin V and propidium iodide. Calcium ion (Ca) release by tumour cells in response to duramycin was determined by spectrofluorometry following incubation with Fluo-3, AM. Confocal microscopy was performed on the cancer cell line AsPC-1 to assess real-time cell response to duramycin treatment. Duramycin could detect cell surface PE expression on all 15 cancer cell lines screened, which was shown to be duramycin concentration dependent. However, higher concentrations induced necrotic cell death. Duramycin induced calcium ion (Ca) release from the cancer cell lines also in a concentration-dependent and time-dependent manner. Confocal microscopy showed an influx of propidium iodide into the cells over time and induced morphological changes. Duramycin induces Ca release from cancer cell lines in a time-dependent and concentration-dependent manner.

  15. α-Synuclein Delays Endoplasmic Reticulum (ER)-to-Golgi Transport in Mammalian Cells by Antagonizing ER/Golgi SNAREs

    Science.gov (United States)

    Thayanidhi, Nandhakumar; Helm, Jared R.; Nycz, Deborah C.; Bentley, Marvin; Liang, Yingjian

    2010-01-01

    Toxicity of human α-synuclein when expressed in simple organisms can be suppressed by overexpression of endoplasmic reticulum (ER)-to-Golgi transport machinery, suggesting that inhibition of constitutive secretion represents a fundamental cause of the toxicity. Whether similar inhibition in mammals represents a cause of familial Parkinson's disease has not been established. We tested elements of this hypothesis by expressing human α-synuclein in mammalian kidney and neuroendocrine cells and assessing ER-to-Golgi transport. Overexpression of wild type or the familial disease-associated A53T mutant α-synuclein delayed transport by up to 50%; however, A53T inhibited more potently. The secretory delay occurred at low expression levels and was not accompanied by insoluble α-synuclein aggregates or mistargeting of transport machinery, suggesting a direct action of soluble α-synuclein on trafficking proteins. Co-overexpression of ER/Golgi arginine soluble N-ethylmaleimide-sensitive factor attachment protein receptors (R-SNAREs) specifically rescued transport, indicating that α-synuclein antagonizes SNARE function. Ykt6 reversed α-synuclein inhibition much more effectively than sec22b, suggesting a possible neuroprotective role for the enigmatic high expression of ykt6 in neurons. In in vitro reconstitutions, purified α-synuclein A53T protein specifically inhibited COPII vesicle docking and fusion at a pre-Golgi step. Finally, soluble α-synuclein A53T directly bound ER/Golgi SNAREs and inhibited SNARE complex assembly, providing a potential mechanism for toxic effects in the early secretory pathway. PMID:20392839

  16. Alpha-synuclein delays endoplasmic reticulum (ER)-to-Golgi transport in mammalian cells by antagonizing ER/Golgi SNAREs.

    Science.gov (United States)

    Thayanidhi, Nandhakumar; Helm, Jared R; Nycz, Deborah C; Bentley, Marvin; Liang, Yingjian; Hay, Jesse C

    2010-06-01

    Toxicity of human alpha-synuclein when expressed in simple organisms can be suppressed by overexpression of endoplasmic reticulum (ER)-to-Golgi transport machinery, suggesting that inhibition of constitutive secretion represents a fundamental cause of the toxicity. Whether similar inhibition in mammals represents a cause of familial Parkinson's disease has not been established. We tested elements of this hypothesis by expressing human alpha-synuclein in mammalian kidney and neuroendocrine cells and assessing ER-to-Golgi transport. Overexpression of wild type or the familial disease-associated A53T mutant alpha-synuclein delayed transport by up to 50%; however, A53T inhibited more potently. The secretory delay occurred at low expression levels and was not accompanied by insoluble alpha-synuclein aggregates or mistargeting of transport machinery, suggesting a direct action of soluble alpha-synuclein on trafficking proteins. Co-overexpression of ER/Golgi arginine soluble N-ethylmaleimide-sensitive factor attachment protein receptors (R-SNAREs) specifically rescued transport, indicating that alpha-synuclein antagonizes SNARE function. Ykt6 reversed alpha-synuclein inhibition much more effectively than sec22b, suggesting a possible neuroprotective role for the enigmatic high expression of ykt6 in neurons. In in vitro reconstitutions, purified alpha-synuclein A53T protein specifically inhibited COPII vesicle docking and fusion at a pre-Golgi step. Finally, soluble alpha-synuclein A53T directly bound ER/Golgi SNAREs and inhibited SNARE complex assembly, providing a potential mechanism for toxic effects in the early secretory pathway.

  17. Hexavalent Chromium Induces Chromosome Instability in Human Urothelial Cells

    Science.gov (United States)

    Wise, Sandra S.; Holmes, Amie L.; Liou, Louis; Adam, Rosalyn M.; Wise, John Pierce

    2016-01-01

    Numerous metals are well-known human bladder carcinogens. Despite the significant occupational and public health concern of metals and bladder cancer, the carcinogenic mechanisms remain largely unknown. Chromium, in particular, is a metal of concern as incidences of bladder cancer have been found elevated in chromate workers, and there is an increasing concern for patients with metal hip implants. However, the impact of Cr(VI) on bladder cells has not been studied. We compared chromate toxicity in two bladder cell lines; primary human urothelial cells and hTERT-immortalized human urothelial cells. Hexavalent chromium (Cr(VI)) induced a concentration- and time-dependent increase in chromosome damage in both cell lines, with the hTERT-immortalized cells exhibiting more chromosome damage than the primary cells. Chronic exposure to Cr(VI) also induced a concentration-dependent increase in aneuploid metaphases in both cell lines which was not observed after a 24 h exposure. Aneuploidy induction was higher in the hTERT-immortalized cells. When we correct for uptake, Cr(VI) induces a similar amount of chromosome damage and aneuploidy suggesting that the differences in Cr(VI) sensitivity between the two cells lines were due to differences in uptake. The increase in chromosome instability after chronic chromate treatment suggests this may be a mechanism for chromate-induced bladder cancer specifically and may be a mechanism for metal-induced bladder cancer in general. PMID:26908176

  18. Hexavalent chromium induces chromosome instability in human urothelial cells.

    Science.gov (United States)

    Wise, Sandra S; Holmes, Amie L; Liou, Louis; Adam, Rosalyn M; Wise, John Pierce

    2016-04-01

    Numerous metals are well-known human bladder carcinogens. Despite the significant occupational and public health concern of metals and bladder cancer, the carcinogenic mechanisms remain largely unknown. Chromium, in particular, is a metal of concern as incidences of bladder cancer have been found elevated in chromate workers, and there is an increasing concern for patients with metal hip implants. However, the impact of hexavalent chromium (Cr(VI)) on bladder cells has not been studied. We compared chromate toxicity in two bladder cell lines; primary human urothelial cells and hTERT-immortalized human urothelial cells. Cr(VI) induced a concentration- and time-dependent increase in chromosome damage in both cell lines, with the hTERT-immortalized cells exhibiting more chromosome damage than the primary cells. Chronic exposure to Cr(VI) also induced a concentration-dependent increase in aneuploid metaphases in both cell lines which was not observed after a 24h exposure. Aneuploidy induction was higher in the hTERT-immortalized cells. When we correct for uptake, Cr(VI) induces a similar amount of chromosome damage and aneuploidy suggesting that the differences in Cr(VI) sensitivity between the two cells lines were due to differences in uptake. The increase in chromosome instability after chronic chromate treatment suggests this may be a mechanism for chromate-induced bladder cancer, specifically, and may be a mechanism for metal-induced bladder cancer, in general. Copyright © 2016. Published by Elsevier Inc.

  19. Glycolaldehyde induces endoplasmic reticulum stress and apoptosis in Schwann cells

    Directory of Open Access Journals (Sweden)

    Keisuke Sato

    2015-01-01

    Full Text Available Schwann cell injury is caused by diabetic neuropathy. The apoptosis of Schwann cells plays a pivotal role in diabetic nerve dysfunction. Glycolaldehyde is a precursor of advanced glycation end products that contribute to the pathogenesis of diabetic neuropathy. In this study, we examined whether glycolaldehyde induces endoplasmic reticulum (ER stress and apoptosis in rat Schwann cells. Schwann cells treated with 500 μM glycolaldehyde showed morphological changes characteristic of apoptosis. Glycolaldehyde activated apoptotic signals, such as caspase-3 and caspase-8. Furthermore, it induced ER stress response involving RNA-dependent protein kinase-like ER kinase (PERK, inositol-requiring ER-to-nucleus signal kinase 1α (IRE1α, and eukaryotic initiation factor 2α (eIF2α. In addition, glycolaldehyde activated CCAAT/enhancer-binding homologous protein (CHOP, an ER stress response factor crucial to executing apoptosis. Knockdown of nuclear factor E2-related factor 2 (Nrf2, which is involved in the promotion of cell survival following ER stress, enhanced glycolaldehyde-induced cytotoxicity, indicating that Nrf2 plays a protective role in the cytotoxicity caused by glycolaldehyde. Taken together, these findings indicate that glycolaldehyde is capable of inducing apoptosis and ER stress in Schwann cells. The ER stress induced by glycolaldehyde may trigger the glycolaldehyde-induced apoptosis in Schwann cells. This study demonstrated for the first time that glycolaldehyde induced ER stress.

  20. Feasibility study of {sup 235}U and {sup 239}Pu characterization in radioactive waste drums using neutron-induced fission delayed gamma rays

    Energy Technology Data Exchange (ETDEWEB)

    Nicol, T. [CEA, DEN, Cadarache, Nuclear Measurement Laboratory, F-13108 Saint-Paul-lez-Durance (France); FZJ, Institute of Energy and Climate Research – Nuclear Waste Management and Reactor Safety, Wilhelm-Johnen-Straße, d-52425 Jülich (Germany); Pérot, B., E-mail: bertrand.perot@cea.fr [CEA, DEN, Cadarache, Nuclear Measurement Laboratory, F-13108 Saint-Paul-lez-Durance (France); Carasco, C. [CEA, DEN, Cadarache, Nuclear Measurement Laboratory, F-13108 Saint-Paul-lez-Durance (France); Brackx, E. [CEA, DEN, Marcoule, Metallography and Chemical Analysis Laboratory, F-30207 Bagnols-sur-Cèze (France); Mariani, A.; Passard, C. [CEA, DEN, Cadarache, Nuclear Measurement Laboratory, F-13108 Saint-Paul-lez-Durance (France); Mauerhofer, E. [FZJ, Institute of Energy and Climate Research – Nuclear Waste Management and Reactor Safety, Wilhelm-Johnen-Straße, d-52425 Jülich (Germany); Collot, J. [Laboratoire de Physique Subatomique et de Cosmologie, Université Grenoble Alpes, CNRS/IN2P3 Grenoble (France)

    2016-10-01

    This paper reports a feasibility study of {sup 235}U and {sup 239}Pu characterization in 225 L bituminized waste drums or 200 L concrete waste drums, by detecting delayed fission gamma rays between the pulses of a deuterium-tritium neutron generator. The delayed gamma yields were first measured with bare samples of {sup 235}U and {sup 239}Pu in REGAIN, a facility dedicated to the assay of 118 L waste drums by Prompt Gamma Neutron Activation Analysis (PGNAA) at CEA Cadarache, France. Detectability in the waste drums is then assessed using the MCNPX model of MEDINA (Multi Element Detection based on Instrumental Neutron Activation), another PGNAA cell dedicated to 200 L drums at FZJ, Germany. For the bituminized waste drum, performances are severely hampered by the high gamma background due to {sup 137}Cs, which requires the use of collimator and shield to avoid electronics saturation, these elements being very penalizing for the detection of the weak delayed gamma signal. However, for lower activity concrete drums, detection limits range from 10 to 290 g of {sup 235}U or {sup 239}Pu, depending on the delayed gamma rays of interest. These detection limits have been determined by using MCNPX to calculate the delayed gamma useful signal, and by measuring the experimental gamma background in MEDINA with a 200 L concrete drum mock-up. The performances could be significantly improved by using a higher interrogating neutron emission and an optimized experimental setup, which would allow characterizing nuclear materials in a wide range of low and medium activity waste packages.

  1. Inflammation-Induced Cell Proliferation Potentiates DNA Damage-Induced Mutations In Vivo

    Science.gov (United States)

    Kiraly, Orsolya; Gong, Guanyu; Olipitz, Werner; Muthupalani, Sureshkumar; Engelward, Bevin P.

    2015-01-01

    Mutations are a critical driver of cancer initiation. While extensive studies have focused on exposure-induced mutations, few studies have explored the importance of tissue physiology as a modulator of mutation susceptibility in vivo. Of particular interest is inflammation, a known cancer risk factor relevant to chronic inflammatory diseases and pathogen-induced inflammation. Here, we used the fluorescent yellow direct repeat (FYDR) mice that harbor a reporter to detect misalignments during homologous recombination (HR), an important class of mutations. FYDR mice were exposed to cerulein, a potent inducer of pancreatic inflammation. We show that inflammation induces DSBs (γH2AX foci) and that several days later there is an increase in cell proliferation. While isolated bouts of inflammation did not induce HR, overlap between inflammation-induced DNA damage and inflammation-induced cell proliferation induced HR significantly. To study exogenously-induced DNA damage, animals were exposed to methylnitrosourea, a model alkylating agent that creates DNA lesions relevant to both environmental exposures and cancer chemotherapy. We found that exposure to alkylation damage induces HR, and importantly, that inflammation-induced cell proliferation and alkylation induce HR in a synergistic fashion. Taken together, these results show that, during an acute bout of inflammation, there is a kinetic barrier separating DNA damage from cell proliferation that protects against mutations, and that inflammation-induced cell proliferation greatly potentiates exposure-induced mutations. These studies demonstrate a fundamental mechanism by which inflammation can act synergistically with DNA damage to induce mutations that drive cancer and cancer recurrence. PMID:25647331

  2. Acute bout of exercise induced prolonged muscle glucose transporter-4 translocation and delayed counter-regulatory hormone response in type 1 diabetes.

    Directory of Open Access Journals (Sweden)

    Koji Sato

    Full Text Available Previous studies have demonstrated that an acute bout of aerobic exercise induces a subsequent delayed onset of hypoglycemia among patients with type 1 diabetes. However, the mechanisms of exercise-induced hypoglycemia in type 1 diabetes are still unclear. Streptozotocin (STZ was injected to 6-week-old male Wistar rats, and three days after STZ injection, animals were randomly assigned into 2 groups: STZ with insulin only (STZ and STZ with insulin and exercise (STZ+EX. Normal Wistar rats with exercise were used as control (CON+EX. Insulin was intraperitoneally injected (0.5 U/kg to both STZ groups (-0.5 h, and a bout of aerobic exercise (15 m/min for 30 min was conducted at euglycemic conditions (0 h. Blood was collected at 0, 1, 3, and 5 h after exercise from the carotid artery. While the blood glucose level was stable during the post-exercise period (0-5 h in the STZ and CON+EX groups, it decreased significantly only in the STZ+EX group at 3 h. Plasma glucagon, adrenalin, and noradrenalin levels significantly increased at 1 h in the STZ group, whereas significant hormonal responses were observed at 5 h in the STZ+EX group. In skeletal muscle glucose metabolism-related pathway, the level of glucose transporter-4 (GLUT-4 translocation was significantly higher at 1 h in the CON and STZ groups. However, in the STZ+EX group, these activations were maintained by 5 h, indicating a sustained glucose metabolism in the STZ+EX group. A single bout of aerobic exercise induced a delayed onset of hypoglycemia in STZ-treated rats. A prolonged enhancement of GLUT-4 translocation and delayed counter-regulatory hormone responses may have contributed to the induction of hypoglycemia.

  3. Dendritic cells fused with different pancreatic carcinoma cells induce different T-cell responses

    Directory of Open Access Journals (Sweden)

    Andoh Y

    2013-01-01

    Full Text Available Yoshiaki Andoh,1,2 Naohiko Makino,2 Mitsunori Yamakawa11Department of Pathological Diagnostics, 2Department of Gastroenterology, Yamagata University School of Medicine, Yamagata, JapanBackground: It is unclear whether there are any differences in the induction of cytotoxic T lymphocytes (CTL and CD4+CD25high regulatory T-cells (Tregs among dendritic cells (DCs fused with different pancreatic carcinomas. The aim of this study was to compare the ability to induce cytotoxicity by human DCs fused with different human pancreatic carcinoma cell lines and to elucidate the causes of variable cytotoxicity among cell lines.Methods: Monocyte-derived DCs, which were generated from peripheral blood mononuclear cells (PBMCs, were fused with carcinoma cells such as Panc-1, KP-1NL, QGP-1, and KP-3L. The induction of CTL and Tregs, and cytokine profile of PBMCs stimulated by fused DCs were evaluated.Results: The cytotoxicity against tumor targets induced by PBMCs cocultured with DCs fused with QGP-1 (DC/QGP-1 was very low, even though PBMCs cocultured with DCs fused with other cell lines induced significant cytotoxicity against the respective tumor target. The factors causing this low cytotoxicity were subsequently investigated. DC/QGP-1 induced a significant expansion of Tregs in cocultured PBMCs compared with DC/KP-3L. The level of interleukin-10 secreted in the supernatants of PBMCs cocultured with DC/QGP-1 was increased significantly compared with that in DC/KP-3L. Downregulation of major histocompatibility complex class I expression and increased secretion of vascular endothelial growth factor were observed with QGP-1, as well as in the other cell lines.Conclusion: The present study demonstrated that the cytotoxicity induced by DCs fused with pancreatic cancer cell lines was different between each cell line, and that the reduced cytotoxicity of DC/QGP-1 might be related to the increased secretion of interleukin-10 and the extensive induction of Tregs

  4. Delayed Puberty

    DEFF Research Database (Denmark)

    Kolby, Nanna; Busch, Alexander Siegfried; Juul, Anders

    2017-01-01

    Delayed puberty can be a source of great concern and anxiety, although it usually is caused by a self-limiting variant of the normal physiological timing named constitutional delay of growth and puberty (CDGP). Delayed puberty can, however, also be the first presentation of a permanent condition...... of diagnostic evaluation today remain in distinguishing the benign CDGP from underlying pathological causes such as hypogonadotropic hypogonadism (HH) and hypergonadotropic hypogonadism. Several techniques have been investigated for this purpose and are reviewed in this chapter; however, no single test is yet...

  5. Cutting edge: TCR stimulation by antibody and bacterial superantigen induces Stat3 activation in human T cells

    DEFF Research Database (Denmark)

    Gerwien, J; Nielsen, M; Labuda, T

    1999-01-01

    -specific human CD4+ T cell lines. In contrast, IL-2 induces a rapid and transient tyrosine and serine phosphorylation of Stat3. Compared with IL-2, CD3 ligation induces a delayed Stat3 binding to oligonucleotide probes from the ICAM-1 and IL-2R alpha promoter. CD3-mediated activation of Stat3 is almost...... completely inhibited by a Src kinase inhibitor (PP1), whereas IL-2-induced Stat3 activation is unaffected. In conclusion, we show that CD3 ligation by mAb and SE triggers a rapid, PP1-sensitive tyrosine and serine phosphorylation of Stat3 in human CD4+ T cells. Moreover, we provide evidence that TCR/CD3...... and IL-2 induce Stat3 activation via distinct signaling pathways....

  6. Protection against {sup 131}I-induced Double Strand DNA Breaks in Thyroid Cells

    Energy Technology Data Exchange (ETDEWEB)

    Hershman, J.M.; Okunyan, A.; Cannon, S.; Hogen, V. [Endocrinology, UCLA-VA, Los Angeles (United States); Rivina, Y. [Radiation Biology, UCLA, Los Angeles (United States)

    2012-07-01

    Radioiodine-131 (I{sup 131}) released from nuclear reactor accidents has dramatically increased the incidence of papillary thyroid cancer in exposed individuals, especially young children. The accepted measure for prevention of radiation-induced thyroid cancer is potassium iodide tablets that contain 100 mg iodide taken daily to block thyroid uptake of I{sup 131}. The deposition of ionizing radiation in cells results in double-strand DNA breaks (DSB) at fragile sites, and this early event can generate oncogenic rearrangements that eventually cause the cancer. We have developed a thyroid cell model to quantify the mitogenic effect of I{sup 131}. I{sup 131} causes double strand DNA breaks in FRTL-5 cells detected by 53BP1 or gamma H2AX and had no effect on cells that do not transport iodide. Perchlorate, iodide, and thiocyanate protect against DSB induced by I{sup 131}. Preincubation with the anion or radioprotective compounds prevents DSB; delayed addition of the anion is much less effective. These data provide a basis for studies of radioprotection against DSB induced by I{sup 131} in animals in order to refine the prevention of thyroid cancer resulting from nuclear fallout

  7. Type I collagen gel protects murine fibrosarcoma L929 cells from TNFα-induced cell death

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Hong-Ju; He, Wen-Qi; Chen, Ling; Liu, Wei-Wei; Xu, Qian; Xia, Ming-Yu; Hayashi, Toshihiko [China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016 (China); Fujisaki, Hitomi; Hattori, Shunji [Nippi Research Institute of Biomatrix, Toride, Ibaraki 302-0017 (Japan); Tashiro, Shin-ichi [Institute for Clinical and Biomedical Sciences, Kyoto 603-8072 (Japan); Onodera, Satoshi [Department of Clinical and Pharmaceutical Sciences, Showa Pharmaceutical University, Tokyo 194-8543 (Japan); Ikejima, Takashi, E-mail: ikejimat@vip.sina.com [China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016 (China)

    2015-02-20

    Murine fibrosarcoma L929 cells have been used to test efficacy of proinflammatory cytokine TNFα. In the present study, we reported on protective effect of type I collagen gel used as L929 cell culture. L929 cell grew and proliferated well on collagen gel. However, the L929 cells exhibited cobblestone-like morphology which was much different from the spread fusiform shape when cultured on conventional cell dishes as well as the cells tended to aggregate. On conventional cell culture dishes, the cells treated with TNFα became round in shape and eventually died in a necroptotic manner. The cells cultured on collagen gel, however, were completely unaffected. TNFα treatment was reported to induce autophagy in L929 cells on the plastic dish, and therefore we investigated the effect of collagen gel on induction of autophagy. The results indicated that autophagy induced by TNFα treatment was much reduced when the cells were cultured on collagen gel. In conclusion, type I collagen gel protected L929 cell from TNFα-induced cell death. - Highlights: • Collagen gel culture changed the morphology of L929 cells. • L929 cell cultured on collagen gel were resistant to TNFα-induced cell death. • Collagen gel culture inhibited TNFα-induced autophagy in L929 cells.

  8. Cell-based optical assay for amyloid β-induced neuronal cell dysfunction using femtosecond-pulsed laser

    Science.gov (United States)

    Lee, Seunghee; Yoon, Jonghee; Choi, Chulhee

    2015-03-01

    Amyloid β-protein (Aβ) is known as a key molecule related to the pathogenesis of Alzheimer's disease (AD). Over time, the amyloid cascade disrupts essential function of mitochondria including Ca2+ homeostasis and reactive oxygen species (ROS) regulation, and eventually leads to neuronal cell death. However, there have been no methods that analyze and measure neuronal dysfuction in pathologic conditions quantitatively. Here, we suggest a cell-based optical assay to investigate neuronal function in AD using femtosecond-pulsed laser stimulation. We observed that laser stimulation on primary rat hippocampal neurons for a few microseconds induced intracellular Ca2+ level increases or produced intracellular ROS which was a primary cause of neuronal cell death depending on delivered energy. Although Aβ treatment alone had little effect on the neuronal morphologies and networks in a few hours, Aβ-treated neurons showed delayed Ca2+ increasing pattern and were more vulnerable to laser-induced cell death compared to normal neurons. Our results collectively indicate that femtosecond laser stimulation can be a useful tool to study neuronal dysfuction related to AD pathologies. We anticipate this optical method to enable studies in the early progression of neuronal impairments and the quantitative evaluation of drug effects on neurons in neurodegenerative diseases, including AD and Parkinson's disease in a preclinical study.

  9. Levobuipivacaine-Induced Dissemination of A549 Lung Cancer Cells.

    Science.gov (United States)

    Chan, Shun-Ming; Lin, Bo-Feng; Wong, Chih-Shung; Chuang, Wen-Ting; Chou, Yu-Ting; Wu, Zhi-Fu

    2017-08-17

    While anaesthetics are frequently used on cancer patients during surgical procedures, their consequence on cancer progression remains to be elucidated. In this study, we sought to investigate the influence of local anesthetics on lung cancer cell dissemination in vitro and in vivo. A549 human non-small lung cancer cells were treated with various local anaesthetics including ropivacaine, lidocaine, levobupivacaine and bupivacaine. Cell barrier property was assessed using an electric cell-substrate impedance sensing (ECIS) system. The epithelial-to-mesenchymal transition (EMT) of treated cells was studied by immunofluorescence staining. In vitro and in vivo cancer cell dissemination were investigated.Gene expression microarray and quantitative real-time PCR (qrt-PCR) assays were used to identify the genes responsible for levobupivacaine-mediated cancer cell dissemination.The results illustrated that only levobupivacaine induced EMT in the treated cells and also caused the dissemination of cancer cells in vitro. In addition, after intravenous injection, levobupivacaine encouraged cancer cell dissemination in vivo. Gene expression microarray, qrt-PCR and immunoblotting revealed that after levobupivacaine treatment, the hypoxia-inducible factor (HIF)- 2α gene was upregulated in cancer cells. Our findings suggest that levobupivacaine may induce A549 lung cancer cell dissemination both in vitro and in vivo. More specifically, HIF-2α signaling possibly contributes to levobupivacaine-mediated A549 lung cancer cell dissemination.

  10. Role of laser pre-pulse wavelength and inter-pulse delay on signal enhancement in collinear double-pulse laser-induced breakdown spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Diwakar, P.K., E-mail: pdiwakar@purdue.edu; Harilal, S.S.; Freeman, J.R.; Hassanein, A.

    2013-09-01

    Dual-pulse (DP) laser-induced breakdown spectroscopy (LIBS) provides significant improvement in signal intensity as compared to conventional single-pulse LIBS. We investigated collinear DPLIBS experimental performance using various laser wavelength combinations employing 1064 nm, 532 nm, and 266 nm Nd:YAG lasers. In particular, the role of the pre-pulse laser wavelength, inter-pulse delay times, and energies of the reheating pulses on LIBS sensitivity improvements is studied. Wavelengths of 1064 nm, 532 nm, and 266 nm pulses were used for generating pre-pulse plasma while 1064 nm pulse was used for reheating the pre-formed plasma generated by the pre-pulse. Significant emission intensity enhancement is noticed for all reheated plasma regardless of the pre-pulse excitation beam wavelength compared to single pulse LIBS. A dual peak in signal enhancement was observed for different inter-pulse delays, especially for 1064:1064 nm combinations, which is explained based on temperature measurement and shockwave expansion phenomenon. Our results also show that 266 nm:1064 nm combination provided maximum absolute signal intensity as compared to 1064 nm:1064 nm or 532 nm:1064 nm. - Highlights: • Role of pre-pulse wavelength and inter-pulse delay on LIBS sensitivity was studied. • For NIR:NIR combination, dual peaks in signal enhancement were observed. • UV:NIR combination resulted in maximum absolute signal intensity. • Persistence of neutral species was increased for double pulse.

  11. Changes from 1992 to 2002 in the pretreatment delay for patients with squamous cell carcinoma of larynx or pharynx: a Danish nationwide survey from DAHANCA

    DEFF Research Database (Denmark)

    Primdahl, Hanne; Nielsen, Anni Linnet; Larsen, Susanne

    2006-01-01

    In Denmark, a general impression of prolonged pretreatment delay for patients with head and neck cancer led to a nationwide study of time spans from symptom debut over first health care contact to start of treatment. Charts of consecutive new patients with squamous cell carcinoma of the pharynx...

  12. Delayed growth

    Science.gov (United States)

    ... 4 years Developmental milestones record - 5 years Causes Constitutional growth delay refers to children who are small ... nutrition expert who can help you choose the right foods to offer your child. What to Expect ...

  13. Delayed Ejaculation

    Science.gov (United States)

    ... bladder rather than out of the penis Psychological causes of delayed ejaculation include: Depression, anxiety or other mental health conditions Relationship problems due to stress, poor communication or other concerns ...

  14. Delayed Ejaculation

    Science.gov (United States)

    ... of stress Delayed ejaculation Symptoms & causes Diagnosis & treatment Advertisement Mayo Clinic does not endorse companies or products. ... a Job Site Map About This Site Twitter Facebook Google YouTube Pinterest Mayo Clinic is a not- ...

  15. Optimization of cell-wall skeleton derived from Mycobacterium bovis BCG Tokyo 172 (SMP-105) emulsion in delayed-type hypersensitivity and antitumor models.

    Science.gov (United States)

    Miyauchi, M; Murata, M; Fukushima, A; Sato, T; Nakagawa, M; Fujii, T; Koseki, N; Chiba, N; Kashiwazaki, Y

    2012-08-01

    Cell-wall skeleton prepared from Mycobacterium bovis BCG (BCG-CWS) is known as a potent adjuvant and has been shown to possess antitumor activity in many non-clinical and clinical studies. As there are no approved BCG-CWS formulations for cancer therapy, we investigated the potential for cancer immunotherapy of SMP-105, our originally produced BCG-CWS. For optimizing SMP-105 emulsion, we compared the effects of drakeoland squalane-based SMP-105 emulsions on IFN-γ production in rats and evaluated their ability to induce skin reaction in guinea pigs. Both emulsions had the same activity in both experiments. We selected squalane as base material and produced two types of squalane-based formulations (vialed emulsion and pumped emulsion) that can easily be prepared as oil-in-water emulsions. Although the vialed emulsion showed the same pattern of distribution as a usual homogenized emulsion, the pumped emulsion showed more uniform distribution than the other two emulsions. Whereas both emulsions enhanced strong delayed type hypersensitivity (DTH) reaction in a mouse model, the pumped emulsion induced slightly smaller edema. Data on oil droplet size distribution suggest that few micrometer oil droplet size might be appropriate for oil-in-water microemulsion of SMP-105. The antitumor potency of SMP-105 emulsion was stronger than that of some of the launched toll-like receptor (TLR) agonists (Aldara cream, Picibanil, and Immunobladder). Aldara and Picibanil showed limited antitumor effectiveness, while Immunobladder had almost the same effect as SMP-105 at the highest dose, but needed about 10 times the amount of SMP-105. These findings first indicate that SMP-105 has great potential in cancer immunotherapy.

  16. Radiation-induced apoptosis in microvascular endothelial cells.

    OpenAIRE

    Langley, R. E.; Bump, E A; Quartuccio, S. G.; Medeiros, D; Braunhut, S. J.

    1997-01-01

    The response of the microvasculature to ionizing radiation is thought to be an important factor in the overall response of both normal tissues and tumours. It has recently been reported that basic fibroblast growth factor (bFGF), a potent mitogen for endothelial cells, protects large vessel endothelial cells from radiation-induced apoptosis in vitro. Microvessel cells are phenotypically distinct from large vessel cells. We studied the apoptotic response of confluent monolayers of capillary en...

  17. Expression of (NES-hTERT in cancer cells delays cell cycle progression and increases sensitivity to genotoxic stress.

    Directory of Open Access Journals (Sweden)

    Olga A Kovalenko

    Full Text Available Telomerase is a reverse transcriptase associated with cellular immortality through telomere maintenance. This enzyme is activated in 90% of human cancers, and inhibitors of telomerase are currently in clinical trials to counteract tumor growth. Many aspects of telomerase biology have been investigated for therapy, particularly inhibition of the enzyme, but little was done regarding its subcellular shuttling. We have recently shown that mutations in the nuclear export signal of hTERT, the catalytic component of telomerase, led to a mutant ((NES-hTERT that failed to immortalize cells despite nuclear localization and catalytic activity. Expression of (NES-hTERT in primary fibroblast resulted in telomere-based premature senescence and mitochondrial dysfunction. Here we show that expression of (NES-hTERT in LNCaP, SQ20B and HeLa cells rapidly and significantly decreases their proliferation rate and ability to form colonies in soft agar while not interfering with endogenous telomerase activity. The cancer cells showed increased DNA damage at telomeric and extra-telomeric sites, and became sensitive to ionizing radiation and hydrogen peroxide exposures. Our data show that expression of (NES-hTERT efficiently counteracts cancer cell growth in vitro in at least two different ways, and suggest manipulation with the NES of hTERT or its subcellular shuttling as a new strategy for cancer treatment.

  18. Cell cycle regulation and radiation-induced cell death; Regulation du cycle cellulaire et de la mort cellulaire radio-induite

    Energy Technology Data Exchange (ETDEWEB)

    Favaudon, V. [Centre Universitaire d' Orsay, Institut Curie, Section de Recherche, Lab. Raymond-Latarjet, Unite 350 Inserm, 91 (France)

    2000-10-01

    Tight control of cell proliferation is mandatory to prevent cancer formation as well as to normal organ development and homeostasis. This occurs through checkpoints that operate in both time and space and are involved in the control of numerous pathways including DNA replication and transcription, cell cycle progression, signal transduction and differentiation. Moreover, evidence has accumulated to show that apoptosis is tightly connected with the regulation of cell cycle progression. In this paper we describe the main pathways that determine checkpoints in the cell cycle and apoptosis. It is also recalled that in solid tumors radiation-induced cell death occurs most frequently through non-apoptotic mechanisms involving oncosis, and mitotic or delayed cell death. (author)

  19. Activation of intracellular angiotensin AT2 receptors induces rapid cell death in human uterine leiomyosarcoma cells

    DEFF Research Database (Denmark)

    Zhao, Yi; Lützen, Ulf; Fritsch, Jürgen

    2015-01-01

    of apoptosis and cell death in cultured human uterine leiomyosarcoma (SK-UT-1) cells and control human uterine smooth muscle cells (HutSMC). The intracellular levels of the AT2 receptor are low in proliferating SK-UT-1 cells but the receptor is substantially up-regulated in quiescent SK-UT-1 cells with high...... densities in mitochondria. Activation of the cell membrane AT2 receptors by a concomitant treatment with angiotensin II and the AT1 receptor antagonist, losartan, induces apoptosis but does not affect the rate of cell death. We demonstrate for the first time that the high-affinity, non-peptide AT2 receptor...... agonist, Compound 21 (C21) penetrates the cell membrane of quiescent SK-UT-1 cells, activates intracellular AT2 receptors and induces rapid cell death; approximately 70% of cells died within 24 h. The cells, which escaped from the cell death, displayed activation of the mitochondrial apoptotic pathway, i...

  20. Modeling familial Alzheimer's disease with induced pluripotent stem cells

    National Research Council Canada - National Science Library

    Yagi, Takuya; Ito, Daisuke; Okada, Yohei; Akamatsu, Wado; Nihei, Yoshihiro; Yoshizaki, Takahito; Yamanaka, Shinya; Okano, Hideyuki; Suzuki, Norihiro

    2011-01-01

    ...). Induced pluripotent stem cell (iPSC) technology can be used to model human disorders and provide novel opportunities to study cellular mechanisms and establish therapeutic strategies against various diseases, including neurodegenerative diseases...

  1. Histone Deacetylase Inhibitor Induced Radiation Sensitization Effects on Human Cancer Cells after Photon and Hadron Radiation Exposure

    Directory of Open Access Journals (Sweden)

    Ariungerel Gerelchuluun

    2018-02-01

    Full Text Available Suberoylanilide hydroxamic acid (SAHA is a histone deacetylase inhibitor, which has been widely utilized throughout the cancer research field. SAHA-induced radiosensitization in normal human fibroblasts AG1522 and lung carcinoma cells A549 were evaluated with a combination of γ-rays, proton, and carbon ion exposure. Growth delay was observed in both cell lines during SAHA treatment; 2 μM SAHA treatment decreased clonogenicity and induced cell cycle block in G1 phase but 0.2 μM SAHA treatment did not show either of them. Low LET (Linear Energy Transfer irradiated A549 cells showed radiosensitization effects on cell killing in cycling and G1 phase with 0.2 or 2 μM SAHA pretreatment. In contrast, minimal sensitization was observed in normal human cells after low and high LET radiation exposure. The potentially lethal damage repair was not affected by SAHA treatment. SAHA treatment reduced the rate of γ-H2AX foci disappearance and suppressed RAD51 and RPA (Replication Protein A focus formation. Suppression of DNA double strand break repair by SAHA did not result in the differences of SAHA-induced radiosensitization between human cancer cells and normal cells. In conclusion, our results suggest SAHA treatment will sensitize cancer cells to low and high LET radiation with minimum effects to normal cells.

  2. MiR-122 Induces Radiosensitization in Non-Small Cell Lung Cancer Cell Line

    Directory of Open Access Journals (Sweden)

    Debin Ma

    2015-09-01

    Full Text Available MiR-122 is a novel tumor suppresser and its expression induces cell cycle arrest, or apoptosis, and inhibits cell proliferation in multiple cancer cells, including non-small cell lung cancer (NSCLC cells. Radioresistance of cancer cell leads to the major drawback of radiotherapy for NSCLC and the induction of radiosensitization could be a useful strategy to fix this problem. The present work investigates the function of miR-122 in inducing radiosensitization in A549 cell, a type of NSCLC cells. MiR-122 induces the radiosensitization of A549 cells. MiR-122 also boosts the inhibitory activity of ionizing radiation (IR on cancer cell anchor-independent growth and invasion. Moreover, miR-122 reduced the expression of its targeted genes related to tumor-survival or cellular stress response. These results indicate that miR-122 would be a novel strategy for NSCLC radiation-therapy.

  3. Islet-cell dysfunction induced by glucocorticoid treatment

    DEFF Research Database (Denmark)

    van Raalte, Daniël H; Kwa, Kelly A A; van Genugten, Renate E

    2013-01-01

    Glucocorticoids impair glucose tolerance by inducing insulin resistance. We investigated the dose-dependent effects of glucocorticoid treatment on islet-cell function in healthy males and studied the role of the autonomic nervous system.......Glucocorticoids impair glucose tolerance by inducing insulin resistance. We investigated the dose-dependent effects of glucocorticoid treatment on islet-cell function in healthy males and studied the role of the autonomic nervous system....

  4. How Kidney Cell Death Induces Renal Necroinflammation.

    Science.gov (United States)

    Mulay, Shrikant R; Kumar, Santhosh V; Lech, Maciej; Desai, Jyaysi; Anders, Hans-Joachim

    2016-05-01

    The nephrons of the kidney are independent functional units harboring cells of a low turnover during homeostasis. As such, physiological renal cell death is a rather rare event and dead cells are flushed away rapidly with the urinary flow. Renal cell necrosis occurs in acute kidney injuries such as thrombotic microangiopathies, necrotizing glomerulonephritis, or tubular necrosis. All of these are associated with intense intrarenal inflammation, which contributes to further renal cell loss, an autoamplifying process referred to as necroinflammation. But how does renal cell necrosis trigger inflammation? Here, we discuss the role of danger-associated molecular patterns (DAMPs), mitochondrial (mito)-DAMPs, and alarmins, as well as their respective pattern recognition receptors. The capacity of DAMPs and alarmins to trigger cytokine and chemokine release initiates the recruitment of leukocytes into the kidney that further amplify necroinflammation. Infiltrating neutrophils often undergo neutrophil extracellular trap formation associated with neutrophil death or necroptosis, which implies a release of histones, which act not only as DAMPs but also elicit direct cytotoxic effects on renal cells, namely endothelial cells. Proinflammatory macrophages and eventually cytotoxic T cells further drive kidney cell death and inflammation. Dissecting the molecular mechanisms of necroinflammation may help to identify the best therapeutic targets to limit nephron loss in kidney injury. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Transfection Agent Induced Nanoparticle Cell Loading

    Directory of Open Access Journals (Sweden)

    Karin Montet-Abou

    2005-07-01

    Full Text Available Loading cells with magnetic nanoparticles, and tracking their fate in vivo by high resolution MRI, is an attractive approach for enhancing the efficacy of cell-based therapies including those utilizing hematopoietic stem cells, neuroprogenitor cells, and T cells. The transfection agent (internalization agent assisted loading with the Feridex IV® nanoparticle is an attractive method of loading because of the low cost of materials, and possible low regulatory barriers for eventual clinical use. We therefore explored the interaction between Feridex IV® and three internalization agents protamine (PRO, polylysine (PLL, and lipofectamine (LFA. Feridex reacted with internalization agents to form aggregates, except when either the internalization agent or Feridex was present in large excess. When Jurkat T cells were incubated with Feridex/LFA or Feridex/PRO mixtures, and washed by centrifugation, nanoparticle aggregates co-purified with cells. With C17.2 cells large iron oxide particles adhered to the cell surface. At 30 μg/mL Feridex and 3 μg/mL LFA, internalization was largely mediated by LFA and was largely cytoplasmic. However, we found that the conditions used to label cells with Feridex and transfection agents need to be carefully selected to avoid the problems of surface adsorption and nanoparticle precipitation.

  6. Delayed radiation-induced inflammation accompanying a marked carbohydrate antigen 19-9 elevation in a patient with resected pancreatic cancer

    Energy Technology Data Exchange (ETDEWEB)

    Mattes, Malcolm D.; Cardinal, Jon S.; Jacobson, Geraldine M. [West Virginia University School of Medicine, Morgantown (United States)

    2016-06-15

    Although carbohydrate antigen (CA) 19-9 is a useful tumor marker for pancreatic cancer, it can also become elevated from a variety of benign and malignant conditions. Herein we describe an unusual presentation of elevated CA 19-9 in an asymptomatic patient who had previously undergone adjuvant chemotherapy and radiation therapy for resected early stage pancreatic cancer. The rise in CA 19-9 might be due to delayed radiation-induced inflammation related to previous intra-abdominal radiation therapy with or without radiation recall induced by gemcitabine. After treatment with corticosteroids the CA 19-9 level decreased to normal, and the patient has not developed any evidence of recurrent cancer to date.

  7. Distribution of gamma-tubulin in multipolar spindles and multinucleated cells induced by dimethylarsinic acid, a methylated derivative of inorganic arsenics, in Chinese hamster V79 cells.

    Science.gov (United States)

    Ochi, T; Nakajima, F; Nasui, M

    1999-08-31

    Localization of gamma-tubulin, a well-characterized component of microtubule-organizing centers (MTOCs), was investigated because of interest in the mechanism of the induction of aberrant mitotic spindles in Chinese hamster V79 cells exposed to dimethylarsinic acid (DMAA). In control cultures, gamma-tubulin in interphase cells was located as a perinuclear dot on which the microtubules were nucleated. In metaphase cells, the location of gamma-tubulin coincided with that of the mitotic spindle poles. DMAA caused mitotic delay and aberrant spindles, such as tripolar- and quadripolar spindles, in the mitotic cells. Gamma-tubulin was co-localized with the aberrant spindles induced by DMAA. The incidence of gamma-tubulin in the mitotic cells coincided with that of the aberrant spindles and rose with an increasing concentration of DMAA. By contrast, DMAA did not influence the number and location of gamma-tubulin signals in interphase cells. These results suggest that multiple microtubule nucleation sites were induced by DMAA during transition from interphase to mitotic phase. DMAA-induced multiple signals of gamma-tubulin were integrated into one signal at the center of multinucleated cells, surrounded by multiple nuclei as the cell cycle progressed to the next interphase, suggesting the presence of a self-integration mechanism of centrosomal MTOCs during the cell cycle.

  8. Perforate on CHO cell membranes induced by electromagnetic ...

    African Journals Online (AJOL)

    Perforate on CHO cell membranes induced by electromagnetic pulses irradiation observed by atomic force microscopy. ... increased with an increase in applied EMP field intensity and an increase in the number of EMP pulses. EMP induced membrane perforate may play a very important role in EMP biological effects.

  9. Are serum levels of immunoglobulin classes and IgG subclasses involved in delayed pulmonary complications induced by sulfur mustard? Sardasht-Iran Cohort Study.

    Science.gov (United States)

    Ghazanfari, Tooba; Mostafaie, Ali; Yaraee, Roya; Pourfarzam, Shahryar; Faghihzadeh, Soghrat; Rezaei, Abbas; Mahmoudi, Mahmoud; Vaez-Mahdavi, Mohammad R; Moaiedmohseni, Sakine; Soroush, Mohammad R; Naghizadeh, Mohammad M; Faghihzadeh, Elham; Hassan, Zuhair M

    2013-11-01

    Respiratory complications are the foremost long term debilitating effects after sulfur mustard toxicity. The underlying immunological mechanisms of sulfur mustard induced lung damage are still poorly understood. The question of the involvement of immunoglobulin classes and subclasses in delayed pulmonary complications induced by SM was addressed in this study as a part of Sardasht-Iran Cohort Study (SICS).In SICS, 372 male participants who were exposed to SM 20 years earlier were compared with 128 unexposed age-matched controls. At the time of study (2007), the clinical evaluations and spirometry was performed for all subjects according to the American Thoracic Society Criteria, and at the same time, the sera were isolated, labeled and aliquots were kept frozen in -80°C. Serum immunoglobulin (Ig) levels including IgM, IgA, IgE, IgG, and IgG subclasses (IgG1, IgG2, IgG3 and IgG4) were measured using quantitative Elisa method. It was found that among immunoglobulin classes and IgG subclasses only IgM and IgG4 were significantly decreased in the peripheral blood of exposed cases. IgM level also positively correlated with FEV1 only in the SM exposed group. These results indicated a weak but significant role for IgA in control of the delayed pulmonary complications. There were no strong correlations between other immunoglobulin classes or IgG subclasses with pulmonary disease severity in sulfur mustard intoxicated subjects. The authors proposed that systemic levels of immunoglobulins do not exert essential roles in severity of delayed pulmonary complications following SM toxicity. However, more studies on local and systemic levels of immunoglobulins in more severe groups are suggested. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Alternating Treatment With Pazopanib and Everolimus vs Continuous Pazopanib to Delay Disease Progression in Patients With Metastatic Clear Cell Renal Cell Cancer: The ROPETAR Randomized Clinical Trial.

    Science.gov (United States)

    Cirkel, Geert A; Hamberg, Paul; Sleijfer, Stefan; Loosveld, Olaf J L; Dercksen, M Wouter; Los, Maartje; Polee, Marco B; van den Berkmortel, Franchette; Aarts, Maureen J; Beerepoot, Laurens V; Groenewegen, Gerard; Lolkema, Martijn P; Tascilar, Metin; Portielje, Johanna E A; Peters, Frank P J; Klümpen, Heinz-Josef; van der Noort, Vincent; Haanen, John B A G; Voest, Emile E

    2017-04-01

    To our knowledge, this is the first randomized clinical trial evaluating an alternating treatment regimen in an attempt to delay disease progression in clear cell renal cell carcinoma. To test our hypothesis that an 8-week rotating treatment schedule with pazopanib and everolimus delays disease progression, exhibits more favorable toxic effects, and improves quality of life when compared with continuous treatment with pazopanib. This was an open-label, randomized (1:1) study (ROPETAR trial). In total, 101 patients with treatment-naive progressive metastatic clear cell renal cell carcinoma were enrolled between September 2012 and April 2014 from 17 large peripheral or academic hospitals in The Netherlands and followed for at least one year. First-line treatment consisted of either an 8-week alternating treatment schedule of pazopanib 800 mg/d and everolimus 10 mg/d (rotating arm) or continuous pazopanib 800 mg/d (control arm) until progression. After progression, patients made a final rotation to either pazopanib or everolimus monotherapy (rotating arm) or initiated everolimus (control arm). The primary end point was survival until first progression or death. Secondary end points included time to second progression or death, toxic effects, and quality of life. A total of 52 patients were randomized to the rotating arm (median [range] age, 65 [44-87] years) and 49 patients to the control arm (median [range] age, 67 [38-82] years). Memorial Sloan Kettering Cancer Center risk category was favorable in 26% of patients, intermediate in 58%, and poor in 15%. Baseline characteristics and risk categories were well balanced between arms. One-year PFS1 for rotating treatment was 45% (95% CI, 33-60) and 32% (95% CI, 21-49) for pazopanib (control). Median time until first progression or death for rotating treatment was 7.4 months (95% CI, 5.6-18.4) and 9.4 months (95% CI, 6.6-11.9) for pazopanib (control) (P = .37). Mucositis, anorexia, and dizziness were more prevalent in

  11. Effector and naturally occurring regulatory T cells display no abnormalities in activation induced cell death in NOD mice.

    Directory of Open Access Journals (Sweden)

    Ayelet Kaminitz

    Full Text Available BACKGROUND: Disturbed peripheral negative regulation might contribute to evolution of autoimmune insulitis in type 1 diabetes. This study evaluates the sensitivity of naïve/effector (Teff and regulatory T cells (Treg to activation-induced cell death mediated by Fas cross-linking in NOD and wild-type mice. PRINCIPAL FINDINGS: Both effector (CD25(-, FoxP3(- and suppressor (CD25(+, FoxP3(+ CD4(+ T cells are negatively regulated by Fas cross-linking in mixed splenocyte populations of NOD, wild type mice and FoxP3-GFP trangeneess. Proliferation rates and sensitivity to Fas cross-linking are dissociated in Treg cells: fast cycling induced by IL-2 and CD3/CD28 stimulation improve Treg resistance to Fas-ligand (FasL in both strains. The effector and suppressor CD4(+ subsets display balanced sensitivity to negative regulation under baseline conditions, IL-2 and CD3/CD28 stimulation, indicating that stimulation does not perturb immune homeostasis in NOD mice. Effective autocrine apoptosis of diabetogenic cells was evident from delayed onset and reduced incidence of adoptive disease transfer into NOD.SCID by CD4(+CD25(- T cells decorated with FasL protein. Treg resistant to Fas-mediated apoptosis retain suppressive activity in vitro. The only detectable differential response was reduced Teff proliferation and upregulation of CD25 following CD3-activation in NOD mice. CONCLUSION: These data document negative regulation of effector and suppressor cells by Fas cross-linking and dissociation between sensitivity to apoptosis and proliferation in stimulated Treg. There is no evidence that perturbed AICD in NOD mice initiates or promotes autoimmune insulitis.

  12. Expression of BMP-2 in Vascular Endothelial Cells of Recipient May Predict Delayed Graft Function After Renal Transplantation.

    Science.gov (United States)

    Basic-Jukic, Nikolina; Gulin, Marijana; Hudolin, Tvrtko; Kastelan, Zeljko; Katalinic, Lea; Coric, Marijana; Veda, Marija Varnai; Ivkovic, Vanja; Kes, Petar; Jelakovic, Bojan

    2016-01-01

    Delayed graft function (DGF) is associated with adverse outcomes after renal transplantation. Bone morphogenetic protein-2 (BMP-2) is involved in both endothelial function and immunological events. We compared expression of BMP-2 in epigastric artery of renal transplant recipients with immediate graft function (IGF) and DGF. 79 patients were included in this prospective study. Patients were divided in IGF group (64 patients) and DGF group (15 patients). BMP-2 expression in intima media (BMP2m) and endothelium (BMP2e) of epigastric artery was assessed by immunohistochemistry. Lower intensity of BMP2e staining was recorded in DGF compared to IGF. In DGF patients, 93% had no expression of BMP2e and 7% had 1st grade expression, compared to 45% and 41% in IGF group, respectively (P=0.001) (P<0.001 for no expression and P = 0.015 for 1st grade expression). Patients who had BMP2e staining positive had lower odds for DGF (OR 0.059 [0.007, 0.477]) and this remained significant even after adjustment for donor and recipient variables, cold ischemia time, and immunological matching (OR 0.038 [0.003, 0.492]). Our results demonstrate that BMP-2 expression in endothelial cells of epigastric arteries may predict development of DGF. © 2016 The Author(s) Published by S. Karger AG, Basel.

  13. Expression of BMP-2 in Vascular Endothelial Cells of Recipient May Predict Delayed Graft Function After Renal Transplantation

    Directory of Open Access Journals (Sweden)

    Nikolina Basic-Jukic

    2016-11-01

    Full Text Available Background/Aims: Delayed graft function (DGF is associated with adverse outcomes after renal transplantation. Bone morphogenetic protein-2 (BMP-2 is involved in both endothelial function and immunological events. We compared expression of BMP-2 in epigastric artery of renal transplant recipients with immediate graft function (IGF and DGF. Methods: 79 patients were included in this prospective study. Patients were divided in IGF group (64 patients and DGF group (15 patients. BMP-2 expression in intima media (BMP2m and endothelium (BMP2e of epigastric artery was assessed by immunohistochemistry. Results: Lower intensity of BMP2e staining was recorded in DGF compared to IGF. In DGF patients, 93% had no expression of BMP2e and 7% had 1st grade expression, compared to 45% and 41% in IGF group, respectively (P=0.001 (Pst grade expression. Patients who had BMP2e staining positive had lower odds for DGF (OR 0.059 [0.007, 0.477] and this remained significant even after adjustment for donor and recipient variables, cold ischemia time, and immunological matching (OR 0.038 [0.003, 0.492]. Conclusions: Our results demonstrate that BMP-2 expression in endothelial cells of epigastric arteries may predict development of DGF.

  14. Characterization of the therapeutic properties of Chinese herbal materials by measuring delayed luminescence and dendritic cell-based immunomodulatory response.

    Science.gov (United States)

    Sun, Mengmeng; Chang, Wen-Te; Van Wijk, Eduard; He, Min; Koval, Slavik; Lin, Ming-Kuem; Van Wijk, Roel; Hankemeier, Thomas; van der Greef, Jan; Wang, Mei

    2017-03-01

    Based on the traditional Chinese medicine theory, the Chinese pharmacopeia assigns a therapeutic description of "taste" to all herbs; thus, an herb's "taste" is valued in traditional Chinese medicine as a major ethnopharmacological category and reflects the herb's therapeutic properties. These properties guide the practitioner with respect to preparing a specific herbal formula in order to provide each patient with a personalized intervention. The key challenge in evidence-based medicine is to characterize herbal therapeutic properties from a multi-target, multi-dimensional systems pharmacology perspective. Here, we used delayed luminescence (DL, the slowly decaying emission of photons following excitation with light) as a rapid, direct, highly sensitive indicator to characterize the properties of herbal medicines. The DL parameters were able to reliably identify a specific category of herbal materials with the so-called "sweet" taste. To support the DL results and provide biological relevance to the DL results, we used a murine bone marrow-derived dendritic cell-based assay to examine the immunomodulatory effects of herbal extracts from various "taste" categories. Our results indicate that DL may serve as a robust and sensitive tool for evaluating the therapeutic properties of herbs based on the traditional Chinese medicine classification of "taste". Thus, DL provides a promising technological platform for investigating the properties of Chinese herbal medicines both qualitatively and quantitatively. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Moral complicity in induced pluripotent stem cell research.

    Science.gov (United States)

    Brown, Mark T

    2009-03-01

    Direct reprogramming of human skin cells makes available a source of pluripotent stem cells without the perceived evil of embryo destruction, but the advent of such a powerful biotechnology entangles stem cell research in other forms of moral complicity. Induced pluripotent stem cell (iPSC) research had its origins in human embryonic stem cell research and the projected biomedical applications of iPS cells almost certainly will require more embryonic stem cell research. Policies that inhibit iPSC research in order to avoid moral complicity are themselves complicit in preventable harms to patients. Moral complicity may be unavoidable, but a Blue Ribbon Panel charged with assessing the need for additional embryonic stem cell lines may ease a transition from embryonic stem cell research to clinical applications of iPS cells.

  16. Progesterone induces adult mammary stem cell expansion.

    Science.gov (United States)

    Joshi, Purna A; Jackson, Hartland W; Beristain, Alexander G; Di Grappa, Marco A; Mote, Patricia A; Clarke, Christine L; Stingl, John; Waterhouse, Paul D; Khokha, Rama

    2010-06-10

    Reproductive history is the strongest risk factor for breast cancer after age, genetics and breast density. Increased breast cancer risk is entwined with a greater number of ovarian hormone-dependent reproductive cycles, yet the basis for this predisposition is unknown. Mammary stem cells (MaSCs) are located within a specialized niche in the basal epithelial compartment that is under local and systemic regulation. The emerging role of MaSCs in cancer initiation warrants the study of ovarian hormones in MaSC homeostasis. Here we show that the MaSC pool increases 14-fold during maximal progesterone levels at the luteal dioestrus phase of the mouse. Stem-cell-enriched CD49fhi cells amplify at dioestrus, or with exogenous progesterone, demonstrating a key role for progesterone in propelling this expansion. In aged mice, CD49fhi cells display stasis upon cessation of the reproductive cycle. Progesterone drives a series of events where luminal cells probably provide Wnt4 and RANKL signals to basal cells which in turn respond by upregulating their cognate receptors, transcriptional targets and cell cycle markers. Our findings uncover a dynamic role for progesterone in activating adult MaSCs within the mammary stem cell niche during the reproductive cycle, where MaSCs are putative targets for cell transformation events leading to breast cancer.

  17. A Case Report and Genetic Characterization of a Massive Acinic Cell Carcinoma of the Parotid with Delayed Distant Metastases

    Directory of Open Access Journals (Sweden)

    Anthony C. Nichols

    2013-01-01

    Full Text Available We describe the presentation, management, and clinical outcome of a massive acinic cell carcinoma of the parotid gland. The primary tumor and blood underwent exome sequencing which revealed deletions in CDKN2A as well as PPP1R13B, which induces p53. A damaging nonsynonymous mutation was noted in EP300, a histone acetylase which plays a role in cellular proliferation. This study provides the first insights into the genetic underpinnings of this cancer. Future large-scale efforts will be necessary to define the mutational landscape of salivary gland malignancies to identify therapeutic targets and biomarkers of treatment failure.

  18. Crystalline structure of pulverized dental calculus induces cell death in oral epithelial cells.

    Science.gov (United States)

    Ziauddin, S M; Yoshimura, A; Montenegro Raudales, J L; Ozaki, Y; Higuchi, K; Ukai, T; Kaneko, T; Miyazaki, T; Latz, E; Hara, Y

    2017-11-20

    Dental calculus is a mineralized deposit attached to the tooth surface. We have shown that cellular uptake of dental calculus triggers nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation, leading to the processing of the interleukin-1β precursor into its mature form in mouse and human phagocytes. The activation of the NLRP3 inflammasome also induced a lytic form of programmed cell death, pyroptosis, in these cells. However, the effects of dental calculus on other cell types in periodontal tissue have not been investigated. The aim of this study was to determine whether dental calculus can induce cell death in oral epithelial cells. HSC-2 human oral squamous carcinoma cells, HOMK107 human primary oral epithelial cells and immortalized mouse macrophages were exposed to dental calculus or 1 of its components, hydroxyapatite crystals. For inhibition assays, the cells were exposed to dental calculus in the presence or absence of cytochalasin D (endocytosis inhibitor), z-YVAD-fmk (caspase-1 inhibitor) or glyburide (NLRP3 inflammasome inhibitor). Cytotoxicity was determined by measuring lactate dehydrogenase (LDH) release and staining with propidium iodide. Tumor necrosis factor-α production was quantified by enzyme-linked immunosorbent assay. Oral epithelial barrier function was examined by permeability assay. Dental calculus induced cell death in HSC-2 cells, as judged by LDH release and propidium iodide staining. Dental calculus also induced LDH release from HOMK107 cells. Following heat treatment, dental calculus lost its capacity to induce tumor necrosis factor-α in mouse macrophages, but could induce LDH release in HSC-2 cells, indicating a major role of inorganic components in cell death. Hydroxyapatite crystals also induced cell death in both HSC-2 and HOMK107 cells, as judged by LDH release, indicating the capacity of crystal particles to induce cell death. Cell death induced by dental

  19. In vitro-induced cell-mediated immune deviation to encephalitogenic antigens.

    Science.gov (United States)

    Farooq, Shukkur M; Ashour, Hossam M

    2014-01-01

    The injection of antigens into the Anterior Chamber (AC) of the eye induces Anterior Chamber Associated Immune Deviation (ACAID), which is a potent form of immune deviation that is largely attributed to the effect of TGFβ2 in the aqueous humor on ocular antigen-presenting cells (APCs). ACAID antigen presentation via APCs and B cells leads to the generation of antigen-specific T regulatory cells. The encephalitogenic antigens Myelin oligodendrocyte glycoprotein (MOG) and Myelin basic protein (MBP) have an obvious clinical relevance. We hypothesized that the intravenous injection of in vitro-generated ACAID APCs or in vitro-generated ACAID B cells specific to the encephalitogenic antigens MOG35-55/MBP induces specific peripheral tolerance in recipient BALB/c mice. We examined the suppression of MOG35-55-specific/MBP-specific inflammatory responses using delayed-type hypersensitivity (DTH) assays and Local Adoptive Transfer (LAT) assays. Results indicated that MOG35-55-specific/MBP-specific tolerance was generated after the intravenous injections of MOG35-55-specific/MBP-specific ACAID APCs, MOG35-55-specific/MBP-specific ACAID B cells, and MOG35-55-specific/MBP-specific ACAID T regulatory cells. The specific immune deviation was in vitro-induced, cell-mediated, and specific to the encephalitogenic antigens MOG35-55/MBP. This in vitro-mediated approach for the generation of MOG35-55/MBP-specific tolerance opens up avenues for the application of ACAID as a tool for the therapy of Multiple Sclerosis, Schizophrenia, and other diseases. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Lipopolysaccharide induces IFN-γ production in human NK cells

    Directory of Open Access Journals (Sweden)

    Leonid M Kanevskiy

    2013-01-01

    Full Text Available NK cells have been shown to play a regulatory role in sepsis. According to the current view, NK cells become activated via macrophages or dendritic cells primed by lipopolysaccharide (LPS. Recently TLR4 gene expression was detected in human NK cells suggesting the possibility of a direct action of LPS on NK cells. In this study, effects of LPS on NK cell cytokine production and cytotoxicity were studied using highly purified human NK cells. LPS induced IFN-γ production in the presence of IL-2 in cell populations containing >98% CD56+ cells. Surprisingly, in the same experiments LPS decreased NK cell degranulation. No significant expression of markers related to blood dendritic cells, monocytes or T or B lymphocytes in the NK cell preparations was observed; the portions of HLA-DRbright, CD14+, CD3+ and CD20+ cells amounted to less than 0.1% within the cell populations. No more than 0.2% of NK cells were shown to be slightly positive for surface TLR4 in our experimental system, although intracellular staining revealed moderate amounts of TLR4 inside the NK cell population. These cells were negative for surface CD14, the receptor participating in LPS recognition by TLR4. Incubation of NK cells with IL-2 or/and LPS did not lead to an increase in TLR4 surface expression. TLR4–CD56+ NK cells isolated by cell sorting secreted IFN-γ in response to LPS. Antibody to TLR4 did not block the LPS-induced increase in IFN-γ production. We have also shown that Re-form of LPS lacking outer core oligosaccharide and O-antigen induces less cytokine production in NK cells than full length LPS. We speculate that the polysaccharide fragments of LPS molecule may take part in LPS-induced IFN-γ production by NK cells. Collectively our data suggest the existence of a mechanism of LPS direct action on NK cells distinct from established TLR4-mediated signaling.

  1. Modeling Catecholaminergic Polymorphic Ventricular Tachycardia using Induced Pluripotent Stem Cell-derived Cardiomyocytes

    Directory of Open Access Journals (Sweden)

    Atara Novak

    2012-07-01

    Full Text Available Catecholaminergic polymorphic ventricular tachycardia (CPVT is an inherited arrhythmogenic cardiac disorder characterized by life-threatening arrhythmias induced by physical or emotional stress, in the absence structural heart abnormalities. The arrhythmias may cause syncope or degenerate into cardiac arrest and sudden death which usually occurs during childhood. Recent studies have shown that CPVT is caused by mutations in the cardiac ryanodine receptor type 2 (RyR2 or calsequestrin 2 (CASQ2 genes. Both proteins are key contributors to the intracellular Ca2+ handling process and play a pivotal role in Ca2+ release from the sarcoplasmic reticulum to the cytosol during systole. Although the molecular pathogenesis of CPVT is not entirely clear, it was suggested that the CPVT mutations promote excessive sarcoplasmic reticulum Ca2+ leak, which initiates delayed afterdepolarizations (DADs and triggered arrhythmias in cardiac myocytes. The recent breakthrough discovery of induced pluripotent stem cells (iPSC generated from somatic cells (e.g. fibroblasts, keratinocytes now enables researches to investigate mutated cardiomyocytes generated from the patient’s iPSC. To this end, in the present article we review recent studies on CPVT iPSC-derived cardiomyocytes, thus demonstrating in the mutated cells catecholamine-induced DADs and triggered arrhythmias.

  2. Chlorpyrifos induces endoplasmic reticulum stress in JEG-3 cells.

    Science.gov (United States)

    Reyna, Luciana; Flores-Martín, Jésica; Ridano, Magali E; Panzetta-Dutari, Graciela M; Genti-Raimondi, Susana

    2017-04-01

    Chlorpyrifos (CPF) is an organophosphorous pesticide widely used in agricultural, industrial, and household applications. We have previously shown that JEG-3 cells are able to attenuate the oxidative stress induced by CPF through the adaptive activation of the Nrf2/ARE pathway. Considering that there is a relationship between oxidative stress and endoplasmic reticulum stress (ER), herein we investigated whether CPF also induces ER stress in JEG-3 cells. Cells were exposed to 50μM or 100μM CPF during 24h in conditions where cell viability was not altered. Western blot and PCR assays were used to explore the protein and mRNA levels of ER stress biomarkers, respectively. CPF induced an increase of the typical ER stress-related proteins, such as GRP78/BiP and IRE1α, a sensor for the unfolded protein response, as well as in phospho-eIF2α and XBP1 mRNA splicing. Additionally, CPF led to a decrease in p53 protein expression. The downregulation of p53 levels induced by CPF was partially blocked when cells were exposed to CPF in the presence of the proteasome inhibitor MG132. Altogether, these findings point out that CPF induces ER stress in JEG-3 cells; however these cells are able to attenuate it downregulating the levels of the pro-apoptotic protein p53. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. PDT-apoptotic tumor cells induce macrophage immune response

    Science.gov (United States)

    Zhou, Fei-fan; Xing, Da; Chen, Wei R.

    2008-02-01

    Photodynamic therapy (PDT) functions as a cancer therapy through two major cell death mechanisms: apoptosis and necrosis. Immunological responses induced by PDT has been mainly associated with necrosis while apoptosis associated immune responses have not fully investigated. Heat shock proteins (HSPs) play an important role in regulating immune responses. In present study, we studied whether apoptotic tumor cells could induce immune response and how the HSP70 regulates immune response. The endocytosis of tumor cells by the activated macrophages was observed at single cell level by LSM. The TNF-α release of macrophages induced by co-incubated with PDT-apoptotic tumor cells was detected by ELISA. We found that apoptotic tumor cells treated by PDT could activate the macrophages, and the immune effect decreased evidently when HSP70 was blocked. These findings not only show that apoptosis can induce immunological responses, but also show HSP70 may serves as a danger signal for immune cells and induce immune responses to regulate the efficacy of PDT.

  4. Delayed Cardiac Rupture Induced by Traumatic Myocardial Infarction: Consequence of a 45-Magnum Blast Injury; A Comprehensive Case Review

    Science.gov (United States)

    Rupprecht, Holger; Gaab, Katharina

    2018-01-01

    A penetrating chest trauma, a myocardial contusion or a myocardial infarction can lead to a cardiac rupture, which is linked to an extreme high death rate. Only few cases with delayed perforation of the myocardium have been reported in literature. We report about a penetrating gunshot injury, which led to a myocardial contusion with secondary delayed rupture of the left ventricle and the left inferior lobe of the lung. The leakage of the lesion in the left ventricle could be sealed sufficiently with fibrin-coated collagen fleeces after adapting stitches with Prolene 2-0. For additional stabilization of the vulnerable myocardium area, a bovine patch has been placed on the damaged ventricle. Fibrin fleeces are used successfully in cardiac surgery, as in our case, to seal the leakage of the lesion in the left ventricle. The implantation of a bovine patch in the pericardium could prevent a cardiac compartment syndrome with a fatal pericardial tamponade. To prohibit a thoracic compartment syndrome a modified Bogota bag could be sewed in for temporarily closure of the chest. In most cases penetrating cardiac injuries can be treated without heart-lung-machines. An immediate transfer to a cardio-surgical center is, due to the acute situation, not possible. If a surgeon with thoraco-surgical expertise is present a transfer is not absolutely necessary. PMID:29379803

  5. Liver sinusoidal endothelial cells induce immunosuppressive IL-10-producing Th1 cells via the Notch pathway

    NARCIS (Netherlands)

    Neumann, Katrin; Rudolph, Christine; Neumann, Christian; Janke, Marko; Amsen, Derk; Scheffold, Alexander

    2015-01-01

    Under homeostasis, liver sinusoidal endothelial cells (LSECs) shift intrahepatic T-cell responses towards tolerance. However, the role of LSECs in the regulation of T-cell-induced liver inflammation is less clear. Here, we studied the capacity of LSECs to modulate pro-inflammatory Th1-cell

  6. Pseudolaric acid B induced cell cycle arrest, autophagy and senescence in murine fibrosarcoma l929 cell.

    Science.gov (United States)

    Yu, Jing hua; Liu, Chun yu; Zheng, Gui bin; Zhang, Li Ying; Yan, Ming hui; Zhang, Wen yan; Meng, Xian ying; Yu, Xiao fang

    2013-01-01

    PAB induced various cancer cell apoptosis, cell cycle arrest and senescence. But in cell line murine fibrosarcoma L929, PAB did not induce apoptosis, but autophagy, therefore it was thought by us as a good model to research the relationship of cell cycle arrest, autophagy and senescence bypass apoptosis. Inhibitory ratio was assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis. Phase contrast microscopy visualized cell morphology. Hoechst 33258 staining for nuclear change, propidium iodode (PI) staining for cell cycle, monodansylcadaverine (MDC) staining for autophagy, and rodanmine 123 staining for mitochondrial membrane potential (MMP) were measured by fluorescence microscopy or flowcytometry. Apoptosis was determined by DNA ladder test. Protein kinase C (PKC) activity was detected by PKC assay kit. SA-β-galactosidase assay was used to detect senescence. Protein expression was examined by western blot. PAB inhibited L929 cell growth in time-and dose-dependent manner. At 12 h, 80 μmol/L PAB induced obvious mitotic arrest; at 24 h, PAB began to induce autophagy; at 36 h, cell-treated with PAB slip into G1 cell cycle; and 3 d PAB induced senescence. In time sequence PAB induced firstly cell cycle arrest, then autophagy, then slippage into G1 phase, lastly senescence. Senescent cells had high level of autophagy, inhibiting autophagy led to apoptosis, and no senescence. PAB activated PKC activity to induce cell cycle arrest, autophagy and senescence, inhibiting PKC activity suppressed cell cycle arrest, autophagy and senescence. PAB induced cell cycle arrest, autophagy and senescence in murine fibrosarcoma L929 cell through PKC.

  7. Bacteria-induced neo-biosynthesis, stabilization, and surface expression of functional class I molecules in mouse dendritic cells

    OpenAIRE

    Rescigno, Maria; Citterio, Stefania; Thèry, Clotilde; Rittig, Michael; Medaglini, Donata; Pozzi, Gianni; Amigorena, Sebastian; Ricciardi-Castagnoli, Paola

    1998-01-01

    Here, we show that bacteria induce de novo synthesis of both major histocompatability complex (MHC) class I and II molecules in a mouse dendritic cell culture system. The neo-biosynthesis of MHC class I molecules is delayed as compared with that of MHC class II. Furthermore, bacteria stabilize MHC class I molecules by a 3-fold increase of their half-life. This has important consequences for the capacity of dendritic cells to present bacterial antigens in the draining lymph nodes. In addition,...

  8. Delayed administration of allogeneic cardiac stem cell therapy for acute myocardial infarction could ameliorate adverse remodeling: experimental study in swine.

    Science.gov (United States)

    Crisostomo, Veronica; Baez-Diaz, Claudia; Maestre, Juan; Garcia-Lindo, Monica; Sun, Fei; Casado, Javier G; Blazquez, Rebeca; Abad, Jose L; Palacios, Itziar; Rodriguez-Borlado, Luis; Sanchez-Margallo, Francisco M

    2015-05-12

    The optimal timing of cardiac stem cells administration is still unclear. We assessed the safety of same-day and delayed (one week) delivery and the possible influence of the timing on the therapeutic outcomes of allogeneic porcine cardiac stem cells administration after acute myocardial infarction in a closed-chest ischemia-reperfusion model. Female swine surviving 90 min occlusion of the mid left anterior descending coronary artery received an intracoronary injection of 25x10(6) porcine cardiac stem cells either two hours (n = 5, D0) or 7 days (n = 6, D7) after reperfusion. Controls received intracoronary injection of vehicle on day 7 (n = 6, CON). Safety was defined in terms of absence of major cardiac events, changes to the ECG during injection, post-administration coronary flow assessed using the TIMI scale and cardiac troponin I determination after the intervention. Cardiac Magnetic Resonance was performed for morphological and functional assessment prior to infarction, before injection (D7 and CON groups only), at one and 10 weeks. Samples were taken from the infarct and transition areas for pathological examination. No major adverse cardiac events were seen during injection in any group. Animals receiving the therapy on the same day of infarction (D0 group) showed mild transient ST changes during injection (n = 4) and, in one case, slightly compromised coronary flow (TIMI 2). Cardiac function parameters and infarct sizes were not significantly different between groups, with a trend towards higher ejection fraction in the treated groups. Ventricular volumes indexed to body surface area increased over time in control animals, and decreased by the end of the study in animals receiving the therapy, significantly so when comparing End Diastolic Volume between CON and D7 groups (CON: 121.70 ml/m(2) ± 26.09 ml/m(2), D7: 98.71 ml/m(2) ± 8.30 ml/m(2), p = 0.037). The treated groups showed less organization of the collagenous scar, and a significantly (p = 0

  9. Nitric-oxide synthase trafficking inducer is a pleiotropic regulator of endothelial cell function and signaling.

    Science.gov (United States)

    Chakraborty, Shreeta; Ain, Rupasri

    2017-04-21

    Endothelial nitric-oxide synthase (eNOS) and its bioactive product, nitric oxide (NO), mediate many endothelial cell functions, including angiogenesis and vascular permeability. For example, vascular endothelial growth factor (VEGF)-mediated angiogenesis is inhibited upon reduction of NO bioactivity both in vitro and in vivo Moreover, genetic disruption or pharmacological inhibition of eNOS attenuates angiogenesis during tissue repair, resulting in delayed wound closure. These observations emphasize that eNOS-derived NO can promote angiogenesis. Intriguingly, eNOS activity is regulated by nitric-oxide synthase trafficking inducer (NOSTRIN), which sequesters eNOS, thereby attenuating NO production. This has prompted significant interest in NOSTRIN's function in endothelial cells. We show here that NOSTRIN affects the functional transcriptome of endothelial cells by down-regulating several genes important for invasion and angiogenesis. Interestingly, the effects of NOSTRIN on endothelial gene expression were independent of eNOS activity. NOSTRIN also affected the expression of secreted cytokines involved in inflammatory responses, and ectopic NOSTRIN overexpression functionally restricted endothelial cell proliferation, invasion, adhesion, and VEGF-induced capillary tube formation. Furthermore, NOSTRIN interacted directly with TNF receptor-associated factor 6 (TRAF6), leading to the suppression of NFκB activity and inhibition of AKT activation via phosphorylation. Interestingly, TNF-α-induced NFκB pathway activation was reversed by NOSTRIN. We found that the SH3 domain of NOSTRIN is involved in the NOSTRIN-TRAF6 interaction and is required for NOSTRIN-induced down-regulation of endothelial cell proteins. These results have broad biological implications, as aberrant NOSTRIN expression leading to deactivation of the NFκB pathway, in turn triggering an anti-angiogenic cascade, might inhibit tumorigenesis and cancer progression. © 2017 by The American Society for

  10. Cilastatin attenuates cisplatin-induced proximal tubular cell damage.

    Science.gov (United States)

    Camano, Sonia; Lazaro, Alberto; Moreno-Gordaliza, Estefania; Torres, Ana M; de Lucas, Carmen; Humanes, Blanca; Lazaro, Jose A; Milagros Gomez-Gomez, M; Bosca, Lisardo; Tejedor, Alberto

    2010-08-01

    A major area in cancer therapy is the search for protective strategies against cisplatin-induced nephrotoxicity. We investigated the protective effect of cilastatin on cisplatin-induced injury to renal proximal tubular cells. Cilastatin is a specific inhibitor of renal dehydrodipeptidase I (DHP-I), which prevents hydrolysis of imipenem and its accumulation in the proximal tubule. Primary cultures of proximal cells were treated with cisplatin (1-30 microM) in the presence or absence of cilastatin (200 microg/ml). Apoptosis and mitochondrial injury were assessed by different techniques. Cisplatin uptake and DNA binding were measured by inductively coupled plasma spectrometry. HeLa cells were used to control the effect of cilastatin on the tumoricidal activity of cisplatin. Cisplatin increased cell death, apoptotic-like morphology, caspase activation, and mitochondrial injury in proximal tubular cells in a dose- and time-dependent way. Concomitant treatment with cilastatin reduced cisplatin-induced changes. Cilastatin also reduced the DNA-bound platinum but did not modify cisplatin-dependent up-regulation of death receptors (Fas) or ligands (tumor necrosis factor alpha, Fas ligand). In contrast, cilastatin did not show any effects on cisplatin-treated HeLa cells. Renal DHP-I was virtually absent in HeLa cells. Cilastatin attenuates cisplatin-induced cell death in proximal tubular cells without reducing the cytotoxic activity of cisplatin in tumor cells. Our findings suggest that the affinity of cilastatin for renal dipeptidase makes this effect specific for proximal tubular cells and may be related to a reduction in intracellular drug accumulation. Therefore, cilastatin administration might represent a novel strategy in the prevention of cisplatin-induced acute renal injury.

  11. Paclitaxel inhibits the hyper-activation of spleen cells by lipopolysaccharide and induces cell death.